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.

Public Health Relevance

Despite the increasing implementation of colonoscopy screening and advances in chemotherapeutic and biological agent-based therapies, colorectal cancer (CRC) remains one of the most common and deadliest malignancies in the United States. The American Cancer Society estimates approximately 140,000 new CRC cases and over 50,000 CRC-related deaths nationwide in 2014. CRC includes hereditary, sporadic, and colitis-associated CRC (CAC). CAC represents a severe medical complication for patients with inflammatory bowel diseases (IBD), and often shows rapid progression, poor response to treatment and high mortality. The etiopathogenesis of CRC/CAC is not clearly defined, but mounting evidence points to an essential role of the intestinal microbiota in CRC/CAC pathogenesis. Hydrogen sulfide-producing bacteria (HSPB) such as Atopobium parvulum and Fusobacterium nucleatum are minor members of the normal gut microbiota but were recently found to be overrepresented in CRC patients. Importantly, H2S has potentially pro-tumorigenic activity. This project investigates the role of HSPB and HSPB-derived H2S in CRC/CAC and the impact of dietary sulfur intervention on HSPB-mediated carcinogenesis. The knowledge obtained from the proposed study will contribute significantly to our understanding of the relationship between bacteria-derived H2S and intestinal pathologies, and will potentially open new paths for CRC/CAC prevention and treatment. In addition, the findings will lay the ground for future studies dissecting mechanisms responsible for carcinogenesis and microbial regulation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA195226-02
Application #
9197276
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Daschner, Phillip J
Project Start
2015-12-17
Project End
2017-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Tomkovich, Sarah; Yang, Ye; Winglee, Kathryn et al. (2017) Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis. Cancer Res 77:2620-2632
Mottawea, Walid; Chiang, Cheng-Kang; Mühlbauer, Marcus et al. (2016) Altered intestinal microbiota-host mitochondria crosstalk in new onset Crohn's disease. Nat Commun 7:13419