Mediterranean Diet and Weight Loss: Targeting the Bile Acid/Gut Microbiome Axis to Reduce Colorectal Cancer Risk

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ABSTRACT. Colorectal cancer (CRC) is associated with multiple risk factors including, obesity, low fiber diets, and diets high in animal protein and saturated fat (SFat). African Americans (AAs) have a higher prevalence of these risk factors and they have the highest incidence of CRC and related mortality. These multiple risk factors are also linked to higher circulating and fecal bile acids (BA) and a shift in BA amino acid conjugation from glycine to taurine. These BA-related changes can alter the composition, structure, and metabolic activity of the gut microbiota, fostering conditions for gut bacteria to expand and metabolize taurine-conjugated BAs to genotoxic hydrogen sulfide (H2S) and the tumor promoter, deoxycholic acid (DCA); a colonic milieu conducive to the formation of CRC. We have shown that the abundance of H2S-producing bacteria is significantly higher in the colon of AAs compared to non-Hispanic whites and is a defining feature among AA CRC cases implicating these bacteria as contributors to CRC development in a race-dependent manner. Moreover, the microbial difference is associated with higher intake of SFat and animal protein in AAs, providing a pivotal intervention target. We hypothesize that targeting the BA-gut microbiome axis to suppress abundance, growth and metabolic activity of H2S and DCA producing bacteria through diet and weight loss (WL) may reduce CRC risk, especially among AAs. A Mediterranean Diet (MedDiet), a largely plant-based dietary pattern, is relevant to CRC prevention and microbial production of anti-cancer metabolites in observational studies. A MedDiet can shift BA metabolism as shown in primates and when combined with calorie restriction, shows superior adherence and weight control in humans, given its palatability. To date, no studies have tested in an RCT the effects of a MedDiet alone (Med- A), WL through lifestyle intervention (WL-A) or a calorie-restricted MedDiet for WL (WL-Med) on the BA-gut microbiome axis and its relevance to CRC prevention among AAs. Our multidisciplinary team combining expertise in psychology, nutrition, microbiology, molecular cell biology, computational biology, medicine and biostatistics, propose to conduct a four-arm RCT in which 200 obese AAs, 45-75 years old complete one of the following 8-month interventions: Med-A, weight stable; WL-A, calorie restriction with no diet pattern change; WL- Med; or Control. We will use samples and data collected at baseline, mid-study (month-4) and post-intervention to compare the effects of the interventions on 1) Concentration and composition of circulating and fecal BAs; 2) Gut microbiota and metabolic function; and 3) Gene expression profiles of exfoliated intestinal epithelial cells. Our approach is strong given our multidisciplinary team, use of evidence-based lifestyle interventions, and sophisticated –omics analyses to examine crosstalk between diet/WL, gut microbiome, and host intestinal physiology. If successful, this study could have profound public health impact on CRC risk among AAs and other high-risk populations, that would translate into timely dissemination opportunities.