WO2025149453A1 - Utilisations d'un micro-organisme de transition bifidobacterium longum - Google Patents

Utilisations d'un micro-organisme de transition bifidobacterium longum

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Publication number
WO2025149453A1
WO2025149453A1 PCT/EP2025/050196 EP2025050196W WO2025149453A1 WO 2025149453 A1 WO2025149453 A1 WO 2025149453A1 EP 2025050196 W EP2025050196 W EP 2025050196W WO 2025149453 A1 WO2025149453 A1 WO 2025149453A1
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Prior art keywords
transitional
longum
microorganism
prebiotic
suitably
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English (en)
Inventor
Claire Laurence Lucie Marie BOULANGE
Jean-Baptiste CAVIN
Stéphane DUBOUX
Cheong Kwet Choy KWONG CHUNG
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Societe des Produits Nestle SA
Nestle SA
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Societe des Produits Nestle SA
Nestle SA
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Publication of WO2025149453A1 publication Critical patent/WO2025149453A1/fr
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    • 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
    • A61K35/745—Bifidobacteria
    • 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
    • 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
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/718—Starch or degraded starch, e.g. amylose, amylopectin
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/719—Pullulans
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/733—Fructosans, e.g. inulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • allergies in childhood can be the first step of an allergic cascade leading to multiple allergies later in life, a process commonly referred to as the “Atopic March”.
  • children with persistent food hypersensitivity early in life have a dramatically increased risk to develop allergic rhinitis (hay fever) or asthma later in childhood.
  • Children with milder forms of food hypersensitivity also have increased risk for development of respiratory allergies but to a lesser degree than children with persistent food hypersensitivity. Therefore, attenuating the severity of food hypersensitivity may be crucial for slowing down the "Atopic March".
  • the management of allergic episodes and the prevention of allergies are, in childhood and infancy, of the highest importance.
  • the immune system of infants is actively developing throughout the few first years of life. Acting on, preventing, avoiding, managing, reducing or modulating the allergic reactions at an early age can influence the allergic profile not only in the short term but also longer term for later in life.
  • Food allergens are among the first allergens that infants encounter in their early life: typically, cow's milk proteins may be encountered by infants not receiving exclusive breast feeding. Milk-proteins are indeed among the most frequently observed causes for food allergy in infancy, followed by eggs and wheat proteins. In general, food allergies can manifest in cutaneous (rash, eczema, others) and gastrointestinal symptoms (abdominal cramps; pain, especially in the abdomen; vomiting) in infants and young children. Food allergies are the most common trigger of severe allergic reactions, which may lead to life-threatening anaphylaxis.
  • Animals particularly small animals such as pets - and especially companion animals such as dogs and cats, may also suffer from food allergies and food intolerances, as well as environmental allergens. These typically manifest in similar symptoms to humans, e.g. gastrointestinal disturbances such as diarrhoea, vomiting and abdominal discomfort, and also dermatitis or pruritis.
  • gastrointestinal disturbances such as diarrhoea, vomiting and abdominal discomfort, and also dermatitis or pruritis.
  • the most frequent cause of chronic diarrhoea is food-responsive enteropathy (diet-responsive enteropathy or food-responsive diarrhoea).
  • the present inventors have determined that a Bifidobacterium longum subspecies microorganism (8. longum transitional) of a clade that is present in the gut microbiome of the transitional feeding period of mammals, particularly humans, may have beneficial effects on reducing the risk of developing an allergy and/or allergic sensitization.
  • the inventors have shown that the B. longum transitional microorganisms may be capable of modulating gut barrier permeability and/or promoting an anti-inflammatory and/or tolerogenic environment in the gut microbiota during the weaning period.
  • the present invention provides a Bifidobacterium longum transitional microorganism for use in treating and/or preventing an allergy and/or allergic sensitization in an infant or young child, wherein the Bifidobacterium longum transitional microorganism comprises a strain deposited with Collection emphasis de cultures de micro-organismes (CNCM) under deposit number CNCM 1-5942 or a B. longum transitional strain having an identifying characteristic of the B. longum transitional strain deposited under deposit number CNCM 1-5942.
  • CNCM CollectionInstitut de cultures de micro-organismes
  • the invention also provides a combination of a Bifidobacterium longum transitional microorganism according to the invention and a prebiotic for use in treating and/or preventing an allergy and/or allergic sensitization in an infant or young child; wherein the prebiotic is: i. a glycan substrate, suitably selected from the group recited in any of Tables 1 to 3; and/or ii. a human milk oligosaccharide (HMO).
  • HMO human milk oligosaccharide
  • the invention relates to the use of a Bifidobacterium longum transitional microorganism according to the invention, prebiotic or combination as defined herein for modulating gut barrier permeability in an infant or young child, preferably by promoting the growth of a Bifidobacterium longum transitional microorganism in the gut of the infant or young child.
  • FIG. 2 Transepithelial electrical resistance (TEER) of Caco-2 monolayers after apical treatment with 2x10 6 CFU of probiotic strains.
  • TEER was measured 2h, 4h, 6h and 24h after treatment, each value was normalized to its corresponding Oh value and is shown as percentage of initial value. Data are plotted as mean ⁇ SEM. For each concentration, differences between the complete medium (CM) control and treatments per timepoint were assessed using a two-way ANOVA with Dunnett’s multiple comparisons test and statistical differences are represented by (*).
  • (*) p ⁇ 0.05;
  • (**) p ⁇ 0.01;
  • NCC5000-5004 B. longum transitional strains
  • NCC2818 B. animalis subsp. lactis and NCC3001 : B. longum subsp. longum
  • FIG 11 Riboflavin biosynthesis genes present in B. longum transitional strains.
  • Panel A shows the organization of the riboflavin biosynthesis operon as found in B. longum NCC 5000.
  • Panel B depicts a heatmap of those genes in closely related strains of B. longum. Genes are colored according to their % identity found by Blast against the NCC 5000 genes.
  • transitional B. longum transitional strains decrease IL-5 expressed by T helper type 2 skewed cells after 48 hours stimulation to a similar or even greater extent than probiotic B. lactis.
  • NCC5000-5004 B. longum transitional strains
  • NCC2818 B. animalis subsp. lactis
  • NCC3089 B. longum subsp. Infantis.
  • FIG 13 Peripheral blood mononuclear cells (PBMC) were stimulated for 36 hours in the presence of different bacterial strains including all transitional B longum isolates at 10 7 CFU/ml and probiotic strains. Cell culture supernatants were collected to assess cytokine expression for IL-10 by ELISA. Standard curve for each cytokine was used to calculate absolute amount (picogram/ml) from optical density readouts.
  • NCC5000-5004 B longum transitional strains
  • NCC2818 B. animalis subsp. lactis
  • NCC3089 B. longum subsp. infantis
  • NCC4007 L rhamnosus
  • NCC2705 B. longum subsp. longum.
  • FIG 14 In-vitro batch fermentations of 3-fucosylactose (3FL) containing infant microbiome with or without the supplementation of Bifidobacterium longum spp infantis or Bifidobacterium longum transitional.
  • Total SCFAs corresponds to the sum of the peak integrals of acetate, butyrate, and propionate.
  • the bar plot indicates the dynamic of consumption and production of total SCFAs between 0 and 24h (blue bar) and 24 and 48h (red bar).
  • subject refers to a vertebrate, preferably a mammal, more preferably a human.
  • Mammals include but are not limited to murines, simians, humans, farm animals, sport animals and pets.
  • infant means a human subject under the age of 12 months or an age equivalent non-human animal.
  • young child or “toddler” as used herein may mean a human subject aged between 12 months and 5 years of age.
  • a “young child” may refer to an age equivalent non- human animal.
  • complementary feeding period can be interchangeably used and refer to the period during which the milk, either breast milk or formula, is substituted by other foods in the diet of an infant or a young child.
  • the infant or the young child is typically moved or transitioned gradually from exclusive milk-feeding, either breast feeding or formula feeding, to mixed diet comprising milk and/or solid foods.
  • the transitional period depends on the infant or young child but typically falls between about 4 months and about 18 months of age, such as between about 6 and about 18 months of age, but can in some instances extend up to about 24 months or more.
  • glycan substrates are cellulose, which is a glycan composed of (3-1 ,4-linked D-glucose, and chitin, which is a glycan composed of (3-1 ,4-linked N-acetyl-D-glucosamine. Glycans may be homo- or heteropolymers of monosaccharide residues and can be linear or branched. “Glycan substrate” as used herein encompasses, for example, oligosaccharides and polysaccharides.
  • GAG glycosaminoglycan
  • mucopolysaccharide refers to long linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units).
  • the repeating two-sugar unit consists of a uronic sugar and an amino sugar, with the exception of keratan, where in the place of the uronic sugar it has galactose.
  • GAGs are classified into four groups based on core disaccharide structures.
  • “Mucins”, as used herein, may refer to a family of high molecular weight, heavily glycosylated proteins (glycoconjugates). Mucins' key characteristic is their ability to form gels; therefore they are a key component in most gel-like secretions, serving functions from lubrication to cell signaling to forming mechanical and chemical barriers.
  • probiotic means microbial cell preparation or components of microbial cells with a beneficial effect on the health or well-being of the host (Salminen S, Ouwehand A. Benno Y. et al. “Probiotics: how should they be defined” Trends Food Sci. Technol. 1999:10 107-10).
  • the microbial cells according to the present invention are generally bacteria.
  • the “gut microbiota” is the composition of microorganisms (including bacteria, archaea and fungi) that live in the digestive tract.
  • gut microbiome may encompass both the “gut microbiota” and their “theater of activity”, which may include their structural elements (nucleic acid, proteins, lipids, polysaccharides), metabolites (signaling molecules, toxins, organic and inorganic molecules) and molecules produced by coexisting hosts and structured by the surrounding environmental conditions (Berg, G., et al., 2020. Microbiome, 8(1), pp.1-22).
  • B. longum microorganisms belonging to this clade are referred to herein as Bifidobacterium longum transitional (B. longum transitional).
  • NCC 5000, NCC 5001 , NCC 5002, NCC 5003 and NCC 5004 were deposited with the Collection Amsterdam de cultures de micro-organisms (CNCM), Institute Pasteur by SOCIETE DES PRODUITS NESTLE S.A according to Budapest Treaty on 11th of May 2021 receiving the deposit numbers CNCM I-5683, CNCM I-5684, CNCM I-5685, CNCM I-5686 and CNCM I-5687, respectively.
  • the B. longum transitional strain referred to herein as NCC 5025 was deposited with the CNCM, Institute Pasteur by SOCIETE DES PRODUITS NESTLE S.A according to Budapest Treaty on the 29th of March 2023 receiving the deposit number CNCM 1-5942.
  • B. longum transitional microorganisms are greater in relative abundance during the transitional feeding period (e.g. weaning period) than either B. longum subsp. infantis (B. infantis) or B. longum subsp. longum. Indeed, the relative abundance of B. longum subsp. infantis decreases at the beginning of the transitional feeding period until the end of the transitional feeding period while B. longum subsp. longum begins to increase in abundance. Vatanen etal.
  • the B. longum transitional microorganism may encode one or more CAZymes selected from the groups recited in T able 1 .
  • the B. longum transitional microorganism may encode one or two CAZymes selected from the group recited in Table 1 .
  • the B. longum transitional microorganism encodes at least one CAZyme selected from the group recited in Table 1 and one or more of the CAZymes selected from the groups recited in Table 2 and 3.
  • the B. longum transitional microorganism may encode at least 2, at least 5, at least 10, at least 20 or at least 30 of the CAZymes selected from the groups recited in Table 2 and 3.
  • B. longum transitional microorganism encodes (i) at least one CAZyme selected from the group recited in Table 1 and (ii) each of the CAZymes recited in Table 3 or each of the CAZymes recited in Table 3 apart from GH5_44.
  • B. longum transitional microorganism encodes (i) at least one CAZyme selected from the group recited in Table 1 and (ii) each of the CAZymes recited in Table 3 or each of the CAZymes recited in Table 3 apart from GH25.
  • the B. longum transitional microorganism does not encode one or more of the CAZymes recited in Table 4.
  • the B. longum transitional microorganism does not encode any of the CAZymes recited in Table 4.
  • the B. longum transitional microorganism of the present invention advantageously harbors genes coding for CAZymes allowing cleavage of sialic residues from glycans such as sialilated oligosachharides, glycoproteins and glycolipids. This allows effective utilization of the sialylated oligosaccharides that are present in the breast milk at weaning and hence can participate to an appropriate development of the gut microbiome of an infant and/or a young child. It may also help in preventing presence of enteropathogens.
  • a B. longum transitional microorganism comprises a sialidase or neuraminidase family 33 (GH33, sialidase or neuraminidase) gene having at least 60% identity with BLON_2348 gene present in B. longum subsp. infantis ATCC 15697.
  • GH33 sialidase or neuraminidase family 33
  • the B. longum transitional microorganism used according to the present invention comprises a glycosyl hydrolase family 95 (GH95, a-L-galactosidase; a-L- fucosidase; a-1 ,2-L-fucosidase) gene having at least 60% of identity with BLON_2335 gene present in B. longum subsp.
  • GH95 glycosyl hydrolase family 95
  • the B. longum transitional strain has an ANI of at least 98.1%, at least 98.2%, at least 98.3%, at least 98.4%, of at least 98.5%, of at least 98.6%, of at least 98.6 %, of at least 98.7 %, of at least 98.8 %, of at least 98.9 %, of at least 99 %, of at least 99.1 %, of at least 99.2 %, of at least 99.3 %, of at least 99.4 %, of at least 99.5 %, of at least 99.6 %, of at least 99.7 %, of at least 99.8 %, or of at least 99.9 % compared to the B. longum strain deposited with the CNCM under deposit number CNCM I-5942 and has at least one identifying characteristics of the B. Longum transitional strain deposited under deposit number CNCM I-5942 - as described herein.
  • ANI is similar to the aforementioned 70% DDH cutoff value and can be used for species delineation. ANI has been evaluated in multiple labs and has become the gold standard for species delineation (see e.g., Kim et al., 2014, “Towards a taxonomic coherence between average nucleotide identity and 16S rRNA gene sequence similarity for species demarcation of prokaryotes”, Int.
  • the B. longum transitional microorganism is provided as a probiotic.
  • the B. longum transitional microorganism is provided in a composition.
  • allergies in childhood can be the first step of an allergic cascade leading to multiple allergies later in life, a process commonly referred to as the “Atopic March”.
  • children with persistent food hypersensitivity early in life have a dramatically increased risk to develop allergic rhinitis (hay fever) or asthma later in childhood (Ostblom, E. et al. (2008); Phenotypes of food hypersensitivity and development of allergic diseases during the first 8 years of life, Clinical and Experimental Allergy, 38 (8): 1325-1332).
  • the compounds and compositions of the present invention may be used for preventing or treating food allergies, respiratory allergies and dermatological allergies.
  • the allergic disorder is selected from one or more of the group consisting of: a food allergy, a respiratory allergy and a dermatological allergy.
  • the allergic disorder is selected from one or more of the group consisting of: rhinitis, asthma, dermatitis, atopic dermatitis, contact dermatitis, eczema, atopic eczema, urticaria, psoriasis, eosinophilic oesophagitis and an eosinophilic-associated gastrointestinal disease.
  • the allergen in the allergic disorder is selected from one or more of: a food allergen, dust mite, pollen, molds or mold spores, weed pollen, tree pollen, grass pollen, fleas, pet hair, feathers, pollution or pet dander.
  • the allergen in the allergic disorder is a food allergen.
  • the food allergen is selected from: a nut, tree nut, peanut, fish, shellfish, molluscs, crustaceans, milk, egg, soy, gluten, cereals, wheat, oats, barley, rye, celery, corn, lupin, sulphites, sesame, mustard, rice, poultry and meat.
  • the allergen is an aeroallergen.
  • the aeroallergen is selected from dust mite, pollen, moulds or mold spores, weed pollen, tree pollen, grass pollen, fleas, pet hair, feathers, pollution or pet dander.
  • treating, preventing or reducing the risk of an allergy and/or allergic sensitization may refer to reducing or ameliorating one or more symptoms as described herein.
  • a “food allergy” as used herein refers to an abnormal immune response to one or more food allergens, typically an IgE reaction caused by the release of histamine but also encompassing non-lgE immune responses. Symptoms of food allergy may include itchiness, swelling of the tongue, vomiting, diarrhea, hives, trouble breathing, or low blood pressure. When the symptoms are severe, it is known as anaphylaxis.
  • the term “food allergen” refers to proteins or derivatives thereof that cause abnormal immune responses. Purified food allergens may be named using the systematic nomenclature of the Allergen Nomenclature Sub-Committee of the World Health Organization and International Union of Immunological Societies.
  • Allergen names are composed of an abbreviation of the scientific name of its source (genus: 3-4 letters; species: 1-2 letters) and an Arabic numeral, for example Der p 1 for the first allergen to be described from the house dust mite Dermatophagoides pteronyssinus.
  • Food allergens are derived from proteins with a variety of biologic functions, including proteases, ligand-binding proteins, structural proteins, pathogenesis-related proteins, lipid transfer proteins, profilins, and calcium-binding proteins.
  • a list of food allergens is provided on the official website of the WHO/IUIS Allergen Nomenclature Database, http://www.allergen.org/index.php. (Radauer, C., et al., 2014. Allergy, 69(4), pp.413-419 and Pomes, A., et al., 2018. Molecular immunology).
  • GHs catalyze the hydrolysis of glycosidic bonds between two or more carbohydrates or between a carbohydrate and a non-carbohydrate moiety.
  • the hydrolysis of the glycosidic bond is catalyzed by two amino acid residues of the enzyme: a general acid (proton donor) and a nucleophile/base.
  • a general acid proton donor
  • a nucleophile/base a nucleophile/base
  • the present B. Longum transitional strain comprises a glycosyl hydrolase family 43_27 (GH43_27) gene.
  • the GH43_27 gene comprises SEQ ID NO: 13 or a sequence with at least 60% sequence identity to SEQ ID NO: 13.
  • the GH43_27 gene comprises a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 13.
  • the GH43_27 gene may encode a protein shown as SEQ ID NO: 14 or a sequence with at least 80% sequence identity to SEQ ID NO: 14.
  • the protein may comprise a sequence with at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 14.
  • the present B. Longum transitional strain comprises a glycosyl hydrolase family 43_29 (GH43_29) gene.
  • the GH43_29 gene comprises SEQ ID NO: 15 or a sequence with at least 60% sequence identity to SEQ ID NO: 15.
  • the GH43_29 gene comprises a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 15.
  • the present B. Longum transitional strain comprises a glycosyl hydrolase family 121 (GH121) gene.
  • the GH121 gene comprises SEQ ID NO: 17 or a sequence with at least 60% sequence identity to SEQ ID NO: 17.
  • the GH121 gene comprises a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 17.
  • one or more of the arabinan-degrading GHs described herein comprises a signal peptide.
  • a ‘signal peptide’ may refer to a short amino acid sequence, typically present at the N-terminus of a polypeptide, which allows the polypeptide to be secreted out of abacterial cell. Without wishing to be bound by theory, this may advantageously allow the present B. longum transitional strain to act as a primary degrader of complex structures of arabinan when present in high molecular weight, usually in the diet.
  • a ‘primary degrader’ may refer to a bacterium that is capable of depolymerizing specific polysaccharides to mono-, di-, and oligosaccharides that they can take up and ferment themselves to acidic end products such as acetate or lactate.
  • the GH43_22, GH43_27, GH43_29, GH_121 , GH43_24 and/or GH30_5 enzyme may comprise a signal peptide.
  • each of the GH43_22, GH43_27, GH43_29, GH_121 , GH43_24 and GH30_5 enzymes may comprise a signal peptide.
  • the present B. longum transitional strain comprises a glycosyl hydrolase family 127 (GH127) gene.
  • the GH127 gene comprises SEQ ID NO: 21 or a sequence with at least 60% sequence identity to SEQ ID NO: 21.
  • the GH127 gene comprises a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 21 .
  • the GH127 gene may encode a protein shown as SEQ ID NO: 22 or a sequence with at least 80% sequence identity to SEQ ID NO: 22.
  • the protein may comprise a sequence with at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 22.
  • the GH30_5 gene may encode a protein shown as SEQ ID NO: 24 or a sequence with at least 80% sequence identity to SEQ ID NO: 24.
  • the protein may comprise a sequence with at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 24.
  • the present B. longum transitional strain comprises a glycosyl hydrolase family 43_32 (GH42_32) gene.
  • the GH42_32 gene comprises SEQ ID NO: 25 or a sequence with at least 60% sequence identity to SEQ ID NO: 25.
  • the GH42_32 gene comprises a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 25.
  • the B. longum transitional strain comprises one or more genes selected from a
  • the B. longum transitional strain comprises a GH43_17 gene and one or more selected from a GH43_24, GH127, GH30_5, and GH 43_32 gene as defined herein.
  • GH43_29 GH121 , GH43_24, GH127, GH30_5, GH 43_32, as defined herein.
  • the GH31 gene may encode a protein shown as SEQ ID NO: 28 or a sequence with at least 80% sequence identity to SEQ ID NO: 28.
  • the protein may comprise a sequence with at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 28.
  • the present B. longum transitional strain comprises a Lac-I type regulator gene.
  • the Lac-I type regulator gene comprises SEQ ID NO: 35 or a sequence with at least 60% sequence identity to SEQ ID NO: 35.
  • the Lac-I type regulator gene comprises a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 35.
  • the Lac-I type regulator gene may encode a protein shown as SEQ ID NO: 36 or a sequence with at least 80% sequence identity to SEQ ID NO: 36.
  • the protein may comprise a sequence with at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 36.
  • the present B. longum transitional strain comprises a facilitator superfamily (MFS) gene.
  • MFS facilitator superfamily
  • the MFS gene comprises SEQ ID NO: 37 or a sequence with at least 60% sequence identity to SEQ ID NO: 37.
  • the MFS gene comprises a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 37.
  • the MFS gene may encode a protein shown as SEQ ID NO: 38 or a sequence with at least 80% sequence identity to SEQ ID NO: 38.
  • the protein may comprise a sequence with at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 38.
  • the xylose isomerase gene comprises SEQ ID NO: 43 or a sequence with at least 60% sequence identity to SEQ ID NO: 43.
  • the xylose isomerase gene comprises a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 43.
  • the xylulose isomerase gene may encode a protein shown as SEQ ID NO: 44 or a sequence with at least 80% sequence identity to SEQ ID NO: 44.
  • the protein may comprise a sequence with at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to SEQ ID NO: 44.
  • T able 1 provides details of CAZymes that are unique to the Bifidobacterium longum transitional strains (i.e., not encoded by Bifidobacterium longum suis/suillum, Bifidobacterium longum longum or Bifidobacterium longum infantis strains). Table 1 also provides a summary of the glycan substrate metabolized by each CAZyme and illustrative dietary fiber sources/ingredients.
  • the CAZyme referred to in any of Tables 1-4 may comprise or consist of the corresponding sequence shown in Figure 9.
  • the CAZyme may comprise or consist of a variant of the corresponding sequence shown in Figure 9, which variant retains at least one of the functions of the corresponding CAZyme as recited in T able 1 -4.
  • the variant may provide each of the functional activities of the corresponding CAZyme as recited in Table 1-4.
  • the prebiotic for use in the present invention may comprise a combination of glycan substrates selected from the groups recited in any of Tables 1 to 3.
  • the prebiotic may comprise one or more glycan substrates selected from the group recited in Table 1 or Table 2.
  • the prebiotic may comprise at least 2, at least 4, at least 10, at least 20, or at least 30 of the glycan substrates recited in Tables 1 and 2.
  • the prebiotic may comprise each of the glycan substrates recited in Tables 1 and 2.
  • the glycan substrate may comprise or consist of pectin, arabinogalactan and/or starch.
  • the glycan substrate may comprise or consist of pectin.
  • the glycan substrate may comprise or consist of arabinogalactan.
  • the glycan substrate may comprise or consist of starch.
  • the glycan substrate is provided in the form of a dietary fiber.
  • the dietary fiber may be a prebiotic fiber.
  • the glycan substrate may be comprised in an ingredient, for example a dietary ingredient.
  • the semi-purified food ingredient may be a fruit, vegetable or cereal extract.
  • the raw food ingredient may be a fruit, vegetable, cereal, algae or microalgae.
  • the pectin may be comprised in fruit or vegetable pectin.
  • suitable ingredients comprising pectin include, but are not limited to, fruits (e.g., apple, pear), vegetables, legumes (peas), and roots (e.g., sugar beet).
  • suitable purified fibers comprising arabinogalactan include peach pectin.
  • the pectin extracted from sugar beet contains arabinan, galactans and arabinogalactans and may be provided as an ingredient.
  • the prebiotic comprises
  • the prebiotic may comprise between 0.01 g/L to 7 g/L of 3-FL, preferably between 0.025 g/L to 6 g/L of 3-FL, more preferably between 0.05 g/L to 5 g/L of 3-FL.
  • the 3’-O-fucosyllactose (3’FL) comprised in the prebiotic promote the growth of a Bifidobacterium longum transitional microorganism that preferentially utilizes 3- fucosyllactose (3-FL).
  • the invention further provides a combination of a B longum transitional microorganism and a prebiotic for use according to the present invention.
  • the B. longum transitional microorganism and prebiotic may be administered separately, simultaneously or sequentially.
  • the B. longum transitional microorganism and prebiotic may be administered in a combined composition.
  • a combination of a B. longum transitional microorganism and a prebiotic may be referred to as a “synbiotic”.
  • each may be selected such that the B longum transitional microorganism is capable of metabolising the glycan substrate provided in the combination.
  • a selection may be made, for example, by selecting a B. longum transitional microorganism that encodes a CAZyme from the same row of Tables 1-3 as the glycan substrate (or selecting an ingredient comprising said glycan substrate).
  • the combinations of the invention are not limited to requiring that the B. longum transitional microorganism is capable of metabolizing the glycan substrate provided in the combination.
  • any combinations of B. longum transitional microorganism(s) and glycan substrates disclosed herein are encompassed by the invention.
  • the composition comprises one or more glycan substrates as described herein.
  • the composition comprises B. longum transitional preferentially utilizing 3- fucosyllactose (3-FL).
  • the composition may comprise between 10 3 to 10 12 cfu of probiotic strain, more preferably between 10 7 and 10 12 cfu such as between 10 8 and 1O 10 cfu of probiotic strain per g of composition on a dry weight basis mixed with 3-FI in an amount between 0.01 g/L to 7 g/L of 3-FL, preferably between 0.025 g/L to 6 g/L of 3-FL, more preferably between 0.05 g/L to 5 g/L of 3-FL.
  • the B. longum transitional microorganism, prebiotic or synbiotic for use in the present invention may be provided in the form of a composition.
  • the composition may suitably be administered to an individual, for example an infant or a young child, in any suitable form such as a nutritional composition in a dosage unit (for example a tablet, a capsule, a sachet of powder, etc), the composition may be in powder, semi-liquid or liquid form.
  • the composition may be added to a nutritional composition, an infant formula, a food composition, a supplement for infant or young child, a baby food, a follow-up formula, a growing-up milk, an infant cereal or a fortifier.
  • the composition of the present invention is an infant formula, a baby food, an infant cereal, a growing-up milk, a supplement or fortifier that may be intended for infants or young child.
  • the composition may comprise further components which may be beneficial in reducing the risk of developing an allergy and/or allergic reaction.
  • the composition may comprise further components may be beneficial during the weaning period.
  • the B longum transitional microorganism can be included in the composition in an amount from about 10 3 to 10 12 cfu of probiotic strain, more preferably between 10 7 and 10 12 cfu such as between 10 8 and 1O 10 cfu of probiotic strain per g of composition on a dry weight basis.
  • the B. longum transitional microorganism is viable.
  • the B. longum transitional microorganism is non-replicating or inactivated. There may be both viable and inactivated Bifidobacterium longum transitional microorganisms in some other embodiments.
  • the composition comprises one or more glycan substrates as described herein.
  • the composition comprises at least one prebiotic oligosaccharide, preferably 3’-O-fucosyl lactose (3FL).
  • the composition comprises
  • the composition may comprise between 0.01 g/L to 7 g/L of 3-FL, preferably between 0.025 g/L to 6 g/L of 3-FL, more preferably between 0.05 g/L to 5 g/L of 3-FL.
  • the composition comprises Bifidobacterium longum transitional microorganism preferentially utilizing 3- fucosyllactose (3-FL).
  • the composition may comprise between 10 3 to 10 12 cfu of probiotic strain, more preferably between 10 7 and 10 12 cfu such as between 10 8 and 10 1 ° cfu of probiotic strain per g of composition on a dry weight basis mixed with 3-FL in an amount between 0.01 g/L to 7 g/L of 3-FL, preferably between 0.025 g/L to 6 g/L of 3-FL, more preferably between 0.05 g/L to 5 g/L of 3-FL.

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Abstract

Traitement et/ou prévention d'une allergie et/ou d'une sensibilisation allergique. La présente invention concerne un micro-organisme de transition Bifidobacterium longum destiné à être utilisé dans le traitement et/ou la prévention d'une allergie et/ou d'une sensibilisation allergique chez un nourrisson ou un jeune enfant.
PCT/EP2025/050196 2024-01-10 2025-01-07 Utilisations d'un micro-organisme de transition bifidobacterium longum Pending WO2025149453A1 (fr)

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