Abstract 6714: GPR109A expression provides a molecular link between the colonic microbiome and the associated reduced risk of colon cancer formation

Abstract Obesity is associated with an increased risk of colorectal cancer (CRC) in both men and women. It has been shown that a body mass index (BMI) of more than 30 has almost twice the risk of early-onset CRC compared with a BMI of 18 - 23. Although the obesity-associated increase in both CRC risk and progression is associated with several systemic and localized factors, the microbiome could play a critical role in obesity-associated CRC. Using mouse models of CRC, we found that dietary patterns shift the normal colonic microbiota populations. Interestingly, the colonic probiotic Lactobacillus abundance negatively correlated with body fat composition, providing evidence that obesity interacts with diet to regulate bacterial populations in the colon. Body fat composition is negatively associated with colonic bacteria-derived host cometabolites, Hippurate, and Butyrate, two agonists of the G-protein coupled receptor 109A (GPR109A). We have shown that GPR109A expression is significantly reduced in human CRC compared to the normal colonic epithelium, and GPR109A activation limits CRC growth and progression. Low GPR109A expression in human CRC limits overall survival. Our preliminary studies show that GPR109A expression is negatively associated with increasing BMI, which in turn reduces the bacterial metabolites Hippurate and Butyrate, especially in African-American (AA) CRC patients than in Caucasian (CA). Dietary supplementation of Hippurate and Butyrate significantly reduced CRC formation, and this effect is mediated through GPR109A. Gpr109a knockout mice are more prone to chemical carcinogens, and genetically engineered mouse models (GEMM) of CRC and dietary supplementation of Hippurate and Butyrate do not show significant beneficial effects. Similarly, the ketogenic metabolite beta-hydroxybutyrate (BHB), an endogenous agonist of GPR109A, levels are significantly lower in obese AA CRC patients than in lean AA CRC and CA CRC patients. Dietary supplementation of the ketogenic diet significantly increases the Lactobacillus abundance and Hippurate, Butyrate, and BHB levels in Gpr109a wild-type mice, but this effect is blunted in Gpr109a knockout mice. Overall, our study provides a novel role of GPR109A in the regulation of the colonic microbiome and its metabolites and associated CRC prevention. Further, our study provides evidence that GPR109A expression links to obesity-associated CRC formation, and GPR109A agonists could have a significant clinical impact on the prevention and treatment of CRC. Citation Format: Muthusamy Thangaraju, Nanditi N. Thangaraju, Sonia Batan, Jabuneesa Khanom, Kunal Kumar, Snigdha Ganjikunta, Subash Sundaram, Sathish Sivaprakasam, Nikhil Patel, Santhakumar Manicassamy, Puttur D. Prasad, Vadivel Ganapathy. GPR109A expression provides a molecular link between the colonic microbiome and the associated reduced risk of colon cancer formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6714.