TWI750342B - Composition comprising a bacterial strain and its use, process of producing and product - Google Patents

Abstract

The present invention provides a strain of Bacteroides thetaiotaomicron and derivatives thereof, and the use of said strain or derivatives in treating inflammatory, autoimmune and allergic disorders. The invention also provides pharmaceutical compositions, nutritional supplements, feedstuffs, food products, dietary supplements, and food additives comprising said strain or derivatives.

Description

Compositions containing strains and their uses, methods of preparation and products

The present invention relates to microorganisms capable of positively regulating inflammatory disorders and useful in therapeutic or preventive medicine.

Bacteroides thetaiotaomicron has potent anti-inflammatory effects in vitro and in vivo. It regulates the molecular signaling pathway of NF-κB. Specifically, it prevents the binding of the active component of NF-κB (RelA) to key genes in the nucleus, thereby preventing the initiation of pro-inflammatory channels (Kelly et al., Commensal anaerobic gut bacteria attenuate inflammation by nuclear regulating-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol. 2004 Jan;5(1):104-12). The whole genome of Bacteroides polymorpha was sequenced and annotated in 2003 by the Gordon Group (Gordon Group) (Washington University School of Medicine, USA) [Xu et al ., A genomic view of the human-Bacteroides thetaiotaomicron symbiosis.Science.2003 Mar 28;299(5615):2074-6].

The present invention is based on the discovery of Bacteroides polymorpha (BT) strains with surprising efficacy against inflammatory disorders. The BT strains are therefore suitable as therapeutics for inflammatory disorders and/or autoimmune disorders and/or allergic disorders or for preventive medicine.

According to a first aspect of the present invention, there is a Bacteroides polymorpha or a derivative thereof deposited under NCIMB Accession No. 42341.

According to a second aspect of the present invention, there is a nutritional supplement comprising Bacteroides polymorpha as defined in claim 1, and a nutritionally acceptable excipient, carrier or diluent.

According to a third aspect of the present invention there is a feed, food product, dietary supplement or food additive comprising Bacteroides polymorpha as defined in claim 1 .

According to a fourth aspect of the present invention, a Bacteroides polymorpha as defined in claim 1, a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, as A nutritional supplement as defined in claim 6 or 7 or a feed, food product, dietary supplement or food supplement as defined in claim 8 or 9 for regulating inflammation in a tissue or organ of an individual.

According to a fifth aspect of the present invention, Bacteroides polymorpha as defined in claim 1, a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, such as A nutritional supplement as defined in claim 6 or 7, or a feed, food product, dietary supplement or food additive as defined in claim 8 or 9, for the treatment and/or prevention of a disorder in an individual; wherein the The disorder is an inflammatory disorder and/or an autoimmune disorder.

According to a sixth aspect of the present invention, a Bacteroides polymorpha as defined in claim 1, a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, as A nutritional supplement as defined in claim 6 or 7, or a feed, food product, dietary supplement or food supplement as defined in claim 8 or 9, for reducing damage to the colon of an individual, preferably the The individual has Inflammatory Bowel Disease (IBD).

According to the seventh aspect of the present invention, the Bacteroides polymorpha as defined in claim 1, the composition as defined in claim 2 or 3, the pharmaceutical composition as defined in claim 4 or 5, as Please A nutritional supplement as defined in claim 6 or 7 or a feed, food product, dietary supplement or food supplement as defined in claim 8 or 9 for reducing the expression of one or more pro-inflammatory genes in the cells of an individual performance in.

According to an eighth aspect of the present invention, a Bacteroides polymorpha as defined in claim 1, a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, as A nutritional supplement as defined in claim 6 or 7 or a feed, food product, dietary supplement or food additive as defined in claim 8 or 9 for increasing regulation in the digestive tract or a part of the digestive tract Percentage of T cells (Treg).

According to the ninth aspect of the present invention, a method for preparing a pharmaceutical composition as claimed in claim 4 or 5, the method comprising the Bacteroides polymorpha with a pharmaceutically acceptable excipient, carrier or dilution agent mixing, wherein the B. polymorpha is optionally encapsulated in the method.

According to a tenth aspect of the present invention, a method for modulating inflammation in a tissue or organ of an individual, wherein the method comprises administering to the individual a Bacteroides polymorpha as defined in claim 1, as in claim 2 or 3 A composition as defined in claim 4 or 5, a pharmaceutical composition as defined in claim 4 or 5, a nutritional supplement as defined in claim 6 or 7 or a feed, food product, as defined in claim 8 or 9, Dietary Supplements or Food Additives.

According to an eleventh aspect of the present invention, a method for treating and/or preventing an inflammatory disorder and/or an autoimmune disorder in an individual, wherein the method comprises administering to the individual an amount as defined in claim 1 Bacteroidetes, a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, a nutritional supplement as defined in claim 6 or 7 or a nutritional supplement as defined in claim 8 or Feed, food product, dietary supplement or food additive as defined in 9.

According to a twelfth aspect of the present invention, a method for reducing damage to the colon of an individual, wherein the method comprises administering to the individual B. polymorpha as defined in claim 1, as in A composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, a nutritional supplement as defined in claim 6 or 7 or as defined in claim 8 or 9 Feed, food product, dietary supplement or food additive, preferably wherein the individual has IBD.

According to a thirteenth aspect of the present invention, a method for reducing the expression of one or more pro-inflammatory genes in cells of an individual, wherein the method comprises administering to the individual B. polymorpha as defined in claim 1 , a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, a nutritional supplement as defined in claim 6 or 7 or as defined in claim 8 or 9 Feed, food product, dietary supplement or food additive as defined.

According to a fourteenth aspect of the present invention, a method for increasing the percentage of regulatory T cells (Treg) in the digestive tract or a portion of the digestive tract, wherein the method comprises administering to an individual an amount as defined in claim 1 Bacteroidetes, a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, a nutritional supplement as defined in claim 6 or 7 or a nutritional supplement as defined in claim 8 or Feed, food product, dietary supplement or food additive as defined in 9.

According to a fifteenth aspect of the present invention, a Bacteroides polymorpha as defined in claim 1, a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, A nutritional supplement as defined in claim 6 or 7, or a feed, food product, dietary supplement or food additive as defined in claim 8 or 9, for the manufacture of a preparation for the regulation of a tissue or organ of an individual Inflammation agent.

According to a sixteenth aspect of the present invention, a Bacteroides polymorpha as defined in claim 1, a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, A nutritional supplement as defined in claim 6 or 7 or a feed, food product, dietary supplement or food additive as defined in claim 8 or 9 for the manufacture of a drug for the treatment and/or prophylaxis of an individual Agents for Inflammatory Disorders and/or Autoimmune Disorders.

According to a seventeenth aspect of the present invention, a Bacteroides polymorpha as defined in claim 1, a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, A nutritional supplement as defined in claim 6 or 7, or a feed, food product, dietary supplement or food supplement as defined in claim 8 or 9, for use in the manufacture for reducing the destruction of the colon in an individual , preferably wherein the subject has IBD.

According to an eighteenth aspect of the present invention, a Bacteroides polymorpha as defined in claim 1, a composition as defined in claim 2 or 3, a pharmaceutical composition as defined in claim 4 or 5, A nutritional supplement as defined in claim 6 or 7, or a feed, food product, dietary supplement or food supplement as defined in claim 8 or 9, for use in the manufacture of a method for reducing one or more pro-inflammatory genes An agent expressed in the cells of an individual.

According to the nineteenth aspect of the present invention, the Bacteroides polymorpha as defined in claim 1, the composition as defined in claim 2 or 3, the pharmaceutical composition as defined in claim 4 or 5, A nutritional supplement as defined in claim 6 or 7 or a feed, food product, dietary supplement or food additive as defined in claim 8 or 9 for the manufacture of a food for use in the augmentation of the digestive tract or the digestive tract An agent that modulates the percentage of T cells (Treg) in a fraction.

The present invention is described with reference to the accompanying drawings, in which:

Figure 1 illustrates reduction of colitis via expansion of Treg cells with Bacteroides polymorpha strain BT2013 in a Dextran sulfate sodium (DSS)-induced colitis model.

Figure 2 illustrates that B. polymorpha strain BT2013 does not affect Treg cells, but affects Teff cells in conventional mice; Figure 3 : illustrates the effects of DSS administration with or without daily intake of B. polymorpha. Myeloperoxidase (MPO) activity in the ileum (a) and cecum (b) of mice

Figure 4 : Illustrates histopathology in the ascending colon of female C57BI/6 mice administered DSS (a) or DSS and B. polymorpha (b).

Figure 5 : Illustrates the mean histopathological tissue score of the ascending colon of mice colonized with B. polymorpha strains E1 and BT2013 during DSS-induced colitis; Figure 6 : Illustrates the pro-inflammatory genes (IL-1β and IL-6 ) and anti-inflammatory gene (IL-10) in the ascending colon of mice treated with B. polymorpha strains E1, E2 and BT2013; Figure 7 : Illustration of IL-8 in Caco-2 incubated with PMA and medium Expression in cells and bacterial cells El, E2 and BT2013.

The present invention is based on the discovery that the BT strain BT2013 has a more potent anti-inflammatory effect than the control BT strain.

The BT strain BT2013 has been deposited with the National Collections of Industrial, Food and Marine Bacteria (NCIMB) on 3 December 2014 under accession number 42341 at NCIMB Ltd, Ferguson Building, Craibstone Estate, Bucksburn, Aberdeen, UK, AB21 9YA. The deposit was made under the terms of the Budapest Treaty. The deposit was made by GT Biologics Ltd. (Life Sciences Innovation Building, Aberdeen, AB25 2ZS, Scotland). GT Biologics Ltd. later changed its name to 4D Pharma Research Limited.

derivative

The present invention encompasses derivatives of the deposited strains. The term "derivative" includes progeny strains (progeny) or strains grown from the original strain (secondary selection) but modified in some way (including at the genetic level) without negatively altering biological activity, i.e., a derivative strain will at least Has the same immunomodulatory activity as the original BT2013 strain.

biotype

The genomic sequence of strain BT2013 is provided in SEQ ID NO:1.

Bacterial strains that are biotypes of the bacteria deposited under Accession No. NCIMB 42341 are also expected to be effective in the treatment or prevention of inflammatory disorders and/or autoimmune disorders and/or allergic disorders. Biotypes are closely related strains with identical or very similar physiological and biochemical characteristics.

In certain embodiments, bacterial strains used in the present invention have at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% of the 16s rRNA sequence of the bacteria deposited under Accession No. NCIMB 42341 Consensus 16s rRNA sequence.

Alternatively, strains that are biotypes of the bacteria deposited under Accession No. NCIMB 42341 and suitable for use in the present invention can be identified by sequencing additional nucleotide sequences of the bacteria deposited under Accession No. NCIMB 42341. For example, substantially the entire genome can be sequenced, and the biotype strain used in the present invention can be in at least 80% of its entire genome (eg, in at least 85%, 90%, 95%, or 99%) , or in its entire genome) have at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% sequence identity. Other sequences suitable for identifying biotype strains may include hsp60 or repeat sequences such as BOX, ERIC, (GTG) ₅ or REP (Masco et al. (2003) Systematic and Applied Microbiology, 26:557-563). The biotype strain may have a sequence that has at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% sequence identity to the corresponding sequence of the bacterium deposited under accession number NCIMB 42341.

In certain embodiments, bacterial strains used in the present invention have a genome with sequence identity to SEQ ID NO:1. In preferred embodiments, the bacterial strain used in the present invention has at least 60% (eg at least 65%, 70%, 75%, 80%, 85%, 95%, 96%, 97%, 98%, 99% or 100%) with at least 90% of SEQ ID NO: 1 Genomes of sequence identity (eg, at least 92%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity). For example, the genome of a bacterial strain used in the present invention may have at least 90% sequence identity to SEQ ID NO: 1 in 70% of SEQ ID NO: 1, or 80% of SEQ ID NO: 1 have at least 90% sequence identity with SEQ ID NO: 1 in SEQ ID NO: 1, or have at least 90% sequence identity with SEQ ID NO: 1 in 90% of SEQ ID NO: 1, or have at least 90% sequence identity with SEQ ID NO: 1 At least 90% sequence identity to SEQ ID NO: 1 in 100%, or at least 95% sequence identity to SEQ ID NO: 1 in 70% of SEQ ID NO: 1, or SEQ ID NO: 1 80% of 1 has at least 95% sequence identity to SEQ ID NO: 1, or 90% of SEQ ID NO: 1 has at least 95% sequence identity to SEQ ID NO: 1, or SEQ ID NO: 1 NO: 1 has at least 95% sequence identity to SEQ ID NO: 1 in 100%, or at least 98% sequence identity to SEQ ID NO: 1 in 70% of SEQ ID NO: 1, or 80% of SEQ ID NO: 1 has at least 98% sequence identity to SEQ ID NO: 1, or 90% of SEQ ID NO: 1 has at least 98% sequence identity to SEQ ID NO: 1, Or have at least 98% sequence identity to SEQ ID NO:1 in 100% of SEQ ID NO:1.

Alternatively, strains that are biotypes of bacteria deposited under Accession No. NCIMB 42341 and suitable for use in the present invention can be identified by depositing using Accession No. NCIMB 42341 and restriction fragment analysis and/or PCR analysis, for example by using fluorescence Amplified Fragment Length Polymorphism (FAFLP) and Repeat DNA Elements (rep) - PCR fingerprinting or protein profiling or partial 16S or 23s rDNA sequencing was performed.

In certain embodiments, strains that are the biotype of the bacteria deposited under Accession No. NCIMB 42341 and suitable for use in the present invention are when analyzed by Amplified Ribosomal DNA Restriction Analysis (ARDRA), such as when using Sau3AI restriction Enzymes (see eg Srůtková et al. (2011) J. Microbiol. Methods, 87(1): 10-6 for exemplary methods and guidance) provide strains of the same model as the bacteria deposited under Accession No. NCIMB 42341. Alternatively, the biotype strain is identified as a strain having the same carbohydrate fermentation profile as the bacterium deposited under Accession No. NCIMB 42341.

Bacterial strains that are biotypes of the bacteria deposited under Accession No. NCIMB 42341 and that are suitable for use in the compositions and methods of the present invention can be identified using any suitable method or strategy. For example, bacterial strains with similar growth patterns, metabolic types and/or surface antigens to those deposited under accession number NCIMB 42341 may be suitable for use in the present invention. The biotype strain will have comparable immunomodulatory activity to the NCIMB 42341 strain. For example, biotype strains will elicit comparable effects on the DSS-induced colitis model and on Treg levels, MPO enzyme activity, inflammation-related gene expression, and colonic histopathology compared to the effects shown in the functional analysis. A comparable effect, which can be identified by using the protocol described in the functional analysis.

disease

Bacteroides polymorpha strain BT2013 can be used to treat and/or prevent a disorder in an individual, wherein the disorder is an inflammatory disorder and/or an autoimmune disorder.

In one embodiment, the disorder affects the digestive tract, a portion of the digestive tract, liver, hepatocytes, immune cells, epithelial cells, epidermal cells, neuronal cells, endothelial cells, fibroblasts, pancreas and/or pancreatic cells (such as pancreatic islets) ).

Examples of portions (ie, components) of the digestive tract include the esophagus, stomach, and intestinal tract such as the small intestine (eg, the duodenum, jejunum, and ileum) and/or the large intestine (eg, the cecum, ascending colon, transverse colon, descending colon, and sigmoid colon).

Examples of epithelial cells include intestinal epithelial cells. Examples of immune cells include dendritic cells, monocytes/macrophages, T cells, and neutrophils.

In one embodiment, the disorder is selected from the group consisting of:

Organ-related disorders such as irritable bowel syndrome (IBS), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), necrotizing enterocolitis, bursitis, celiac disease, multiple Sclerosis (brain), Type I diabetes, Goodpasture's syndrome, Hashimoto thyroiditis, chronic active hepatitis, cardiomyopathy, uveitis and rhinitis.

Systemic disorders such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, psoriasis, atopic dermatitis, vitiligo, multiple sclerosis, alopecia areata, sarcoidosis, polymyositis, and combinations thereof.

In one aspect, the disorder affects the gut.

In one aspect, the disorder is an inflammatory disorder. For example, the disorder is an inflammatory bowel disorder (IBD), such as Crohn's disease.

In one aspect, the disorder is an autoimmune disorder. For example, the autoimmune disorder is selected from the group consisting of ulcerative colitis, capsulitis, rheumatoid arthritis, psoriasis, multiple sclerosis, type 1 diabetes, allergies (including celiac disease), special Atopic dermatitis and rhinitis.

individual

In one embodiment, the individual is a monogastric animal.

Examples of monogastric animals include birds, humans, rats, pigs, dogs, cats, horses, and rabbits.

In another embodiment, the individual is a mammal, such as a monogastric mammal.

Examples of monogastric mammals include omnivores (such as humans, rats, and pigs), carnivores (such as dogs and cats), and herbivores (such as horses and rabbits).

Preferably, the individual is a human.

In one aspect, the individual has a disorder selected from the group consisting of: inflammatory bowel disorder (IBD), colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, type 1 diabetes, celiac disease, atopic dermatitis, rhinitis, irritable bowel syndrome (IBS), ulcerative colitis, bursitis , Crohn's disease, functional dyspepsia, atopic disease, necrotizing enterocolitis, nonalcoholic fatty liver disease, gastrointestinal infections, and combinations thereof. For example, an individual has IBD.

regulation / regulation

The terms "modulate" and "modulate" may be used interchangeably herein.

In one embodiment, Bacteroides polymorpha strain BT2013 is used to modulate inflammation in a cell, tissue or organ of an individual.

In one embodiment, the term "modulate" refers to increasing and/or inducing and/or promoting and/or initiating. In an alternative embodiment, the term "modulate" refers to reducing and/or reducing and/or inhibiting.

In one embodiment, the term "modulate" refers to up-regulation. In an alternative embodiment, the term "modulate" refers to down-regulation.

In one embodiment, Bacteroides polymorpha strain BT2013 as described herein reduces inflammation in a cell, tissue or organ. For example, relieve the digestive tract, a portion (ie, a component) of the digestive tract (such as the gut), liver, hepatocytes, epithelial cells, epidermal cells, neuronal cells, endothelial cells, fibroblasts, pancreas, and/or pancreatic cells (such as pancreatic islets).

In one example, inflammation of the digestive tract or parts thereof, such as the intestinal tract, is reduced.

In another example, inflammation caused by immune cells of a tissue or organ is reduced.

In another example, inflammation caused by tissue or organ epithelial cells is reduced.

The term "inflammation" as used herein refers to one or more of the following: redness, swelling, pain, tenderness, warmth, and cells, tissues or organs due to inflammatory processes triggered by an overreaction of the immune system Functional disruption.

In one embodiment, when and when a strain BT2013 as described herein is administered to an individual The number of inflamed cells in an individual is at least 10%, 20%, 30%, 40% lower after administration of a polypeptide or polynucleotide as described herein or a host cell when compared to the number of inflamed cells in the previous individual or 50%.

In one embodiment, the amount of inflamed tissue or organ in the individual is at least 10% lower after administration of strain BT2013 when compared to the amount of inflamed tissue or organ in the individual prior to administration of strain BT2013 to the individual, 20%, 30%, 40% or 50%.

In one embodiment, strain BT2013 reduces inflammation caused by tissue or organ epithelial cells.

For example, the epithelial cells are the epithelial cells of the digestive tract or parts thereof, such as the gut.

Without wishing to be bound by theory, strain BT2013 increases the production of T cells, such as regulatory T cells, which may also be referred to as Tregs, in an individual. This increase in Treg numbers may counteract the effects of other effector T cells (also known as Teffs, such as Th1, Th17 and Th2) that drive inflammation, autoimmunity and allergic/atopic conditions. In Crohn's disease and ulcerative colitis, Teff/Treg cell balance is lost.

In one embodiment, the production of T cells in the individual is increased such that upon administration of a polypeptide or polynucleotide as described herein or a host, when compared to the number of T cells in the individual prior to administration of strain BT2013 to the individual The cells are followed by at least 10%, 20%, 30%, 40% or 50% more T cells, or more than 100% more T cells.

Intestinal barrier integrity

In one embodiment, strain BT2013 is used to improve intestinal barrier integrity in an individual.

The term "improved gut barrier integrity" as used herein refers to the number and/or type of microorganisms that spread from the gut to other cells in an individual prior to administration of strain BT2013 as described herein, After administration of strain BT2013, spread from the gut to others in individuals Decreased number and/or type of microorganisms in cells.

In one embodiment, after administration of strain BT2013, the number of microorganisms in an individual that diffuses from the gut to other cells when compared to the number of microorganisms that diffuse from the gut to other cells in the individual prior to administration The number is at least 10%, 20%, 30%, 40% or 50% lower.

In one embodiment, after administration of strain BT2013, there are fewer types of microorganisms in an individual that diffuse from the gut to other cells when compared to the types of microbes that diffused from the gut to other cells in the individual prior to administration At least 5%, 10%, 15% or 20%.

gut damage

In one embodiment, strain BT2013 is used to reduce disruption of the gut (eg, large intestine) of an individual, such as an individual with IBD.

The term "disruption of the gut of an individual" as used herein refers to the effect on the integrity of the mucosal epithelium and/or on the number of goblet cells in the epithelium and/or on the number of immune cells infiltrating the lamina propria Influence.

In one embodiment, strain BT2013 reduces or prevents disruption of the integrity of the mucosal epithelium and/or reduces or prevents a reduction in the number of goblet cells in the epithelium and/or reduces or prevents immune cell infiltration into the lamina propria.

In one embodiment, the reduction in disruption of the integrity of the mucosal epithelium is, after administration of strain BT2013, a The number of bacteria penetrating intestinal cells is reduced by at least 5%, 10%, 15% or 20%.

In one embodiment, the reduction in the number of goblet cells in the epithelium is the number of goblet cells in the epithelium of an individual after administration of strain BT2013 when compared to the number of goblet cells in the epithelium of the individual prior to administration Reduce by at least 2%, 5%, 10%, 15% or 20%.

In one embodiment, immune cell infiltration into the lamina propria is reduced such that after administration of strain BT2013, when compared to the number of immune cells (eg, T cells) penetrating the lamina propria cells in the individual prior to administration , the number of immune cells (eg, T cells) penetrating the lamina propria cells is reduced by at least 5%, 10%, 15%, 20% or 30% over a fixed period of time (such as 24 hours).

Pro-inflammatory genes and barrier integrity genes

In one embodiment, strain BT2013 is used to modulate the expression of one or more pro-inflammatory genes and/or one or more barrier integrity genes in cells of an individual.

In one embodiment, the term "modulate" refers to the up-regulation of the expression of one or more pro-inflammatory genes. In an alternative embodiment, the term "modulate" refers to down-regulation of the expression of one or more pro-inflammatory genes.

In one embodiment, strain BT2013 downregulates the expression of one or more pro-inflammatory genes in cells of the individual.

The term "pro-inflammatory gene" as used herein refers to a gene that promotes inflammation when expressed. Examples of pro-inflammatory genes include, but are not limited to, genes encoding IL1-beta, IL4, IL5, IL6, IL8, IL12, IL13, IL17, IL21, IL22, IL23, IL27, IFN, CCL2, CCL3, CCL5, CCL20, CXCL5, CXCL10, CXCL12, CXCL13 and TNF-α.

In one embodiment, the pro-inflammatory gene is selected from the group consisting of IL1-beta, IL6, and IL8.

In one embodiment, the expression level (eg, mRNA level) of one or more pro-inflammatory genes is reduced (ie, down-regulated) such that after administration of strain BT2013, the level is low when compared to the level in the individual prior to administration At least 10%, 20%, 30%, 40% or 50%.

The term "barrier integrity gene" as used herein refers to a gene that, when expressed, plays a role in barrier function of the gut, such as repairing the barrier and preventing microorganisms from passing through the barrier. Examples of barrier integrity genes include genes encoding Retnlg|Retnlb, Si, Defa24, Hsd11b2, Hsd17b2, and Nr1d1|Thra.

In one embodiment, the term "modulate" refers to the up-regulation of the expression of one or more barrier integrity genes. In an alternative embodiment, the term "modulate" refers to the down-regulation of the expression of one or more barrier integrity genes.

In one embodiment, strain BT2013 upregulates expression of barrier integrity genes in cells of an individual

In one embodiment, the barrier integrity genes are selected from the group consisting of: Retnlg|Retnlb, Si, Defa24, Hsd11b2, Hsd17b2, and Nr1d1|Thra.

In one embodiment, the expression level (eg, mRNA level) of one or more barrier integrity genes is increased (ie, up-regulated) such that after administration of strain BT2013, the level is increased (ie, up-regulated) when compared to the level in the individual prior to administration At least 10%, 20%, 30%, 40% or 50% higher.

digestive tract

Components of the digestive tract include the esophagus, stomach, and intestinal tract (such as the small intestine (eg, the duodenum, jejunum, and ileum) and/or the large intestine (eg, the cecum, ascending colon, transverse colon, descending colon, and sigmoid colon)).

Herein, the term "large intestine" may be used interchangeably with the term "colon".

In one embodiment, strain BT2013 is used to improve digestive tract health in an individual.

The term "improving digestive tract health" as used herein refers to reducing the degree of inflammation in the digestive tract or components thereof and/or improving the gut microbiota.

In one embodiment, after administration of strain BT2013, the degree of inflammation in the digestive tract is at least 10%, 20%, 30%, 40% or 50%.

In one embodiment, strain BT2013 is used to improve the gut microbiota of an individual.

The term "gut microbiota" as used herein refers to the microorganisms that live in the digestive tract of a host animal. These microorganisms perform a variety of metabolic, structural, protective and other beneficial functions.

As used herein, the term "modified gut microbiota" refers to increasing the number and/or type of desired microorganisms present in the gut of an individual (eg, a host), and/or increasing the metabolism, structure of such desired microorganisms , protective and other beneficial functions. The term "modified gut microbiota" may also refer to reducing the number and/or type of unwanted microorganisms present in the gut of an individual (eg, host), and/or reducing the Activity in protective and other beneficial functions.

The microorganisms required in the host gut are those with protective and beneficial functions. Firmicutes and Bacteroidetes are examples of desirable microorganisms in the host gut.

Unwanted microorganisms in the host gut are those microorganisms that may interfere with the metabolism, structure, protection and other beneficial functions of desired microorganisms in the gut with protective and beneficial functions. Alternatively or additionally, unwanted microorganisms are those that cause, for example, inflammation and/or diarrhea. Escherichia coli ( E.coli ) is an example of an unwanted microorganism in the host gut.

For example, once strain BT2013 has been administered to an individual, in individuals with inflammatory bowel disease (IBD), desired microbes in the gut (such as Firmicutes and Bacteroidetes) and non-specific bacteria can be produced. Changes in microbiota balance among desired microorganisms such as E. coli: ETEC, EPEC, EIEC, EHEC and EAEC.

In one embodiment, the number of desired microorganisms (such as Firmicutes and Bacteroidetes) present in the gut of an individual (eg, host) is increased such that, compared to the level in the individual prior to administration, there is a After administration of strain BT2013, the number of microorganisms increased by at least 10%, 20%, 30%, 40% or 50%, or higher than 100%. Alternatively or additionally, the types of desired microorganisms (such as Firmicutes and Bacteroidetes) present in the gut of an individual (eg, host) are increased such that upon administration, when compared to the types in the individual prior to administration. After strain BT2013, the types of microorganisms were increased by at least 2%, 5%, 10% or 15%.

In one embodiment, the number of unwanted microorganisms (such as E. coli ETEC, EPEC, EIEC, EHEC, and EAEC) present in the gut of an individual (eg, host) is reduced such that the level when compared to the level in the individual prior to administration When compared, the number of microorganisms was at least 10%, 20%, 30%, 40% or 50% lower after administration of strain BT2013. Alternatively or additionally, the types of unwanted microorganisms (such as E. coli ETEC, EPEC, EIEC, EHEC, and EAEC) present in the gut of an individual (eg, host) are reduced such that when compared to the type in the individual prior to administration At least 1%, 2%, 5% or 10% fewer types of unwanted microorganisms after administration of strain BT2013.

encapsulation

In one embodiment, the Bacteroides polymorpha strain BT2013 is encapsulated.

In another embodiment, the pharmaceutical composition comprising strain BT2013 is encapsulated.

In another embodiment, the nutritional supplement comprising strain BT2013 is encapsulated.

In another embodiment, the feed, food product, dietary supplement or food additive as described herein is encapsulated.

The term "encapsulation" as used herein refers to protection by physical separation such that strain BT2013 can be delivered to a target site (eg, the gut) without degradation or significantly degraded so that it can affect the target site Means that strain BT2013 is not affected by incompatible environments. An example is an enteric-coated capsule or an enteric-tolerant capsule.

Protection against desired effects even when the purpose of encapsulation is to isolate the strain from its environment The sexual coating or shell must also be ruptured. Rupture of the protective coating or shell is typically caused by the application of chemical and physical stimuli, such as pressure, enzymatic attack, chemical reactions, and physical disintegration.

For example, encapsulation ensures that ingestible strains are delivered to a target site (eg, the gut) in an amount that allows the microorganism to be effective at the target site.

pharmaceutical composition

In one embodiment, the pharmaceutical composition comprises the microorganism of strain BT2013 and optionally a pharmaceutically acceptable excipient, carrier or diluent.

The pharmaceutical composition can be any pharmaceutical composition. In one aspect, the pharmaceutical composition is to be administered orally, enterally or rectally. For example, the composition can be an edible composition. "Edible" means that the material is approved for human or animal consumption.

The pharmaceutical compositions can be used for human or animal use in human and veterinary medicine.

Examples of such excipients suitable for use in the various forms of pharmaceutical compositions described herein can be found in "Handbook of Pharmaceutical Excipients", ed. by A Wade and PJ Weller, 2nd Edition, (1994).

Carriers or diluents acceptable for therapeutic use are well known in the art of medicine and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (Ed. A.R. Gennaro 1985).

Examples of suitable carriers include lactose, starch, dextrose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like.

Examples of suitable diluents include one or more of the following: water, ethanol, glycerol, propylene glycol, and glycerin, and combinations thereof.

The choice of pharmaceutical carrier, excipient or diluent can be selected taking into account the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions may be included as carriers, excipients or diluents or in addition to Any suitable binders, lubricants, suspending agents, coatings, solubilizers other than agents, excipients or diluents.

Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate ), carboxymethyl cellulose and polyethylene glycol.

Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

Preservatives, stabilizers, dyes and even flavoring agents can be provided in the pharmaceutical compositions. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

In one aspect, the microorganism of the pharmaceutical composition of strain BT2013 is encapsulated.

The medicament can be in solution form or in solid form, depending on the use and/or mode of application and/or mode of administration.

As used herein, the term "pharmaceutical agent" encompasses both human and veterinary pharmaceutical agents for both human and animal use. Furthermore, the term "agent" as used herein means any substance that provides a therapeutic and/or beneficial effect. The term "agent" as used herein is not necessarily limited to substances requiring marketing approval, but may include substances that can be used in cosmetics, nutritional products, foods (including, for example, feeds and beverages), probiotic cultures, nutritional supplements, and natural remedies. Furthermore, the term "pharmaceutical" as used herein encompasses products designed for incorporation into animal feed, such as livestock feed and/or pet food.

nutritional supplements

Nutritionally acceptable carriers, diluents and excipients include those suitable for human or animal consumption and used as standards in the food industry. Typical nutritionally acceptable carriers, diluents and excipients will be familiar to those skilled in the art.

In one embodiment, the nutritional supplement comprises a microorganism of strain BT2013 or a host cell comprising an expression vector comprising the polynucleotide sequence and a nutritionally acceptable excipient, carrier or diluent.

In one example, the microorganisms of strain BT2013 are encapsulated.

Feed/Product

Another aspect of the present invention relates to feedstuffs, food products, dietary supplements and food additives comprising microorganisms of strain BT2013.

The terms "feed", "food product", "food additive" and "dietary supplement" as used herein are intended to cover all consumable products that may be solid, jelly-like or liquid.

The term "food product" is used in a broad sense and covers food for humans as well as food for animals (ie, feed). In one aspect, the food product is for human consumption. Examples of food products include dairy products (such as milk, cheese, beverages containing whey protein, milk drinks, lactic acid bacteria drinks, curds, drinking curds), bakery products, beverages, and beverage powders.

"Feed", "food product", "food additive" and "dietary supplement" may be in solution or solid form, depending on the use and/or mode of application and/or mode of administration.

As used herein, the term "dietary supplement" includes formulations that are or can be added to a food product or feed as a nutritional supplement. The term "dietary supplement" as used herein also refers to a variety of products that can be used at low levels in a variety of products that require gelling, texturing, stabilization, suspending, film-forming and structuring, maintaining juiciness and improving mouthfeel without increasing viscosity of the preparation.

Suitable food products may include, for example, functional food products, food compositions, pet food, livestock feed, health food, feed, and the like. In one aspect, the food product is a health food.

As used herein, the term "functional food product" means a food that not only provides a nutritional effect but also delivers another beneficial effect to the consumer. Thus, functional foods are ordinary foods that have components or ingredients (such as those described herein) incorporated into them to impart a specific function (eg, medical or physiological benefit) to the food in addition to a purely nutritional effect.

Examples of specific food products suitable for use in the present invention include milk-based products for human use, ready-to-eat desserts, powders for reconstitution with, for example, milk or water, chocolate milk drinks, malt drinks, ready-to-eat dishes, instant meals A dish or drink or a food composition representing all or part of a meal intended for pets or livestock.

In one aspect, the feed, food product, dietary supplement or food additive according to the present invention is intended for use by humans, pets or livestock, such as monogastric animals. Feeds, food products, dietary supplements or food additives may be intended for use by animals selected from the group consisting of dogs, cats, pigs, horses or poultry. In another embodiment, the food product, dietary supplement or food additive is intended for use by an adult species, particularly an adult human.

The term "milk-based product" as used herein means any liquid or semi-solid milk or whey based product with varying fat content. Milk-based products can be, for example, cow's milk, goat's milk, sheep's milk, skim milk, whole milk, powdered milk and whey without any processing, or processed products such as yogurt, curd, curd , yogurt, sour milk, buttermilk and other yogurt products. Another important group includes milk beverages, such as whey beverages, fermented milk, concentrated milk, infant or baby milk; flavored milk, ice cream; milk-containing foods, such as sweets.

The feeds, food products, dietary supplements or food additives of the present invention can be or can be added to food supplements, which are also referred to herein as dietary or nutritional supplements or food additives.

Feeds, food products, dietary supplements or food additives according to the present invention can also be used for In animal nutrition (eg in pig nutrition), especially during early weaning and growth and fattening. Feeds, food products, dietary supplements or food additives are expected to enhance immune function, mitigate and prevent infectious diseases, favorably alter microbiota composition, and improve animal growth and performance, such as through increased feed conversion efficiency.

In one embodiment, the feed, food product, dietary supplement or food additive is encapsulated.

Active Biotherapeutic Products

The microorganism of strain BT2013 can be used or used as an active biotherapeutic product (LBP).

In one aspect, the LBP is a metabolically active orally administrable composition, ie, live and/or lyophilized or inactive heat-killed, irradiated or lysed bacteria. LBP may contain other ingredients. LBP can be administered orally, ie in tablet, capsule or powder form. The LBP may additionally comprise other bacterial species, such as the bacterial species R. hominis . The encapsulated product helps R. hominis because it is an anaerobic bacteria. Other ingredients, such as vitamin C, may be included as oxygen scavengers and substrates (such as those that improve colonization and in vivo survival). Alternatively, the LBPs of the present invention can be administered orally as a food or nutritional product, such as a milk- or whey-based fermented dairy product, or as a pharmaceutical product.

A suitable daily dose of bacteria in LBP is from about 1 x 10 ³ to about 1 x 10 ¹² colony forming units (CFU); eg, from about 1 x 10 ⁷ to about 1 x 10 ¹⁰ CFU; in another example, about 1 x 10 ⁶ to about 1 x 10 ¹⁰ CFU.

In one aspect, the LBP contains the bacterial species in an amount from ^{about 1×10 6} to about 1×10 ¹² CFU/g relative to the weight of the composition; eg, from about 1×10 ⁸ to about 1×10 ^{10 CFU/g} and/or cellular components thereof as active ingredients. Typically, LBP is optionally combined with at least one suitable prebiotic compound. Prebiotics are generally non-digestible carbohydrates, such as oligo- or polysaccharides, or sugar alcohols, which are not degraded or absorbed in the upper digestive tract. Known prebiotics include commercial products such as inulin and transgalacto-oligosaccharides.

In one aspect, the LBP of the present specification includes the prebiotic in an amount of about 1 to about 30 wt % (eg, 5 to 20 wt %) relative to the total weight of the composition. The carbohydrate may be selected from the group consisting of: fructose-oligosaccharide (or FOS), short-chain fructose-oligosaccharide, inulin, isomalt-oligosaccharide, pectin, xylose-oligosaccharide (or XOS), shell Glycan-oligosaccharide (or COS), beta-glucan, acacia modified and resistant starch, polydextrin, D-tagatose, acacia fiber, carob, oat and citrus fiber. In one aspect, the prebiotic is a short-chain fructose-oligosaccharide (shown below as FOSs-cc for simplicity); the FOSs-cc are not digestible carbohydrates, typically obtained by conversion of beet sugars and Including sucrose molecules bound by three glucose molecules.

Dosing

The pharmaceutical composition, nutritional supplement, feed, food product, dietary supplement or food additive of the present invention may be suitable for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial , subcutaneous, intradermal, intravenous, intranasal, buccal or sublingual routes of administration.

In one aspect, the pharmaceutical composition, nutritional supplement, feed, food product, dietary supplement or food additive of the present invention is suitable for oral, rectal, vaginal, parenteral, intranasal, buccal or sublingual administration way.

In another aspect, the pharmaceutical composition, nutritional supplement, feed, food product, dietary supplement or food additive of the present invention is suitable for oral administration.

For oral administration, specific uses consist of compressed tablets, pills, lozenges, capsules, drops and capsules.

Other forms of administration include solutions or emulsions, which may be intravenous, intraarterial, intrathecal, dermal subcutaneous, intraperitoneal, or intramuscular injection, and are prepared from sterile or sterilizable solutions. The pharmaceutical compositions of the present invention may also be in the form of suppositories, pessaries and suspensions. Pharmaceutical compositions, nutritional supplements, feeds, food products, dietary supplements, or food additives can be formulated in unit dosage form, ie, in the form of discrete portions containing a unit dose or a plurality of units or subunit elements of a unit dose.

dose

An appropriate dose of strain BT2013 to administer to an individual can be readily determined by one of ordinary skill in the art without undue experimentation. Typically, the physician will determine the actual dose that will be most appropriate for the individual patient and it will depend on a variety of factors including the activity of the strain used, the metabolic stability and length of action of the strain, age, body weight, general health, sex , diet, mode and time of administration, rate of excretion, drug combination, severity of a particular condition, and subject undergoing treatment. The dosages disclosed herein exemplify the general situation. There may of course be individual cases deserving higher or lower dosage ranges and such cases are within the scope of this invention.

combination

In one aspect, the microorganism of strain BT2013 is administered in combination with one or more other active agents. In such cases, the microorganism of strain BT2013 can be administered consecutively, simultaneously or sequentially with one or more other active agents.

Functional Analysis:

In vivo model

C57BL/6 mice (6 weeks old) were used to evaluate the therapeutic effect of B. polymorpha strains El, E2 and BT2013 during DSS-induced colitis. Mice were colonized with one of the B. polymorpha strains and then treated with DSS. Animals were euthanized and intestinal tissue sampling was performed. The small intestine was collected for immunoassay by flow cytometry and measurement of myeloperoxidase (MPO) enzymatic activity. The ascending colon was aliquoted and transferred into neutral buffered formalin (NBF; Sigma-Aldrich) For tissue analysis or RNAlater (Ambion) for molecular analysis.

Flow cytometric analysis of T cell populations in the lamina propria of the small intestine was performed (Figures 1 and 2). DSS and B. polymorpha treatment alone did not affect the overall percentage of the CD3+CD4+CD8 population. Populations affected by DSS and B. polymorpha alone were Treg (CD25+FoxP3+* and FR4 ^hi CD25+*) and Teff cells (FR4 ^lo CD25+*) (Figures 1 and 2). The percentage of Tregs was increased in mice treated with B. polymorpha strain BT2013 compared to DSS alone. Strain E1W did not appear to have any effect on Treg (Figure 1). The effect of BT2013 on Tregs was only evident in mice co-treated with DSS. The strain had no effect on Tregs in untreated mice, but affected the Teff cell population (Figure 2).

The enzymatic activity of MPO was determined in the ileum and cecum (Figures 3a and 3b). MPO is a pro-inflammatory enzyme that is stored in cyanophilic granules of neutrophils. MPO is used as an indicator of inflammation, especially neutrophil recruitment and accumulation. The detection of lower levels of MPO activity in ileal or cecal tissue samples from B. polymorpha/DSS-treated mice compared to DSS alone is indicative of reduced neutrophil recruitment and thus reduced inflammation.

Tissue analysis was performed on the ascending colon (Figures 4 and 5 and Table 1). The histopathological grading algorithm is based on the Berg et al. 1996 guidelines, which are summarized as follows:

= Shallow crypts, no or little infiltrating inflammatory cells, intact epithelium, goblet cells appearing to be filled with mucin. That is, no disease.

= Crypts may exhibit slight epithelial hyperplasia, some diffuse infiltrating inflammatory cells are seen between crypts, luminal epithelium appears intact, and goblet cells may appear slightly reduced in mucin.

2 = Crypts appear deeper and have clear evidence of epithelial hyperplasia, goblet cells are depleted of mucin, infiltrating inflammatory cells are evident and may be multifocal in nature, although no infiltration is seen in the submucosa.

3 = Lesions involving a larger area of mucosa and/or more frequently than seen in grade 2. The lesions do not involve the submucosa. The luminal epithelial cells exhibit small-scale erosions. The lesion is not transmural.

4 = Crypt epithelium appears eroded. Abscesses may be present. The luminal epithelium appears irregular and sometimes completely lost. Transmural infiltration was observed - this was often associated with complete loss of epithelial cells into the lumen.

The damage to the colon due to DSS-induced colitis was significantly reduced by treating mice with B. polymorpha strains El, E2 and BT2013. Expression of inflammation-related genes in the ascending colon was reduced in mice colonized with B. polymorpha compared to mice treated with DSS alone. Strain E1 and BT2013 greatly reduced IL1B and IL6 inflammatory gene expression compared to strain E2. (Image 6)

In vitro models

In the presence of B. polymorpha strains El, E2 and BT2013, the expression of IL-8-induced inflammatory genes in intestinal epithelial cells following PMA exposure was modulated (Figure 7).

Strain BT2013 genome sequencing

DNA samples from strain BT2013 were sequenced on MiSeq (v2 nano 2x250bp) using the Nextera XT library for rapid fragmentation and tagged with sequencing adapters, resulting in a total of 4605120 reads (1115615927 bases).

The following summarizes the data analysis:

a. Map to reference sequences (NC_004663 and NC_004703) using bowtie2 (2.2.2)

b. Use VarScan (2.3.7) and SNVer (0.5.3) for SNV and small InDel detection (calling) to perform common detection to avoid false positives

c. Annotate the variant with the reference gff

d. Use pindel (0.2.5a3) for large InDel detection

e. De novo assembly of unmapped reads using SOAPdenovo (2.04)

f. Blast the assembled contigs to the NCBI nucleotide database

g. Subsample all read lengths of the sample to 50%

h. De novo assembly of subsampled reads using SOAPdenovo (2.04)

Sequences were mapped to reference sequences (NC_004663 and NC_004703) using bowtie2 (2.2.2). During sequencing, VarScan (2.3.7) and SNVer (0.5.3) were used to identify nucleotide variations and small insertions and/or deletions to avoid false positives, and variations were annotated with reference sequences. Large indels were identified using pindel (0.2.5a3). Unmapped reads were assembled from scratch using SOAPdenovo (2.04). The sequenced fragments were reassembled into contigs, which were blast aligned to the NCBI nucleotide database. All sample reads were subsampled to 50% and then assembled de novo using SOAPdenovo (2.04) to provide a tandem version of BT2013 de novo sequence assembly.

sequence

SEQ ID NO: 1 (tandem version of BT2013 de novo sequence assembly) - see Sequence Listing.

【Biological Material Deposit】

Domestic storage information [please note in the order of storage institution, date and number]

1. Food Industry Development Institute; 14 Apr 105; BCRC 910727

Foreign deposit information [please note in the order of deposit country, institution, date and number]

1. United Kingdom; National Collections of Industrial, Food and Marine Bacteria (NCIMB); 3 December 2014; NCIMB 42341

Claims (26)

A composition comprising a derivative strain of a Bacteroides thetaiotaomicron strain deposited in the Food Industry Development Institute of a consortium with deposit number BCRC 910727, wherein the 16s rRNA of the derivative strain is deposited with the consortium under deposit number BCRC 910727 The 16s rRNA of Bacteroides polymorpha has at least 99.5% sequence identity, wherein the derivative strain is used in mouse ascending colon tissue samples treated with Bacteroides polymorpha/dextran sulfate sodium (DSS). The reduced expression of IL1-β and/or IL6 of IL1-β and/or IL6 is comparable to that caused by the following strains: Polymorphism deposited with the Institute of Food Industry Development, a consortium under accession number BCRC 910727 Bacillus. The composition of claim 1 , wherein the derivative strain has a dextran sodium sulfate (DSS)-induced colitis model, regulates T cell (Treg) levels, myeloperoxidase (MPO) enzyme activity, inflammation-related gene expression And the efficacy in colon histopathology is comparable to that of Bacteroides polymorpha deposited with the Food Industry Development Institute under the accession number BCRC 910727. The composition of claim 1 or 2, wherein the derivative strain is encapsulated. The composition of claim 1 or 2, wherein the composition is a pharmaceutical composition, which further comprises a pharmaceutically acceptable excipient, carrier or diluent. A use of the composition according to any one of claims 1 to 4 for the preparation of a medicament for the treatment or prevention of inflammatory disorders and/or autoimmune disorders and/or allergic disorders. The use of claim 5, wherein the disorder affects the digestive tract, a part of the digestive tract and/or epithelial cells. The use of claim 5 or 6, wherein the disorder is selected from the group consisting of inflammatory bowel disorder (IBD), colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, type I diabetes, celiac disease Disease, atopic dermatitis, rhinitis, irritable bowel syndrome (IBS), ulcerative colitis, bursitis, Crohn's disease, functional dyspepsia, atopic disease, necrotizing enterocolitis, nonalcoholic Fatty liver disease, gastrointestinal infections, and combinations thereof. A use of the composition of any one of claims 1 to 4 for the preparation of a medicament for reducing inflammation in a tissue or organ. The use of claim 8, wherein the derivative strain reduces inflammation caused by epithelial cells of the tissue or organ. The use of claim 9, wherein the epithelial cells are digestive tract epithelial cells. A use of a composition as claimed in any one of claims 1 to 4 for the manufacture of a medicament for reducing the destruction of the colon in an individual. The use of claim 11, wherein the individual has IBD. The use of claim 11 or 12, wherein the derivative strain: a) reduces or prevents damage to the integrity of the mucosal epithelium; b) reduces or prevents a reduction in the number of goblet cells in the epithelium; and/or c) reduces or prevents Immune cells infiltrated into the lamina propria. Use of a composition as claimed in any one of claims 1 to 4 for the manufacture of a medicament for reducing the expression of one or more pro-inflammatory genes in cells of an individual. The use of claim 14, wherein the pro-inflammatory genes are selected from the group consisting of IL1-beta, IL6, IL8, IL10, and combinations thereof. The use according to claim 14 or 15, wherein the cells are digestive tract cells or epithelial cells. The use of claim 16, wherein: the digestive tract cells are cells of the ascending colon; or the epithelial cells are intestinal epithelial cells. A use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for increasing the percentage of regulatory T cells (Treg) in the digestive tract or a part of the digestive tract. The use of claim 18, wherein the portion of the digestive tract is the lamina propria of the small intestine. A method for preparing the composition of claim 4, the method comprising the derivative strain Mixed with a pharmaceutically acceptable excipient, carrier or diluent. The method of claim 20, wherein in the method, the derivative strain is encapsulated. A nutritional supplement comprising the composition of any one of claims 1 to 4. A feed comprising the composition of any one of claims 1 to 4. A food product comprising the composition of any one of claims 1 to 4. A dietary supplement comprising the composition of any one of claims 1 to 4. A food additive comprising the composition of any one of claims 1 to 4.

Images