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Colorectal Cancer Gut Microbial Signatures May Lead to New Diagnostic Tests

NEW YORK (GenomeWeb) – Two new meta-analyses of metagenomic data are spelling out some of the roles that gut microbes play in colorectal cancer (CRC) and are suggesting new biomarkers for diagnostic and prognostic tests.

For the first of these studies, published online today in Nature Medicine, researchers from Italy, Brazil, and elsewhere brought together metagenomic data for 624 fecal samples from CRC patients and controls that were sequenced for five past studies and data from 140 newly-sequenced samples from two new cohorts. In the CRC samples, their analysis revealed gut microbial community enrichment and an increase in species typically linked to the oral microbiome — results they verified using data for two more cohorts comprised of 100 CRC cases and 105 controls.

When the team focused on the specific microbial pathways that were over- or underrepresented in the CRC cases, it saw an apparent rise in choline metabolism and enhanced activity by gluconeogenesis, putrefaction, and fermentation pathways. Compared to unaffected control individuals, the cases also appeared to have gut microbial communities with less active starch degradation and stachyose pathways.

The researchers also used the data to come up with a microbiome-based signature for distinguishing between individuals with or without CRC, including microbes such as Fusobacterium nucleatum, which has been implicated in CRC in the past.

"We not only established a panel of gut microbes associated with colorectal cancer across populations, but also found signatures in microbial metabolism that have similar predictive power. These will enable new research aiming at understanding how gut microbes may contribute causally to cancer development," co-senior and corresponding author Nicola Segata, a researcher with the University of Trento's Centre for Integrative Biology, said in a statement, noting that the gut microbial community "is heavily dependent on factors such as diet, lifestyle, and environment."

She and her co-authors noted that "[f]uture shotgun metagenomic studies of the intestinal mucosa-associated microbiome, which are currently infeasible due to excessive human DNA contamination, will be important to further refine the list of CRC-associated gut microbes."

In another Nature Medicine study, some members of the same team presented insights gleaned from fecal metagenomes for 386 individuals with CRC and 392 unaffected controls, spanning five discovery and three validation cohorts in Europe, Asia, or North America that were assessed with varied sample preparation and sequencing protocols.

After looking at potential confounders and training their taxonomy- and function-based models, investigators involved in that study demonstrated that they could come up with a microbe-based signature for CRC that was generalizable for finding and classifying CRC cases in cohorts not used to train the models.

"We used a rigorous machine learning analysis to identify microbial signatures for colorectal cancer. We validated these signatures in early cancer stages and in multiple studies, so they can serve as the basis for future non-invasive cancer screening," Georg Zeller, a structural and computational biology researcher at European Molecular Biology Laboratory, said in a statement. Zeller was co-senior and co-corresponding author on that study, and a co-author on the first metagenome meta-analysis paper.

He and his colleagues noted that "taxonomic and metabolic gut microbial marker genes established in these meta-analyses could form the basis of future diagnostic assays that are sufficiently robust, sensitive, and cost-effective for clinical application."

Their work also highlighted more than two-dozen species found at higher levels in the CRC samples. On the functional side, for example, such shifts appeared to correspond with a CRC-linked rise in microbes associated with protein and mucin breakdown or bile acid metabolism, and declines in carbohydrate breakdown.

"[W]e inferred elevated production of secondary bile acids from CRC metagenomes, suggesting a metabolic link between cancer-associated gut microbes and a fat- and meat-rich diet," the authors wrote.