AU2018205072B2 - Immune modulation - Google Patents
Immune modulation Download PDFInfo
- Publication number
- AU2018205072B2 AU2018205072B2 AU2018205072A AU2018205072A AU2018205072B2 AU 2018205072 B2 AU2018205072 B2 AU 2018205072B2 AU 2018205072 A AU2018205072 A AU 2018205072A AU 2018205072 A AU2018205072 A AU 2018205072A AU 2018205072 B2 AU2018205072 B2 AU 2018205072B2
- Authority
- AU
- Australia
- Prior art keywords
- subject
- strain
- composition according
- bacteroides thetaiotaomicron
- cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 230000008102 immune modulation Effects 0.000 title description 2
- 241000606123 Bacteroides thetaiotaomicron Species 0.000 claims abstract description 72
- 235000015872 dietary supplement Nutrition 0.000 claims abstract description 64
- 235000013305 food Nutrition 0.000 claims abstract description 54
- 235000013373 food additive Nutrition 0.000 claims abstract description 35
- 239000002778 food additive Substances 0.000 claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
- 230000000172 allergic effect Effects 0.000 claims abstract description 8
- 208000010668 atopic eczema Diseases 0.000 claims abstract description 8
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 62
- 210000004027 cell Anatomy 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 47
- 108090000623 proteins and genes Proteins 0.000 claims description 38
- 230000004054 inflammatory process Effects 0.000 claims description 30
- 206010061218 Inflammation Diseases 0.000 claims description 29
- 210000001519 tissue Anatomy 0.000 claims description 27
- 208000035475 disorder Diseases 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 25
- 230000014509 gene expression Effects 0.000 claims description 25
- 230000000770 proinflammatory effect Effects 0.000 claims description 22
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 claims description 21
- 210000002919 epithelial cell Anatomy 0.000 claims description 19
- 210000003289 regulatory T cell Anatomy 0.000 claims description 19
- 241000699670 Mus sp. Species 0.000 claims description 18
- 230000009467 reduction Effects 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 210000000056 organ Anatomy 0.000 claims description 17
- 210000001815 ascending colon Anatomy 0.000 claims description 16
- 102000003896 Myeloperoxidases Human genes 0.000 claims description 13
- 108090000235 Myeloperoxidases Proteins 0.000 claims description 13
- 210000000981 epithelium Anatomy 0.000 claims description 13
- 208000027866 inflammatory disease Diseases 0.000 claims description 13
- 210000004400 mucous membrane Anatomy 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 208000023275 Autoimmune disease Diseases 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 12
- 210000001072 colon Anatomy 0.000 claims description 11
- 206010009887 colitis Diseases 0.000 claims description 9
- 210000002175 goblet cell Anatomy 0.000 claims description 9
- 210000002865 immune cell Anatomy 0.000 claims description 9
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 210000000813 small intestine Anatomy 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 6
- 210000002490 intestinal epithelial cell Anatomy 0.000 claims description 6
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
- 108090000174 Interleukin-10 Proteins 0.000 claims description 5
- 102000003814 Interleukin-10 Human genes 0.000 claims description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 208000015943 Coeliac disease Diseases 0.000 claims description 4
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 4
- 208000002389 Pouchitis Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- 230000002255 enzymatic effect Effects 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 206010051606 Necrotising colitis Diseases 0.000 claims description 3
- 230000002519 immonomodulatory effect Effects 0.000 claims description 3
- 230000008595 infiltration Effects 0.000 claims description 3
- 238000001764 infiltration Methods 0.000 claims description 3
- 206010039083 rhinitis Diseases 0.000 claims description 3
- 208000012657 Atopic disease Diseases 0.000 claims description 2
- 206010017964 Gastrointestinal infection Diseases 0.000 claims description 2
- 208000019836 digestive system infectious disease Diseases 0.000 claims description 2
- 201000006549 dyspepsia Diseases 0.000 claims description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 2
- 241000606125 Bacteroides Species 0.000 claims 1
- 230000001363 autoimmune Effects 0.000 abstract 1
- 244000005700 microbiome Species 0.000 description 41
- 210000000936 intestine Anatomy 0.000 description 31
- 239000000047 product Substances 0.000 description 18
- 241000894006 Bacteria Species 0.000 description 17
- 102100039019 Nuclear receptor subfamily 0 group B member 1 Human genes 0.000 description 16
- 241001465754 Metazoa Species 0.000 description 13
- 230000004888 barrier function Effects 0.000 description 12
- 230000001580 bacterial effect Effects 0.000 description 11
- 235000013336 milk Nutrition 0.000 description 10
- 239000008267 milk Substances 0.000 description 10
- 210000004080 milk Anatomy 0.000 description 10
- 210000001744 T-lymphocyte Anatomy 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 244000005709 gut microbiome Species 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000012163 sequencing technique Methods 0.000 description 7
- 108090001005 Interleukin-6 Proteins 0.000 description 6
- 108090001007 Interleukin-8 Proteins 0.000 description 6
- 230000002503 metabolic effect Effects 0.000 description 6
- 230000001681 protective effect Effects 0.000 description 6
- 235000014966 Eragrostis abyssinica Nutrition 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 102000026633 IL6 Human genes 0.000 description 5
- 102000004890 Interleukin-8 Human genes 0.000 description 5
- 108010046377 Whey Proteins Proteins 0.000 description 5
- 102000007544 Whey Proteins Human genes 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 235000013361 beverage Nutrition 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000000968 intestinal effect Effects 0.000 description 5
- 235000016709 nutrition Nutrition 0.000 description 5
- 241000605059 Bacteroidetes Species 0.000 description 4
- 241000252983 Caecum Species 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- 241000192125 Firmicutes Species 0.000 description 4
- 108091058560 IL8 Proteins 0.000 description 4
- 239000005862 Whey Substances 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 210000004534 cecum Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000378 dietary effect Effects 0.000 description 4
- 210000003405 ileum Anatomy 0.000 description 4
- 210000002429 large intestine Anatomy 0.000 description 4
- 244000144972 livestock Species 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229920001542 oligosaccharide Polymers 0.000 description 4
- 235000013406 prebiotics Nutrition 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 241000283086 Equidae Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical class OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000282887 Suidae Species 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 230000003828 downregulation Effects 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 238000002825 functional assay Methods 0.000 description 3
- 235000013376 functional food Nutrition 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 210000004969 inflammatory cell Anatomy 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000007358 intestinal barrier function Effects 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 108091033319 polynucleotide Proteins 0.000 description 3
- 102000040430 polynucleotide Human genes 0.000 description 3
- 239000002157 polynucleotide Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000013589 supplement Substances 0.000 description 3
- 230000003827 upregulation Effects 0.000 description 3
- 108020004465 16S ribosomal RNA Proteins 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 241000220479 Acacia Species 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- -1 CCL3 Proteins 0.000 description 2
- 101100152865 Danio rerio thraa gene Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 101150008463 Hsd11b2 gene Proteins 0.000 description 2
- 101150058165 Hsd17b2 gene Proteins 0.000 description 2
- 229920001202 Inulin Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 241000736262 Microbiota Species 0.000 description 2
- 101100331388 Mus musculus Defa24 gene Proteins 0.000 description 2
- 101100301584 Mus musculus Retnlb gene Proteins 0.000 description 2
- 101150081376 NR1D1 gene Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 2
- 241000058754 Rarimicrobium hominis Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 101150059155 Retnlg gene Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000001609 comparable effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 210000001731 descending colon Anatomy 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 210000001339 epidermal cell Anatomy 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 235000013350 formula milk Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 235000013402 health food Nutrition 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 2
- 229940029339 inulin Drugs 0.000 description 2
- 210000004153 islets of langerhan Anatomy 0.000 description 2
- 210000001630 jejunum Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 235000020124 milk-based beverage Nutrition 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000006041 probiotic Substances 0.000 description 2
- 235000018291 probiotics Nutrition 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000011253 protective coating Substances 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 210000001599 sigmoid colon Anatomy 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 235000021262 sour milk Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 210000004876 tela submucosa Anatomy 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 101150014006 thrA gene Proteins 0.000 description 2
- 210000003384 transverse colon Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 235000008939 whole milk Nutrition 0.000 description 2
- 235000013618 yogurt Nutrition 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 235000007319 Avena orientalis Nutrition 0.000 description 1
- 244000075850 Avena orientalis Species 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 229920002498 Beta-glucan Polymers 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 102100036848 C-C motif chemokine 20 Human genes 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 1
- 102100025277 C-X-C motif chemokine 13 Human genes 0.000 description 1
- 102100036150 C-X-C motif chemokine 5 Human genes 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 241001466804 Carnivora Species 0.000 description 1
- 235000013912 Ceratonia siliqua Nutrition 0.000 description 1
- 240000008886 Ceratonia siliqua Species 0.000 description 1
- 102000006303 Chaperonin 60 Human genes 0.000 description 1
- 108010058432 Chaperonin 60 Proteins 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- LKDRXBCSQODPBY-OEXCPVAWSA-N D-tagatose Chemical compound OCC1(O)OC[C@@H](O)[C@H](O)[C@@H]1O LKDRXBCSQODPBY-OEXCPVAWSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000007023 DNA restriction-modification system Effects 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 206010019755 Hepatitis chronic active Diseases 0.000 description 1
- 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 description 1
- 101000713099 Homo sapiens C-C motif chemokine 20 Proteins 0.000 description 1
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 1
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 1
- 101000858064 Homo sapiens C-X-C motif chemokine 13 Proteins 0.000 description 1
- 101000947186 Homo sapiens C-X-C motif chemokine 5 Proteins 0.000 description 1
- 101000959820 Homo sapiens Interferon alpha-1/13 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001033249 Homo sapiens Interleukin-1 beta Proteins 0.000 description 1
- 101000998146 Homo sapiens Interleukin-17A Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101001010626 Homo sapiens Interleukin-22 Proteins 0.000 description 1
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102100040019 Interferon alpha-1/13 Human genes 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 102100039065 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 102000003816 Interleukin-13 Human genes 0.000 description 1
- 102100033461 Interleukin-17A Human genes 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- 102100030704 Interleukin-21 Human genes 0.000 description 1
- 102100030703 Interleukin-22 Human genes 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- 102000013264 Interleukin-23 Human genes 0.000 description 1
- 108010066979 Interleukin-27 Proteins 0.000 description 1
- 102100036678 Interleukin-27 subunit alpha Human genes 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102000000743 Interleukin-5 Human genes 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229940123973 Oxygen scavenger Drugs 0.000 description 1
- 238000010222 PCR analysis Methods 0.000 description 1
- 229920001100 Polydextrose Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108091081062 Repeated sequence (DNA) Proteins 0.000 description 1
- 229920000294 Resistant starch Polymers 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 108020001027 Ribosomal DNA Proteins 0.000 description 1
- CZMRCDWAGMRECN-UHFFFAOYSA-N Rohrzucker Natural products OCC1OC(CO)(OC2OC(CO)C(O)C(O)C2O)C(O)C1O CZMRCDWAGMRECN-UHFFFAOYSA-N 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 101000872823 Xenopus laevis Probable histone deacetylase 1-A Proteins 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 235000019728 animal nutrition Nutrition 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 235000015173 baked goods and baking mixes Nutrition 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 235000015155 buttermilk Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000020140 chocolate milk drink Nutrition 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000011278 co-treatment Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 235000020186 condensed milk Nutrition 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 235000020247 cow milk Nutrition 0.000 description 1
- 235000015140 cultured milk Nutrition 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 235000011850 desserts Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 235000021001 fermented dairy product Nutrition 0.000 description 1
- 235000019541 flavored milk drink Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 235000020251 goat milk Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000007773 growth pattern Effects 0.000 description 1
- 244000038280 herbivores Species 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 108010074108 interleukin-21 Proteins 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- 235000021140 nondigestible carbohydrates Nutrition 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 235000020912 omnivore Nutrition 0.000 description 1
- 244000054334 omnivore Species 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001259 polydextrose Substances 0.000 description 1
- 235000013856 polydextrose Nutrition 0.000 description 1
- 229940035035 polydextrose Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 235000008476 powdered milk Nutrition 0.000 description 1
- 230000004647 pro-inflammatory pathway Effects 0.000 description 1
- 230000000529 probiotic effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000021254 resistant starch Nutrition 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000020254 sheep milk Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000031068 symbiosis, encompassing mutualism through parasitism Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000021119 whey protein Nutrition 0.000 description 1
- 235000008924 yoghurt drink Nutrition 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
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 5 pharmaceutical compositions, nutritional supplements, feedstuffs, food products, dietary supplements, and food additives comprising said strain or derivatives.
Description
IMMUNE MODULATION
Field of the Invention
The present invention relates to microorganisms that are able to positively 5 modulate inflammatory 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 10 vivo (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). It modulates molecular signalling pathways of NF-κΒ (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). 15 In particular, it stops binding of the active component (RelA) of NF-κΒ 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 Medicine, USA) in 2003 [Xu et al, A genomic view of the human-Bacteroides thetaiotaomicron symbiosis. Science. 2003 Mar 20 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. 25 Accordingly the strain of BT is useful as a therapeutic or in preventative medicine against inflammatory disorders and/or autoimmune disorders and /or allergic disorders.
According to a first 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.
According to a second aspect, the present invention provides the use of the composition according to the invention in the manufacture of a medicament for treating or preventing inflammatory disorders and/or autoimmune disorders and/or allergic disorders in a subject.
According to a third aspect, the present invention provides a method of treating or 35 preventing inflammatory disorders and/or autoimmune disorders and/or allergic disorders
2018205072 03 Mar 2020 in a subject, the method comprising administering to the subject the composition according to the invention.
According to a fourth aspect, the present invention the use of the composition according to the invention in the manufacture of a medicament for reducing the inflammation 5 of a tissue or an organ.
According to a fifth aspect, the present invention provides a method of reducing the inflammation of a tissue or an organ, the method comprising administering to the subject the composition according to any one of the invention.
According to a sixth aspect, the present invention provides the use of the 10 composition according to the invention in the manufacture of a medicament for reducing disruption to the colon of a subject, optionally wherein said subject has IBD.
According to a seventh aspect, the present invention provides a method for reducing disruption to the colon of a subject, optionally wherein said subject has IBD, the method comprising administering to the subject the composition according to the 15 invention.
According to an eighth aspect, the present invention provides the use of the composition according to the invention in the manufacture of a medicament for reducing the expression of one or more pro-inflammatory genes in a cell or cells of a subject, optionally wherein said pro-inflammatory genes is selected from the group consisting of 20 ILI-β, IL6, IL8, IL10 and combinations thereof, and/or 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).
According to a ninth aspect, the present invention provides a method for reducing the expression of one or more pro-inflammatory genes in a cell or cells of a subject, 25 optionally wherein said pro-inflammatory genes is selected from the group consisting of IL1β, IL6, IL8, IL10 and combinations thereof, and/or 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), the method comprising administering to the subject the composition according to the invention.
According to a tenth 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, optionally wherein said section of the alimentary canal is the small intestine lamina propria.
According to an eleventh aspect, the present invention provides a method for increasing the percentage of T regs in the alimentary canal or a section of the alimentary canal in a subject, optionally wherein said section of the alimentary canal is the small
2018205072 03 Mar 2020 intestine lamina propria, the method comprising administering to the subject the composition according to the invention.
According to a twelfth aspect, the present invention provides process for producing a composition according to the invention, said process comprising admixing said 5 Bacteroides thetaiotaomicron strain with a pharmaceutically acceptable excipient, carrier or diluent, optionally wherein said Bacteroides thetaiotaomicron strain is encapsulated in said process.
According to a thirteenth aspect, the present invention provides a nutritional supplement, feedstuff, food product, dietary supplement or food additive comprising the 10 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 nutritional supplement comprising a Bacteroides thetaiotaomicron as defined herein, and a nutritionally acceptable excipient, carrier or 15 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 composition as defined herein, a pharmaceutical composition as defined herein, a 20 nutritional supplement as defined herein or a feedstuff, a food product, a dietary supplement, or a food additive as defined herein, may be for use in modulating the inflammation 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 25 nutritional supplement as defined herein or a feedstuff, a food product, a dietary supplement, or a food additive as defined herein, may be 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 defined herein, a 30 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 may be for use in reducing disruption to the colon of a subject, preferably said subject has IBD.
Also disclosed herein, is a Bacteroides thetaiotaomicron as defined herein, a 35 composition as defined herein, a pharmaceutical composition as defined herein, a nutritional supplement as defined herein or a feedstuff, a food product, a dietary
2018205072 03 Mar 2020 supplement, or a food additive as defined herein may be 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 5 nutritional supplement as defined herein or a feedstuff, a food product, a dietary supplement, or a food additive as defined herein may be 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 10 described herein, said process comprising admixing said Bacteroides thetaiotaomicron with a pharmaceutically acceptable excipient, carrier or diluent, wherein said Bacteroides thetaiotaomicron is optionally encapsulated in said process.
Also disclosed herein, is a method for modulating the inflammation of a tissue or an organ in a subject wherein said method comprises administering to the subject a 15 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 defined herein.
Also disclosed herein, is a method for treating and/or preventing of an 20 inflammatory disorder and/or an autoimmune disorder in 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 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 feedstuff, a food product, a dietary supplement, or a food additive as defined herein, preferably 30 wherein the subject 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 method comprises administering to the subject a Bacteroides thetaiotaomicron as defined herein, a composition as defined herein, a pharmaceutical composition as defined herein, a 35 nutritional supplement as defined herein or a feedstuff, a food product, a dietary supplement, or a food additive as defined herein.
2018205072 03 Mar 2020
Also disclosed herein, is a method for increasing the percentage of Regulatory T cells (Tregs) in the alimentary canal or a section of the alimentary canal wherein said method comprises administering to the subject a Bacteroides thetaiotaomicron as defined herein, a composition as defined herein, a pharmaceutical composition as 5 defined herein, a nutritional 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 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 10 supplement, or a food additive as defined herein, for the manufacture of a medicament for modulating the inflammation 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 supplement as defined herein or a feedstuff, a food product, a dietary 15 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 thetaiotaomicron as defined herein, a composition as defined herein, a pharmaceutical composition as defined herein, a 20 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 composition as defined herein, a 25 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 disclosed herein, is a Bacteroides thetaiotaomicron as defined herein, a 30 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 manufacture of a medicament for increasing the percentage of Regulatory T cells (Tregs) in the alimentary canal or a section of the alimentary canal.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that
2018205072 03 Mar 2020
5A any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
Brief Description of the Figures
The invention is described with reference 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 C57BI/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 DSSinduced colitis;
Figure 6: illustrates the expression of proinflammatory genes (IL-1 β and IL-6) and anti-inflammatory gene (IL-10) in the ascending colon of mice treated with B. thetaiotaomicron strains 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 Description of the Invention
The present invention is based on the finding that BT strain BT2013 has more potent anti-inflammatory effects compared to control BT strains.
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,
2018205072 09 Jul 2018
Aberdeen, UK, AB21 9YA. The deposit was made under the terms of the Budapest Treaty. The deposit was made by GT Biologies Ltd. (Life Sciences Innovation Building, Aberdeen, AB25 2ZS, Scotland). GT Biologies 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 (subcloned) from the original but modified in some way (including at the genetic level), without altering negatively the biological activity, i.e. the derivative strain will have at least the same immune modulatory activity as the original BT2013 strain.
Biotypes
A genome sequence for strain BT2013 is provided in SEQ ID NO:1.
Bacterial strains that are biotypes of the bacterium deposited under accession number NCI MB 42341 are also expected to be effective for treating or preventing inflammatory disorders and/or autoimmune disorders and/or allergic disorders. A biotype is a closely related strain that has the same or very similar physiological and biochemical characteristics.
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 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, (GTG)s, or REP ( Masco etal. (2003) Systematic and Applied Microbiology, 2Q:557563). Biotype strains may have sequences with at least 95%, 96%, 97%, 98%,
2018205072 09 Jul 2018
99%, 99.5% or 99.9% sequence identity to the corresponding sequence of the bacterium deposited under accession number NCI MB 42341.
In certain 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% sequence 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% sequence 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 identity 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 analysis 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 16S 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 Sau3AI restriction enzyme (for exemplary methods and guidance see, for example, SrCitkova et al.
2018205072 09 Jul 2018 (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 NCI MB 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 antigens to the bacterium deposited under accession number NCIMB 42341 may be useful in the invention. A biotype strain will have comparable immune modulatory activity to the NCIMB 42341 strain. 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 treatment 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 affects 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 alimentary 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 intestine (e.g. the caecum, ascending colon, transverse colon, descending colon, and sigmoid colon)).
Examples of epithelial cells include intestinal epithelial cells. Examples of immune cells include dendritic cells, monocytes/macrophages, Tcells and neutrophils.
In one embodiment, the disorder is selected from the group consisting of:
2018205072 09 Jul 2018
1. Organ associated disorders such as irritable bowel syndrome (IBS), inflammatory bowel disease including Crohn’s disease and ulcerative colitis, necrotising enterocolitis, pouchitis, coeliac disease, multiple sclerosis (brain), type I diabetes, Goodpasture’s syndrome, Hashimoto thyroiditis, chronic active hepatitis, cardiomyopathy, uveitis and rhinitis.
2. Systemic disorders such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, psoriasis, atopic dermatitis, vitiligo, multiple sclerosis, alopecia areata, sarcoidosis, polymyositis and combinations thereof.
In one aspect, the disorder affects the intestine.
In one aspect, the disorder is an inflammatory disorder. For example, the disorder is an inflammatory bowel disorder (IBD) such as Crohn’s disease.
In one aspect, the disorder is an autoimmune disorder. For example, the autoimmune disorder is selected from the group consisting of ulcerative colitis, 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 include 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 subject is a human.
In one aspect, the subject has a disorder is selected from the group consisting of inflammatory bowel disorder (IBD), colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, type I diabetes, coeliac disease, atopic dermatitis, rhinitis, irritable bowel syndrome (IBS), ulcerative colitis, pouchitis, Crohn's disease, functional dyspepsia, atopic diseases, necrotising enterocolitis, non alcoholic fatty liver disease, gastrointestinal infection and combinations thereof. For example, the subject has IBD.
2018205072 09 Jul 2018
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 promotion 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 embodiment, the B. thetaiotaomicron strain BT2013 as described 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, endothelial cells, fibroblasts, the pancreas, and/or pancreatic cells (such as the islets of Langerhans) is reduced.
In one example, 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 reduced.
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 process 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 subject.
In one embodiment, the amount of a tissue or organ which is inflamed in a subject is at least 10%, 20%, 30%, 40% or 50% lower after administration of strain
2018205072 09 Jul 2018
BT2013 when compared to the amount of tissue or organ which is inflamed in a subject before the strain BT2013 is administered to the subject.
In one embodiment, the strain BT2013 reduces the inflammation by epithelial cells of the tissue or the organ.
For example, the epithelial 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, Th17 and Th2 which drive inflammation, autoimmunity and allergic/atopic conditions. In Crohn’s disease and ulcerative colitis the Teff/Treg cell balance is lost.
In one embodiment, the production of T cells in a subject 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 barrier integrity
In one embodiment, the strain BT2013 is used to improve intestine barrier integrity in a subject.
The term “improving intestine barrier integrity” as used herein refers to a reduction in the numbers and/or types of microorganisms 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 microorganisms 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 of microorganisms which spread from the intestine into other cells in a subject
2018205072 09 Jul 2018 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 BT2013, is used to reduce disruption to the intestine (e.g. large intestine) 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 propria.
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 disruption to the integrity of the mucosal epithelium is a reduction 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 epithelium of a subject after administration of strain BT2013 when compared 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) crossing into the lamina propria in a subject before administration.
2018205072 09 Jul 2018
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 pro-inflammatory genes.
In one embodiment, strain BT2013 downregulates 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 include genes encoding but not limited to Ι1_1-β, 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 -β, IL6 and IL8.
In one embodiment, the expression level (e.g. 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. Examples of barrier integrity genes include genes encoding Retnlg|Retnlb, Si, Defa24, Hsd11b2, Hsd17b2, and Nr1d1|Thra.
In one embodiment, 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 embodiment, strain BT2013 upregulates the expression of barrier integrity genes in a cell or cells of a subject
In one embodiment, the barrier integrity gene is selected from the group consisting of Retnlg|Retnlb, Si, Defa24, Hsd11b2, Hsd17b2, and Nr1d1|Thra.
2018205072 09 Jul 2018
In one embodiment, the expression level (e.g. mRNA level) of one or more barrier integrity genes is increased (i.e. upregulated) such that the level is at least 10%, 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 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 intestine (e.g. the caecum, ascending colon, transverse colon, descending colon, and sigmoid colon)).
Herein, the term “large intestine” may be used interchangeably with the term “colon”.
In one embodiment, strain BT2013 is used for improving alimentary canal health in a subject.
The term “improving 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 embodiment, the level of inflammation 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 microorganisms 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 microbiota” 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
2018205072 09 Jul 2018 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 microorganisms 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, inflammation 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.coli: ETEC, EPEC, EIEC, EHEC and EAEC) within the intestine may occur in subjects with inflammatory 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 bacteria) present in the intestine of a subject (e.g. the host), is increased such that the number of microorganisms is at least 10%, 20%, 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 alternatively, the types of desirable microorganisms (such as firmicutes and bacteroidetes) present 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 administration of strain BT2013 when compared to the types in the subject before administration.
In one embodiment, the number of undesirable microorganisms (such as E. coli ETEC, EPEC, EIEC, EHEC and EAEC) present in the intestine of a subject (e.g. the host), is decreased such that the number of microorganisms is at least 10%, 20%, 30%, 40% or 50% lower after administration strain BT2013 when compared to the level in the subject before administration. In addition, or alternatively, the types of undesirable microorganisms (such as E. coli ETEC,
2018205072 09 Jul 2018
EPEC, EIEC, EHEC and EAEC) present in the intestine of a 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 comprising 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 incompatible 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 capsule or an enterically-resistant capsule.
Even when the objective of the encapsulation is the isolation of the strain from its surroundings, the protective coating or shell must be ruptured at the time of desired action. The rupturing of the protective coating or shell is typically brought about through the application of chemical and physical stimuli such as pressure, enzyme attack, chemical reaction and physical 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 effective 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 acceptable excipient, carrier or diluent.
2018205072 09 Jul 2018
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 pharmaceutical compositions described herein may be found in the “Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A Wade 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. Gennaro edit. 1985).
Examples of suitable carriers include 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 combinations thereof.
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, tree-flow lactose, beta-lactose, com sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
Preservatives, stabilizers, dyes and even 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.
In one aspect, the microorganisms of strain BT2013 pharmaceutical composition are encapsulated.
2018205072 09 Jul 2018
The pharmaceutical 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 medicament encompasses medicaments for both human and animal usage in human and veterinary medicine. In addition, the term medicament as used herein means any substance, which provides 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 (including 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 livestock feed and/or pet food.
Nutritional supplements
Nutritionally acceptable carriers, diluents and excipients include those suitable for human or animal consumption and that are used as standard in the food industry. Typical nutritionally acceptable carriers, diluents and excipients 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 encapsulated.
Feedstuff/products
A further aspect of the invention relates to feedstuffs, food products, dietary supplements and food additives comprising microorganisms of strain BT2013.
The terms “feedstuff”, food product “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 is for human consumption. Examples of food products include diary products (such as milk, cheese, beverages comprising whey protein, milk drinks, lactic acid
2018205072 09 Jul 2018 bacteria drinks, yoghurt, drinking 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 formulations 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 products may include, for example, functional food products, food compositions, petfood, livestock feed, health foods, feedstuffs and the like. In one aspect, the food product is a health food.
As used herein, the term functional food product means food that is capable of providing not only a nutritional 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 herein) incorporated into them that impart to the food a specific 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 reconstitution with, e.g., milk or water, chocolate milk drinks, malt drinks, ready-toeat 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 animals selected from the group consisting of dogs, cats, pigs, horses, or poultry. In a further embodiment, the food product, dietary supplement or food additive is intended for adult species, in particular human adults.
The term milk-based product as used herein means any liquid or semisolid milk or whey based product having a varying fat content. The milk-based
2018205072 09 Jul 2018 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; flavoured milks, ice cream; milk-containing food such as sweets.
The feedstuffs, food products, 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 supplements or food additives according to the invention 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 or food additives are expected to enhance immune function reduce and prevent infectious diseases, beneficially alter the 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, or food 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 non-viable 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 powder. The LBP may additionally comprise other bacterial species, for example, the bacterial species R. hominis. Encapsulated products are favoured for R. hominis as it is an anaerobe. Other ingredients (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 fermented dairy product, or as a pharmaceutical product.
2018205072 09 Jul 2018
A suitable 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 x 101° CFU; in another example from about 1 x 106 to about 1 x 101°CFU.
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 1012CFU/g, respect to the weight of the composition; for example, from about 1 x 108 to about 1 x 101° CFU/g. Typically, a LBP is optionally combined with at least one suitable prebiotic compound. A prebiotic is usually a nondigestible 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 transgalacto-oligosaccharides.
In one aspect, the LBP of the present description includes a prebiotic 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 fructooligosaccharides, inulin, isomalt-oligosaccharides, pectins, xylo-oligosaccharides (orXOS), chitosan-oligosaccharides (or COS), beta-glucans, arable gum modified and resistant starches, polydextrose, D-tagatose, acacia fibers, carob, oats, and citrus fibers. In one aspect, the probiotics are the short-chain fructooligosaccharides (for simplicity shown hereinbelow 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 molecule to which three glucose molecules are bonded.
Administration
The pharmaceutical compositions, the nutritional supplements, feedstuffs, food products, dietary supplements or food additives of the present invention may be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration.
In one aspect, the pharmaceutical compositions, the nutritional supplements, feedstuffs, food products, dietary supplements or food additives of the present invention are adapted for oral, rectal, vaginal, parenteral, nasal, buccal or sublingual routes of administration.
2018205072 09 Jul 2018
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 capsules.
Other forms of administration comprise solutions or emulsions which may be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, 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 suppositories, 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 metabolic stability and length of action of that strain, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. The dosages disclosed herein are exemplary 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 administered consecutively, simultaneously or sequentially with the one or more other active agents.
2018205072 09 Jul 2018
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). DSS 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. thetaiotaomicron were the Tregs (CD25+FoxP3+* and FR4hiCD25+*) and Teff cells (FR4|OCD25+*) (figure 1 and 2). The percentage 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 population (figure 2).
The enzymatic activity of MPO in the ileum and caecum was determined (Figure 3 a and 3b). MPO is a proinflammatory enzyme stored in the azurophilic granules of neutrophilic granulocytes. MPO is used as an indicator of inflammation, specifically neutrophil recruitment and accumulation. The lower levels of MPO activity detected in ileal or caecal tissue samples from the B. thetaiotaomicron/DSS treated mice compared to DSS alone indicates a reduction in neutrophil recruitment and therefore a reduction in inflammation.
Histological analysis of ascending colon was carried out (Figures 4 and 5 and Table 1). The histopathology grading scheme was based on the criteria of Berg et al 1996, as summarised:
= Shallow crypts, no or few infiltrating inflammatory cells, intact epithelium, goblet cells appear full of mucin, ie no pathology = Crypts may exhibit slight epithelial cell hyperplasia, some diffuse
2018205072 09 Jul 2018 infiltrating inflammatory cells may be seen between crypts, luminal epithelium appears intact, goblet cells may appear slightly depleted of mucin.
= Crypts appear deeper with distinct evidence of epithelial hyperplasia, depletion of mucin from goblet cells, infiltrating inflammatory cells evident and may be multifocal in nature .though the infiltrates are not seen in the submucosa.
= Lesions involved a larger area of the mucosa and /or were more frequent than that seen in grade 2. The lesions did not involve the submucosa.
The luminal epithelial cells exhibited small erosions. The lesions are not transmural.
= Crypt epithelium appears eroded. Abscesses 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 IL1B and IL6 inflammatory gene expression compared to strain E2. (Figure 6)
Table 1
TTEST | CONTROL | BT E1 | BT 2013 | BT E2 |
DSS | 0.000 | 0.032 | 0.041 | 0.089 |
In Vitro Model
The expression of the inflammatory gene interleukin-8 induced in intestinal epithelial cells after PMA exposure was modulated in the presence of B. thetaiotaomicron strains E1, E2 and BT2013 (Figure 7).
2018205072 09 Jul 2018
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 summarised below:
a. Mapping to reference sequence (NC_004663 and NC_004703) using bowtie2 (2.2.2)
b. SNV and small InDei calling using VarScan (2.3.7) and SNVer (0.5.3) performing a consensus call to avoid false positives
c. Annotation of variations using reference gff
d. Large InDei 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 subsampled reads using SOAPdenovo (2.04)
The sequences were mapped to the reference sequence (NC_004663 and NC_004703) using bowtie2 (2.2.2). Nucleotide variations and small insertions and/or deletions 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 (0.2.5a3). Unmapped reads were assembled de novo using SOAPdenovo (2.04). The sequencing 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 sequence assembly of BT2013.
Sequences
SEQ ID NO:1 (concatenated version of the de novo sequence assembly of BT2013) - see electronic sequence listing.
Claims (26)
- Claims1. A composition comprising a Bacteroides thetaiotaomicron strain with a sequence that has at least 99.5% sequence identity to SEQ ID NO: 1.
- 2. The composition according to claim 1, wherein said Bacteroides thetaiotaomicron5 strain has immune modulatory activity comparable to that of Bacteroides thetaiotaomicron deposited as Accession Number 42341 at NCIMB.
- 3. The composition according to claim 2, wherein said strain has effects on DSSinduced colitis models, regulatory T cell (Treg) levels, myeloperoxidase (MPO)10 enzymatic activity, inflammation-associated gene expression and colon histopathology comparable to those of Bacteroides thetaiotaomicron deposited as Accession Number 42341 at NCIMB.
- 4. The composition according to claim 2, wherein said strain has a comparable15 increase in the percentage of Treg cells in small intestine lamina propria tissue samples from Bacteroides thetaiotaomicron/DSS treated mice to that of Bacteroides thetaiotaomicron deposited as Accession Number 42341 at NCIMB.
- 5. The composition according to claim 2, wherein said strain has a comparable20 reduction in the level of MPO activity in ileal or caecal tissue samples from Bacteroides thetaiotaomicron/DSS treated mice to that of Bacteroides thetaiotaomicron deposited as Accession Number 42341 at NCIMB.
- 6. The composition according to claim 2, wherein said strain has a comparable25 reduction in the histopathology tissue score of ascending colon tissue samples from Bacteroides thetaiotaomicron/DSS treated mice to that of Bacteroides thetaiotaomicron deposited as Accession Number 42341 at NCIMB.
- 7. The composition according to claim 2, wherein said strain has a comparable30 reduction in the expression of IL1 β and/or IL6 in ascending colon tissue samples from Bacteroides thetaiotaomicron/DSS treated mice to that of Bacteroides thetaiotaomicron deposited as Accession Number 42341 at NCIMB.
- 8. The composition according to claim 2, wherein said strain has a comparable:35 a) increase in the percentage of Treg cells in small intestine lamina propria tissue samples;b) reduction in the level of MPO activity in ileal or caecal tissue samples;c) reduction in the histopathology tissue score in ascending colon tissue samples; and40 d) reduction in the expression of IL1 β and/or IL6 in ascending colon tissue samples,2018205072 03 Mar 2020 from Bacteroides thetaiotaomicron/DSS treated mice to that of Bacteroides thetaiotaomicron deposited as Accession Number 42341 at NCIMB.
- 9. The composition according to any one of claims 1-8, wherein said Bacteroides5 thetaiotaomicron strain is encapsulated.
- 10. The composition according to any one of claims 1-9, wherein the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, carrier or diluent.
- 11. Use of the composition according to any one of claims 1 -10 in the manufacture of a medicament for treating or preventing inflammatory disorders and/or autoimmune disorders and/or allergic disorders in a subject.15
- 12. A method of treating or preventing inflammatory disorders and/or autoimmune disorders and/or allergic disorders in a subject, the method comprising administering to the subject the composition according to any one of claims 1-10.
- 13. The use according to claim 11 or the method according to claim 12, wherein said20 disorder affects the alimentary canal, a section of the alimentary canal, and/or epithelial cells.
- 14. The use according to claim 11 or claim 13 or the method according to claim 12 or claim 13, wherein said disorder is selected from the group consisting of inflammatory25 bowel disorder (IBD), colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, type I diabetes, coeliac disease, atopic dermatitis, rhinitis, irritable bowel syndrome (IBS), ulcerative colitis, pouchitis, Crohn's disease, functional dyspepsia, atopic diseases, necrotising enterocolitis, non-alcoholic fatty liver disease, gastrointestinal infection and combinations thereof.
- 15. Use of the composition according to any one of claims 1-10 in the manufacture of a medicament for reducing the inflammation of a tissue or an organ.
- 16. A method of reducing the inflammation of a tissue or an organ, the method comprising 35 administering to the subject the composition according to any one of claims 1-10.
- 17. The use according to claim 15 or the method according to claim 16, wherein said Bacteroides thetaiotaomicron strain reduces the inflammation by epithelial cells of the tissue or the organ, optionally wherein said epithelial cells are epithelial cells of the40 alimentary canal.
- 18. Use of the composition according to any one of claims 1-10 in the manufacture of a medicament for reducing disruption to the colon of a subject, optionally wherein said subject has IBD.2018205072 03 Mar 2020
- 19. A method of reducing disruption to the colon of a subject, optionally wherein said subject has IBD, the method comprising administering to the subject the composition according to any one of claims 1-10.
- 20. The use according to claim 18 or the method according to claim 19, wherein said Bacteroides thetaiotaomicron strain:a) reduces or prevents disruption to the integrity of the mucosal epithelium;b) reduces or prevents a reduction in the number of goblet cells in the epithelium;10 and/orc) reduces or prevents the infiltration of immune cells into the lamina propria.
- 21. Use of the composition according to any one of claims 1-10 in the manufacture of a medicament for reducing the expression of one or more pro-inflammatory genes in a cell15 or cells of a subject, optionally wherein said pro-inflammatory genes is selected from the group consisting of IL1 -β, IL6, IL8, IL10 and combinations thereof, and/or 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
- 22. A method for reducing the expression of one or more pro-inflammatory genes in a cell or cells of a subject, optionally wherein said pro-inflammatory genes is selected from the group consisting of IL1 -β, IL6, IL8, IL10 and combinations thereof, and/or 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), the method comprising administering to the 25 subject the composition according to any one of claims 1 -10.
- 23. Use of the composition according to any one of claims 1-10 in the manufacture of a medicament for increasing the percentage of T regs in the alimentary canal or a section of the alimentary canal, optionally wherein said section of the alimentary canal is the30 small intestine lamina propria.
- 24. A method for increasing the percentage of T regs in the alimentary canal or a section of the alimentary canal in a subject, optionally wherein said section of the alimentary canal is the small intestine lamina propria, the method comprising administering to the35 subject the composition according to any one of claims 1 -10.
- 25. A process for producing a composition according to claim 9, said process comprising admixing said Bacteroides thetaiotaomicron strain with a pharmaceutically acceptable excipient, carrier or diluent, optionally wherein said Bacteroides thetaiotaomicron strain is encapsulated in said process.
- 26. A nutritional supplement, feedstuff, food product, dietary supplement or food additive comprising the composition according to any one of claims 1-10.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2018205072A AU2018205072B2 (en) | 2014-12-23 | 2018-07-09 | Immune modulation |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1423084.1 | 2014-12-23 | ||
GB201423084 | 2014-12-23 | ||
PCT/GB2015/054112 WO2016102950A1 (en) | 2014-12-23 | 2015-12-22 | Immune modulation |
AU2015370664A AU2015370664B2 (en) | 2014-12-23 | 2015-12-22 | Immune modulation |
AU2018205072A AU2018205072B2 (en) | 2014-12-23 | 2018-07-09 | Immune modulation |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2015370664A Division AU2015370664B2 (en) | 2014-12-23 | 2015-12-22 | Immune modulation |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2018205072A1 AU2018205072A1 (en) | 2018-07-26 |
AU2018205072B2 true AU2018205072B2 (en) | 2020-05-21 |
Family
ID=62945667
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2018205072A Active AU2018205072B2 (en) | 2014-12-23 | 2018-07-09 | Immune modulation |
Country Status (1)
Country | Link |
---|---|
AU (1) | AU2018205072B2 (en) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003046580A1 (en) * | 2001-11-21 | 2003-06-05 | Rowett Research Institute | Assay for screening candidate drugs for the treatment of inflammatory diseases |
WO2011153226A2 (en) * | 2010-06-01 | 2011-12-08 | Moore Research Enterprises Llc | Cellular constituents from bacteroides, compositions thereof, and therapeutic methods employing bacteroides or cellular constituents thereof |
WO2012142605A1 (en) * | 2011-04-15 | 2012-10-18 | Samaritan Health Services | Rapid recolonization deployment agent |
WO2013154725A1 (en) * | 2012-04-13 | 2013-10-17 | Trustees Of Boston College | Prebiotic compositions and methods of use |
WO2014121304A1 (en) * | 2013-02-04 | 2014-08-07 | Seres Health, Inc. | Compositions and methods |
WO2014152338A1 (en) * | 2013-03-14 | 2014-09-25 | Kabadi Mohan | Targeted gastrointestinal tract delivery of probiotic organisms and/or therapeutic agents |
-
2018
- 2018-07-09 AU AU2018205072A patent/AU2018205072B2/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003046580A1 (en) * | 2001-11-21 | 2003-06-05 | Rowett Research Institute | Assay for screening candidate drugs for the treatment of inflammatory diseases |
WO2011153226A2 (en) * | 2010-06-01 | 2011-12-08 | Moore Research Enterprises Llc | Cellular constituents from bacteroides, compositions thereof, and therapeutic methods employing bacteroides or cellular constituents thereof |
WO2012142605A1 (en) * | 2011-04-15 | 2012-10-18 | Samaritan Health Services | Rapid recolonization deployment agent |
WO2013154725A1 (en) * | 2012-04-13 | 2013-10-17 | Trustees Of Boston College | Prebiotic compositions and methods of use |
WO2014121304A1 (en) * | 2013-02-04 | 2014-08-07 | Seres Health, Inc. | Compositions and methods |
WO2014152338A1 (en) * | 2013-03-14 | 2014-09-25 | Kabadi Mohan | Targeted gastrointestinal tract delivery of probiotic organisms and/or therapeutic agents |
Non-Patent Citations (1)
Title |
---|
NUALA MORAN, "Microbial wealth", CHEMISTRY & INDUSTRY, GB, (2014-06-01), vol. 78, no. 6, doi:10.1002/cind.786_6.x, ISSN 0009-3068, pages 20 - 23 * |
Also Published As
Publication number | Publication date |
---|---|
AU2018205072A1 (en) | 2018-07-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11723933B2 (en) | Composition of bacteroides thetaiotaomicron for immune modulation | |
US11266698B2 (en) | Bacterium for use as a probiotic for nutritional and medical applications | |
Oakley et al. | The chicken gastrointestinal microbiome | |
CN104080903B (en) | The bacterial strain detached from pig | |
TWI621708B (en) | Immune modulation | |
Guo et al. | Lacticaseibacillus rhamnosus reduces the pathogenicity of Escherichia coli in chickens | |
AU2018205072B2 (en) | Immune modulation | |
TWI750342B (en) | Composition comprising a bacterial strain and its use, process of producing and product | |
TWI782800B (en) | Composition comprising a bacterial strain and its use, process of producing and product | |
OA18349A (en) | Immune modulation. | |
NZ764713B2 (en) | A Bacteroides thetaiotaomicron strain and its use in reducing inflammation | |
NZ732667B2 (en) | A Bacteroides thetaiotaomicron strain and its use in reducing inflammation | |
Kim et al. | Nutritional Intervention for the Intestinal |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FGA | Letters patent sealed or granted (standard patent) | ||
PC | Assignment registered |
Owner name: CJ BIOSCIENCE, INC. Free format text: FORMER OWNER(S): 4D PHARMA RESEARCH LIMITED |