Dataset Information

Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures.

ABSTRACT: 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.

SUBMITTER: Sobhani I

PROVIDER: S-EPMC6883805 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures.

Sobhani Iradj I Bergsten Emma E Couffin Séverine S Amiot Aurélien A Nebbad Biba B Barau Caroline C de'Angelis Nicola N Rabot Sylvie S Canoui-Poitrine Florence F Mestivier Denis D Pédron Thierry T Khazaie Khashayarsha K Sansonetti Philippe J PJ

Proceedings of the National Academy of Sciences of the United States of America 20191111 48

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 patient ...[more]

PMID: 31712445

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Project description:Colorectal adenomas are precancerous lesions of colorectal cancer (CRC) that offer a means of viewing the events key to early CRC development. A number of studies have investigated the changes and roles of gut microbiota in adenoma and carcinoma development, highlighting its impact on carcinogenesis. However, there has been less of a focus on the gut metabolome, which mediates interactions between the host and gut microbes. Here, we investigated metabolomic profiles of stool samples from patients with advanced adenoma (n = 102), matched controls (n = 102), and patients with CRC (n = 36). We found that several classes of bioactive lipids, including polyunsaturated fatty acids, secondary bile acids, and sphingolipids, were elevated in the adenoma patients compared to the controls. Most such metabolites showed directionally consistent changes in the CRC patients, suggesting that those changes may represent early events of carcinogenesis. We also examined gut microbiome-metabolome associations using gut microbiota profiles in these patients. We found remarkably strong overall associations between the microbiome and metabolome data and catalogued a list of robustly correlated pairs of bacterial taxa and metabolomic features which included signatures of adenoma. Our findings highlight the importance of gut metabolites, and potentially their interplay with gut microbes, in the early events of CRC pathogenesis.IMPORTANCE Colorectal adenomas are precursors of CRC. Recently, the gut microbiota, i.e., the collection of microbes residing in our gut, has been recognized as a key player in CRC development. There have been a number of gut microbiota profiling studies for colorectal adenoma and CRC; however, fewer studies have considered the gut metabolome, which serves as the chemical interface between the host and gut microbiota. Here, we conducted a gut metabolome profiling study of colorectal adenoma and CRC and analyzed the metabolomic profiles together with paired microbiota composition profiles. We found several chemical signatures of colorectal adenoma that were associated with some gut microbes and potentially indicative of future CRC. This study highlights potential early-driver metabolites in CRC pathogenesis and guides further targeted experiments and thus provides an important stepping stone toward developing better CRC prevention strategies.

Project description:The gut microbiome is dynamic and shaped by diet, age, geography, and environment. The disruption of normal gut microbiota (dysbiosis) is closely related to colorectal cancer (CRC) risk and progression. To better identify and characterize CRC-associated dysbiosis, we collected six independent cohorts with matched normal pairs (when available) for comparison and exploration of the microbiota and their interactions with the host. Comparing the microbial community compositions between cancerous and adjacent noncancerous tissues, we found that more microbes were depleted than enriched in tumors. Despite taxonomic variations among cohorts, consistent depletion of normal microbiota (members of Clostridia and Bacteroidia) and significant enrichment of oral-originated pathogens (such as Fusobacterium nucleatum and Parvimonas micra) were observed in CRC compared to normal tissues. Sets of hub and hub-connecting microbes were subsequently identified to infer microbe-microbe interaction networks in CRC. Furthermore, biclustering was used for identifying coherent patterns between patients and microbes. Two patient-microbe interaction patterns, named P0 and P1, can be consistently identified among the investigated six CRC cohorts. Characterization of the microbial community composition of the two patterns revealed that patients in P0 and P1 differed significantly in microbial alpha and beta diversity, and CRC-associated microbiota changes consist of continuous populations of widespread taxa rather than discrete enterotypes. In contrast to the P0, the patients in P1 have reduced microbial alpha diversity compared to the adjacent normal tissues, and P1 possesses more oral-related pathogens than P0 and controls. Collectively, our study investigated the CRC-associated microbiome changes, and identified reproducible microbial signatures across multiple independent cohorts. More importantly, we revealed that the CRC heterogeneity can be partially attributed to the variety and compositional differences of microbes and their interactions to humans.

Dataset Information

Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures.

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Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures.

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