Interaction between dietary taurine and microbiota sulfur metabolism in the development of colorectal cancer

Colorectal cancer (CRC) incidence has been steadily increasing in subjects younger than 50 years old. A relatively recent body of literature suggests CRC could be the result of interaction between dietary components and specific microorganisms. Identification of carcinogenic diet-bacteria interplay would deliver potentially new insight for CRC prevention and treatment. Previous studies revealed that diet rich in microbially accessible sulfur is associated with relative enrichment of Bilophila wadsworthia in the gut and higher risks of CRC including early onset CRC. Energy drinks, the second most popular dietary supplement of teenagers and young adults, commonly contain high amounts of the sulfur amino acid taurine. Taurine can be metabolized by Bilophila wadsworthia to produce H2S, which exhibits DNA-damaging activity at physiological levels. Our preliminary data show that while taurine supplementation protects against colitis and colonic cancer development in the absence of B. wadsworthia, B. wadsworthia colonization together with taurine supplementation promotes development of neoplastic lesions in DSS/Apcmin/+ mice. Taurine and B. wadsworthia, alone or in combination, significantly alter the microbiota composition along CRC development. Importantly, taurine supplementation favors B. wadsworthia gut colonization in mice, suggesting active taurine-B. wadsworthia interplay. In this application, we propose to test the hypothesis that B. wadsworthia-mediated taurine-H2S biotransformation determines the impact of dietary taurine on individual’s gut homeostasis, inflammation and carcinogenesis. We plan to test this hypothesis with the following specific aims: Aim 1. Determine the interaction between dietary taurine and B. wadsworthia in intestinal inflammation and tumorigenesis. The hypothesis is that taurine favors production of disease-promoting H2S by sulfurmetabolizing bacteria such as B. wadsworthia. We will define the impact of taurine and energy drink supplementation on mouse colonic inflammation and tumorigenesis in relation to B. wadsworthia colonization status and metabolic activity. Aim 2. Determine the mechanism by which H2S exerts neoplastic effect. We will determine host genes regulating responses to H2S genotoxicity using whole genome CRISPR/Cas9 genetic screen, and elucidate the in vitro and in vivo mutational signatures induced by H2S and B. wadsworthia taurine metabolism respectively. Aim 3. Evaluate the impact of energy drink consumption on microbiota function from a healthy young adult cohort. We will leverage an ongoing interventional trial where longitudinal stool samples are collected from healthy young adults before and after energy drink consumption to determine microbiota functional capacity changes. We will perform fecal microbiota transplantation in gnotobiotic DSS/Apcmin/+ mice to compare carcinogenic activities of feces collected pre- and post-energy drink consumption. This project will provide key knowledge to prevent intestinal inflammation and carcinogenesis through modulation of taurine intake or bacterial metabolic activity.