Microbiota metabolic exchange is critical for colorectal cancer redox homeostasis and growth

Intestinal microbiota play a fundamental role in human health and disease. Microbial dysbiosis is a hallmark of colorectal cancer (CRC) as tumor stage-specific shifts potentiate tumor growth, influence the inflammatory microenvironment, and alter response to therapy. Recent work has demonstrated a critical role for microbial metabolite exchange in host response. However, the role of most microbial metabolites in colon cancer growth is unclear. To better understand how metabolic exchange between the microbiota and tumor epithelium alter CRC growth, a screen of the most abundant bacterially derived metabolites was assessed. Several metabolites were found to alter CRC growth, but reuterin most significantly suppressed CRC cell proliferation. Reuterin is a bifunctional metabolite containing both hydroxy and aldehyde functional groups. Reuterin is primarily synthesized from glycerol by Lactobacillus reuteri, a commensal bacterium found throughout the gastrointestinal tract. We found that reuterin suppresses growth via alterations to the redox balance of CRC cells. Mechanistically, reuterin potentiates reactive oxygen species (ROS) which leads to irreversible cysteine oxidation and enhanced cell death. Supplementation of either antioxidants or hydrogen sulfide fully rescued growth, suggesting that reuterin is suppressing CRC growth through protein oxidation. These studies demonstrate the potential of reuterin to act as a potent chemotherapeutic for treating colorectal cancers.