OA18660A - Compositions comprising bacterial strains. - Google Patents

Abstract

The invention provides compositions comprising bacterial strains for treating and preventing inflammatory and autoimmune diseases.

Description

COMPOSITIONS COMPRISING BACTERIAL STRAINS

TECHNICAL FIELD

This invention is in the field of compositions comprising bacterial strains isolated from the mammalian digestive tract and the use of such compositions in the treatment of disease.

BACKGROUND TO THE INVENTION

The human intestine is thought to be stérile in utero, but it is exposed to a large variety of maternai and environmental microbes immediately after birth. Thereafter, a dynamic period of microbial colonization and succession occurs, which is infiuenced by factors such as delivery mode, environment, diet and host génotype, ail of which impact upon the composition of the gut microbiota, particularly during early life. Subsequently, the microbiota stabilizes and becomes adult-like [1]. The human gut microbiota contains more than 500-1000 different phylotypes belonging essentially to two major bacterial divisions, the Bacteroidetes and the Firmicutes [2], The successful symbiotic relationships arising from bacterial colonization of the human gut hâve yielded a wide variety of metabolic, structural, protective and other bénéficiai fiinctions. The enhanced metabolic activities of the colonized gut ensure that otherwise indigestible dietary components are degraded with release of by-products providing an important nutrient source for the host. Similarly, the immunological importance of the gut microbiota is well-recognized and is exemplified in germfree animais which hâve an impaired immune System that is functionally reconstituted following the introduction of commensal bacteria [3-5].

Dramatic changes in microbiota composition hâve been documented in gastrointestinal disorders such as inflammatory bowel disease (IBD). For example, the levels of Clostridium cluster XlVa bacteria are reduced in IBD patients whilst numbers of E. coli are increased, suggesting a shift in the balance of symbionts and pathobionts within the gut [6-9], Interestingly, this microbial dysbiosis is also associated with imbalances in T effector cell populations.

In récognition of the potential positive effect that certain bacterial strains may hâve on the animal gut, various strains hâve been proposed for use in the treatment of varions diseases (see, for example, [10-13]). Also, certain strains, including mostly Lactobacillus and Bifidobacterium strains, hâve been proposed for use in treating various inflammatory and autoimmune diseases that are not directly linked to the intestines (see [14] and [15] for reviews). However, the relationship between different diseases and different bacterial strains, and the précisé effects ofparticular bacterial strains on the gut and at a systemic level and on any particular types of diseases, are poorly characterised.

There is a requirement in the art for new methods of treating inflammatory and autoimmune diseases. There is also a requirement for the potential effects of gut bacteria to be characterised so that new thérapies using gut bacteria can be developed.

SUMMARY OF THE INVENTION

The inventors hâve developed new thérapies for treating and preventing inflammatory and autoimmune diseases. In particular, the inventors hâve developed new thérapies for treating and preventing diseases and conditions mediated by IL-17 or the Th 17 pathway. In particular, the inventors hâve identified that bacterial strains from the genus Parabacteroides can be effective for reducing the Thl7 inflanunatoiy response. As described in the examples, oral administration of compositions comprising Parabacteroides distasonis may reduce the severity of the inflammatory response, including the Th 17 inflammatory response, in mouse models of asthma, rheumatoid arthritis and multiple sclerosis. Also, as described in the examples, oral administration of compositions comprising Parabacteroides distasonis may reduce the severity of the inflammatory response, including the Thl7 inflammatory response, in mouse models of uveitis.

Therefore, in a fîrst embodiment, the invention provides a composition comprising a bacterial strain of the genus Parabacteroides, for use in a method of treating or preventing a disease or condition mediated by IL-17 or the Thl 7 pathway. The inventors hâve identified that treatment with bacterial strains from this genus can reduce levels of cytokines that are part of the Thl 7 pathway, including IL-17, can alleviate the Thl 7 inflammatory response and can provide clinical benefits in mouse models of inflammatory and autoimmune diseases mediated by IL-17 and the Thl 7 pathway.

In particular embodiments, the invention provides a composition comprising a bacterial strain of the genus Parabacteroides, for use in a method of treating or preventing a disease or condition selected from the group consisting of: multiple sclerosis; arthritis, such as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, or juvénile idiopathic arthritis; neuromyelitis optica (Devic's disease); ankylosing spondylitis; spondyloarthritis; psoriasis; systemic lupus erythematosus; inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis; celiac disease; asthma, such as allergie asthma or neutrophilie asthma; chronic obstructive pulmonaiy disease (COPD); cancer, such as breast cancer, colon cancer, lung cancer or ovarian cancer; uveitis; scleritis; vasculitis; Behcet’s disease; atherosclerosis; atopie dermatitis; emphysema; periodontitis; allergie rhinitis; and allograft rejection. The effect shown for the bacterial strains from the genus Parabacteroides on the Th 17 inflammatory response may provide therapeutic benefits for diseases and conditions mediated by IL-17 and the Thl 7 pathway, such as those listed above.

In preferred embodiments, the invention provides a composition comprising a bacterial strain of the genus Parabacteroides, for use in a method of treating or preventing asthma, such as neutrophilie asthma or allergie asthma. The inventors hâve identified that treatment with Parabacteroides strains can reduce recruitment of neutrophils and eosinophils into the lungs, which can help treat or prevent asthma. Furthermore, the inventors hâve tested and demonstrated the efficacy of Parabacteroides strains in mouse models of asthma. In certain embodiments, the composition is for use in a method of treating or preventing neutrophilie asthma or éosinophilie asthma. The effect shown for the compositions of the invention on neutrophils and eosinophils mean that they may be particularly effective for treating or preventing neutrophilie asthma and éosinophilie asthma. Indeed, in certain embodiments, the composition is for use in a method of reducing a neutrophilie inflammatory response in the treatment or prévention of asthma, or the composition is for use in a method of reducing an éosinophilie inflammatory response in the treatment or prévention of asthma. In preferred embodiments, the invention provides a composition comprising a bacterial strain of the species Parabacteroides distasonis for use in the treatment of asthma, and in particular neutrophilie asthma. Parabacteroides distasonis is shown to hâve a particularly pronounced effect on neutrophils in asthma models and treatment with Parabacteroides distasonis may be particularly effective for treating neutrophilie asthma.

In further preferred embodiments, the invention provides a composition comprising a bacterial strain of the genus Parabacteroides, for use in a method of treating or preventing rheumatoid arthritis. The inventors hâve identified that treatment with Parabacteroides strains can provide clinical benefits in a mouse model of rheumatoid arthritis and can reduce joint swelling. In preferred embodiments, the invention provides a composition comprising a bacterial strain of the species Parabacteroides distasonis, for use in the treatment of rheumatoid arthritis. Compositions using Parabacteroides distasonis may be particularly effective for treating rheumatoid arthritis.

In further preferred embodiments, the invention provides a composition comprising a bacterial strain of the genus Parabacteroides, for use in a method of treating or preventing multiple sclerosis. The inventors hâve identified that treatment with Parabacteroides strains can reduce disease incidence and disease severity in a mouse model of multiple sclerosis. In preferred embodiments, the invention provides a composition comprising a bacterial strain of the species Parabacteroides distasonis, for use in the treatment of multiple sclerosis. Compositions using Parabacteroides distasonis may be particularly effective for treating multiple sclerosis.

In further preferred embodiments, the invention provides a composition comprising a bacterial strain of the genus Parabacteroides, for use in a method of treating or preventing uveitis, such as posterior uveitis. The inventors hâve identified that treatment with Parabacteroides strains can reduce disease incidence and disease severity in a mouse model of uveitis and can prevent or reduce retinal damage. In preferred embodiments, the invention provides a composition comprising a bacterial strain of the species Parabacteroides distasonis, for use in the treatment of uveitis.

In further preferred embodiments, the invention provides a composition comprising a bacterial strain of the genus Parabacteroides, for use in a method of treating or preventing cancer, such as breast, lung or liver cancer. Compositions comprising a bacterial strain of the genus Parabacteroides may reduce tumour growth in mouse models of breast, lung and liver cancer. In certain embodiments, the composition is for use in a method of reducing tumour size or preventing tumour growth in the treatment of cancer. In certain embodiments, the invention provides a composition comprising a bacterial strain of the species Parabacteroides distasonis, for use in the treatment of cancer.

In certain embodiments, the compositions of the invention are for use in a method of reducing IL-17 production or reducing Th 17 cell différentiation in the treatment or prévention of a disease or condition mediated by IL-17 or the Th 17 pathway. In particular, the compositions of the invention may be used in reducing IL-17 production or reducing Thl7 cell différentiation in the treatment or prévention of asthma, rheumatoid arthritis or multiple sclerosis, or of asthma, rheumatoid arthritis, multiple sclerosis, uveitîs or cancer. Preferably, the invention provides compositions comprising a bacterial strain of the species Parabacteroides distasonis, for use in reducing IL-17 production or reducing Th 17 cell différentiation in the treatment or prévention of asthma, rheumatoid arthritis or multiple sclerosis. The invention also provides compositions comprising a bacterial strain of the species Parabacteroides distasonis, for use in reducing IL-17 production or reducing Thl7 cell différentiation in the treatment or prévention of uveitis.

In certain embodiments, the composition is for use in a patient with elevated IL-17 levels or Th.17 cells. The effect on the Thl7 inflammatory response shown for Parabacteroides strains may be particularly bénéficiai for such patients.

In preferred embodiments of the invention, the bacterial strain in the composition is of Parabacteroides distasonis. Closely related strains may also be used, such as bacterial strains that hâve a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to the 16s rRNA sequence of a bacterial strain of Parabacteroides distasonis. Preferably, the bacterial strain has a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to SEQ ID NO:1, 2, 3, 4, 5, 6, 7 8 or 9. Preferably, the sequence identity is to SEQ ID NO:9. Preferably, the bacterial strain for use in the invention has the 16s rRNA sequence represented by SEQ ID NO:9.

In certain embodiments, the composition of the invention is for oral administration. Oral administration of the strains of the invention can be effective for treating IL-17- or Th 17 pathwaymediated diseases and conditions. Also, oral administration is convenient for patients and practitioners and allows delivery to and / or partial or total colonisation of the intestine.

In certain embodiments, the composition of the invention comprises one or more pharmaceutically acceptable excipients or carriers.

In certain embodiments, the composition of the invention comprises a bacterial strain that has been lyophilised. Lyophilisation is an effective and convenient technique for preparing stable compositions that allow delivery of bacteria.

In certain embodiments, the invention provides a food product comprising the composition as described above.

In certain embodiments, the invention provides a vaccine composition comprising the composition as described above.

Additionally, the invention provides a method of treating or preventing a disease or condition mediated by IL-17 or the Th 17 pathway, comprising administering a composition comprising a bacterial strain of the genus Parabacteroides.

In developing the above invention, the inventors hâve identifîed and characterised a bacterial strain that is particularly useful for therapy. The Parabacteroides distasonis strain of the invention is shown to be effective for treating the diseases described herein, such as arthritis, asthma, multiple sclerosis and uveitis. Therefore, in another aspect, the invention provides a cell of the Parabacteroides distasonis strain deposited under accession number NCIMB 42382, or a dérivative thereof. The invention also provides compositions comprising such cells, or biologically pure cultures of such cells. The invention also provides a cell of the Parabacteroides distasonis strain deposited under accession number NCIMB 42382, or a dérivative thereof, for use in therapy, in particular for the diseases described herein.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: Mouse model of house dust mite-induced asthma - Total BAL fluid cell counts.

Figure 2: Mouse model of house dust mite-induced asthma - Total eosinophil count in BALF.

Figure 3: Mouse model of house dust mite-induced asthma - Proportion of eosinophils in BALF.

Figure 4: Mouse model of house dust mite-induced asthma - Total macrophage count in BALF.

Figure 5: Mouse model of house dust mite-induced asthma - Proportion of macrophages in BALF.

Figure 6: Mouse model of house dust mite-induced asthma - Total neutrophil count in BALF.

Figure 7: Mouse model of house dust mite-induced asthma - Proportion of neutrophils in BALF.

Figure 8: Mouse model of house dust mite-induced asthma - Total lymphocyte count in BALF.

Figure 9: Mouse model of house dust mite-induced asthma - Proportion of lymphocytes in BALF.

Figure 10: Mouse model of severe neutrophilie asthma - Total BAL fluid cell counts.

Figure 11: Mouse model of severe neutrophilie asthma - Total eosinophil count in BALF.

Figure 12: Mouse model of severe neutrophilie asthma - Proportion of eosinophils in BALF.

Figure 13: Mouse model of severe neutrophilie asthma - Total macrophage count in BALF.

Figure 14: Mouse model of severe neutrophilie asthma - Proportion of macrophages in BALF.

Figure 15: Mouse model of severe neutrophilie asthma - Total neutrophil count in BALF.

Figure 16: Mouse model of severe neutrophilie asthma - Proportion of neutrophils in BALF.

Figure 17: Mouse model of severe neutrophilie asthma - Total lymphocyte count in BALF.

Figure 18: Mouse model of severe neutrophilie asthma - Proportion of lymphocytes in BALF.

Figure 19: Mouse model of rheumatoid arthritis - Bodyweights, days -14 to 0. Data are presented as Mean ± SEM percentages of the initial (Day -14) bodyweights.

Figure 20: Mouse model of rheumatoid arthritis - Bodyweights, days 0 to 42. Data are presented as Mean ± SEM percentages of the initial (Day 0) bodyweights. ···· p < 0.0001 when compared to the vehicle-treated group.

Figure 21: Mouse model of rheumatoid arthritis - Clinical Scores. Data are presented as Mean ± SEM. **** p < 0.0001 when compared to Day 21 in the vehicle-treated group. ♦ ,0 p < 0.05 when compared to the vehicle-treated group on a given day.

Figure 22: Mouse model of rheumatoid arthritis - Splénocyte proliférative response to Collagen IL Media background subtracted [ClI-stimulated - media background] counts per minute based on 3HTdR incorporation. Ail data are presented as Mean ± SEM. *** p < 0.001 compared to Vehicle group.

Figure 23: Mouse model of rheumatoid arthritis - Levels of IFNy in tissue culture supematants. Lines represent group médian values.

Figure 24: Mouse model of rheumatoid arthritis - Levels of IL-17A in tissue culture supematants. Lines represent group médian values.

Figure 25: Mouse model of rheumatoid arthritis - Levels of IL-10 in tissue culture supematants. Lines represent group médian values.

Figure 26: Mouse model of rheumatoid arthritis - Levels of IL-6 in tissue culture supematants. Lines represent group médian values.

Figure 27: Mouse model of house dust mite-induced asthma - Total IgE in Sérum

Figure 28: Mouse model of house dust mite-induced asthma HDM spécifie IgGl in Sérum

Figure 29: Mouse model of house dust mite-induced asthma - Total IgE in BALF

Figure 30: Mouse model of house dust mite-induced asthma HDM spécifie IgGl in BALF

Figure 31: Mouse model of house dust mite-induced asthma Hîstological Analysis - Mean Peribronchiolar Infiltration Score

Figure 32: Mouse model of house dust mite-induced asthma - Hîstological Analysis - Mean Perivascular Infiltration Score

Figure 33: Mouse model of house dust mite-induced asthma Hîstological Analysis - Mean Inflammatory Score (Average of both Peribronchiolar and Perivascular Infiltration Score)

Figure 34: Mouse model of house dust mite-induced asthma - Hîstological Analysis - Mucus Score

Figure 35: Mouse model of house dust mite-induced asthma - IL-9 level in lung tissue

Figure 36: Mouse model of house dust mite-induced asthma - IL-la level in lung tissue

Figure 37 : Mouse model of house dust mite-induced asthma - IFNy level in lung tissue

Figure 38: Mouse model of house dust mite-induced asthma - IL-17A level in lung tissue

Figure 39: Mouse model of house dust mite-induced asthma IL-4 level in lung tissue

Figure 40: Mouse model of house dust mite-induced asthma - IL-5 level in lung tissue

Figure 41: Mouse model of house dust mite-induced asthma - IL-lb level in lung tissue

Figure 42: Mouse model of house dust mite-induced asthma - RANTES level in lung tissue

Figure 43: Mouse model of house dust mite-induced asthma - ΜΙΡ-la level in lung tissue

Figure 44: Mouse model of house dust mite-induced asthma - KC level in lung tissue

Figure 45: Mouse model of house dust mite-induced asthma - MIP-2 level in lung tissue

Figure 46: Mouse model of severe neutrophilie asthma - HDM spécifie IgGl in Sérum

Figure 47: Mouse model of severe neutrophilie asthma - HDM spécifie IgG2a in Sérum

Figure 48: Mouse model of severe neutrophilie asthma - HDM spécifie IgGl in BALF

Figure 49: Mouse model of severe neutrophilie asthma HDM spécifie IgG2a in BALF

Figure 50: Mouse model of severe neutrophilie asthma — Hîstological Analysis - Mean Peribronchiolar Infiltration Score

Figure 51: Mouse model of severe neutrophilie asthma - Hîstological Analysis - Mean Perivascular Infiltration Score

Figure 52: Mouse model of severe neutrophilie asthma - Histological Analysis Mean Inflammatory Score (Average of both Peribronchiolar and Perivascular Infiltration Score)

Figure 53: Mouse model of severe neutrophilie asthma - TNFa level in lung tissue

Figure 54: Mouse model of severe neutrophilie asthma - IL-la level in lung tissue

Figure 55: Mouse model of severe neutrophilie asthma - IFNy level in lung tissue

Figure 56: Mouse model of severe neutrophilie asthma - IL-17F level in lung tissue

Figure 57: Mouse model of severe neutrophilie asthma - IL-lb level in lung tissue

Figure 58: Mouse model of severe neutrophilie asthma - RANTES level in lung tissue

Figure 59: Mouse model of severe neutrophilie asthma - MIP-2 level in lung tissue

Figure 60: Mouse model of severe neutrophilie asthma - KC level in lung tissue

Figure 61: Mouse model of severe neutrophilie asthma IL-17A level in lung tissue

Figure 62: Mouse model of severe neutrophilie asthma -ΜΙΡ-la level in lung tissue

Figure 63: Mouse model of severe neutrophilie asthma - IL-33 level in lung tissue

Figure 64: Mouse model of rheumatoid arthritis - Visual Template for Histopathology Scoring. Représentative images showing composite scores from mouse tarsal joints in a collagen-induced arthritis study.

Figure 65: Mouse model of rheumatoid arthritis - Histopathology: Inflammation Scores. Data are presented as Mean ± SEM. * p < 0.05 when compared to the vehicle-treated group.

Figure 66: Mouse model of rheumatoid arthritis - Histopathology: Cartilage Scores. Data are presented as Mean ± SEM. * p < 0.05 when compared to the vehicle-treated group.

Figure 67: Mouse model of rheumatoid arthritis - Histopathology: Bone Scores. Data are presented as Mean ± SEM. * p < 0.05 when compared to the vehicle-treated group.

Figure 68: Mouse model of rheumatoid arthritis - Histopathology: Total Scores. Data are presented as Mean ± SEM. * p < 0.05 when compared to the vehicle-treated group.

Figure 69: Mouse model of rheumatoid arthritis - Histopathology: Représentative Pictures. Animal ID (#n.n) and limb (R for right, L for left) are indicated between brackets. Left image (vehicle): extensive joint and bone destruction with inflammation and fîbrosis extending to the peri-articular soft tissues.

Figure 70: Mouse model of multiple sclerosis - clinical score.

Figure 71: Mouse model of multiple sclerosis - disease incidence.

Figure 72: Mouse model of uveitis - TEFI Scores in the control group. Data are presented as Mean ± SEM.

Figure 73: Mouse model of uveitis - TEFI Scores on Day 28. Data are presented as Mean± SEM.

DISCLOSURE OF THE INVENTION

Bacterial strains

The compositions of the invention comprise a bacterial strain of the genus Parabacteroides. The examples demonstrate that bacteria of this genus are useful for treating or preventing diseases and conditions mediated by IL-17 or the Thl7 pathway. The preferred bacterial strains are of the species Parabacteroides distasonis.

Examples of Parabacteroides species for use in the invention include Parabacteroides distasonis, Parabacteroides goldsteinii, Parabacteroides merdae and Parabacteroides johnsonii. The Parabacteroides resemble the Bacteroides and are Gram-negative, obligately anaérobie, non-sporeforming, non-motile and rod-shaped, and 0.8-1.6^X 1.2— 12pm in size. Parabacteroides distasonis is one of the most common species in human faeces. The type strain of P. distasonis is JCM 5825^T (=CCUG 4941^T=DSM 20701^T=ATCC 8503^T) The GenBank/EMBL/DDBJ accession numbers for the 16S rRNA gene sequences of P distasonis strains JCM 5825T, JCM 13400, JCM 13401, JCM 13402, JCM 13403 and JCM 13404 and P. merdae strains JCM 9497T and JCM 13405 are AB238922—AB238929, respectively (disclosed herein as SEQ ID NOs:l-8). Exemplary strains are also described in [16].

The Parabacteroides distasonis bacterium deposited under accession number NCIMB 42382 was tested in the Examples and is also referred to herein as strain 755 or MRX005. A 16S rRNA sequence for the 755 strain that was tested is provîded in SEQ ID NO:9. Strain 755 was deposited with the international depositary authority NCIMB, Ltd. (Ferguson Building, Aberdeen, AB21 9YA, Scotland) by GT Biologics Ltd. (Life Sciences Innovation Building, Aberdeen, AB25 2ZS, Scotland) on 12th March 2015 as “Parabacteroides sp 755” and was assigned accession number NCIMB 42382. GT Biologics Ltd. subsequently changed its name to 4D Pharma Research Limited.

A genome sequence for strain 755 is provîded in SEQ ID NO: 10 of WO2016203220. This sequence was generated using the PacBio RS II platform.

Bacterial strains closely related to the strain tested in the examples are also expected to be effective for treating or preventing diseases and conditions mediated by IL-17 or the Thl 7 pathway. In certain embodiments, the bacterial strain for use in the invention has a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to the 16s rRNA sequence of a bacterial strain of Parabacteroides distasonis. Preferably, the bacterial strain for use in the invention has a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8 or 9. Preferably, the sequence identity is to SEQ ID NO:9. Preferably, the bacterial strain for use in the invention has the 16s rRNA sequence represented by SEQ ID NO: 9.

Bacterial strains that are biotypes of the bacterium deposited under accession number 42382 are also expected to be effective for treating or preventing diseases and conditions mediated by IL-17 or the Thl7 pathway. A biotype is a closely related strain that has the saine or very similar physiological and biochemical characteristics.

Strains that are biotypes of the bacterium deposited under accession number NCIMB 42382 and that are suitable for use in the invention may be identified by sequencing other nucléotide sequences for the bacterium deposited under accession number NCIMB 42382, For example, substantially the whole genome may be sequenced and a biotype strain for use in the invention may hâve at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% sequence identity across at least 80% of its whole genome (e.g. across at least 85%, 90%, 95% or 99%, or across its whole genome). Other suitable sequences for use in identifying biotype strains may include hsp60 or répétitive sequences such as BOX, ERIC, (GTG)₅, or REP or [17]. Biotype strains may hâve sequences with 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 42382.

In certain embodiments, the bacterial strain for use in the invention has a genome with sequence identity to SEQ ID NO:10 of W02016203220. In preferred embodiments, the bacterial strain for use in the invention has a genome with at least 90% sequence identity (e.g. at least 92%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to SEQ ID NO: 10 across at least 60% (e.g. at least 65%, 70%, 75%, 80%, 85%, 95%, 96%, 97%, 98%, 99% or 100%) of SEQ ID NO: 10. For example, the bacterial strain for use in the invention may hâve a genome with at least 90% sequence identity to SEQ ID NO: 10 across 70% of SEQ ID NO: 10, or at least 90% sequence identity to SEQ ID NO: 10 across 80% of SEQ ID NO: 10, or at least 90% sequence identity to SEQ ID NO: 10 across 90% of SEQ ID NO: 10, or at least 90% sequence identity to SEQ ID NO: 10 across 100% of SEQ ID NO: 10, or at least 95% sequence identity to SEQ ID NO: 10 across 70% of SEQ ID NO:10, or at least 95% sequence identity to SEQ ID NO: 10 across 80% of SEQ ID NO: 10, or at least 95% sequence identity to SEQ ID NO:10 across 90% of SEQ ID NO:10, or at least 95% sequence identity to SEQ ID NO:10 across 100% of SEQ ID NO:10, or at least 98% sequence identity to SEQ ID NO:10 across 70% of SEQ ID NO: 10, or at least 98% sequence identity to SEQ ID NO: 10 across 80% of SEQ ID NO: 10, or at least 98% sequence identity to SEQ ID NO: 10 across 90% of SEQ ID NO: 10, or at least 98% sequence identity to SEQ ID NO:10 across 100% of SEQ ID NO: 10.

Altematively, strains that are biotypes of the bacterium deposited under accession number NCIMB 42382 and that are suitable for use in the invention may be identifïed by using the accession number NCIMB 42382 deposit and restriction fragment analysis and/or PCR analysis, for example by using fluorescent amplified fragment length polymorphism (FAFLP) and répétitive DNA element (rep)PCR fingerprinting, or protein profiling, or partial 16S or 23s rDNA sequencing. In preferred embodiments, such techniques may be used to identify other Parabacteroides distasonis strains.

In certain embodiments, strains that are biotypes of the bacterium deposited under accession number NCIMB 42382 and that are suitable for use in the invention are strains that provide the same pattern as the bacterium deposited under accession number NCIMB 42382 when analysed by amplified ribosomal DNA restriction analysis (ARDRA), for example when using Sau3AI restriction enzyme (for exemplary methods and guidance see, for example,[18]). Altematively, biotype strains are identifïed as strains that hâve the same carbohydrate fermentation patterns as the bacterium deposited under accession number NCIMB 42382.

Other Parabacteroides strains that are useful in the compositions and methods of the invention, such as biotypes of the bacteria deposited under accession number NCIMB 42382, may be identifïed using any appropriate method or strategy, including the assays described in the examples. For instance, strains for use in the invention may be identifïed by culturing in anaérobie YCFA and/or administering the bacteria to the type II collagen-induced arthritis mouse model and then assessing cytokine levels. In particular, bacterial strains that hâve similar growth patterns, metabolic type and/or surface antigens to the bacterium deposited under accession number NCIMB 42382 may be useful in the invention. A useful strain will hâve comparable immune modulatory activity to the NCIMB 42382 strain. In particular, a biotype strain will elicit comparable effects on the asthma, arthritis, multiple sclerosis and uveitis disease models and comparable effects on cytokine levels to the effects shown in the Examples, which may be identifïed by using the culturing and administration protocols described in the Examples.

A particularly preferred strain of the invention is the Parabacteroides distasonis strain deposited under accession number NCIMB 42382, This is the exemplary 755 strain tested in the examples and shown to be effective for treating disease. Therefore, the invention provides a cell, such as an isolated cell, of the Parabacteroides distasonis strain deposited under accession number NCIMB 42382, or a dérivative thereof. The invention also provides a composition comprising a cell of the Parabacteroides distasonis strain deposited under accession number NCIMB 42382, or a dérivative thereof. The invention also provides a biologically pure culture of the Parabacteroides distasonis strain deposited under accession number NCIMB 42382. The invention also provides a cell of the Parabacteroides distasonis strain deposited under accession number NCIMB 42382, or a dérivative thereof, for use in therapy, in particular for the diseases described herein.

A dérivative of the strain deposited under accession number NCIMB 42382 may be a daughter strain (progeny) or a strain cultured (subcloned) from the original. A dérivative of a strain of the invention may be modified, for example at the genetic level, without ablating the biological activity. In particular, a dérivative strain of the invention is therapeutically active. A dérivative strain will hâve comparable immune modulatory activity to the original NCIMB 42382 strain. In particular, a dérivative strain will elicit comparable effects on the asthrna, arthritis, multiple sclerosis and uveitis disease models and comparable effects on cytokine levels to the effects shown in the Examples, which may be identified by using the culturing and administration protocols described in the Examples. A dérivative of the NCIMB 42382 strain will generally be a biotype of the NCIMB 42382 strain.

Référencés to cells of the Parabacteroides distasonis strain deposited under accession number NCIMB 42382 encompass any cells that hâve the same safety and therapeutic efficacy characteristics as the strains deposited under accession number NCIMB 42382, and such cells are encompassed by the invention.

In preferred embodiments, the bacterial strains in the compositions of the invention are viable and capable of partially or totally colonising the intestine.

Therapeutic uses

As demonstrated in the examples, the bacterial compositions of the invention are effective for reducing the Thl7 inflammatory response. In particular, treatment with compositions of the invention achieves a réduction in IL-17A levels and other Thl7 pathway cytokines, and clinical improvements in animal models of conditions mediated by IL-17 and the Th 17 pathway. Therefore, the compositions of the invention may be usefùl for treating or preventing inflammatory and autoimmune diseases, and in particular diseases or conditions mediated by IL-17. In particular, the compositions of the invention may be usefùl for reducing or preventing élévation of the IL-17 inflammatory response.

Thl7 cells are a subset of T helper cells that produce, for example, IL-17A, IL17-F, IL-21 and IL-22. Thl7 cell différentiation and IL-17 expression may be driven by IL-23, These cytokines and others form important parts of the Thl7 pathway, which is a well-established inflammatory signalling pathway that contributes to and underlies a number of inflammatory and autoimmune diseases (as described in, for example, [19-24]). Diseases wherein the Thl7 pathway is activated are Thl7 pathway-mediated diseases. Thl7 pathway-mediated diseases can be ameliorated or alleviated by repressing the Th 17 pathway, which may be through a réduction in the différentiation of Th 17 cells or a réduction in their activity or a réduction in the level of Thl7 pathway cytokines. Diseases mediated by the Th 17 pathway may be characterised by increased levels of cytokines produced by Thl7 cells, such as IL-17A, IL-17F, IL-21, IL-22, IL-26, IL-9 (reviewed in [25]). Diseases mediated by the Th 17 pathway may be characterised by increased expression of Th-17-related genes, such as Stat3 or IL-23R. Diseases mediated by the Thl7 pathway may be associated with increased levels of Thl7cells.

IL-17 is a pro-inflammatory cytokine that contributes to the pathogenesis of several inflammatory and autoimmune diseases and conditions. IL-17 as used herein may refer to any member of the IL-17 family, including IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. IL-17-mediated diseases and conditions are characterised by high expression of IL-17 and/or the accumulation or presence of IL-17-positive cells in a tissue affected by the disease or condition. Similarly, IL-17-mediated diseases and conditions are diseases and conditions that are exacerbated by high IL-17 levels or an increase in IL-17 levels, and that are alleviated by low IL-17 levels or a réduction in IL-17 levels. The IL-17 inflammatory response may be local or systemic.

Examples of diseases and conditions that may be mediated by IL-17 or the Thl7 pathway include multiple sclerosis; arthritis, such as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, or juvénile idiopathic arthritis; neuromyelitis optica (Devic's disease); ankylosing spondylitis; spondyloarthritis; psoriasis; systemic lupus erythematosus; inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis; celiac disease; asthma, such as allergie asthma or neutrophilie asthma; chronic obstructive pulmonary disease (COPD); cancer, such as breast cancer, colon cancer, lung cancer or ovarian cancer; uveitis; scleritis; vasculitis; Behcet's disease; atherosclerosis; atopie dermatitis; emphysema; periodontitis; allergie rhinitis; and allograft rejection. In preferred embodiments, the compositions of the invention are used for treating or preventing one or more of these conditions or diseases. In fùrther preferred embodiments, these conditions or diseases are mediated by IL-17 or the Th 17 pathway.

In certain embodiments, the compositions of the invention are for use in a method of reducing IL-17 production or reducing Thl7 cell différentiation in the treatment or prévention of a disease or condition mediated by IL-17 or the Thl7 pathway. In certain embodiments, the compositions of the invention are for use in treating or preventing an inflammatory or autoimmune disease, wherein said treatment or prévention is achieved by reducing or preventing élévation of the Th 17 inflammatory response. In certain embodiments, the compositions of the invention are for use in treating a patient with an inflammatory or autoimmune disease, wherein the patient has elevated IL-17 levels or elevated Th 17 cells or is exhibiting a Th 17 inflammatory response. In certain embodiments, the patient may hâve been diagnosed with a chronic inflammatory or autoimmune disease or condition, or the composition of the invention may be for use in preventing an inflammatory or autoimmune disease or condition developing into a chronic inflammatory or autoimmune disease or condition. In certain embodiments, the disease or condition may not be responsive to treatment with TNF-a inhibitors. These uses of the invention may be applied to any of the spécifie disease or conditions listed in the preceding paragraph.

IL-17 and the Thl7 pathway are often associated with chronic inflammatory and autoimmune diseases, so the compositions of the invention may be particularly useful for treating or preventing chronic diseases or conditions as listed above. In certain embodiments, the compositions are for use in patients with chronic disease. In certain embodiments, the compositions are for use in preventing the development of chronic disease.

The compositions ofthe invention may be useful for treating diseases and conditions mediated by IL17 or the Thl7 pathway and for addressing the Thl7 inflammatory response, so the compositions of the invention may be particularly useful for treating or preventing chronic disease, treating or preventing disease in patients that hâve not responded to other thérapies (such as treatment with TNF-α inhibitors), and/or treating or preventing the tissue damage and symptoms associated with IL17 and Thl7 cells. For example, IL-17 is known to activate matrix destruction in cartilage and bone tissue and IL-17 has an inhibitory effect on matrix production in chondrocytes and osteoblasts, so the compositions of the invention may be useful for treating or preventing bone érosion or cartilage damage.

In certain embodiments, treatment with compositions of the invention provides a réduction or prevents an élévation in IL-17 levels, in particular IL-17A levels. In certain embodiments, treatment with compositions of the invention provides a réduction or prevents an élévation in IFN-γ, IL-Ιβ or IL-6 levels. Such réduction or prévention of elevated levels of these cytokines may be useful for treating or preventing inflammatory and autoimmune diseases and conditions, in particular those mediated by IL-17 or the Th 17 pathway.

Asthma

In preferred embodiments, the compositions of the invention are for use in treating or preventing asthma. The examples demonstrate that the compositions of the invention achieve a réduction in the recruitment of neutrophils and/or eosinophils into the airways following sensitisation and challenge with house dust mite extract and so they may be useful in the treatment or prévention of asthma. Asthma is a chronic disease characterised by inflammation and restriction of the airways. The inflammation in asthma may be mediated by IL-17 and/or Th 17 cells, and so the compositions of the invention may be particularly effective for preventing or treating asthma. The inflammation in asthma may be mediated by eosinophils and/or neutrophils.

In certain embodiments, the asthma is éosinophilie or allergie asthma. Eosinophilie and allergie asthma are characterised by increased numbers of eosinophils in peripheral blood and in airway sécrétions and is associated pathologically with thickening of the basement membrane zone and pharmacologically by corticosteroid responsiveness [26], Compositions that reduce or inhibit eosinophil recruitment or activation may be usefùl for treating or preventing éosinophilie and allergie asthma.

In additional embodiments, the compositions of the invention are for use in treating or preventing neutrophilie asthma (or non-eosinophilic asthma). High neutrophil numbers are associated with severe asthma that may be insensitive to corticosteroid treatment. Compositions that reduce or inhibit neutrophil recruitment or activation may be useful for treating or preventing neutrophilie asthma.

Eosinophilie and neutrophilie asthma are not mutually exclusive conditions and treatments that help address either the eosinophil and neutrophil responses may be useful for treating asthma in general.

Increased IL-17 levels and activation of the Th 17 pathway are associated with severe asthma, so the compositions of the invention may be useful for preventing the development of severe asthma or for treating severe asthma.

In certain embodiments, the compositions of the invention are for use in methods reducing an éosinophilie inflammatory response in the treatment or prévention of asthma, or for use in methods of reducing a neutrophilie inflammatory response in the treatment or prévention of asthma. As noted above, high levels of eosinophils in asthma is associated pathologically with thickening of the basement membrane zone, so reducing éosinophilie inflammatory response in the treatment or prévention of asthma may be able to specifically address this feature of the disease. Also, elevated neutrophils, either in combination with elevated eosinophils or in their absence, is associated with severe asthma and chronic airway narrowing, Therefore, reducing the neutrophilie inflammatory response may be particularly useful for addressing severe asthma.

In certain embodiments, the compositions reduce peribronchiolar infiltration in allergie asthma, or are for use in reducing peribronchiolar infiltration in the treatment of allergie asthma. In certain embodiments, the compositions reduce peribronchiolar and/or perivascular infiltration in neutrophilie asthma, or are for use in reducing peribronchiolar and/or perivascular infiltration in the treatment of allergie neutrophilie asthma.

In certain embodiments, treatment with compositions of the invention provides a réduction or prevents an élévation in IL-lb or IFNy levels.

In certain embodiments, the compositions of the invention are for use in a method of treating asthma that results in a réduction of the éosinophilie and/or neutrophilie inflammatory response. In certain embodiments, the patient to be treated has, or has previously been identified as having, elevated neutrophil or eosinophil levels, for example as identified through blood sampling or sputum analysis.

The compositions of the invention may be usefiil for preventing the development of asthma in a newbom when administered to the new-bom, or to a prégnant woman. The compositions may be usefiil for preventing the development of asthma in children. The compositions of the invention may be usefiil for treating or preventing adult-onset asthma. The compositions of the invention may be usefiil for managing or alleviating asthma. The compositions of the invention may be particularly usefiil for reducing symptoms associated with asthma that is aggravated by allergens, such as house dust mites.

Treatment or prévention of asthma may refer to, for example, an alleviation of the severity of symptoms or a réduction in the frequency of exacerbations or the range of triggers that are a problem for the patient.

Arthritis

In preferred embodiments, the compositions of the invention are for use in treating or preventing rheumatoid arthritis (RA). The examples demonstrate that the compositions of the invention achieve a réduction in the clinical signs of RA in a mouse model, reduce cartilage and bone damage, and reduce the IL-17 inflammatory response, and so they may be usefiil in the treatment or prévention of RA. RA is a systemic inflammatory disorder that primarily affects joints. RA is associated with an inflammatory response that results in swelling of joints, synovial hyperplasia, and destruction of cartilage and bone. IL-17 and Thl7 celle may hâve a key rôle in RA, for example because IL-17 inhibits matrix production in chondrocytes and osteoblasts and activâtes the production and fonction of matrix metalloproteinases and because RA disease activity is correlated to IL-17 levels and Th-17 cell numbers [27,28], so the compositions of the invention may be particularly effective for preventing or treating RA.

In certain embodiments, the compositions of the invention are for use in lowering IL-17 levels or preventing élévation of IL-17 levels in the treatment or prévention of RA. In certain embodiments, treatment with compositions of the invention provides a réduction or prevents an élévation in IL-17 levels, in particular IL-17A levels. In certain embodiments, treatment with compositions of the invention provides a réduction or prevents an élévation in IFN-γ or IL-6 levels.

In certain embodiments, treatment with the compositions of the invention results in a réduction in the swelling of joints. In certain embodiments, the compositions of the invention are for use in patients with swollen joints or patients identified as at risk of having swollen joints. In certain embodiments, the compositions of the invention are for use in a method of reducing joint swelling in RA.

In certain embodiments, treatment with the compositions of the invention results in a réduction in cartilage damage or bone damage. In certain embodiments, the compositions of the invention are for use in reducing or preventing cartilage or bone damage in the treatment of RA. In certain embodiments, the compositions are for use in treating patient with severe RA that are at risk of cartilage or bone damage.

Increased IL-17 levels and Thl7 cell numbers are associated with cartilage and bone destruction in RA [27,28]. IL-17 is known to activate matrix destruction in cartilage and bone tissue and IL-17 has an inhibitory effect on matrix production in chondrocytes and osteoblasts. Therefore, in certain embodiments, the compositions of the invention are for use in preventing bone érosion or cartilage damage in the treatment of RA. In certain embodiments, the compositions are for use in treating patients that exhibit bone érosion or cartilage damage or patients identified as at risk of bone érosion or cartilage damage.

TNF-α îs also associated with RA, but TNF-α is not involved in the pathogenesis of the later stages of the disease. In contrast, IL-17 has a rôle throughout ail stages of chronic disease [29], Therefore, in certain embodiments the compositions of the invention are for use in treating chronic RA or latestage RA, such as disease that includes joint destruction and loss of cartilage. In certain embodiments, the compositions of the invention are for treating patients that hâve previously received anti-TNF-α therapy. In certain embodiments, the patients to be treated do not respond or no longer respond to anti-TNF-α therapy.

The compositions of the invention may be useful for modulating a patient’s immune System, so in certain embodiments the compositions of the invention are for use in preventing RA in a patient that has been identified as at risk of RA, or that has been diagnosed with early-stage RA. The compositions of the invention may be useful for preventing the development of RA.

The compositions of the invention may be useful for managing or alleviating RA. The compositions of the invention may be particularly useful for reducing symptoms associated with joint swelling or bone destruction. Treatment or prévention of RA may refer to, for example, an alleviation of the severity of symptoms or a réduction in the frequency of exacerbations or the range of triggers that are a problem for the patient.

Multiple sclerosis

In preferred embodiments, the compositions of the invention are for use in treating or preventing multiple sclerosis. The examples demonstrate that the compositions of the invention achieve a réduction in the disease incidence and disease severity in a mouse model of multiple sclerosis (the EAE model), and so they may be useful in the treatment or prévention of multiple sclerosis. Multiple sclerosis is an inflammatory disorder associated with damage to the myelin sheaths of neurons, particularly in the brain and spinal column. Multiple sclerosis is a chronic disease, which is progressively incapacitating and which evolves in épisodes. IL-17 and Thl7 cells may hâve a key rôle in multiple sclerosis, for example because IL-17 levels may correlate with multiple sclerosis lésions, IL-17 can disrupt blood brain barrier endothélial cell tight junctions, and Thl7 cells can migrate into the central nervous System and cause neuronal loss [30,31]. Therefore, the compositions of the invention may be particularly effective for preventing or treating multiple sclerosis.

In certain embodiments, treatment with the compositions of the invention results in a réduction in disease incidence or disease severity. In certain embodiments, the compositions of the invention are for use in reducing disease incidence or disease severity. In certain embodiments, treatment with the compositions of the invention prevents a décliné in motor fonction or results in improved motor fonction. In certain embodiments, the compositions of the invention are for use in preventing a décliné in motor functîon or for use in improving motor fonction. In certain embodiments, treatment with the compositions of the invention prevents the development of paralysis. In certain embodiments, the compositions of the invention are for use in preventing paralysis in the treatment of multiple sclerosis.

The compositions of the invention may be useful for modulating a patient’s immune System, so in certain embodiments the compositions of the invention are for use in preventing multiple sclerosis in a patient that has been identified as at risk of multiple sclerosis, or that has been diagnosed with early-stage multiple sclerosis or “relapsing-remitting” multiple sclerosis. The compositions of the invention may be useful for preventing the development of sclerosis. Indeed, the examples show that administration of compositions of the invention prevented the development of disease in many mice.

The compositions of the invention may be useful for managing or alleviating multiple sclerosis. The compositions of the invention may be particularly useful for reducing symptoms associated with multiple sclerosis. Treatment or prévention of multiple sclerosis may refer to, for example, an alleviation of the severity of symptoms or a réduction in the frequency of exacerbations or the range of triggers that are a problem for the patient.

Uveitis

In preferred embodiments, the compositions of the invention are for use in treating or preventing uveitis. The examples demonstrate that the compositions of the invention achieve a réduction in disease incidence and disease severity in an animal model of uveitis and so they may be usefol in the treatment or prévention of uveitis. Uveitis is inflammation of the uvea and can resuit in retinal tissue destruction. It can présent in different anatomical forms (anterior, intermediate, posterior or diffuse) and resuit from different, but related, causes, including systemic autoimmune disorders. IL-17 and the Thl7 pathway are centrally involved in uveitis, so the compositions of the invention may be particularly effective for preventing or treating uveitis. References [32-39] describe elevated sérum levels of interleukin-17A in uveitis patients, spécifie association of IL17A genetic variants with panuveitis, the rôle of Thl7-associated cytokines in the pathogenesis of experimental autoimmune uveitis, the imbalance between Thl 7 Cells and regulatory T Cells during monophasic experimental autoimmune uveitis, the up-regulation of IL-17A in patients with uveitis and active AdamantiadesBehçet and Vogt-Koyanagi-Harada (VKH) diseases, the treatment of non-infectious uveitis with secukinumab (anti-IL-17A antibody), and Thl7 inuveitic eyes.

In certain embodiments, the uveitis is posterior uveitis. Posterior uveitis présents primarily with inflammation of the retina and choroid and the examples demonstrate that the compositions of the invention are effective for reducing retinal inflammation and damage.

In certain embodiments, treatment with the compositions of the invention results in a réduction in retinal damage. In certain embodiments, the compositions of the invention are for use in reducing or preventing retinal damage in the treatment of uveitis. In certain embodiments, the compositions are for use in treating patients with severe uveitis that are at risk of retinal damage. In certain embodiments, treatment with the compositions of the invention results in a réduction in optic dise inflammation. In certain embodiments, the compositions of the invention are for use in reducing or preventing optic dise inflammation. In certain embodiments, treatment with the compositions of the invention results in a réduction in retinal tissue infiltration by inflammatory cells. In certain embodiments, the compositions of the invention are for use in reducing retinal tissue infiltration by inflammatory cells. In certain embodiments, treatment with the compositions of the invention results in vision being maintained or improved. In certain embodiments, the compositions of the invention are for use in maintaining or improving vision.

In certain embodiments, the compositions are for use in treating or preventing uveitis associated with a non-infectious or autoimmune disease, such as Behçet disease, Crohn's disease, Fuchs hétérochromie iridocyclitis, granulomatosis with polyangiitis, HLA-B27 related uveitis, juvénile idiopathic arthritis, sarcoidosis, spondyloarthritis, sympathetic ophthalmia, tubulointerstitial nephritis and uveitis syndrome or Vogt-Koyanagi-Harada syndrome. IL-17A has been shown to be involved in, for example, Behçet and Vogt-Koyanagi-Harada diseases.

Treatment or prévention of uveitis may refer to, for example, an alleviation of the severity of symptoms or a prévention of relapse.

Cancer

In preferred embodiments, the compositions of the invention are for use in treating or preventing cancer. IL-17 and the Th 17 pathway hâve central rôles in cancer development and progression, and so the compositions of the invention may be useful for treating or preventing cancer.

Although the rôles of IL-17 and Th 17 cells in cancer are not fully understood, numerous pro-tumour effects of IL-17 and Thl7 cells are known. For example, Thl7 cells and IL-17 can promote angiogenesis, increase prolifération and survival of tumor cells and activaie tumour-promoting transcription factors [40-42],

In certain embodiments, treatment with the compositions of the invention results in a réduction in tumour size or a réduction in tumour growth. In certain embodiments, the compositions of the invention are for use in reducing tumour size or reducing tumour growth. The compositions of the invention may be effective for reducing tumour size or growth. In certain embodiments, the compositions of the invention are for use in patients with solid tumours. In certain embodiments, the compositions of the invention are for use in reducing or preventing angiogenesis in the treatment of cancer. IL-17 and Thl7 cells hâve central rôles in angiogenesis. In certain embodiments, the compositions of the invention are for use in preventing metastasis.

In certain embodiments, the compositions of the invention are for use in treating or preventing breast cancer. The compositions of the invention may be effective for treating breast cancer, and IL-17 and Th 17 cells hâve important rôles in breast cancer [43], In certain embodiments, the compositions of the invention are for use in reducing tumour size, reducing tumour growth, or reducing angiogenesis in the treatment of breast cancer. In preferred embodiments the cancer is mammary carcinoma. In preferred embodiments the cancer is stage IV breast cancer.

In certain embodiments, the compositions of the invention are for use in treating or preventing lung cancer. The compositions of the invention may be effective for treating lung cancer, and IL-17 and Th 17 cells hâve important rôles in lung cancer [44]. In certain embodiments, the compositions of the invention are for use in reducing tumour size, reducing tumour growth, or reducing angiogenesis in the treatment of lung cancer. In preferred embodiments the cancer is lung carcinoma.

In certain embodiments, the compositions of the invention are for use in treating or preventing liver cancer. The compositions of the invention may be effective for treating liver cancer, and IL-17 and Thl7 cells hâve important rôles in liver cancer [45]. In certain embodiments, the compositions of the invention are for use in reducing tumour size, reducing tumour growth, or reducing angiogenesis in the treatment of liver cancer. In preferred embodiments the cancer is hepatoma (hepatocellular carcinoma).

In certain embodiments, the compositions of the invention are for use in treating or preventing carcinoma. The compositions of the invention may be particularly effective for treating carcinoma. In certain embodiments, the compositions of the invention are for use in treating or preventing nonimmunogenic cancer. The compositions of the invention may be effective for treating nonimmunogenic cancers.

In further embodiments, the compositions of the invention are for use in treating or preventing acute lymphoblastic leukemia (ALL), acute myeloid leukemia, adrenocortical carcinoma, basal-cell carcinoma, bile duct cancer, bladder cancer, bone tumor, osteosarcoma/malignant fibrous histiocytoma, brainstem glioma, brain tumor, cerebellar astrocytoma, cérébral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, breast cancer, bronchial adenomas/carcinoids, Burkitt's lymphoma, carcinoid tumor, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, endométrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, glioma, childhood visual pathway and hypothalamic, Hodgkin lymphoma, melanoma, islet cell carcinoma, Kaposi sarcoma, rénal cell cancer, laryngeal cancer, leukaemias, lymphomas, mesothelioma, neuroblastoma, non-Hodgkin lymphoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary adenoma, plasma cell neoplasia, prostate cancer, rénal cell carcinoma, retinoblastoma, sarcoma, testicular cancer, thyroid cancer, or uterine cancer.

The compositions of the invention may be particularly effective when used in combination with further therapeutic agents. The immune-modulatory effects of the compositions of the invention may be effective when combined with more direct anti-cancer agents. Therefore, in certain embodiments, the invention provides a composition comprising a bacterial strain of the genus Parabacteroides and an anticancer agent. In preferred embodiments the anticancer agent is an immune checkpoint inhibitor, a targeted antibody immunotherapy, a CAR-T cell therapy, an oncolytic virus, or a cytostatic drug. In preferred embodiments, the composition comprises an anti-cancer agent selected from the group consisting of: Yervoy (ipilimumab, BMS); Keytruda (pembrolizumab, Merck); Opdivo (nivolumab, BMS); MEDI4736 (AZ/Medlmmune); MPDL3280A (Roche/Genentech); Tremelimumab (AZ/Medlmmune); CT-011 (pidilizumab, CureTech); BMS-986015 (lirilumab, BMS); MEDIO68O (AZ/Medlmmune); MSB-0010718C (Merck); PF-05082566 (Pfizer); MEDI6469 (AZ/Medlmmune); BMS-986016 (BMS); BMS-663513 (urelumab, BMS); IMP321 (Prima Biomed); LAG525 (Novartis); ARGX-UO (arGEN-X); PF-05082466 (Pfizer); CDX-1127 (varlilumab; CellDex Therapeutics); TRX-518 (GITR Inc.); MK-4166 (Merck); JTX-2011 (Jounce Therapeutics); ARGX-115 (arGEN-X); NLG-9189 (indoximod, NewLink Genetics); INCB024360 (Incyte); IPH2201 (Innate Immotherapeutics/AZ); NLG-919 (NewLink Genetics); anti-VISTA (JnJ); Epacadostat (INCB24360, Incyte); F001287 (Flexus/BMS); CP 870893 (University of Pennsylvania); MGA271 (Macrogenix); Emactuzumab (Roche/Genentech); Galunisertib (Eli Lilly); Ulocuplumab (BMS); BKT140/BL8040 (Biokine Therapeutics); Bavituximab (Peregrine Pharmaceuticals); CC 90002 (Celgene); 852A (Pfizer); VTX-2337 (VentiRx Pharmaceuticals); IMO2055 (Hybridon, Idera Pharmaceuticals); LY2I57299 (Eli Lilly); EW-7197 (Ewha Women's University, Korea); Vemurafenib (Plexxikon); Dabrafenib (Genentech/GSK); BMS-777607 (BMS); BLZ945 (Memorial Sloan-Kettering Cancer Centre); Unituxin (dinutuximab, United Therapeutics Corporation); Blincyto (blinatumomab, Amgen); Cyramza (ramucirumab, Eli Lilly); Gazyva (obinutuzumab, Roche/Biogen); Kadcyla (ado-trastuzumab emtansine, Roche/Genentech); Perjeta (pertuzumab, Roche/Genentech); Adcetris (brentuximab vedotin, Takeda/Millennium); Arzerra (ofatumumab, GSK); Vectibix (panitumumab, Amgen); Avastin (bevacizumab, Roche/Genentech); Erbitux (cetuximab, BMS/Merck); Bexxar (tositumomab-1131, GSK); Zevalin (ibritumomab tiuxetan, Biogen); Campath (alemtuzumab, Bayer); Mylotarg (gemtuzumab ozogamicin, Pfizer); Herceptin (trastuzumab, Roche/Genentech); Rituxan (rituximab, Genentech/Biogen); volociximab (Abbvie); Enavatuzumab (Abbvie); ABT-414 (Abbvie); Elotuzumab (Abbvie/BMS); ALX-0141 (Ablynx); Ozaralizumab (Ablynx); Actimab-C (Actinium); Actimab-P (Actinium); Milatuzumab-dox (Actinium); Emab-SN-38 (Actinium); Naptumonmab estafenatox (Active Biotech); AFM13 (Affimed); AFM11 (Affimed); AGS-16C3F (Agensys); AGS-16M8F (Agensys); AGS-22ME (Agensys); AGS-15ME (Agensys); GS-67E (Agensys); ALXN6000 (samalizumab, Alexion); ALT836 (Altor Bioscience); ALT-801 (Altor Bioscience); ALT-803 (Altor Bioscience); AMG780 (Amgen); AMG 228 (Amgen); AMG820 (Amgen); AMG172 (Amgen); AMG595 (Amgen); AMG110 (Amgen); AMG232 (adecatumumab, Amgen); AMG211 (Amgen/Medlmmune); BAY2010112 (Amgen/Bayer); Rilotumumab (Amgen); Denosumab (Amgen); AMP-514 (Amgen); MEDI575 (AZ/Medlmmune); MEDI3617 (AZ/Medlmmune); MEDI6383 (AZ/Medlmmune); MEDI551 (AZ/Medlmmune); Moxetumomab pasudotox (AZ/Medlmmune); MEDI565 (AZ/Medlmmune); MEDI0639 (AZ/Medlmmune); MEDI0680 (AZ/Medlmmune); MEDI562 (AZ/Medlmmune); AV-380 (AVEO); AV203 (AVEO); AV299 (AVEO); BAY79-4620 (Bayer); Anetumab ravtansine (Bayer); vantictumab (Bayer); BAY94-9343 (Bayer); Sibrotuzumab (Boehringer Ingleheim); BI-836845 (Boehringer Ingleheim); B-701 (BioClin); BIIB015 (Biogen); Obinutuzumab (Biogen/Genentech); BI-505 (Bioinvent); BI-1206 (Bioinvent); TB-403 (Bioinvent); BT-062 (Biotest) BIL-OlOt (Biosceptre); MDX-1203 (BMS); MDX-1204 (BMS); Necitumumab (BMS); CAN-4 (Cantargia AB); CDX-011 (Celldex); CDX1401 (Celldex); CDX301 (Celldex); U31565 (Daiichi Sankyo); patritumab (Daiichi Sankyo); tigatuzumab (Daiichi Sankyo); nimotuzumab (Daiichi Sankyo); DS-8895 (Daiichi Sankyo); DS-8873 (Daiichi Sankyo); DS-5573 (Daiichi Sankyo); MORab-004 (Eisai); MORab-009 (Eisai); MORab-003 (Eisai); MORab-066 (Eisai); LY3012207 (Eli Lilly); LY2875358 (Eli Lilly); LY2812176 (Eli Lilly); LY3012217(Eli Lilly); LY2495655 (Eli Lilly); LY3012212 (Eli Lilly); LY3012211 (Eli Lilly); LY3009806 (Eli Lilly); cixutumumab (Eli Lilly); Flanvotumab (Eli Lilly); IMC-TR1 (Eli Lilly); Ramucirumab (Eli Lilly); Tabalumab (Eli Lilly); Zanolimumab (Emergent Biosolution); FG-3019 (FibroGen); FPA008 (Five Prime Therapeutics); FP-1039 (Five Prime Therapeutics); FPA144 (Five Prime Therapeutics); catumaxomab (Fresenius Biotech); IMAB362 (Ganymed); IMAB027 (Ganymed); HuMax-CD74 (Genmab); HuMax-TFADC (Genmab); GS-5745 (Gilead); GS-6624 (Gilead); OMP-21M18 (demcizumab, GSK); mapatumumab (GSK); IMGN289 (ImmunoGen); IMGN901 (ImmunoGen); IMGN853 (ImmunoGen); IMGN529 (ImmunoGen); IMMU-130 (Immunomedics); milatuzumabdox (Immunomedics); IMMU-115 (Immunomedics); IMMU-132 (Immunomedics); IMMU-106 (Immunomedics); IMMU-102 (Immunomedics); Epratuzumab (Immunomedics); Clivatuzumab (Immunomedics); IPH41 (Innate Immunotherapeutics); Daratumumab (Janssen/Genmab); CNTO-95 (Intetumumab, Janssen); CNTO-328 (siltuximab, Janssen); KB004 (KaloBios); mogamulizumab (Kyowa Hakko Kirrin); KW-2871 (ecromeximab, Life Science); Sonepcizumab (Lpath); Margetuximab (Macrogenics); Enoblituzumab (Macrogenics); MGD006 (Macrogenics); MGF007 (Macrogenics); MK-0646 (dalotuzumab, Merck); MK-3475 (Merck); Sym004 (Symphogen/Merck Serono); DI17E6 (Merck Serono); MOR208 (Morphosys); MOR202 (Morphosys); Xmab5574 (Morphosys); BPC-1C (ensituximab, Précision Biologics); TAS266 (Novartis); LFA102 (Novartis); BHQ88O (Novartis/Morphosys); QGE031 (Novartis); HCD122 (lucatumumab, Novartis); LJM716 (Novartis); AT355 (Novartis); OMP-21M18 (Demcizumab, OncoMed); OMP52M51 (Oncomed/GSK); OMP-59R5 (Oncomed/GSK); vantictumab (Oncomed/Bayer); CMC-544 (inotuzumab ozogamicin, Pfizer); PF-03446962 (Pfizer); PF-04856884 (Pfizer); PSMA-ADC (Progenics); REGN1400 (Regeneron); REGN910 (nesvacutnab, Regeneron/Sanofi); REGN421 (enoticumab, Regeneron/Sanofi); RG7221, RG7356, RG7155, RG7444, RG7116, RG7458, RG7598, RG7599, RG7600, RG7636, RG7450, RG7593, RG7596, DCDS3410A, RG7414 (parsatuzumab), RG7160 (imgatuzumab), RG7159 (obintuzumab), RG7686, RG3638 (onartuzumab), RG7597 (Roche/Genentech); SAR307746 (Sanofi); SAR566658 (Sanofi); SAR650984 (Sanofi); SARI 53192 (Sanofî); SAR3419 (Sanofi); SAR256212 (Sanofi), SGN-LIV1A (lintuzumab, Seattle Genetics); SGN-CD33A (Seattle Genetics); SGN-75 (vorsetuzumab mafodotin, Seattle Genetics); SGN-19A (Seattle Genetics) SGN-CD70A (Seattle Genetics); SEA-CD40 (Seattle Genetics); ibritumomab tiuxetan (Spectrum); MLN0264 (Takeda); ganitumab (Takeda/Amgen); CEP-37250 (Teva); TB-403 (Thrombogenic); VB4-845 (Viventia); Xmab2512 (Xencor); Xmab5574 (Xencor); nimotuzumab (YM Biosciences); Carlumab (Janssen); NY-ESO TCR (Adaptimmune); MAGE-A-10 TCR (Adaptimmune); CTL019 (Novartis); JCAR015 (Juno Therapeutics); KTE-C19 CAR (Kite Pharma); UCART19 (Cellectis); BPX-401 (Bellicum Pharmaceuticals); BPX-601 (Bellicum Pharmaceuticals); ATTCK20 (Unum Therapeutics); CAR-NKG2D (Celyad); Onyx-015 (Onyx Pharmaceuticals); H101 (Shanghai Sunwaybio); DNX-2401 (DNAtrix); VCN-01 (VCN Biosciences); Colo-Adl (PsiOxus Therapeutics); ProstAtak (Advantagene); Oncos-102 (Oncos Therapeutics); CG0070 (Cold Genesys); Pexa-vac (JX-594, Jennerex Biotherapeutics); GL-ONC1 (Genelux); T-VEC (Amgen); G207 (Medigene); HF10 (Takara Bio); SEPREHVIR (HSV1716, Virttu Biologics); OrienXOlO (OrienGene Biotechnology); Reolysin (Oncolytics Biotech); SW-001 (Neotropix); Cacatak (CVA21, Viralytics); Alimta (Eli Lilly), cisplatin, oxaliplatin, irinotecan, folinic acid, methotrexate, cyclophosphamide, 5-fluorouracil, Zykadia (Novartis), Tafinlar (GSK), Xalkori (Pfizer), Iressa (AZ), Gilotrif (Boehringer Ingelheim), Tarceva (Astellas Pharma), Halaven (Eisai Pharma), Veliparib (Abbvie), AZD9291 (AZ), Alectinib (Chugai), LDK378 (Novartis), Genetespib (Synta Pharma), Tergenpumatucel-L (NewLink Genetics), GV1001 (Kael-GemVax), Tivantînib (ArQule); Cytoxan (BMS); Oncovin (Eli Lilly); Adriamycin (Pfizer); Gemzar (Eli Lilly); Xeloda (Roche); Ixempra (BMS); Abraxane (Celgene); Trelstar (Debiopharm); Taxotere (Sanofi); Nexavar (Bayer);

IMMU-132 (Immunomedics); E7449 (Eisai); Thermodox (Celsion); Cometriq (Exellxis); Lonsurf (Taiho Pharmaceuticals); Camptosar (Pfizer); UFT (Taiho Pharmaceuticals); and TS-1 (Taiho Pharmaceuticals).

Modes of administration

Preferably, the compositions of the invention are to be administered to the gastrointestinal tract in order to enable delivery to and / or partial or total colonisation of the intestine with the bacterial strain of the invention. Generally, the compositions of the invention are administered orally, but they may be administered rectally, intranasally, or via buccal or sublingual routes.

In certain embodiments, the compositions of the invention may be administered as a foam, as a spray or a gel.

In certain embodiments, the compositions of the invention may be administered as a suppository, such as a rectal suppository, for example in the form of a theobroma oil (cocoa butter), synthetic hard fat (e.g. suppocire, witepsol), glycero-gelatin, polyethylene glycol, or soap glycerin composition.

In certain embodiments, the composition of the invention is administered to the gastrointestinal tract via a tube, such as a nasogastric tube, orogastric tube, gastric tube, jejunostomy tube (J tube), percutaneous endoscopie gastrostomy (PEG), or a port, such as a chest wall port that provides access to the stomach, jéjunum and other suitable access ports.

The compositions of the invention may be administered once, or they may be administered sequentially as part of a treatment regimen. In certain embodiments, the compositions of the invention are to be administered daily.

In certain embodiments of the invention, treatment according to the invention is accompanied by assessment of the patienfs gut microbiota. Treatment may be repeated if delivery of and / or partial or total colonisation with the strain of the invention is not achieved such that efficacy is not observed, or treatment may be ceased if delivery and / or partial or total colonisation is successful and efficacy is observed.

In certain embodiments, the composition of the invention may be administered to a prégnant animal, for example a mammal such as a human in order to prevent an inflammatory or autoimmune disease developing in her child in utero and / or after it is bom.

The compositions of the invention may be administered to a patient that has been diagnosed with a disease or condition mediated by IL-17 or the Th 17 pathway, or that has been identified as being at risk of a disease or condition mediated by IL-17 or the Thl 7 pathway. The compositions may also be administered as a prophylactic measure to prevent the development of diseases or conditions mediated by IL-17 or the Thl 7 pathway in a healthy patient.

The compositions of the invention may be administered to a patient that has been identified as having an abnormal gut microbiota. For example, the patient may hâve reduced or absent colonisation by Parabacteroides, and in particular Parabacteroides distasonis.

The compositions of the invention may be administered as a food product, such as a nutritional supplément.

Generally, the compositions of the invention are for the treatment of humans, although they may be used to treat animais including monogastric mammals such as poultry, pigs, cats, dogs, horses or rabbits. The compositions of the invention may be useful for enhancing the growth and performance of animais. If administered to animais, oral gavage may be used.

Compositions

Generally, the composition of the invention comprises bacteria. In preferred embodiments of the invention, the composition is formulated in freeze-dried form. For example, the composition of the invention may comprise granules or gelatin capsules, for example hard gelatin capsules, comprising a bacterial strain of the invention.

Preferably, the composition of the invention comprises lyophilised bacteria. Lyophilisation of bacteria is a well-established procedure and relevant guidance is available in, for example, references [46-48],

Altematively, the composition of the invention may comprise a live, active bacterial culture.

In preferred embodiments, the composition of the invention is encapsulated to enable delivery of the bacterial strain to the intestine. Encapsulation protects the composition from dégradation until delivery at the target location through, for example, rupturing with Chemical or physical stimuli such as pressure, enzymatic activity, or physical disintegration, which may be triggered by changes in pH. Any appropriate encapsulation method may be used. Exemplary encapsulation techniques include entrapment within a porous matrix, attachaient or adsorption on solid carrier surfaces, selfaggregation by flocculation or with cross-linking agents, and mechanical containment behind a microporous membrane or a microcapsule. Guidance on encapsulation that may be useful for preparing compositions of the invention is available in, for example, references [49] and [50].

The composition may be administered orally and may be in the form of a tablet, capsule or powder. Encapsulated products are preferred because Parabacteroides are anaerobes. Other ingrédients (such as vitamin C, for example), may be included as oxygen scavengers and prebiotic substrates to improve the delivery and / or partial or total colonisation and survival in vivo. Altematively, the probiotic composition of the invention may be administered orally as a food or nutritional product, such as milk or whey based fermented dairy product, or as a pharmaceutical product.

The composition, may be formulated as a probiotic.

A composition of the invention includes a therapeutically effective amount of a bacterial strain of the invention. A therapeutically effective amount of a bacterial strain is sufficient to exert a bénéficiai effect upon a patient. A therapeutically effective amount of a bacterial strain may be sufficient to result in deliveiy to and / or partial or total colonisation of the patient’s intestine.

A suitable daily dose of the bacteria, for example for an adult human, may be from about 1 x 10³ to about 1 x 10¹¹ colony forming units (CFU); for example, from about 1 x 10⁷ to about 1 x 1O¹⁰ CFU; in another example from about 1 x 10⁶ to about 1 x 1O¹⁰ CFU.

In certain embodiments, the composition contains the bacterial strain in an amount of from about 1 x 10⁶ to about 1 x 10¹¹ CFU/g, respect to the weight of the composition; for example, from about 1 x 10⁸ to about 1 x 10^to CFU/g. The dose may be, for example, 1 g, 3g, 5g, and 10g.

Typically, a probiotic, such as the composition of the invention, is optionally combined with at least one suitable prebiotic compound. A prebiotic compound is usually a non-digestible carbohydrate such as an oligo- or polysaccharide, or a sugar alcohol, which is not degraded or absorbed in the upper digestive tract. Known prebiotics include commercial products such as inulin and transgalactooligosaccharides.

In certain embodiments, the probiotic composition of the présent invention includes a prebiotic compound in an amount of from about 1 to about 30% by weight, respect to the total weight composition, (e.g. from 5 to 20% by weight). Carbohydrates may be selected from the group consisting of: fructo- oligosaccharides (or FOS), short-chain fructo-oligosaccharides, inulin, isomaltoligosaccharides, pectins, xylo-oligosaccharides (or XOS), chitosan-oligosaccharides (or COS), betaglucans, arable gum modified and résistant starches, polydextrose, D-tagatose, acacia fibers, carob, oats, and citrus fibers. In one aspect, the prebiotics are the short-chain fructo-oligosaccharides (for simplicity shown herein below as FOSs-c.c); said FOSs-c.c. are not digestible carbohydrates, generally obtained by the conversion of the beet sugar and including a saccharose molécule to which three glucose molécules are bonded.

The compositions of the invention may comprise pharmaceutically acceptable excipients or carriers. Examples of such suitable excipients may be found in the reference [51]. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in reference [52]. Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnésium stéarate, mannitol, sorbitol and the like. Examples of suitable diluents include éthanol, glycerol and water. The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s). Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, freeflow 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 stéarate, magnésium stéarate, sodium benzoate, sodium acetate, sodium chlorîde and the like. Preservatives, stabilizers, dyes and even flavouring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

The compositions of the invention may be formulated as a food product. For example, a food product may provide nutritional benefit in addition to the therapeutic effect of the invention, such as in a nutritional supplément. Similarly, a food product may be formulated to enhance the taste of the composition of the invention or to make the composition more attractive to consume by being more similar to a common food item, rather than to a pharmaceutical composition. In certain embodiments, the composition of the invention is formulated as a milk-based product. The terni milk-based product means any liquid or semi-solid milk- or whey- based product having a varying fat content. The milk-based product can be, e.g., cow's milk, goat’s milk, sheep's milk, skimmed milk, whole milk, milk recombined from powdered milk and whey without any processing, or a processed product, such as yoghurt, curdled milk, curd, sour milk, sour whole milk, butter milk and other sour milk products. Another important group includes milk beverages, such as whey beverages, fermented milks, condensed milks, infant or baby milks; Ilavoured milks, ice cream; milk-containing food such as sweets.

In certain embodiments, the compositions of the invention contain a single bacterial strain or species and do not contain any other bacterial strains or species. Such compositions may comprise only de minimis or biologically irrelevant amounts of other bacterial strains or species. Such compositions may be a culture that is substantially frcc from other species of organism.

The compositions for use in accordance with the invention may or may not require marketing approval.

In some cases, the lyophilised bacterial strain is reconstituted prior to administration. In some cases, the reconstitution is by use of a diluent described herein.

The compositions of the invention can comprise pharmaceutically acceptable excipients, diluents or carriers.

In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain of the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder is selected from the group consisting of asthma, allergie asthma, neutrophilie asthma, osteoarthritis, psoriatic arthritis, juvénile idiopathic arthritis, neuromyelitis optica (Devic's disease), ankylosing spondylitis, spondyloarthritis, systemic lupus erythematosus, celiac disease, chronic obstructive pulmonary disease (COPD), cancer, breast cancer, colon cancer, lung cancer, ovarian cancer, uveitis, scleritis, vasculitis, Behcet's disease, atherosclerosis, atopie dermatitis, emphysema, perîodontitis, allergie rhinitis, and allograft rejection.

In certain embodiments, the invention provides pharmaceutical composition comprising: a bacterial strain of the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat or prevent a disease or condition mediated by IL-17 or the Thl7 pathway. In preferred embodiments, said disease or condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatoiy bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, asthma, allergie asthma, neutrophilie asthma, osteoarthritis, psoriatic arthritis, juvénile idiopathic arthritis, neuromyelitis optica (Devic's disease), ankylosing spondylitis, spondyloarthritis, systemic lupus erythematosus, chronic obstructive pulmonary disease (COPD), cancer, breast cancer, colon cancer, lung cancer, ovarian cancer, uveitis, scleritis, vasculitis, Behcet’s disease, atherosclerosis, atopie dermatitis, emphysema, periodontitis, allergie rhinitis, and allograft rejection.

In certain embodiments, the invention provides the above pharmaceutical composition, wherein the amount of the bacterial strain is from about 1 x 10³ to about 1 x 10¹¹ colony forming units per gram with respect to a weight of the composition.

In certain embodiments, the invention provides the above pharmaceutical composition, wherein the composition is administered at a dose of 1 g, 3 g, 5 g or 10 g.

In certain embodiments, the invention provides the above pharmaceutical composition, wherein the composition is administered by a method selected from the group consisting of oral, rectal, subeutaneous, nasal, buccal, and sublingual.

In certain embodiments, the invention provides the above pharmaceutical composition, comprising a carrier selected from the group consisting of lactose, starch, glucose, methyl cellulose, magnésium stéarate, mannitol and sorbitol.

In certain embodiments, the invention provides the above pharmaceutical composition, comprising a diluent selected from the group consisting of éthanol, glycerol and water.

In certain embodiments, the invention provides the above pharmaceutical composition, comprising an excipient selected from the group consisting of starch, gelatin, glucose, anhydrous lactose, freeflow lactose, beta-lactose, corn sweetener, acacia, tragacanth, sodium alginate, carboxymethyl cellulose, polyethylene glycol, sodium oleate, sodium stéarate, magnésium stéarate, sodium benzoate, sodium acetate and sodium chloride.

In certain embodiments, the invention provides the above pharmaceutical composition, further comprising at least one of a preservative, an antioxidant and a stabilizer.

In certain embodiments, the invention provides the above pharmaceutical composition, comprising a preservative selected from the group consisting of sodium benzoate, sorbic acid and esters of phydroxybenzoic acid.

In certain embodiments, the invention provides the above pharmaceutical composition, wherein said bacterial strain is lyophilised.

iïi certain embodiments, the invention provides the above pharmaceutical composition, wherein when the composition is stored in a sealed container at about 4°C or about 25°C and the container is placed in an atmosphère having 50% relative humidity, at least 80% of the bacterial strain as measured in colony forming units, remains after a period of at least about: 1 month, 3 months, 6 months, 1 year, 1.5 years, 2 years, 2.5 years or 3 years.

Culturing methods

The bacterial strains for use in the présent invention can be cultured using standard microbiology techniques as detailed in, for example, references [53-55].

The solid or liquid medium used for culture may be YCFA agar or YCFA medium. YCFA medium may include (per 100ml, approximate values): Casitone (1.0 g), yeast extract (0.25 g), NaHCCh (0.4 g), cysteine (0.1 g), K₂HPO₄ (0.045 g), KH₂PO₄ (0.045 g), NaCl (0.09 g), (NH₄)₂SO₄ (0.09 g), MgSO₄ · 7H₂O (0.009 g), CaCl₂ (0.009 g), resazurin (0.1 mg), hemin (1 mg), biotin (1 pg), cobalamin (1 pg), p-aminobenzoîc acid (3 pg), folie acid (5 pg), and pyridoxamine (15 pg).

Bacterial strains for use in vaccine compositions

The inventors hâve identified that the bacterial strains of the invention are usefiil for treating or preventing diseases or conditions mediated by IL-17 or the Th 17 pathway. This is likely to be a resuit of the effect that the bacterial strains of the invention hâve on the host immune System. Therefore, the compositions of the invention may also be usefiil for preventing diseases or conditions mediated by IL-17 or the Thl7 pathway, when administered as vaccine compositions. In certain such embodiments, the bacterial strains of the invention may be killed, inactivated or attenuated. In certain such embodiments, the compositions may comprise a vaccine adjuvant. In certain embodiments, the compositions are for administration via injection, such as via subeutaneous injection.

General

The practice of the présent invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, immunology and pharmacology, within the skill of the art. Such techniques are explained fùlly in the literature. See, e.g., references [56] and [57-63], etc,

The terni “comprising” encompasses “including” as well as “consisting” e.g. a composition “comprising” X may consist exclusively of X or may include something additional e.g. X + Y.

The term “about” in relation to a numerical value x is optional and means, for example, x+10%.

The word “substantially” does not exclude “completely” e.g. a composition which is “substantially Iree” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the définition of the invention.

References to a percentage sequence identity between two nucléotide sequences means that, when aligned, that percentage of nucléotides are the same in comparing the two sequences. This alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in section 7.7.18 of ref. [64], A preferred alignment is determined by the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, BLOSUM matrix of 62. The SmithWaterman homology search algorithm is disclosed in ref. [65],

Unless specîfically stated, a process or method comprising numerous steps may comprise additional steps at the beginning or end of the method, or may comprise additional intervening steps. Also, steps may be combined, omitted or performed in an alternative order, if appropriate.

Various embodiments of the invention are described herein. It will be apprecîated that the features specified in each embodiment may be combined with other specified features, to provide fiirther embodiments. In particular, embodiments highlighted herein as being suitable, typical or preferred may be combined with each other (except when they are mutually exclusive).

MODES FOR CARRYING OUT THE INVENTION

Example 1 — Efflcacy of bacterial inocula in a mouse model of house dust mite-induced asthma

Summary

Mice were administered with compositions comprising bacterial strains according to the invention and were subsequently challenged with house dust mite (HDM) extract to elicit an allergie inflammatory response. The inflammatory response to HDM includes éosinophilie and neutrophilie components, is mediated by IL-17 and the Thl7 pathway, and is a model for asthma. The magnitude and characteristics of the inflammatory response exhibited by mice treated with compositions of the invention were compared to control groups. The compositions of the invention were found to alleviate the inflammatory response, and to reduce recruitment of eosinophils and neutrophils, indicating that they may be useful for treating IL-17- and Thl7- mediated conditions such as eosinophilia, neutrophilia and asthma.

Strain

755: Parabacteroides distasonis

Study design

Groups:

1. Négative control group. Treatment with vehicle control (per oral).

5. Treatment with therapeutic bacteria inoculum strain 755 (per oral).

7. Positive control group. Treatment with Dexamethasone (i.p.).

8. Untreated Control Group.

Number of mice per group = 5

Day -14 to day 13: Daily administration of vehicle control per oral (Group 1).

Day -14 to day 13: Daily administration of therapeutic bacteria inoculum per oral (Group 2-6).

Day 0, 2, 4, 7, 9, 11 Administration of 15ug HDM (house dust mite extract - Catalogue number: XPB70D3A25, Lot number: 231897, Greer Laboratories, Lenoir, NC, USA) in a volume of 30ul PBS per nasal (Group 1-8).

Day 0, 2, 4, 7, 9, 11 Administration of Dexamethasone (i.p., 3mg/kg, Sigma-Aldrich, Catalogue number DI 159) (Group 7).

Day 14 Sacrifice of ail animais for analysis.

Total number of mice = 40.

Endpoints and analysis

On day 14 animais were sacrificed by léthal intraperitoneal injection with pentabarbitol (Streuli Pharma AG, Uznach, Cat: 1170139A) immediately followed by a bronchoalveolar lavage (BAL).

Cells were isolated from the BAL (bronchoalveolar lavage) fluid and differential cell counts performed (200 cell counts/ samples).

Material and Methods

Mice. Female 7 week old BALB/c mice were purchased from Charles River Laboratories and randomly allocated to cages totally 5 mice per cage (Ventilated cages sourced from Indulab AG, Gams, Switzerland Cage type: “The SealsafeTM IVC cage. Product number 1248L). Cages were labeled with study number, group number and experimental starting date. Mice were monitored weekly and acclimatized to facility for 7 days prior to initiation of study (Study Day -14). Animais were 8 weeks old on Study Day -14. Potable water and food were available ad libitum. Cage enrichment was présent. Daily care of the animais was performed according to local authorization license number 2283.1 (issued and approved by: Service de la consommation et des affaires vétérinaires du Canton de Vaud). Potable water and food were available ad libitum and refreshed once daily. Cage enrichment was présent. Animal welfare régulations were observed as given by official authorities of Switzerland under ordinance 455.163 ofthe FVO (Fédéral Veterinary Office) on laboratory animal husbandry, production of genetically modified animais, and methods of animal expérimentation,

Culturing of bacteria inoculum. Within a stérile workstation, a cryo-vial of bacteria was thawed by warming in gloved hand and ~0.7 ml of contents injected into a Hungate tube (Cat Number, 1020471, Glasgerâtebau Ochs, Bovenden-Lenglem, Germany), containing 8 ml of anaérobie YCFA. Two tubes per strain were usually prepared. The Hungate tubes were then incubated (static) at 37°C for 16h (for strain 755).

Culturing of vehicle control. A Hungate tube containing 8 ml of anaérobie YCFA was incubated (static) at 37°C for 16h.

Administration of bacteria inoculum or vehicle control. 400ul of cultured bacteria inoculum or vehicle control were adminîstered per day per oral gavage.

Intranasal sensitization. Mice were anesthetized by i.p. injection with 9.75 mg xylasol and 48.75 mg ketasol per kg (Dr. E. Graeub AG, Bem, Switzerland) and adminîstered with 15ug of HDM (Catalogue number: XPB70D3A25, Lot number: 231897, Greer Laboratories, Lenoir, NC, USA) in a volume of 3 Oui PB S per nasal.

Préparation and administration of positive control compound Dexamethasone. Déxaméthasone 21-phosphate disodium sait (Sigma-Aldrich, Catalogue number DI 159, Lot N° SLBD.1030V) was solved in HiO and adminîstered to the animais in a dose of 3mg/kg in a volume of 200ul per oral at days indicated in study protocol above.

Terminal procedure. On day 14 animais were sacrifïced by léthal i.p. injection with pentabarbitol (Streuli Pharma AG, Uznach, Cat: 1170139A) immediately followed by bronchoalveolar lavage (BAL) in 500 ul of saline.

Measurement of cellnlar infiltrâtes into BAL. Cells were isolated from the BAL fluid and differential cell counts were performed based upon standard morphological and cytochemical criteria.

Graphs and statistical analysis. Ail graphs were generated with Graphpad Prism Version 6 and a one-way ANOVA was applied. Résulte from the statistical analysis were provided with the individual data tables. Error bars represent Standard Error of the Mean (SEM).

Résulta and analysis

The results of the experiments are shown in Figures 1-9.

No morbidity or mortality was noted in the mice treated with the bacteria or the vehicle. The two Controls, vehicle treatment (négative control) and the dexamethasone treatment (positive control) behaved as expected, with impaired eosinophilia and neutrophilia noted following dexamethasone treatment.

The most important results of this experiment are displayed in Figures 6 and 7, which report on the total number and percentage of neutrophils detected in bronchiolar lavage following challenge with HDM. Administration of strain 755 resulted in a statistically significant réduction in total neutrophils and the proportion of neutrophils in BAL relative to the vehicle-only control.

Example 2 — Efficacy of bacterial inocula in a mouse model of severe neutrophilie asthma

Summary

Mice were administered with compositions comprising bacterial strains according to the invention and were subsequently sensitised with subeutaneous administrations of house dust mite (HDM) extract and challenged with an intranasal administration of HDM in order to model the inflammatory response of severe neutrophilie asthma. The magnitude and characteristics of the inflammatory response exhibited by mice treated with compositions of the invention were compared to control groups. The compositions of the invention were found to alleviate the inflammatory response, and in particular to reduce recruitment of neutrophils, in a manner comparable to the positive control comprising administrations of anti-IL-17 antibodies. The data therefore indicate that the compositions of the invention may be useful for treating IL-17- and Thl7-mediated conditions such as neutrophilia and asthma.

Strain

755: Parabacteroides distasonis

Study design

Groups:

1. Négative control group. Treatment with vehicle control (per oral).

5. Treatment with therapeutic bacteria inoculum strain 755 (per oral).

7. Positive control group. Treatment anti-IL-17 (i.p.).

8. Untreated Control Group.

9: Healthy mice (baseline).

Number of mice per group (Group 1-8) = 5

Day -14 to day 17: Daily administration of vehicle control per oral (Group 1).

Day -14 to day 17: Daily administration of therapeutic bacteria inoculum per oral (Group 2-6).

Day 0: Sensitization with HDM in CFA (s.c.) (Group 1-8).

Day 7: Sensitization with HDM in CFA (s.c.) (Group 1-8).

Day 13, 15, 17: Administration of anti IL-17 neutralizing antibody per i.p. (Group 7).

Day 14, 15, 16, 17: Challenge with HDM in 30ul PBS per nasal (Group 1-8).

Day 18: Sacrifice of ail animais for analysis.

Endpoints and analysis:

On day 14 animais were sacrificed by léthal intraperitoneal injection with pentabarbitol (Streuli Pharma AG, Uznach, Cat: 1170139A) immediately followed by a bronchoalveolar lavage (BAL). Cells were isolated from the BAL fluid and differential cell counts performed (200 cell counts/ samples).

Material and Methods,

Mice. Female 7 week old C57BL/6 mice were purchased from Charles River Laboratories and randomly allocated to cages totally 5 mice per cage (Ventilated cages sourced from Indulab AG, Gams, Switzerland Cage type: “The SealsafeTM - IVC cage. Product number 1248L). Cages were labelled with study number, group number and experimental starting date. Mice were monitored weekly and acclimatized to facility for 7 days prior to initiation of study (Study Day -14). Animais were 8 weeks old on Study Day -14. Potable water and food were available ad libitum. Cage enrichment was présent. Daily care of the animais was performed according to local authorization license number 2283.1 (issued and approved by: Service de la consommation et des affaires vétérinaires du Canton de Vaud). Potable water and food were available ad libitum and refreshed once daily. Cage enrichment was présent. Animal welfare régulations were observed as given by official authorities of Switzerland under ordinance 455.163 of the FVO (Fédéral Veterinary Office) on laboratory animal husbandry, production of genetically modified animais, and methods of animal expérimentation.

Culturing of bacteria inoculum. Within a stérile workstation, a cryo-vial of bacteria was thawed by warming in gloved hand and ~0.7 ml of contents injected into a Hungate tube (Cat Number, 1020471, Glasgerâtebau Ochs, Bovenden-Lenglem, Germany), containing 8 ml of anaérobie YCFA. Two tubes per strain were usually prepared. The Hungate tubes were then incubated (static) at 37°C for 16h (for strain 755).

Culturing of vehicle control. A Hungate tube containing 8 ml of anaérobie YCFA was incubated (static) at 37°C for 16h.

Administration of bacteria inoculum or vehicle control. 400ul of cultured bacteria inoculum or vehicle control were administered per day per oral gavage.

HDM sensitization. 50 gg of HDM (Catalogue number: XPB70D3A25, Lot number: 231897, Greer Laboratories, Lenoir, NC, USA) in PBS was emulsified in equal volume of complété Freund’s adjuvant (CFA Chondrex Inc. Washington, USA) and administered subcutaneously in a volume of 200 μΐ, twice over two weeks on opposite flanks. A week after the second immunization, mice were anesthetized by i.p. injection with 9.75 mg xylasol and 48.75 mg ketasol per kg (Dr. E. Graeub AG, Bern, Switzerland) and then given intranasal challenges of 15 pg of HDM in a volume of 3Oui PBS on 4 consecutive days. Analysis was performed one day after the final challenge.

Préparation and administration of positive control compound anti mouse IL-17 antibody. Anti-IL-17 neutralizing antibody was sourced from Bio X Cell and was stored at 4°C (Clone 17F3, Cat. Number BE0173, Bio X Cell) and administered per i.p. at a dose of 12.5 mg/kg at days indicated in study protocol above.

Terminal procedure. On day 18 animais were sacrificed by léthal i.p. injection with pentabarbitol (Streuli Pharma AG, Uznach, Cat: 1170139A) immediately followed by bronchoalveolar lavage (BAL) in 500 ul of saline.

Measurement of cellular infiltrâtes into BAL. Cells were isolated from the BAL fluid and differential cell counts were performed based upon standard morphological and cytochemical criteria.

Graphs and statistical analysis. Ail graphs were generated with Graphpad Prism Version 6 and a one-way ANOVA was applied. Results from the statistical analysis are provided with the individual data tables. Error bars represent Standard Error of the Mean (SEM).

Results and analysis

The results of the experiment are shown in Figures 10-18.

No morbidity or mortality was noted in the mice treated with the bacteria or the vehicle. As shown in Figures 15 and 16, strain 755 was highly effîcacious in alleviating the magnitude of the neutrophilie inflammatory response. In addition, strain 755 reduced eosinophil numbers relative to the Controls, as shown in Figures 11 and 12.

Example 3 - Efficacy of bacterial inocula to treat arthritis in a type II collagen-induced arthritis mouse model

Materials and methods

Strain

755: Parabacteroides distasonis

Bacterial cultures

Bacterial cultures were grown up for administration in an anaérobie workstation (Don Whitley Scientific).

Bacterial strain #755 was grown using glycerol stocks. The glycerol stocks were stored at -80°C. 5 Three times per week, glycerol stocks were thawed at room température and streaked on YCFA plates. A new glycerol aliquot was used on each occasion. Bacteria were allowed to grow on a given plate for up to 72 hours.

Solutions to be administered to the animais were prepared twice daily with an eight hour interval for moming (AM) and aftemoon (PM) treatments. A bacterial colony was picked from the streaked plate 10 and transferred into a tube containing YCFA media. Bacterial strain #755 was allowed to grow for 24 hours before AM administrations. Bacteria were sub-cultured at 1% into YCFA media for PM administrations. OD values were recorded for each strain after moming and aftemoon treatment préparations.

Type II collagen-induced arthritis mouse model

Adult male DBA/1 mice were randomly allocated to experimental groups and allowed to acclimatise for two weeks. On Day 0, animais were administered by subeutaneous injection with 100 microliters of an émulsion containing 100 micrograms of type II collagen (Cil) in incomplète’s Freund’s adjuvant supplemented with 4 mg/ml Mycobacterium tuberculosis H37Ra. On Day 21, animais were administered by subeutaneous injection with a booster émulsion containing 100 pg of type II 20 collagen in incomplète Freund’s adjuvant.

Treatments were given according to the administration schedule below. From Day -14 until the end of the experiment on Day 45, animais were weighed three times per week. From Day 21 until the end of the experiment, animais were scored three times per week for clinical signs of arthritis to include swelling of the hind- and front paws, radio-carpal (wrist) joints and tibio-tarsal (ankle) joints.

On Day 45 mice were culled and terminal blood samples were taken for cytokine analysis.

On Day -14, Day 0 and Day 45, faecal samples were collected for microbiological analysis, immediately snap-frozen and stored at -80°C.

The collagen-induced arthritis (CIA) mouse model is a well-established mouse model for rheumatoid arthritis [66]. Immunisation with CII causes a pathogenesis that includes several important 30 pathological features of rheumatoid arthritis, including synovial hyperplasia, mononuclear cell infiltration and cartilage dégradation. Significantly, the development of CIA is mediated by Thl7 cells through sécrétion of IL-17A [67], The immune response underlying the arthritis model is enhanced by the use of Freund’s adjuvant supplemented with Mycobacterium tuberculosis.

On Day 21, spleens were collected from three satellite animais in each group. Cells were cultured for 72 hours in the presence or absence of type II collagen. Cytokines, including TNF-α, IL-6, IFN-γ, IL4, IL-10 and IL-17, were quantified in the culture supcmatants and in terminal sérum by Luminex. Cell prolifération was quantified using a tritiated thymidine incorporation method.

Treatment Groups and Dosages

Ail Groups were n=15 (n=12 for the main study group and n=3 for satellite groups)

The vehicle used for the biotherapeutics was Yeast extract-Casitone-Fatty Acids (YCFA) medium.

	Group	Dose	Administration	Disease Induction
Route	Regimen
1	Vehicle	5 ml/kg	PO	BID: Day -14-End	Day 0: Collagen/CFA, once, SC Day 21: Collagen/IFA, once, SC
5	Biotherapeutic #755	5 ml/kg

PO: oral gavage, SC: subcutaneous injection, BID: twice a day, CFA: complété Freund’s adjuvant.

Bodyweights

From Day -14 until the end of the experiment, animais were weighed three times per week. Data were graphed (Mean ± SEM).

N on-spécifie clinical observations

From Day -14 until the end of the experiment, animais were checked daily for non-specific clinical signs to include abnormal posture (hunched), abnormal coat condition (piloerection) and abnormal activity levels (reduced or increased activity).

Clinical Observations

From Day 21 until the end of the experiment on Day 45, animais were scored three times per week for clinical signs of arthritis to include swelling of the hind- and front paws, radio-carpal (wrist) joints and tibio-tarsal (ankle) joints. Each limb was scored using the following scale: (0) normal, (1) slight swelling, (2) mild swelling, (3) moderate swelling and (4) severe swelling. A clinical score was calculated by adding each limb score. The maximum possible clinical score for an animal was (16). Animais with a score equal to (12) on two consecutive occasions and animais with a score greater than (12) on any one occasion were culled. Data were graphed (Mean ± SEM).

Cell prolifération analysis

On Day 21, three satellite animais per group were culled and spleens were dissected out. Spleen cells were cultured for 72 hours in presence or absence of type II Collagen. After 72 hours, cells were pulsed ovemight in the presence of tritiated thymidine. Cell prolifération was quantified by measuring thymidine incorporation. Data were graphed (Mean ± SEM). Supematants were taken and tested for the presence of key cytokines.

Cytokine analysis

Terminal supematants from the spleen cell cultures were tested in order to quantitate TNF-α, IL-6, IFN-γ, IL-4, IL-10 and IL-17 by Luminex. Data were graphed (Mean ± SEM).

Microbiological analysis

On Day -14, Day 0 and Day 45, faecal samples were collected from each animal, immediately snapfrozen, and stored at -80°C. Caeca (including content) were immediately snap-frozen and stored at -80°C. A bacterial identification test was performed daily by plating the bacteria.

Histopathology

At the end of the experiment, hind paws were stored in tissue fixative. Samples were transferred into décalcification solution. Tissue samples were processed, sectioned and stained with Haematoxylin & Eosin. Sections were scored by a qualified histopathologîst, blind to the experimental design, for signs of arthritis to include inflammation, articular cartilage damage and damage to the underlying metaphyseal bone. A detailed scoring System was used (see below). Data were graphed (Mean ± SEM). Raw and analysed data were provided as well as représentative pictures.

Table 1: Histopathology Scoring System

Grade Description

Inflammation

Normal joint

Mild synovial hyperplasia with inflammation dominated by neutrophils. Low numbers of neutrophils and macrophages in joint space.

Synovial hyperplasia with moderate to marked inflammation involvîng both neutrophils and macrophages. Neutrophils and macrophages in joint space; may be some necrotic tissue débris.

Synovial hyperplasia with marked inflammation involving both neutrophils and macrophages. Loss of synoviocyte lining. Inflammation may extend from synovium to surrounding tissue including muscle. Numerous neutrophils and macrophages in joint space, together with significant necrotic tissue débris.

Articular cartilage damage

Normal joint

Articular cartilage shows only mild degenerative change. Early pannus formation may be présent peripherally.

Articular cartilage shows moderate degenerative change and focal loss. Pannus formation is présent focally.

Significant disruption and loss of articular cartilage with extensive pannus formation.

Damage to the underlying metaphyseal b one

Normal joint

No change to underlying metaphyseal bone.

May be focal necrosis or fibrosis of metaphyseal bone.

Disruption or collapse of metaphyseal bone. Extensive inflammation, necrosis or fibrosis extending to medullary space of the metaphysis.

Results and analysis

Survival and Non-specific Clinical Observations

Some animais were culled prior to the scheduled end of the study due to the severity of the clinical signs of arthritis or due to the severity of the non-specific clinical observations.

Three animais were culled or found dead during the pre-treatment period (Day -14 to Day 0): one animal in Group 1 (vehicle-treated, animal arrived from supplier with broken leg and was culled) and two animais in Group 5 (biotherapeutic #755-treated).

Seven animais were culled due to the severity of the clinical signs of arthritis: five animais in Group 1 (vehicle-treated) and two animais in Group 5 (biotherapeutic #755-treated).

Three animais in Group 1 (vehicle-treated) were culled due to the severity of the non-specific clinical signs including abnormal posture (hunched), abnormal coat condition (piloerection), abnormal activity levels (reduced activity).

Bodyweights

Bodyweight data recorded from Day -14 until Day 0 and expressed as a percentage of the initial (Day 15 -14) bodyweights were analysed by two-way ANOVA followed by Dunnett’s post-test for multiple comparisons with Day -14 then for multiple comparison with the vehicle-treated group. The data are presented in Figure 19. Data from animais culled prior to the scheduled end of the experiment were excluded from the analyses.

When compared to Day -14, twice daily administrations by oral gavage induced a significant bodyweight loss in the vehicle-treated group on Day -9 and Day -7.

Bodyweight data recorded from Day 0 until Day 28 and expressed as a percentage of the initial (Day 0) bodyweights were analysed by two-way ANOVA followed by Dunnett’s post-test for multiple comparisons with Day 0 in the Vehicle group then for multiple comparison with the vehicle-treated group. The data are presented in Figure 20. Data from animais culled prior to the scheduled end of the experiment and from Satellite animais were excluded from the analyses. Day 28, Day 35 and Day 42 data were further analysed by one-way ANOVA followed by Dunnett’s post-test for multiple comparisons to the vehicle-treated group.

The onset of clinical signs of arthritis was associated with a significant bodyweight loss on Day 26 and Day 28 (p < 0.0001) when compared to Day 0 in the vehicle-treated group.

When compared to the vehicle-treated group, the bodyweights were significantly higher in Group 5 (biotherapeutic #755 treated) on Day 28 (<0.0001).

Clinical Observations

Clinical score data were analysed by two-way ANOVA followed by Dunnett’s post-test for multiple comparisons between days in the vehicle-treated group then for multiple comparisons between experimental groups and the vehicle-treated group each day. The data are presented in Figure 21. Data recorded from animais culled prior to the end of the experiment were excluded from the analysis. When animais were culled due to the severity of the clinical signs of arthritis, the last recorded score was reported for the following days and used in the statistical analyses.

A significant increase of the clinical scores was observed in the vehicle-treated group from Day 28 until Day 45 (p < 0.0001) when compared to Day 21.

Biotherapeutic #755 induced a réduction of the clinical scores when compared to the vehicle-treated group from Day 28 until Day 45. The réduction was statistically significant on Day 31 and Day 38 (p<0.05).

Cell prolifération analysis

To validaie the assay, splénocytes were cultured in the presence of soluble anti-CD3 and anti-CD28 (anti-CD3/CD28) as positive control stimuli to confirm the proliférative potential of the cells. î

Strong proliférative responses to anti-CD3/CD28 were seen in ail experimental groups, showing cells were healthy, viable and able to respond to activation signais.

To test the proliférative response in presence of Collagen II (CII), splénocytes were cultured in the presence of Cil at 50 pg/ml. Splénocyte proliférative response to Cil were analysed by two-way ANOVA followed by Sydak’s post-test for multiple comparisons between unstimulated and CIIstimulated splénocytes and one-way ANOVA followed by Dunnett’s post-test for comparison of CIIstimulated response in different experimental groups with the vehicle-treated group. The data are presented in Figure 22.

Cil induced a highly significant increase of ³H-thymidine incorporation (cpm) when compared to the unstimulated splénocytes in the vehicle-treated group (p < 0.0001).

The groups treated with biotherapeutic #755 demonstrated signifïcantly lower levels of ClI-induced splénocyte prolifération than the vehicle-treated group.

Cytokine levels in tissue culture supernatants

Levels of each cytokine were measured in tissue culture supernatants derived from anti-CD3/CD28 stimulated cultures by luminex analysis. These showed robust responses for ail cytokines measured (mean levels in vehicle group were as follows: IL-4 = 6,406 pg/ml; IL-6 = 306 pg/ml; IL-10 = 10,987 pg/ml; IL-17A = 11,447 pg/ml; IFN-γ = 15,581 pg/ml; TNF-α = 76 pg/ml).

The following sections summarise the data obtained from the Collagen II-stimulated cultures. Where applicable, statistical analyses of the différences between cytokine levels in supernatants of unstimulated and ClI-stimulated splénocytes were conducted using two-way ANOVA followed by Sidak’s post-test for multiple comparisons, while one-way ANOVA followed by Dunnett’s post-test was used for comparison of ClI-stimulated response in biotherapeutîc-treated groups with the vehicle-treated group. There was no significant différence in cytokine levels between the groups in both cases. This is likely due to the small sample size used (n=3).

In order to more accurately présent the distribution of the data for the cytokines with substantial spread of the data, these are presented as scatter plots.

The group means of IL-4 in tissue culture supernatants after stimulation with Cil were <5pg/ml. These are not considered biologically significant and not included here. The group means of TNF-a in tissue culture supernatants after stimulation with collagen were below limit of quantitation.

Supernatant levels of IFN-γ (Figure 23)

Along with IL-17, IFN-γ is the major cytokine driving disease in the CIA model. The scatter plot in Figure 23 demonstrates IFN-γ levels after Cil stimulation, with group médian being higher for the Vehicle-treated group compared to the biotherapeutic.

Supernatant levels of IL-17A (Figure 24)

Levels of IL-17A were 50pg/mI in Cil-stimulated cultures for the Vehicle-treated group. The levels of this cytokine appeared to be lower in the biotherapeutic group compared to the Vehîcle-treated group.

Supernatant levels of IL-10 (Figure 25)

Levels of IL-10 in Vehicle-treated group were 13 pg/ml and 2.1 pg/ml for ClI-stimulated, and media control cultures, respectively. Higher levels of IL-10 (which is an anti-inflammatory cytokine) for the vehicle-treated group may be expected because inflammation and pro-inflammatory cytokine induction could be accompanied by an anti-inflammatory feedback mechanism.

Supernatant levels of IL-6 (Figure 26)

Inflammatory cytokines such as IL-6 and TNF-α are not typically produced at high levels in anti-CII cultures. However, their levels may be altered as a resuit of immune modulation. Levels of IL-6 in ClI-stimulated cultures were modest, reaching lOpg/ml. Although higher than in media control cultures, these différences were too small to provide rationale for performing statistical analyses.

Microbiological analysis

Bacterial growth was confirmed by measuring the optîcal density at 600 nm using a spectrophotometer. Bacterial identity was confirmed by comparing streaked plate pictures to reference pictures.

Foliowing the improved bacterial préparation method, consistently high doses of bacterial strain were administered from Day -2 and Day -3 as indicated by the high OD values measured.

Faecal samples were collected and snap-frozen on Day -14, Day 0 and at termination.

Histopathology

The histopathology résulte are shown in Figures 65-69. As expected for this model, intra-individual and inter-individual variability was observed in terms of the presence/absence of arthritis or the severity of change présent,

The nature of the pathology was as expected for this model, with extensive mixed chronic-active inflammation of the synovium and bursa extending to involve the peri-articular soft tissues (muscle, adipose tissue, dermal collagen). In the most severely affected joints there was articular cartilage degeneration and loss with intra-articular débris and inflammation and disruption of the joint and bone structure by fibrosis and inflammation.

The incidence of histopathological changes was: vehicle - 80% (16/20); Biotherapeutic #755 - 41% (9/22). Treatment with Biotherapeutic #755 reduced the incidence of histopathological scores in mouse hind limbs when compared to the vehicle-treated group (see Figures 65-68). Histopathology scores were analysed by one-way ANOVA for non-parametric data (Kruskal-Wallis test) followed by

Dunn’s post-test for multiple comparisons to the vehicle-treated group. Biotherapeutic #755 induced a significant réduction of the joint inflammation scores observed in histopathology when compared to the vehicle-treated group (p < 0.05). Biotherapeutic #755 induced a significant réduction of the cartilage damage scores observed in histopathology when compared to the vehicle-treated group (p < 0.05). Biotherapeutic #755 induced a signifîcant réduction of the bone damage scores observed in histopathology when compared to the vehicle-treated group (p < 0.05). Biotherapeutic #755 induced a signifîcant réduction of the total histopathology scores when compared to the vehicle-treated group (p<0.05).

Summary

Increased clinical scores were observed from Day 28 after the first administration of type II collagen, as expected in this model of arthritis in DBA/1 mice. Biotherapeutic #755 was shown to be effective at treating arthritis in this model. Biotherapeutic #755 was effective for reducing the severity of the clinical scores and for reducing pathological disease in the joints, as demonstrated in the histopathological analysis.

Proliférative recall responses to Collagen II were seen in splénocyte cultures from ail experimental groups. The collagen-specific response was significantly reduced following treatment with biotherapeutic #755 (Group 5).

Most of the T cell cytokines tested showed détectable increases between Collagen Π-stimulated and media Controls in the Vehicle-treated group. These increases were not as obvions in the biotherapeutic-treated group. This broadly supports the proliférative recall responses to Collagen II described above.

There was evidence of suppression of the Thl/Thl7 axis, which is the pathogenic response in this model and in human RA. Corrélation of reduced levels of cytokines with reduced prolifération is suggestive of immune modulation. There was no evidence that this modulation resulted either from enhanced levels of Th2 associated IL-4 or with increases in the immune modulating cytokine, IL-10.

Example 4 — Further analysis of the effect of bacterial inocula in the mouse model of house dust mite-induced asthma

The mice tested in Example 1 were subjected to further analyses to further characterise the effect of the compositions of the invention on the allergie asthma inflammatory response.

Materials and methods

Blood withdrawal and sérum préparation on day 14. Blood samples of animais were collected via cardiac puncture. Sérum was isolated from the blood sample by centrifugation for 5 min at 14000g and stored at -20 °C.

Organ removal on day 14. Collection of the left lung lobe in formalin for follow-on histological analysis. Collection of the right lung lobes (ail remaining lobes) and removal of sérum for snap freezing and follow-on analysis. Remaining BAL fluid was snap frozen for follow-on analysis.

Measurement of antibody levels in sérum and BAL fluid

Total IgE and house-dust-mite (HDM) spécifie IgGl antibody production were measured in the BAL and sérum by ELISA assay.

Isolation of lung and histological analysis

Left lung lobes were fixed in formalin followed by embedment in paraffin, sectioning, and staining with hematoxylin and eosin and PAS. Subséquent histological scoring was performed blinded as followed: Five random fields of view per sample were scored for inflammation (peribronchial infiltration and perivascular infiltration) and mucus production. Inflammatory infiltration was scored with the following grading System:

- normal

- mild inflammatory infiltrâtes

- moderate inflammatory infiltrâtes

- marked inflammatory infiltrâtes

- severe inflammatory infiltrâtes

- very severe inflammatory infiltrâtes

In each field of view, airways were measured in size and mucus cell numbers were quantified/ um.

Measurement of inflammatory mediators in lung tissue

Right lung lobes (ail remaining lobes) isolated for quantification of inflammatory mediators were snap frozen for subséquent measurement of CCL11, IFN-gamma, IL-1 alpha, IL-1 beta, IL-4, IL-5, IL-9, IL-17A, CXCL1, CCL3, CXCL2 and CCL5 by commercially available multiplex assay (Merck-Millipore). Analysis was performed according to the manufacturées instructions.

Results and analysis

The results of the experiments are shown in Figures 27-45.

In support of the findings described in Example 1, analysis of the cellular infiltrâtes in the lung tissue of mice treated with strain 755 showed a notable and statistically significant réduction in mean inflammation score (see Figures 31 and 33).

Antibody levels in the BAL fluid and sérum were analysed (see Figures 27-30). No clear effect of the bacterial treatment on sérum antibody levels was observed. This may reflect a failure in the experiment, because the spread of data and the error bars for each treatment are large, and the positive and négative Controls do not appear to hâve behaved as would be expected. Also, the baseline sérum antibody levels could hâve masked any changes.

Similarly, no clear effect of the bacterial treatment on cytokine levels in lung tissue was observed (see Figures 35-45). Again, this may reflect a failure in the experiment, because the spread of data and the error bars for each treatment are large, and the positive and négative contrais do not appear to hâve behaved as would be expected. It is also possible that the mechanism of action involved influences earlier cytokine responses that were no longer détectable on day 4 post the final HDM airway challenge. Some care should be taken when interpreting the cytokine data in the current study, due to the variability in the levels detected. This variability could in part be explained by the fact that the lung tissue was separated for the different analyses, and thus one lung lobe might not hâve been fully représentative or comparable to the same lobe in other mice due to patchy distribution of the inflammation.

Example 5 — Further analysis of the effect of bacterial inocula in the mouse model of severe neutrophilie asthma

The mice tested in Example 2 were subjected to further analyses to further characterise the effect of the compositions of the invention on the neutrophilie response associated with severe asthma.

Materials and methods

Organ removal on day 18. Collection of the left lung lobe in formalin for follow-on histological analysis. Collection of the right lung lobes (ail remaining lobes) and removal of sérum for snap freezing and follow-on analysis. Remaining BAL fluid was snap ffozen for follow-on analysis.

Measurement of inflammatory mediators in lung tissue (follow-on analysis). Right lung lobes (ail remaining lobes) isolated for quantification of inflammatory mediators were snap ffozen for subséquent measurement of IFN-gamma, IL-1 alpha, IL-1 beta, CXCL1, CCL3, CXCL2, CCL5, IL17A, TNF-alpha, IL-17F, IL-23 and IL-33 by commercially available multiplex assay (MerckMillipore). Analysis was performed according to the manufacturer’s instructions.

Measurement of antibody levels in sérum and BAL fluid (follow-on analysis). House-dust-mite (HDM) spécifie IgGl and IgG2a antibody production were measured in the BAL and sérum by ELISA assay.

Isolation of lung and histological analysis (follow-on analysis). Left lung lobes were fixed in formalin followed by embedment in paraffin, sectioning, and staining with hematoxylin and eosin and PAS. Subséquent histological scoring was performed blinded as followed: Five random fields of view per sample were scored for inflammation (peribronchial infiltration and perivascular infiltration) and mucus production. Inflammatory infiltration was scored with the following grading System:

- normal

- mild inflammatory infiltrâtes

- moderate inflammatory infiltrâtes

- marked inflammatory infiltrâtes

- severe inflammatory infiltrâtes

- very severe inflammatory infiltrâtes

Results and analysis

The results of the experiments are shown in Figures 46-63.

Further analysis of antibody levels revealed that the efficacy of bacterial strain 755 was also reflected in reduced HDM-specific IgGl levels in the BAL fluid and sérum (see Figures 46 and 48). Firm conclusions regarding an effect on IgG2a levels cannot be drawn. Overall, the data from the antibody analysis is suggestive of a réduction related to an overall reduced inflammatory response, as opposed to a sélective effect on antibody isotype switching.

Histological analysis supported the differential cell counts from the BAL fluid, showing a reduced cellular infîltrate in mice treated with strain 755 (see Figures 50-52).

In relation to cytokine levels, as for Example 4, the spread of data and the error bars for each treatment are large, and the positive and négative Controls do not appear to hâve behaved as necessarily would be expected. It is also possible that the mechanism of action involves influencing earlier cytokine responses that were no longer détectable on day 4 post the final HDM airway challenge. Some care should be taken when interpreting the cytokine data in the current study, due to the variability in the levels detected. This variability could in part be explained by the fact that the lung tissue was separated for the different analyses, and thus one lung lobe might not hâve been fully représentative or comparable to the same lobe in other mice due to patchy distribution of the inflammation. Despite this variability, a clear anti-inflammatory effect on cytokine levels for strain 755 was shown, and the positive control anti-IL-17 Ab generally behaved as expected.

With the above caveats, the data in Figures 55 and 57 suggest that treatment with strain 755 may achieve a réduction in the levels of IL-lb and IFNy, which may be indicative of a mechanism of action related to influences on chemokine release (and thus recruitment of cells) by stromal or innate immune cells. These cytokines are part of the Thl7 pathway. Taking this dataset together, a clear conclusion can be drawn that strain 755 was highly effective at protecting mice against inflammation in this mouse model of severe neutrophilie asthma.

Example 6 — Efficacy of bacterial inocula in a mouse model of multiple sclerosis

Summary

Mice were adminîstered with compositions comprising bacterial strains according to the invention and the mice were subsequently immunised with myelin oligodendrocyte glycoprotein to induce experimental autoimmune encephalomyelitis (EAE). EAE is the most commonly used experimental model for human multiple sclerosis. The compositions of the invention were found to hâve a striking effect on disease incidence and disease severity,

Strain

755: bacteria deposited under accession number NCIMB 43282

Study design

Groups:

1, Négative control group. Treatment with vehicle control (per oral).

5. Treatment with therapeutic bacteria inoculum strain 755 (per oral).

9. Positive control group. Treatment with Dexamethasone (i.p.).

10. Untreated Control Group.

Number of mice per group =10

Days -14 to day 27: Daily administration of vehicle control per oral (Group 1).

Days -14 to day 27: Daily administration of therapeutic bacteria inoculum per oral (Group 5).

Days 0-28: administration of Dexamethasone (i.p.) three rimes a week (Group 9)

Day 0: MOG35-55 (myelin oligodendrocyte glycoprotein - 2mg/ml) and CFA (2mg/ml MTB) were mixed 1:1 resulting in Img/ml solutions. ΙΟΟμΙ of the peptide-CFA mixture was injected subcutaneously into each hind leg. Administration ofpertussis toxin intraperitoneally (300ng).

Day 1 : Administration of pertussis toxin intraperitoneally (300ng).

Days 7-onwards: Measurement of disease incidence and weight three times a week.

Endpoints and analysis

Mice were analysed for disease incidence and disease severity three times a week. Scoring was performed blind. Disease severity was assessed using a clinical score ranging from 0 to 5, with 5 indicating a dead mouse (see clinical scoring System below).

Monitorins

On the indicated days mice were weighed and observed for disease activity score and disease incidence.

Disease activity score observations:

- No obvions changes in motor function compared to non-immunized mice.

0.5 - Tip of tail is limp.

1.0- Limp tail.

1.5- Limp tail and hind leg inhibition.

2.0 - Limp tail and weakness of hind legs.

OR - There are obvious signs of head tilting when the walk is observed. The balance is poor.

2.5 - Limp tail and dragging of hind legs.

- OR - There is a strong head tilt that causes the mouse to occasionally fall over.

3.0 - Limp tail and complété paralysis of hind legs.

3.5 - Limp tail and complété paralysis of hind legs. .

In addition to: Mouse is moving around the cage, but when placed on its side, is unable to right itself.

Hînd legs are together on one side of body.

4.0 - Limp tail, complété hind leg and partial front leg paralysis.

- Mouse is minimally moving around the cage but appears alert and feeding

4.5 - Complété hind and partial front leg paralysis, no movement around the cage.

Mouse is immediately euthanized and removed from cage.

5.0 Mouse is euthanized due to severe paralysis.

When an animal has equal or greater disease activity score of 1, it is considered to hâve a positive disease incidence score.

Results

The results of the study are shown in Figures 70 and 71.

Disease induction in the négative control groups was successful with high scores shown by the vehicle control and the untreated control. The effect of treatment with strain 755 was striking and the mice treated with strain 755 exhibited notably reduced disease incidence and disease severity. Indeed, the réduction in disease incidence and disease severity was comparable to the positive control group. These data indicate the strain 755 may be useful for treating or preventing multiple sclerosis.

Example 7 - Efficacy of bacterial inocula in a mouse model of uveitis

Summary

This study used a mouse model of interphotoreceptor retinoid-binding protein (IRBP)-induced uveitis to test the effects of bacterial administration on uveitis. Uveitis is a sight-threatening condition resulting from intraocular inflammation and retinal tissue destruction. This disease can be studied in rodents in a model of experimental autoimmune uveoretinitis (EAU) [68]. EAU is an organ-spécifie disorder where Th 1/Th 17 cells are directed toward retinal antigens and produce cytokines that activate résident and infiltrating mononuclear cells leading to tissue destruction. EAU can be induced in mice by challenge with retinal antigens including interphotoreceptor retinoid binding protein peptide (IRBPp). Disease onset normally occurs from day 8-9 and peaks after days 14-15. Signs of clinical disease can be monitored using topical endoscopie fundal imaging (TEFI).

Strain

MRX005: Parabacteroides distastonis, bacteria deposited under accession number NCIMB 42382.

Biotherapeutic was provided in glycerol stock. Microbiological growth media (YCFA) was used for the culture of the agent.

Mice

The mice were strain C57BL/6 and were over 6 weeks old at the beginning of the study. 72 mice were used (+36 Satellite animais). Unhealthy animais were excluded from the study. Animais were housed in spécifie pathogen free (spf) conditions, in a thermostatically monitored holding room (22 ± 4°C). Animais were allowed to acclimatise under standard animal house conditions for a minimum of one week prior to use. The health status of the animais was monitored throughout this period and the suitability of each animal for experimental use was assessed prior to study start. Mice were housed in groups of up to 10 animais per cage for the duration of the study. Irradiated pellet diet (Lab diet, EU Rodent diet 22%, 5LF5) and water were available ad libitum throughout the acclimatisation and study periods. It is unlikely that any constituent of the diet or water interfered with the study.

Experimental Outline

Adult female C57BL/6 mice were randomly allocated to experimental groups and allowed to acclimatise for one week. Treatments were administered according to the schedule below. On Day 0, animais were administered with an émulsion containing 200 pg of interphotoreceptor retinoid binding protein peptide 1-20 (IRBP pl-20) in complété Freund’s adjuvant (CFA) supplemented with

2.5 mg/ml Mycobacterium Tuberculosis H37 Ra by subeutaneous injection. Also on Day 0, animais were administered with 1.5 pg Bordetella Pertussis toxin by intra-peritoneal injection, From Day 14, animais are weighed three times per week. From Day -1 until the end of the experiment on Day 42, animais are monitored twice per week for clinical signs of uveitis using topical endoscopie fundal imaging (TEFI).

Administration schedule

Ail Groups are n=12

Vehicle for oral administration is YCFA medium.

Administration volume for twice daily oral administration is 5 ml/kg.

Group	Treatment	Dose	Route	Frequency	Disease Induction
1	Vehicle	5 ml/kg	PO	BID Day -14-End	Day 0: IRBP/CFA, SC Day 0: PTx, IP
2	MRX005	5 ml/kg

PO: oral administration, BID: twice daily, SC: subcutaneous injection, IP: intra-peritoneal injection, IRBP: interphotoreceptor binding protein, CFA: complété Freund’s adjuvant, PTx:

Pertussis toxin

A positive control group was also tested using treatment with the drug cyclosporin A.

Readouts

Bodyweights. From Day -14, animais are weighed three times a week. Animais with a bodyweight loss equal to or greater than 15% of their initial (Day 0) bodyweight on two consecutive occasions 10 areculled.

Non-specific clinical observations. From Day -14 until the end of the experiment, animais are checked daily for non-specific clinical signs to include abnormal posture (hunched), abnormal coat condition (piloerection) and abnormal activity levels (reduced or increased activity).

Clinical Scores: Retinal imaging by topical endoscopie fondai imaging (TEFI). From Day -1 15 until the end of the experiment, animais are scored twice per week for clinical signs of uveitis.

Retinal images are captured using TEFI in non-anaesthetised but restrained animais following pupil dilatation using Tropicamide 1% then Phenylephrine hydrochloride 2.5%. Retinal images are scores using the following System. The maximum cumulative score is 20.

Score	Optic dise Inflammation	Retinal vessels	Retinal tissue Infiltration	Structural damage
1	Minimal	1-4 mild cuffmgs	1-4 small lésions or 1 linear lésion	Retinal lésions or atrophy involving % to % of retinal area
2	Mild	>4 mild cuffmgs or 1-3 moderate cuffmgs	5-10 small lésions or 2-3 linear lésions	Panretinal atrophy with multiple small lésions (scars) or <3 linear lésions (scars)
3	Moderate	>3 moderate cuffmgs	>10 small lésions or >3 linear lésions	Panretinal atrophy with >3 linear lésions or confluent lésions (scars)

4	Severe	> I severe euffings	Linear confluent	lésion	Retinal detachment with folding
5	Not visible (white-out or severe detachment)

Results

The results of the study are shown in Figures 72 and 73.

Clînical Scores: Retinal imaging by topical endoscopie fondai imaging (TEFI). TEFI scores data measured in the Control group from Day 0 until Day 28 were analysed by Kruskal-Wallis test for non-parametric data followed by Dunn's post-test for multiple comparisons between experimental days.

IRBP administration induced a signifïcant increase in the TEFI scores measured from Day 14 (p < 0.01) and on Day 28 (p < 0.0001) when compared to Day 0 in the Control group (Figure 72).

TEFI scores measured in the experimental groups on Day 28 were analysed using a one-way ANOVA. As expected, a signifïcant decrease in the scores was observed in the positive control cyclosporine A group. There was also a statistically signifïcant decrease in the scores for the MRX005-treated group (p<0.01), relative to the négative control (Figure 73).

Conclusions. Clinical scores determined by TEFI increased from Day 14, as expected in this model of IRBP-induced uveitis. By Day 28, a striking and statistically signifïcant réduction in disease incidence and disease severity was observed in the MRX005-treated group, which was comparable to that seen for the positive control group. In particular, these data indicate that treatment with the strain MRX005 reduced retinal damage, optic dise inflammation and/or retinal tissue infiltration by inflammatory cells (see TEFI retinal image scoring System above). These data indicate the strain MRX005 may be usefùl for treating or preventing uveitis.

Example 8 — Stability testing

A composition described herein containing at least one bacterial strain described herein is stored in a sealed container at 25°C or 4°C and the container is placed in an atmosphère having 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90% or 95% relative humidity. After 1 month, 2 months, 3 months, 6 months, 1 year, 1.5 years, 2 years, 2.5 years or 3 years, at least 50%, 60%, 70%, 80% or 90% of the bacterial strain shall remain as measured in colony forming units determined by standard protocols.

Sequences

SEQ ID N0:l (Parabacteroides distasonis gene for 16S ribosomal RNA, partial sequence, strain: JCM 5825 - AB238922) agagtttgat cctggctcag gatgaacgct agcgacaggc ttaacacatg caagtcgagg ggcagcgggg tgtagcaata caccgccggc gaccggcgca cgggtgagta acgcgtatgc

121 aacttgccta tcagaggggg ataacccggc gaaagtcgga ctaataccgc atgaagcagg

181 gatcccgcat gggaatattt gctaaagatt catcgctgat agataggcat gcgttccatt

241 aggcagttgg cggggtaacg gcccaccaaa ccgacgatgg ataggggttc tgagaggaag

301 gtcccccaca ttggtactga gacacggacc aaactcctac gggaggcagc agtgaggaat

361 attggtcaat gggcgtaagc ctgaaccagc caagtcgcgt gagggatgaa ggttctatgg

421 atcgtaaacc tcttttataa gggaataaag tgcgggacgt gtcccgtttt gtatgtacct

481 tatgaataag gatcggctaa ctccgtgcca gcagccgcgg taatacggag gatccgagcg

541 ttatccggat ttattgggtt taaagggtgc gtaggcggcc ttttaagtca gcggtgaaag

601 tctgtggctc aaccatagaa ttgccgttga aactgggggg cttgagtatg tttgaggcag

661 gcggaatgcg tggtgtagcg gtgaaatgca tagatatcac gcagaacccc gattgcgaag

721 gcagcctgcc aagccattac tgacgctgat gcacgaaagc gtggggatca aacaggatta

781 gataccctgg tagtccacgc agtaaacgat gatcactagc tgtttgcgat acactgtaag

841 cggcacagcg aaagcgttaa gtgatccacc tggggagtac gccggcaacg gtgaaactca

901 aaggaattga cgggggcccg cacaagcgga ggaacatgtg gtttaattcg atgatacgcg

961 aggaacctta cccgggtttg aacgcattcg gaccgaggtg gaaacacctt ttctagcaat

1021 agccgtttgc gaggtgctgc atggttgtcg tcagctcgtg ccgtgaggtg tcggcttaag

1081 tgccataacg agcgcaaccc ttgccactag ttactaacag gttaggctga ggactctggt

1141 gggactgcca gcgtaagctg cgaggaaggc ggggatgacg tcaaatcagc acggccctta

1201 catccggggc gacacacgtg ttacaatggc gtggacaaag ggaggccacc tggcgacagg

1261 gagcgaatcc ccaaaccacg tctcagttcg gatcggagtc tgcaacccga ctccgtgaag

1321 ctggattcgc tagtaatcgc gcatcagcca tggcgcggtg aatacgttcc cgggccttgt

1381 acacaccgcc cgtcaagcca tgggagccgg gggtacctga agtccgtaac cgaaaggatc

1441 ggcctagggt aaaactggtg actggggcta agtcgtaaca aggtaacc

SEQ ID NO:2 (Parabacteroides distasonis gene for 16S ribosomal RNA, partial sequence, strain: JCM 13400 - AB238923) agagtttgat cctggctcag gatgaacgct agcgacaggc ttaacacatg caagtcgagg ggcagcacag gtagcaatac cgggtggcga ccggcgcacg ggtgagtaac gcgtatgcaa

121 cttacctatc agagggggat aacccggcga aagtcggact aataccgcat gaagcagggg

181 ccccgcatgg ggatatttgc taaagattca tcgctgatag ataggcatgc gttccattag

241 gcagttggcg gggtaacggc ccaccaaacc gacgatggat aggggttctg agaggaaggt

301 cccccacatt ggtactgaga cacggaccaa actcctacgg gaggcagcag tgaggaatat

361 tggtcaatgg gcgtaagcct gaaccagcca agtcgcgtga gggatgaagg ttctatggat

421 cgtaaacctc ttttataagg gaataaagtg cgggacgtgt cctgttttgt atgtacctta

481 tgaataagga tcggctaact ccgtgccagc agccgcggta atacggagga tccgagcgtt

541 atccggattt attgggttta aagggtgcgt aggcggcctt ttaagtcagc ggtgaaagtc

601 tgtggctcaa ccatagaatt gccgttgaaa ctggggggct tgagtatgtt tgaggcaggc

661 ggaatgcgtg gtgtagcggt gaaatgctta gatatcacgc agaaccccga ttgcgaaggc

721 agcctgccaa gccatgactg acgctgatgc acgaaagcgt ggggatcaaa caggattaga

781 taccctggta gtccacgcag taaacgatga tcactagctg tttgcgatac agtgtaagcg

5k

841 gcacagcgaa agcgttaagt gatccacctg gggagtacgc cggcaacggt gaaactcaaa

901 ggaattgacg ggggcccgca caagcggagg aacatgtggt ttaattcgat gatacgcgag

961 gaaccttacc cgggtttgaa cgcattcgga ccgaggtgga aacacctttt ctagcaatag

1021 ccgtttgcga ggtgctgcat ggttgtcgtc agctcgtgcc gtgaggtgtc ggcttaagtg

1081 ccataacgag cgcaaccctt gccactagtt actaacaggt aaagctgagg actctggtgg

1141 gactgccagc gtaagctgcg aggaaggcgg ggatgacgtc aaatcagcac ggcccttaca

1201 tccggggcga cacacgtgtt acaatggcgt ggacaaaggg aagccacctg gcgacaggga

1261 gcgaatcccc aaaccacgtc tcagttcgga tcggagtctg caacccgact ccgtgaagct

1321 ggattcgcta gtaatcgcgc atcagccatg gcgcggtgaa tacgttcccg ggccttgtac

1381 acaccgcccg tcaagccatg ggagccgggg gtacctgaag tccgtaaccg aaaggatcgg

1441 cctagggtaa aactggtgac tggggctaag tcgtaacaag gtaacc

SEQ ID NO:3 (Parabacteroides distasonis gene for 16S ribosomal RNA, partial sequence, strain: JCM 13401 -AB23 8924) agagtttgat cctggctcag gatgaacgct agcgacaggc ttaacacatg caagtcgagg ggcagcacag gtagcaatac ccgccggcga ccggcgcacg ggtgagtaac gcgtatgcaa

121 cttgcctatc agagggggat aacccggcga aagtcggact aataccgcat gaagcagggg

181 ccccgcatgg ggatatttgc taaagattca tcgctgatag ataggcatgc gttccattag

241 gcagttggcg gggtaacggc ccaccaaacc gacgatggat aggggttctg agaggaaggt

301 cccccacatt ggtactgaga cacggaccaa actcctacgg gaggcagcag tgaggaatat

361 tggtcaatgg gcgtaagcct gaaccagcca agtcgcgtga gggatgaagg ttctatggat

421 cgtaaacctc ttttataagg gaataaagtg tgggacgtgt cctgttttgt atgtacctta

481 tgaataagga tcggctaact ccgtgccagc agccgcggta atacggagga tccgagcgtt

541 atccggattt attgggttta aagggtgcgt aggcggcctt ttaagtcagc ggtgaaagtc

601 tgtggctcaa ccatagaatt gccgttgaaa ctgggaggct tgagtatgtt tgaggcaggc

661 ggaatgcgtg gtgtagcggt gaaatgctta gatatcacgc agaaccccga ttgcgaaggc

721 agcctgccaa gccatgactg acgctgatgc acgaaagcgt ggggatcaaa caggattaga

781 taccctggta gtccacgcag taaacgatga tcactagctg tttgcgatac actgtaagcg

841 gcacagcgaa agcgttaagt gatccacctg gggagtacgc cggcaacggt gaaactcaaa

901 ggaattgacg ggggcccgca caagcggagg aacatgtggt ttaattcgat gatacgcgag

961 gaaccttacc cgggtttgaa cgcattcgga ccgaggtgga aacacctttt ctagcaatag

1021 ccgtttgcga ggtgctgcat ggttgtcgtc agctcgtgcc gtgaggtgtc ggcttaagtg

1081 ccataacgag cgcaaccctt gccactagtt actaacaggt gatgctgagg actctggtgg

1141 gactgccagc gtaagctgcg aggaaggcgg ggatgacgtc aaatcagcac ggcccttaca

1201 tccggggcga cacacgtgtt acaatggcgt ggacaaaggg atgccacctg gcgacaggga

1261 gcgaatcccc aaaccacgtc tcagttcgga tcggagtctg caacccgact ccgtgaagct

1321 ggattcgcta gtaatcgcgc atcagccatg gcgcggtgaa tacgttcccg ggccttgtac

1381 acaccgcccg tcaagccatg ggagccgggg gtacctgaag tccgtaaccg aaaggatcgg

1441 cctagggtaa aactggtgac tggggctaag tcgtaacaag gtaacc

SEQ ID NO:4 (Parabacteroides distasonis gene for 16S ribosomal RNA, partial sequence, strain:

JCM 13402 - AB238925) agagtttgat cctggctcag gatgaacgct agcgacaggc ttaacacatg caagtcgagg ggcagcacag gtagcaatac cgggtggcga ccggcgcacg ggtgagtaac gcgtatgcaa

121 cttacctatc agagggggat aacccggcga aagtcggact aataccgcat gaagcagggg

181 ccccgcatgg ggatatttgc taaagattca tcgctgatag ataggcatgc gttccattag

241 gcagttggcg gggtaacggc ccaccaaacc gacgatggat aggggttctg agaggaaggt

301 cccccacatt ggtactgaga cacggaccaa actcctacgg gaggcagcag tgaggaatat

361 tggtcaatgg gcgtaagcct gaaccagcca agtcgcgtga gggatgaagg ttctatggat

421 cgtaaacctc ttttataagg gaataaagtg cgggacgtgt cccgttttgt atgtacctta

481 tgaataagga tcggctaact ccgtgccagc agccgcggta atacggagga tccgagcgtt

541 atccggattt attgggttta aagggtgcgt aggcggcctt ttaagtcagc ggtgaaagtc

601 tgtggctcaa ccatagaatt gccgttgaaa ctgggaggct tgagtatgtt tgaggcaggc

661 ggaatgcgtg gtgtagcggt gaaatgctta gatatcacgc agaaccccga ttgcgaaggc

721 agcctgccaa gccatgactg acgctgatgc acgaaagcgt ggggatcaaa caggattaga

781 taccctggta gtccacgcag taaacgatga tcactagctg tttgcgatac actgtaagcg

841 gcacagcgaa agcgttaagt gatccacctg gggagtacgc cggcaacggt gaaactcaaa

901 ggaattgacg ggggcccgca caagcggagg aacatgtggt ttaattcgat gatacgcgag

961 gaaccttacc cgggtttgaa cgcattcgga ccgaggtgga aacacctttt ctagcaatag

1021 ccgtttgcga ggtgctgcat ggttgtcgtc agctcgtgcc gtgaggtgtc ggcttaagtg

1081 ccataacgag cgcaaccctt gccactagtt actaacaggt aaagctgagg actctggtgg

1141 gactgccagc gtaagctgcg aggaaggcgg ggatgacgtc aaatcagcac ggcccttaca

1201 tccggggcga cacacgtgtt acaatggcgt ggacaaaggg aggccacctg gcgacaggga

1261 gcgaatcccc aaaccacgtc tcagttcgga tcggagtctg caacccgact ccgtgaagct

1321 ggattcgcta gtaatcgcgc atcagccatg gcgcggtgaa tacgttcccg ggccttgtac

1381 acaccgcccg tcaagccatg ggagccgggg gtacctgaag tccgtaaccg aaaggatcgg

1441 cctagggtaa aactggtgac tggggctaag tcgtaacaag gtaacc

SEQ ID NO:5 (Parabacteroides distasonis gene for 16S ribosomal RNA, partial sequence, strain: JCM 13403 - AB238926) agagtttgat cctggctcag gatgaacgct agcgacaggc ttaacacatg caagtcgagg ggcagcacag gtagcaatac cgggtggcga ccggcgcacg ggtgagtaac gcgtatgcaa

121 cttacctatc agagggggat aacccggcga aagtcggact aataccgcat gaagcagggg

181 ccccgcatgg ggatatttgc taaagattca tcgctgatag ataggcatgc gttccattag

241 gcagttggcg gggtaacggc ccaccaaacc gacgatggat aggggttctg agaggaaggt

301 cccccacatt ggtactgaga cacggaccaa actcctacgg gaggcagcag tgaggaatat

361 tggtcaatgg gcgtaagcct gaaccagcca agtcgcgtga gggatgaagg ttctatggat

421 cgtaaacctc ttttataagg gaataaagtg tgggacgtgt cccgttttgt atgtacctta

481 tgaataagga tcggctaact ccgtgccagc agccgcggta atacggagga tccgagcgtt

541 atccggattt attgggttta aagggtgcgt aggcggcctt ttaagtcagc ggtgaaagtc

601 tgtggctcaa ccatagaatt gccgttgaaa ctgggaggct tgagtatgtt tgaggcaggc

661 ggaatgcgtg gtgtagcggt gaaatgctta gatatcacgc agaaccccga ttgcgaaggc

721 agcctgccaa gccatgactg acgctgatgc acgaaagcgt ggggatcaaa caggattaga

781 taccctggta gtccacgcag taaacgatga tcactagctg tttgcgatac attgtaagcg

841 gcacagcgaa agcgttaagt gatccacctg gggagtacgc cggcaacggt gaaactcaaa

901 ggaattgacg ggggcccgca caagcggagg aacatgtggt ttaattcgat gatacgcgag

961 gaaccttacc cgggtttgaa cgcattcgga ccgaggtgga aacacctttt ctagcaatag

1021 ccgtttgcga ggtgctgcat ggttgtcgtc agctcgtgcc gtgaggtgtc ggcttaagtg

1081 ccataacgag cgcaaccctt gccactagtt actaacaggt aaagctgagg actctggtgg

1141 gactgccagc gtaagctgcg aggaaggcgg ggatgacgtc aaatcagcac ggcccttaca

1201 tccggggcga cacacgtgtt acaatggcgt ggacaaaggg aggccacctg gcgacaggga

1261 gcgaatcccc aaaccacgtc tcagttcgga tcggagtctg caacccgact ccgtgaagct

1321 ggattcgcta gtaatcgcgc atcagccatg gcgcggtgaa tacgttcccg ggccttgtac

1381 acaccgcccg tcaagccatg ggagccgggg gtacctgaag tccgtaaccg aaaggatcgg

1441 cctagggtaa aactggtgac tggggctaag tcgtaacaag gtaacc

SEQ ID NO:6 (Parabacteroides distasonis gene for 16S ribosomal RNA, partial sequence, strain: JCM 13404-AB23 8927) agagtttgat cctggctcag gatgaacgct agcgacaggc ttaacacatg caagtcgagg ggcagcacag gtagcaatac cgggtggcga ccggcgcacg ggtgagtaac gcgtatgcaa

121 cttacctatc agagggggat aacccggcga aagtcggact aataccgcat gaagcagggg

181 ccccgcatgg ggatatttgc taaagattca tcgctgatag ataggcatgc gttccattag

241 gcagttggcg gggtaacggc ccaccaaacc gacgatggat aggggttctg agaggaaggt

301 cccccacatt ggtactgaga cacggaccaa actcctacgg gaggcagcag tgaggaatat

361 tggtcaatgg gcgtaagcct gaaccagcca agtcgcgtga gggatgaagg ttctatggat

421 cgtaaacctc ttttataagg gaataaagtg tgggacgtgt cccgttttgt atgtacctta

481 tgaataagga tcggctaact ccgtgccagc agccgcggta atacggagga tccgagcgtt

541 atccggattt attgggttta aagggtgcgt aggcggcctt ttaagtcagc ggtgaaagtc

601 tgtggctcaa ccatagaatt gccgttgaaa ctgggaggct tgagtatgtt tgaggcaggc

661 ggaatgcgtg gtgtagcggt gaaatgctta gatatcacgc agaaccccga ttgcgaaggc

721 agcctgccaa gccatgactg acgctgatgc acgaaagcgt ggggatcaaa caggattaga

781 taccctggta gtccacgcag taaacgatga tcactagctg tttgcgatac attgtaagcg

841 gcacagcgaa agcgttaagt gatccacctg gggagtacgc cggcaacggt gaaactcaaa

901 ggaattgacg ggggcccgca caagcggagg aacatgtggt ttaattcgat gatacgcgag

961 gaaccttacc cgggtttgaa cgcattcgga ccgaggtgga aacacctttt ctagcaatag

1021 ccgtttgcga ggtgctgcat ggttgtcgtc agctcgtgcc gtgaggtgtc ggcttaagtg

1081 ccataacgag cgcaaccctt gccactagtt actaacaggt aaagctgagg actctggtgg

1141 gactgccagc gtaagctgcg aggaaggcgg ggatgacgtc aaatcagcac ggcccttaca

1201 tccggggcga cacacgtgtt acaatggcgt ggacaaaggg aggccacctg gcgacaggga

1261 gcgaatcccc aaaccacgtc tcagttcgga tcggagtctg caacccgact ccgtgaagct

1321 ggattcgcta gtaatcgcgc atcagccatg gcgcggtgaa tacgttcccg ggccttgtac

1381 acaccgcccg tcaagccatg ggagccgggg gtacctgaag tccgtaaccg aaaggatcgg

1441 cctagggtaa aactggtgac tggggctaag tcgtaacaag gtaacc

SEQ ID NO:7 (Parabacteroides merdae gene for 16S ribosomal RNA, partial sequence, strain: JCM 9497 - AB238928) agagtttgat cctggctcag gatgaacgct agcgacaggc ttaacacatg caagtcgagg ggcagcatga tttgtagcaa tacagattga tggcgaccgg cgcacgggtg agtaacgcgt

121 atgcaactta cctatcagag ggggatagcc cggcgaaagt cggattaata ccccataaaa

181 caggggtccc gcatgggaat atttgttaaa gattcatcgc tgatagatag gcatgcgttc

241 cattaggcag ttggcggggt aacggcccac caaaccgacg atggataggg gttctgagag

301 gaaggtcccc cacattggta ctgagacacg gaccaaactc ctacgggagg cagcagtgag

361 gaatattggt caatggccga gaggctgaac cagccaagtc gcgtgaagga agaaggatct

421 atggtttgta aacttctttt ataggggaat aaagtggagg acgtgtcctt ttttgtatgt

481 accctatgaa taagcatcgg ctaactccgt gccagcagcc gcggtaatac ggaggatgcg

541 agcgttatcc ggatttattg ggtttaaagg gtgcgtaggt ggtgatttaa gtcagcggtg

601 aaagtttgtg gctcaaccat aaaattgccg ttgaaactgg gttacttgag tgtgtttgag

661 gtaggcggaa tgcgtggtgt agcggtgaaa tgcatagata tcacgcagaa ctccgattgc

721 gaaggcagct tactaaacca taactgacac tgaagcacga aagcgtgggg atcaaacagg

781 attagatacc ctggtagtcc acgcagtaaa cgatgattac taggagtttg cgatacaatg

841 taagctctac agcgaaagcg ttaagtaatc cacctgggga gtacgccggc aacggtgaaa

901 ctcaaaggaa ttgacggggg cccgcacaag cggaggaaca tgtggtttaa ttcgatgata

961 cgcgaggaac cttacccggg tttgaacgta gtctgaccgg agtggaaaca ctccttctag

1021 caatagcaga ttacgaggtg ctgcatggtt gtcgtcagct cgtgccgtga ggtgtcggct

1081 taagtgccat aacgagcgca acccttatca ctagttacta acaggtgaag ctgaggactc

1141 tggtgagact gccagcgtaa gctgtgagga aggtggggat gacgtcaaat cagcacggcc

1201 cttacatccg gggcgacaca cgtgttacaa tggcatggac aaagggcagc tacctggcga

1261 caggatgcta atctccaaac catgtctcag ttcggatcgg agtctgcaac tcgactccgt

1321 gaagctggat tcgctagtaa tcgcgcatca gccatggcgc ggtgaatacg ttcccgggcc

1381 ttgtacacac cgcccgtcaa gccatgggag ccgggggtac ctgaagtccg taaccgcaag

1441 gatcggccta gggtaaaact ggtgactggg gctaagtcgt aacaaggtaa cc

SEQ ID NO:8 (Parabacteroides merdae gene for 16S ribosomal RNA, partial sequence, strain: JCM 13405 - AB238929) agagtttgat cctggctcag gatgaacgct agcgacaggc ttaacacatg caagtcgagg ggcagcatga tttgtagcaa tacagattga tggcgaccgg cgcacgggtg agtaacgcgt

121 atgcaactta cctatcagag ggggatagcc cggcgaaagt cggattaata ccccataaaa

181 caggggttcc gcatgggaat atttgttaaa gattcatcgc tgatagatag gcatgcgttc

241 cattaggcag ttggcggggt aacggcccac caaaccgacg atggataggg gttctgagag

301 gaaggtcccc cacattggta ctgagacacg gaccaaactc ctacgggagg cagcagtgag

361 gaatattggt caatggccga gaggctgaac cagccaagtc gcgtgaagga agaaggatct

421 atggtttgta aacttctttt ataggggaat aaagtggagg acgtgtcctt ttttgtatgt

481 accctatgaa taagcatcgg ctaactccgt gccagcagcc gcggtaatac ggaggatgcg

541 agcgttatcc ggatttattg ggtttaaagg gtgcgtaggt ggtgatttaa gtcagcggtg

601 aaagtttgtg gctcaaccat aaaattgccg ttgaaactgg gttacttgag tgtgtttgag

661 gtaggcggaa tgcgtggtgt agcggtgaaa tgcatagata tcacgcagaa ctccgattgc

721 gaaggcagct tactaaacca taactgacac tgaagcacga aagcgtgggg atcaaacagg

781 attagatacc ctggtagtcc acgcagtaaa cgatgattac taggagtttg cgatacaatg

841 taagctctac agcgaaagcg ttaagtaatc cacctgggga gtacgccggc aacggtgaaa

901 ctcaaaggaa ttgacggggg cccgcacaag cggaggaaca tgtggtttaa ttcgatgata

961 cgcgaggaac cttacccggg tttgaacgta gtctgaccgg agtggaaaca ctccttctag

1021 caatagcaga ttacgaggtg ctgcatggtt gtcgtcagct cgtgccgtga ggtgtcggct

1081 taagtgccat aacgagcgca acccttatca ctagttacta acaggtgaag ctgaggactc

1141 tggtgagact gccagcgtaa gctgtgagga aggtggggat gacgtcaaat cagcacggcc

1201 cttacatccg gggcgacaca cgtgttacaa tggcatggac aaagggcagc tacctggcga

1261 caggatgcta atctccaaac catgtctcag ttcggatcgg agtctgcaac tcgactccgt

1321 gaagctggat tcgctagtaa tcgcgcatca gccatggcgc ggtgaatacg ttcccgggcc

1381 ttgtacacac cgcccgtcaa gccatgggag ccgggggtac ctgaagtccg taaccgcaag

1441 gatcggccta gggtaaaact ggtgactggg gctaagtcgt aacaaggtaa cc

SEQ ID NO:9 (consensus 16S rRNA sequence for Parabacteroides distasonis strain 755)

AMCCGGGTGGCGACCGGCGCACGGGTGAGTAACGCGTATGCAACTTGCCTATCAGAGGGGGATAACCCGGCGAAAGT CGGACTAATACCGCATGAAGCAGGGATCCCGCATGGGAATATTTGCTAAAGATTCATCGCTGATAGATAGGCATGCG TTCCATTAGGCAGTTGGCGGGGTAACGGCCCACCAAACCGACGATGGATAGGGGTTCTGAGAGGAAGGTCCCCCACA

TTGGTACTGAGACACGGACCAAACTCCTACGGGAGGCAGCAGTGAGGAATATTGGTCAATGGGCGTGAGCCTGAACC

AGCCAAGTCGCGTGAGGGATGAAGGTTCTATGGATCGTAAACCTCTTTTATAAGGGAATAAAGTGCGGGACGTGTCC CGTTTTGTATGTACCTTATGAATAAGGATCGGCTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGATCCGAGCGT TATCCGGATTTATTGGGTTTAAAGGGTGCGTAGGCGGCCTTTTAAGTCAGCGGTGAAAGTCTGTGGCTCAACCATAG

AATTGCCGTTGAAACTGGGAGGCTTGAGTATGTTTGAGGCAGGCGGAATGCGTGGTGTAGCGGTGAAATGCATAGAT ATCACGCAGAACCCCGATTGCGAAGGCAGCCTGCCAAGCCATTACTGACGCTGATGCACGAAAGCGTGGGGATCAAA CAGGATTAGATACCCTGGTAGTCCACGCAGTAAACGATGATCACTAGCTGTTTGCGATACACTGTAAGCGGCACAGC

GAAAGCGTTAAGTGATCCACCTGGGGAGTACGCCGGCAACGGTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAG

CGGAGGAACATGTGGTTTAATTCGATGATACGCGAGGAACCTTACCCGGGTTTGAACGCATTCGGACMGAKGTGGAA

ACACATTTTCTAGCAATAGCCATTTGCGAGGTGCTGCATGGTTGTCGTCAGCTCGTGCCGTGAGGTGTCGGCTTAAG

TGCCATAACGAGCGCAACCCTTGCCACTAGTTACTAACAGGTAAAGCTGAGGACTCTGGTGGGACTGCCAGCGTAAG

CTGCGAGGAAGGCGGGGATGACGTCAAATCAGCACGGCCCTTACATCCGGGGCGACACACGTGTTACAATGGCGTGG

ACAAAGGGAAGCCACCTGGCGACAGGGAGCGAATCCCCAAACCACGTCTCAGTTCGGATCGGAGTCTGCAACCCGAC TCCGTGAAGCTGGATTCGCTAGTAATCGCGCATCAGCCATGGCGCGGTGAATACGTTCCCGGGCCTTGTACACACCG CCCGTCAAGCCATGGGAGCCGGGGGTACCTGAAGTCCGTAACCGCGAGGATCGGCCTAGGGTAAAACTGGTGACTGG

GGCTAAGTCGTACGGGG

SEQ ID NO: 10 (strain 755 genome sequence) - see W02016203220.

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Claims (22)

1. A composition comprising a bacterial strain of the species Parabacteroides distasonis, for use in a method of treating or preventing an inflammatory or autoimmune disease, or cancer.

2. The composition of claim 1, wherein the composition is for use in a method of treating or preventing a disease or condition selected from the group consisting of asthma, including allergie asthma or neutrophilie asthma; arthritis, including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, or juvénile idiopathic arthritis; multiple sclerosis; neuromyelitis optica (Devic's disease); ankylosing spondylîtis; spondyloarthritis; psoriasis; systemic lupus erythematosus; inflammatory bowel disease, including Crohn’s disease or ulcerative colitis; celiac disease; chronic obstructive pulmonary disease (COPD); cancer, including breast cancer, colon cancer, lung cancer or ovarian cancer; uveitis; scleritis; vasculitis; Behcet's disease; atherosclerosis; atopie dermatitis; emphysema; periodontitis; allergie rhinitis; and allograft rejection.

3. The composition of claim 2, wherein the composition is for use in a method of treating or preventing asthma, including neutrophilie asthma or allergie asthma.

4. The composition of claim 3, wherein the composition is for use in a method of reducing neutrophilia or eosinophilia in the treatment of asthma.

5. The composition of claim 2, wherein the composition is for use in a method of treating or preventing rheumatoid arthritis.

6. The composition of claim 5, wherein the composition is for use in a method of reducing joint swelling in rheumatoid arthritis.

7. The composition of claim 2, wherein the composition is for use in a method of treating or preventing multiple sclerosis.

8. The composition of claim 7, wherein the composition is for use in a method of reducing disease incidence or disease severity.

9. The composition of claim 2, wherein the composition is for use in a method of treating or preventing uveitis.

10. The composition of claim 9, wherein the composition is for use in a method of reducing or preventing retinal damage in uveitis.

11. The composition of claim 2, wherein the composition is for use in a method of treating or preventing cancer, including lung cancer, breast cancer or liver cancer.

12. The composition of claim 11, wherein the composition is for use in a method of reducing tumour size, reducing tumour growth, preventing metastasis or preventing angiogenesis.

13. The composition of any preceding claim, wherein the composition is for use in a method of reducing IL-17 production or reducing Th 17 cell différentiation in the treatment or prévention of the inflammatory or autoimmune disease, or cancer.

14. The composition of any preceding claim, wherein the composition is for use in a patient with elevated IL-17 levels or Th 17 cells.

15. The composition of any of daims 1-14, wherein the bacterial strain has a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to SEQ ID NO:1, 2, 3, 4, 5, 6, or 9.

16. The composition of claim 15, wherein the bacterial strain has a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to SEQ ID NO:9, or wherein the bacterial strain has the 16s rRNA sequence represented by SEQ ID NO:9.

17. The composition of any preceding claim, wherein the bacterial strain is lyophilised.

18. A food product or vaccine composition comprising the composition of any preceding claim, for the use of any preceding claim.

19. A cell of the Parabacteroides distasonis strain deposited under accession number NCIMB 42382, or a dérivative thereof.

20. A biologically pure culture of the Parabacteroides distasonis strain deposited under accession number NCIMB 42382, or a dérivative thereof.

21. A cell of the Parabacteroides distasonis strain deposited under accession number NCIMB 42382, or a dérivative thereof, for use in therapy.

22. The cell of claim 21, wherein the cell is for use in a method defined in any of daims 1-14.