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WO2016019505A1 - Utilisation d'eubacterium dans la prévention et le traitement de maladies liées à un cancer colorectal - Google Patents

Utilisation d'eubacterium dans la prévention et le traitement de maladies liées à un cancer colorectal Download PDF

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WO2016019505A1
WO2016019505A1 PCT/CN2014/083688 CN2014083688W WO2016019505A1 WO 2016019505 A1 WO2016019505 A1 WO 2016019505A1 CN 2014083688 W CN2014083688 W CN 2014083688W WO 2016019505 A1 WO2016019505 A1 WO 2016019505A1
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eubacterium
eubacterium eligens
eligens
staff
atcc
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PCT/CN2014/083688
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English (en)
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Qiang FENG
Dongya ZHANG
Chuan Liu
Liang Xiao
Longqing TANG
Jun Wang
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Bgi Shenzhen Co., Limited
Bgi Shenzhen
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Priority to CN201480080819.1A priority Critical patent/CN106573044B/zh
Priority to PCT/CN2014/083688 priority patent/WO2016019505A1/fr
Publication of WO2016019505A1 publication Critical patent/WO2016019505A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K2035/11—Medicinal preparations comprising living procariotic cells
    • A61K2035/115—Probiotics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales

Definitions

  • the invention relates to microbiology, specifically, this invention relates to Eubacterium bacterial strains in the treatment and prevention of colorectal cancer-related diseases in the application, and also involves the composition comprising Eubacterium bacteria and its application.
  • CRC Colorectal cancer
  • IBD inflammatory bowel disease
  • CRC colorectal cancer
  • ulcerative colitis ulcerative colitis
  • the human gut microflora which contains about 100 trillion microbial organisms, plays a critical role in maintaining host health, both in the gastrointestinal tract and systemically through the absorption of metabolites (e. g. vitamins and short chain fatty acids) (Moore WE, Holdeman LV (1974) Human fecal flora: the normal flora of 20 Japanese-Hawaiians. Appl Microbiol 27: 961-979, incorporated herein by reference) .
  • metabolites e. g. vitamins and short chain fatty acids
  • Embodiments of the present disclosure seek to solve at least one of the problems existing in the prior art to at least some extent.
  • the present invention is based on the following findings by the inventors:
  • gut microbiota has become a major research area in human disease, including colorectal cancer (CRC) , one of the commonest causes of death among all types of cancers.
  • CRC colorectal cancer
  • MWAS Metagenome-Wide Association Study
  • the inventors identified 2 probiotic bacteria.
  • the inventors validated the probiotic bacteria in animal experiment related to colitis and CRC respectively. Results from the animal experiment demonstrated the ability of Eubacterium ventriosum and Eubacterium eligens to prevent and treat both colitis and colorectal cancer effectively.
  • Fig. 1 shows distribution of P-value association statistics of all microbial genes in this study.
  • the association analysis of CRC p-value distribution identified a disproportionate over-representation of strongly associated markers at lower P-values, with the majority of genes following the expected P-value distribution under the null hypothesis. This suggests that the significant markers likely represent true rather than spurious associations.
  • Fig. 2 Protective effects of intragastric administration of Eubacterium ventriosum ATCC 27560, Eubacterium ventriosum L2-12, Eubacterium ventriosum STAFF 1042, Eubacterium eligens ATCC 27750, Eubacterium eligens STAFF 1020, Eubacterium eligens TSDC10.2-1.1 respectively on DSS-induced colitis in C57Bl/6J considering (A) weight loss, (B) disease activity index and (C) Colon length. Data are represented as mean ⁇ standard error. Different asterisks (*) indicate significant differences (*P ⁇ 0.05, **P ⁇ 0.01, ***p ⁇ 0.001) .
  • FIG. 3 Quantification using ELISA of (A) TNF- ⁇ and (B) IL-10 in colons obtained at day 15 after induction of colitis. Data are represented as mean ⁇ standard error. Different asterisks (*) indicate significant differences (*P ⁇ 0.05, **P ⁇ 0.01, ***p ⁇ 0.001)
  • Fig. 4 Effect of Eubacterium ventriosum ATCC 27560, Eubacterium ventriosum L2-12, Eubacterium ventriosum STAFF 1042, Eubacterium eligens ATCC 27750, Eubacterium eligens STAFF 1020, Eubacterium eligens TSDC10.2-1.1 respectively treatment on (A) _Disease activity indices and (B) colon histopathology. Different asterisks (*) indicate significant differences (*P ⁇ 0.05, **P ⁇ 0.01, ***p ⁇ 0.001)
  • Fig. 5 Eubacterium ventriosum ATCC 27560, Eubacterium ventriosum L2-12, Eubacterium ventriosum STAFF 1042, Eubacterium eligens ATCC 27750, Eubacterium eligens STAFF 1020, Eubacterium eligens TSDC10.2-1.1 respectively modulate colonic gene expression in BABL/C mice (relatived with ⁇ -actin) . Data are represented as meant ⁇ standard error. Different asterisks (*) indicate significant differences (*P ⁇ 0.05, **P ⁇ 0.01, ***p ⁇ 0.001) .
  • the present application provides Eubacterium eligens or Eubacterium ventriosum for use in the prevention or treatment of colitis and/or colorectal cancer.
  • the present application provides use of Eubacterium eligens or Eubacterium ventriosum for manufacture of a medicament for prevention or treatment of colitis and/or colorectal cancer.
  • the present application provides a method for the prevention or treatment of colitis and/or colorectal cancer comprising administering an effective amount of Eubacterium eligens or Eubacterium ventriosum to a patient in need thereof.
  • the present application provides a kit comprising Eubacterium eligens or Eubacterium ventriosum and instructions for its use as a medicament.
  • the present application further provides a pharmaceutical composition comprising Eubacterium eligens or Eubacterium ventriosum and a pharmaceutically acceptable vehicle.
  • the Eubacterium eligens is a strain selected from the group consisting of Eubacterium eligens ATCC 27750, Eubacterium eligens STAFF 1020 and Eubacterium eligens TSDC10.2-1.1.
  • the Eubacterium ventriosum is a strain selected from the group consisting of Eubacterium ventriosum ATCC27560, Eubacterium ventriosum L2-12, and Eubacterium ventriosum STAFF 1042.
  • the Eubacterium eligens or Eubacterium ventriosum is administered in the form of living Eubacterium eligens or Eubacterium ventriosum or metabolites thereof.
  • Example 1 Identifying probiotic bacteria from 128 Chinese individuals
  • BMI body mass index
  • eGFR epidermal growth factor receptor
  • DM diabetes mellitus type 2.
  • DNA library construction was performed following the manufacturer's instruction (IIlumina HiSeq 2000 platform).
  • the inventors used the same workflow as described previously to perform cluster generation, template hybridization, isothermal amplification, linearization, blocking and denaturation, and hybridization of the sequencing primers (Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55-60 (2012), incorporated herein by reference) .
  • the inventors constructed one paired-end (PE) library with insert size of 350bp for each sample, followed by a high-throughput sequencing to obtain around 30 million PE reads of length 2x100bp.
  • High quality reads were extracted by filtering low quality reads with ‘N’ base, adapter contamination and human DNA contamination from the raw data, and by trimming low quality terminal bases of reads at the same time. 751 million metagenomic reads (high quality reads) were generated (5.86 million reads per individual on average, Table 2) .
  • the inventors created a set of 2,110,489 (2.1M) genes that were present in at least 6 subjects, and generated 128 gene abundance profiles using these 2.1 million genes.
  • the inventors used the permutational multivariate analysis of variance (PERMANOVA) test to assess the effect of different characteristics, including age, BMI, eGFR, TCHO, LDL, HDL, TG, gender, DM, CRC status, smoking status and location, on gene profiles of 2.1M genes.
  • the inventors performed the analysis using the method implemented in package “vegan” in R, and the permuted p-value was obtained by 10,000 times permutations.
  • the inventors also corrected formultiple testing using “p. adjust” in R with Benjamini-Hochberg method to get the q-value for each gene.
  • BMI body mass index
  • DM diabetes mellitus type 2
  • HDL high density lipoprotein
  • TG triglyceride
  • eGFR epidermal growth factor receptor
  • TCHO total cholesterol
  • LDL low density lipoprotein
  • MWAS metagenome wide association study
  • a two-tailed Wilcoxon rank-sum test was used in the 2.1M (2,110,489) gene profiles.
  • the inventors got 140, 455 gene markers, _which were enriched in either case or control with P ⁇ 0.01 (Fig. 1) .
  • FDR false discovery rate
  • the inventors examined the taxonomic differences between control and CRC-associated microbiomes to identify microbial taxa contributing to the dysbiosis. For this, the inventors used taxonomic profiles derived from three different methods, as supporting evidence from multiple methods would strengthen an association. First, the inventors mapped metagenomic reads to 4650 microbial genomes in the IMG database (version 400) and estimated the abundance of microbial species included in that database (denoted IMG species) . Second, the inventors estimated the abundance of species-level molecular operational taxonomic units (mOTUs) using universal phylogenetic marker genes.
  • mOTUs species-level molecular operational taxonomic units
  • MLGs metagenomic linkage groups
  • the inventors For each IMG genome, using the NCBI taxonomy identifier provided by IMG, the inventors identified the corresponding NCBI taxonomic classification at species and genus levels using NCBI taxonomy dump files. The genomes without corresponding NCBI species names were left with its original IMG names, most of which were unclassified.
  • Clean reads (high quality reads in Example 1) were aligned to mOTU reference (total 79268 sequences) with default parameters (S. Sunagawa et al. , Metagenomic species profiling using universal phylogenetic marker genes. Nature methods 10, 1196 (Dec, 2013) , incorporated herein by reference) . 549 species level mOTUs were identified, including 307 annotated species and 242 mOTU linkage groups without representative genomes, which were putatively Firmicutes or Bacteroidetes.
  • the inventors constructed the colorectal cancer associated MLGs using the method described in the previous type 2 diabetes study as Qin et al. 2012, supra. All genes were aligned to the reference genomes of IMG database v400 to get genome level annotation. An MLG was assigned to a genome if > 50% constitutive genes were annotated to that genome, otherwise it was termed as unclassified. Total 87 MLGs with gene number over than 100 were selected as colorectal cancer associated MLGs. These MLGs were grouped based on the species annotation of these genomes to construct MLG species.
  • the inventors estimated the average abundance of the genes of the MLG species, after removing the 5% lowest and 5% highest abundant genes. Relative abundance of IMG species was estimated by summing the abundance of IMG genomes belonging to that species.
  • Parvimonas micra (q ⁇ 1.80x10 -5 )
  • Peptostreptococcus stomatis (q ⁇ 1.80x10 -5 )
  • Solobacterium moorei (q ⁇ 0.004331)
  • Fusobacterium nucleatum (q ⁇ 0.004565) were consistently enriched in CRC patient microbiomes across all three methods.
  • P. stomatis has been associated with oral cancer (S. Pushalkar et al. , Comparison of oral microbiota in tumor and non-tumor tissues of patients with oral squamous cell carcinoma. BMC microbiology 12, 144 (2012) , incorporated herein by reference)
  • S. moorei has been associated with bacteremia (R. M.
  • micra is involved in the etiology of periodontis (B. H. Kremer et al. , Peptostreptococcus micros smooth and rough genotypes in periodontitis and gingivitis. Journal of periodontology 71, 209 (Feb, 2000) , incorporated herein by reference) , and it produces a wide range of proteolytic enzymes and uses peptones and amino acids as energy source (D. A. Murdoch, H. N. Shah, Reclassification of Peptostreptococcus magnus (Prevot 1933) Holdeman and Moore 1972 as Finegoldia magna comb. nov.
  • mice Ten to twelve weeks old C57BL/6J mice used for DSS-induced colitis study were prepared in SPF condition. After acclimatization, part of mice have ad libitum access to drinking water containing 3.5-5% DSS (dextran sodium sulfate) for five days for colitis induction.
  • DSS extran sodium sulfate
  • C57BL/6J mice were purchased from Laboratory Animal Center of Southern Medical University, China.
  • Eubacterium ventriosum ATCC 27560 and Eubacterium eligens ATCC 27750 were purchased from American Type Culture Collection (ATCC) .
  • Eubacterium ventriosum L2-12 Estelle Devillard, Freda M. McIntosh, Sylvia H. Duncan, and R. John Wallace (March 2007) . Metabolism of Linoleic Acid by Human Gut Bacteria: Different Routes for Biosynthesis of Conjugated Linoleic Acid. Journal of Bacteriology 189 (6) : 2566-2570.
  • mice were observed daily and recorded clinical measurements.
  • Body weights and the disease activity index (Table 6) (Alex P, Zachos NC, Nguyen T, Gonzales L, Chen TE, Conklin , LS, et al. 2009 Distinct cytokine patterns identified from multiplexprofiles of murine DSS and TNBS-induced colitis. Inflamm Bowel Dis; 15 (3) : 341-52. incorporated herein by reference. )
  • a composite score reflecting clinical signs of the disease i. e. perianal soiling, rectal bleeding and diarrhea
  • the colon was removed, dissected free of fat and mesentery, carefully opened, and cleaned with PBS (phosphate buffered saline) . Colon length was measured. Colonic damage and inflammation were assessed blindly according to the Wallace criteria. Colon was also collected into liquid nitrogen and stored at-80°C for ELISA (Enzyme Linked Immunosorbent Assay) examinations.
  • PBS phosphate buffered saline
  • the inventors explored the anti-inflammatory effects in vivo by testing the ability of E. eligens ATCC 27750, STAFF 1020, TSDC10.2-1.1 and E. ventriosum L2-12, STAFF 1042, ATCC 27560 respectively to recover acute colitis induced by DSS.
  • a severe acute inflammatory was observed in the colitis control group after DSS treated, and no significant protective effect was observed in mice receiving sterile culture medium.
  • daily intragastric administration of 6 living Eubacterium strains respectively all resulted in a marked attenuation of colitis with reduced weight loss (Table 7, Fig.
  • ATCC 27560 represents Eubacterium ventriosum ATCC 27560; L2-12 represents Eubacterium ventriosum L2-12, STAFF 1042 represents Eubacterium ventriosum STAFF 1042, ATCC 27750 represents Eubacterium eligens ATCC 27750, STAFF 1020 represents Eubacterium eligens STAFF 1020, TSDC10.2-1.1 represents Eubacterium eligens TSDC10.2-1.1.
  • TNF- ⁇ tumor necrosis factor alpha
  • IL-10 anti-inflammatory IL-10
  • mice were challenged with azoxymethane (AOM, 10 mg/kg) at the age of 10 weeks followed by a 2.0% dextran sodium sulfate (DSS) treatment in the drinking water for 7 days beginning on week 2, week 5 and week 8 to induce colitis-associated colorectal cancer (CRC) .
  • BABL/c mice were purchased from Laboratory Animal Center of Southern Medical University, China.
  • RNA isolation and real-time polymerase chain reaction of cytokines tTotal RNA from colon was isolated using the Qiagen RNA isolation kit (Qiagen) according to the manufacturer’s instructions, and then was used to generate the cDNA template using the iScript cDNA synthesis kit (Bio-Rad, Hercules, CA) and real-time RT-PCR was performed as previously described (Bassaganya-Riera J, Reynolds K, Martino-Catt S, Cui Y, Hennighausen L, et al. (2004) Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease. Gastroen-terology 127: 777-791, incorporated herein by reference) .
  • mRNA expression of CD36, and PPAR ⁇ peroxisome proliferator-activated receptor ⁇
  • mice challenged with azoxymethane and DSS were euthanized in the tumor-bearing phase of the disease.
  • Those mice treated with E. eligens ATCC 27750 or E. eligens STAFF 1020 or E. eligens TSDC10.2-1.1 or E. ventriosum L2-12 or E. ventriosum STAFF 1042 or E. ventriosum ATCC 27560 shoeed increased mRNA expression of CD36 and PPAR ⁇ in the colon compared with medium-treated control group (Fig. 5, Table 9) .

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Abstract

La présente invention concerne l'application de micro-organismes, en particulier de souches d'Eubacterium, dans le traitement et la prévention de maladies liées au cancer colorectal. L'invention porte en outre sur une composition comprenant lesdites souches d'Eubacterium.
PCT/CN2014/083688 2014-08-05 2014-08-05 Utilisation d'eubacterium dans la prévention et le traitement de maladies liées à un cancer colorectal WO2016019505A1 (fr)

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PCT/CN2014/083688 WO2016019505A1 (fr) 2014-08-05 2014-08-05 Utilisation d'eubacterium dans la prévention et le traitement de maladies liées à un cancer colorectal

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WO2018036503A1 (fr) * 2016-08-25 2018-03-01 The Chinese University Of Hong Kong Marqueurs bactériens fécaux pour le cancer colorectal
WO2019028402A1 (fr) 2017-08-04 2019-02-07 Second Genome, Inc. Roseburia hominis, eubacterium eligens et combinaisons de celles-ci en tant qu'agents biothérapeutiques
US11007233B2 (en) 2017-06-14 2021-05-18 4D Pharma Research Limited Compositions comprising a bacterial strain of the genus Megasphera and uses thereof
US11123379B2 (en) 2017-06-14 2021-09-21 4D Pharma Research Limited Compositions comprising bacterial strains
US11224620B2 (en) 2016-07-13 2022-01-18 4D Pharma Plc Compositions comprising bacterial strains
US11266698B2 (en) 2011-10-07 2022-03-08 4D Pharma Research Limited Bacterium for use as a probiotic for nutritional and medical applications

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CN110150228A (zh) * 2019-06-04 2019-08-23 于涛 一种糖尿病小鼠结直肠肿瘤模型的构建方法
CN110903998B (zh) * 2019-10-23 2021-09-21 上海市第十人民医院 一株肠道分离的具核梭杆菌文氏亚种菌株及其应用
CN111205994B (zh) * 2019-10-23 2021-09-21 上海市第十人民医院 一株具核梭杆菌动物亚种菌株及其应用

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11266698B2 (en) 2011-10-07 2022-03-08 4D Pharma Research Limited Bacterium for use as a probiotic for nutritional and medical applications
US11224620B2 (en) 2016-07-13 2022-01-18 4D Pharma Plc Compositions comprising bacterial strains
WO2018036503A1 (fr) * 2016-08-25 2018-03-01 The Chinese University Of Hong Kong Marqueurs bactériens fécaux pour le cancer colorectal
US11007233B2 (en) 2017-06-14 2021-05-18 4D Pharma Research Limited Compositions comprising a bacterial strain of the genus Megasphera and uses thereof
US11123379B2 (en) 2017-06-14 2021-09-21 4D Pharma Research Limited Compositions comprising bacterial strains
US11660319B2 (en) 2017-06-14 2023-05-30 4D Pharma Research Limited Compositions comprising bacterial strains
US11779613B2 (en) 2017-06-14 2023-10-10 Cj Bioscience, Inc. Compositions comprising a bacterial strain of the genus Megasphera and uses thereof
WO2019028402A1 (fr) 2017-08-04 2019-02-07 Second Genome, Inc. Roseburia hominis, eubacterium eligens et combinaisons de celles-ci en tant qu'agents biothérapeutiques
CN111163785A (zh) * 2017-08-04 2020-05-15 第二基因组股份有限公司 作为生物疗法的人罗斯拜瑞氏菌、挑剔真杆菌及其组合
EP3661525A4 (fr) * 2017-08-04 2020-07-22 Second Genome, Inc. Roseburia hominis, eubacterium eligens et combinaisons de celles-ci en tant qu'agents biothérapeutiques

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