NZ764713B2 - A Bacteroides thetaiotaomicron strain and its use in reducing inflammation - Google Patents
A Bacteroides thetaiotaomicron strain and its use in reducing inflammationInfo
- Publication number
- NZ764713B2 NZ764713B2 NZ764713A NZ76471315A NZ764713B2 NZ 764713 B2 NZ764713 B2 NZ 764713B2 NZ 764713 A NZ764713 A NZ 764713A NZ 76471315 A NZ76471315 A NZ 76471315A NZ 764713 B2 NZ764713 B2 NZ 764713B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- kjm
- strain
- cells
- annotation
- subject
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
Abstract
The present invention provides a strain of Bacteroides thetaiotaomicron and derivatives thereof, and the use of said strain or derivatives in treating inflammatory, autoimmune and allergic disorders. The invention also provides pharmaceutical compositions, nutritional supplements, feedstuffs, food products, dietary supplements, and food additives comprising said strain or derivatives. roducts, dietary supplements, and food additives comprising said strain or derivatives.
Description
A Bacteroides thetaiotaomicron strain and its use in reducing inflammation
Related applications
This application is a divisional application of New Zealand patent application no. 732667, a
New Zealand national phase entry application derived from International Patent Application No.
, filed on 22 December 2015, which claims the t of UK Patent
Application No. 1423084.1, filed on 23 December 2014, the contents of each of which are
incorporated herein in their entirety by nce.
Field of the Invention
The present invention relates to microorganisms that are able to positively modulate
matory disorders and which may be used in therapy or preventative medicine.
Background of the Invention
Bacteroides thetaiotaomicron has potent anti-inflammatory effects in vitro and in vivo
(Kelly et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclearcytoplasmic
shuttling of PPAR-gamma and RelA. Nat Immunol. 2004 Jan;5(1):104-12). It
modulates molecular signalling pathways of NF-κB (Kelly et al, Commensal anaerobic gut
bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma
and RelA. Nat Immunol. 2004 Jan;5(1):104-12). In particular, it stops binding of the active
ent (RelA) of NF-κB to key genes in the nucleus, thereby preventing the activation of
pro-inflammatory pathways (Kelly et al, Supra 2004). The full genome of B. thetaiotaomicron
was sequenced and annotated by the Gordon Group (Washington University School of
ne, USA) in 2003 [Xu et al, A genomic view of the Bacteroides thetaiotaomicron
symbiosis. e. 2003 Mar 28;299(5615):2074-6].
Summary of the Invention
The present invention is based on the discovery of a strain of Bacteroides
thetaiotaomicron (BT) that has surprising efficacy against inflammatory disorders. ingly
the strain of BT is useful as a therapeutic or in preventative medicine against inflammatory
disorders and/or autoimmune disorders and /or allergic ers.
ing to one aspect, the present invention provides a composition comprising a
Bacteroides thetaiotaomicron strain with a sequence that has at least 99.5% sequence identity
to SEQ ID NO: 1, n said Bacteroides thetaiotaomicron strain has a comparable increase
in the percentage of Treg cells in the small intestine lamina a tissue samples from
Bacteroides otaomicron/DSS treated mice to that of oides thetaiotaomicron
deposited as Accession Number 42341 at NCIMB, and wherein said Bacteroides
thetaiotaomicron strain is not the Bacteroides thetaiotaomicron deposited as Accession
Number 42341 at NCIMB.
According to another aspect, the present invention provides the use of the ition
ing to the invention in the cture of a medicament for treating or preventing
inflammatory disorders and/or autoimmune ers and/or allergic disorders in a subject.
According to another aspect, the present invention provides the use of the composition
according to the invention in the manufacture of a medicament for reducing the inflammation
of a tissue or an organ.
According to another aspect, the present invention es the use of the composition
according to the invention in the cture of a medicament for reducing disruption to the
colon of a subject.
According to another aspect, the present invention provides the use of the composition
according to the invention in the cture of a medicament for reducing the sion of
one or more pro-inflammatory genes in a cell or cells of a subject.
According to another aspect, the present invention provides the use of the composition
according to the invention in the manufacture of a medicament for increasing the percentage
of T regs in the alimentary canal or a section of the alimentary canal.
According to another aspect, the present invention es a process for producing a
composition ing to the invention, said process comprising admixing said Bacteroides
thetaiotaomicron strain with a pharmaceutically acceptable excipient, r or diluent.
According to another , the present invention provides a nutritional supplement,
feedstuff, food product, dietary supplement or food additive comprising the composition
according to the invention.
Also disclosed herein is a Bacteroides thetaiotaomicron deposited as NCIMB
Accession Number 42341, or a derivative thereof.
Also disclosed herein is a ional supplement comprising a Bacteroides
thetaiotaomicron as defined , and a nutritionally acceptable excipient, carrier or diluent.
Also disclosed herein is a feedstuff, food product, dietary supplement, or food additive
comprising a Bacteroides thetaiotaomicron as defined herein.
Also disclosed herein is a Bacteroides thetaiotaomicron as defined herein, a
ition as defined herein, a pharmaceutical composition as d herein, a nutritional
supplement as defined herein or a feedstuff, a food product, a dietary supplement, or a food
additive as defined herein, for use in modulating the inflammation of a tissue or an organ in a
subject.
Also disclosed herein is a Bacteroides otaomicron as d herein, a
composition as defined herein, a pharmaceutical composition as defined herein, a nutritional
supplement as defined herein or a feedstuff, a food product, a dietary supplement, or a food
additive as defined herein, for use in the treatment and/or prevention of a disorder in a subject;
wherein said disorder is an inflammatory disorder and/or an autoimmune disorder.
Also disclosed herein is a Bacteroides thetaiotaomicron as d herein, a
composition as d herein, a pharmaceutical composition as defined , a nutritional
ment as defined herein or a feedstuff, a food product, a y supplement, or a food
additive as defined herein for use in ng disruption to the colon of a subject, preferably
said subject has IBD.
Also disclosed herein is a Bacteroides thetaiotaomicron as defined herein, a
composition as defined herein, a pharmaceutical composition as defined herein, a nutritional
ment as defined herein or a feedstuff, a food product, a dietary ment, or a food
additive as defined herein for use in reducing the expression of one or more pro-inflammatory
genes in a cell or cells of a subject.
Also disclosed herein is a Bacteroides thetaiotaomicron as defined herein, a
composition as defined herein, a pharmaceutical composition as defined herein, a nutritional
supplement as defined herein or a feedstuff, a food t, a dietary supplement, or a food
additive as defined herein for use in increasing the percentage of regulatory T cells (Tregs) in
the alimentary canal or a section of the alimentary canal.
Also disclosed herein is a process for producing a pharmaceutical composition
described herein, said process comprising admixing said Bacteroides thetaiotaomicron with a
pharmaceutically acceptable ent, carrier or diluent, wherein said Bacteroides
otaomicron is optionally encapsulated in said process.
Also sed hereinis a method for modulating the inflammation of a tissue or an
organ in a subject wherein said method comprises administering to the subject a Bacteroides
thetaiotaomicron as defined herein, a composition as defined , a pharmaceutical
composition as defined herein, a ional supplement as defined herein or a feedstuff, a food
product, a dietary supplement, or a food additive as defined herein.
Also disclosed herein is a method for treating and/or preventing of an matory
disorder and/or an autoimmune disorder in a subject wherein said method comprises
administering to the subject a Bacteroides thetaiotaomicron as d , a ition
as defined herein, a pharmaceutical composition as defined herein, a ional supplement
as defined herein or a feedstuff, a food product, a dietary supplement, or a food additive as
defined herein.
Also disclosed herein is a method for reducing disruption to the colon of a subject
wherein said method comprises administering to the subject a Bacteroides thetaiotaomicron
as defined herein, a composition as defined herein
, a pharmaceutical composition as defined herein, a nutritional supplement as defined
herein or a uff, a food product, a dietary supplement, or a food additive as defined
herein, preferably wherein the t has IBD.
Also disclosed herein is a method for reducing the expression of one or more pro-inflammatory
genes in a cell or cells of a subject wherein said methodcomprises administering to the subject
a Bacteroides thetaiotaomicron as defined herein, a composition as defined herein, a
pharmaceutical composition as defined herein, a nutritional supplement as defined herein or a
feedstuff, a food product, a dietary supplement, or a food additive as d herein.
Also disclosed herein is a method for increasing the percentage of Regulatory T cells
(Tregs) in the alimentary canal or a n of the alimentary canal wherein said method
ses administering to the subject a Bacteroides thetaiotaomicron as d herein, a
composition as defined herein, a pharmaceutical composition as defined herein, a nutritional
ment as defined herein or a uff, a food product, a dietary supplement, or a food
additive as defined herein.
Also disclosed herein is a Bacteroides thetaiotaomicron as defined herein, a
composition as d herein, a pharmaceutical composition as defined herein, a ional
ment as defined herein or a uff, a food product, a dietary ment, or a food
additive as defined herein, for the manufacture of a medicament for modulating the
mation of a tissue or an organ in a subject.
Also disclosed herein is a Bacteroides thetaiotaomicron as defined herein, a
composition as defined herein, a pharmaceutical composition as defined herein, a nutritional
ment as defined herein or a feedstuff, a food product, a dietary supplement, or a food
additive as defined herein, for the manufacture of a medicament for the treatment and/or
prevention of an inflammatory disorder and/or an autoimmune disorder in a subject.
Also disclosed herein is a Bacteroides otaomicron as defined herein, a
composition as d herein, a pharmaceutical composition as defined herein, a nutritional
supplement as defined herein or a feedstuff, a food product, a dietary supplement, or a food
additive as defined herein for the manufacture of a medicament for reducing disruption to the
colon of a subject, preferably wherein the subject has IBD.
Also disclosed herein is a Bacteroides thetaiotaomicron as defined herein, a
composition as defined herein, a pharmaceutical ition as defined herein, a nutritional
supplement as defined herein or a feedstuff, a food product, a dietary supplement, or a food
additive as defined herein for the manufacture of a medicament for reducing the expression of
one or more pro-inflammatory genes in a cell or cells of a subject.
Also sed herein is a Bacteroides thetaiotaomicron as defined , a
composition as defined herein, a pharmaceutical composition as defined herein, a nutritional
supplement as defined herein or a feedstuff, a food product, a dietary supplement, or a food
additive as defined herein for the cture of a medicament for
increasing the percentage of Regulatory T cells (Tregs) in the alimentary canal or a section of
the alimentary canal.
Brief Description of the Figures
The ion is described with nce to the accompanying figures,
wherein:
Figure 1 illustrates the attenuation of colitis via expansion of Treg cells with B.
thetaiotaomicron strain BT2013 in a DSS induced colitis model.
Figure 2 illustrates that B. thetaiotaomicron strain BT2013 does not influence Treg cells, but
influences Teff cells, in conventional mice;
Figure 3: illustrates the myeloperoxidase (MPO) activity in ileum (a) and caecum (b) of mice
dosed with DSS with or without a daily intake of B. thetaiotaomicron
Figure 4: illustrates histopathology in ascending colon of female C57Bl/6 mice dosed with
DSS (a) or DSS and B. thetaiotaomicron (b)
Figure 5: illustrates the mean histopathological tissue scores for the ascending colon from
mice colonised with B. thetaiotaomicron strains E1 and BT2013 during DSS-induced colitis;
Figure 6: illustrates the expression of lammatory genes (IL-1β and IL-6) and antiinflammatory
gene (IL-10) in the ascending colon of mice treated with B. otaomicron
s E1, E2 and BT2013;
Figure 7: illustrates the expression of IL-8 in Caco-2 cells incubated with
PMA and medium or bacterial cells E1, E2 and BT2013.
Detailed ption of the Invention
The present invention is based on the finding that BT strain BT2013 has more potent
anti-inflammatory effects compared to l BT s.
BT strain BT2013 has been deposited under Accession number 42341 on 3 December
2014 at National Collections of Industrial, Food and Marine Bacteria (NCIMB) at NCIMB Ltd,
Ferguson Building, Craibstone Estate, Bucksburn,
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Aberdeen, UK, AB21 9YA. The t was made under the terms of the
Budapest Treaty. The t was made by GT Biologics Ltd. (Life Sciences
Innovation Building, en, AB25 2ZS, Scotland). GT Biologics Ltd. has
subsequently changed its name to 4D Pharma Research Limited.
Derivative
The present invention encompasses derivatives of the deposited strain.
The term “derivative” includes daughter strains (progeny) or stains cultured (sub-
cloned) from the original but modified in some way (including at the genetic level),
without ng negatively the biological activity, i.e. the derivative strain will have
at least the same immune modulatory activity as the original BT2013 strain.
A genome ce for strain BT2013 is provided in SEQ ID NO:1.
Bacterial strains that are es of the bacterium deposited under
accession number NCIMB 42341 are also expected to be effective for treating or
preventing inflammatory disorders and/or autoimmune disorders and/or allergic
disorders. A e is a y related strain that has the same or very similar
physiological and biochemical characteristics.
In certain ments, 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 ce of the bacterium deposited under accession
number NCIMB 42341.
Alternatively, strains that are biotypes of the bacterium deposited under
accession number NCIMB 42341 and that are suitable for use in the invention may
be identified by sequencing other nucleotide sequences for the bacterium
deposited under accession number NCIMB 42341. For example substantially the
whole genome may be sequenced and a biotype strain for use in the invention
may have 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 repetitive sequences such as BOX, ERIC,
dGTG)5, or REP ( Masco et al. (2003) Systematic and Applied Microbiology, 26:557-63). Biotype strains may have sequences with at least 95%, 96%, 97%, 98%,
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99%, 99.5% or 99.9% ce ty to the corresponding sequence of the
bacterium ted under accession number NCIMB 42341.
In n embodiments, the bacterial strain for use in the invention has a
genome with sequence identity to SEQ ID NO:1. 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:1 across at least 60% (e.g. at least 65%, 70%, 75%, 80%,
85%, 95%, 96%, 97%, 98%, 99% or 100%) of SEQ ID NO:1. For example, the
bacterial strain for use in the invention may have a genome with at least 90%
ce identity to SEQ ID NO:1 across 70% of SEQ ID NO:1, or at least 90%
sequence identity to SEQ ID NO:1 across 80% of SEQ ID NO:1, or at least 90%
sequence identity to SEQ ID NO:1 across 90% of SEQ ID NO:1, or at least 90%
ce identity to SEQ ID NO:1 across 100% of SEQ ID NO:1, or at least 95%
sequence identity to SEQ ID NO:1 across 70% of SEQ ID NO:1, or at least 95%
sequence identity to SEQ ID NO:1 across 80% of SEQ ID NO:1, or at least 95%
sequence ty to SEQ ID NO:1 across 90% of SEQ ID NO:1, or at least 95%
sequence identity to SEQ ID NO:1 across 100% of SEQ ID NO:1, or at least 98%
sequence identity to SEQ ID NO:1 across 70% of SEQ ID NO:1, or at least 98%
sequence identity to SEQ ID NO:1 across 80% of SEQ ID NO:1, or at least 98%
sequence identity to SEQ ID NO:1 across 90% of SEQ ID NO:1, or at least 98%
sequence identity to SEQ ID NO:1 across 100% of SEQ ID NO:1.
Alternatively, strains that are biotypes of the bacterium deposited under
accession number NCIMB 42341 and that are suitable for use in the invention may
be identified by using the accession number NCIMB 42341 deposit and restriction
fragment is and/or PCR analysis, for example by using fluorescent
amplified fragment length polymorphism (FAFLP) and repetitive DNA element
(rep)-PCR fingerprinting, or protein profiling, or partial 168 or 23s rDNA
sequencing.
In certain embodiments, strains that are biotypes of the bacterium
deposited under accession number NCIMB 42341 and that are suitable for use in
the invention are strains that provide the same pattern as the bacterium deposited
under accession number NCIMB 42341 when analysed by amplified ribosomal
dNA restriction analysis (ARDRA), for example when using Sau3Al ction nzyme (for exemplary methods and guidance see, for example, Srutkova et al.
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(2011) J. Microbiol. Methods, 87(1):10-6). Alternatively, biotype strains are
identified as strains that have the same carbohydrate fermentation patterns as the
bacterium deposited under accession number NCIMB 42341.
Bacterial strains that are biotypes of the bacterium deposited under
accession number NCIMB 42341 and that are useful in the compositions and
methods of the invention may be identified using any appropriate method or
strategy. For example, bacterial strains that have similar growth patterns,
metabolic type and/or surface ns to the bacterium deposited under
accession number NCIMB 42341 may be useful in the invention. A biotype strain
will have comparable immune modulatory ty to the NCIMB 42341 . For
example, a biotype strain will elicit comparable effects on the DSS-induced colitis
models and comparable effects on Treg levels, MPO enzymatic activity,
inflammation-associated gene expression and colon histopathology to the effects
shown in the Functional Assays, which may be identified by using the protocols
described in the Functional Assays.
Disorders
The Bacteroides thetaiotaomicron strain BT2013 may be used for the
ent and/or prevention of a disorder in a subject, wherein said disorder is an
inflammatory disorder and/or an autoimmune disorder.
In one embodiment, the disorder s the alimentary canal, a section of
the alimentary canal, the liver, liver cells, immune cells, epithelial cells, epidermal
cells, neuronal cells, endothelial cells, fibroblasts, the pancreas, and/or pancreatic
cells (such as the islets of Langerhans).
Examples of sections (i.e. parts) of the tary canal include the
oesophagus, the stomach and the intestine (such as the small intestine (e.g. the
duodenum, the jejunum and the ileum) and/or the large ine (e.g. the caecum,
ascending colon, transverse colon, descending colon, and sigmoid colon)).
Examples of lial cells include intestinal lial cells. Examples of
immune cells include dendritic cells, monocytes/macrophages, Tcells and
neutrophils.
In one embodiment, the er is selected from the group consisting of:
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1. Organ associated ers such as irritable bowel syndrome (IBS),
inflammatory bowel e including Crohn’s disease and ulcerative colitis,
necrotising enterocolitis, pouchitis, coeliac disease, multiple sclerosis (brain), type
I diabetes, Goodpasture’s me, Hashimoto ditis, chronic active
hepatitis, cardiomyopathy, uveitis and rhinitis.
2. Systemic disorders such as rheumatoid arthritis, systemic lupus
erythematosus, scleroderma, psoriasis, atopic itis, vitiligo, multiple
sclerosis, alopecia areata, sarcoidosis, polymyositis and combinations thereof.
In one aspect, the disorder affects the intestine.
In one aspect, the disorder is an inflammatory disorder. For example, the
disorder is an inflammatory bowel disorder (IBD) such as Crohn’s e.
In one aspect, the er is an autoimmune disorder. For example, the
autoimmune disorder is selected from the group consisting of ulcerative colitis,
pouchitis, rheumatoid arthritis, psoriasis, multiple sclerosis, type I diabetes,
allergies (including coeliac disease), atopic dermatitis and rhinitis.
Subject
In one embodiment, the subject is a monogastric animal.
Examples of monogastric animals e poultry, humans, rats, pigs,
dogs, cats, horses and rabbits.
In another embodiment, the subject is a mammal such as a monogastric
mammal.
Examples of monogastric mammals include omnivores (such as humans,
rats, and pigs), carnivores (such as dogs and cats), and herbivores (such as
horses and rabbits).
Preferably, the t is a human.
In one , the subject has a disorder is selected from the group
consisting of inflammatory bowel disorder (IBD), s, rheumatoid arthritis,
psoriasis, multiple sclerosis, type I diabetes, coeliac disease, atopic dermatitis,
is, irritable bowel syndrome (IBS), ulcerative colitis, pouchitis, Crohn's
e, functional dyspepsia, atopic diseases, necrotising enterocolitis, non
alcoholic fatty liver disease, gastrointestinal infection and combinations thereof.
dor e, the subject has IBD.
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Modulation/regulation
The terms “modulation” and “regulation” may be used interchangeably
herein.
In one embodiment The B. thetaiotaomicron strain BT2013 is used to
modulate the inflammation of a cell, a tissue or an organ in a subject.
In one embodiment, the term “modulation” refers to an increase and/or
induction and/or ion and/or activation. In an alternative embodiment, the
term “modulation” refers to a decrease and/or reduction and/or inhibition.
In one embodiment, the term “regulation” refers to an upregulation. In an
alternative embodiment, the term “regulation” refers to a downregulation.
In one ment, the B. thetaiotaomicron strain BT2013 as bed
herein reduces the inflammation of a cell, a tissue or an organ. For example,
inflammation of the alimentary canal, a section (i.e. part) of the alimentary canal
(such as the intestine), the liver, liver cells, epithelial cells, epidermal cells,
neuronal cells, elial cells, fibroblasts, the pancreas, and/or atic cells
(such as the islets of Langerhans) is reduced.
In one e, inflammation of the alimentary canal or part thereof (such
as the intestine) is reduced.
In another example, inflammation by immune cells of the tissue or the
organ is d.
In another example, inflammation by epithelial cells of the tissue or the
organ is reduced.
The term “inflammation” as used herein refers to one or more of the
following: redness, swelling, pain, tenderness, heat, and disturbed function of a
cell, a tissue or organ due to an inflammatory s triggered by over-reaction
of the immune system.
In one embodiment, the numbers of cells which are inflamed in a subject
is at least 10%, 20%, 30%, 40% or 50% lower after administration of the
polypeptide or polynucleotide or host cell as described herein when compared to
the numbers of cells which are inflamed in a subject before the strain BT2013 as
described herein is administered to the t.
In one embodiment, the amount of a tissue or organ which is inflamed in a
dubject is at least 10%, 20%, 30%, 40% or 50% lower after administration of strain
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BT2013 when compared to the amount of tissue or organ which is inflamed in a
subject before the strain BT2013 is stered to the subject.
In one embodiment, the strain BT2013 reduces the inflammation by
epithelial cells of the tissue or the organ.
For example, the lial cells are epithelial cells of the alimentary canal
or part thereof (such as the intestine).
Without wishing to be bound by theory, the strain BT2013 increases the
production of T cells (such as regulatory T cells which may also be referred to as
Tregs) in a subject. This increase in Treg numbers may combat the effects of
other effector T cells (also referred to as Teffs), such as Th1, Th1? and Th2 which
drive inflammation, autoimmunity and allergic/atopic conditions. In Crohn’s
disease and ulcerative s the Teff/Treg cell balance is lost.
In one embodiment, the production ofT cells in a t is increased such
that there are at least 10%, 20%, 30%, 40% or 50% more T cells, or greater than
100% more T cells after administration of the polypeptide or polynucleotide or host
cell as described herein when compared to the number of T cells in the subject
before the strain BT2013 is administered to the subject.
Intestine r integrity
In one embodiment, the strain BT2013 is used to e intestine r
integrity in a subject.
The term “improving intestine barrier integrity” as used herein refers to a
reduction in the numbers and/or types of rganisms which spread from the
intestine into other cells in a subject after administration of the strain BT2013 when
compared to the numbers and/or types of microorganisms which spread from the
intestine into other cells in a subject before administration of the strain BT2013 as
described herein.
In one embodiment, the numbers of rganisms which spread from
the intestine into other cells in a subject are at least 10%, 20%, 30%, 40% or 50%
lower after administration of the strain BT2013 when compared to the numbers of
microorganisms which spread from the intestine into other cells in a subject
administration.
In one embodiment, there are at least 5%, 10%, 15% or 20% fewer types
f microorganisms which spread from the intestine into other cells in a subject
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after administration of the strain BT2013 when compared to the types of
microorganisms which spread from the intestine into other cells in a subject before
the administration.
Intestine disruption
In one embodiment strain , is used to reduce disruption to the
intestine (e.g. large ine) of a subject (such as a subject with IBD).
The term “disruption to the intestine of a subject” as used herein refers to
an affect on the integrity of the mucosal epithelium and/or an affect on the number
of goblet cells in the epithelium and/or an affect on the number of immune cells
infiltrating the lamina a.
In one embodiment, strain BT2013 reduces or prevents disruption to the
integrity of the mucosal epithelium and/or reduces or prevents a reduction in the
number of goblet cells in the epithelium and/or reduces or prevents the infiltration
of immune cells into the lamina propria.
In one embodiment, a reduction in tion to the integrity of the mucosal
epithelium is a ion of at least 5%, 10%, 15% or 20% in the numbers of
bacteria crossing from the intestinal lumen into intestinal cells after administration
of strain BT2013 when compared to the numbers of bacteria crossing from the
intestinal lumen into intestinal cells in a subject before administration.
In one embodiment, a reduction in the number of goblet cells in the
epithelium is a reduction of at least 2%, 5%, 10%, 15% or 20% in the numbers of
goblet cells in the lium of a subject after administration of strain BT2013
when ed to the number of goblet cells in the epithelium of a subject before
administration.
In one embodiment, the reduction in the infiltration of immune cells into the
lamina propria is such that over a fixed time period (such as 24 hours) there is a
reduction of at least 5%, 10%, 15%, 20% or 30% in the numbers of immune cells
(e.g. T cells) crossing into lamina propria cells after administration of strain
BT2013 when compared to the numbers of immune cells (e.g. T cells) ng
into the lamina propria in a subject before administration.
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Pro-inflammatory genes and barrier integrity genes
In one embodiment, strain BT2013 is used to regulate the expression of
one or more pro-inflammatory genes and/or one or more barrier integrity genes in
a cell or cells of a subject.
In one embodiment, the term “regulate” refers to an upregulation in the
expression of one or more pro-inflammatory genes. In an alternative embodiment,
the term “regulate” refers to a downregulation in the expression of one or more
flammatory genes.
In one embodiment, strain BT2013 gulates the expression of one
or more pro-inflammatory genes in a cell or cells of a subject.
The term “pro-inflammatory gene” as used herein refers to a gene which,
when expressed, promotes inflammation. Examples of pro-inflammatory genes
e genes encoding but notlimited to IL1-B, IL4, IL5, IL6, IL8, IL12, IL13, IL17,
IL21, IL22, IL23, IL27, IFN, CCL2, CCL3, CCL5, CCL20, CXCL5, CXCL10,
CXCL12, CXCL13, and TNF-oc.
In one embodiment, the pro-inflammatory gene is selected from the group
consisting of IL1-B, IL6 and IL8.
In one ment, the expression level (eg. mRNA level) of one or more
pro-inflammatory genes is decreased (i.e. downregulated) such that the level is at
least 10%, 20%, 30%, 40% or 50% lower after administration of the strain BT2013
when compared to the level in the subject before administration.
The term “barrier integrity genes” as used herein refers to a gene which,
when expressed, has a role in the function of the barrier of the intestine such as
the repair of the barrier and the prevention of microorganisms crossing the barrier.
es of barrier ity genes include genes encoding Retnlg|Retnlb, Si,
Defa24, Hsd11b2, Hsd17b2, and Thra.
In one ment, the term “regulate” refers to an upregulation in the
expression of one or more barrier integrity genes. In an alternative embodiment,
the term “regulate” refers to a downregulation in the expression of one or more
barrier integrity genes.
In one ment, strain BT2013 upregulates the expression of barrier
ity genes in a cell or cells of a subject
In one embodiment, the barrier integrity gene is selected from the group
gonsisting of Retnlg|Retnlb, Si, Defa24, Hsd11b2, Hsd17b2, and Nr1d1|Thra.
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In one embodiment, the expression level (e.g. mRNA level) of one or more
barrier integrity genes is sed (i.e. upregulated) such that the level is at least
%, 20%, 30%, 40% or 50% higher after administration of strain BT2013 when
compared to the level in the subject before administration.
Alimentary canal
Parts of the alimentary canal e the oesophagus, the stomach and the
intestine (such as the small intestine (e.g. the duodenum, the jejunum and the
ileum) and/or the large intestine (e.g. the caecum, ascending colon, transverse
colon, descending colon, and sigmoid ).
Herein, the term “large intestine” may be used interchangeably with the
term “colon”.
In one embodiment, strain BT2013 is used for improving alimentary canal
health in a subject.
The term ving alimentary canal health” as used herein refers to
reducing the level of inflammation in the alimentary canal or part thereof and/or
improving intestinal microbiota.
In one ment, the level of mation in the alimentary canal is at
least 10%, 20%, 30%, 40% or 50% lower after administration of strain BT2013
when compared to the level of inflammation in the alimentary canal of a subject
before administration.
In one embodiment, strain BT2013 is used for improving intestinal
microbiota in a subject.
The term “intestinal microbiota” as used herein refers to microorganisms
that live in the digestive tract of the host animals. These microorganisms perform
a wide variety of metabolic, structural, protective and other beneficiary functions.
As used herein, the term “improving intestinal microbiota” refers to
increasing the number and/or type of desirable rganisms present in the
intestine of a subject (e.g. the host), and/or increasing the activity of said desirable
microorganisms in terms of their metabolic, structural, protective and other
beneficiary functions. The term “improving intestinal iota” may also refer to
decreasing the number and/or type of undesirable microorganisms present in the
intestine of a subject (e.g. the host), and/or decreasing the activity of said
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undesirable microorganisms in terms of their metabolic, structural, protective and
other beneficiary functions.
Microorganisms which are desirable in the intestine of a host are those
rganisms which have a protective and beneficiary function. Firmicutes and
bacteroidetes bacteria are examples of desirable microorganisms in the intestine
of a host.
Microorganisms which are undesirable in the intestine of a host are those
microorganisms which can interfere with the metabolic, structural, protective and
other beneficiary functions of desirable microorganisms in the intestine have a
protective and beneficiary function. In addition or alternatively, undesirable
microorganisms are those which cause, for example, mation and/or
diarrhoea. E. coli is an example of an undesirable microorganism in the intestine
of a host.
For example, a change in the microbiota balance between desirable
microorganism (such as firmicutes and bacteroidetes bacteria) and undesirable
microorganisms (such as E.co/i: ETEC, EPEC, EIEC, EHEC and EAEC) within the
intestine may occur in subjects with matory bowel disease (IBD) once strain
BT2013 has been administered to the subject.
In one embodiment, the number of desirable microorganisms (such as
firmicutes and bacteroidetes ia) present in the intestine of a subject (e.g.
the host), is increased such that the number of microorganisms is at least 10%,
%, 30%, 40% or 50% higher, or greater than 100% higher after administration
of the strain BT2013 compared to the level in the subject before administration.
In addition, or atively, the types of desirable microorganisms (such as
utes and bacteroidetes) t in the intestine of a subject (e.g. the host),
are increased such that there are at least 2%, 5%, 10%, or 15% more types of
microorganisms after stration of strain BT2013 when compared to the types
in the subject before stration.
In one embodiment, the number of undesirable microorganisms (such as
E. coli ETEC, EPEC, EIEC, EHEC and EAEC) present in the intestine ofa subject
(e.g. the host), is decreased such that the number of microorganisms is at least
%, 20%, 30%, 40% or 50% lower after administration strain BT2013 when
dompared to the level in the subject before administration. In addition, or
lternatively, the types of rable microorganisms (such as E. coli ETEC,
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EPEC, EIEC, EHEC and EAEC) present in the intestine ofa subject (e.g. the host),
are decreased such that there are at least 1%, 2%, 5%, or 10%, fewer types of
undesirable microorganisms after administration of strain BT2013 when compared
to the types in the subject before administration.
Encapsulation
In one embodiment, the B. thetaiotaomicron strain BT2013 is
encapsulated.
In a further embodiment, a pharmaceutical composition sing the
strain BT2013 is encapsulated.
In another embodiment, a nutritional supplement comprising the strain
BT2013 is encapsulated.
In a further embodiment, a feedstuff, food product, dietary supplement, or
food additive as described herein is encapsulated.
The term “encapsulated” as used herein refers to a means for protecting
the strain BT2013 from an atible environment by physical separation so
that it can be delivered to the target site (e.g. the intestine) without degradation or
significant degradation in order that the strain BT2013 can have an effect on the
target site. An example is an enteric coated e or an enterically-resistant
capsule.
Even when the objective of the encapsulation is the isolation of the strain
from its ndings, the protective coating or shell must be ruptured at the time
of desired action. The rupturing of the protective coating or shell is typically
t about through the application of chemical and al stimuli such as
pressure, enzyme attack, chemical on and al disintegration.
For example, encapsulation ensures that the strain can be ingested so that
the microorganisms can be delivered to the target site (e.g. the intestine) in an
amount which is ive to produce an effect at the target site.
Pharmaceutical composition
In one embodiment, a pharmaceutical composition comprises
microorganisms of the strain BT2013 and optionally a pharmaceutically
dcceptable excipient, carrier or diluent.
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The pharmaceutical composition may be any pharmaceutical composition.
In one aspect, the pharmaceutical composition is to be administered orally,
enterally or rectally. For example, the composition may be an edible composition.
"Edible" means a material that is approved for human or animal consumption.
The pharmaceutical compositions may be for human or animal usage in
human and veterinary medicine.
Examples of such suitable excipients for the various different forms of
ceutical compositions described herein may be found in the “Handbook of
Pharmaceutical Excipients, 2nd Edition, (1994), Edited by AWade and PJ Weller.
Acceptable carriers or diluents for therapeutic use are well known in the
pharmaceutical art, and are described, for example, in Remington's
Pharmaceutical Sciences, Mack Publishing Co. (A. R. o edit. 1985).
Examples of le carriers e lactose, starch, glucose, methyl
cellulose, magnesium stearate, mannitol, sorbitol and the like.
Examples of suitable diluents include one or more of: water, ethanol,
glycerol, propylene glycol and glycerin, and ations thereof.
The choice of pharmaceutical carrier, excipient or diluent can be selected
with regard to the intended route of administration and rd 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 e starch, n, natural sugars such
as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners,
natural and tic gums, such as acacia, tragacanth or sodium alginate,
carboxymethyl cellulose and polyethylene glycol.
Examples of suitable lubricants include sodium oleate, sodium stearate,
magnesium stearate, sodium te, sodium e, sodium de and the
like.
Preservatives, stabilizers, dyes and even flavouring agents may be
provided in the pharmaceutical ition. Examples of preservatives include
sodium te, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants
and suspending agents may be also used.
In one aspect, the microorganisms of strain BT2013 pharmaceutical
nomposition are encapsulated.
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The pharmaceutical may be in the form of a solution or as a solid —
depending on the use and/or the mode of ation and/or the mode of
administration.
As used herein, the term "medicament" encompasses medicaments for
both human and animal usage in human and veterinary medicine. In addition, the
term ament" as used herein means any substance, which es a
therapeutic and/or beneficial effect. The term "medicament" as used herein is not
necessarily limited to substances, which need Marketing Approval, but may
include substances which, can be used in cosmetics, nutraceuticals, food
ding feeds and beverages for example), probiotic cultures, nutritional
supplements and natural remedies. In addition, the term "medicament" as used
herein encompasses a product designed for incorporation in animal feed, for
example ock feed and/or pet food.
Nutritional supplements
Nutritionally acceptable rs, diluents and excipients e those
suitable for human or animal consumption and that are used as standard in the
food industry. Typical nutritionally acceptable carriers, ts and ents will
be familiar to the skilled person in the art.
In one embodiment, a nutritional supplement comprises microorganisms of
strain BT2013 or a host cell comprising an expression vector comprising said
polynucleotide sequence, and a nutritional acceptable excipient, carrier or diluent.
In one example, the microorganisms of strain BT2013 are ulated.
Feedstufflproducts
A further aspect of the invention s to feedstuffs, food products, dietary
supplements and food additives comprising microorganisms of strain BT2013.
The terms “feedstuff”, "food t" “food additive” and “dietary
supplement” as used herein are intended to cover all consumable products that
can be solid, jellied or liquid.
The term “food product” is used in a broad sense — and covers food for
humans as well as food for animals (i.e. a feed). In one aspect, the food product
a: for human consumption. Examples of food products include diary products
uch as milk, cheese, beverages comprising whey protein, milk drinks, lactic acid
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bacteria drinks, yoghurt, ng yoghurt), bakery products, beverages and
beverage powders.
The “feedstuff”, "food product" “food additive” and “dietary supplement”
may be in the form of a solution or as a solid — depending on the use and/or the
mode of application and/or the mode of administration.
As used herein the term “dietary supplement” includes a formulation which
is or can be added to a food product or feedstuff as a nutritional supplement. The
term “dietary supplement” as used here also refers to ations which can be
used at low levels in a wide variety of products that require gelling, texturising,
stabilising, suspending, film-forming and structuring, retention of juiciness and
improved mouthfeel, without adding viscosity.
Suitable food ts may e, for example, functional food products,
food compositions, pet food, livestock feed, health foods, feedstuffs and the like.
In one aspect, the food product is a health food.
As used herein, the term ional food product" means food that is
capable of providing not only a ional effect, but is also capable of delivering
a further beneficial effect to the consumer. Accordingly, functional foods are
ordinary foods that have components or ingredients (such as those described
) orated into them that impart to the food a ic functional - e.g.
medical or physiological benefit - other than a purely nutritional effect.
Examples of specific food products that are applicable to the present
invention include milk-based products, ready to eat desserts, powders for re-
constitution with, e.g., milk or water, chocolate milk , malt drinks, ready-to-
eat dishes, instant dishes or drinks for humans or food compositions representing
a complete or a partial diet intended for pets or livestock.
In one aspect, the feedstuff, food product, dietary supplement or food
additive according to the present invention are intended for humans, pets or
livestock such as monogastric animals. The feedstuff, food product, dietary
supplement or food additive may be intended for s selected from the group
consisting of dogs, cats, pigs, horses, or y. In a r embodiment, the food
product, dietary supplement or food additive is intended for adult species, in
particular human adults.
The term based product" as used herein means any liquid or semi-
QOlid milk or whey based product having a varying fat content. The milk-based
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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, d 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; flavoured milks, ice cream; milk-containing food such as sweets.
The uffs, food ts, dietary supplements or food additives of the
present invention may be - or may be added to - food supplements, also referred
to herein as dietary or nutritional supplements or food additives.
The feedstuffs, food products, dietary ments or food ves
according to the ion may also be used in animal nutrition (e.g. in pig
nutrition), particularly in the early-weaned period and growing fattening period.
The feedstuffs, food products, dietary supplements orfood additives are expected
to enhance immune function reduce and prevent infectious diseases, beneficially
alterthe microbiota composition, and improve growth and performance of animals,
for example, through increased feed conversion efficiency.
In one embodiment the feedstuff, food product, dietary supplement, orfood
additive is encapsulated.
Live biotherapeutic product
The microorganisms of strain BT2013 may be used in or as a live
biotherapeutic product (LBP).
In one aspect, the LBP is an orally administrable composition of
metabolically active, i.e., live and/or lyophilized, or able heat-killed,
irradiated or lysed bacteria. The LBP may contain other ingredients. The LBP can
be administered orally, i.e., in the form of a tablet, capsule or . The LBP
may additionally comprise other bacterial species, for example, the bacterial
species R. hominis. ulated products are favoured for R. hominis as it is an
anaerobe. Other ients (such as vitamin C, for example), may be included
as oxygen scavengers and substrates (such as these improve the colonisation
and survival in vivo). Alternatively, the LBP of the invention may be administered
orally as a food or nutritional product, such as milk or whey based ted dairy
droduct, or as a pharmaceutical product.
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A le daily dose of the bacteria in the LBP is from about 1 x 103 to
about 1 x 1012 colony forming units (CFU); for example, from about 1 x 107 to
about 1 x1010 CFU; in another example from about 1 x 106 to about 1 FU.
In one aspect, the LBP contains the bacterial species and/or cellular
components thereof, as active ingredients, in an amount of from about 1 x 106 to
about 1 x 1012 CFU/g, respect to the weight of the composition; for example, from
about 1 x 108 to about 1 x 1010 CFU/g. Typically, a LBP is optionally combined
with at least one suitable prebiotic compound. A prebiotic 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 alacto-oligosaccharides.
In one aspect, the LBP of the present description includes a tic 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, isomalt-oligosaccharides, pectins, xylo-oligosaccharides
(or XOS), chitosan-oligosaccharides (or COS), beta-glucans, arable gum modified
and resistant starches, polydextrose, tose, acacia fibers, carob, oats, and
citrus fibers. In one aspect, the prebiotics are the short-chain fructo-
oligosaccharides (for city shown hereinbelow as FOSs-cc); said FOSs-cc.
are not digestible carbohydrates, lly ed by the conversion of the beet
sugar and including a saccharose molecule to which three glucose molecules are
bonded.
Administration
The pharmaceutical compositions, the nutritional supplements, feedstuffs,
food products, dietary ments or food additives of the present invention may
be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal,
intraarterial, intrathecal, intrabronchial, aneous, intradermal, intravenous,
nasal, buccal or sublingual routes of administration.
In one aspect, the pharmaceutical compositions, the nutritional
supplements, feedstuffs, food products, dietary ments or food additives of
de present invention are adapted for oral, rectal, l, parenteral, nasal, buccalr sublingual routes of administration.
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In a further aspect, the pharmaceutical compositions, the nutritional
supplements, feedstuffs, food products, dietary supplements or food additives of
the present invention are adapted for oral administration.
For oral administration, particular use is made of compressed tablets, pills,
tablets, gellules, drops, and es.
Other forms of administration se solutions or emulsions which may
be injected intravenously, rterially, intrathecally, subcutaneously,
ermally, intraperitoneally or intramuscularly, and which are prepared from
sterile or sterilisable solutions. The pharmaceutical compositions of the present
invention may also be in form of itories, pessaries and suspensions.
Pharmaceutical compositions, the nutritional supplements, feedstuffs, food
products, dietary supplements or food additives may be formulated in unit dosage
form, i.e., in the form of discrete portions containing a unit dose, or a multiple or
sub-unit of a unit dose.
Dosage
A person of ordinary skill in the art can easily determine an appropriate
dosage amount of the strain BT2013 to administer to a subject without undue
experimentation. Typically, a physician will determine the actual dosage which
will be most suitable for an individual patient and it will depend on a variety of
factors including the activity of the strain employed, the lic stability and
length of action of that strain, the age, body , general health, sex, diet, mode
and time of administration, rate of excretion, drug combination, the severity of the
particular condition, and the dual undergoing therapy. The dosages
disclosed herein are ary of the average case. There can of course be
individual instances where higher or lower dosage ranges are merited, and such
are within the scope of this invention.
Combinations
In one aspect, microorganisms of strain BT2013 are administered in
combination with one or more other active agents. In such cases, the
microorganisms of strain BT2013 may be stered utively,
dimultaneously or sequentially with the one or more other active agents.
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Functional Assays:
In Vivo Model
C57BL/6 mice (6 weeks old) were used to evaluate the therapeutic effect
of B. thetaiotaomicron strains E1, E2 and BT2013 during DSS-induced colitis. The
mice were colonised with one of the B. thetaiotaomicron strains prior to treatment
with DSS. The animals were euthanized and intestinal tissue sampling was
performed. Small intestine was collected for immunological analysis by flow
cytometry and enzymatic activity measurements of the enzyme myeloperoxidase
(MPO). Ascending colon were divided into equal parts and transferred to neutral
buffered formalin (NBF; Sigma-Aldrich) for histological analysis or RNAIater
(Ambion) for molecular analysis..
Flow cytometry analysis of T cell populations in small intestine lamina
propria was carried out (figure 1 and figure 2). D88 alone and B. thetaiotaomicron
treatment did not affect the total percentage of the CD3+CD4+CD8— population.
The populations influenced by DSS alone and B. otaomicron were the Tregs
(CD25+FoxP3+* and FR4'“CD25+*) and Teff cells (FR4'°CD25+*) (figure 1 and 2).
The tage of Tregs was increased in mice treated with B. thetaiotaomicron
strain BT2013 compared to DSS alone. The strain E1W did not appear to have
any effect on Tregs. (figure 1). The effects of BT2013 in Tregs were only apparent
in mice co-treatment with DSS. The strain had no effect on Tregs in untreated
mice but did influence the Teff cell tion (figure 2).
The enzymatic activity of MPO in the ileum and caecum was determined
(Figure 3 a and 3b). MP0 is a proinflammatory enzyme stored in the azurophilic
granules of philic granulocytes. MP0 is used as an indicator of
inflammation, specifically neutrophil recruitment and accumulation. The lower
levels of MPO activity detected in i|ea| or caecal tissue samples from the B.
thetaiotaomicron/D88 treated mice ed to DSS alone indicates a reduction
in phil recruitment and ore a reduction in inflammation.
Histological is of ascending colon was carried out (Figures 4 and 5
and Table 1). The histopathology grading scheme was based on the ia of
Berg et al 1996, as summarised:
O = Shallow crypts, no or few rating inflammatory cells, intact
lium, goblet cells appearfull of mucin. ie no pathology
D 1 = Crypts may exhibit slight epithelial cell hyperplasia, some diffuse
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infiltrating inflammatory cells may be seen between crypts, luminal
epithelium
appears intact, goblet cells may appear slightly depleted of mucin.
2 = Crypts appear deeper with ct evidence of epithelial hyperplasia,
depletion of mucin from goblet cells, infiltrating inflammatory cells evident
may be multifocal in nature ,though the infiltrates are not seen in the
submucosa.
3 = Lesions involved a larger area of the mucosa and /or were more
frequent than that seen in grade 2. The lesions did not e the
submucosa.
The luminal epithelial cells exhibited small erosions. The lesions are not
transmural.
4 = Crypt lium appears eroded. ses may be present.
Luminal epithelial cells appear irregular, sometimes with complete loss.
Transmural infiltrate is observed - this was often associated with complete
loss
of epithelial cells into the lumen.
The disruption to the colon as a result of DSS induced colitis was
significantly reduced by treatment of mice with B. thetaiotaomicron strains E1, E2
and BT2013. The expression of inflammation—associated genes in the ascending
colon was reduced in mice colonised with B. thetaiotaomicron compared to mice
treated with DSS alone. The strains E1 and BT2013 greatly reduced lL1B and
lL6 inflammatory gene expression compared to strain E2. (Figure 6)
Table 1
TTEST L BT E1 BT 2013 BT E2
DSS 0.000 0.032 0.041 0.089
In Vitro Model
The expression of the matory gene interleukin-8 induced in inal
pithelial cells after PMA exposure was modulated in the presence of B.
aomicron strains E1, E2 and BT2013 (Figure 7).
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Sequencing of strain BT2013 genome
A DNA sample from strain BT2013 was subjected to sequencing on
MiSeq (v2 nano 2x250bp) using a Nextera XT library for fast fragmentation and
tagging with sequencing adaptors, to give a total of 4605120 reads (1115615927
bases).
The data analysis is ised below:
a. Mapping to reference sequence (NC_004663 and NC_004703) using
bowtie2 (2.2.2)
b. SNV and small lnDel calling using VarScan (2.3.7) and SNVer (0.5.3)
performing a sus call to avoid false positives
c. Annotation of variations using reference gff
d. Large lnDel calling using pindel (0.2.5a3)
e. De-novo assembly of unmapped reads using SOAPdenovo (2.04)
f. Blast of assembled contigs against NCBI nt database
g. Subsampling of all reads of the sample to 50%
h. De-novo assembly on the pled reads using SOAPdenovo
(2.04)
The sequences were mapped to the reference sequence (NC_004663
and NC_004703) using 2 (2.2.2). tide variations and small
insertions and/or ons were identified using VarScan (2.3.7) and SNVer
(0.5.3) to avoid false positives during sequencing and variations were annotated
using a reference sequence. Large insertions and deletions were identified
using pindel a3). Unmapped reads were assembled de novo using
SOAPdenovo (2.04). The cing fragments were reassembled into contigs
which were blasted against the NCBI nucleotide database. All the reads of the
sample were subsampled to 50% and were then assembled de novo using
SOAPdenovo (2.04) to provide_a concatenated version of the de novo ce
assembly of BT2013.
Sequences
SEQ ID NO:1 (concatenated version of the de novo sequence ly of
BT2013) — see electronic sequence listing.
Claims (20)
1. A ition comprising a oides thetaiotaomicron strain with a sequence that has at least 99.5% sequence identity to SEQ ID NO: 1, wherein said Bacteroides thetaiotaomicron strain has a comparable increase in the percentage of Treg cells in small intestine lamina propria tissue samples from Bacteroides thetaiotaomicron/DSS treated mice to that of oides thetaiotaomicron deposited as Accession Number 42341 at NCIMB, and wherein said Bacteroides thetaiotaomicron strain is not the Bacteroides thetaiotaomicron ted as ion Number 42341 at NCIMB.
2. The composition according to claim 1, wherein said Bacteroides thetaiotaomicron 5 strain is encapsulated.
3. The composition according to claim 1 or claim 2, wherein the composition is a pharmaceutical composition r sing a pharmaceutically acceptable excipient, carrier or diluent.
4. Use of the composition according to any one of claims 1-3 in the manufacture of a medicament for treating or preventing inflammatory disorders and/or autoimmune disorders and/or allergic disorders in a subject. 15
5. The use ing to claim 4, wherein said disorder affects the alimentary canal, a section of the alimentary canal, and/or epithelial cells.
6. The use according to claim 4 or claim 5, wherein said disorder is selected from the group consisting of inflammatory bowel disorder (IBD), colitis, rheumatoid arthritis, 20 psoriasis, multiple sclerosis, type I diabetes, c disease, atopic dermatitis, rhinitis, ble bowel syndrome (IBS), tive colitis, pouchitis, Crohn's disease, functional dyspepsia, atopic diseases, necrotising enterocolitis, non-alcoholic fatty liver disease, gastrointestinal infection and combinations thereof. 25
7. Use of the composition according to any one of claims 1-3 in the manufacture of a medicament for reducing the mation of a tissue or an organ.
8. The use according to claim 7, wherein said Bacteroides thetaiotaomicron strain reduces the inflammation by epithelial cells of the tissue or the organ.
9. The use according to claim 8, wherein said epithelial cells are lial cells of the alimentary canal.
10. Use of the composition according to any one of claims 1-3 in the manufacture of a 35 medicament for reducing disruption to the colon of a subject.
11. The use according to claim 10, wherein said subject has IBD.
12. The use according to claim 10 or claim 11, n said Bacteroides thetaiotaomicron strain: a) reduces or prevents disruption to the integrity of the mucosal epithelium; 5 b) reduces or prevents a ion in the number of goblet cells in the epithelium; and/or c) reduces or prevents the infiltration of immune cells into the lamina propria.
13. Use of the composition according to any one of claims 1-3 in the manufacture of a 10 medicament for reducing the expression of one or more pro-inflammatory genes in a cell or cells of a subject.
14. The use according to claim 13, wherein said one or more pro-inflammatory genes is ed from the group consisting of IL1-β, IL6, IL8, IL10 and combinations thereof.
15. The use according to claim 13 or claim 14, wherein said cell is an alimentary canal cell (such as a cell of the ascending colon), or an epithelial cell (such as an intestinal epithelial cell). 20
16. Use of the composition according to any one of claims 1-3 in the manufacture of a medicament for increasing the percentage of T regs in the tary canal or a section of the alimentary canal.
17. The use according to claim 16, wherein said section of the alimentary canal is the 25 small intestine lamina propria.
18. A process for producing a composition according to claim 2, said process comprising ng said Bacteroides thetaiotaomicron strain with a pharmaceutically acceptable excipient, carrier or diluent.
19. The process according to claim 18, wherein said Bacteroides thetaiotaomicron strain is encapsulated in said process.
20. A ional supplement, feedstuff, food product, y supplement or food additive 35 comprising the composition according to any one of claims 1-3.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1423084.1 | 2014-12-23 | ||
GB201423084 | 2014-12-23 | ||
NZ732667A NZ732667B2 (en) | 2014-12-23 | 2015-12-22 | A Bacteroides thetaiotaomicron strain and its use in reducing inflammation |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ764713A NZ764713A (en) | 2021-06-25 |
NZ764713B2 true NZ764713B2 (en) | 2021-09-28 |
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