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WO2025099322A1 - Compositions comprenant des oligosaccharides de lait humain - Google Patents

Compositions comprenant des oligosaccharides de lait humain Download PDF

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Publication number
WO2025099322A1
WO2025099322A1 PCT/EP2024/081899 EP2024081899W WO2025099322A1 WO 2025099322 A1 WO2025099322 A1 WO 2025099322A1 EP 2024081899 W EP2024081899 W EP 2024081899W WO 2025099322 A1 WO2025099322 A1 WO 2025099322A1
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WO
WIPO (PCT)
Prior art keywords
hmo
combination
gut
microorganism
mammal
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English (en)
Inventor
Kristine ROTHAUS CHRISTENSEN
Erik Robert Mathias ECKHARDT
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DSM IP Assets BV
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DSM IP Assets BV
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Publication of WO2025099322A1 publication Critical patent/WO2025099322A1/fr
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis

Definitions

  • the present invention relates to a combination of a human milk oligosaccharides (HMOs) and inanimate cells of a microorganism, compositions comprising the combination and the use of the combination or the compositions to promote y-aminobutyric acid production in the gut of a mammal.
  • HMOs human milk oligosaccharides
  • GABA is an important neurotransmitter that plays a crucial role in brain development and function. It is involved in regulating neuronal activity and is believed to have a calming effect on the brain. Studies have suggested that GABA may have a number of health benefits including children, including improving cognitive function, reducing anxiety and stress, and promoting healthy sleep patterns. GABA has also been shown to have a positive impact on certain developmental disorders, such as autism and attention deficit hyperactivity disorder (ADHD).
  • ADHD attention deficit hyperactivity disorder
  • cytokines such as TNF- a, IL6 and IL8
  • MNK mitogen-activated protein kinase
  • GABA may help to regulate gut motility, which could help to alleviate symptoms of constipation or diarrhoea (Kerr and Ong: GABA and Gut Motility. In: Erdd, S.L. (eds) GABA Outside the CNS. Springer, Berlin, Heidelberg, pp 29- 44, 1992)).
  • Gut barrier function refers to the ability of the gut to prevent the leakage of harmful substances, such as toxins, bacteria, and undigested food particles, from the gut lumen into the bloodstream.
  • the gut barrier is composed of several different components, including the gut epithelium, which is the layer of cells that lines the gut, as well as the mucus layer, which acts as a physical barrier to prevent direct contact between the gut epithelium and the gut lumen.
  • the gut barrier also includes the tight junctions between gut epithelial cells, which help to regulate the passage of substances across the gut epithelium.
  • harmful substances can leak into the bloodstream, and potentially trigger inflammation and immune responses.
  • NSAIDs nonsteroidal antiinflammatory drugs
  • the mucosal barrier is part of the gut barrier function and is a layer of mucus that lines the gastrointestinal tract and protects the body from harmful microorganisms and substances.
  • the mucosal barrier function is not fully developed at birth, and the mucosal barrier continues to mature during the first year of life. In infants, this barrier is thinner and more permeable than in adults, which can make them more susceptible to infections and food allergies.
  • Human milk oligosaccharides are a heterogeneous mixture of soluble glycans found in human milk.
  • HMOs Human milk oligosaccharides and their beneficial effects, in: Handbook of dietary and nutritional aspects of human breast milk (Zibadi et al., eds.), pp. 515-31 , Wageningen Academic Publishers (2013)).
  • the structure of the HMOs is similar to the O-glycans found in mucus and the N-glycans found on human cells. HMOs are resistant to enzymatic hydrolysis in the small intestine and are thus largely undigested and unabsorbed.
  • HMOs The majority of HMOs that reach the colon serve as substrates to shape the gut ecosystem by selectively stimulating the growth of specific bacteria. HMOs are believed to substantially modulate the infant gut microbiota and play a decisive role in the differences in the microbiota of formula-fed and breast-fed infants.
  • Non-viable microorganisms or microbial cell extracts mainly heat-killed (including tyndallized) bacteria (lactic acid bacteria and bifidobacteria), are able to produce beneficial effects.
  • dead cells of Lactobacillus strains are useful to produce a psychobiotic effect in a human (WO 2019/180263), in stimulating the growth of bifidobacteria in the human gut (WO 2021/219846) or to treat or prevent an allergic disease (EP-A-2796142).
  • WO 2019/180263 in stimulating the growth of bifidobacteria in the human gut
  • EP-A-2796142 an allergic disease
  • the first aspect of this invention relates to a combination of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism.
  • the combination in the present context, means that it comprises a HMO and inactivated cells of a microorganism, preferably consists essentially of or consists of one or more HMOs and dead/inactivated cells of one or more microorganisms optionally with or in its/their concentrated or dried fermentation medium from which the microorganism is derived and the medium components therein. If the combination above contains the dried fermentation medium of the inactivated cells, it may optionally further contain lactose as carrier facilitating the drying process.
  • the combination consists or consists essentially of one or more HMOs and dead/inactivated cells of one or more microorganisms in or with its/their dried fermentation medium comprising medium components and optionally lactose.
  • the second aspect of the invention relates to a synthetic composition comprising the combination of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism as defined in the first aspect.
  • the synthetic composition is, in one embodiment, a nutritional composition that confers a nutritional (that is non-therapeutical) benefit to the mammal consuming it.
  • the synthetic composition in other embodiment, is a pharmaceutical composition that restores the organism of a mammal from a pathological to its original condition.
  • the synthetic composition comprising the combination of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism as defined in the first aspect contains nutritionally or pharmaceutically acceptable ingredients other than the components of the combination.
  • the third aspect of the invention relates to a combination of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism, as defined in the first aspect of the invention, for use in a therapy or as a medicament, preferably for use in treating conditions of a mammal wherein enhanced level of GABA production in the gut of the mammal contributes to treat pathological conditions or clinical situations.
  • HMO human milk oligosaccharide
  • the fourth aspect of the invention relates to a synthetic composition
  • a synthetic composition comprising the combination of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism as defined in the second aspect of the invention for use in therapy or as a medicament, preferably for use in treating conditions of a mammal wherein enhanced level of GABA production in the gut of the mammal contributes to treat pathological conditions or clinical situations.
  • HMO human milk oligosaccharide
  • the fifth aspect of the invention relates to a method for promoting or increasing the GABA production in the gut of a mammal, the method comprising orally or enterally administering to, or providing for consumption by, the mammal an effective amount of a combination of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism, as defined in the first aspect of the invention, the combination optionally being comprised in a synthetic composition, as defined in the second aspect of the invention.
  • HMO human milk oligosaccharide
  • the sixth aspect of the invention relates to a non-therapeutic use of the combination of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism, as defined in the first aspect of the invention, for promoting or enhancing the GABA production in the gut of a mammal.
  • the seventh aspect of the invention relates to a non-therapeutic use of the synthetic composition comprising the combination of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism, as defined in the second aspect of the invention, for promoting or enhancing the GABA production in the gut of a mammal.
  • the HMO can be a neutral HMO or an acidic HMO, preferably a neutral HMO.
  • the neutral HMO can be one or more fucosylated HMOs or one or more non- fucosylated HMOs.
  • the HMO is 2’-FL, 3-FL, DFL, LNT, LNnT, LNFP-I, LNDFH-I or a mixture thereof.
  • the HMO comprises 2’-FL, LNnT, 3’-SL, 6’-SL or any combination thereof.
  • the microorganism is preferably a Lactobacillus, more preferably a mixture of L. fermentum and L. delbrueckii.
  • the mammal is preferably human, more preferably a non-infant human.
  • Effective amount means an amount of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism, optionally in a suitable composition, that provides these ingredients in a sufficient amount to render a desired health outcome in a human.
  • An effective amount can be administered or provided for consumption in one or more doses to achieve the desired health outcome.
  • Enteral administration means any conventional form for delivery of a composition to a human that causes the deposition of the composition in the gastrointestinal tract (including the stomach). Methods of enteral administration include feeding through a naso-gastric tube or jejunum tube, oral, sublingual and rectal.
  • Human milk oligosaccharide or "HMO” means a complex carbohydrate found in human breast milk (Urashima et al.: Milk Oligosaccharides. Nova Science Publisher (2011); Chen Adv.
  • the HMOs have a core structure comprising a lactose unit at the reducing end that can be elongated by one or more p-N-acetyl-lactosaminyl and/or one or p-more lacto-N-biosyl units, and which core structure can be substituted by an a L-fucopyranosyl and/or an a-N-acetyl-neuraminyl (sialyl) moiety.
  • the non-acidic (or neutral) HMOs are devoid of a sialyl residue, and the acidic HMOs have at least one sialyl residue in their structure.
  • the non-acidic (or neutral) HMOs can be fucosylated or non- fucosylated.
  • neutral non-fucosylated HMOs include lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-neohexaose (LNnH), para-lacto-N-neohexaose (pLNnH), para-lacto-N-hexaose (pLNH) and lacto-N-hexaose (LNH).
  • neutral fucosylated HMOs examples include 2'-fucosyl lactose (2’-FL), lacto-N-fucopentaose I (LNFP-I), lacto-N-difucohexaose I (LNDFH-I), 3-fucosyllactose (3-FL), difucosy I lactose (DFL), lacto-N-fucopentaose II (LNFP-II), lacto-N-fucopentaose III (LNFP-III), lacto-N-difucohexaose III (LNDFH-I II), fucosyl-lacto-N- hexaose II (FLNH-II), lacto-N-fucopentaose V (LNFP-V), lacto-N-fucopentaose VI (LNFP-VI), lacto-N-difucohexaose II (LNDFH-
  • “Inactivated cells of a microorganism” preferably means inanimate microorganism that has been made deliberately lifeless (dead or killed), therefore is not able to colonize under appropriate conditions, for example in the host’s gut.
  • the degree of inactivation is at least 90 %, preferably at least 95 %, more preferably at least 98 %, even more preferably at least 99 %, advantageously substantially all cell of the microorganism is dead or killed, more advantageously the entire population of the microorganism is dead or killed.
  • Microbiota mean a community of living microorganisms that typically inhabits a bodily organ or part, particularly the gastro-intestinal organs of non-infant humans.
  • the most dominant members of the gastrointestinal microbiota include microorganisms of the phyla of Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Synergistetes, Verrucomicrobia, Fusobacteria, and Euryarchaeota; at genus level Bacteroides, Faecalibacterium, Bifidobacterium, Roseburia, Alistipes, Collinsella, Blautia, Coprococcus, Ruminococcus, Eubacterium and Dorea; at species level Bacteroides uniformis, Alistipes putredinis, Parabacteroides merdae, Ruminococcus bromii, Dorea longicatena, Bacteroides caccae, Bacter
  • Oral administration means any conventional form for the delivery of a composition to a human through the mouth. Accordingly, oral administration is a form of enteral administration.
  • “Therapy” means treatment given or action taken to reduce or eliminate symptoms of a disease or pathological condition.
  • Treat means to address a medical condition or disease with the objective of improving or stabilising an outcome in the person being treated or addressing an underlying nutritional need. Treat, therefore, includes the dietary or nutritional management of the medical condition or disease by addressing nutritional needs of the person being treated. “Treating” and “treatment” have grammatically corresponding meanings.
  • HMOs human milk oligosaccharides
  • the HMO in the combination may be a single HMO or a mixture of any HMOs.
  • the HMO can be a neutral HMO or an acidic HMO.
  • the neutral HMO is, in one embodiment, one or more non-fucosylated HMOs; in another embodiment the neutral HMO is one or more fucosylated HMOs.
  • the fucosylated neutral HMO is selected from the list consisting of 2’-FL, 3-FL, DFL, a LNFP (LNFP-I, LNFP-II, LNFP-III, LNFP-V or LNFP-VI), a LNDFH (LNDFH-I, LNDFH-II or LNDFH-II I), FLNH-I, FLNH-II, FLNnH, FpLNH-l and F-pLNnH II, preferably 2’-FL, 3-FL, DFL, a LNFP (preferably LNFP-I) or a LNDFH (preferably LNDFH-I), and the non-fucosylated neutral HMO is selected from the list consisting of LNT, LNnT, LNH, LNnH, pLNH and pLNnH, preferably LNnT or LNT, more preferably LNnT.
  • the acidic (sialylated) HMO is selected from the
  • the HMO comprises neutral HMOs, preferably at least a first neutral HMO and at least a second neutral HMO, wherein the first neutral HMO is a fucosylated neutral HMO as disclosed above and the second neutral HMO is a non-fucosylated neutral HMO as disclosed above.
  • the fucosylated neutral HMO(s) and the non-fucosylated neutral HMO(s) may be present in a mass ratio of about 4:1 to 1 :1.
  • the mixture of neutral HMOs contains, consists of or consists essentially of, a fucosylated HMO selected from the list consisting of 2’- FL, 3-FL and DFL, and a non-fucosylated neutral HMO selected from the list consisting of LNT and LNnT ; advantageously the mixture comprises, consists of or consists essentially of, 2’-FL and at least one of LNnT and LNT ; or at least one of 2’-FL and DFL and at least one of LNnT and LNT; or 2’-FL, DFL and at least one of LNnT and LNT; most preferably 2’-FL and LNnT.
  • the neutral HMOs comprises at least a first fucosylated neutral HMO and a second fucosylated neutral HMO.
  • the mixture of fucosylated neutral HMOs contains, consists of or consists essentially of, a first fucosylated neutral HMO selected from the list consisting of 2’-FL and 3-FL, and a second fucosylated neutral HMO selected from the list consisting of DFL and LNFP-I; advantageously the mixture comprises, consists of or consists essentially of, 2’-FL and DFL; or 2’-FL and LNFP-I.
  • 2’-FL and DFL may be present in a mass ratio of about 4:1 to 19:1 , such as about 9:1
  • 2’-FL and LNFP-I may be present in a mass ratio of about 1 :1 to 5: 1 , such as about 2:1.
  • the mixture of HMOs comprises, consists of or consists essentially of, at least a first (acidic) HMO as disclosed above and at least a second (neutral) HMO as disclosed above.
  • the mixture comprises, consists of or consists essentially of, 2’-FL and 3’-SL; or LNnT and 3’-SL; or 2’-FL, LNnT and 3’-SL.
  • the inactivated cells of a microorganism are inactivated microbial cells that - optionally with cell components and/or metabolites - confer a health benefit on the host when administered, and usually referred to as postbiotic.
  • inactivation method makes the vast majority of the cells lifeless (dead or killed): at least 90 %, preferably at least 95 %, more preferably at least 98 %, even more preferably at least 99 %, advantageously substantially all cell of the microorganism is dead or killed, more advantageously the entire population of the microorganism is dead or killed.
  • a preparation of the inanimate microorganism When combined with the HMO, preferably a preparation of the inanimate microorganism is used. Said preparation is typically made by concentration and then optionally, but preferably drying the dead cells together with the fermented culture medium after inactivation to a powder (that is removing water from the medium).
  • the preparation of the inactivated cells contains substances other than the intact cells, for example cell components (pili, cell wall components, etc.), fermentation additives like carbon and/or energy source used in the fermentation, microbial metabolites and/or end products like amino acids, peptides.
  • the drying method comprises spray-drying, lyophilization, fluid bed drying or other appropriate process.
  • a suitable carrier for example lactose is added to preparation before or during drying.
  • the living strain of the microorganism the cells of which are to be inactivated is not considered to be a probiotic.
  • the inactivated cells is not derived from a probiotic strain.
  • the inactivated cells of the microorganism is derived from a Lactobacillus or Bifidobacterium, more preferably Lactobacillus, for example L. rhamnosus, L. acidophylus, L. plantarum, L. casei, L. delbrueckii, L. delbrueckii subsp. bulgaricus, L. brevis, L. johnsonii, L. fermentum or L. reuteri, more preferably the strains of the above mentioned Lactobacilli or Bifidobacteria are not considered to be probiotic strains.
  • Lactobacillus or Bifidobacterium more preferably Lactobacillus, for example L. rhamnosus, L. acidophylus, L. plantarum, L. casei, L. delbrueckii, L. delbrueckii subsp. bulgaricus, L. brevis, L. johnsonii, L. fermentum or L.
  • the Lactobacillus is L. fermentum (Limosilactobacillus fermentum) as deposited at the Collection Nationale de Cultures de Microorganismes (CNCM) with the reference code 1-2998.
  • the Lactobacillus is L. delbrueckii as deposited at the Collection Nationale de Cultures de Microorganismes (CNCM) with the reference code 1-4831.
  • the Lactobacillus comprises or consists of two independent species: L. fermentum and L. delbrueckii.
  • the ratio of L. fermentum to L. delbrueckii by weight or cell count may be any suitable ratio from about 99:1 to about 1 :99, e.g.
  • the Lactobacillus is Lactobacillus LB consisting of L. fermentum CNCM I-2998 and L. delbrueckii CNCM 1-4831, preferably in about a 9:1-19:1 ratio (by intact cell count).
  • the Lactobacillus LB may conveniently be isolated from human faeces.
  • Lactobacillus LB in fermented culture medium (together with components of the culture medium fermentation including peptides, amino acids carbohydrates carbon and minerals) is deposited at the Collection Nationale de Cultures de Microorganismes (CNCM) with the reference code MA 65/4E.
  • Dead Lactobacillus LB cells may be obtained by heating the live cells in fermented culture medium at about 110 °C for about 1 hour.
  • the inactivated cells of a microorganism in the combination concerning all aspects of the present invention such as in particular the mixture of the inactivated cells of Limosilactobacillus fermentum (previously known as Lactobacillus fermentum) and the inactivated cells Lactobacillus delbrueckii together with their culture media can be used in the form of a powder, which can be prepared by drying the dead cells together with the fermented culture medium by conventional drying methods such as by lyophilization, spray-drying, freeze drying or fluid-bed drying prior to formulating into a suitable composition for use according to the present invention.
  • lactose may be added to the wet fermented product prior to drying.
  • lactose may also be added in the course of drying as part of the formulation step.
  • the ratio of the inanimate cells in proportion to the weight of the HMO can be any suitable ratio, preferably around 0.5 billion cells per g of HMO or more, more preferably around 1 billion cells per g of HMO or more, such as 1-25 or 1-10 billion cells per g of HMO, more preferably around 4-5 billion cells per g of HMO or more, up to 60-80 billion cells per g of HMO. This relates also to all preferred embodiments of the combination disclosed above.
  • the invention relates to, also particularly, a combination consisting of a fucosylated HMO, preferably 2’-FL, 3-FL or DFL, more preferably 2’-FL, and dead or inactivated Lactobacillus LB cells in or with their dried fermentation medium comprising medium components and optionally lactose, advantageously wherein the combination comprises about 1-10, preferably 4-5 billion cells per g of fucosylated HMO, preferably 2’-FL, 3-FL or DFL, more preferably 2’-FL.
  • the inactivated cells of Limosilactobacillus fermentum (CNCM 1-4831) and Lactobacillus delbrueckii (CN-I2998) (together known as Lactobacillus LB (CNCM MA 65/4E)) along with their culture media is used in powder form, preferably comprising lactose as carrier material, even more preferably comprising around 60 billion inactivated bacteria per g of powder.
  • Said powder form is e.g. commercially available under the tradename LBiomeTM or Humiome® Post LB at dsm-firmenich.
  • the synthetic composition comprising a combination of an HMO and inactivated cells of a microorganism, including the preferred and more preferred embodiments as disclosed above, can be a pharmaceutical composition.
  • the pharmaceutical composition can contain a pharmaceutically acceptable carrier, e.g. phosphate buffered saline solution, mixtures of ethanol in water, water and emulsions such as an oil/water or water/oil emulsion, as well as various wetting agents or excipients.
  • the pharmaceutical composition can also contain other materials that do not produce an adverse, allergic or otherwise unwanted reaction when administered to humans.
  • the carriers and other materials can include solvents, dispersants, coatings, absorption promoting agents, controlled release agents, and one or more inert excipients, such as starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, and disintegrating agents.
  • tablet dosages of the anti-infective compositions can be coated by standard aqueous or non-aqueous techniques.
  • compositions can be administered orally, e.g. as a tablet, capsule, or pellet containing a predetermined amount, or as a powder or granules containing a predetermined concentration or a gel, paste, solution, suspension, emulsion, syrup, bolus, electuary, or slurry, in an aqueous or non-aqueous liquid, containing a predetermined concentration.
  • Orally administered compositions can include binders, lubricants, inert diluents, flavouring agents, and humectants.
  • Orally administered compositions such as tablets can optionally be coated and can be formulated to provide sustained, delayed or controlled release of the mixture therein.
  • compositions can also be administered by rectal suppository, aerosol tube, naso-gastric tube or direct infusion into the Gl tract or stomach.
  • the pharmaceutical compositions can also include therapeutic agents such as antiviral agents, antibiotics, probiotics, analgesics, and anti-inflammatory agents.
  • the proper dosage of these compositions for a human can be determined in a conventional manner, based upon factors such immune status, body weight and age. In some cases, the dosage will be at a concentration similar to that found for the HMO in human breast milk. The required amount would generally be in the range from about 200 mg to about 20 g per day, in certain embodiments from about 300 mg to about 15 g per day, from about 400 mg to about 10 g per day, in certain embodiments from about 500 mg to about 10 g per day, in certain embodiments from about 1 g to about 10 g per day.
  • the pharmaceutical composition contains the dead cells so that they amount about 1- 60 billion per g of HMO(s) in the composition.
  • the synthetic composition can preferably be a nutritional composition. It can contain sources of protein, lipids and/or digestible carbohydrates and can be in powdered or liquid forms. The composition can be designed to be the sole source of nutrition or a nutritional supplement. The nutritional composition is preferably for non-therapeutic use.
  • Suitable protein sources include milk proteins, soy protein, rice protein, pea protein and oat protein, or mixtures thereof.
  • Milk proteins can be in the form of milk protein concentrates, milk protein isolates, whey protein or casein, or mixtures of both.
  • the protein can be whole protein or hydrolysed protein, either partially hydrolysed or extensively hydrolysed. Hydrolysed protein offers the advantage of easier digestion which can be important for humans with inflamed Gl tracts.
  • the protein can also be provided in the form of free amino acids.
  • the protein can comprise about 5 % to about 30 % of the energy of the nutritional composition, normally about 10 % to 20 %.
  • the protein source can be a source of glutamine, threonine, cysteine, serine, proline, or a combination of these amino acids.
  • the glutamine source can be a glutamine dipeptide and/or a glutamine enriched protein.
  • Glutamine can be included due to the use of glutamine by enterocytes as an energy source.
  • Threonine, serine and proline are important amino acids for the production of mucin. Mucin coats the Gl tract and can improve mucosal healing.
  • Cysteine is a major precursor of glutathione, which is key for the antioxidant defences of the body.
  • Suitable digestible carbohydrates include maltodextrin, hydrolysed or modified starch or corn starch, corn syrup, corn syrup solids, high fructose corn syrup, rice-derived carbohydrates, pea- derived carbohydrates, potato-derived carbohydrates, tapioca, sucrose, glucose, fructose, sucrose, lactose, honey, sugar alcohols (e.g., maltitol, erythritol, sorbitol), or mixtures thereof.
  • Generally digestible carbohydrates provide about 35 % to about 55 % of the energy of the nutritional composition.
  • a particularly suitable digestible carbohydrate is a low dextrose equivalent (DE) maltodextrin.
  • Suitable lipids include medium chain triglycerides (MCT) and long chain triglycerides (LCT).
  • MCT medium chain triglycerides
  • LCT long chain triglycerides
  • MCTs can comprise about 30 % to about 70 % by weight of the lipids, more specifically about 50 % to about 60 % by weight.
  • MCTs offer the advantage of easier digestion which can be important for humans with inflamed Gl tracts.
  • the lipids provide about 35 % to about 50 % of the energy of the nutritional composition.
  • the lipids can contain essential fatty acids (omega-3 and omega-6 fatty acids). Preferably these polyunsaturated fatty acids provide less than about 30 % of total energy of the lipid source.
  • Suitable sources of long chain triglycerides are rapeseed oil, sunflower seed oil, palm oil, soy oil, milk fat, corn oil, high oleic oils, and soy lecithin.
  • Fractionated coconut oils are a suitable source of medium chain triglycerides.
  • the lipid profile of the nutritional composition is preferably designed to have a polyunsaturated fatty acid omega-6 (n-6) to omega-3 (n-3) ratio of about 4:1 to about 10:1.
  • the n-6 to n-3 fatty acid ratio can be about 6:1 to about 9:1.
  • the nutritional composition preferably also includes vitamins and minerals. If the nutritional composition is intended to be a sole source of nutrition, it preferably includes a complete vitamin and mineral profile.
  • vitamins include vitamins A, B-complex (such as B1 , B2, B6 and B12), C, D, E and K, niacin and acid vitamins such as pantothenic acid, folic acid and biotin.
  • minerals include calcium, iron, zinc, magnesium, iodine, copper, phosphorus, manganese, potassium, chromium, molybdenum, selenium, nickel, tin, silicon, vanadium and boron.
  • the nutritional composition can also include a carotenoid such as lutein, lycopene, zeaxanthin, and beta-carotene.
  • a carotenoid such as lutein, lycopene, zeaxanthin, and beta-carotene.
  • the total amount of carotenoid included can vary from about 0.001 pg/ml to about 10 pg/ml.
  • Lutein can be included in an amount of from about 0.001 pg/ml to about 10 pg/ml, preferably from about 0.044 pg/ml to about 5 g/ml of lutein.
  • Lycopene can be included in an amount from about 0.001 pg/ml to about 10 pg/ml, preferably about 0.0185 mg/ml to about 5 g/ml of lycopene.
  • Beta-carotene can comprise from about 0.001 pg/ml to about 10 mg/ml,
  • the nutritional composition preferably also contains reduced concentrations of sodium; for example, from about 300 mg/l to about 400 mg/l.
  • the remaining electrolytes can be present in concentrations set to meet needs without providing an undue renal solute burden on kidney function.
  • potassium is preferably present in a range of about 1180 to about 1300 mg/l; and chloride is preferably present in a range of about 680 to about 800 mg/l.
  • the nutritional composition can also contain various other conventional ingredients such as preservatives, emulsifying agents, thickening agents, buffers, fibres and prebiotics (e.g. fructooligosaccharides, galactooligosaccharides), probiotics (e.g. B. animalis subsp. lactis BB- 12, B. lactis HN019, B. lactis Bi07, B. infantis ATCC 15697, L. rhamnosus GG, L. rhamnosus HNOOI, L. acidophilus LA-5, L. acidophilus NCFM, L. fermentum CECT5716, B. longum BB536, B. longum AH 1205, B. longum AH1206, B.
  • prebiotics e.g. fructooligosaccharides, galactooligosaccharides
  • probiotics e.g. B. animalis subsp. lactis BB- 12, B. lactis HN019, B. lactis
  • the nutritional composition can be in the form of a soluble powder, a liquid concentrate, or a ready-to-use formulation.
  • the composition can be fed to a human via a nasogastric tube or orally.
  • Various flavours, fibres and other additives can also be present.
  • the nutritional compositions can be prepared by any commonly used manufacturing techniques for preparing nutritional compositions in solid or liquid form.
  • the composition can be prepared by combining various feed solutions.
  • a protein-in-fat feed solution can be prepared by heating and mixing the lipid source and then adding an emulsifier (e.g. lecithin), fat soluble vitamins, and at least a portion of the protein source while heating and stirring.
  • a carbohydrate feed solution is then prepared by adding minerals, trace and ultra-trace minerals, thickening or suspending agents to water while heating and stirring. The resulting solution is held for 10 minutes with continued heat and agitation before adding carbohydrates (e.g. the HMOs and digestible carbohydrate sources) and postbiotics.
  • carbohydrates e.g. the HMOs and digestible carbohydrate sources
  • the resulting feed solutions are then blended together while heating and agitating and the pH adjusted to 6.6-7.0, after which the composition is subjected to high-temperature short-time processing during which the composition is heat treated, emulsified and homogenized, and then allowed to cool.
  • Water soluble vitamins and ascorbic acid are added, the pH is adjusted to the desired range if necessary, flavours are added, and water is added to achieve the desired total solid level.
  • the components may be dry-blended under suitably sterile conditions.
  • the daily dosage of HMOs for nutritional purposes is around 3-7 g, preferably 3-5 g.
  • the nutritional composition contains the dead cells so that they amount about 1-60 billion per g of HMO(s) in the composition.
  • the resulting solution can then be aseptically packed to form an aseptically packaged nutritional composition.
  • the nutritional composition can be in ready-to- feed or concentrated liquid form.
  • the composition can be spray-dried and processed and packaged as a reconstitutable powder.
  • the total concentration of HMOs in the liquid, by weight of the liquid is from about 0.0001 % to about 2.0 %, including from about 0.001 % to about 1.5 %, including from about 0.01 % to about 1.0 %.
  • the total concentration of HMOs in the liquid, by weight of the liquid is from about 0.0002 % to about 4.0 %, including from about 0.002 % to about 3.0 %, including from about 0.02 % to about 2.0 %.
  • the nutritional composition can also be in a unit dosage form such as a capsule, tablet or sachet.
  • the synthetic composition can be in a tablet form comprising the HMOs, and one or more additional components to aid formulation and administration, such as diluents, excipients, antioxidants, lubricants, colorants, binders, disintegrants, and the like.
  • Suitable diluents, excipients, lubricants, colorants, binders, and disintegrants include polyethylene, polyvinyl chloride, ethyl cellulose, acrylate polymers and their copolymers, hydroxyethyl-cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethylcellulose, polyhydroxyethyl methylacrylate (PHEMA), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO), or polyacrylamide (PA), carrageenan, sodium alginate, polycarbophil, polyacrylic acid, tragacanth, methyl cellulose, pectin, natural gums, xanthan gum, guar gum, karaya gum, hypromellose, magnesium stearate, microcrystalline cellulose, and colloidal silicon dioxide.
  • Suitable antioxidants are vitamin A, carotenoids, vitamin C, vitamin E, selenium, flavonoids, polyphenols, ly
  • the unit dosage forms can also include various nutrients including macronutrients.
  • Another aspect of the invention relates to the non-therapeutic use of the combination of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism, as defined in the first aspect of the invention, or the synthetic composition comprising said combination, as defined in the second aspect of the invention, for promoting or enhancing the GABA production in the gut of a mammal, preferably a human, more preferably a non-infant human.
  • HMO human milk oligosaccharide
  • Promoting the GABA production in the gut of a mammal who is in a healthy state and/or in a state in which the mammal is not likely to develop any pathological condition contributes to regulating metabolism of the consumer and the stability of the gut microbiome, and thus resulting in improvement of the quality of life and perception of well-being.
  • Another aspect of the invention relates to a combination of a human milk oligosaccharide (HMO) and inactivated cells of a microorganism, as defined in the first aspect of the invention, or a synthetic composition comprising said combination, as defined in the second aspect of the invention, for use in a therapy or as a medicament.
  • HMO human milk oligosaccharide
  • the use is managing conditions of a mammal wherein enhanced level of GABA production in the gut of the mammal contributes to treat pathological conditions or clinical situations, preferably one or more of supporting or improving emotional and behavioural development such as reduction of anxiety and/or stress, better mood regulation, improved sleep quality such as better sleep pattern and reduced insomnia, enhanced gut health through regulated improved gut barrier function and/or gut motility, reducing gut inflammation, neuroprotection, immune modulation resulting in better protection against infections and supporting or improving cognitive development, such as motor skills, learning, language skills, and spatial cognition ability.
  • supporting or improving emotional and behavioural development such as reduction of anxiety and/or stress, better mood regulation, improved sleep quality such as better sleep pattern and reduced insomnia
  • enhanced gut health through regulated improved gut barrier function and/or gut motility
  • reducing gut inflammation neuroprotection
  • immune modulation resulting in better protection against infections and supporting or improving cognitive development, such as motor skills, learning, language skills, and spatial cognition ability.
  • the synthetic composition for use in managing conditions of a mammal wherein enhanced level of GABA production in the gut of the mammal contributes to treat pathological conditions or clinical situations is a nutraceutical composition for use in supporting or improving in a subject one or more of the following: - cognitive development, such as motor skills, learning, language skills, and spatial cognition ability,
  • the samples were analysed to determine GABA content with LC-MS/MS using external standard.
  • delbrueckii (CNCM 1-4831) together with components of the culture medium fermentation including peptides, amino acids, carbohydrates carbon and minerals), 0.34 g/l, and the mixture of the HMO (5 g/l) and Humiome® Post LB (0.34 g ⁇ l).

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Abstract

La présente invention concerne une combinaison d'oligosaccharides de lait humain (HMO) et de cellules inanimées d'un micro-organisme, des compositions comprenant la combinaison et l'utilisation de la combinaison ou des compositions pour favoriser la production de GABA dans l'intestin d'un mammifère.
PCT/EP2024/081899 2023-11-09 2024-11-11 Compositions comprenant des oligosaccharides de lait humain Pending WO2025099322A1 (fr)

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Citations (7)

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Publication number Priority date Publication date Assignee Title
EP2796142A1 (fr) 2011-12-19 2014-10-29 Dae Hyun Kim Composition pharmaceutique comprenant des cellules mortes de la souche lb de lactobacillus acidophilus pour le traitement ou la prévention d'une maladie allergique
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EP3494807A1 (fr) * 2017-12-11 2019-06-12 Jennewein Biotechnologie GmbH Sialyllactose séché par pulvérisation
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WO2020001863A1 (fr) * 2018-06-25 2020-01-02 Societe Des Produits Nestle S.A. Composition comprenant des oligosaccharides de lait humain destinée à être utilisée dans l'amélioration, le perfectionnement, la promotion ou la modulation d'une fonction gabaergique dans le système nerveux central
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EP2796142A1 (fr) 2011-12-19 2014-10-29 Dae Hyun Kim Composition pharmaceutique comprenant des cellules mortes de la souche lb de lactobacillus acidophilus pour le traitement ou la prévention d'une maladie allergique
US20180064739A1 (en) * 2016-09-06 2018-03-08 Mead Johnson Nutrition Company Nutritional composition with human milk oligosaccharides and uses thereof
EP3494807A1 (fr) * 2017-12-11 2019-06-12 Jennewein Biotechnologie GmbH Sialyllactose séché par pulvérisation
WO2019180263A2 (fr) 2018-03-22 2019-09-26 Adare Pharmaceuticals Sas Nouvelle utilisation de compositions microbiologiques
WO2020001863A1 (fr) * 2018-06-25 2020-01-02 Societe Des Produits Nestle S.A. Composition comprenant des oligosaccharides de lait humain destinée à être utilisée dans l'amélioration, le perfectionnement, la promotion ou la modulation d'une fonction gabaergique dans le système nerveux central
US20230066020A1 (en) * 2020-01-20 2023-03-02 Morinaga Milk Industry Co., Ltd. Composition
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