Mechanism by which H2S-producing bacteria influence development of colorectal cancer

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 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a common malignancy and the third leading cause of cancer-related deaths in the United Sates. Patients with inflammatory bowel diseases (IBD) are particularly susceptible to developing colitis-associated CRC (CAC), which often shows rapid progression, poor response to treatment and high mortality. Growing evidence links the intestinal microbiota, more specifically microbial dysbiosis, to CRC/CAC pathogenesis. In particular, certain commensal bacteria can be influenced by environmental cues (e.g., inflammation) and exert carcinogenic functions by producing pro-tumorigenic metabolites. Atopobium parvulum and Fusobacterium nucleatum produce H2S during fermentation of sulfate-containing compounds such as methionine. Both hydrogen sulfide-producing bacteria (HSPB) are minor members of the normal gut microbiota but were recently found to be overrepresented in CRC patients. Importantly, H2S has the capacity to induce inflammation and possesses genotoxic and potentially pro-tumorigenic properties. Recently, F. nucleatum was shown to enhance colonic tumor development in the Apcmin/+ mouse model, a commonly used animal model for CRC. However, the role of H2S in F. nucleatum-mediated carcinogenesis has not been established. In preliminary studies, we found that the relative abundance of A. parvulum positively correlated with the severity of pediatric IBD and that A. parvulum exacerbated colitis in Il10-/- mice through production of H2S. Whether A. parvulum-derived H2S plays a role in CRC pathogenesis is not clear. Furthermore, dietary methionine levels were reported to modulate intestinal carcinogenesis. Whether HSPB are implicated in the cancer-modulating effect of dietary methionine is unknown. Our central hypothesis is that HSPB, specifically A. parvulum and F. nucleatum, promote intestinal tumorigenesis through production of H2S. The goal of this project is to determine the role of HSPB and HSPB-derived H2S in CRC/CAC and evaluate the impact of dietary methionine on HSPB-mediated carcinogenesis. Our specific aims are as follows: 1) Determine the cancer-promoting potential of A. parvulum and F. nucleatum using germ- free Apcmin/+ and Il10-/-;Apcmin/+ mice; 2) Determine the impact of dietary methionine on HSPB-mediated intestinal tumorigenesis. Our findings will significantly move forward the field of research on the interplay between microbial metabolic activities and intestinal pathologies by establishing that HSPB are important contributors to intestinal tumorigenesis and that dietary intervention could modulate this activity. These findings will constitute the background for more detailed analysis of HSPB gene regulation and intervention to alleviate their carcinogenic potential.