Combination for enhancing bone length

Abstract

Human milk oligosaccharides, combinations, compositions comprising the same, and methods for enhancing bone length.

Description

[0001] COMBINATION FOR ENHANCING BONE LENGTH

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to human milk oligosaccharides, combinations, compositions comprising the same, and methods for enhancing bone length, for example in a subject who has suffered from and / or is suffering from stunted growth and / or faltering growth, or in a subject who has or is at risk of developing a metabolic bone disease.

[0004] BACKGROUND TO THE INVENTION

[0005] The growth and development of the human skeleton requires an adequate supply of many different nutritional factors. Classical nutrient deficiencies are associated with stunting (e.g. energy, protein, Zn), rickets (e.g. vitamin D) and other bone abnormalities (e.g. Cu, Zn, vitamin C). There is evidence to suggest that peak bone mass and later fracture risk are influenced by the pattern of growth and nutritional exposures in childhood. However, it is challenging to define dietary reference values using bone health as a criterion, and the question of what type of diet constitutes the best support for optimal bone development remains open (see e.g. Prentice, A., et al., 2006. Proceedings of the Nutrition Society, 65(4), pp.348-360).

[0006] Several approaches may be taken to improve the intake of bone growth-limiting nutrients, including administration of micronutrient supplements, fortification of food with micronutrients or improved dietary intake. However, particularly in populations where dietary quality is poor, deficiencies can co-occur, in which case bone growth may be affected.

[0007] Accordingly, there is a need for new nutritional interventions to enhance bone length in a subject.

[0008] SUMMARY OF THE INVENTION

[0009] The present inventors studied a human cohort from birth to 1 year of age by measuring human milk oligosaccharide (HMO) levels in breast milk and performing associations to bone length of the members of the cohort from birth to 6 months of age using the tibia and radius bones as a model. HMO levels were measured at 1 month and 3 month age points, and association to bone outcome at 6 months was performed. From these studies, the inventors surprisingly discovered both HMOs and particular groups of HMOs that are strongly associated with enhancement in bone length, as shown in Figure 1.

[0010] In one aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N- neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I).

[0011] In another aspect, the invention provides use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I).

[0012] In one embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’- fucosyllactose (2FL), lactodifucotetraose (LDFT), and 3-fucosyllactose (3FL).

[0013] In another embodiment, the invention provides use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and 3-fucosyllactose (3FL).

[0014] In one embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’- fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), and lacto-N- neotetraose (LNnT).

[0015] In another embodiment, the invention provides use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), and lacto-N-neotetraose (LNnT).

[0016] In one embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’- fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), and lacto-N- fucopentaose I (LNFP-I).

[0017] In another embodiment, the invention provides use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyl lactose (3FL), and lacto-N-fucopentaose I (LNFP-I).

[0018] In one embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; and (f) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0019] In one embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is 6’- sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In one embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0020] In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; and (f) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0021] In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is lacto-N- tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0022] In one embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0023] In one embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is 3-fucosy I lactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0024] In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0025] In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is 6’- sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is lacto- N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is lacto-N-fucopentaose II (LNFP- II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L. In one aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

[0026] In another aspect, the invention provides use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

[0027] In one aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyl lactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0028] In another aspect, the invention provides use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0029] In one aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I).

[0030] In another aspect, the invention provides use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’- sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I).

[0031] In one embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyl lactose (2FL), 6'-sialyllactose (6SL) and 3'-sialyllactose (3SL).

[0032] In another embodiment, the invention provides use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL) and 3'-sialyllactose (3SL).

[0033] In one embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'-sialyllactose (3SL) and lacto-N- fucopentaose I (LNFP-I).

[0034] In another embodiment, the invention provides use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'-sialyllactose (3SL) and lacto-N-fucopentaose I (LNFP-I).

[0035] In one embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).,

[0036] In another embodiment, the invention provides use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N- fucopentaose I (LNFP-I).

[0037] In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (e) lacto-N-fucopentaose II (LNFP- II), wherein the LNFP-I I is used at a total amount of greater than 279 mg / L.

[0038] In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0039] In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP- II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0040] In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is lacto-N-hexaose (LNH), wherein the LNH is used at a total amount of greater than 65 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is lacto- N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0041] In some embodiments, the bone is long bone of the subject. In some embodiments, the bone is a tibia and / or a radius.

[0042] In some embodiments, long bone length is enhanced in the subject. In some embodiments, tibia length is enhanced in the subject. In some embodiments, radius length is enhanced in the subject.

[0043] In some embodiments, the combination of HMOs consists essentially of: i. 16 wt% to 69 wt% of 2FL, preferably 22 wt% to 59 wt%; ii. 9 wt% to 24 wt% of LNT, preferably 12 wt% to 21 wt%; iii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; iv. 8 wt% to 26 wt% of 6SL and 3SL combined, preferably 11 wt% to 22 wt%; and at least one of: v. 18 wt% to 50 wt% of 3FL, preferably 11 wt% to 43 wt%; and / or vi. 1 wt% to 25 wt% of LNnT, preferably 1 wt% to 18 wt%; and / or vii. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%.

[0044] In some embodiments, the combination of HMOs consists essentially of: i. 16 wt% to 69 wt% of 2FL, preferably 22 wt% to 59 wt%; ii. 9 wt% to 24 wt% of LNT, preferably 12 wt% to 21 wt%; iii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; iv. 8 wt% to 26 wt% of 6SL and 3SL combined, preferably 11 wt% to 22 wt%; and v. 18 wt% to 50 wt% of 3FL, preferably 11 wt% to 43 wt%.

[0045] In some embodiments, the combination of HMOs consists essentially of: i. 20 wt% to 60 wt% of 2FL, preferably 22 wt% to 55 wt%; ii. 4 wt% to 30 wt% of LNT, preferably 6 wt% to 20 wt%; iii. 1 wt% to 12 wt % of LDFT, preferably 2 wt% to 8 wt %; iv. 7 wt% to 23 wt% of 6SL and 3SL combined, preferably 8 wt% to 22 wt%; v. 10 wt% to 50 wt% of 3FL, preferably 13 wt% to 46 wt%; and vi. 3 wt% to 25 wt% of LNnT, preferably 5 wt% to 20 wt%.

[0046] In some embodiments, the combination of HMOs consists essentially of: i. 29 wt% to 40 wt% of 2FL, preferably 32 wt% to 39 wt%; ii. 8 wt% to 13 wt% of LNT, preferably 9 wt% to 12 wt%; iii. 3 wt% to 11 wt % of LDFT, preferably 3 wt% to 11 wt %; iv. 3 wt% to 15 wt% of 6SL and 3SL combined, preferably 4 wt% to 15 wt%; v. 11 wt% to 35 wt% of 3FL, preferably 12 wt% to 35 wt%; vi. 1 wt% to 18 wt% of LNnT, preferablyl wt% to 17 wt%; and vii. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%.

[0047] In some embodiments, the combination of HMOs consists essentially of: i. 29 wt% to 40 wt% of 2FL, preferably 32 wt% to 39 wt%; ii. 3 wt% to 11 wt % of LDFT, preferably 3 wt% to 11 wt %; iii. 1 wt% to 40 wt% of A-tetra, preferably 2 wt% to 30 wt%; iv. 10 wt% to 35 wt% of LNDFH-I, preferably12 wt% to 30 wt%; v. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%; and vi. 2 wt% to 24 wt% of DFLNHa, preferably 2 wt% to 15 wt%.

[0048] In some embodiments, the combination of HMOs consists essentially of: i. 48 wt% to 77 wt% of 2FL, preferably 58 wt% to 74 wt%; ii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; and iii. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

[0049] In some embodiments, the combination of HMOs consists essentially of: i. 60 wt% to 96 wt% of 2FL, preferably 71 wt% to 80 wt%; ii. 2 wt% to 25 wt% of 6SL, preferably 4 wt% to 16 wt%; iii. 2 wt% to 35 wt% of 3SL, preferably 4 wt% to 25 wt%; optionally iv. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; and / or v. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%. In some embodiments, the combination of HMOs consists essentially of: i. 60 wt% to 96 wt% of 2FL, preferably 71 wt% to 80 wt%; ii. 2 wt% to 25 wt% of 6SL, preferably 4 wt% to 16 wt%; and iii. 2 wt% to 35 wt% of 3SL, preferably 4 wt% to 25 wt%.

[0050] In some embodiments, the combination of HMOs consists essentially of: i. 48 wt% to 77 wt% of 2FL, preferably 58 wt% to 74 wt%; ii. 3 wt% to 16 wt% of 6SL, preferably 3 wt% to 15 wt%; iii. 2 wt% to 23 wt% of 3SL, preferably 3 wt% to 22 wt%; and iv. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

[0051] In some embodiments, the combination of HMOs consists essentially of: i. 48 wt% to 77 wt% of 2FL, preferably 58 wt% to 74 wt%; ii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; iii. 3 wt% to 15 wt% of 6SL and 3SL combined, preferably 4 wt% to 15 wt%; and iv. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

[0052] In some embodiments, the subject is a human. In some embodiments, the subject is an infant, a young child, or a child.

[0053] In some embodiments, the subject is an infant or a young child. For example, the subject may be a human about 0-36 months of age, such as 0-12 months or 0-6 months of age.

[0054] In some embodiments, the subject is a child. For example, the subject may be a human about 3 years of age or older and / or about 10 years of age or younger. In some embodiments, the subject is a human from about 3 years to about 10 years of age.

[0055] In some embodiments, the subject is an adult. In some embodiments, the subject is a pet.

[0056] In some embodiments, the subject suffered from and / or is suffering from stunted growth and / or faltering growth.

[0057] In some embodiments, the subject was born preterm, with low-birth weight, and / or experienced intra-uterine growth retardation.

[0058] In some embodiments, the subject has or is at risk of developing a metabolic bone disease.

[0059] In some embodiments, the subject has or is at risk of developing osteoporosis or osteopenia.

[0060] Suitably, the enhancement of bone length may occur during administration of the combination of the invention, for example either immediately after the start of the administration or some time after, e.g. some days or weeks after the start. Suitably, the enhancement may occur later in life. The term “later in life” encompasses the effect after the termination of the administration. The effect “later in life” can be from 1 week to several months, or even years, for example from 2 to 4 weeks, from 2 to 6 weeks, from 2 to 8 weeks, from 1 to 6 months or from 2 to 12 months. Suitably, the effect “later in life” can be from 12 months to 12 years, such as from 2 years to 10 years, or from 4 years to 5 years, after the termination of the administration. Suitably, the effect “later in life” lasts until the subject is at least 5 years of age, such as at least 10 years of age, at least 20 years of age or at least 30 years of age.

[0061] Suitably, the enhancement of bone length may occur for a period of time up to 3 months, up to 6 months, up to 12 months, or longer than 12 months after the start of administration of the combination of the invention. Suitably, the enhancement of bone length may occur for a period of time up to 3 months after the start of administration of the combination of the invention. Suitably, the enhancement of bone length may occur for a period of time up to 6 months after the start of administration of the combination of the invention. Suitably, the enhancement of bone length may occur for a period of time up to 12 months after the start of administration of the combination of the invention.

[0062] In some embodiments, the combination is in the form of a composition. In some embodiments, the combination is in the form of a nutritional composition.

[0063] In some embodiments, the combination is in the form of a medical food product for clinical nutrition. In some embodiments, the combination is in the form of a milk formula. In some embodiments, the nutritional composition is selected from: an infant formula, a starter infant formula, a follow-on or follow-up formula, a baby food, an infant cereal composition, a growing-up-milk, a fortifier such as a human milk fortifier, or a supplement.

[0064] In some embodiments, the nutritional composition is an infant formula. In some embodiments, the nutritional composition is a supplement.

[0065] In some embodiments, the nutritional composition further comprises vitamin B1 , vitamin B3, vitamin C, vitamin E, calcium, potassium, zinc, or a combination thereof.

[0066] In some embodiments, the nutritional composition further comprises one or more prebiotic.

[0067] In some embodiments, the nutritional composition further comprises one or more probiotic. Suitably, the probiotic may belong to Bifidobacterium longum species.

[0068] In another aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3- fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I).

[0069] In another embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and 3-fucosyl lactose (3FL).

[0070] In another embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N- tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL) and lacto-N-neotetraose (LNnT).

[0071] In another aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N- tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), lacto-N-neotetraose (LNnT), and lacto-N-fucopentaose I (LNFP-I). In another aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose

[0072] V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto- N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0073] In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N- hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-fucopentaose

[0074] V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0075] In another aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

[0076] In another aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0077] In another aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I).

[0078] In another embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL) and 3'- sialyllactose (3SL).

[0079] In another embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'- sialyllactose (3SL) and lacto-N-fucopentaose I (LNFP-I). In another embodiment, the invention provides a combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0080] In another aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N- fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0081] In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is disialyllacto-N- tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0082] In some embodiments, the metabolic bone disease is osteoporosis or osteopenia.

[0083] In some embodiments, bone length is enhanced in the subject.

[0084] In another aspect, the invention provides a method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N- fucopentaose I (LNFP-I).

[0085] In another aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I).

[0086] In another aspect, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’- fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I).

[0087] In another aspect, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I).

[0088] In another embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and 3- fucosyllactose (3FL).

[0089] In another embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’- sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and 3-fucosyllactose (3FL).

[0090] In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and 3-fucosyllactose (3FL). In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and 3-fucosyl lactose (3FL).

[0091] In another embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3- fucosyllactose (3FL) and lacto-N-neotetraose (LNnT).

[0092] In another embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’- sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL) and lacto-N-neotetraose (LNnT).

[0093] In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N- tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL) and lacto-N-neotetraose (LNnT).

[0094] In another embodiment the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL) and lacto-N-neotetraose (LNnT).

[0095] In another embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3- fucosyllactose (3FL), lacto-N-neotetraose (LNnT), and lacto-N-fucopentaose I (LNFP-I).

[0096] In another embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’- sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), lacto-N-neotetraose (LNnT), and lacto-N- fucopentaose I (LNFP-I).

[0097] In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), lacto-N- neotetraose (LNnT), and lacto-N-fucopentaose I (LNFP-I).

[0098] In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), lacto-N-neotetraose (LNnT), and lacto-N-fucopentaose I (LNFP-I).

[0099] In another embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; and (f) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0100] In one embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In one embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0101] In another embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3- fucosy I lactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; and (f) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0102] In one embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L In one embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0103] In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; and (f) lacto-N- tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0104] In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is 2’-fucosyl lactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0105] In another embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is selected from the group consisting of: (a) 2’- fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L;

[0106] (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L;

[0107] (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L;

[0108] (e) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; and (f) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0109] In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is 3- fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In one embodiment, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0110] In another aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N- fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0111] In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto- N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0112] In another aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose

[0113] (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose

[0114] (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N- tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0115] In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 6’- sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto- N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto- N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0116] In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N- fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0117] In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is 3-fucosy I lactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is sialyl-lacto- N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0118] In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3- fucosy I lactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N- tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0119] In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is disialyllacto-N- tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0120] In another aspect, the invention provides a method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha- Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto- N-difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

[0121] In another aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

[0122] In another aspect, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N- fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa). In another aspect, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

[0123] In another aspect, the invention provides a method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0124] In another aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0125] In another aspect, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N- fucopentaose I (LNFP-I).

[0126] In another aspect, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0127] In a further embodiment, the combination of HMOs does not contain any sialylated HMO’s.

[0128] In another aspect, the invention provides a method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N- fucopentaose I (LNFP-I).

[0129] In another aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I). In another aspect, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyl lactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I).

[0130] In another aspect, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I).

[0131] In another embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL) and 3'-sialyllactose (3SL).

[0132] In another embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'- fucosyllactose (2FL), 6'-sialyllactose (6SL) and 3'-sialyllactose (3SL).

[0133] In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL) and 3'- sialyllactose (3SL).

[0134] In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'- sialyllactose (6SL) and 3'-sialyllactose (3SL).

[0135] In another embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'-sialyllactose (3SL) and lacto-N-fucopentaose I (LNFP-I).

[0136] In another embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'- fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'-sialyllactose (3SL) and lacto-N-fucopentaose I (LNFP-I).

[0137] In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'- sialyllactose (3SL) and lacto-N-fucopentaose I (LNFP-I).

[0138] In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'- sialyllactose (6SL), 3'-sialyllactose (3SL) and lacto-N-fucopentaose I (LNFP-I).

[0139] In another embodiment, the invention provides a method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP- I).

[0140] In another embodiment, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'- fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0141] In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0142] In another embodiment, the invention provides use of a combination of HMOs for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’- sialyllactose (3SL), 6’-sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N- fucopentaose I (LNFP-I).

[0143] In another aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl- lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0144] In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides a method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0145] In another aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N- hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0146] In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto- N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides a method of treating or preventing a metabolic bone disease in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0147] In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl- lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0148] In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for enhancing bone length in a subject, wherein the HMO is lacto-N- fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0149] In another aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N- tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0150] In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L. In one aspect, the invention provides use of a human milk oligosaccharide (HMO) for the manufacture of a nutritional composition for treating or preventing a metabolic bone disease in a subject, wherein the HMO is lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0151] DESCRIPTION OF THE DRAWINGS

[0152] FIGURE 1 Effects of HMOs on bone length (sensitive analysis). We observed a linear trajectory of radius and tibia length from birth until 1 year. Significant positive Spearman’s rank-order correlations were seen between Total HMO (r = 0.2138, p = 0.0270), 2’FL HMO (r = 0.1938, p = 0.0455), LNFP-I (r=0.1988, p=0.04) and other individual HMOs (r~0.1835, p ~ 0.05) aswell as HMO groups 3'SL + 6'SL + LNT + 2'FL + LDFT + 3FL, 3'SL + 6'SL + LNT + LNnT + 2'FL + LDFT + 3FL, and 3'SL + 6'SL + LNT + LNnT + 2'FL + LDFT + 3FL + LNFP-I, 2’FL + A-tetra + LNFP-I + LDFT + LNDFH-I + DFLNHa, 2FL + LDFT + LNFP-I, 2FL+ 3SL + 6SL and optionally LDFT, and / or LNFP-I.

[0153] (r~0.1835, p ~ 0.05). The Spearman’s rank-order correlations also remain after adjustments by either: 1) Nutrient: Vitamin B1 , B3, C, E, and Ca, K, and Zn. 2) Complementary food groups: grain and grain products, meat and other protein sources, milk and milk products.

[0154] DETAILED DESCRIPTION OF THE INVENTION

[0155] As used herein, the following terms have the following meanings.

[0156] The term "subject" may, for example, refer to an infant, young child, child, an infant small for gestational age (SGA), a preterm infant, or an adult.

[0157] The term "infant" means a child under the age of 12 months.

[0158] The expression "young child" means a child aged between one and three years, also called toddler.

[0159] The term “child” means a child aged between three and twelve years. Preferably, the term “child” means a child aged between three and six years.

[0160] A "preterm" or "premature" subject means an infant or young child who was not born at term. Generally it refers to an infant or young child born prior 36 weeks of gestation.

[0161] By the expression "small for gestational age" or "SGA" it is referred to an infant or young child who is smaller in size than normal for their gestational age at birth, most commonly defined as a weight below the 10th percentile for the gestational age. In some embodiments, SGA may be associated with intrauterine growth restriction (IUGR), which refers to a condition in which a foetus is unable to achieve its potential size.

[0162] By the expression “low birth weight”, it should be understood as any body weight under 2500g at birth. The expression "nutritional composition" means a composition which nourishes a subject. This nutritional composition is usually to be taken orally or intravenously. It may include a lipid or fat source, a carbohydrate source and / or a protein source. In a particular embodiment the nutritional composition is a ready-to-drink composition such as a ready-to-drink formula.

[0163] In a particular embodiment, the nutritional composition of the present invention is a "synthetic nutritional composition". The expression "synthetic nutritional composition" means a mixture obtained by chemical and / or biological means, which can be chemically identical to the mixture naturally occurring in mammalian milks (i.e. the synthetic nutritional composition is not breast milk).

[0164] The expression "infant formula" as used herein refers to a foodstuff intended for particular nutritional use by infants during the first months of life and satisfying by itself the nutritional requirements of this category of person (Article 2(c) of the European Commission Directive 91 / 321 / EEC 2006 / 141 / EC of 22 December 2006 on infant formulae and follow-on formulae). It also refers to a nutritional composition intended for infants and as defined in Codex Alimentarius (Codex STAN 72-1981) and Infant Specialities (incl. Food for Special Medical Purpose).

[0165] The expression "infant formula" encompasses both "starter infant formula" and "follow-up formula" or "follow-on formula".

[0166] A "follow-up formula" or "follow-on formula" is given from the 6th month onwards and includes “growing-up milk”. It constitutes the principal liquid element in the progressively diversified diet of this category of person.

[0167] The expression “growing-up milk” (or “GUM”) refers to a milk-based drink generally with added vitamins and minerals, that is intended for young children or children.

[0168] The expression "baby food" means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.

[0169] The expression "infant cereal composition" means a foodstuff intended for particular nutritional use by infants or young children during the first years of life.

[0170] The term "fortifier" refers to liquid or solid nutritional compositions suitable for mixing with breast milk or infant formula.

[0171] The expression “weaning period” means the period during which the mother's milk is substituted by other food in the diet of an infant or young child. The "mother's milk" should be understood as the breast milk or the colostrum of the mother.

[0172] An “oligosaccharide” is a saccharide polymer containing a small number (typically three to ten) of simple sugars (monosaccharides).

[0173] The term "HMO" or "HMOs" refers to human milk oligosaccharide(s). These carbohydrates are resistant to enzymatic hydrolysis by digestive enzymes (e.g. pancreatic and / or brush border), indicating that they may display functions not directly related to their caloric value. It has especially been illustrated that they play a vital role in the early development of infants and young children, such as the maturation of the immune system. Many different kinds of HMOs are found in the human milk. Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose and / or N- acetylglucosamine with many and varied linkages between them, thus accounting for the enormous number of different oligosaccharides in human milk - over 130 such structures have been identified so far. Almost all of them have a lactose moiety at their reducing end while sialic acid and / or fucose (when present) occupy terminal positions at the non-reducing ends. The HMOs can be acidic (e.g. charged sialic acid containing oligosaccharide) or neutral (e.g. fucosylated oligosaccharide). Some examples of HMOs are the fucosylated oligosaccharides, the N-acetylated oligosaccharides and / or the sialylated oligosaccharides.

[0174] A "fucosylated oligosaccharide" is an oligosaccharide having a fucose residue. It has a neutral nature. Some examples are LNFP-I (lacto-N-fucopentaose I), 2’-FL (2' fucosyllactose), 3-FL (3-fucosyllactose).

[0175] The expressions “fucosylated oligosaccharides comprising an alpha-1, 2-fucosyl- epitope” and “2-fucosylated oligosaccharides” encompass fucosylated oligosaccharides with a certain homology of form since they contain an alpha-1 , 2'-fucosyl-epitope, therefore a certain homology of function can be expected.

[0176] The expression “N-acetylated oligosaccharide(s)” encompasses both “N-acetyl- lactosamine” and “oligosaccharide(s) containing N-acetyl-lactosamine”. They are neutral oligosaccharides having an N-acetyl-lactosamine residue. Suitable examples are LNT (lacto- N-tetraose), para-lacto-N-neohexaose (para-LNnH), LNnT (lacto-N-neotetraose) and any combinations thereof. Other examples are lacto-N-hexaose, lacto-N-neohexaose, para-lacto- N-hexaose, para-lacto-N-neohexaose, lacto-N-octaose, lacto-N-neooctaose, iso-lacto-N- octaose, para- lacto-N-octaose and lacto-N-decaose.

[0177] A "sialylated oligosaccharide" is a charged sialic acid containing oligosaccharide, i.e. an oligosaccharide having a sialic acid residue. It has an acidic nature. Some examples are 3’- SL (3’-sialyllactose) and 6’-SL (6’-sialyllactose). The expressions "sialylated oligosaccharide" and "sialyllactose (SL)" can be used interchangeably. The trisaccharide sialyllactose consists of lactose at the reducing terminus and one sialic acid residue at the non-reducing end via an alpha-2,3 binding or alpha-2,6 binding, resulting in 3'-SL and 6'-SL, respectively.

[0178] A "precursor of HMO" is a key compound that intervenes in the manufacture of HMO, such as sialic acid and / or fucose.

[0179] The term “GOS” as used herein means “Galacto-oligosaccharide". Galacto-oligosaccharides (GOS) as used herein typically consist of p-linked galactose moieties with galactose or glucose at the reducing end. Such GOS contains p-(1— >2), p-(1— >3), p-(1— >4), or p-(1— >6) linked galactose moieties and may have a degree of polymerization (DP) of 3-8 galactose units. The term GOS is therefore preferably referred to as oligosaccharide(s) comprising at least three galactose units, more preferably as oligosaccharide(s) comprising at least four galactose units, preferably having a degree of polymerization (DP) of 3-8 galactose units.

[0180] The nutritional composition of the present invention can be in solid form (e.g. powder) or in liquid form. The amount of the various ingredients (e.g. the oligosaccharides) can be expressed in g / 100g of composition on a dry weight basis when it is in a solid form, e.g. a powder, or as a concentration in g / L of the composition when it refers to a liquid form (this latter also encompasses liquid composition that may be obtained from a powder after reconstitution in a liquid such as milk, water, e.g. a reconstituted infant formula or a follow- on / follow-up formula or a growing-up milk or an infant cereal product or any other formulation designed for infant nutrition).

[0181] The expressions “infants / young children fed exclusively with human breast milk”, “infants or young children exclusively breast fed”, “exclusive breast fed infants or young children” and “breast-fed infants / young children” can be used interchangeably. They refer to infants or young children fed with a great majority (i.e. at least 90%, or at least 95%, or at least 99%) or all (100%) of nutrients and / or energy originating from human breast milk.

[0182] The expression “conventional nutritional composition” refers to standard synthetic nutritional compositions such as infant formula, follow-up milks or growing-up milks already found in the market.

[0183] The terms “microbial”, “microflora” and “microbiota” can be used interchangeably.

[0184] The expressions “microbiota in the gut”, “microbiota of the gut”, “gut microbiota” and “intestinal microbiota” can be used interchangeably. By the expressions “preventing” or “prevention”, it is meant avoiding that a physical state, a condition or their consequences occurs and / or decreasing its incidence (i.e. reduction of the frequency). Prevention also encompasses delay or prevention of the onset of the symptoms of the disease, disorder or condition. Prevention may be absolute (such that no disease occurs) or may be effective only in some individuals or for a limited amount of time.

[0185] By the expressions “treating” or “treatment”, it is meant a decrease of the duration and / or of the severity of a physical state, a condition or their consequences (e.g. a decrease or elimination of symptoms of the condition). Treatment also encompasses to reduce, alleviate or eliminate one or more symptoms associated with the disease, disorder or condition which is being treated and / or to slow down, reduce or block the progression of the disease, disorder or condition which is being treated.

[0186] The prevention and / or the treatment of a physical state, a condition or their consequences can occur during the treatment (i.e. during the administration of the composition of the present invention, either immediately after the start of the administration or some time after, e.g. some days or weeks after the start). But it can also encompass the prevention and / or the treatment later in life. The term “later in life” encompasses the effect after the termination of the intervention or treatment. The effect “later in life” can be from 1 week to several months, or even years, for example from 2 to 4 weeks, from 2 to 6 weeks, from 2 to 8 weeks, from 1 to 6 months or from 2 to 12 months. Suitably, the effect “later in life” can be from 12 months to 12 years, such as from 2 years to 10 years, or from 4 years to 5 years, after the termination of the intervention or treatment. Suitably, the effect “later in life” lasts until the subject is at least 5 years of age, such as at least 10 years of age, at least 20 years of age or at least 30 years of age.

[0187] The term “prebiotic” means non-digestible carbohydrates that beneficially affect the host by selectively stimulating the growth and / or the activity of healthy bacteria such as bifidobacteria in the colon of humans (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995;125:1401-12).

[0188] The term “probiotic” means microbial cell preparations or components of microbial cells with a beneficial effect on the health or well-being of the host. (Salminen S, Ouwehand A. Benno Y. et al. “Probiotics: how should they be defined” Trends Food Sci. Technol. 1999:10 107-10). The microbial cells are generally bacteria or yeasts.

[0189] The term “synbiotic” may refer to a component that contains both probiotics and prebiotics, or a live microbe and a substrate that is selectively utilized by the co-administered live microbe (see e.g. Swanson, K.S., et al., 2020. Nature Reviews Gastroenterology & Hepatology, 17(11), pp.687-701).

[0190] The term “cfu” should be understood as colony-forming unit.

[0191] All percentages are by weight unless otherwise stated.

[0192] All weights expressed in g per 100g of composition are dry weight unless otherwise stated.

[0193] The term “SOFA” means short chain fatty acid(s).

[0194] The expression “increasing SCFA production” means that the amount of systemic and / or colonic SCFA, is higher in an individual fed with the nutritional composition according to the present invention in comparison with a standard. The SCFA production may be measured by techniques known by the skilled person such as by Gas-Liquid Chromatography.

[0195] In the present context, the term “gastrointestinal tract” includes the mouth, pharynx, oesophagus, stomach, small intestine, large intestine, rectum and anus. The term “intestine” includes the small intestine, the large intestine and rectum.

[0196] In the present context, the term “respiratory tract” refers to the passage formed by the nose, nasal cavity, pharynx, larynx, trachea, bronchi and the lungs through which air passes during breathing.

[0197] In addition, in the context of the invention, the terms "comprising" or "comprises" do not exclude other possible elements. The composition of the present invention, including the many embodiments described herein, can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise depending on the needs.

[0198] Any reference to prior art documents in this specification is not to be considered an admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0199] The invention will now be described in further details. It is noted that the various aspects, features, examples and embodiments described in the present application may be compatible and / or combined together in any combination thereof.

[0200] METHODS FOR ENHANCING BONE LENGTH

[0201] The present inventors have shown that the combination of the invention may be used to enhance bone length in a subject. Within the context of the invention, the term “enhancing bone length” may refer to, in particular, enhancement of the length of one or more bones of the subject, in particular long bones of the subject. Long bones may include: femora, tibiae, and fibulae (bones of the legs); the humeri, radii, and ulnae (bones of the arms); metacarpals and metatarsals (bones of the hands and feet); phalanges (bones of the fingers and toes); and clavicles.

[0202] In one aspect, the invention provides a combination according to the invention for use in enhancing bone length in a subject.

[0203] In one aspect, the invention provides use of a combination according to the invention in the manufacture of a nutritional composition or medical food product for enhancing bone length in a subject.

[0204] In one aspect, the present invention provides a method for enhancing length in a subject, said method comprising administering a therapeutically effective amount of a combination according to the invention to a subject in need thereof.

[0205] As used herein, “enhancing bone length” may refer to the support of development of normal bone length, for example during childhood and adolescence. Supporting normal bone length may result in normal bone anatomy and physiology. Suitable methods to determine bone length will be available to the skilled person, for example bone length may be readily measured using a segmometer. The skilled person may utilise example methods such as those disclosed herein.

[0206] In some embodiments, the enhancement of bone length is determined in absolute terms (e.g. the bone length deficit from the healthy reference population mean is reduced). In some embodiments, the enhancement of bone length is determined in relative terms (e.g. the bone- length-for-age z-score is improved and / or passes the -2SD or -1SD cut-off points).

[0207] SUBJECT

[0208] In some embodiments, the subject is a mammal, such as a human.

[0209] In some embodiments, the subject is an infant, a young child, or a child.

[0210] In one embodiment, the subject is an infant. In one embodiment, the subject is a young child. In one embodiment, the subject is a child.

[0211] In some embodiments, the subject is an adult. The combination or composition according to the invention may be for use in infants or young children. It is particularly adapted for infants under 6 months of age.

[0212] The infants, young children or children may be born term or preterm. In a particular embodiment, the combination or composition of the invention is for use in infants, young children or children that were born preterm. Preterm infants may be at increased risk of poor nutrient utilization, impaired lean body mass growth, fat accumulation in the visceral area and metabolic disease later in life. Thus, in one embodiment the combination or composition of the invention is for use in preterm infants.

[0213] In one embodiment, the subject is an infant or a young child that was born small for gestational age or low birth weight.

[0214] Infants or young children with low birth weight may or may not be preterm, and similarly, infants or young children who are small for gestational age may or may not be preterm.

[0215] The combination or composition of the present invention may also be used in an infant or a young child that was born by C-section or that was vaginally delivered.

[0216] All infants and young children can benefit from the invention as all of them are or can be, at a certain age, susceptible to acquiring an unbalanced intestinal / gut microbiota.

[0217] In some advantageous embodiments of the invention, the combination or composition is for use in infants or young children having a fragile or unbalanced microbiota or dysbiosis of microbiota, such as preterm infants, infants born by Caesarean-section, infants born small for gestational age or with low birth weight, hospitalized infants / young children, infants / young children treated or having been treated by antibiotics and / or infants / young children suffering or having suffered from gut infection and / or gut inflammation.

[0218] It is indeed foreseen that the combination or composition of the invention may be even more beneficial to infants born with possibly impaired gut microbiota or fragile infants / young children (such as prematurely born infants and / or infants born by C-section). It is also foreseen that the combination or composition of the invention may be even more beneficial to infants / young children exhibiting intestinal disorders (such as diarrhea, infections or colic), especially after birth, for example, during the first 4 weeks after birth.

[0219] In embodiments of the invention, the infants born prematurely or born by caesarean section or born small for gestational age or with low birth weight, or exhibiting unbalanced or abnormal gut microbiota or suffering or having suffered from gut infection and / or gut inflammation, are targeted by the combination or composition of the present invention, and especially when the infants are 0-6 months of age. Without being bound by the theory, it is believed that younger infants benefit even more from the combination or composition of the invention, especially when the infants have (or are at risk of having) an unbalanced intestinal microbiota and / or have a fragile health condition (as exemplified by the conditions cited above).

[0220] The combination or composition can be administered (or given or fed) at an age and for a period that depends on the needs.

[0221] In one embodiment, the infants or young children are 0-36 months of age, such as 0-12 months or 0-6 months of age. It is foreseen that the combination or composition of the invention may be even more beneficial to infants just after birth (0-4 weeks or 0-8 weeks) as their intestinal tract may be more fragile.

[0222] The mammal to be treated is preferably a human being, but the mammal may also be nonhuman mammal, such as a non-human mammal selected from the group consisting of pig, cow, horse, dog, cat, goat, sheep and rabbit.

[0223] In other embodiments, the subject is a juvenile animal, preferably wherein the animal is a pet.

[0224] A pet may be a mammal such as dogs or cats, or rodents such as mice, rats, and guinea pigs, rabbits, etc. In some embodiments, the pet is a small dog breed.

[0225] The term “juvenile” may refer to an individual that has not yet reached adulthood.

[0226] In some embodiments the combination or composition according to the invention can be for use before and / or during the weaning period.

[0227] In some embodiments the combination or composition according to the invention is for use in a subject at risk and / or in need.

[0228] The subject at risk and / or in need may be bottle-fed and / or formula-fed.

[0229] In one embodiment the combination or composition of the invention is given to the subject as a supplementary composition to the mother's milk. In some embodiments the subject receives the mother's milk during at least the first 2 weeks, first 1 , 2, 4, or 6 months. In one embodiment the combination or composition of the invention is given to the subject after such period of mother's nutrition, or is given together with such period of mother's milk nutrition. In another embodiment the combination or composition is given to the subject as the sole or primary nutritional composition during at least one period of time, e.g. after the 1st, 2ndor 4thmonth of life, during at least 1 , 2, 4 or 6 months. In one embodiment the nutritional composition of the invention is a complete nutritional composition (fulfilling all or most of the nutritional needs of the subject). In another embodiment the nutrition composition of the invention is a supplement or a fortifier intended for example to supplement human milk or to supplement an infant formula or a follow- on formula.

[0230] The present invention is particularly suitable for children who were born preterm or with low- birth weight or experienced intra-uterine growth retardation or who suffered from growth stunting because of malnutrition or experienced disease such as Crohn’s disease and / or celiac disease and / or cancer or who were treated with drugs leading to malabsorption, anorexia and / or metabolic bone disease, such as chemotherapy drugs and / or corticosteroids. The present invention is particularly preferred for use in children who were born preterm or with low-birth weight or experienced intra-uterine growth retardation, or with intra-uterine malnutrition or who suffered growth delay. The present invention is also suitable for children at risk of bone disease, having a family history of bone disease.

[0231] In some embodiments, the subject suffered from and / or is suffering from stunted growth. The definition of stunting may refer to the "height for age" value to be less than two standard deviations of the WHO Child Growth Standards median (see e.g. De Onis, M. and Branca, F., 2016. Maternal & child nutrition, 12, pp.12-26).

[0232] In some embodiments, the subject suffered from and / or is suffering from faltering growth. The term “faltering growth” may describe a pattern of slower weight gain than expected for age and sex in children and other adolescents (see e.g. King, C. and Davis, T., 2010. European journal of clinical nutrition, 64(1), pp.S11-S13). In some embodiments, the subject suffered from and / or is suffering from growth stunting and / or faltering growth because of malnutrition or experienced disease such as anorexia, Crohn’s disease and / or celiac disease. In some embodiments, the subject suffered from and / or is suffering from growth stunting and / or faltering growth because of treatment with drugs leading to malabsorption, anorexia and / or metabolic bone disease, such as chemotherapy drugs and / or corticosteroids.

[0233] HUMAN MILK OLIGOSACCHARIDES AND COMBINATIONS

[0234] In one aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N- neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I).

[0235] In one aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

[0236] In one aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyl lactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0237] In one aspect, the invention provides a combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I).

[0238] The combination of the present invention may be referred to as a combination therapy. As used herein, a “combination therapy” may refer to a therapy comprising the administration of two or more agents, mixtures (e.g. an oligosaccharide mixture), or compositions (e.g. an oligosaccharide mixture).

[0239] The combination may be administered by any suitable route and in any suitable form. Suitably, the combination is administered by oral and / or enteral administration. In preferred embodiments, the combination is administered by oral administration. The combination may be administered separately, simultaneously or sequentially. In preferred embodiments, the combination is administered simultaneously.

[0240] In one embodiment, the combination of HMOs comprises 2FL in an amount of from 16 wt% to 85 wt%. Suitably, the combination of HMOs may comprise 2FL in an amount of from 31 wt% to 82 wt%, preferably from 41 wt% to 70 wt%. Suitably, the combination of HMOs may comprise 2FL in an amount of from 16 wt% to 69 wt%, preferably from 22 wt% to 59 wt%. Suitably, the combination of HMOs may comprise 2FL in an amount of from 34 wt% to 85 wt%, preferably from 40 wt% to 71 wt%. Suitably, the combination of HMOs may comprise 2FL in an amount of from 20 wt% to 60 wt%, preferably from 22 wt% to 55 wt%.

[0241] In one embodiment, the combination of HMOs comprises LNT in an amount of from 4 wt% to 40 wt%. Suitably, the combination of HMOs may comprise LNT in an amount of from 10 wt% to 27 wt%, preferably from 14 wt% to 23 wt%. Suitably, the combination of HMOs may comprise LNT in an amount of from 9 wt% to 24 wt%, preferably 12 wt% to 21 wt%. Suitably, the combination of HMOs may comprise LNT in an amount of from 10 wt% to 40 wt%, preferably 12 wt% to 26 wt%. Suitably, the combination of HMOs may comprise LNT in an amount of from 4 wt% to 30 wt%, preferably 6 wt% to 20 wt%. In one embodiment, the combination of HMOs comprises LDFT in an amount of from 1 wt% to 14 wt%. Suitably, the combination of HMOs may comprise LDFT in an amount of from 4 wt% to 11 wt%, preferably from 6 wt% to 10 wt%. Suitably, the combination of HMOs may comprise LDFT in an amount of from 2 wt% to 10 wt%, preferably from 3 wt% to 8 wt%. Suitably, the combination of HMOs may comprise LDFT in an amount of from 4 wt% to 14 wt %, preferably from 5 wt% to 10 wt%. Suitably, the combination of HMOs may comprise LDFT in an amount of from 1 wt% to 12 wt %, preferably from 2 wt% to 8 wt%.

[0242] In one embodiment, the combination of HMOs comprises 6SL and 3SL combined in an amount of from 7 wt% to 34 wt%. Suitably, the combination of HMOs may comprise 6SL and 3SL combined in an amount of from 9 wt% to 34 wt%, preferably from 11 wt% to 29 wt%. Suitably, the combination of HMOs may comprise 6SL and 3SL combined in an amount of from 8 wt% to 26 wt%, preferably from 11 wt% to 22 wt%. Suitably, the combination of HMOs may comprise 6SL and 3SL combined in an amount of from 9 wt% to 31 wt%, preferably from 10 wt% to 28 wt%. Suitably, the combination of HMOs may comprise 6SL and 3SL combined in an amount of from 7 wt% to 23 wt%, preferably from 8 wt% to 22 wt%.

[0243] In one embodiment, the combination of HMOs comprises 3FL in an amount of from 10 wt% to 50 wt%. Suitably, the combination of HMOs may comprise 3FL in an amount of from 18 wt% to 50 wt%, preferably from 11 wt% to 43 wt%. Suitably, the combination of HMOs may comprise 3FL in an amount of from 10 wt% to 50 wt%, preferably from 13 wt% to 46 wt%.

[0244] In one embodiment, the combination of HMOs comprises LNnT in an amount of from 6 wt% to 30 wt%. Suitably, the combination of HMOs comprises LNnT in an amount of from 6 wt% to 30 wt%, preferably from 7 wt% to 22 wt%. Suitably, the combination of HMOs comprises LNnT in an amount of from 3 wt% to 25 wt%, preferably from 5 wt% to 20 wt%.

[0245] In one embodiment, the HMO mixture comprises LNFP-I in an amount of from 2 wt% to 32 wt %. Suitably, the HMO mixture may comprise LNFP-I in an amount of from 5 wt% to 32 wt%, preferably from 10 wt% to 19 wt%. Suitably, the HMO mixture may comprise LNFP-I in an amount of from 2 wt% to 24 wt%, preferably from 5 wt% to 14 wt%.

[0246] In one embodiment, the combination of HMOs comprises A-Tetra in an amount of from 2 wt% to 35 wt%. Suitably, the combination of HMOs comprises A-Tetra in an amount of from 2 wt% to 30 wt%, preferably from 2 wt% to 25 wt%. Suitably, the combination of HMOs comprises A- Tetra in an amount of from 3 wt% to 25 wt%, preferably from 3 wt% to 20 wt%. In one embodiment, the combination of HMOs comprises LNDFH-I in an amount of from 10 wt% to 32 wt%. Suitably, the combination of HMOs comprises LNDFH-I in an amount of from 12 wt% to 30 wt%, preferably from 12 wt% to 27 wt%. Suitably, the combination of HMOs comprises LNDFH-I in an amount of from 12 wt% to 25 wt%, preferably from 12 wt% to 20 wt%.

[0247] In one embodiment, the HMO mixture comprises LNFP-I in an amount of from 2 wt% to 32 wt %. Suitably, the HMO mixture may comprise LNFP-I in an amount of from 5 wt% to 32 wt%, preferably from 10 wt% to 19 wt%. Suitably, the HMO mixture may comprise LNFP-I in an amount of from 2 wt% to 24 wt%, preferably from 5 wt% to 14 wt%.

[0248] In one embodiment, the combination of HMOs comprises DFLNHa in an amount of from 2 wt% to 32 wt%. Suitably, the combination of HMOs comprises DFLNHa in an amount of from 2 wt% to 27 wt%, preferably from 2 wt% to 25 wt%. Suitably, the combination of HMOs comprises DFLNHa in an amount of from 2 wt% to 20 wt%, preferably from 5 wt% to 15wt%.

[0249] In one embodiment, the combination of HMOs comprises 2FL in an amount of from 16 wt% to 85 wt%. Suitably, the combination of HMOs may comprise 2FL in an amount of from 31 wt% to 82 wt%, preferably from 41 wt% to 70 wt%. Suitably, the combination of HMOs may comprise 2FL in an amount of from 16 wt% to 69 wt%, preferably from 22 wt% to 59 wt%. Suitably, the combination of HMOs may comprise 2FL in an amount of from 34 wt% to 85 wt%, preferably from 40 wt% to 71 wt%. Suitably, the combination of HMOs may comprise 2FL in an amount of from 20 wt% to 60 wt%, preferably from 22 wt% to 55 wt%.

[0250] In one embodiment, the combination of HMOs comprises LDFT in an amount of from 1 wt% to 14 wt%. Suitably, the combination of HMOs may comprise LDFT in an amount of from 4 wt% to 11 wt%, preferably from 6 wt% to 10 wt%. Suitably, the combination of HMOs may comprise LDFT in an amount of from 2 wt% to 10 wt%, preferably from 3 wt% to 8 wt%. Suitably, the combination of HMOs may comprise LDFT in an amount of from 4 wt% to 14 wt %, preferably from 5 wt% to 10 wt%. Suitably, the combination of HMOs may comprise LDFT in an amount of from 1 wt% to 12 wt %, preferably from 2 wt% to 8 wt%.

[0251] In one embodiment, the combination of HMOs comprises 6SL and 3SL combined in an amount of from 7 wt% to 34 wt%. Suitably, the combination of HMOs may comprise 6SL and 3SL combined in an amount of from 9 wt% to 34 wt%, preferably from 11 wt% to 29 wt%. Suitably, the combination of HMOs may comprise 6SL and 3SL combined in an amount of from 8 wt% to 26 wt%, preferably from 11 wt% to 22 wt%. Suitably, the combination of HMOs may comprise 6SL and 3SL combined in an amount of from 9 wt% to 31 wt%, preferably from 10 wt% to 28 wt%. Suitably, the combination of HMOs may comprise 6SL and 3SL combined in an amount of from 7 wt% to 23 wt%, preferably from 8 wt% to 22 wt%.

[0252] In one embodiment, the HMO mixture comprises LNFP-I in an amount of from 2 wt% to 32 wt %. Suitably, the HMO mixture may comprise LNFP-I in an amount of from 5 wt% to 32 wt%, preferably from 10 wt% to 19 wt%. Suitably, the HMO mixture may comprise LNFP-I in an amount of from 2 wt% to 24 wt%, preferably from 5 wt% to 14 wt%.

[0253] In some embodiments, the combination of HMOs consists essentially of: i. 16 wt% to 69 wt% of 2FL, preferably 22 wt% to 59 wt%; ii. 9 wt% to 24 wt% of LNT, preferably 12 wt% to 21 wt%; iii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; iv. 8 wt% to 26 wt% of 6SL and 3SL combined, preferably 11 wt% to 22 wt%; and at least one of: v. 18 wt% to 50 wt% of 3FL, preferably 11 wt% to 43 wt%; and / or vi. 1 wt% to 25 wt% of LNnT, preferably 1 wt% to 18 wt%; and / or vii. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%.

[0254] In some embodiments, the combination of HMOs consists essentially of: i. 16 wt% to 69 wt% of 2FL, preferably 22 wt% to 59 wt%; ii. 9 wt% to 24 wt% of LNT, preferably 12 wt% to 21 wt%; iii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; iv. 8 wt% to 26 wt% of 6SL and 3SL combined, preferably 11 wt% to 22 wt%; and v. 18 wt% to 50 wt% of 3FL, preferably 11 wt% to 43 wt%.

[0255] In some embodiments, the combination of HMOs consists essentially of: i. 20 wt% to 60 wt% of 2FL, preferably 22 wt% to 55 wt%; ii. 4 wt% to 30 wt% of LNT, preferably 6 wt% to 20 wt%; iii. 1 wt% to 12 wt % of LDFT, preferably 2 wt% to 8 wt %; iv. 7 wt% to 23 wt% of 6SL and 3SL combined, preferably 8 wt% to 22 wt%; v. 10 wt% to 50 wt% of 3FL, preferably 13 wt% to 46 wt% and vi. 3 wt% to 25 wt% of LNnT, preferably 5 wt% to 20 wt%.

[0256] In some embodiments, the combination of HMOs consists essentially of: i. 29 wt% to 40 wt% of 2FL, preferably 32 wt% to 39 wt%; ii. 8 wt% to 13 wt% of LNT, preferably 9 wt% to 12 wt%; iii. 3 wt% to 11 wt % of LDFT, preferably 3 wt% to 11 wt %; iv. 3 wt% to 15 wt% of 6SL and 3SL combined, preferably 4 wt% to 15 wt%; v. 11 wt% to 35 wt% of 3FL, preferably 12 wt% to 35 wt%; vi. 1 wt% to 18 wt% of LNnT, preferablyl wt% to 17 wt%; and vii. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%.

[0257] In some embodiments, the combination of HMOs consists essentially of: i. 29 wt% to 40 wt% of 2FL, preferably 32 wt% to 39 wt%; ii. 3 wt% to 11 wt % of LDFT, preferably 3 wt% to 11 wt %; iii. 1 wt% to 40 wt% of A-tetra, preferably 2 wt% to 30 wt%; iv. 10 wt% to 35 wt% of LNDFH-I, preferably12 wt% to 30 wt%; v. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%; and vi. 2 wt% to 24 wt% of DFLNHa, preferably 2 wt% to 15 wt%.

[0258] In some embodiments, the combination of HMOs consists essentially of: i. 48 wt% to 77 wt% of 2FL, preferably 58 wt% to 74 wt%; ii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; and iii. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

[0259] In some embodiments, the combination of HMOs consists essentially of: i. 60 wt% to 96 wt% of 2FL, preferably 71 wt% to 80 wt%; ii. 2 wt% to 25 wt% of 6SL, preferably 4 wt% to 16 wt%; iii. 2 wt% to 35 wt% of 3SL, preferably 4 wt% to 25 wt%; optionally iv. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; and / or v. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

[0260] In some embodiments, the combination of HMOs consists essentially of: i. 60 wt% to 96 wt% of 2FL, preferably 71 wt% to 80 wt%; ii. 2 wt% to 25 wt% of 6SL, preferably 4 wt% to 16 wt%; and iii. 2 wt% to 35 wt% of 3SL, preferably 4 wt% to 25 wt%.

[0261] In some embodiments, the combination of HMOs consists essentially of: i. 48 wt% to 77 wt% of 2FL, preferably 58 wt% to 74 wt%; ii. 3 wt% to 16 wt% of 6SL, preferably 3 wt% to 15 wt%; iii. 2 wt% to 23 wt% of 3SL, preferably 3 wt% to 22 wt%; and iv. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

[0262] In some embodiments, the combination of HMOs consists essentially of: i. 48 wt% to 77 wt% of 2FL, preferably 58 wt% to 74 wt%; ii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; iii. 3 wt% to 15 wt% of 6SL and 3SL combined, preferably 4 wt% to 15 wt%;and iv. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%. Suitable doses of human oligosaccharides are described in e.g. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015. EFSA Journal, 13(11), p.4299; EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2019. EFSA Journal, 17(6), p.e05717; EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2020. EFSA Journal, 18(5), p.e06097; EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2022. EFSA Journal, 20(5), p.e07331 ; and EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2019. EFSA Journal, 17(12), p.e05907.

[0263] Suitably, the combination is administered to the subject in an amount of at least about 0.5 g / day, at least about 1 g / day, or at least about 2 g / day. Suitably, the combination is administered to the subject in an amount of about 10 g / day or less, about 8 g / day or less, or about 5 g / day or less. Suitably, the combination is administered to the subject in an amount of from about 0.5 g / day to about 10 g / day, from about 1 g / day to about 8 g / day or from about 2 g / day to about 5 g / day.

[0264] Suitably, 3SL is administered to the subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, 3SL is administered to the subject in an amount of about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, 3SL is administered to the subject in an amount of from about 0.1 g / day to about 1 g / day, from about 0.15 g / day to about 0.8 g / day or from about 0.2 g / day to about 0.6 g / day.

[0265] Suitably, 6SL is administered to the subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, 6SL is administered to the subject in an amount of about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, 6SL is administered to the subject in an amount of from about 0.1 g / day to about 1 g / day, from about 0.15 g / day to about 0.8 g / day or from about 0.2 g / day to about 0.6 g / day.

[0266] Suitably, LNT is administered to the subject in an amount of at least about 0.2 g / day, at least about 0.3 g / day, or at least about 0.4 g / day. Suitably, LNT is administered to the subject in an amount of about 2.5 g / day or less, about 2 g / day or less, or about 1 .5 g / day or less. Suitably, LNT is administered to the subject in an amount of from about 0.2 g / day to about 2.5 g / day, from about 0.3 g / day to about 2 g / day or from about 0.4 g / day to about 1 .5 g / day.

[0267] Suitably, 2FL is administered to the subject in an amount of at least about 0.5 g / day, at least about 0.8 g / day, or at least about 1 g / day. Suitably, 2FL is administered to the subject in an amount of about 5 g / day or less, about 4 g / day or less, or about 3 g / day or less. Suitably, 2FL is administered to the subject in an amount of from about 0.5 g / day to about 5 g / day, from about 0.8 g / day to about 4 g / day or from about 1 g / day to about 3 g / day. Suitably, LDFT is administered to the subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LDFT is administered to the subject in an amount of about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LDFT is administered to the subject in an amount of from about 0.1 g / day to about 1 g / day, from about 0.15 g / day to about 0.8 g / day or from about 0.2 g / day to about 0.6 g / day.

[0268] Suitably, 3FL is administered to the subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, 3FL is administered to the subject in an amount of about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, 3FL is administered to the subject in an amount of from about 0.1 g / day to about 1 g / day, from about 0.15 g / day to about 0.8 g / day or from about 0.2 g / day to about 0.6 g / day.

[0269] Suitably, LNnT is administered to the subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LNnT is administered to the subject in an amount of about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LNnT is administered to the subject in an amount of from about 0.1 g / day to about 1 g / day, from about 0.15 g / day to about 0.8 g / day or from about 0.2 g / day to about 0.6 g / day.

[0270] Suitably, LNFP-I is administered to the subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LNFP-I is administered to the subject in an amount of about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LNFP-I is administered to the subject in an amount of from about 0.1 g / day to about 1 g / day, from about 0.15 g / day to about 0.8 g / day or from about 0.2 g / day to about 0.6 g / day.

[0271] In some embodiments, LNFP-I is present in a total amount of from 10 mg / L to 5000 mg / L of the composition according to the invention or of from 0.01 g / 100 g to 4 g / 100 g of the nutritional composition according to the invention.

[0272] In some embodiments, LNFP-I is present in a total amount of from 25 mg / L to 4000 mg / L of the composition according to the invention or of from 0.02 g / 100 g to 3.75 g / 100 g of the nutritional composition according to the invention. Suitably, LNFP-I is present in a total amount of from 50 mg / L to 2500 mg / L, for example from 60 mg / L to 2000 mg / L, for example from 80 mg / L to 1500 mg / L, for example from 100 mg / L to 1000 mg / L, for example from 200 mg / L to 800 mg / L of the composition according to the invention. Suitably, LNFP-I is present in a total amount of from 0.04 g / 100 g to 2 g / 100 g, for example from 0.05 g / 100 g to 1.6 g / 100 g, for example from 0.06 to 1.2 g / 100g, for example from 0.07 g / 100 g to 0.8 g / 100 g, for example from 0.1 g / 100g to 0.7 g / 100g of the composition (dry weight). Suitably, A-Tetra is present in a total amount of from 25 mg / L to 4000 mg / L of the composition according to the invention or of from 0.02 g / 100 g to 3.75 g / 100 g of the nutritional composition according to the invention. Suitably, A-Tetra is present in a total amount of from 50 mg / L to 2500 mg / L, for example from 60 mg / L to 2000 mg / L, for example from 80 mg / L to 1500 mg / L, for example from 100 mg / L to 1000 mg / L, for example from 200 mg / L to 800 mg / L of the composition according to the invention. Suitably, A-Tetra is present in a total amount of from 0.04 g / 100 g to 2 g / 100 g, for example from 0.05 g / 100 g to 1.6 g / 100 g, for example from 0.06 to 1.2 g / 100g, for example from 0.07 g / 100 g to 0.8 g / 100 g, for example from 0.1 g / 100g to 0.7 g / 100g of the composition (dry weight).

[0273] Suitably, LN DFH-I is present in a total amount of from 25 mg / L to 4000 mg / L of the composition according to the invention or of from 0.02 g / 100 g to 3.75 g / 100 g of the nutritional composition according to the invention. Suitably, LNDFH-I is present in a total amount of from 50 mg / L to 2500 mg / L, for example from 60 mg / L to 2000 mg / L, for example from 80 mg / L to 1500 mg / L, for example from 100 mg / L to 1500 mg / L, for example from 200 mg / L to 1250 mg / L of the composition according to the invention, preferably from 400 mg / L to 1000 mg / L. Suitably, LNDFH-I is present in a total amount of from 0.04 g / 100 g to 2 g / 100 g, for example from 0.05 g / 100 g to 1.6 g / 100 g, for example from 0.06 to 1.2 g / 100g, for example from 0.07 g / 100 g to 0.8 g / 100 g, for example from 0.1 g / 100g to 0.7 g / 100g of the composition (dry weight).

[0274] In some embodiments, DFLNHa is present in a total amount of from 25 mg / L to 4000 mg / L of the composition according to the invention or of from 0.02 g / 100 g to 3.75 g / 100 g of the nutritional composition according to the invention. Suitably, DFLNHa is present in a total amount of from 50 mg / L to 2500 mg / L, for example from 60 mg / L to 2000 mg / L, for example from 80 mg / L to 1500 mg / L, for example from 100 mg / L to 1000 mg / L, for example from 100 mg / L to 800 mg / L of the composition according to the invention, preferably 150 mg / L to 400 mg / L. Suitably, DFLNHa is present in a total amount of from 0.04 g / 100 g to 2 g / 100 g, for example from 0.05 g / 100 g to 1.6 g / 100 g, for example from 0.06 to 1.2 g / 100g, for example from 0.07 g / 100 g to 0.8 g / 100 g, for example from 0.1 g / 100g to 0.7 g / 100g of the composition (dry weight).

[0275] Suitably, 2FL is administered to the subject in an amount of at least about 0.5 g / day, at least about 0.8 g / day, or at least about 1 g / day. Suitably, 2FL is administered to the subject in an amount of about 5 g / day or less, about 4 g / day or less, or about 3 g / day or less. Suitably, 2FL is administered to the subject in an amount of from about 0.5 g / day to about 5 g / day, from about 0.8 g / day to about 4 g / day or from about 1 g / day to about 3 g / day. Suitably, LDFT is administered to the subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LDFT is administered to the subject in an amount of about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LDFT is administered to the subject in an amount of from about 0.1 g / day to about 1 g / day, from about 0.15 g / day to about 0.8 g / day or from about 0.2 g / day to about 0.6 g / day.

[0276] Suitably, LNFP-I is administered to the subject in an amount of at least about 0.1 g / day, at least about 0.15 g / day, or at least about 0.2 g / day. Suitably, LNFP-I is administered to the subject in an amount of about 1 g / day or less, about 0.8 g / day or less, or about 0.6 g / day or less. Suitably, LNFP-I is administered to the subject in an amount of from about 0.1 g / day to about 1 g / day, from about 0.15 g / day to about 0.8 g / day or from about 0.2 g / day to about 0.6 g / day.

[0277] In another embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0278] As used herein, the term “used at a total amount” may mean that the HMO is at the stated concentration, for example in a composition, such as a nutritional composition, for example for administration to the subject. The HMO may, for example, be formulated in the nutritional composition at the stated concentration. The HMO may, for example, be administered to the subject at the stated concentration.

[0279] In some embodiments, the 2FL is used at a total amount of greater than 2100 mg / L, for example greater than 2250 mg / L, 2500 mg / L, 3000 mg / L, 4000 mg / L or 5000 mg / L. In some embodiments, the 2FL is used at a total amount of less than 7500 mg / L, for example less than 5000 mg / L, 4000 mg / L, 3000 mg / L or 2500 mg / L.

[0280] In some embodiments, the 3FL is used at a total amount of greater than 530 mg / L, for example greater than 550 mg / L, 600 mg / L, 700 mg / L, 800 mg / L, 900 mg / L or 1000 mg / L. In some embodiments, the 3FL is used at a total amount of less than 1500 mg / L, for example less than 1000 mg / L, 900 mg / L or 750 mg / L.

[0281] In some embodiments, the 6SL is used at a total amount of greater than 460 mg / L, for example greater than 500 mg / L, 600 mg / L, 700 mg / L, 800 mg / L, 900 mg / L or 1000 mg / L. In some embodiments, the 6SL is used at a total amount of less than 1500 mg / L, for example greater than, for example less than 1000 mg / L, 900 mg / L or 750 mg / L.

[0282] In some embodiments, the 3SL is used at a total amount of greater than 103 mg / L, for example greater than 150 mg / L, 200 mg / L, 300 mg / L, 400 mg / L or 500 mg / L. In some embodiments, the 3SL is used at a total amount of less than 750 mg / L, for example less than 600 mg / L, 500 mg / L, 400 mg / L or 250 mg / L.

[0283] In some embodiments, the DSLNT is used at a total amount of greater than 200 mg / L, for example greater than 250 mg / L, 300 mg / L, 400 mg / L or 500 mg / L. In some embodiments, the DSLNT is used at a total amount of less than 750 mg / L, for example less than 600 mg / L, 500 mg / L, 400 mg / L or 250 mg / L.

[0284] In some embodiments, the LNH is used at a total amount of greater than 65 mg / L, for example greater than 75 mg / L, 80 mg / L, 90 mg / L or 100 mg / L. In some embodiments, the LNH is used at a total amount of less than 150 mg / L, for example less than 125 mg / L, 100 mg / L or 75 mg / L.

[0285] In some embodiments, the LNFP-V is used at a total amount of greater than 37 mg / L, for example greater than 40 mg / L, 50 mg / L, 60 mg / L, 70 mg / L, 80 mg / L, 90 mg / L or 100 mg / L. In some embodiments, the LNFP-V is used at a total amount of less than 150 mg / L, for example less than 125 mg / L, 100 mg / L, 75 mg / L or 50 mg / L.

[0286] In some embodiments, the LNnT is used at a total amount of greater than 115 mg / L, for example greater than 150 mg / L, 200 mg / L, 300 mg / L, 400 mg / L or 500 mg / L. In some embodiments, the LNnT is used at a total amount of less than 750 mg / L, for example less than 600 mg / L, 500 mg / L, 400 mg / L, 250 mg / L or 150 mg / L.

[0287] In some embodiments, the LSTb is used at a total amount of greater than 49 mg / L, for example greater than 50 mg / L, 60 mg / L, 70 mg / L, 80 mg / L, 90 mg / L or 100 mg / L. In some embodiments, the LSTb is used at a total amount of less than 150 mg / L, for example less than 125 mg / L, 100 mg / L, 75 mg / L or 60 mg / L.

[0288] In some embodiments, the LNFP-II is used at a total amount of greater than 279 mg / L, for example greater than 300 mg / L, 400 mg / L or 500 mg / L. In some embodiments, the LNFP-II is used at a total amount of less than 750 mg / L, for example less than 600 mg / L, 500 mg / L, 400 mg / L or 300 mg / L.

[0289] In some embodiments, the LNT is used at a total amount of greater than 585 mg / L, for example greater than 600 mg / L, 700 mg / L, 800 mg / L, 900 mg / L or 1000 mg / L. In some embodiments, the LNT is used at a total amount of less than 1500 mg / L, for example less than 1000 mg / L, 900 mg / L or 750 mg / L.

[0290] COMPOSITION

[0291] In some embodiments, the combination is in the form of a composition (preferably a nutritional composition). The composition may include further components, for example components as described herein.

[0292] In one embodiment, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; and (f) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0293] In one aspect, the invention provides a human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L. As used herein, the term “used at a total amount” may mean that the HMO is at the stated concentration, for example in a composition, such as a nutritional composition, for example for administration to the subject. The HMO may, for example, be formulated in the nutritional composition at the stated concentration. The HMO may, for example, be administered to the subject at the stated concentration.

[0294] In some embodiments, the 2FL is used at a total amount of greater than 2100 mg / L, for example greater than 2250 mg / L, 2500 mg / L, 3000 mg / L, 4000 mg / L or 5000 mg / L. In some embodiments, the 2FL is used at a total amount of less than 7500 mg / L, for example less than 5000 mg / L, 4000 mg / L, 3000 mg / L or 2500 mg / L.

[0295] In some embodiments, the 3FL is used at a total amount of greater than 530 mg / L, for example greater than 550 mg / L, 600 mg / L, 700 mg / L, 800 mg / L, 900 mg / L or 1000 mg / L. In some embodiments, the 3FL is used at a total amount of less than 1500 mg / L, for example less than 1000 mg / L, 900 mg / L or 750 mg / L.

[0296] In some embodiments, the 6SL is used at a total amount of greater than 460 mg / L, for example greater than 500 mg / L, 600 mg / L, 700 mg / L, 800 mg / L, 900 mg / L or 1000 mg / L. In some embodiments, the 6SL is used at a total amount of less than 1500 mg / L, for example greater than, for example less than 1000 mg / L, 900 mg / L or 750 mg / L.

[0297] In some embodiments, the 3SL is used at a total amount of greater than 103 mg / L, for example greater than 150 mg / L, 200 mg / L, 300 mg / L, 400 mg / L or 500 mg / L. In some embodiments, the 3SL is used at a total amount of less than 750 mg / L, for example less than 600 mg / L, 500 mg / L, 400 mg / L or 250 mg / L.

[0298] In some embodiments, the LNnT is used at a total amount of greater than 115 mg / L, for example greater than 150 mg / L, 200 mg / L, 300 mg / L, 400 mg / L or 500 mg / L. In some embodiments, the LNnT is used at a total amount of less than 750 mg / L, for example less than 600 mg / L, 500 mg / L, 400 mg / L, 250 mg / L or 150 mg / L.

[0299] In some embodiments, the LNT is used at a total amount of greater than 585 mg / L, for example greater than 600 mg / L, 700 mg / L, 800 mg / L, 900 mg / L or 1000 mg / L. In some embodiments, the LNT is used at a total amount of less than 1500 mg / L, for example less than 1000 mg / L, 900 mg / L or 750 mg / L.

[0300] In some embodiments, the DSLNT is used at a total amount of greater than 200 mg / L, for example greater than 250 mg / L, 300 mg / L, 400 mg / L or 500 mg / L. In some embodiments, the DSLNT is used at a total amount of less than 750 mg / L, for example less than 600 mg / L, 500 mg / L, 400 mg / L or 250 mg / L.

[0301] In some embodiments, the LNH is used at a total amount of greater than 65 mg / L, for example greater than 75 mg / L, 80 mg / L, 90 mg / L or 100 mg / L. In some embodiments, the LNH is used at a total amount of less than 150 mg / L, for example less than 125 mg / L, 100 mg / L or 75 mg / L.

[0302] In some embodiments, the LNFP-V is used at a total amount of greater than 37 mg / L, for example greater than 40 mg / L, 50 mg / L, 60 mg / L, 70 mg / L, 80 mg / L, 90 mg / L or 100 mg / L. In some embodiments, the LNFP-V is used at a total amount of less than 150 mg / L, for example less than 125 mg / L, 100 mg / L, 75 mg / L or 50 mg / L.

[0303] In some embodiments, the LSTb is used at a total amount of greater than 49 mg / L, for example greater than 50 mg / L, 60 mg / L, 70 mg / L, 80 mg / L, 90 mg / L or 100 mg / L. In some embodiments, the LSTb is used at a total amount of less than 150 mg / L, for example less than 125 mg / L, 100 mg / L, 75 mg / L or 60 mg / L.

[0304] In some embodiments, the LNFP-II is used at a total amount of greater than 279 mg / L, for example greater than 300 mg / L, 400 mg / L or 500 mg / L. In some embodiments, the LNFP-II is used at a total amount of less than 750 mg / L, for example less than 600 mg / L, 500 mg / L, 400 mg / L or 300 mg / L.

[0305] Suitable doses of human oligosaccharides are described in e.g. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), 2015. EFSA Journal, 13(11), p.4299; EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2019. EFSA Journal, 17(6), p.e05717; EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2020. EFSA Journal, 18(5), p.e06097; EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2022. EFSA Journal, 20(5), p.e07331 ; and EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), 2019. EFSA Journal, 17(12), p.e05907.

[0306] NUTRITIONAL COMPOSITION

[0307] In some embodiments, the composition of the invention is in the form of a nutritional composition.

[0308] The nutritional composition according to the invention can be for example an infant formula, a starter infant formula, a follow-on or follow-up formula, a growing-up milk, a baby food, an infant cereal composition, a fortifier such as a human milk fortifier, a supplement such as a paediatric supplement, a pet food, or a pet food supplement. In some particular embodiments, the composition of the invention is an infant formula, a fortifier or a supplement that may be intended for the first 4 or 6 months of age. In a preferred embodiment the nutritional composition of the invention is an infant formula.

[0309] In some other embodiments, the nutritional composition of the present invention is a fortifier. The fortifier can be a breast milk fortifier (e.g. a human milk fortifier) or a formula fortifier such as an infant formula fortifier or a follow-on / follow-up formula fortifier.

[0310] When the nutritional composition is a supplement, it can be provided in the form of unit doses. In such cases it is particularly useful to define the amount of oligosaccharides in terms of daily dose to be administered, for example to the infant, young child or child. In some embodiments, the supplement is a paediatric supplement.

[0311] The composition according to the present invention may also comprise other types of oligosaccharide(s), polysaccharides and / or a fiber(s) and / or a precursor(s) thereof.

[0312] When the composition is in liquid form, the total HMO concentration is typically in the range from 0.5 to 10 g / L, preferably in the range from 1 to 7.5 g / L. Specific examples of the concentration level of total HMO, when the composition is in liquid form, include 1 to 5 g / L, 1 to 4 g / L, 2 to 5 g / L, 1 to 3 g / L or 2 to 4 g / L.

[0313] When the composition is in solid form, the total HMO concentration is typically in the range from 0.35 to 7 wt% (g total HMO / 100 g dry composition), preferably in the range from 0.35 to 5 wt%. Specific examples of the concentration level of total HMO, when the composition is in dry form, include 0.5 to 3.5 wt% (g total HMO per 100 g dry composition), 0.5 to 2.5 wt%, 1 to 3.5 wt%, 0.5 to 2 wt% or 1 to 2.5 wt%.

[0314] When the nutritional composition is a supplement, it may comprise the combination as described herein, and no other additional nutrient on top of the excipients necessary to obtain a stable nutritional composition.

[0315] The nutritional composition of the present invention can be in solid (e.g. powder), liquid or gelatinous form. In a specific embodiment the nutritional composition is a supplement, wherein the supplement is in powder form and provided in a sachet, preferably a sachet with 0.1 to 20 g per sachet, for example 1 to 10 g per sachet, or in the form of a syrup, preferably a syrup with a total solid concentration of 5 to 75 g / 100 mL (5 to 75% (w / v)). When the supplement is in powder form, it may comprise a carrier. It is however preferred that the supplement is devoid of a carrier. When the supplement is in the form of a syrup, the components are preferably dissolved or suspended in water acidified with citrate. In a particular embodiment the nutritional composition according to the invention is a hypoallergenic composition. In another particular embodiment the composition according to the invention is a hypoallergenic nutritional composition.

[0316] In some embodiments, the composition according to the invention comprises at least one additional HMO.

[0317] In other embodiments, the composition according to the present invention is devoid of any further HMOs.

[0318] OTHER INGREDIENTS

[0319] In some embodiments, the composition of the present invention does not comprise at least one probiotic (or probiotic strain), such as at least one probiotic bacterial strain. In some embodiments, the composition of the present invention does not comprise any Bifidobacterium, such as Bifidobacterium longum subsp. infantis, such as Bifidobacterium longum subsp. infantis LMG 11588 (also known as Bifidobacterium longum subsp. infantis NCC3039 or Bifidobacterium longum subsp. infantis ATCC 17930). Bifidobacterium longum subsp. infantis LMG 11588 is sold by the Belgian Coordinated Collections of Microorganisms (BCCM) under the LMG accession number LMG 11588.

[0320] The composition of the present invention can further comprise at least one probiotic (or probiotic strain), such as at least one probiotic bacterial strain.

[0321] The probiotic microorganisms most commonly used are principally bacteria and yeasts of the following genera: Lactobacillus spp., Lacticaseibacillus spp, Limosilactobacillus spp, Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp.

[0322] In some particular embodiments, the probiotic is a probiotic bacterial strain. In some specific embodiments, it is particularly Bifidobacteria and / or Lactobacilli.

[0323] Suitable probiotic bacterial strains according to the present invention include Bifidobacterium animalis subsp. lactis CNCM 1-3446 deposited according to the Budapest Treaty on 7th June 2005 at Collection Nationale Cultures De Microorganismes [French National Collection Of Microorganism Cultures] (CNCM), Institut Pasteur, 25 Rue Du Docteur Roux, F-75724 Paris Cedex 15 (France), or BL818 or Bifidobacterium animalis subsp. lactis sold inter alia by the Christian Hansen company of Denmark under the trademark Bb 12 (also known as DSM- 15954), B. longum CNCM 1-2618 (B. longum NCC2705), Bifidobacterium breve sold by Danisco under the trademark Bb-03, Bifidobacterium breve sold by Morinaga under the trade mark M-16V, Bifidobacterium breve sold by Morinaga under the trade mark B-3, Bifidobacterium breve sold by sold by Yakult under the trade mark BBG-01 , Bifidobacterium breve sold by Institut Rosell (Lallemand) under the trademark R0070, Lactobacillus rhamnosus ATCC 53103 available from Valio Oy of Finland under the trademark LGG, Lactobacillus rhamnosus CGMCC 1.3724, Lactobacillus paracasei CNCM 1-2116, Lactobacillus johnsonii CNCM 1-1225, Streptococcus salivarius DSM 13084 sold by BLIS Technologies Limited of New Zealand under the designation KI2, Bifidobacterium longum subsp. infantis LMG 11588 (also known as DSM 20218; ATCC 17930; JCM1260) sold by the Belgian Coordinated Collections of Microorganisms (BCCM) under the LMG accession number LMG 11588, and Bifidobacterium longum subsp. infantis sold for example by Procter & Gamble Co. under the trademark Bifantis.

[0324] The composition according to the invention may contain from 10e3 to 10e12 cfu of the at least one probiotic strain, more preferably between 10e7 and 10e12 cfu such as between 10e8 and 10e10 cfu of probiotic strain per g of composition on a dry weight basis.

[0325] In one embodiment, the probiotics are viable. In another embodiment, the probiotics are nonreplicating or inactivated. There may be both viable probiotics and inactivated probiotics in some other embodiments. Probiotic components and metabolites can also be added.

[0326] The nutritional composition according to the invention generally contains a protein source. The protein can be in an amount of from 1 .6 to 3 g per 100 kcal. In some embodiments, especially when the composition is intended for premature infants, the protein amount can be between 2.4 and 4 g / 100kcal or more than 3.6 g / 100kcal (or 3.6 g / 100kcal or more). In some other embodiments the protein amount can be below 2.0 g per 100 kcal, e.g. between 1.8 to 2 g / 100 kcal, or in an amount below 1.8 g per 100 kcal.

[0327] Protein sources based on whey, casein and mixtures thereof may be used as well as protein sources based on soy. As far as whey proteins are concerned, the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha-lactalbumin and beta-lactoglobulin in any desired proportions.

[0328] In some advantageous embodiments the protein source is whey predominant (i.e. more than 50% of proteins are coming from whey proteins, such as 51%, 60% or 70%).

[0329] The proteins may be intact or hydrolysed or a mixture of intact and hydrolysed proteins. By the term “intact” is meant that the main part of the proteins are intact, i.e. the molecular structure is not altered, for example at least 80% of the proteins are not altered, such as at least 85% of the proteins are not altered, preferably at least 90% of the proteins are not altered, even more preferably at least 95% of the proteins are not altered, such as at least 98% of the proteins are not altered. In a particular embodiment, 100% of the proteins are not altered.

[0330] The term “hydrolysed” means in the context of the present invention a protein which has been hydrolysed or broken down into its component amino acids. The proteins may be either fully or partially hydrolysed. It may be desirable to supply partially hydrolysed proteins (degree of hydrolysis between 2 and 20%), for example for infants or young children believed to be at risk of developing cow’s milk allergy. If hydrolysed proteins are required, the hydrolysis process may be carried out as desired and as is known in the art. For example, whey protein hydrolysates may be prepared by enzymatically hydrolysing the whey fraction in one or more steps. If the whey fraction used as the starting material is substantially lactose free, it is found that the protein suffers much less lysine blockage during the hydrolysis process. This enables the extent of lysine blockage to be reduced from about 15% by weight of total lysine to less than about 10% (or to about 10% or less) by weight of lysine; for example about 7% by weight of lysine which greatly improves the nutritional quality of the protein source.

[0331] In an embodiment of the invention at least 70% of the proteins are hydrolysed, preferably at least 80% of the proteins are hydrolysed, such as at least 85% of the proteins are hydrolysed, even more preferably at least 90% of the proteins are hydrolysed, such as at least 95% of the proteins are hydrolysed, particularly at least 98% of the proteins are hydrolysed. In a particular embodiment, 100% of the proteins are hydrolysed.

[0332] In one particular embodiment the proteins of the nutritional composition are hydrolyzed, fully hydrolyzed or partially hydrolyzed. The degree of hydrolysis (DH) of the protein can be between 8 and 40, or between 20 and 60 or between 20 and 80 or more than 10, 20, 40, 60, 80 or 90 (or 10, 20, 40, 60, 80 or 90 or more).

[0333] The protein component can alternatively be replaced by a mixture or synthetic amino acid, for example for preterm or low birth weight infants.

[0334] In a particular embodiment, the nutritional composition or the growing-up milk according to the invention is a hypoallergenic composition. In another particular embodiment, the composition according to the invention is a hypoallergenic nutritional composition or growing-up milk.

[0335] The nutritional composition according to the present invention generally contains a carbohydrate source. This is particularly preferable in the case where the nutritional composition of the invention is an infant formula. In this case, any carbohydrate source conventionally found in infant formulae such as lactose, sucrose, saccharose, maltodextrin, starch and mixtures thereof may be used although one of the preferred sources of carbohydrates is lactose.

[0336] The nutritional composition according to the present invention generally contains a source of lipids. This is particularly relevant if the nutritional composition of the invention is an infant formula. In this case, the lipid source may be any lipid or fat which is suitable for use in infant formulae. Some suitable fat sources include palm oil, structured triglyceride oil, high oleic sunflower oil and high oleic safflower oil, medium-chain-triglyceride oil. The essential fatty acids linoleic and a-linolenic acid may also be added, as well small amounts of oils containing high quantities of preformed arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils. The fat source may have a ratio of n-6 to n-3 fatty acids of about 5:1 to about 15: 1 ; for example about 8: 1 to about 10: 1.

[0337] The nutritional composition of the invention may also contain all vitamins and minerals understood to be essential in the daily diet and in nutritionally significant amounts. Minimum requirements have been established for certain vitamins and minerals. Examples of minerals, vitamins and other nutrients optionally present in the composition of the invention include vitamin A, vitamin B1 , vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorous, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in salt form. The presence and amounts of specific minerals and other vitamins will vary depending on the intended population.

[0338] If necessary, the nutritional composition of the invention may contain emulsifiers and stabilisers such as soy, lecithin, citric acid esters of mono- and di-glycerides, and the like.

[0339] The nutritional composition of the invention may also contain other substances which may have a beneficial effect such as nucleotides, nucleosides, and the like.

[0340] The nutritional composition of the invention may also contain carotenoid(s). In some particular embodiments of the invention, the nutritional composition of the invention does not comprise any carotenoid.

[0341] MANUFACTURE OF A NUTRITIONAL COMPOSITION

[0342] The nutritional composition according to the invention may be prepared in any suitable manner. A composition will now be described by way of example. For example, a formula such as an infant formula may be prepared by blending together the protein source, the carbohydrate source and the fat source in appropriate proportions. If used, the emulsifiers may be included at this point. The vitamins and minerals may be added at this point but they are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved into the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture. The temperature of the water is conveniently in the range between about 50°C and about 80°C to aid dispersal of the ingredients. Commercially available liquefiers may be used to form the liquid mixture.

[0343] The oligosaccharide(s) may be added at this stage, especially if the final product is to have a liquid form. If the final product is to be a powder, they may likewise be added at this stage if desired.

[0344] The liquid mixture is then homogenised, for example in two stages.

[0345] The liquid mixture may then be thermally treated to reduce bacterial loads, by rapidly heating the liquid mixture to a temperature in the range between about 80°C and about 150°C for a duration between about 5 seconds and about 5 minutes, for example. This may be carried out by means of steam injection, an autoclave or a heat exchanger, for example a plate heat exchanger.

[0346] Then, the liquid mixture may be cooled to between about 60°C and about 85°C for example by flash cooling. The liquid mixture may then be again homogenised, for example in two stages between about 10 MPa and about 30 MPa in the first stage and between about 2 MPa and about 10 MPa in the second stage. The homogenised mixture may then be further cooled to add any heat sensitive components, such as vitamins and minerals. The pH and solids content of the homogenised mixture are conveniently adjusted at this point.

[0347] If the final product is to be a powder, the homogenised mixture is transferred to a suitable drying apparatus such as a spray dryer or freeze dryer and converted to powder. The powder should have a moisture content of less than about 5% (or about 5% or less) by weight. The oligosaccharide(s) may also or alternatively be added at this stage by dry-mixing or by blending them in a syrup form of crystals, along with the probiotic strain(s), and the mixture is spray-dried or freeze-dried.

[0348] If a liquid composition is preferred, the homogenised mixture may be sterilised then aseptically filled into suitable containers or may be first filled into the containers and then retorted. In another embodiment, the composition of the invention may be a supplement, such as a paediatric supplement. The supplement may be in the form of tablets, capsules, pastilles or a liquid for example. The supplement may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, cocompounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste masking agents, weighting agents, jellifying agents and gel forming agents. The supplement may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatine of any origin, vegetable gums, lignin- sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.

[0349] Further, the supplement may contain an organic or inorganic carrier material suitable for oral or parenteral administration as well as vitamins, minerals trace elements and other micronutrients in accordance with the recommendations of Government bodies such as the USRDA.

[0350] This disclosure is not limited by the exemplary methods and materials disclosed herein, and any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this disclosure. Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, any nucleic acid sequences are written left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation, respectively.

[0351] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within this disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure. It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0352] The terms "comprising", "comprises" and "comprised of' as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. The terms "comprising", "comprises" and "comprised of' also include the term "consisting of.

[0353] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of chemistry, biochemistry, molecular biology, microbiology and immunology, which are within the capabilities of a person of ordinary skill in the art. Such techniques are explained in the literature. See, for example, Sambrook, J., Fritsch, E.F. and Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory Press; Ausubel, F.M. et al. (1995 and periodic supplements) Current Protocols in Molecular Biology, Ch. 9, 13 and 16, John Wiley & Sons; Roe, B., Crabtree, J. and Kahn, A. (1996) DNA Isolation and Sequencing: Essential Techniques, John Wiley & Sons; Polak, J.M. and McGee, J.O’D. (1990) In Situ Hybridization: Principles and Practice, Oxford University Press; Gait, M.J. (1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press; and Lilley, D.M. and Dahlberg, J.E. (1992) Methods in Enzymology: DNA Structures Part A: Synthesis and Physical Analysis of DNA, Academic Press. Each of these general texts is herein incorporated by reference.

[0354] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto.

[0355] The invention will now be further described by way of Examples, which are meant to serve to assist one of ordinary skill in the art in carrying out the invention and are not intended in any way to limit the scope of the invention.

[0356] EXAMPLES

[0357] EXAMPLE 1

[0358] RESULTS

[0359] We identified that total amount of human milk oligosaccharides (HMOs), 2FL and HMO groups 3'SL + 6'SL + LNT + 2'FL + LDFT + 3FL, 3'SL + 6'SL + LNT + LNnT + 2'FL + LDFT + 3FL, and 3'SL + 6'SL + LNT + LNnT + 2'FL + LDFT + 3FL + LNFP-I, 2’FL + A-tetra + LNFP-I + LDFT + LNDFH-I + DFLNHa, 2FL + LDFT + LNFP-I, 2FL + LDFT + LNFP-I, 2FL+ 3SL + 6SL and optionally LDFT, and / or LNFP-I, 2FL+ 3SL + 6SL + LDFT, 2FL+ 3SL + 6SL + LDFT + LNFP-I (r~0.1835, p ~ 0.05), and certain human milk oligosaccharides (HMOs) 2FL, 3FL, 6SL, 3SL, LNnT, LSTb, LNFP-II and LNT, and DSLNT, LNH, LNFP-V, LNFP-II, and LSTb (see Figure 1) were positively associated with tibia or radius length. Figure 1 shows the levels of association through simple regression analysis. These analyses remain significant after adjustment by key nutrients known to impact bone length in our study (including Vitamin B1 , B3, C, and E, and Ca, K, and Zn). After adjustment, as an example, a one unit increase in the 2’FL at 1 month is associated with a 0.0001 unit increase in the tibia length at 6 months, on average (p-value=0.0267). After adjustment, LNFP-I association with tibia length became significant with a one unit increase in the LNFP-I at 1 month associated with a 0.0004 unit increase in the tibia length at 6 months, (p-value=0.0256).

[0360] Additionally, the effect of individual or groups of HMOs at 1 and 3 months on tibia SoS at visit of interest were modelled using 3-knot linear spline regression (LSP) and the positive associations of HMOs on bone length shown (Table 1). In the 3-knot LSP model the knot locations is according to the 10th, 50th and 90th percentile of respective HMO concentration. The LSP model also adjust for tibia SoS at birth, body weight at the visit of interest, gender and delivery mode as covariates.

[0361] Table 1 : Effect of individual HMOs on bone length using 3-knot LSP model

[0362] The main benefit of using a 3-knot spline regression is its ability to adapt to non-linear trends while maintaining interpretability, smoothness, and avoiding overfitting. It is a practical, robust tool when working with data that cannot be well-represented by simple linear or global polynomial models (Modeling non-linear relationships in epidemiological data: The application and interpretation of spline models, Schuster Noah A., Rijnhart Judith J. M., Twisk Jos W. R., Heymans Martijn W.).

[0363] MATERIALS AND METHODS

[0364] Length of the tibia and radius

[0365] Radius and tibia length were determined at birth, 3 and 6 months of age using a rubber as previously described (Bonnet N, Capeding MR, Siegwald L, Garcia-Garcera M, Desgeorges T, Tytgat HLP, et al. A young child formula supplemented with L reuteri and galactooligosaccharides modulates the composition and function of the gut microbiome supporting bone and muscle development in toddlers. BioRxiv. 2024; Dec Online.).

[0366] Statistical analysis between HMO levels in breast milk and length of the tibia and radius

[0367] The influence of specific or groups of HMOs from breastmilk (at 1 month and 3 months) on bone outcomes at 6 months (tibia mass index, tibia length, radius mass index and radius length trajectories) was performed. Spearman’s rank-order correlations were determined between HMOs at 1 month or 3 months with bone outcomes at 6 months.

[0368] Embodiments

[0369] Various preferred features and embodiments of the present invention will now be described with reference to the following numbered clauses:

[0370] 1. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N- neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I).

[0371] 2. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N- tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N- fucopentaose I (LNFP-I). 3. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and 3-fucosyl lactose (3FL).

[0372] 4. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N- hexaose a (DFLNHa).

[0373] 5. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0374] 6. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I).

[0375] 7. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N- fucopentaose I (LNFP-I).

[0376] 8. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL) and 3'-sialyllactose (3SL).

[0377] 9. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL) and 3'- sialyllactose (3SL).

[0378] 10. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'-sialyllactose (3SL) and lacto-N-fucopentaose I (LNFP- I). 11 . Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto- N-tetraose (LNT), 2’-fucosyl lactose (2FL), lactodifucotetraose (LDFT), and 3- fucosyllactose (3FL).

[0379] 12. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL) and lacto-N-neotetraose (LNnT).

[0380] 13. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto- N-tetraose (LNT), 2’-fucosyl lactose (2FL), lactodifucotetraose (LDFT), 3- fucosyllactose (3FL) and lacto-N-neotetraose (LNnT).

[0381] 14. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), lacto-N-neotetraose (LNnT), and lacto-N-fucopentaose I (LNFP-I).

[0382] 15. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N- tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), lacto-N-neotetraose (LNnT), and lacto-N-fucopentaose I (LNFP-I).

[0383] 16. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A- tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N- difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

[0384] 17. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0385] 18. A human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is selected from the group consisting of (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L. Use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L. A human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3- fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L. Use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3- fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L. . Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'- sialyllactose (3SL) and lacto-N-fucopentaose I (LNFP-I). . A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I). . Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).. The combination of HMOs for use or the use according to any one of clauses 1 , 2 or 15, wherein the combination of HMOs consists essentially of: i. 16 wt% to 69 wt% of 2FL, preferably 22 wt% to 59 wt%; ii. 9 wt% to 24 wt% of LNT, preferably 12 wt% to 21 wt%; iii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; iv. 8 wt% to 26 wt% of 6SL and 3SL combined, preferably 11 wt% to 22 wt%; and at least one of: v. 18 wt% to 50 wt% of 3FL, preferably 11 wt% to 43 wt%; and / or vi. 1 wt% to 25 wt% of LNnT, preferably 1 wt% to 18 wt%; and / or vii. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%. . The combination of HMOs for use or the use according to any one of clauses 1 , 2, or 15, wherein the combination of HMOs consists essentially of: i. 16 wt% to 69 wt% of 2FL, preferably 22 wt% to 59 wt%; ii. 9 wt% to 24 wt% of LNT, preferably 12 wt% to 21 wt%; iii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; iv. 8 wt% to 26 wt% of 6SL and 3SL combined, preferably 11 wt% to 22 wt%; and v. 18 wt% to 50 wt% of 3FL, preferably 11 wt% to 43 wt%.

[0386] 27. The combination of HMOs for use or the use according to any one of clauses 1 , 2, or 15, wherein the combination of HMOs consists essentially of: i. 20 wt% to 60 wt% of 2FL, preferably 22 wt% to 55 wt%; ii. 4 wt% to 30 wt% of LNT, preferably 6 wt% to 20 wt%; iii. 1 wt% to 12 wt % of LDFT, preferably 2 wt% to 8 wt %; iv. 7 wt% to 23 wt% of 6SL and 3SL combined, preferably 8 wt% to 22 wt%; v. 10 wt% to 50 wt% of 3FL, preferably 13 wt% to 46 wt% and vi. 3 wt% to 25 wt% of LNnT, preferably 5 wt% to 20 wt%.

[0387] 28. The combination of HMOs for use or the use according to any one of clauses 1 , 2 or

[0388] 15, wherein the combination of HMOs consists essentially of: i. 29 wt% to 40 wt% of 2FL, preferably 32 wt% to 39 wt%; ii. 8 wt% to 13 wt% of LNT, preferably 9 wt% to 12 wt%; iii. 3 wt% to 11 wt % of LDFT, preferably 3 wt% to 11 wt %; iv. 3 wt% to 15 wt% of 6SL and 3SL combined, preferably 4 wt% to 15 wt%; v. 11 wt% to 35 wt% of 3FL, preferably 12 wt% to 35 wt%; vi. 1 wt% to 18 wt% of LNnT, preferablyl wt% to 17 wt%; and vii. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%.

[0389] 29. The combination of HMOs for use or the use according to clauses 4, or 16, wherein the combination of HMOs consists essentially of: i. 29 wt% to 40 wt% of 2FL, preferably 32 wt% to 39 wt%; ii. 3 wt% to 11 wt % of LDFT, preferably 3 wt% to 11 wt %; iii. 1 wt% to 40 wt% of A-tetra, preferably 2 wt% to 30 wt%; iv. 10 wt% to 35 wt% of LNDFH-I, preferably12 wt% to 30 wt%; v. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%; and vi. 2 wt% to 24 wt% of DFLNHa, preferably 2 wt% to 15 wt%.

[0390] 30. The combination of HMOs for use or the use according to clauses 5 or 17, wherein the combination of HMOs consists essentially of: i. 48 wt% to 77 wt% of 2FL, preferably 58 wt% to 74 wt%; ii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; and iii. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

[0391] 31 . The combination of HMOs for use or the use according to any one of clauses 3 or 10-14, wherein the combination of HMOs consists essentially of: i. 60 wt% to 96 wt% of 2FL, preferably 71 wt% to 80 wt%; ii. 2 wt% to 25 wt% of 6SL, preferably 4 wt% to 16 wt%; iii. 2 wt% to 35 wt% of 3SL, preferably 4 wt% to 25 wt%; optionally iv. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; and / or v. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

[0392] 32. The combination of HMOs for use or the use according to any one of clauses 3 or 10-14, wherein the combination of HMOs consists essentially of: i. 60 wt% to 96 wt% of 2FL, preferably 71 wt% to 80 wt%; ii. 2 wt% to 25 wt% of 6SL, preferably 4 wt% to 16 wt%; and iii. 2 wt% to 35 wt% of 3SL, preferably 4 wt% to 25 wt%.

[0393] 33. The combination of HMOs for use or the use according to any one of clauses 3 or 10-14, wherein the combination of HMOs consists essentially of: i. 48 wt% to 77 wt% of 2FL, preferably 58 wt% to 74 wt%; ii. 3 wt% to 16 wt% of 6SL, preferably 3 wt% to 15 wt%; iii. 2 wt% to 23 wt% of 3SL, preferably 3 wt% to 22 wt%; and iv. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%. 34. The combination of HMOs for use or the use according to any one of clauses 3 or 10-14, wherein the combination of HMOs consists essentially of: i. 48 wt% to 77 wt% of 2FL, preferably 58 wt% to 74 wt%; ii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; iii. 3 wt% to 15 wt% of 6SL and 3SL combined, preferably 4 wt% to 15 wt%; and iv. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

[0394] 35. The HMOs or combination of HMOs for use or the use according to any one of the preceding clauses, wherein the bone is a tibia and / or a radius.

[0395] 36. The HMOs or combination of HMOs for use or the use according to any preceding clause, wherein the subject is a human.

[0396] 37. The HMOs or combination of HMOs for use or the use according to any preceding clause, wherein the subject is an infant, a young child, or a child.

[0397] 38. The HMOs or combination of HMOs for use or the use according to any preceding clause, wherein the subject is an infant.

[0398] 39. The HMOs or combination of HMOs for use or the use according to any one of clauses 1-36, wherein the subject is an adult.

[0399] 40. The HMOs or combination of HMOs for use or the use according to any one of clauses 1-35, wherein the subject is a pet.

[0400] 41 . The HMOs or combination of HMOs for use or the use according to any one of clauses 1-38 or 40, wherein the subject suffered from and / or is suffering from stunted growth and / or faltering growth.

[0401] 42. The HMOs or combination of HMOs for use or the use according to any preceding clause, wherein the subject has or is at risk of developing a metabolic bone disease.

[0402] 43. The HMOs or combination of HMOs for use or the use according to any preceding clause, wherein the subject has or is at risk of developing osteoporosis or osteopenia.

[0403] 44. The HMOs or combination of HMOs for use or the use according to any preceding clause, wherein the combination of HMOs are in the form of a nutritional composition.

[0404] 45. The HMOs or combination of HMOs for use or the use according to clause 44, wherein the nutritional composition is selected from: an infant formula, a starter infant formula, a follow-on or follow-up formula, a baby food, an infant cereal composition, a growing- up-milk, a fortifier such as a human milk fortifier, or a supplement.

[0405] 46. The HMOs or combination of HMOs for use or the use according to clause 44, wherein the nutritional composition is an infant formula. The HMOs or combination of HMOs for use or the use according to any one of clauses 44-46, wherein the nutritional composition further comprises vitamin B1 , vitamin B3, vitamin C, vitamin E, calcium, potassium, zinc, or a combination thereof. The HMOs or combination of HMOs for use or the use according to any one of clauses 44-47, wherein the nutritional composition further comprises one or more prebiotic. The HMOs or combination of HMOs for use or the use according to any one of clauses 44-48, wherein the nutritional composition further comprises one or more probiotic, such as Bifidobacterium longum. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I). A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and 3-fucosyllactose (3FL). A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL) and lacto-N-neotetraose (LNnT). A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), lacto-N-neotetraose (LNnT), and lacto-N-fucopentaose I (LNFP-I). A human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is selected from the group consisting of: (a) 2’- fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N- fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP- II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0406] 55. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

[0407] 56. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0408] 57. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I).

[0409] 58. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyl lactose (2FL), 6'-sialyllactose (6SL) and 3'-sialyllactose (3SL).

[0410] 59. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'-sialyllactose (3SL) and lacto-N- fucopentaose I (LNFP-I).

[0411] 60. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0412] 61 . A human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0413] 62. The HMO or combination of HMOs for use according to clauses 50-61 , wherein the metabolic bone disease is osteoporosis or osteopenia.

[0414] 63. The combination of HMOs for use according to any one of clauses 50-62, wherein bone length is enhanced in the subject.

[0415] 64. A method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N- tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N- fucopentaose I (LNFP-I).

[0416] 65. A method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N- tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and 3- fucosyllactose (3FL).

[0417] 66. A method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N- tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), 3-fucosyllactose (3FL), lacto-N-neotetraose (LNnT), and lacto-N-fucopentaose I (LNFP-I).

[0418] 67. A method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N- hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

[0419] 68. A method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A- tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N- difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

[0420] 69. A method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0421] 70. A method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N- fucopentaose I (LNFP-I).

[0422] 71. A method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL) and 3'- sialyllactose (3SL).

[0423] 72. A method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'- sialyllactose (3SL) and lacto-N-fucopentaose I (LNFP-I).

[0424] 73. A method of enhancing bone length in a subject comprising administering a combination of human milk oligosaccharides (HMOs) to the subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

[0425] 74. A method of enhancing bone length in a subject comprising administering a human milk oligosaccharide (HMO) to the subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP- V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl- lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

[0426] All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the disclosed combinations, compositions, uses, and methods of the invention will be apparent to the skilled person without departing from the scope and spirit of the invention. Although the invention has been disclosed in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the disclosed modes for carrying out the invention, which are obvious to the skilled person are intended to be within the scope of the following claims.

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[0433] FOR RECEIVING OFFICE USE ONLY

[0434] FOR INTERNATIONAL BUREAU USE ONLY

Claims

CLAIMS1. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N- neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I).

2. A human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3- fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-I I is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

3. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N- hexaose a (DFLNHa).

4. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

5. A combination of human milk oligosaccharides (HMOs) for use in enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I).

6. A human milk oligosaccharide (HMO) for use in enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b)lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

7. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N- tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N- fucopentaose I (LNFP-I).

8. Use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) 2’-fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3- fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

9. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A- tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N- difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

10. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 6'-sialyllactose (6SL), 3'- sialyllactose (3SL) and lacto-N-fucopentaose I (LNFP-I).

11. Use of a combination of HMOs for enhancing bone length in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’- sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N- fucopentaose I (LNFP-I).

12. Use of a human milk oligosaccharide (HMO) for enhancing bone length in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

13. The HMO for use, combination of HMOs for use or the use according to any one of the preceding claims, wherein the bone is a tibia and / or a radius.

14. The HMO for use, combination of HMOs for use or the use according to claims 1 and / or 7 , wherein the combination of HMOs consists essentially of: i. 16 wt% to 69 wt% of 2FL, preferably 22 wt% to 59 wt%; ii. 9 wt% to 24 wt% of LNT, preferably 12 wt% to 21 wt%; iii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; iv. 8 wt% to 26 wt% of 6SL and 3SL combined, preferably 11 wt% to 22 wt%; and at least one of: v. 18 wt% to 50 wt% of 3FL, preferably 11 wt% to 43 wt%; and / or vi. 1 wt% to 25 wt% of LNnT, preferably 1 wt% to 18 wt%; and / or vii. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%.

15. The combination of HMOs for use or the use according to claims 3 or 9, wherein the combination of HMOs consists essentially of: i. 29 wt% to 40 wt% of 2FL, preferably 32 wt% to 39 wt%; ii. 3 wt% to 11 wt % of LDFT, preferably 3 wt% to 11 wt %; iii. 1 wt% to 40 wt% of A-tetra, preferably 2 wt% to 30 wt%; iv. 10 wt% to 35 wt% of LNDFH-I, preferably12 wt% to 30 wt%; v. 2 wt% to 24 wt% of LNFP-I, preferably 4 wt% to 14 wt%; and vi. 2 wt% to 24 wt% of DFLNHa, preferably 2 wt% to 15 wt%.

16. The combination of HMOs for use or the use according to claim 4, wherein the combination of HMOs consists essentially of:i. 48 wt% to 77 wt% of 2FL, preferably 58 wt% to 74 wt%; ii. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; and iii. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

17. The combination of HMOs for use or the use according to claims 5 or 11 , wherein the combination of HMOs consists essentially of: i. 60 wt% to 96 wt% of 2FL, preferably 71 wt% to 80 wt%; ii. 2 wt% to 25 wt% of 6SL, preferably 4 wt% to 16 wt%; iii. 2 wt% to 35 wt% of 3SL, preferably 4 wt% to 25 wt%; optionally iv. 2 wt% to 10 wt% of LDFT, preferably 3 wt% to 8 wt%; and / or v. 3 wt% to 39 wt% of LNFP-I, preferably 7 wt% to 27 wt%.

18. The HMO for use, combination of HMOs for use or the use according to any one of the preceding claims, wherein the subject is an infant, a young child, or a child.

19. The HMO for use, combination of HMOs for use or the use according to any one of claims 1-17, wherein the subject is an adult.

20. The HMO for use, combination of HMOs for use or the use according to any one of claims 1-18, wherein the subject suffered from and / or is suffering from stunted growth and / or faltering growth.

21. The HMO for use, combination of HMOs for use or the use according to any one of the preceding claims, wherein the subject has or is at risk of developing: (a) a metabolic bone disease; and / or (b) osteoporosis or osteopenia.

22. The HMO for use, combination of HMOs for use or the use according to any one of the preceding claims , wherein the combination or HMO is in the form of a nutritional composition, optionally wherein the nutritional composition is selected from: an infant formula, a starter infant formula, a follow-on or follow-up formula, a baby food, an infant cereal composition, a growing-up-milk, a fortifier such as a human milk fortifier, or a supplement.

23. The HMO for use, combination of HMOs for use or the use according to claim 22, wherein the nutritional composition further comprises vitamin B1 , vitamin B3, vitamin C, vitamin E, calcium, potassium, zinc, or a combination thereof.

24. The HMO for use, combination of HMOs for use or the use according to any one of claims 22 or 23, wherein the nutritional composition further comprises one or more prebiotic.

25. The HMO for use, combination of HMOs for use or the use according to any one of claims 22 to 24, wherein the nutritional composition further comprises one or more probiotic, such as Bifidobacterium longum.

26. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), lacto-N-tetraose (LNT), 2’-fucosyllactose (2FL), lactodifucotetraose (LDFT), and at least one of 3-fucosyllactose (3FL), and / or lacto-N-neotetraose (LNnT), and / or lacto-N-fucopentaose I (LNFP-I).

27. A human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is selected from the group consisting of: (a) 2’- fucosyllactose (2FL), wherein the 2FL is used at a total amount of greater than 2100 mg / L; (b) 3-fucosyllactose (3FL), wherein the 3FL is used at a total amount of greater than 530 mg / L; (c) 6’-sialyllactose (6SL), wherein the 6SL is used at a total amount of greater than 460 mg / L; (d) 3’-sialyllactose (3SL), wherein the 3SL is used at a total amount of greater than 103 mg / L; (e) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (f) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (g) lacto-N- fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (h) lacto-N-neotetraose (LNnT), wherein the LNnT is used at a total amount of greater than 115 mg / L; (i) sialyl-lacto-N-tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; (j) lacto-N-fucopentaose II (LNFP- II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L; and (k) lacto-N-tetraose (LNT), wherein the LNT is used at a total amount of greater than 585 mg / L.

28. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2’-fucosyllactose (2FL), Alpha-Tetrasaccharide (A-tetra), lacto-N-fucopentaose I (LNFP-I), lactodifucotetraose (LDFT), lacto-N-difusohexaose I (LNDFH-I) and difucosyllacto-N-hexaose a (DFLNHa).

29. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), lactodifucotetraose (LDFT), and lacto-N-fucopentaose I (LNFP-I).

30. A combination of human milk oligosaccharides (HMOs) for use in treating or preventing a metabolic bone disease in a subject, wherein the combination of HMOs consists of 2'-fucosyllactose (2FL), 3’-sialyllactose (3SL), 6’-sialyllactose (6SL), and optionally lactodifucotetraose (LDFT), and / or lacto-N-fucopentaose I (LNFP-I). 31 . A human milk oligosaccharide (HMO) for use in treating or preventing a metabolic bone disease in a subject, wherein the HMO is selected from the group consisting of: (a) disialyllacto-N-tetraose (DSLNT), wherein the DSLNT is used at a total amount of greater than 200 mg / L; (b) lacto-N-hexaose (LNH), an wherein the LNH is used at a total amount of greater than 65 mg / L; (c) lacto-N-fucopentaose V (LNFP-V), wherein the LNFP-V is used at a total amount of greater than 37 mg / L; (d) sialyl-lacto-N- tetraose b (LSTb), wherein the LSTb is used at a total amount of greater than 49 mg / L; and (e) lacto-N-fucopentaose II (LNFP-II), wherein the LNFP-II is used at a total amount of greater than 279 mg / L.

32. The HMO for use, combination of HMOs for use according to any one of claims 26 to 31 , wherein the metabolic bone disease is osteoporosis or osteopenia.

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