The Human Gut Microbiome as a Screening Tool for Colorectal Cancer

scfa.JPGOur results suggest that relative abundance data from the human gut microbiome differentiates individuals with healthy colons from those with adenomas and carcinomas. Most importantly, there was a significant difference in the gut microbiome of people with colonic adenomas compared with those with healthy colons. This has considerable importance in secondary prevention because screening for early-stage colorectal cancer hinges on the ability to detect early pathologic changes. In this regard, we found that failure to detect at least 1 of the 5 OTUs served as a signal of the presence of adenoma. The probability of having an adenoma rose more than 50-fold with this added information about microbiome. Taken with the existing literature about the importance of the gut microbiome in health and disease, our study further suggests that the microbiome may play a crucial role in the etiology of colorectal cancer.

A strength of our study design was that we collected samples from 3 clinical groups that represented the multistage progression in colorectal cancer (healthy, adenoma, and carcinoma). This allowed us to identify a panel of bacterial populations that could indicate both the progression from healthy tissue to adenoma and the progression from adenoma to carcinoma. Interestingly, when we looked at each patient, we rarely observed significant enrichment of every bacterial population among the OTUs incorporated in the logit models. For example, 11 of the 30 carcinoma patients had no detectable levels of Fusobacterium. However using the relative abundance data for the remaining panel of microbial biomarkers, such as Porphyromonas, Bacteroides, and Enterobacteriaceae, we were able to accurately classify these subjects. This strongly suggests that there may be multiple underlying mechanisms by which the microbiome is involved in colorectal cancer and that colorectal cancer is likely a polymicrobial disease.

Our findings are supported by previous evidence. Three research groups reported that Fusobacterium spp. were enriched on the surface of tumors compared with adjacent healthy tissue (22, 37, 38). Building upon these clinical studies, animal and tissue culture-based studies have provided evidence that Fusobacterium may contribute to tumor multiplicity through the recruitment of immune cells to tumors (22, 37). These mechanistic studies agree with our findings that Fusobacterium may be a marker for the presence of tumors. In addition, enterotoxigenic Bacteroides fragilis (ETBF), a pathogenic variant of a common commensal, has been shown to directly influence the development of colorectal cancer in murine genetic models through the production of a metalloprotease toxin (39). In our samples, subjects with carcinomas showed an increase in the relative abundance of one Bacteroides population (OTU 1882) compared with subjects with adenomas. However, PCR-based screens for the toxin producing genes did not reveal the presence of ETBF. In addition, we observed a significant decrease in the relative abundance of Bacteroides populations (OTUs 1889 and 1913) associated with the advancement of tumorigenesis. Finally, a polyketide synthetase operon from Escherichia coli was shown to influence the progression of tumors using a murine model of inflammation-derived tumorigenesis (21, 23). Although we did see an enrichment for non–E. coli Enterobacteriaceae in the carcinoma subjects relative to the healthy subjects, we were unable to detect significant differences in the relative abundance of E. coli across the 3 clinical groups.

It is tempting to speculate on the enrichment of Fusobacterium and Porphyromonas spp. in subjects with colorectal cancer. Both of these bacterial taxa are common commensals of the mouth and a wealth of literature has linked them to chronic inflammation and periodontal disease (40, 41). It is possible that the mouth is a reservoir for these pathogens, allowing for colonization of the gastrointestinal tract under abnormal environmental conditions. During colorectal carcinogenesis, dramatic physiologic changes occur in the microenvironment of colonic lesions (42). Tumor-associated fluxes in nutrients and shifts in inflammatory mediators may favor colonization by opportunistic pathogens such as Fusobacterium and Porphyromonas. As demonstrated by Kostic and colleagues, colonization by such pathogens can support the development and progression of colorectal cancer (22, 37). We were unable to detect a significant association between either population and carcinoma severity or location. Additional studies are needed to examine how and at what stage these bacterial populations are affecting the development of colorectal cancer and how they may be linked to the oral microbiome and related to oral disease.

As highlighted above, there is a clear association with the enrichment of pathogenic bacterial populations and colon tumorigenesis; however, in this study we emphasize that the depletion of potentially protective bacteria likely plays a similar role colorectal cancer pathology. We identified several bacterial populations that were significantly depleted in colorectal cancer. Individuals with both adenomas and carcinomas showed a dramatic loss in OTUs associated with the genera Clostridium and Bacteroides, and the family Lachnospiraceae (43–45). Each of these bacterial taxa are well known producers of short chain fatty acids (SCFA) in the colon. SCFAs are important microbial metabolites that supply nutrients to colonocytes and help maintain epithelial health and homeostasis. Specifically, the SCFA, butyrate, has been shown to have substantial antitumorigenenic properties, including the ability to inhibit tumor cell proliferation, initiate apoptosis in tumor cells (46), and mediate T-regulatory cell homeostasis (44). Loss of these important bacterial populations in concert with an enrichment of pathogenic populations likely plays a synergistic role in potentiating tumorigenesis.

Joseph P. Zackular, Mary A.M. Rogers, Mack T. Ruffin IV and Patrick D. Schloss

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connie dello buono

Health educator, author and enterpreneur or ; cell 408-854-1883 Helping families in the bay area by providing compassionate and live-in caregivers for homebound bay area seniors. Blogs at Currently writing a self help and self cure ebook to help transform others in their journey to wellness, Healing within, transform inside and out. This is a compilation of topics Connie answered at and posts in this site.

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