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Colorectal Cancer Study Reveals Gut Microbe, Methylation Shifts

NEW YORK – A team from France has uncovered epigenetic changes in the blood that appear to coincide with sporadic colorectal cancer (CRC) and gut microbiome changes, both in human samples and in mouse models.

After demonstrating that fecal microbiota transfer (FMT) from humans with CRC could prompt increased DNA methylation and other changes in the guts of germ-free mice, the researchers used targeted methylation profiling to narrow in on a small set of genes that were hypermethylated in blood samples from individuals with CRC, who also tended to show gut microbial shifts. Their findings appeared online yesterday in the Proceedings of the National Academy of Sciences.

From these and other findings, co-senior and co-corresponding author Philippe Sansonetti, a researcher affiliated with the Pasteur Institute and the College of France, and his colleagues suggested that gene methylation may "serve as a marker for CRC and likely for predicting efficacy of prebiotic supplementation in average-risk individuals."

The researchers transferred fecal samples from nine CRC patients and nine healthy human controls into germ-free mice, using histology, immune cell profiling, colon and spleen tissue sequencing, fecal 16S rRNA gene sequencing, array-based methylation profiling, and other approaches to follow the mice for up to 14 weeks, while characterizing corresponding gut microbiome, methylation, and colonic differences in human donors with or without CRC.

With these strategies, the team was able to track DNA methylation, mutation, and other features in colon tissue, blood serum, and stool samples, comparing the environmental stress effects of the gut microbes with those induced by the carcinogenic chemical azoxymethane.

"The objective of this study was to assess the hypothesis that CRC-associated environmental factors may act by altering the composition of the gut microbiota," the authors explained, "and to investigate the underlying epigenetic pathways involved in CRC promotion."

The researchers saw an increase in hypermethylated genes in colon samples from the mice receiving fecal samples from individuals with CRC, including a sharp rise in methylation at several gene promoters.

"Overall, significant DNA epigenetic rather than mutation changes in several genes were associated with [CRC microbiota] human FMT in the mouse colonic mucosa," they report. They noted that the DNA alterations detected pointed to a role for genes involved in cell growth, signal transduction, and other cell processes.

Such data prompted the team to use quantitative PCR to track methylation levels at three of the same genes — WIF1, PENK, and NPY — in blood samples from 266 humans. In that cohort, and in follow-up analyses that included more than 1,000 individuals, the investigators found that a cumulative methyl index based on qPCR measurements of blood serum could help pick up CRC cases.

In a subset of CRC cases with available stool and blood samples, the researchers saw apparent ties between disease, the blood-based methylation index, gut dysbiosis based on 16S rRNA sequence data, and the presence of specific gut microbial species in the gut, based on metagenomic sequence clues.

"[O]ur data present evidence for the association between a dysbiosis and CRC-causing alterations in gene methylation," the authors wrote, noting that specific bacterial species "were significantly associated with higher levels of methylation test by using whole genomic analysis."