Commensal Bacteria, Redox Stress, and Colorectal Cancer: Mechanisms and Models

Abstract

The potential role for commensal bacteria in colorectal carcinogenesis is explored in this review. Most colorectal cancers (CRCs) occur sporadically and arise from the gradual accumulation of mutations in genes regulating cell growth and DNA repair. Genetic mutations followed by clonal selection result in the transformation of normal cells into malignant derivatives. Numerous toxicological effects of colonic bacteria have been reported. However, those recognized as damaging epithelial cell DNA are most easily reconciled with the currently understood genetic basis for sporadic CRC. Thus, we focus on mechanisms by which particular commensal bacteria may convert dietary procarcinogens into DNA damaging agents (e.g., ethanol and heterocyclic amines) or directly generate carcinogens (e.g., fecapentaenes). Although these and other metabolic activities have yet to be linked directly to sporadic CRC, several lines of investigation are reviewed to highlight difficulties and progress in the area. Particular focus is given to commensal bacteria that alter the epithelial redox environment, such as production of oxygen radicals by Enterococcus faecalis or production of hydrogen sulfide by sulfate-reducing bacteria (SRB). Super-oxide-producing E. faecalis has conclusively been shown to cause colonic epithelial cell DNA damage. Though SRB-derived hydrogen sulfide (H(2)S) has not been reported thus far to induce DNA damage or function as a carcinogen, recent data demonstrate that this reductant activates molecular pathways implicated in CRC. These observations combined with evidence that SRB carriage may be genetically encoded evoke a working model that incorporates multifactorial gene-environment interactions that appear to underlie the development of sporadic CRC.

Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans

“…The role of host-associated microbiota (Hope et al, 2005) has also been frequently proposed as a critical factor in CRC development (Huycke and Gaskins, 2004;Scanlan et al, 2008). Recent technological breakthroughs now allow for the study of the human-associated microbiome at a level of detail that was unimaginable only a few years ago (Margulies et al, 2005;Petrosino et al, 2009).…”

Gut bacteria–host metabolic interplay during conventionalisation of the mouse germfree colon

“…Dysbiosis of the microbial community has been associated with a variety of diseases including inflammatory bowel disease and colon cancer (Azcárate-Peril et al, 2011) along with systemic diseases (Huycke and Gaskins 2004) such as obesity (Bäckhed et al 2004;Bäckhed et al 2007). In view of the increasing awareness of diseaseassociated shifts in intestinal microbiota communities, it is important to improve our understanding of the molecular basis and dynamics of homoeostatic host-microbe interactions.…”

Hydrogen Sulfide Induces Direct Radical-Associated DNA Damage

“…Sulfide concentrations range from 0.2 to 1 mmol/L H 2 S in mouse intestine (2) to 0.3 to 3.4 mmol/L H 2 S in human feces (3)(4)(5). In clinical studies, the presence of either H 2 S or SRB in the intestine has been associated with certain chronic diseases including inflammatory bowel disease and colorectal cancer (6)(7)(8)(9)(10)(11), although a causal relationship has not been established for either disorder. Pitcher et al (12) did not detect differences between counts and carriage rates of SRB in feces of ulcerative colitis patients versus control subjects.…”

“…Regardless, understanding the effects of H 2 S on the colonic epithelium and the extent of interindividual differences in the responsive pathways is crucial to determine how this intestinal insult may contribute to chronic disorders. Published data indicate that H 2 S can damage the intestinal epithelium, leading to the chronic inflammation (10,11,(14)(15)(16), as well as perturb the delicate balance between cellular proliferation and apoptosis (17)(18)(19).…”