Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures
| Autor: | Sylvie Rabot, Séverine Couffin, Aurelien Amiot, Biba Nebbad, Emma Bergsten, Khashayarsha Khazaie, Philippe J. Sansonetti, Denis Mestivier, Caroline Barau, Florence Canoui-Poitrine, Thierry Pedron, Iradj Sobhani, Nicola de’Angelis |
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| Přispěvatelé: | Service de gastro-entérologie [Henri Mondor AP-HP, Créteil], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Early detection of Colon Cancer using Molecular Markers and Microbiota (EA 7375) (EC2M3), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Pathogénie microbienne moléculaire, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Henri Mondor, Plateforme de Ressources Biologiques [Henri Mondor AP-HP, Créteil] (PRB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Service de chirurgie digestive, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Mayo Clinic [Rochester], Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), French Institut of CancerMinistry of Health - Turkey : PHRC 2011-VatnimadAOM09268French Society of GastroenterologyLigue Nationale Contre le Cancer for fecal test screening Institut National du CAncer (INCA, Cancéropôle Ile de France, Grant for Microbiota and CRC) National Institute of Health and Medical Research (INSERM) under the Institut Thématique Multi-Organisme program (ITMO)., We thank all patients for their participation and physicians who invited them to participate, they are the following gastroenterologists: Drs. E. Zrihen, O. Pecriaux, J. Samama, M. Petit, Ph. Cattan, M. Cavicchi, Ch. Locher, G. Gattineau, M. Parieto, M. Mozer, A. Rosenbaum, Ph. Capelle, D. Levoir, F. Maille, Ph. Lebourgeois, Ph. De Land, E. Chanteloup, M. Simon, F. Mal, and F. Iglicki. We thank also Drs. J. Tran VanHieu and M. L. Auriault for pathology analyses in human and animals, Prof. S. Loric for biochemistry analysis in mice, Prof. T. Simon, A. Touati, J. Tap, V. Jarrousse, A. Bado, and J. P. Fouret for animal experiments and help managing, A. Wolfe for revising the English, S. Peyvandi for assisting with the animal and molecular experiments, E. Guery and L. Segaux for their statistical contributions, C. Vialette for data managing, A. Caidia (Bioinformatics Core Laboratory) for 16S rRNA analysis, and Catherine Philippe for SCFA analyses in mice. We thank all technicians and scientific consultants from Faculté de Médecine site Pitié Salpêtrière (Assistance Publique-Hôpitaux de Paris [APHP]), Unité Mixte de Service (UMS) 29 Omic Platform p3s for technical help on EPIC methylation array study in mice, and all members of clinical monitoring group from the Unité de Recherche Clinique de l’Est Parisien (URC-Est) Hôpital Saint-Antoine, APHP. We thank all the technicians from the Anaxem germ-free animal facility of the Micalis Institute for breeding the germ-free mice and carrying out FMT and gnotobiotic mice care and monitoring. We thank Dr. Abdulmohammad Pezeshki and Ms. Shatha Awaad for assistance with the analysis of inflammation in mouse colons and Katja Brunner for editing the manuscript., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Microbiologie et Maladies infectieuses, PEDRON, Thierry, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor [Créteil], Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) |
| Rok vydání: | 2019 |
| Předmět: |
Male
Colorectal cancer [SDV]Life Sciences [q-bio] [SDV.CAN]Life Sciences [q-bio]/Cancer Biology Epigenesis Genetic Cohort Studies Feces 03 medical and health sciences 0302 clinical medicine [SDV.CAN] Life Sciences [q-bio]/Cancer RNA Ribosomal 16S microbiota medicine cancer Animals Germ-Free Life Humans Epigenetics Intestinal Mucosa Promoter Regions Genetic 030304 developmental biology Mice Inbred C3H 0303 health sciences Multidisciplinary colon Cancer Promoter Methylation Biological Sciences DNA Methylation Fecal Microbiota Transplantation medicine.disease digestive system diseases Gastrointestinal Microbiome 3. Good health [SDV] Life Sciences [q-bio] Gene Expression Regulation 030220 oncology & carcinogenesis DNA methylation Immunology biomarker Dysbiosis Female Colorectal Neoplasms gene methylation Aberrant crypt foci |
| Zdroj: | Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2019, 116 (48), pp.24285-24295. ⟨10.1073/pnas.1912129116⟩ Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (48), pp.24285-24295. ⟨10.1073/pnas.1912129116⟩ |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls’ microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study ( n = 266), the blood methylation levels of 3 genes ( Wif1 , PENK , and NPY ) were shown closely associated with CRC dysbiosis. In a validation study ( n = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC. |
| Databáze: | OpenAIRE |
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