Compositions for reducing noxious sensation and / or other health benefits in infants and young children

Abstract

The present invention relates to a composition comprising 2 '-fucosyllactose (2'-FL) for reducing the nociceptive sensation in an infant or young child by increasing kynuric acid produced by microflora in an infant or young child eating a nutritional composition in the form of growing milk. The compositions are particularly useful for reducing abdominal pain, such as pain associated with infant colic, irritable bowel syndrome (IBS) and / or recurrent abdominal pain (RAP), and thus also contribute to reducing crying and improving sleep quality and overall quality of life in infants and young children.

Description

[0001] This application is a divisional application of Chinese Patent Application 202080085485.2, filed on December 10, 2020, entitled "Composition for reducing the sense of harm and / or other health benefits in infants and young children". Technical Field

[0002] This invention relates to compositions containing 2'-FL, which are intended to promote health benefits by increasing kynurenic acid produced by the microbiota of infants or young children consuming the compositions.

[0003] Specifically, the present invention relates to compositions containing 2'-FL, which reduce the sense of harm in infants or young children by increasing kynurenic acid produced by the microbiota of the infants or young children who consume the composition.

[0004] The composition is particularly useful for reducing abdominal pain, such as pain associated with intestinal discomfort and / or bowel disorders, and thus also helps reduce crying periods and improve sleep quality and overall quality of life in infants and young children.

[0005] The present invention also relates to compositions comprising 2'-FL, said compositions providing additional health benefits by increasing kynurenic acid produced by the microbiota of infants or young children consuming said compositions, such as for the prevention and / or treatment of obesity or obesity-related metabolic disorders, the prevention and / or treatment of depression, the promotion of neuroprotection, and the prevention and / or treatment of inflammatory conditions. Background Technology

[0006] Infants (including newborns) experience pain in the same way as adults, as exemplified by Goksan et al.; fMRI reveals neural activity overlap between adult and infant pain As revealed in eLife 2015; 4:e06356. Other studies have even suggested that infants may experience pain more acutely than adults and older children.

[0007] Infants and young children may experience a range of types of pain, from acute pain to established pain (which may be caused, for example, by inflammation that can become chronic). In infants and young children, as in adults, pain is associated with responses such as increased heart rate, faster and shallower breathing (leading to lower oxygen saturation), and higher arterial pressure. Such responses caused by prolonged or repeated exposure to pain have been found to have negative effects on the development of infants and young children and can lead to, for example, abnormal development of the pain system, such as hyperalgesia, or 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 is available on the application date at http: / / digitalcommons.liberty.edu / honors / 198.

[0008] Infants and young children are particularly exposed to pain from specific sources, such as abdominal pain. Causes of abdominal pain include abdominal discomfort and abdominal disorders. A common example of a cause of discomfort is, for example, colic. The causes of colic are not fully understood, but it appears to be related to a hypersensitive response of the intestines to pain, causing intestinal distension caused by the normal passage of gas or stool to result in pain in colic infants, leading to prolonged crying periods, poor sleep, and reduced quality of life for both the infant and parents. Abdominal pain can also be caused by other causes of discomfort, such as disrupted stool patterns, exposure to new foods, flatulence, and painful cramps. Disorders also occur, such as inflammatory bowel disease (IBD), diarrhea (e.g., infectious diarrhea), necrotizing enterocolitis (NEC), and functional abdominal pain disorders. Inflammatory bowel disease (IBD) is a serious, chronic, and destructive disorder of the gastrointestinal tract. It includes Crohn's disease (CD) and ulcerative colitis (UC). Functional abdominal pain disorders and non-destructive gastrointestinal disorders include irritable bowel syndrome (IBS), abdominal migraine, and nonspecific functional abdominal pain (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.

[0009] Therefore, it is desirable to reduce the sense of harm in infants and young children. However, the 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 the sense of harm in infants and young children that are associated with low risk to infants or young children. Identifying ingredients that are particularly suitable for human infants and / or young children and capable of reducing the sense of harm will also be particularly beneficial.

[0010] Breastfeeding is recommended for all infants. However, in some cases, breastfeeding is insufficient or unsuccessful due to medical reasons, or the mother does not choose to breastfeed. Infant formula has 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 preferable to provide means to reduce the infant's and toddler's sense of harm 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 synthetic compositions comprising one or more human milk monosaccharides or oligosaccharides for the treatment of 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 compositions intended for use in improving the consistency or frequency of stools in infants or young children, with such effects associated with the prevention and / or treatment of colic and / or intestinal discomfort. For this benefit, a nutritional composition comprising at least one fucoidylated oligosaccharide and at least one N-acetylated oligosaccharide is used. The fucoidylated oligosaccharide and N-acetylated oligosaccharide can be selected from a wide list. The most preferred fucoidylated oligosaccharide is 2-FL, and the most preferred N-acetylated oligosaccharide is LNnT.

[0013] Further optimization of the nutritional composition would be useful in reducing the sense of harm in all infants and children.

[0014] Certain populations of infants and young children have a particular need for compositions that can reduce pain. These include, for example, premature infants, low birth weight infants, and / or infants or young children with growth retardation. In fact, these infants often experience adverse medical conditions and require significantly more frequent medical interventions than full-term infants and infants experiencing normal development. Unfortunately, many of these medical interventions are painful for infants or young children, resulting in recurrent and sometimes acute pain. For these infants, supplementing pharmacological pain management with nutritional compositions that can reduce the sensation of harm is particularly beneficial.

[0015] To reduce the sense of harm experienced by infants and young children, it is clear that appropriate methods need to be developed.

[0016] Furthermore, because these infants or young children are particularly vulnerable, the delivery of these health benefits should be done in a way that is especially suitable for young individuals (infants and young children) and does not involve traditional drug interventions.

[0017] These health benefits need to be delivered to these infants or young children in a way that does not cause side effects and / or is not only easy to deliver but also widely accepted by parents or healthcare professionals.

[0018] These benefits also need to be delivered in a way that keeps such deliveries affordable and accessible to most people.

[0019] Therefore, at least in part due to the associated risks of side effects, there is clearly a need to develop alternative methods rather than traditional drug interventions such as the use of analgesics.

[0020] There is also a need to develop alternative methods to reduce the sense of harm experienced by infants and young children, which can also provide additional health benefits to them. Summary of the Invention

[0021] The inventors have discovered that compositions containing 2'-FL can be advantageously used to reduce the sensation of injury in infants or young children. Not wishing to be bound by theory, it is believed that this oligosaccharide achieves this benefit by increasing kynurenic acid production in the microbiome of individuals consuming 2'-FL and via subsequent activation of G protein-coupled receptor 35 (GPR35) by kynurenic acid. Indeed, it has been found that kynurenic acid can trigger activation of the GPR35 receptor (Wang et al., 2006, Kynurenic acid as a ligand fororphan G protein-coupled receptor GPR35, J Biol Chem. 281:22021-22028).

[0022] In many studies, the receptor GPR35, which is highly expressed in the gastrointestinal tract, has been identified as being involved in reducing nociceptive sensation, and its activation has been described as causing analgesia (see, for example, Resta et al.). Kynurenic acid and zaprinast induce analgesia by modulating HCN channels through GPR35 activation Neuropharmacology 108 (2016), 136-143; Cosi et al. G-protein coupled receptor 35 (GPR35) activation and inflammatory pain: Studies on the antinociceptive effect of kynurenic acid and zaprinast , Neuropharmacology 60(2011), 1227-1231; and Zhao et al.; Targeting of the Orphan Receptor GPR35 by Pamoic Acid: A Potent Activator of Extracellular Signal-Regulated Kinase and β-Arrestin2 with Antinociceptive Activity (Mol Pharmacol 78(2010):560-568). Based on such studies, compounds capable of activating the GPR35 receptor have been considered for use as analgesics, and screening GPR35 activators has been suggested as a method for identifying new analgesics. Therefore, the activation of the GPR35 receptor via kynurenic acid produced through fermentation of 2'FL in the gut microbiota provides a strong basis for obtaining the benefit of reducing nociceptive sensation using compositions containing such human milk oligosaccharides.

[0023] In view of the ability of the compositions according to the invention and compositions containing 2'-FL to increase the production of kynurenic acid through the microbiota of the receptor, such compositions are also intended for the prevention and / or treatment of conditions that may benefit from the presence or increase of kynurenic acid production in the gut, as described in the literature. These conditions include, but are not limited to: prevention and / or treatment of obesity or obesity-related metabolic disorders (Milart et al., 2019. Kynurenic acid as the neglected ingredient of commercial baby formulas. Sci Rep. 9:6108 and Agudelo et al., 2018. Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation. Cell Metab. 27:378-392 e375.); prevention and / or treatment of depression (Savitz, 2017. Role of Kynurenine Metabolism Pathway Activation in Major Depressive Disorders. Curr Top Behav Neurosci. 31:249-267.); and promotion of neuroprotection (Klein et al., 2013. The neuroprotector kynurenic acid increases neuronal cell survival through neprilysin induction. Neuropharmacology). 70:254-260.); Prevention and / or treatment of inflammatory conditions (Wang et al., 2018. Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells. Cell Death Differ. 25:1209-1223, and Wang et al., 2006. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35, J Biol Chem. 281:22021-22028).

[0024] Therefore, the present invention provides a nutritional composition comprising 2'-FL, said nutritional composition for promoting health benefits by increasing kynurenic acid produced by the microbiota of an infant or young child consuming said nutritional composition.

[0025] Therefore, the present invention provides a nutritional composition comprising 2-fucosyllactose (2'-FL), said nutritional composition being used to reduce the sense of harm in infants or young children by increasing kynurenic acid produced by the microbiota of the infants or young children consuming said nutritional composition.

[0026] The present invention also provides a growth milk, 2-fucosyllactose (2'-FL), which is used to reduce a child's sense of harm by increasing kynurenic acid produced by the microbiota of a child consuming said growth milk.

[0027] The nutritional compositions or growth milk of the present invention are particularly advantageous for use in the following methods: - Reduce abdominal pain; - Reduce pain associated with gastrointestinal discomfort and / or gastrointestinal disorders; - Reduce the crying period; - Improve sleep quality; and - Improve quality of life In infants or young children, and correspondingly children, this is achieved by increasing the amount of kynurenic acid produced by the microbiota of infants or young children who consume the nutritional composition, and correspondingly children who consume growing milk.

[0028] This invention also relates to the following uses: The use of a nutritional composition containing 2-fucosylated lactose (2'-FL) in infants or young children by increasing kynurenic acid produced by the microbiota of the infant or young child consuming the nutritional composition. - Reduce the crying period; - Improve sleep quality; and - Improve quality of life ;and The use of a nutritional composition in the form of growing milk containing 2-fucosylated lactose (2'-FL) in children by increasing kynurenic acid produced by the microbiota of children consuming said growing milk, - Reduce the crying period; - Improve sleep quality; and - Improve quality of life.

[0029] In addition, the present invention therefore provides a nutritional composition comprising 2-fucosyllactose (2'-FL), 6'-sialyllactose (6'SL) and lactose-N-tetrasaccharide (LNT) for reducing the sense of harm in infants or young children by increasing kynurenic acid produced by the microbiota of the infants or young children consuming said nutritional composition.

[0030] The present invention also provides a growth milk, which is a combination of 2-fucosyllactose (2'-FL), 6'-sialyllactose (6'SL) and lactose-N-tetrasaccharide (LNT), for a method of reducing a child's sense of harm by increasing kynurenic acid produced by the microbiota of a child consuming said growth milk.

[0031] The nutritional compositions or growth milk of the present invention are particularly advantageous for use in the following methods: - Reduce abdominal pain; - Reduce pain associated with gastrointestinal discomfort and / or gastrointestinal disorders; - Reduce the crying period; - Improve sleep quality; and - Improve quality of life In infants or young children, and correspondingly children, this is achieved by increasing the amount of kynurenic acid produced by the microbiota of infants or young children who consume the nutritional composition, and correspondingly children who consume growing milk.

[0032] This invention also relates to the following uses: The use of a nutritional composition comprising 2-fucosyllactose (2'-FL), 6'-sialyllactose (6'SL), and lactose-N-tetrasaccharide (LNT) in infants or young children by means of increasing kynurenic acid produced by the microbiota of an infant or young child consuming said nutritional composition. - Reduce the crying period; - Improve sleep quality; and - Improve quality of life ;and The use of a nutritional composition in the form of growing milk containing 2-fucosylated lactose (2'-FL), 6'-sialyl lactose (6'-SL), and lactose-N-tetrasaccharide (LNT) in children by increasing kynurenic acid produced by the microbiota of children consuming said growing milk, - Reduce the crying period; - Improve sleep quality; and - Improve quality of life. Attached Figure Description

[0033] Figure 1The relative abundance of kynurenic acid in the supernatant of fermented infant feces is shown in the presence of lactose, 2'FL, 2'FL+LNT, or 2'FL, DFL, LNT, LNnT, 3'SL, and 6'SL (6-HMO), demonstrating the increased kynurenic acid content compared to lactose in the presence of any combination of HMOs containing 2'FL. P<0.05, P<0.01 (Example 1).

[0034] Figure 2 The dose response of GPR35 activation in the inhibition protein mode to equimolar 6'SL+LNT with or without 200 µM kynuronic acid (KYNA) and to 100 µM and 200 µM KYNA was shown, thus demonstrating a cumulative effect at concentrations between 940 µM and 2500 µM. The experiment was performed three times with comparable results (Example 2). Detailed Implementation

[0035] As used herein, the following terms have the following meanings.

[0036] The term "infant" refers to a child under 12 months of age. The term "toddler" refers to a child between one and three years of age, also known as a toddler. The term "child" refers to a child between three and seven years of age.

[0037] "Babies or toddlers born via cesarean section" refers to babies or toddlers delivered via cesarean section. This means that the baby or toddler was not delivered vaginally.

[0038] "Vaginal delivery of infants or young children" refers to infants or young children delivered vaginally rather than via cesarean section.

[0039] Premature infants are babies or toddlers born before full term. This typically refers to infants or toddlers born before 37 weeks of gestation.

[0040] "Low birth weight infants" refers to newborns who weigh less than 2500g (5.5 lbs) due to premature birth or fetal growth restriction. Therefore, it encompasses: - Infants or toddlers who weigh between 1500g and 2500g at birth (often referred to as "low birth weight" or LBW) - Infants or toddlers who weigh between 1000g and 1500g at birth (referred to as "very low birth weight" or VLBW) - Infants or toddlers who weigh less than 1000g at birth (referred to as "extremely low birth weight" or ELBW).

[0041] "Small-at-gestational-age (SGA)" refers to an infant whose birth weight is below the 10th percentile for infants of the same gestational age.

[0042] The term "nutritional composition" refers to a composition that supplies nutrients to an individual. Such nutritional compositions are typically administered orally or intravenously and generally include lipid or fat sources and protein sources. In one embodiment, the nutritional composition of the present invention is a synthetic nutritional composition.

[0043] In one specific embodiment, the composition of the present invention is a hypoallergenic nutritional composition. The term "hypoallergenic nutritional composition" refers to a nutritional composition that is unlikely to cause an allergic reaction.

[0044] In one specific embodiment, the composition of the present invention is a "synthetic nutritional composition". The term "synthetic nutritional composition" refers to a mixture obtained by chemical and / or biological methods, the chemical properties of which may be the same as those naturally present in mammalian milk (that is, the synthetic composition is not breast milk).

[0045] As used herein, the term "infant formula" refers to a food intended specifically for the nutrition of infants during the first few months of life, and which meets the diverse nutritional needs of such infants (in accordance with Article 2(c) of European Commission Directive 91 / 321 / EEC 2006 / 141 / EC of 22 December 2006 concerning infant formula and follow-up formula). It also refers to nutritional compositions intended for use in infants, as defined in the Codex Alimentarius Commission (Codex STAN 72-1981) and in infant specialties (including foods for specific medical purposes). The term "infant formula" encompasses both "starter infant formula," "follow-up formula," and "follow-on formula."

[0046] Stage 2 infant formula or follow-up formula is introduced starting from the 6th month. Infant formula constitutes the main liquid component of this group's gradually diversifying diet.

[0047] The term "infant food" refers to food designed specifically to provide nutrition for infants or young children during the first year of their lives.

[0048] The term "infant cereal composition" refers to food designed specifically for supplying nutrition to infants or young children during the first year of life.

[0049] The term "GUM" refers to a milk-based beverage that is typically fortified with vitamins and minerals and is intended for use by toddlers or children.

[0050] The term "fortifier" refers to a liquid or solid nutritional composition suitable for fortifying or mixing with human milk, infant formula, growing milk, or human breast milk fortified with other nutrients. Therefore, the fortifier of the present invention can be applied after being dissolved in human breast milk, infant formula, growing milk, or human breast milk fortified with other nutrients or otherwise fortified, and it can be applied as a stand-alone composition. When applied as a stand-alone composition, the milk fortifier of the present invention can also be identified as a "supplement." In one embodiment, the milk fortifier of the present invention is a supplement.

[0051] The term "weaning period" refers to the period during which breast milk is gradually replaced by other foods in the diet of infants or young children.

[0052] The expressions "age in days / weeks / months / age" and "number of days / weeks / months / years of birth" can be used interchangeably.

[0053] The expression "reducing the feeling of harm" encompasses one or more of the following: - Reduce abdominal pain; - Reduce pain associated with gastrointestinal discomfort and / or gastrointestinal disorders; - Reduce the crying period; - Improve sleep quality; and - Improve quality of life.

[0054] "Breast milk" should be understood as the mother's milk or colostrum.

[0055] "Oligosaccharides" are carbohydrate polymers containing small amounts (usually three to ten parts) of common sugars (monosaccharides).

[0056] The term "HMO" refers to human milk oligosaccharides. These carbohydrates are highly resistant to enzymatic hydrolysis, suggesting that their important functions may not be directly related to their calorific value. It has been specifically noted in the art that these carbohydrates play a crucial role in early infant and toddler development, such as the maturation of the immune system. Many different types of HMOs have been found in human milk. Each individual oligosaccharide is based on a variety of combinations of glucose, galactose, sialic acid (N-acetylneuraminic acid), fucose, and / or N-acetylglucosamine with these molecules, resulting in a large number of diverse oligosaccharides in human milk; more than 130 such structures have been identified to date. Almost all oligosaccharides have a lactose molecule at the reducing end, and the non-reducing end is occupied by sialic acid and / or fucose (if present). HMOs can be acidic (e.g., oligosaccharides containing charged sialic acid) or neutral (e.g., fucoidylated oligosaccharides).

[0057] "Fucosylated oligosaccharides" are oligosaccharides containing fucose residues. These oligosaccharides are neutral. Some examples are 2-FL (2'-fucosyllactose), 3-FL (3-fucosyllactose), difucosyllactose, lactose-N-fucopentose (e.g., lactose-N-fucopentose I, lactose-N-fucopentose II, lactose-N-fucopentose III, lactose-N-fucopentose V), lactose-N-fucohexasose, lactose-N-difucohexasose I, fucosyllactose-N-hexasose, fucosyllactose-N-neohexose, difucosyllactose-N-hexasose I, difucosyllactose-N-neohexose II, and any combination thereof. While not wishing to be bound by theory, it is believed that the fucosyl epitope of fucosylated oligosaccharides can act as a "decoy" at mucosal surfaces. This epitope can utilize a competitive effect to prevent and / or limit the action of infectious pathogens (viral or bacterial in origin) or their secretions (such as toxins), particularly by preventing the pathogen or its secretions from binding to natural ligands. While not wishing to be bound by theory, it is believed this will thus reduce the risk of infection / inflammation, especially LRT / ear infections and / or inflammation. Additionally, fucosylated oligosaccharides are thought to promote the growth and metabolic activity of specific symbiotic microorganisms, thereby reducing inflammatory responses and creating an environment unfavorable to pathogens, thus generating colonization resistance.

[0058] The terms "fucosylated oligosaccharides containing a 2'-fucosylation epitope" and "2-fucosylated oligosaccharides" encompass fucosylated oligosaccharides with certain homologous forms. These homologous forms of fucosylated oligosaccharides all contain a 2'-fucosylation epitope, thus suggesting that they may have some homologous function. While not wishing to be bound by theory, it is believed that the 2'-fucosylation epitope of these fucosylated oligosaccharides is specifically targeted at pathogens (or substances secreted by pathogens) associated with LRT and / or ear infections.

[0059] The term "N-acetylated oligosaccharide" encompasses both "N-acetyl-lactosamine" and "oligosaccharides containing N-acetyl-lactosamine." Such oligosaccharides are neutral oligosaccharides containing N-acetyl-lactoside residues. Suitable examples are LNT (lactose-N-tetrasaccharide), para-lactose-N-neohexose (para-LNnH), LNnT (lactose-N-neohexose), and any combination thereof. Other examples are lactose-N-hexasaccharide, lactose-N-neohexose, para-lactose-N-hexasaccharide, para-lactose-N-neohexose, lactose-N-octasaccharide, lactose-N-neohexose, isol-lactose-N-octasaccharide, para-lactose-N-octasaccharide, and lactose-N-decansaccharide.

[0060] The expressions “at least one fucoidylated oligosaccharide” and “at least one N-acetylated oligosaccharide” refer to “at least one type of fucoidylated oligosaccharide” and “at least one type of N-acetylated oligosaccharide”.

[0061] "HMO precursors" are key compounds used in the interference production of HMOs, such as sialic acid and / or fucose.

[0062] "Sialinated oligosaccharides" are oligosaccharides containing charged sialic acid, that is, oligosaccharides with sialic acid residues. These oligosaccharides are acidic. Some examples are 3-SL (3'-sialyl-lactose) and 6'SL (6'-sialyl-lactose).

[0063] The nutritional compositions of the present invention may be in solid form (e.g., powder) or liquid form. The amounts of various ingredients (e.g., oligosaccharides) may be expressed in g / 100g composition based on dry weight when the composition is in solid form (e.g., powder), or in g / L concentration of the composition when the composition refers to liquid form (the latter also covers liquid compositions that can be obtained by reconstituted powder in a liquid (such as milk, water, etc.), such as reconstituted infant formula or stage 2 infant formula or growing milk or infant cereal products or any other formulation designed to provide nutrition for infants).

[0064] The term "prebiotic" refers to non-digestible carbohydrates that exert a beneficial effect 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 ).

[0065] The term "probiotics" refers to microbial cell preparations or microbial cell components that are beneficial to the health or well-being of a host. (Salminen S, Ouwehand A. Benno Y. et al., " Probiotics: how should they be defined (Trends Food Sci. Technol. 1999: 10 107-10). Microbial cells are generally bacteria or yeast.

[0066] The term "cfu" should be understood as colony-forming unit.

[0067] The term "increased kynurenic acid production" means an increase, enhancement, and / or promotion of the production of such molecules (and / or their physiologically acceptable salts or ions) through the action of the microbiota of infants and / or young children consuming the nutritional composition according to the invention. In one embodiment, increased kynurenic acid production occurs in the intestines of infants and / or young children consuming the nutritional composition according to the invention. In another embodiment, the term "increased kynurenic acid production" means a promotion of the production of such molecules (and / or their physiologically acceptable salts or ions) through the action of the microbiota of infants and / or young children consuming the nutritional composition according to the invention.

[0068] Unless otherwise specified, all percentages are by weight.

[0069] Furthermore, in the context of this invention, the terms "comprising" or "including" do not exclude other possible elements. The compositions of this invention (including the various embodiments described herein) may comprise, consist of, or be substantially composed of the following elements: the essential elements and necessary limitations of the invention as described herein, and any additional or optional ingredients, components, or limitations as described herein or as required.

[0070] Any references to prior art documents in this specification should not be construed as an admission that such prior art is well-known or part of common knowledge in the field.

[0071] The invention will now be described in more detail. It should be noted that the various aspects, features, embodiments, and implementations described in this application are compatible and / or can be combined together.

[0072] Therefore, the first object of the present invention is a nutritional composition comprising 2-fucosylated lactose (2'-FL) for reducing the sense of harm in infants or young children by increasing kynurenic acid produced by the microbiota of the infants or young children consuming the nutritional composition.

[0073] A second object of the present invention is a growth milk containing 2-fucosylated lactose (2'-FL), which is intended to reduce a child's sense of harm by increasing kynurenic acid produced by the microbiota of an infant or toddler consuming the growth milk.

[0074] To achieve these benefits, the nutritional composition of the present invention, or the growth milk, is preferably used in the following methods: - Reduces abdominal pain in individuals; - Reduce pain associated with gastrointestinal discomfort and gastrointestinal disorders, wherein the gastrointestinal discomfort is preferably caused by colic, bloating and / or spasms, and wherein the gastrointestinal disorders are preferably selected from inflammatory bowel disease (IBD), diarrhea such as infectious diarrhea, necrotizing enterocolitis (NEC) and functional abdominal pain disorders, such functional abdominal pain disorders are preferably selected from irritable bowel syndrome (IBS), abdominal migraine and nonspecific functional abdominal pain (FAP-NOS). - Reduce the crying period of individuals, preferably reduce the crying period of individuals experiencing pain, preferably reduce the crying period of individuals experiencing abdominal pain, and most preferably reduce the crying period of individuals experiencing pain related to gastrointestinal discomfort and / or gastrointestinal disorders as defined above. - Improve sleep quality in individuals, preferably in individuals experiencing pain, more preferably in individuals experiencing abdominal pain, and most preferably in individuals experiencing pain related to gastrointestinal discomfort and / or gastrointestinal disorders as defined above; and - To improve the quality of life of individuals, preferably to improve the quality of life of individuals experiencing pain, more preferably to improve the quality of life of individuals experiencing abdominal pain, and most preferably to improve the quality of life of individuals experiencing pain related to gastrointestinal discomfort and / or gastrointestinal disorders as defined above.

[0075] The individuals mentioned therein are infants or toddlers, and correspondingly children.

[0076] For the purposes of this invention, pain reduction is achieved by reducing the sensation of pain. The compositions of this invention affect the nociceptive mechanism, and therefore are able to reduce the sensation of pain regardless of its source. Thus, they effectively reduce pain, for example, caused by medical or surgical procedures or by certain injuries, diseases, impairments, and / or discomforts. The mechanism of pain reduction differs from pain reduction achieved by treating the injury, disease, impairment, or discomfort that causes the pain. Therefore, the compositions of this invention are not intended to treat the injury, disease, impairment, or discomfort that causes the pain, but only to alleviate an individual's pain.

[0077] In a particularly advantageous embodiment of the invention, 2'-fucosylated lactose (2'-FL) is present in certain amounts in the nutritional composition or growing milk.

[0078] In a preferred embodiment of the invention, 2'-FL is present in the nutritional composition or growing milk in an amount from 0.005 g / L to 8 g / L of the composition. In some embodiments, the amount of 2'-FL may be from 0.01 g / L to 3 g / L of the composition, such as from 0.04 g / L to 2 g / L of the composition, or from 0.05 g / L to 1.5 g / L of the composition, or from 0.09 g / L to 1.2 g / L of the composition. In one specific embodiment, the amount of 2'-FL is 1 g / L of the composition. In another specific embodiment, the amount of 2'-FL is 0.2 g / L of the composition.

[0079] 2'-FL may be present in the nutritional composition or growing milk in amounts from 0.004 g / 100 g of the composition to 6.8 g / 100 g of the composition based on dry weight. 2'-FL may be present in amounts from 0.008 g / 100 g of the composition to 2.4 g / 100 g of the composition, such as from 0.03 g / 100 g of the composition to 1.6 g / 100 g of the composition, or from 0.04 g / 100 g of the composition to 1.2 g / 100 g of the composition, or from 0.07 g / 100 g of the composition to 1.0 g / 100 g of the composition. In one specific embodiment, 2'-FL is present in an amount of 0.8 g / 100 g of the composition. In another specific embodiment, 2'-FL is present in an amount of 0.16 g / 100 g of the composition.

[0080] In another specific embodiment, the amount of 2'FL is 5 g / L to 500 g / L, 10 g / L to 400 g / L, 40 g / L to 300 g / L, 60 g / L to 200 g / L, 80 g / L to 180 g / L, 100 g / L to 150 g / L, or 110 g / L to 130 g / L. In one specific embodiment, the amount of the HMO mixture is 120 g / L. Such amounts are particularly sufficient when the nutritional composition is in the form of a supplement or fortifier.

[0081] When the supplement or fortifier is in powder form, 2'FL is preferably provided in the nutritional composition of the present invention in amounts 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.

[0082] In one embodiment of the invention, the nutritional composition or growing milk contains human milk oligosaccharides consisting of 2'FL. It should be understood that when the expression "human milk oligosaccharides consisting of 2'FL" is used in the context of this invention, such an expression does not include the presence of human milk oligosaccharides other than 2'FL in the nutritional composition or growing milk.

[0083] 2'FL can be synthesized as described, for example, in "Large-scale synthesis of H-antigen oligosaccharides by expressing Helicobacter pylori alpha1,2-fucosyltransferase in metabolically engineered Escherichia coli cells" (Drouillard S, Driguez H, Samain E. AngewChem Int Ed Engl., 3 March 2006; 45(11):1778-80) or obtained from commercial sources.

[0084] In one embodiment of the invention, 2'FL is combined with 6-SL and LNT. Not wishing to be bound by theory, in such embodiments, 2'-FL is used to activate the GPR35 receptor by increasing kynurenic acid produced in the gut microbiota of infants or young children. In such embodiments, 6SL and LNT are also considered for GPR35 activation, as described in International Patent Application WO 2019 / 121929 (by the same applicant).

[0085] In one embodiment of the invention, LNT is present in the nutritional composition or growing milk in amounts ranging from 0.005 g / L to 3 g / L of the composition. In some embodiments, the amount of LNT may be 0.01-1.5 g / L of the composition, such as 0.04-1.2 g / L, 0.05-1 g / L, or 0.09-0.8 g / L of the composition. In one specific embodiment, the amount of LNT is 0.5 g / L of the composition. In another specific embodiment, the amount of LNT is 0.1 g / L of the composition.

[0086] LNT may be present in the nutritional composition or growing milk at an amount of 0.004-2.3 g / 100 g of the composition based on dry weight. LNT may also be present at amounts such as 0.008-1.2 g / 100 g of the composition, for example, 0.03-0.9 g / 100 g, 0.04-0.8 g / 100 g, or 0.07-0.6 g / 100 g of the composition. In one specific embodiment, LNT is present at an amount of 0.38 g / 100 g of the composition. In another specific embodiment, LNT is present at an amount of 0.08 g / 100 g of the composition.

[0087] LNTs can be synthesized chemically by enzymatic transfer, which involves using glycosyltransferases to transfer sugar units from the donor portion to the acceptor portion, as described, for example, in U.S. Patent Nos. 5,288,637 and WO 96 / 10086.

[0088] In another embodiment of the invention, the nutritional composition or growing milk may contain 0.005 g / L-5 g / L, or 0.008 g / L-2.5 g / L, or 0.01 g / L-1 g / L, or 0.03 g / L-0.7 g / L, for example 0.04 g / L or 0.5 g / L of 6'SL.

[0089] The nutritional composition or growing milk according to the invention may contain 0.004g-3.8g of 6'SL per 100g of dry weight of the composition, for example, 0.006g-1.9g, 0.008g-0.8g, 0.023g-0.5g, or 0.031g-0.4g of 6'SL per 100g of dry weight of the composition, for example, 0.18g or 0.04g of 6'SL per 100g of dry weight of the composition.

[0090] 6'SL can be isolated from natural sources (such as animal milk) using chromatographic or filtration techniques. Alternatively, it can be produced using specific sialyltransferases or sialidases, neuraminidases, via biotechnological means, through enzyme-based fermentation (recombinant or natural enzymes), through chemical synthesis, or through microbial fermentation. In the latter case, the microorganisms can express their natural enzymes and substrates, or can be engineered to produce the corresponding substrates and enzymes. Single or mixed microbial cultures can be used. The formation of 6'SL can be initiated by a receptor substrate starting at any degree of polymerization (DP), beginning with DP=1. Alternatively, 6'SL can be produced via chemical synthesis from lactose and free N'-acetylneuraminic acid (sialic acid).

[0091] In one specific embodiment, the 6'SL and LNT contained in the nutritional composition or growing milk according to the invention are generally present in a 6'SL:LNT ratio of 3:1 to 1:3, such as 2:1 to 1:2 or 2:1 to 1:1. In a particularly advantageous embodiment, the ratio is 2:1 or about 2.1, preferably 1:1 or about 1:1.

[0092] In one specific aspect of the invention, the nutritional composition or growth milk comprises 6'SL and LNT, wherein: - The amount of 6'SL is 0.005 g / L composition - 5 g / L composition, and / or the amount is based on dry weight of 0.004 g / 100 g composition - 3.8 g / 100 g composition; and / or - The amount of LNT is 0.005 g / L of the composition to 3 g / L of the composition, and / or the amount is based on dry weight of 0.004 g / 100 g of the composition to 2.3 g / 100 g of the composition.

[0093] In one specific aspect of the invention, the nutritional composition or growth milk comprises 6'SL and LNT, wherein: - The amount of 6'SL is 0.008 g / L composition - 2.5 g / L composition, and / or the amount is 0.006 g / L composition - 1.9 g / 100 g composition based on dry weight; and / or - The amount of LNT is 0.01 g / L composition to 1.5 g / L composition, and / or the amount is based on dry weight of 0.008 g / 100 g composition to 1.2 g / 100 g composition.

[0094] In another specific embodiment, the nutritional composition or growth milk of the present invention comprises 6'SL and LNT, wherein: - The amount of 6'SL is 0.01 g / L of composition to 1 g / L of composition, and / or the amount is 0.008 g / 100 g of composition to 0.8 g / 100 g of composition based on dry weight; and / or - The amount of LNT is 0.04 g / L of the composition to 1.2 g / L of the composition, and / or the amount is 0.03 g / 100 g of the composition to 0.9 g / 100 g of the composition based on dry weight.

[0095] In another specific embodiment, the nutritional composition or growth milk of the present invention comprises 6'SL and LNT, wherein: - The amount of 6'SL is 0.03 g / L composition - 0.7 g / L composition, and / or the total amount is 0.023 g / 100 g composition - 0.5 g / 100 g composition based on dry weight; and / or - The amount of LNT is 0.05 g / L of the composition to 1 g / L of the composition, and / or the amount is 0.04 g / 100 g of the composition to 0.8 g / 100 g of the composition based on dry weight.

[0096] In another specific embodiment, the nutritional composition or growth milk of the present invention comprises 6'SL and LNT, wherein: - The amount of 6'SL is 0.04 g / L composition - 0.5 g / L composition, and / or the amount is based on dry weight of 0.031 g / 100 g composition - 0.4 g / 100 g composition; and / or - The amount of LNT is 0.09 g / L composition - 0.8 g / L composition, and / or the amount is 0.07 g / 100 g composition - 0.6 g / 100 g composition based on dry weight.

[0097] In one specific embodiment, the nutritional composition or growth milk according to the invention comprises 6'SL and LNT, wherein: - The amount of 6'SL is 0.24 g / L of the composition or 0.05 g / L of the composition, and / or the amount is 0.18 g / 100 g of the composition or 0.04 g / 100 g of the composition based on dry weight; and / or - The amount of LNT is 0.5 g / L of the composition or 0.1 g / L of the composition, and / or the amount is 0.38 g / 100 g of the composition or 0.08 g / 100 g of the composition based on dry weight.

[0098] In one specific embodiment, 6'SL is provided in a certain amount in the nutritional composition or growing milk of the present invention, such that normal consumption of the nutritional composition or growing milk will provide the infant or toddler (corresponding child) consuming it with a total daily dose of 0.003g to 6.5g, preferably 0.005g-3.3g, 0.006g-1.3g, or 0.02g-0.9g per day, for example 0.024g-0.7g.

[0099] In one specific embodiment, LNT is provided in a certain amount in the nutritional composition or growing milk of the present invention, such that normal consumption of the nutritional composition or growing milk will provide the infant or toddler (corresponding child) consuming it with a total daily dose of 0.003g-3.9g, preferably 0.006g-2g, 0.02g-1.6g, or 0.03g-1.3g per day, for example 0.05g-1g.

[0100] In specific embodiments of the invention, the nutritional composition of the invention, and the corresponding growing milk, may contain additional human milk oligosaccharides. Even when such human milk oligosaccharides cannot effectively activate GPR35 receptors, these human milk oligosaccharides may be added to provide other health benefits.

[0101] Therefore, in one specific embodiment, the nutritional composition or growing milk further comprises at least one additional fucosylated oligosaccharide. One or more types of fucosylated oligosaccharides may be present. The fucosylated oligosaccharides may actually be selected from a list including: 3'-fucosylvose, difucosylvose, lactose-N-fucopentose (such as lactose-N-fucopentose I, lactose-N-fucopentose II, lactose-N-fucopentose III, lactose-N-fucopentose V), lactose-N-fucohexasaccharide, lactose-N-difucohexasaccharide I, fucosylvose-N-hexasaccharide, fucosylvose... Sugar-N-neohexoses (such as fucosyllactose-N-neohexose I, fucosyllactose-N-neohexose II), difucosyllactose-N-neohexose I, difucosyl-lactose-N-neohexose, difucosyllactose-N-neohexose I, difucosyllactose-N-neohexose II, fucosyl-para-lactose-N-neohexose, trifucosyl-para-lactose-N-neohexose I, and any combination thereof.

[0102] In some specific embodiments, the fucoidylated oligosaccharide contains a 2'-fucosylation epitope. The fucoidylated oligosaccharide may be selected, for example, from a list including: 2'-fucosylation lactose, difucosylation lactose, lactose-N-fucopentose, lactose-N-fucohexases, lactose-N-difucohexases, fucoidyllacto-N-hexases, fucoidyllacto-N-neohexose, difucosylation lactose-N-hexases, difucosylation lactose-N-hexases, difucosylation lactose-N-neohexose, difucosylation lactose-N-neohexose, fucoidyl-p-lacto-N-hexases, and any combination thereof.

[0103] Fucosylated oligosaccharides can be isolated from natural sources such as animal milk using chromatographic or filtration techniques. Alternatively, fucosylated oligosaccharides can be prepared using specific fucosyltransferases and / or fucosidases via biotechnological means, employing enzyme-based fermentation techniques (recombinant or natural enzymes) or microbial fermentation techniques. In the latter case, the microorganisms can express their 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. Fucosylated oligosaccharides can be formed starting with acceptor substrates initially having any degree of polymerization (DP), beginning with DP = 1. Alternatively, fucosylated oligosaccharides can be prepared by chemical synthesis from lactose and free fucose. Fucosylated oligosaccharides are also available, for example, from Kyowa Hakko Kogyo Co., Ltd.

[0104] In another specific aspect of the invention, in addition to LNT, the nutritional composition or growing milk may also contain at least one N-acetylated oligosaccharide. One or more types of N-acetylated oligosaccharides may be present. In some embodiments, the N-acetylated oligosaccharide is lactose-N-neotetrasaccharide (LNnT), p-lactose-N-neohexose (p-LNnH), or any combination thereof. In some embodiments, the N-acetylated oligosaccharide is LNnT. In some embodiments where LNnT is present, the nutritional composition or growing milk may contain LNT and LNnT in a ratio of LNT:LNnT between 5:1 and 1:2, or 2:1 to 1:1, or 2:1.2 to 2:1.6.

[0105] N-acetylated oligosaccharides can be chemically synthesized by enzymatic transfer, i.e., by using glycosyltransferases to transfer sugar units from the donor moiety to the acceptor moiety, as described, for example, in U.S. Patent Nos. 5,288,637 and WO 96 / 10086. Alternatively, LNnT can be prepared by chemically converting free or oligosaccharide-bound ketohexoses (e.g., fructose) into N-acetylated hexosamine or oligosaccharides containing N-acetylated hexosamine, as described below: Wrodnigg, TM; Stutz, AE (1999) Angew. Chem. Int. Ed. 38:827-828. The N-acetylated lactosamine obtained in this manner can then be transferred to lactose, which serves as the acceptor moiety.

[0106] In a particularly advantageous embodiment of the invention, the nutritional composition or growing milk contains lactose-N-neotetrasaccharide (LNnT).

[0107] In one specific embodiment, in addition to 6'SL, the nutritional composition or growing milk according to the invention may also contain other sialylated oligosaccharides, such as 3'-sialyl lactose (3-SL).

[0108] Sialized oligosaccharides can be isolated from natural sources such as animal milk using chromatographic or filtration techniques. Alternatively, sialylated oligosaccharides can be prepared using specific sialyltransferases or sialic acid phosphatases via biotechnological means, such as enzyme-based fermentation (recombinant or natural enzymes), chemical synthesis, or microbial fermentation. In the latter case, the microorganisms can express their natural enzymes and substrates, or can be engineered to produce the corresponding substrates and enzymes. Single or mixed microbial cultures can be used. Sialized oligosaccharides can be formed starting with acceptor substrates initially having any degree of polymerization (DP), beginning with DP = 1. Alternatively, sialylated lactose can be produced through chemical synthesis from lactose and free N'-acetylneuraminic acid (sialic acid). Sialized lactose is also commercially available, for example, from Kyowa HakkoKogyo in Japan.

[0109] In one particular embodiment, the nutritional composition of the present invention comprises a mixture of oligosaccharides consisting of 2'FL, 6'SL, LNT, DiFL, LNnT and 3'SL.

[0110] In another specific embodiment, the nutritional composition of the present invention comprises a mixture of oligosaccharides consisting of 2'FL, 6'SL, LNT, DiFL and 3'SL.

[0111] The nutritional composition or growing milk according to the invention may also contain other types of oligosaccharides (i.e., in addition to the human milk oligosaccharides mentioned above) and / or at least their fiber and / or at least their precursors. Other oligosaccharides and / or their fiber and / or precursors may be selected from galactooligosaccharides (GOS), fructooligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose, and any combination thereof. Their amounts may be between 0% by weight and 10% by weight of the composition. In one specific embodiment, the nutritional composition or growing milk may also contain at least one BMO (bovine milk oligosaccharide).

[0112] The nutritional composition or growing milk according to the invention may optionally further comprise at least one oligosaccharide precursor. One or more oligosaccharide precursors may be present. For example, precursors of human milk oligosaccharides are sialic acid, fucose, or mixtures thereof.

[0113] In a specific example, the nutritional composition or growing milk contains 0 g / L to 3 g / L of oligosaccharide precursors, or 0 g / L to 2 g / L, or 0 g / L to 1 g / L, or 0 g / L to 0.7 g / L, or 0 g / L to 0.5 g / L, or 0 g / L to 0.3 g / L, or 0 g / L to 0.2 g / L of oligosaccharide precursors. The compositions according to the invention may contain 0 g to 2.1 g of oligosaccharide precursors per 100 g of composition based on dry weight, for example, 0 g to 1.5 g, 0 g to 0.8 g, or 0 g to 0.15 g of oligosaccharide precursors per 100 g of composition based on dry weight.

[0114] The nutritional composition or growing milk of the present invention may further contain at least one probiotic (or probiotic strain), such as a probiotic strain.

[0115] The most commonly used probiotics are mainly bacteria and yeasts belonging to the following genera: Lactobacillus species ( Lactobacillus spp. Streptococcus species ( Streptococcus spp. ), Enterococcus species ( Enterococcus spp. Bifidobacterium species ( Bifidobacterium spp. ) and yeast species ( Saccharomyces spp. ).

[0116] In some specific embodiments, the probiotics are probiotic bacterial strains. In some specific embodiments, they are specifically Bifidobacterium and / or Lactobacillus.

[0117] Suitable probiotic strains include Lactobacillus rhamnosus, trademarked LGG, from Valio Oy, Finland. Lactobacillus rhamnosus ATCC 53103, Lactobacillus rhamnosus CGMCC 1.3724, Lactobacillus paracasei ( Lactobacillus paracasei CNCM I-2116, Lactobacillus johnsonii ( Lactobacillus johnsonii CNCM I-1225, BLIS Technologies Limited, New Zealand, sells Streptococcus salivarius under the trade name KI2. Streptococcus salivarius DSM13084, Bifidobacterium lactis specially marketed by Christian Hansen company, Denmark under the trademark Bb 12. Bifidobacterium lactis CNCM 1-3446. Bifidobacterium longum sold by Morinaga Milk Industry Co., Ltd., Japan under the trademark BB536. Bifidobacterium longum ATCC BAA-999, and Bifidobacterium breve sold by Danisco under the trademark Bb-03 ( Bifidobacterium breve Bifidobacterium breve, sold by Morinaga under the trademark M-16V, and Bifidobacterium infantis, sold by Procter & Gamble Co. under the trademark Bifantis. Bifidobacterium infantis ), and the Rosell Institute for Biological Studies in Canada (Institut Rosell-Lallemand sells Bifidobacterium breve under the trademark R0070.

[0118] Based on dry weight, each gram of the nutritional composition or growing milk according to the present invention may contain a probiotic strain of 10e3cfu to 10e12cfu, more preferably between 10e7cfu and 10e12cfu, such as a probiotic strain between 10e8cfu and 10e10cfu.

[0119] In one embodiment, the probiotics are live. In another embodiment, the probiotics are non-replicating or inactivated. In some other embodiments, both live and inactivated probiotics may be present simultaneously. Probiotic components and metabolites may also be added.

[0120] The nutritional compositions according to the invention may be, for example, infant formula, stage 1 infant formula, follow-up or stage 2 infant formula, growing milk, baby food, infant cereal compositions, fortifiers (such as human milk fortifiers), or supplements. In some specific embodiments, the compositions of the invention are infant formula, fortifiers, or supplements intended for infants aged 4 months or 6 months. In a preferred embodiment, the nutritional compositions of the invention are infant formula.

[0121] In some other embodiments, the nutritional composition of the present invention is a fortifier. The fortifier may be a breast milk fortifier (e.g., human milk fortifier) ​​or a formula food fortifier (such as an infant formula fortifier or a stage 2 infant formula fortifier).

[0122] When the nutritional composition is a supplement, it can be provided in unit dose form. In such cases, it is particularly useful to limit the amount of 2'FL and optional other oligosaccharides, as described above, according to the daily dose administered to an infant or young child.

[0123] When the nutritional composition is a supplement, it may contain 2'-FL and does not contain any other additional nutrients necessary to obtain a stable nutritional composition on the top layer of the excipients.

[0124] The nutritional compositions of the present invention may be in solid (e.g., powder), liquid, or gel form. In one particular embodiment, the nutritional composition is a supplement containing 2'-fucosylated lactose (2'-FL), wherein the supplement is in powder form and provided in sachets, preferably with 0.1 g / sachet to 20 g / sachet, for example, 1 g / sachet to 10 g / sachet of 2'-fucosylated lactose (2'-FL), or provided in syrup form, preferably with a total solids concentration of 5 g / 100 mL to 75 g / 100 mL (5% to 75% (w / v)). When the supplement is in powder form, it may contain a carrier. However, it is preferred that the supplement does not contain a carrier. When the supplement is in syrup form, the HMO is preferably dissolved or suspended in water acidified with citrate.

[0125] The nutritional compositions or growing milks according to the invention typically contain a protein source. The amount of protein can be from 1.6 g / 100 kcal to 3 g / 100 kcal. In some embodiments, particularly when the composition is intended for preterm infants, the amount of protein can 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 can be less than 2.0 g / 100 kcal, for example, from 1.8 g / 100 kcal to 2 g / 100 kcal, or less than 1.8 g / 100 kcal.

[0126] The type of protein is considered irrelevant to this invention, provided that the minimum requirements for essential amino acid content are met and satisfactory growth is ensured. Therefore, protein sources based on whey, casein, and mixtures thereof, as well as soybean-based protein sources, can be used. Regarding the whey protein of interest, the protein source may be based on acidic whey or sweet whey, or mixtures thereof, and may contain any desired proportions of α-lactalbumin and β-lactoglobulin.

[0127] In some advantageous implementations, the protein source is whey-based (i.e., more than 50% of the protein comes from whey protein, such as 60% or 70%).

[0128] The protein may be intact or hydrolyzed, or a mixture of intact and hydrolyzed proteins. The term "intact" means that the major components of the protein are intact, i.e., the molecular structure is not altered, for example, at least 80% of the protein is unchanged, such as at least 85% of the protein is unchanged, preferably at least 90% of the protein is unchanged, even more preferably at least 95% of the protein is unchanged, such as at least 98% of the protein is unchanged. In one specific embodiment, 100% of the protein is unchanged.

[0129] The term "hydrolyzed" means, in the context of this invention, that a protein has been hydrolyzed or broken down into its constituent amino acids. The protein may be completely or partially hydrolyzed. For example, providing partially hydrolyzed protein (with a degree of hydrolysis between 2% and 20%) may be desirable for infants or young children considered at risk of bovine milk allergies. If a hydrolyzed protein is required, the hydrolysis process can be carried out as needed and as is known in the art. For example, whey protein hydrolysates can be prepared by enzymatic hydrolysis of whey fractions in one or more steps. If the whey fraction used as a raw material is substantially lactose-free, it has been found that the protein undergoes far less lysine blockage during the hydrolysis process. This allows the degree of lysine blockage to be reduced 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 significantly improves the nutritional quality of the protein source.

[0130] In one embodiment of the invention, at least 70% of the protein is hydrolyzed, preferably at least 80%, such as at least 85%, even more preferably at least 90%, such as at least 95%, and particularly at least 98%. In one specific embodiment, 100% of the protein is hydrolyzed.

[0131] In one specific embodiment, the protein in 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 greater than 10, 20, 40, 60, 80, or 90.

[0132] Alternatively, the protein component can be replaced with a mixture or synthetic amino acids, for example, for premature or low birth weight infants.

[0133] In one embodiment, the nutritional composition or growing milk according to the invention is a hypoallergenic composition. In another embodiment, the composition according to the invention is a hypoallergenic nutritional composition or growing milk.

[0134] The nutritional compositions or growing milk according to the invention typically contain a carbohydrate source. This is particularly preferred when the nutritional compositions of the invention are infant formula. In this case, any carbohydrate source commonly found in infant formula can be used, such as lactose, sucrose, saccharin, maltodextrin, starch, and mixtures thereof, but one of the preferred carbohydrate sources is lactose.

[0135] Nutritional compositions or growing milk according to the invention typically contain a lipid source. This is particularly relevant when the nutritional compositions of the invention are infant formula. In this case, the lipid source can be any lipid or fat suitable for use in infant formula. Some suitable fat sources include palm oil, structured triglyceride oil, high-oleic sunflower oil and high-oleic safflower oil, and medium-chain triglyceride oil. Essential fatty acids linoleic acid and α-linolenic acid, as well as small amounts of oils containing large amounts of pre-formed arachidonic acid and docosahexaenoic acid, such as fish oil or microbial oil, may also be added. The ratio of n-6 fatty acids to n-3 fatty acids in the fat source can be from about 5:1 to about 15:1; for example, from about 8:1 to about 10:1.

[0136] The nutritional compositions or growth milk of the present invention may also contain all vitamins and minerals considered essential for a daily diet and required in significant amounts. Minimum requirements for certain vitamins and minerals have been determined. Examples of minerals, vitamins, and other nutrients optionally present in the compositions 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 typically added in salt form. The presence and amount of specific minerals and other vitamins will vary depending on the target population.

[0137] If necessary, the nutritional composition or growth milk of the present invention may contain emulsifiers and stabilizers, such as soybean, lecithin, monoglyceride citrate, and diglyceride citrate.

[0138] The nutritional composition or growth milk of the present invention may also contain other substances that may have benefits, such as lactoferrin, nucleotides, nucleosides, etc.

[0139] The nutritional composition or growth milk of the present invention may also contain carotenoids. In some specific embodiments of the present invention, the nutritional composition of the present invention does not contain any carotenoids.

[0140] The nutritional compositions or growth milks according to the present invention can be prepared in any suitable manner. The compositions will now be described by way of example.

[0141] For example, formula foods such as infant formula can be prepared by blending protein sources, carbohydrate sources, and fat sources together in appropriate proportions. If used, an emulsifier can be added at this stage. Vitamins and minerals can be added at this stage, but they are usually added later to avoid thermal degradation. Before blending, any lipophilic vitamins, emulsifiers, etc., can be dissolved in the fat source. Water (preferably water subjected to reverse osmosis) can then be added to form a liquid mixture. The water temperature is suitably in the range of about 50°C to about 80°C to aid in the dispersion of the components. Commercially available liquefying agents can be used to form the liquid mixture.

[0142] Especially if the final product is in liquid form, fucoidylated oligosaccharides and N-acetylated oligosaccharides can be added at this stage. If the final product is in powder form, these components can also be added at this stage as needed.

[0143] Then, the liquid mixture is homogenized in, for example, in two stages.

[0144] The liquid mixture can then be heat-treated to reduce the bacterial load, for example by rapidly heating the liquid mixture to a temperature ranging from about 80°C to about 150°C for a duration between about 5 seconds and about 5 minutes. This can be done by steam injection, autoclaving, or a heat exchanger (e.g., a plate heat exchanger).

[0145] The liquid mixture is then cooled, for example, to between about 60°C and about 85°C by rapid cooling. It is then homogenized again, for example, in two stages, where the pressure in the first stage is between about 10 MPa and about 30 MPa, and the pressure in the second stage is between about 2 MPa and about 10 MPa. 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 can then be conveniently adjusted.

[0146] If the final product is to be a powder, the homogenized mixture is transferred to a suitable drying apparatus, such as a spray dryer or freeze dryer, and converted into a powder. The moisture content of the powder should be less than about 5% by weight. Fucosylated oligosaccharides and N-acetylated oligosaccharides can also be added at this stage, or alternatively, by dry mixing them with probiotic strains (if used), or by blending them with probiotic strains in the form of crystalline syrups, followed by spray drying or freeze drying of the mixture.

[0147] If a liquid composition is preferred, the homogenized mixture can be sterilized and then filled into a suitable container under aseptic conditions, or it can be filled into a container first and then distilled.

[0148] In another embodiment, the composition of the present invention may be a supplement. The supplement may be in the form of, for example, tablets, capsules, lozenges, or liquids. The supplement may also contain protective hydrophilic colloids (such as gums, proteins, modified starches), binders, film-forming agents, encapsulation agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithin, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, flavor masking agents, weighting agents, gelling agents, and gelling agents. The supplement may also contain conventional pharmaceutical additives and adjuvants, excipients, and diluents, including but not limited to: water, gelatin of any source, plant gums, lignin sulfonates, talc, sugars, starches, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifiers, buffers, lubricants, colorants, wetting agents, fillers, etc.

[0149] In addition, supplements may contain organic or inorganic carrier materials suitable for oral or parenteral administration, as well as vitamins, trace minerals, and other micronutrients recommended by government agencies such as the USRDA.

[0150] The nutritional composition according to the present invention is for use in infants or young children. The infant or young child may be a full-term or premature infant. In one specific embodiment, the nutritional composition of the present invention is for premature infants, infants with low birth weight, and / or small for gestational age (SGA) infants or young children. In one specific embodiment, the nutritional composition of the present invention is for premature infants, low birth weight infants, and / or small for gestational age (SGA) infants.

[0151] The nutritional composition of the present invention can also be used for infants or young children born by cesarean section or vaginal delivery.

[0152] In some embodiments, the compositions according to the invention can be used before and / or during weaning.

[0153] The age and duration of administration (or administration or feeding) of the nutritional composition can be determined as needed.

[0154] The nutritional composition may be provided, for example, immediately after the infant's birth. The composition of the invention may also be given during the first week of the infant's life, or during the first two weeks of life, or during the first three weeks of life, or during the first month of life, or during the first two months of life, or during the first three months of life, or during the first four months of life, or during the first six months of life, or during the first eight months of life, or during the first ten months of life, or during the first year of life, or during the first two years of life, or even longer. In some particularly advantageous embodiments of the invention, the nutritional composition is given (or applied) to the infant during the first four, six, or twelve months after birth. In some other embodiments, the nutritional composition of the present invention is given a few days (e.g., 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 20 days…), a few weeks (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks…), or a few 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 specifically refer to cases where the infant is premature, but it is not necessary.

[0155] In one embodiment, the composition of the present invention is given to an infant or young child as a supplemental composition to breast milk. In some embodiments, the infant or young child receives breast milk for at least the first 2 weeks, first 1 month, first 2 months, first 4 months, or first 6 months. In one embodiment, the nutritional composition of the present invention is given to the infant or young child after this period of breastfeeding, or given to the infant or young child together with breast milk during this period of breastfeeding. In another embodiment, the composition is given to the infant or young child as the sole or primary nutritional composition for at least a period of time (e.g., after the first, second, or fourth month of life), for at least one month, two months, four months, or six months.

[0156] In one embodiment, the nutritional composition of the present invention is a complete nutritional composition (meeting all or most of an individual's nutritional needs). In another embodiment, the nutritional composition is a supplement or fortifier used, for example, to supplement human milk or infant formula or stage 2 infant formula.

[0157] Example

[0158] 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 invention.

[0159] Example 1: HMO 2'FL increased the amount of KYNA (kynurenic acid) produced by the microbial community.

[0160] Fecal fermentation and quantitative uric acid testing

[0161] Fecal samples from 10 infants aged 3 to 4 months (7 breastfed (BF) and 3 formula-fed (FF)) were inoculated into carbohydrate-free (CHO-free) YCFA medium. The study design involved supplementing the CHO-free YCFA medium with different carbohydrates to a final concentration of 0.5%. The different carbohydrates were lactose alone (F1 control group), or a combination of 2'FL, 2'FL, and LnNT, or a combination of 2'FL, diFL, 3'SL, 6'SL, LNT, and LNnT. Each individual underwent four replicate fermentations (F1 to F4), and the supernatant was collected at 24 and 48 hours. YCFA is a complex medium containing tryptone, yeast extract, and various minerals, vitamins, and short-chain fatty acids; however, in this case, it did not contain the typical CHO components (glucose, maltose, and cellobiose).

[0162] For metabolite analysis, samples are extracted and aliquoted for analysis on LC / MS / MS and polar LC platforms. Proprietary software is used to match ions with an internal standard library for metabolite identification and quantification via peak area integration.

[0163] result

[0164] We evaluated the effects of various combinations of HMOs on KYNA in culture media from in vitro fermented infantile fecal samples. We found that, in the fermentation supernatant, 2'FL or the combination of 2'FL and LNnT significantly increased KYNA levels by 1.76-fold and 1.61-fold, respectively, compared to lactose (P<0.01 and P<0.05, respectively). Figure 1 The blends of the six HMOs tended to increase KYNA (an average increase of 1.56-fold compared to lactose, p=0.07). No significant differences were found between any of the HMO treatments, suggesting that the increase in KYNA was primarily due to 2'FL.

[0165] Example 2 : 6'SL+LNT and KYNA have a cumulative effect on the activation of GPR35.

[0166] method

[0167] Cell lines stably expressing GPR35 were amplified from cryogenic stock solution according to standard procedures. Cells were seeded in 20 µL total volume into white-walled 384-well microplates and incubated at 37 °C for an appropriate time prior to testing. All tests were performed twice. On each test day, a 5x compound working intermediate was prepared in phosphate-buffered saline (PBS) for each test concentration. 5 µL of the 5x sample was added to the cells and incubated at 37 °C or room temperature for 90 min. Assay signals were generated by a single addition of 12.5 µL or 15 µL (50% v / v) PathHunter assay reagent mixture (DiscoverX) followed by incubation at room temperature for one hour. Microplates were read using a PerkinElmer Envision™ instrument for chemiluminescence signal detection after signal generation. Compound activity was analyzed using the CBIS Data Analysis Suite (ChemInnovation, CA). Percentage of activity was calculated using the following formula: % Activity = 100% x (average RLU of test sample – average RLU of solvent control) / (average maximum control ligand – average RLU of solvent control).

[0168] result

[0169] Stimulation of GPR35 with 6'SL, LNT, and 200µM KYNA showed an additive effect at HMO concentrations between 940µM and 2500µM.

[0170] Example 3

[0171] Table 1 below provides examples of the composition of nutritional compositions (e.g., infant formula) according to the present invention. These compositions are given by way of example only.

[0172] surface 1 Example 1 Composition of infant formula .

Claims

1. A nutritional composition comprising 2-fucosyllactose (2'-FL), said nutritional composition being used to promote health benefits in infants or young children by increasing kynurenic acid produced by the microbiota of an infant or young child consuming said nutritional composition or a nutritional composition in the form of growing milk containing 2-fucosyllactose (2'-FL), for promoting health benefits by increasing kynurenic acid produced by the microbiota of an infant or young child consuming said nutritional composition in the form of growing milk.

2. A nutritional composition according to claim 1 for reducing the sense of harm in infants or young children by increasing kynurenic acid produced by the microbiota of an infant or young child consuming the nutritional composition or the nutritional composition in the form of a growth milk, and for reducing the sense of harm in children by increasing kynurenic acid produced by the microbiota of an infant or young child consuming the nutritional composition in the form of a growth milk, according to claim 1.

3. A nutritional composition according to claim 1 for preventing and / or treating obesity or obesity-related metabolic disorders, preventing and / or treating depression, promoting neuroprotection, and preventing and / or treating inflammatory conditions in infants or young children by increasing kynurenic acid produced by the microbiota of infants or young children consuming the nutritional composition or in the form of a growth milk; and according to claim 1 for preventing and / or treating obesity or obesity-related metabolic disorders, preventing and / or treating depression, promoting neuroprotection, and preventing and / or treating inflammatory conditions in children by increasing kynurenic acid produced by the microbiota of infants or young children consuming the nutritional composition in the form of a growth milk.

4. The nutritional composition for the purpose according to claim 1 or 2, wherein the purpose is to reduce abdominal pain in infants or young children, and consequently children.

5. The nutritional composition for the purpose according to claim 1 or 2, wherein the purpose is for reducing pain associated with gastrointestinal discomfort and / or gastrointestinal disorders.

6. A nutritional composition for the purpose according to any one of the preceding claims, wherein the purpose is to reduce the duration of crying in infants or young children, and consequently children.

7. A nutritional composition for the purpose according to any one of the preceding claims, wherein the purpose is to improve the sleep quality of an infant or young child, and consequently a child.

8. A nutritional composition for the purpose of any of the preceding claims, wherein the purpose is to improve the quality of life of an infant or young child, and consequently a child.

9. The nutritional composition for the purpose according to any one of claims 4 to 6, wherein the infant, the toddler, or the child experiences pain.

10. The nutritional composition for the purpose according to claim 7, wherein the infant, the toddler, or the child experiences abdominal pain.

11. The nutritional composition for the stated purpose according to claim 7, wherein the infant, the toddler, or the child experiences pain associated with gastrointestinal discomfort and / or gastrointestinal disorders.

12. The nutritional composition for the stated use according to claim 9, wherein the gastrointestinal discomfort is caused by colic, bloating and / or spasms, and / or wherein the gastrointestinal disorder is selected from inflammatory bowel disease (IBD), diarrhea such as infectious diarrhea, necrotizing enterocolitis (NEC), and functional abdominal pain disorders, such functional abdominal pain disorders preferably selected from irritable bowel syndrome (IBS), abdominal migraine and nonspecific functional abdominal pain (FAP-NOS).

13. A nutritional composition for the purpose according to any one of the preceding claims, wherein 2'FL is present in an amount of 0.005 g / L composition to 8 g / L composition or based on a dry weight of 0.004 g / 100 g composition to 6.8 g / 100 g composition.

14. The nutritional composition for the said use according to any one of the preceding claims further comprises 6'SL and LNT, and wherein 6'SL and LNT are present in a 6'SL:LNT weight ratio of 3:1 to 1:3, such as 2:1 to 1:2 or 2:1 to 1:

1.

15. A nutritional composition for the purpose according to any one of the preceding claims, wherein 6'SL is present in an amount of 0.005 g / L composition to 5 g / L composition or in an amount of 0.004 g / 100 g composition to 3.8 g / 100 g composition based on dry weight.

16. A nutritional composition for the said use according to any one of the preceding claims, wherein LNT is present in an amount of 0.005 g / L composition to 3 g / L composition or in an amount of 0.004 g / 100 g composition to 2.3 g / 100 g composition based on dry weight.

17. A nutritional composition for the purpose according to any one of the preceding claims, wherein the nutritional composition comprises human milk oligosaccharides composed of 2'-FL.

18. A nutritional composition for the purpose according to any one of the preceding claims, wherein the nutritional composition is infant formula, stage 1 infant formula, follow-up or stage 2 infant formula, growing milk, baby food, infant cereal composition, fortifier or supplement.

Images