Composition for reducing pain and / or feeling of pain in infants and young children

Abstract

The present invention relates to a composition comprising a mixture of human milk oligosaccharides consisting of 2 '-fucosyllactose and difucosyllactose for use in reducing pain and / or pain in infants or young children. The composition is particularly effective in restoring the sensitivity of the bi-directional pain transmission pathway in the braingut axis to a normal level. The composition is particularly useful for reducing abdominal pain, such as pain associated with gastrointestinal discomfort, functional gastrointestinal disorders and / or gastrointestinal diseases, and thus also helps to reduce crying and improve sleep quality, overall quality of life, mood, paddling, personality and / or happiness in the infants and young children.

Description

[0001] This application is a divisional application of PCT application PCT / EP2020 / 084620, filed on December 4, 2020, with the invention name of “Compositions for reducing pain and / or pain in infants and young children”. The date on which the PCT application entered the Chinese national phase is May 13, 2022, and the application number is 202080079889.0. Technical Field

[0002] The present invention relates to a composition comprising a mixture of human milk oligosaccharides, the mixture of human milk oligosaccharides consisting of 2'-fucosyllactose and difucosyllactose, for reducing pain and / or pain perception in infants or young children. The composition is particularly effective in restoring the sensitivity of the bidirectional pain transmission pathway in the brain-gut axis to normal levels. The composition is particularly useful for reducing abdominal pain, such as pain associated with gastrointestinal discomfort, functional gastrointestinal disorders and / or gastrointestinal diseases, and therefore also helps to reduce crying periods and improve the sleep quality, overall quality of life, mood, playfulness, personality and / or happiness of the infants and young children. Background Art

[0003] Infants (including newborns) experience pain in the same way as adults, as revealed, for example, by Goksan et al.; fMRI reveals neural activity overlap between adult and infant pain; eLife 2015; 4: e06356. Other studies even suggest that infants may experience pain more acutely than adults and older children.

[0004] Infants and young children may experience various types of pain (which may, for example, be caused by inflammation that may become chronic). In infants and young children, as in adults, pain is associated with reactions such as increased heart rate, changes in heart rate variability, faster and shallower breathing (which leads to lower oxygen saturation), and higher arterial pressure. Such reactions caused by prolonged or repeated exposure to pain have been found to have a negative impact on the development of infants and young children, and may lead to, for example, abnormal development of the pain system, such as hyperalgesia, or to impaired regulation of stress-related hormones, such as increased production of cortisol. See, for example, Ziraldo, Breanne, "Infant Pain Management" (2010); Senior Honors Theses; 198, which is available from Liberty University, Virginia, USA and available on the filing date at http: / / digitalcommons.liberty.edu / honors / 198.

[0005] Infants and young children are particularly exposed to specific sources of pain, such as abdominal pain. Causes of abdominal pain include abdominal discomfort, functional gastrointestinal disorders, and gastrointestinal diseases.

[0006] An example of common causes of discomfort is, for example, colic (Benninga et al., Childhood Functional Gastrointestinal Disorders:Neonate / Toddler Gastroenterology 150 (2016): 1443-55). The cause of colic is not fully understood, but it seems to be associated with intestinal hypersensitivity to pain, causing intestinal distension caused by the normal passage of gas or feces to cause colic infant pain, thereby causing a long period of crying, poor sleep, and reduced quality of life for infants or young children, and affecting mood, playfulness, personality, and happiness, which in turn has a negative impact on the quality of life of parents. Abdominal pain can also be caused by other causes of discomfort, such as impaired stool patterns, exposure to new foods, bloating and cramps, and functional gastrointestinal disorders.

[0007] Functional gastrointestinal disorders are non-destructive disorders of the gastrointestinal tract and include functional dyspepsia, functional constipation, functional diarrhea, irritable bowel syndrome (IBS), abdominal migraine, recurrent abdominal pain (RAP), and functional abdominal pain not specific (FAP-NOS). Further detailed definitions of functional abdominal pain disorders are provided in Hyams et al.; Childhood Functional Gastrointestinal Disorders: Child / Adolescent; Gastroenterology 150 (2016): 1456–1468.

[0008] Gastrointestinal diseases such as inflammatory bowel disease (IBD), infectious diarrhea, and necrotizing enterocolitis (NEC) can also occur. Inflammatory bowel disease (IBD) is a serious, chronic and devastating disorder of the gastrointestinal tract. It includes Crohn's disease (CD) and ulcerative colitis (UC).

[0009] It is therefore desirable to reduce pain and / or pain perception in infants and young children. However, side effects associated with pain management drugs may be even more problematic in infants and young children than in adults. Therefore, it is of particular interest to identify non-pharmacological means of reducing nociception in infants and young children and associated with low risk to the infant or young child. It would also be particularly advantageous to identify ingredients that are particularly suitable for human infants and / or young children and that are capable of reducing pain and / or pain perception.

[0010] Breastfeeding is recommended for all infants. However, in some cases, breastfeeding is not sufficient or successful, or the mother does not choose to breastfeed, due to certain medical reasons. Infant formulas have been developed for these situations. Fortifiers that enrich breast milk or infant formula with special ingredients have also been developed. In such cases, it is even more preferred to provide a means to reduce the nociception of infants and young children and thus reduce the incidence of pain through nutritional intervention.

[0011] The effects of nutrients (such as human milk oligosaccharides) on pain have been studied in the prior art. US2016 / 0243139 discloses the use of a synthetic composition comprising one or more human milk monosaccharides or oligosaccharides for treating visceral pain. According to the teachings of this document, a variety of human milk monosaccharides and oligosaccharides can be used, preferably 2'-FL, 3'FL, DFL, LNnT, 3'-SL, 6'-SL or LNFP-1, and most preferably a mixture of 2'-FL and LNnT or LNT.

[0012] WO2016 / 139329 relates to a composition for improving stool consistency or frequency in infants or young children, such effects being associated with the prevention and / or treatment of colic and / or intestinal discomfort. For this benefit, a nutritional composition comprising at least one fucosylated oligosaccharide and at least one N-acetylated oligosaccharide is used. The fucosylated oligosaccharide and the N-acetylated oligosaccharide can be selected from a wide range of lists. The most preferred fucosylated oligosaccharide is 2-FL, and the most preferred N-acetylated oligosaccharide is LNnT.

[0013] It would be useful to further optimize the effectiveness of nutritional compositions for reducing nociception in all infants and young children, or at least to provide alternative compositions that are effective for reducing nociception in infants and young children.

[0014] Some specific populations of infants and young children are particularly in need of compositions that can reduce abdominal pain and / or pain sensation. Such infants and young children are, for example, premature infants, low birth weight infants, and / or infants or young children with growth retardation. In fact, such infants usually experience adverse medical conditions and require significantly more frequent medical interventions than full-term infants and infants experiencing normal development. Unfortunately, many such medical interventions are painful for infants or young children, and therefore face repeated and sometimes acute pain. For such infants, it is particularly advantageous to supplement pharmacological pain management with a nutritional composition that can reduce nociception.

[0015] Clearly, there is a need to develop suitable methods for reducing pain and / or pain perception, and in particular colic and / or visceral sensitivity, in infants and young children.

[0016] Furthermore, since such infants or young children are particularly fragile, there is also a need to deliver such health benefits in a manner that is particularly suitable for young individuals (infants and young children) and does not involve traditional pharmaceutical interventions.

[0017] There is a need to deliver such health benefits to these infants or young children in a manner that does not induce side effects and / or in a manner that is not only easily delivered but also widely accepted by parents or health care providers.

[0018] There is also a need to deliver such benefits in a manner that keeps the price of such delivery reasonable and affordable to the majority of the population.

[0019] Therefore, there is a clear need to develop alternative approaches rather than traditional pharmaceutical interventions such as the use of pharmacological analgesics, at least in part due to the associated risks of side effects. Summary of the invention

[0020] The inventors have found that a composition comprising a mixture of human milk oligosaccharides consisting of 2'-fucosyllactose and difucosyllactose can be advantageously used to reduce pain and / or pain sensations, particularly abdominal pain and / or visceral sensitivity, in infants or young children. The inventors have found that this particular mixture of human milk oligosaccharides is particularly effective in reducing pain and / or pain sensations, particularly abdominal pain and / or visceral sensitivity, in infants and young children. The human milk oligosaccharide mixture consisting of 2'-fucosyllactose and difucosyllactose is more effective than other oligosaccharide mixtures (such as, for example, sialylated oligosaccharide mixtures). It was even surprisingly found that the oligosaccharide mixture consisting of 2'-fucosyllactose and difucosyllactose is more effective than a mixture of these two oligosaccharides with additional human milk oligosaccharides (such as N-acetylated oligosaccharides, sialylated oligosaccharides and / or other fucosylated oligosaccharides), as demonstrated by the examples.

[0021] The present invention thus provides a nutritional composition comprising a mixture of human milk oligosaccharides consisting of 2'-fucosyllactose (2'-FL) and difucosyllactose (DiFL) for use in a method of reducing pain and / or pain perception in an infant or young child. In a preferred embodiment, the nutritional composition is used to restore the sensitivity of a bidirectional pain transmission pathway in the brain-gut axis to normal levels.

[0022] The present invention also provides a growing-up milk comprising a human milk oligosaccharide mixture, the human milk oligosaccharide mixture consisting of 2'-FL and DiFL, the growing-up milk being used in a method for reducing pain and / or pain perception in children. In a preferred embodiment, the growing-up milk is used to restore the sensitivity of the bidirectional pain transmission pathway in the brain-gut axis to normal levels.

[0023] The nutritional composition of the present invention is particularly advantageous for use in infants or young children in the following methods

[0024] - Reduce visceral sensitivity

[0025] - Reduce abdominal pain;

[0026] - Reduce pain associated with gastrointestinal discomfort, functional gastrointestinal disorders and / or gastrointestinal diseases;

[0027] -Reduce crying periods;

[0028] - Improve sleep quality; and / or

[0029] - Improve the quality of life.

[0030] The present invention also relates to the use of a composition comprising a mixture of human milk oligosaccharides consisting of 2'-FL and DiFL in the following methods:

[0031] - Reduce visceral sensitivity

[0032] - Reduce abdominal pain;

[0033] - Reduce pain associated with gastrointestinal discomfort, functional gastrointestinal disorders and / or gastrointestinal diseases;

[0034] -Reduce crying periods;

[0035] - Improve sleep quality; and / or

[0036] - Improve the quality of life.

[0037] The present invention also relates to the use of a composition comprising a mixture of human milk oligosaccharides consisting of 2'-FL and DiFL in the following methods:

[0038] - Improve mood,

[0039] - Improve playfulness,

[0040] - Improved character, and / or

[0041] - Improved happiness. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 : Contraction amplitude measured according to colorectal distension in non-sensitized mice (AIN93; dots), in sensitized mice (was:AIN93; squares) and in sensitized mice to which 2'-FL and DiFL had been administered (was:2'FL+DiFL; diamonds).

[0043] Figure 2: Contraction amplitude measured according to colorectal distension in non-sensitized mice (AIN93; dots), in sensitized mice (was:AIN93; squares) and in sensitized mice to which 2'-FL, DiFL and LNT had been administered (was:2'FL+DiFL; diamonds).

[0044] Figure 3 : Contraction amplitude measured upon colorectal distension in non-sensitized mice (AIN93; dots), in sensitized mice (was:AIN93; squares) and in sensitized mice to which 3'-SL and 6'-SL had been administered (was:3'SL+6'SL; diamonds).

[0045] Figure 4 : Contraction amplitude measured upon colorectal distension in nonsensitized mice (AIN93; dots), in sensitized mice (was:AIN93; squares) and in sensitized mice to which 2'-FL, DiFL, LNT, LNnT, 3'-SL and 6'-SL had been administered (was:HMO6; diamonds). DETAILED DESCRIPTION

[0046] As used herein, the following terms have the following meanings.

[0047] The term "infant" refers to a child under the age of 12 months. The expression "toddler" refers to a child between the ages of one year and less than three years old, also known as a toddler. The expression "child" refers to a child between the ages of three and seven years old.

[0048] A "caesarean-born baby or child" is a baby or child who was delivered by caesarean section. This means the baby or child was not delivered vaginally.

[0049] A "vaginally delivered infant or child" is one that was delivered vaginally rather than by cesarean section.

[0050] "Premature babies" refer to babies or young children who are born before the full term, usually before 37 weeks of pregnancy.

[0051] "Low birth weight infant" is a newborn baby who weighs less than 2500g (5.5 pounds) due to premature birth or fetal growth restriction. It therefore covers:

[0052] - Infants or young children who weigh 1500 g to 2500 g at birth (often called 'low birth weight' or LBW)

[0053] -Infants or young children who weigh 1000 g to 1500 g at birth (called "very low birth weight" or VLBW)

[0054] - Babies or young children who weigh less than 1000g at birth (called 'extremely low birth weight' or ELBW).

[0055] "Small for gestational age (SGA)" refers to an infant whose birth weight is below the 10th percentile for infants of the same gestational age.

[0056] The expression "nutritional composition" refers to a composition that supplies nutrition to an individual. Such nutritional compositions are usually administered orally or intravenously and they usually comprise a lipid or fat source and a protein source.

[0057] In a particular embodiment, the composition of the invention is a hypoallergenic nutritional composition.The expression "hypoallergenic nutritional composition" refers to a nutritional composition which is unlikely to cause an allergic reaction.

[0058] In a specific embodiment, the composition of the invention is a "synthetic nutritional composition". The expression "synthetic nutritional composition" refers to a mixture obtained by chemical and / or biological methods, the chemical properties of which may be identical to the mixture naturally present in mammalian milk (that is, the synthetic composition is not breast milk).

[0059] As used herein, the expression "infant formula" refers to a food intended specifically for the supply of nutrition to infants during the first few months of life and which itself meets the various nutritional needs of such people (in accordance with Article 2(c) of Directive 91 / 321 / EEC 2006 / 141 / EC of the European Commission of 22 December 2006 on infant formula and follow-on formula). It also refers to a nutritional composition intended for infants and as defined in the Codex Alimentarius Commission (Codex STAN 72-1981) and Special Infants (including foods for special medical purposes). The expression "infant formula" covers both "starter infant formula" and "follow-up formula" or "follow-on formula".

[0060] "Second infant formula" or "follow-on formula" is given from the 6th month onwards. Infant formula constitutes the main liquid element in the gradually diversified diet of such persons.

[0061] The expression "baby food" refers to a food material intended specifically for the nutrition of infants or young children during the first year of life.

[0062] The expression "infant cereal composition" refers to a foodstuff which is intended specifically for the nutrition of an infant or young child during the first year of life.

[0063] The expression "growing-up milk" (or GUM) refers to a milk-based beverage, usually with added vitamins and minerals, which is intended for infants or children.

[0064] By the term "fortifier" is meant any composition used to fortify or supplement human breast milk, infant formula, growing-up milk, or human breast milk fortified with other nutrients. Thus, the fortifier may be administered after being dissolved in human breast milk, infant formula, growing-up milk, or human breast milk fortified with other nutrients, or it may be administered as a separate composition. When administered as a separate composition, the fortifier may also be identified as a "supplement." In one embodiment, the fortifier is a supplement.

[0065] The expression "weaning" refers to the period during which breast milk is gradually replaced by other foods in the diet of an infant or young child.

[0066] The expressions "age in days / weeks / months / years" and "days / weeks / months / years" are used interchangeably.

[0067] The expression "reducing nociception" encompasses one or more of the following:

[0068] - Reduce visceral sensitivity

[0069] - Reduce abdominal pain;

[0070] - Reduce pain associated with gastrointestinal discomfort, functional gastrointestinal disorders and / or gastrointestinal diseases

[0071] -Reduce crying periods;

[0072] - Improve sleep quality; and

[0073] - Improve the quality of life.

[0074] The expression "reducing visceral sensitivity" refers to reducing the sensation of pain and / or discomfort in the gastrointestinal tract.

[0075] The expression "reducing abdominal pain" refers to reducing the intensity of abdominal pain. A reduction in "visceral sensitivity" refers to a reduction in the perception of pain in the gastrointestinal tract of an individual and results in a reduction in the intensity of abdominal pain in the individual, regardless of the cause of the pain. Abdominal pain may be caused by several factors. A specific example is pain associated with gastrointestinal discomfort, functional gastrointestinal disorders and / or gastrointestinal diseases.

[0076] "Breast milk" is understood to mean mother's breast milk or colostrum.

[0077] "Oligosaccharides" are carbohydrate polymers containing small amounts (usually three to ten parts) of common sugars (monosaccharides).

[0078] The term "HMO" refers to human milk oligosaccharides. These carbohydrates are highly resistant to enzymatic hydrolysis, which indicates that they perform important functions that may not be directly related to their caloric value. It has been specifically pointed out in the art that these carbohydrates play a key role in the early development of infants and young children (such as the maturation of the immune system). Many different types of HMO are found in human milk. Each individual oligosaccharide is based on a combination of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose and / or N-acetylglucosamine with a variety of bonds between these molecules, so human milk contains a large number of different types of oligosaccharides, and more than 130 such structures have been identified to date. Almost all oligosaccharides have a lactose molecule at the reducing end, and the terminal position of the non-reducing end is occupied by sialic acid and / or fucose (if any). HMOs can be acidic (e.g., oligosaccharides containing charged sialic acid) or neutral (e.g., fucosylated oligosaccharides).

[0079] "A composition comprising a human milk oligosaccharide mixture consisting of 2'-FL and DiFL" refers to a composition comprising 2'-FL and DiFL as the only human milk oligosaccharides (as defined above). In particular, the composition does not contain N-acetylated oligosaccharides, sialylated oligosaccharides, fucosylated oligosaccharides other than 2'-FL and DiFL, and precursors of HMOs (such as sialic acid or fucose). The composition also does not contain human milk oligosaccharide precursors.

[0080] "Fucosylated oligosaccharides" are oligosaccharides with fucose residues. Such oligosaccharides are neutral. Some examples are 2-FL (2'-fucosyllactose), 3-FL (3-fucosyllactose), difucosyllactose (DiFL), lactose difucotetraose (LDFT)), lactose-N-fucopentaose (e.g., lactose-N-fucopentaose I, lactose-N-fucopentaose II, lactose-N-fucopentaose III, lactose-N-fucopentaose V), lactose-N-fucohexaose, lactose-N-difucohexaose I, fucosyllactose-N-hexaose, fucosyllactose-N-neohexaose, difucosyllactose-N-hexaose I, difucosyllactose-N-neohexaose II, and any combination of these substances. Although not wishing to be bound by theory, it is believed that the fucosylated epitopes of fucosylated oligosaccharides may act as "decoys" at the mucosal surface. Such epitopes may prevent and / or limit the effects of infectious pathogens (viral or bacterial origin) or pathogen secreted substances (such as toxins) by means of a competitive effect, in particular avoiding binding of pathogens or pathogen secreted substances to natural ligands, and without wishing to be bound by theory, it is believed that this will thereby reduce the risk of infection / inflammation, in particular the risk of LRT / ear infection and / or inflammation. In addition, fucosylated oligosaccharides are believed to promote the growth and metabolic activity of specific commensal microorganisms, thereby reducing the inflammatory response and creating an environment that is unfavorable to pathogens, thereby producing colonization resistance.

[0081] The expressions "fucosylated oligosaccharides comprising a 2'-fucosyl epitope" and "2-fucosylated oligosaccharides" encompass fucosylated oligosaccharides having certain homologous forms, which all contain a 2'-fucosyl epitope, and thus it can be inferred that they have certain homologous functions. Without wishing to be bound by theory, it is believed that the 2'-fucosyl epitope of these fucosylated oligosaccharides is specifically directed against pathogens (or substances secreted by pathogens) associated with LRT and / or ear infections.

[0082] The expression "N-acetylated oligosaccharide" encompasses both "N-acetyl-lactosamine" and "oligosaccharides containing N-acetyl-lactosamine". Such oligosaccharides are neutral oligosaccharides with N-acetyl-lactosamine residues. Suitable examples are LNT (lactose-N-tetraose), p-lactose-N-neohexose (p-LNnH), LNnT (lactose-N-neotetraose) and any combination thereof. Other examples are lactose-N-hexaose, lactose-N-neohexose, p-lactose-N-hexaose, p-lactose-N-neohexose, lactose-N-octose, lactose-N-neooctose, iso-lactose-N-octose, p-lactose-N-octose and lactose-N-decasaccharide.

[0083] "HMO precursors" are key compounds that interfere with the production of HMOs, such as sialic acid and / or fucose.

[0084] "Sialyl oligosaccharides" are oligosaccharides containing charged sialic acid, ie oligosaccharides having sialic acid residues. Such oligosaccharides are acidic. Some examples are 3-SL (3' sialyllactose) and 6'SL (6' sialyllactose).

[0085] The nutritional composition of the present invention may be in solid form (e.g., powder) or in liquid form. The amount of each ingredient (e.g., oligosaccharide) may be expressed as g / 100 g of the composition on a dry weight basis when the composition is in solid form (e.g., powder), or as a concentration of g / L of the composition when the composition is in liquid form (the latter also encompasses liquid compositions that can be obtained after reconstitution of the powder in a liquid (such as milk, water, ...), such as reconstituted infant formula or larger / stage 2 infant formula or infant cereal products or any other formulation designed to provide nutrition to infants).

[0086] The term "prebiotic" refers to non-digestible carbohydrates that have beneficial effects on the host by selectively stimulating the growth and / or activity of healthy bacteria, such as bifidobacteria in the human colon (Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995; 125: 1401-12).

[0087] The term "probiotic" refers to a microbial cell preparation or microbial cell component that has 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: 10107-10). Microbial cells are generally bacteria or yeast.

[0088] The term "cfu" is to be understood as colony forming units.

[0089] Unless otherwise indicated, all percentages are by weight.

[0090] In addition, in the context of the present invention, the term "comprising" or "including" does not exclude other possible elements. The composition of the present invention (including the various embodiments described herein) may comprise, consist of or consist essentially of the following elements: the basic elements and necessary limitations of the present invention described herein, and any additional or optional ingredients, components or limitations described herein or as required.

[0091] Any reference to prior art documents in this specification is not to be taken as an admission that such prior art is well known or forms part of the common general knowledge in the art.

[0092] Now the invention will be described in more detail. It should be noted that the various aspects, features, embodiments and implementations described in this application can be compatible and / or can be combined together.

[0093] Therefore, a first object of the present invention is a nutritional composition comprising a human milk oligosaccharide mixture consisting of 2'-FL and DiFL for use in reducing pain and / or pain perception in an infant or young child. In a preferred embodiment, the nutritional composition is used to restore the sensitivity of a bidirectional pain transmission pathway in the brain-gut axis to normal levels.

[0094] A second object of the present invention is a growing-up milk comprising a mixture of human milk oligosaccharides consisting of 2'-FL and DiFL, the growing-up milk being used to reduce pain and / or pain perception in children. In a preferred embodiment, the growing-up milk comprises any of the ingredients described below with respect to the nutritional composition of the present invention, in any described amount. In a preferred embodiment, the growing-up milk is used for any of the purposes described herein with respect to the nutritional composition. In a preferred embodiment, the growing-up milk is used to restore the sensitivity of the bidirectional pain transmission pathway in the brain-gut axis to normal levels.

[0095] To achieve these benefits, the nutritional composition of the present invention is preferably used in the following methods

[0096] - Reduces individual visceral sensitivity;

[0097] - Reduce abdominal pain in individuals;

[0098] - Reduce pain associated with gastrointestinal discomfort, functional gastrointestinal disorders and / or gastrointestinal diseases,

[0099] - reducing the crying period of a subject, preferably reducing the crying period of a subject experiencing pain, preferably reducing the crying period of a subject experiencing abdominal pain, most preferably reducing the crying period of a subject experiencing pain associated with gastrointestinal discomfort, functional gastrointestinal disorders and / or gastrointestinal diseases such as defined herein;

[0100] - improving the sleep quality of an individual, preferably improving the sleep quality of an individual experiencing pain, more preferably improving the sleep quality of an individual experiencing abdominal pain, most preferably improving the sleep quality of an individual experiencing pain associated with gastrointestinal discomfort, functional gastrointestinal disorders and / or gastrointestinal diseases such as defined herein; and

[0101] - improving the quality of life of an individual, preferably improving the quality of life of an individual experiencing pain, more preferably improving the quality of life of an individual experiencing abdominal pain, most preferably improving the quality of life of an individual experiencing pain associated with gastrointestinal discomfort, functional gastrointestinal disorders and / or gastrointestinal diseases such as defined herein.

[0102] Wherein the individual is an infant or a young child.

[0103] In a preferred aspect, gastrointestinal discomfort is caused by colic, bloating and / or cramps. In another preferred aspect, functional gastrointestinal disorders are selected from functional dyspepsia, functional constipation, functional diarrhea, irritable bowel syndrome (IBS), abdominal migraine and recurrent abdominal pain (RAP), non-specific functional abdominal pain (FAP-NOS). In a preferred aspect, gastrointestinal diseases are selected from inflammatory bowel disease (IBD), infectious diarrhea and / or necrotizing enterocolitis (NEC).

[0104] For the purposes of the present invention, pain reduction is achieved by reducing pain sensation. The composition of the present invention affects the nociceptive mechanism, so no matter how the source of such pain is, the composition can reduce pain sensation. Therefore, it effectively reduces the pain sensation caused by, for example, the performance of medical or surgical behavior or by some injuries, diseases, obstacles and / or discomfort. The mechanism of reducing pain sensation is different from the pain reduction that can be achieved by treating the injury, disease, obstacle or discomfort that causes pain. Therefore, the composition of the present invention is not intended to treat the injury, disease, obstacle or discomfort that causes pain, but is only used to reduce the way in which an individual perceives pain, thereby relieving individual pain.

[0105] In a particularly advantageous embodiment of the invention, 2'-FL and DiFL are present in the nutritional composition in certain specific amounts.

[0106] In a preferred embodiment of the invention, the HMO mixture may be present in an amount of 0.15 g / L to 15 g / L relative to the composition, such as 0.5 g / L to 10 g / L or 0.75 g / L to 7.5 g / L or 1 g / L to 5 g / L or 1 g / L to 2 g / L relative to the composition. In a specific embodiment, the amount of the HMO mixture relative to the composition is 1.5 g / L. Such amounts are particularly sufficient when the nutritional composition is in the form of a complete nutrition, such as an infant formula, or in the case of a growing-up milk.

[0107] In the case where the nutritional composition is in powder form, the HMO mixture may be present in an amount of preferably 0.11 g / 100 g to 11 g / 100 g by dry weight relative to the composition, such as 0.4 g / 100 g to 7.5 g / 100 g or 0.6 g / L to 6 g / L or 0.8 g / 100 g to 3.8 g / 100 g or 0.8 g / 100 g to 1.5 g / 100 g by dry weight relative to the composition. In a specific embodiment, the amount of the HMO mixture relative to the composition is 1.1 g / 100 g by dry weight. Such amounts are particularly sufficient when the nutritional composition is in the form of a complete nutrition, such as an infant formula, or in the case of a growing-up milk.

[0108] In another specific embodiment, the amount of the HMO mixture relative to the composition is 5g / L to 500g / L, 10g / L to 400g / L, 40g / L to 300g / L, 60g / L to 200g / L, 80g / L to 180g / L, 100g / L to 150g / L, or 110g / L to 130g / L. In a specific embodiment, the amount of the HMO mixture is 120g / L. Such amounts are particularly sufficient when the nutritional composition is in the form of a supplement or fortifier.

[0109] When the supplement or fortifier is in powder form, the HMO mixture is preferably provided in the nutritional composition of the present invention in an amount of 0.05g to 5g, 0.1g to 4.5g, 0.15g to 4g, 0.2g to 3.5g, 0.25g to 3g, 0.3g to 2.5g, 0.35g to 2g, 0.4g to 1.5g, 0.45g to 1g, 0.5g to 0.75g, for example 0.6g per serving.

[0110] In one embodiment, the HMO mixture is provided in the nutritional composition of the present invention in an amount such that normal consumption of the nutritional composition will provide a total daily dose of 0.1 g / day to 10 g / day, such as 0.2 g / day to 9 g / day, 0.3 g / day to 8 g / day, 0.4 g / day to 7 g / day, 0.5 g / day to 6 g / day, 0.6 g / day to 5 g / day, 0.8 g / day to 3 g / day, 0.9 g / day to 2 g / day or 1 g / day to 1.5 g / day to an infant or toddler (respectively a child) consuming it.

[0111] In particular aspects, 2'-FL and DiFL are present in the HMO mixture in a 2'-FL:DiFL ratio of 5:1 to 14:1, such as 5:1 to 12:1, 5:1 to 10:1, 6:1 to 10:1, or 7:1 to 9: 1. In particularly advantageous embodiments, the ratio is 7:1 or about 7:1.

[0112] In a particular aspect of the invention, the nutritional composition is an infant formula comprising an HMO mixture consisting of 2'-FL and DiFL, wherein:

[0113] - 2'-FL in an amount of 1 g / L to 2 g / L, preferably 1.3 g / L, relative to the composition, and / or in an amount of 0.8 g / 100 g to 1.5 g / 100 g, preferably 1 g / 100 g, relative to the composition on a dry weight basis; and / or

[0114] - the amount of DiFL relative to the composition is from 0.1 g / L to 0.3 g / L, preferably 0.2 g / L,

[0115] and / or in an amount of 0.08 g / 100 g to 0.2 g / 100 g relative to the composition on a dry weight basis,

[0116] Preferably 0.2g / 100g.

[0117] In another specific aspect of the invention, the nutritional composition is a supplement or a fortifier and comprises a HMO mixture consisting of 2'-FL and DiFL, wherein:

[0118] -2'-FL relative to the amount of the composition is 100 g / L to 110 g / L, preferably 105 g / L;

[0119] and / or

[0120] - The amount of DiFL relative to the composition is between 10 g / L and 20 g / L, preferably 15 g / L.

[0121] 2'-FL and DiFL can be isolated from natural sources (such as animal milk) by chromatography or filtration techniques. Alternatively, fucosylated oligosaccharides can also be prepared by biotechnological means, using enzyme-based (recombinant or natural enzyme) fermentation techniques or microbial fermentation techniques, using specific fucosyltransferases and / or fucosidases. In the latter case, the microorganism can express its natural enzymes and substrates, or can be engineered to produce the corresponding substrates and enzymes. Single microbial cultures and / or mixed cultures can be used. The formation of 2'-FL and DiFL can be initiated by acceptor substrates starting from any degree of polymerization (DP) (starting from DP=1). Alternatively, 2'-FL and DiFL can be prepared by chemical synthesis from lactose and free fucose. 2'-FL and DiFL can also be commercially available, for example, from Glycom A / S in Denmark or Jennewein GmBH in Germany.

[0122] The nutritional composition according to the present invention may also comprise other types of oligosaccharides (i.e., in addition to human milk oligosaccharides) and / or at least their fibers and / or at least their precursors. Other oligosaccharides and / or their fibers and / or their precursors may preferably be selected from a list comprising galacto-oligosaccharides (GOS), fructo-oligosaccharides (FOS), inulin, xylo-oligosaccharides (XOS), polydextrose and any combination thereof. Their amount may be between 0% by weight and 10% by weight of the composition. In a specific embodiment, the nutritional composition may also comprise at least one BMO (cow's milk oligosaccharide).

[0123] Suitable commercial products that can be used to prepare the nutritional composition according to the invention include combinations of FOS and inulin, such as the product sold under the trademark Orafti by BENEO or the product sold under the trademark Inulin by Tate & Lyle. Polydextrose for sale.

[0124] In a particular embodiment, the human milk oligosaccharide mixture consisting of 2'-FL and DiFL is the only source of oligosaccharides in the nutritional composition.

[0125] The nutritional composition of the present invention may further comprise at least one probiotic (or probiotic strain), such as a probiotic bacterial strain.

[0126] The most commonly used probiotic microorganisms are mainly most bacteria and yeasts of the following genera: Lactobacillus spp., Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp.

[0127] In some embodiments, the probiotics are probiotic bacterial strains. In some embodiments, they are specifically bifidobacteria and / or lactobacilli.

[0128] Suitable probiotic bacterial strains include Lactobacillus rhamnosus ATCC 53103 available from Valio Oy, 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 under the trade name KI2 by BLIS Technologies Limited, New Zealand, Bifidobacterium lactis CNCM 1-3446 sold specifically under the trademark Bb 12 by Christian Hansen company, Denmark, and Lactobacillus johnsonii CNCM 1-1225 sold under the trade name KI2 by Morinaga Milk Industry Co., Ltd., Japan. Co. Ltd., Japan), Bifidobacterium longum ATCC BAA-999 sold under the trademark BB536 by Danisco, Bifidobacterium breve sold under the trademark Bb-03 by Danisco, Bifidobacterium breve sold under the trademark M-16V by Morinaga, Bifidobacterium infantis sold under the trademark Bifantis by Procter & Gamble Co., and Bifidobacterium breve sold under the trademark R0070 by Institut Rosell-Lallemand in Canada.

[0129] Based on dry weight, the nutritional composition according to the present invention may contain 10 3 cfu to 10 12 cfu of probiotic strains, preferably between 10 7 cfu with 10 12 cfu, such as between 10 8 cfu and 10 10 Probiotic strains between cfu.

[0130] In one embodiment, the probiotics are live. In another embodiment, the probiotics are non-replicating or inactivated. In some other embodiments, live and inactivated probiotics may be present simultaneously. Probiotic components and metabolites may also be added.

[0131] The nutritional composition according to the present invention may be, for example, an infant formula, a stage 1 infant formula, an older infant formula or a stage 2 infant formula, a baby food, an infant cereal composition, a fortifier (such as a human milk fortifier) ​​or a supplement. In some specific embodiments, the composition of the present invention is an infant formula, a fortifier or a supplement intended for the first 4 months or 6 months of age. In a preferred embodiment, the nutritional composition of the present invention is an infant formula.

[0132] In some other embodiments, the nutritional composition of the present invention is a fortifier. The fortifier can be a breast milk fortifier (eg, a human milk fortifier) ​​or a formula fortifier (such as an infant formula fortifier or a follow-on / second infant formula fortifier).

[0133] In another embodiment, the composition of the present invention can be a supplement. The supplement can be in the form of, for example, tablets, capsules, lozenges, powders, gels or liquids. The supplement can also contain protective hydrophilic colloids (such as gums, proteins, modified starches), binders, film formers, encapsulants / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithins, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, taste masking agents, weighting agents, gelling agents and gel forming agents. The supplement can also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including but not limited to: water, gelatin from any source, vegetable gums, lignin sulfonates, talcum, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavors, preservatives, stabilizers, emulsifiers, buffers, lubricants, colorants, wetting agents, fillers, etc.

[0134] Additionally, supplements may contain vitamins, minerals trace elements and other micronutrients as recommended by government agencies such as the USRDA.

[0135] When the nutritional composition is a supplement, it can be provided in the form of a unit dose. 2'-FL and DiFL are administered to an infant or young child according to a daily dose, as described above. In a specific embodiment, the nutritional composition is a supplement in powder form and is provided in a sachet. When the supplement is in powder form, it may contain a carrier. However, it is preferred that the supplement does not contain a carrier. In another embodiment, the supplement is in the form of a syrup. In such cases, 2'-FL and DiFL are preferably dissolved or suspended in water acidified with citrate.

[0136] The nutritional composition according to the present invention generally contains a protein source. The amount of protein may be 1.6 g / 100 kcal to 3 g / 100 kcal. In some embodiments, particularly when the composition is intended for premature infants, the amount of protein may be between 2.4 g / 100 kcal and 4 g / 100 kcal or more than 3.6 g / 100 kcal. In some other embodiments, the amount of protein may be less than 2.0 g / 100 kcal, for example, 1.8 g / 100 kcal to 2 g / 100 kcal, or less than 1.8 g / 100 kcal.

[0137] The type of protein is considered to be immaterial to the present invention, as long as the minimum requirements for the essential amino acid content are met and satisfactory growth is ensured. Thus, 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 contain alpha-lactalbumin and beta-lactoglobulin in any desired ratio.

[0138] In some advantageous embodiments, the protein source is predominantly whey (ie, greater than 50% of the protein is derived from whey protein, such as 60% or 70%).

[0139] The protein may be intact or hydrolyzed, or a mixture of intact and hydrolyzed proteins. The term "intact" means that the major part of the protein is intact, i.e. the molecular structure is not changed, for example at least 80% of the protein is not changed, such as at least 85% of the protein is not changed, preferably at least 90% of the protein is not changed, even more preferably at least 95% of the protein is not changed, such as at least 98% of the protein is not changed. In a specific embodiment, 100% of the protein is not changed.

[0140] The term "hydrolyzed" means that in the context of the present invention, the protein has been hydrolyzed or broken down into its constituent amino acids. The protein can be fully hydrolyzed or partially hydrolyzed. For example, for infants or young children who are considered to be at risk of developing cow's milk allergy, it may be desirable to provide partially hydrolyzed proteins (the degree of hydrolysis is between 2% and 20%). If hydrolyzed protein is required, a hydrolysis process can be performed as required and as known in the art. For example, a whey protein hydrolyzate can be prepared by enzymatic hydrolysis of a whey fraction in one or more steps. If the whey fraction used as a raw material is substantially lactose-free, it is found that the protein undergoes much less lysine blockage during the hydrolysis process. This makes it possible to reduce the degree of lysine blocking from about 15% by weight of total lysine to less than about 10% by weight of lysine; for example, about 7% by weight of lysine, which greatly improves the nutritional quality of the protein source.

[0141] In one embodiment of the invention, at least 70% of the protein is hydrolyzed, preferably at least 80% of the protein is hydrolyzed, such as at least 85% of the protein is hydrolyzed, even more preferably at least 90% of the protein is hydrolyzed, such as at least 95% of the protein is hydrolyzed, in particular at least 98% of the protein is hydrolyzed. In a specific embodiment, 100% of the protein is hydrolyzed.

[0142] In a particular embodiment, the protein of the nutritional composition is hydrolyzed, fully hydrolyzed or partially hydrolyzed. The degree of hydrolysis (DH) of the protein may 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.

[0143] Alternatively, the protein component may be replaced with a mixture or synthetic amino acids, for example for premature or low birth weight infants.

[0144] 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.

[0145] The nutritional composition according to the invention typically contains a carbohydrate source. This is particularly preferred in the case where the nutritional composition according to the invention is an infant formula. In this case, any carbohydrate source typically present in infant formulas may be used, such as lactose, sucrose, saccharose, maltodextrin, starch and mixtures thereof, but one of the preferred carbohydrate sources is lactose.

[0146] The nutritional composition according to the present invention generally contains a lipid source. This is particularly relevant in the case where the nutritional composition of the present invention is an infant formula. In this case, the lipid source may be any lipid or fat suitable for use in an infant formula. Some suitable fat sources include palm oil, structured triglyceride oils, high oleic sunflower oil and high oleic safflower oil, medium chain triglyceride oils. The essential fatty acids linoleic acid and alpha-linolenic acid may also be added, as well as small amounts of oils containing large amounts of preformed arachidonic acid and docosahexaenoic acid, such as fish oil or microbial oils. The ratio of n-6 fatty acids to n-3 fatty acids in the fat source may be from about 5:1 to about 15:1; for example from about 8:1 to about 10:1.

[0147] The nutritional composition of the present invention may also contain all vitamins and minerals that are considered to be necessary for daily diet and in a significant amount of nutrition. The minimum requirements of some vitamins and minerals have been determined. The examples of minerals, vitamins and other nutrients optionally present in the composition of the present 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, phosphorus, 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 amount of specific minerals and other vitamins will vary according to the target population.

[0148] If necessary, the nutritional composition of the present invention may contain an emulsifier and a stabilizer such as soybean, lecithin, citric acid monoglyceride, citric acid diglyceride, and the like.

[0149] The nutritional composition of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, nucleotides, nucleosides, etc.

[0150] The nutritional composition of the present invention may further contain carotenoids. In some embodiments of the present invention, the nutritional composition of the present invention does not contain any carotenoids.

[0151] The nutritional composition according to the invention may be prepared in any suitable manner. The composition will now be described by way of example.

[0152] For example, formula foods such as infant formula foods can be prepared by blending a protein source, a carbohydrate source, and a fat source in an appropriate ratio. If used, an emulsifier can be added at this time. Vitamins and minerals can be added at this time, but they are usually added later to avoid thermal degradation. Before blending, any lipophilic vitamins, emulsifiers, etc. can be dissolved in a fat source. Then water (preferably water subjected to reverse osmosis) can be mixed to form a liquid mixture. The water temperature is suitably in the range of about 50°C to about 80°C to help disperse the ingredients. A commercially available liquefier can be used to form a liquid mixture. Especially if the final product is in liquid form, 2'-FL and DiFL can be added at this stage. If the final product is a powder, these ingredients can also be added at this stage as needed.

[0153] The liquid mixture is then homogenized, for example in two stages.

[0154] The liquid mixture may then be heat treated to reduce the bacterial load, for example by rapidly heating the liquid mixture to a temperature in the range of about 80°C to about 150°C for a duration between about 5 seconds and about 5 minutes. This may be performed by steam injection, an autoclave, or a heat exchanger (e.g., a plate heat exchanger).

[0155] The liquid mixture is then cooled to between about 60°C and about 85°C, for example by rapid cooling. The liquid mixture is then homogenized again, for example in two stages, with a pressure of 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 homogenized mixture can then be further cooled to add any heat-sensitive components, such as vitamins and minerals. The pH and solids content of the homogenized mixture are conveniently adjusted at this point.

[0156] If the final product is to be a powder, the homogenized mixture is transferred to a suitable drying device, such as a spray dryer or freeze dryer and converted to a powder. The moisture content of the powder should be less than about 5% by weight. 2'-FL and DiFL may also or alternatively be added at this stage by dry mixing them with the probiotic strain (if used), or blending them with the probiotic strain in the form of a crystalline syrup and then spray drying or freeze drying the mixture.

[0157] If a liquid composition is preferred, the homogenised mixture may be sterilised and then filled into suitable containers under aseptic conditions or filled into containers first and then retorted.

[0158] The nutritional composition according to the present invention is used for infants or young children. The infant or young child may be a full-term infant or a premature infant. In a specific embodiment, the nutritional composition of the present invention is used for premature infants, infants with low birth weight and / or infants born small for gestational age (SGA). In a specific embodiment, the nutritional composition of the present invention is used for premature infants, infants with low birth weight and / or infants born small for gestational age (SGA).

[0159] The nutritional composition of the present invention may also be used for infants or young children born by caesarean section or vaginally.

[0160] In some embodiments, the composition according to the invention may be used prior to and / or during the weaning period.

[0161] The age and duration of administration (or giving or feeding) of the nutritional composition can be determined according to needs.

[0162] The nutritional composition can be provided, for example, immediately after the infant is born. The composition of the present invention can also be given during the first 1 week of the infant's life, or during the first 2 weeks of life, or during the first 3 weeks of life, or during the first 1 month of life, or during the first 2 months of life, or during the first 3 months of life, or during the first 4 months of life, or during the first 6 months of life, or during the first 8 months of life, or during the first 10 months of life, or during the first 1 year of life, or during the first 2 years of life, or even longer. In some particularly advantageous embodiments of the present invention, the nutritional composition is given (or administered) to the infant within the first 4, 6 or 12 months after the infant is born. In some other embodiments, the nutritional composition of the present invention is administered a few days (e.g., 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 20 days...), or weeks (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks...) or months (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months...) after birth. This may particularly refer to the case where the infant is a premature infant, but this is not required.

[0163] In one embodiment, the composition of the present invention is given to an infant or young child as a supplementary composition of breast milk. In some embodiments, an infant or young child receives breast milk during at least the first 2 weeks, the first 1 month, the first 2 months, the first 4 months, or the first 6 months. In one embodiment, the nutritional composition of the present invention is given to an infant or young child after this period of time when breast milk is used to provide nutrition, or is given to an infant or young child together with breast milk during this period of time when breast milk is used to provide nutrition. In another embodiment, during at least a period of time (e.g., after the 1st, 2nd, 4th month of life), during at least 1 month, 2 months, 4 months, or 6 months, the composition is given to an infant or young child as the only or main nutritional composition.

[0164] Example

[0165] The following examples illustrate some specific embodiments of the compositions used according to the present invention. The examples are given for illustrative purposes only and should not be construed as limiting the present invention.

[0166] Example 1

[0167] Table 1 below gives an example of the composition of an infant formula according to the invention. The composition is given by way of example only.

[0168] Table 1: Composition of the infant formula of Example 1

[0169]

[0170] Example 2

[0171] The effectiveness of the combination of 2'-FL and DiFL in reducing nociception was evaluated in vivo in animal studies and compared with other mixtures of human milk oligosaccharides.

[0172] Water avoidance stress (WAS) and nutritional intervention

[0173] C57Bl.6 / J mice were purchased from Janvier SA (Le Genest St.Isle, France). After their arrival, they were kept in polypropylene cages in a temperature-controlled room with a 12-hour black light cycle within 1 week before electrode implantation (see below). Five days after surgery, daily WAS was delivered by placing mice individually on a 3×3cm platform in a 40×40cm size pool for 1h during 9 days, and the pool was filled with cold tap water up to 1cm from the top of the platform. Sham WAS included placing the animal on a platform in a waterless pool for 1h / day. Animals had free access to water and food. A specific diet was started 3 days before the WAS procedure and continued until the end of the experiment. Six groups of 12 mice were randomly assigned to the following nutritional interventions:

[0174] Group 1: Control diet (AIN93), sham WAS (non-sensitized)

[0175] Group 2: control diet (was:AIN93), WAS (sensitized)

[0176] Group 3: Experimental diet (WAS:2'FL+DiFL), AIN93 supplemented with 0.55% w / w 2'-FL and 0.06% w / w DiFL, WAS (sensitized)

[0177] Group 4: Experimental diet (WAS: 2'FL+DiFL+LNT), AIN93 supplemented with 0.55% w / w 2'-FL, 0.06% w / w DiFL and 0.18% w / w LNT, WAS (sensitized)

[0178] Group 5: Experimental diet (WAS: 3'SL + 6'SL), AIN93 supplemented with 0.07% w / w 3'-SL and 0.09% w / w 6'-SL, WAS (sensitized)

[0179] Group 6: experimental diet (WAS:6HMO), supplemented with 0.55% w / w 2'-FL, 0.06% w / w DiFL, 0.07% w / w 3'-SL, 0.09% w / v 6'-SL, 0.05% w / w LNnt and 0.18% w / w LNT of AIN93, WAS (sensitized)

[0180] Colorectal dilatation (CRD)

[0181] In order to measure the abdominal muscle contraction as a pain index, 2 nickel-chromium wire electrodes implanted in the external oblique muscle of the abdomen are placed in mice and one is placed under the abdominal skin. Under xylazine / ketamine anesthesia (all 1.2mg, subcutaneous injection), surgery is performed. A small balloon (Fogarty, Edwards Laboratories Inc., Santa Anna, USA) is introduced into the rectum and fixed to the base of the tail. The balloon is gradually expanded from 0 to 0.10ml by a step length of 0.02ml. Each expansion step lasts 10 seconds, with a 5-minute recovery period without expansion.

[0182] Assessment of visceral sensitivity to CRD by abdominal electromyography

[0183] result

[0184] Results are available on Figures 1 to 4 The fact that WAS mice were sensitized (was:AIN93, group 2) significantly increased the amplitude of the contraction associated with the mice’s perception of pain compared to non-sensitized mice (AIN93, group 1). Figure 1 As shown, administration of a blend of 2'-FL and DiFL was able to reduce the contraction amplitude and therefore the perceived pain in sensitized mice (was: 2'FL + DiFL, group 3). For CRDs of 0.06 mL and above, the contraction amplitude was not even statistically distinguishable from that observed in non-sensitized mice. This is a very relevant finding, since a CRD of 0.06 mL corresponds to a typical pain threshold, whereas smaller expansion volumes are more associated with discomfort.

[0185] In contrast, the contraction amplitude was reduced to a lesser extent for the other HMO mixtures tested. In particular, the addition of additional human milk oligosaccharides in addition to 2'-FL and DiFL limited the reduction in contraction amplitude. For example, the addition of LNT to 2'-FL and DiFL (was: 2'FL+DiFL+LNT, Group 4) resulted in a contraction amplitude that was not statistically distinguishable from that of sensitized mice that did not receive any HMO supplementation ( Figure 2 ). Therefore, when LNT was added, the positive effects of 2'-FL and DiFL on reducing pain perception were lost, as shown in Figure 1 and Figure 2 This can be seen in the comparison.

[0186] The mixture of the six HMOs 2'-FL, DiFL, 3'-SL, 6'-SL, LNT and LNnT (was: 6HMO, group 5) was less effective than the mixture consisting of 2'-FL and DiFL in reducing the contraction amplitude and thus the pain perception of the tested individuals, especially for CRDs of 0.06 or above ( Figure 4 ).

[0187] Administration of the sialylated oligosaccharides 3'-SL and 6'-SL (was: 3'SL + 6'SL, Group 6) also provided a much smaller reduction in contraction amplitude, and thus a much smaller reduction in pain sensation, compared to the mixture consisting of 2'-FL and DiFL ( Figure 3 ).

[0188] Example 3

[0189] The supplement for colic infants is provided in a stick pack as a 5 mL syrup and consists of 105 g / L 2'FL and 15 g / L DiFL dissolved in water. The dosage regimen is two stick packs per day.

Claims

1. A nutritional composition comprising a human milk oligosaccharide mixture consisting of 2'-fucosyllactose (2'-FL) and difucosyllactose (DiFL), for use in a method for reducing pain and / or pain sensation in infants under 12 months of age or young children between one and three years of age.

2. The nutritional composition for use according to claim 1, wherein the use is for reducing colic and / or visceral sensitivity in infants or young children.

3. The nutritional composition for use according to claim 1 or 2, wherein the use is to restore the sensitivity of the bidirectional pain transmission pathway in the brain-gut axis to normal levels.

4. Nutritional composition for use according to any one of the preceding claims, wherein the use is for reducing pain associated with gastrointestinal discomfort and / or with functional gastrointestinal disorders and / or with gastrointestinal diseases.

5. The nutritional composition for use according to any one of the preceding claims, wherein the infant or the young child experiences pain.

6. The nutritional composition for use according to claim 5, wherein the infant or the young child experiences abdominal pain.

7. The nutritional composition for use according to claim 6, wherein the infant or the young child experiences pain associated with gastrointestinal discomfort and / or functional gastrointestinal disorders and / or gastrointestinal diseases.

8. The nutritional composition for use according to claim 7, wherein the gastrointestinal discomfort is selected from colic, bloating and / or cramps, the functional gastrointestinal disorder is selected from functional dyspepsia, functional constipation, functional diarrhea, irritable bowel syndrome (IBS), abdominal migraine and / or recurrent abdominal pain (RAP), non-specific functional abdominal pain (FAP-NOS), and the gastrointestinal disease is selected from inflammatory bowel disease (IBD), infectious diarrhea and / or necrotizing enterocolitis (NEC).

9. A nutritional composition for use according to any one of the preceding claims, wherein 2'-FL and DiFL are present in a 2'-FL:DiFL weight ratio of 5:1 to 14:1, such as 5:1 to 12:1, 5:1 to 10:1, 6:1 to 10:1 or 7:1 to 9:

1.

10. A nutritional composition for use according to any one of the preceding claims, wherein the human milk oligosaccharide mixture is present in an amount of 0.15 g / L to 15 g / L relative to the composition, such as 0.5 g / L to 10 g / L, 0.75 g / L to 7.5 g / L, 1 g / L to 5 g / L or 1 g / L to 2 g / L relative to the composition.

11. A nutritional composition for use according to any one of the preceding claims, wherein the human milk oligosaccharide mixture is present in an amount of 0.11 g / 100g to 11 g / 100g by dry weight relative to the composition, such as 0.4 g / 100g to 7.5 g / 100g, 0.6 g / L to 6 g / L, 0.8 g / 100g to 3.8 g / 100g or 0.8 g / 100g to 1.5 g / 100g by dry weight relative to the composition.

12. The nutritional composition for use according to any one of the preceding claims, wherein the HMO mixture is provided in the nutritional composition of the invention in an amount such that normal consumption of the nutritional composition provides a total daily dose of 0.1 g / day to 10 g / day, such as 0.2 g / day to 9 g / day, 0.3 g / day to 8 g / day, 0.4 g / day to 7 g / day, 0.5 g / day to 6 g / day, 0.6 g / day to 5 g / day, 0.8 g / day to 3 g / day, 0.9 g / day to 2 g / day or 1 g / day to 1.5 g / day to the infant or toddler consuming it.

13. The nutritional composition for use according to any one of the preceding claims, comprising at least one further oligosaccharide and / or fiber thereof and / or a precursor thereof selected from the list comprising galacto-oligosaccharides (GOS), fructo-oligosaccharides (FOS), xylo-oligosaccharides (XOS), inulin, polydextrose, any combination thereof.

14. The nutritional composition for use according to any one of the preceding claims, further comprising at least one probiotic in an amount of 10% relative to the composition (dry weight). 3 cfu / g to 10 12 cfu / g.

15. The nutritional composition for use according to any one of the preceding claims, wherein the nutritional composition is an infant formula, a step 1 infant formula, a follow-on or step 2 infant formula, a baby food, an infant cereal composition, a fortifier or a supplement.

16. The nutritional composition for use according to any one of the preceding claims, wherein the nutritional composition is an infant formula comprising a HMO mixture consisting of 2'-FL and DiFL, wherein: - 2'-FL in an amount of 1 g / L to 2 g / L, preferably 1.3 g / L, relative to the composition, and / or in an amount of 0.8 g / 100 g to 1.5 g / 100 g, preferably 1 g / 100 g, relative to the composition on a dry weight basis; and / or - DiFL is present in an amount ranging from 0.1 g / L to 0.3 g / L, preferably 0.2 g / L, relative to the composition and / or in an amount ranging from 0.08 g / 100 g to 0.2 g / 100 g, preferably 0.2 g / 100 g, relative to the composition, by dry weight.

17. The nutritional composition for use according to any one of the preceding claims, wherein the nutritional composition is a supplement or a fortifier and comprises a HMO mixture consisting of 2'-FL and DiFL, wherein: - the amount of 2'-FL relative to the composition is 100 g / L to 110 g / L, preferably 105 g / L; and / or - The amount of DiFL relative to the composition is between 10 g / L and 20 g / L, preferably 15 g / L.

18. The nutritional composition for use according to any one of the preceding claims, wherein the nutritional composition is for premature infants, low birth weight infants and / or infants born small for gestational age (SGA).

19. A growing-up milk comprising a human milk oligosaccharide mixture consisting of 2'-FL and DiFL, for use in reducing nociception in children between three and seven years of age.

20. The growing-up milk for use according to claim 19, wherein the use is as described in any one of claims 2 to 8 or 18.

21. The growing-up milk for use according to claim 19 or 20, wherein the composition of the growing-up milk is as described in any one of claims 9 to 17.

22. Use of a composition comprising a mixture of human milk oligosaccharides consisting of 2'-FL and DiFL in the following method: - Improve mood, - Improve playfulness, - Improved character, and / or; - Improved happiness.

23. Use of a growing-up milk comprising a mixture of human milk oligosaccharides consisting of 2'-FL and DiFL in a method for treating a child between three and seven years of age - Improve mood, - Improve playfulness, - Improved character, and / or; - Improved happiness.

24. The use according to claim 21 or 22, wherein the composition of the growing-up milk is as described in any one of claims 8 to 16.

Images