Coffee and metabolites modulating the gut microbiome for improved colorectal cancer survival - PROJECT SUMMARY / ABSTRACT More than 1.5 million Americans are currently living with colorectal cancer (CRC). Improving CRC survivorship is a high priority. Diet is an important factor influencing CRC prognosis. The use of dietary modification to supplement conventional cancer therapy is an eminently practical approach. Growing data indicate the anti- cancer benefit of coffee consumption. In the US, 64% of adults drink coffee daily, with an average consumption of 2.7 cups per day. Coffee contains hundreds of antioxidants and other bioactive compounds, which are degraded and modified by the gut microbiota and endogenous enzymes to generate secondary metabolites. These metabolites may protect against CRC by reduction of inflammation, modulation of metabolism, and inhibition of tumor growth and invasion. In particular, compelling data indicate the benefit of coffee for reducing risk of fatty liver and liver fibrosis, conditions that have been linked to worse survival of CRC, possibly by promotion of liver metastasis, the major cause of CRC death. Recently, we showed in four independent prospective cohorts that CRC patients consuming 4 cups/d or more of coffee had a 40-50% lower risk of recurrence and CRC-specific death compared with nondrinkers. However, the causality and specific mechanisms for this relationship remain unknown. To address this knowledge gap, we propose to conduct a biomarker-based randomized placebo-controlled trial and assess the prognostic influence of the interplay between coffee intake and the metabolomic and microbial signatures in patients with stage III CRC. We hypothesize that compounds in coffee and their metabolites improve CRC survival by modulating the gut microbiome and ameliorating liver fatness and fibrosis. In Aim 1, we will determine the effect of coffee consumption on the gut microbiome and metabolome, liver fatness and fibrosis, and markers of CRC recurrence in a randomized controlled trial of freeze-dried instant coffee and placebos for 3 months among 80 stage III colon cancer patients who have completed chemotherapy. In Aim 2, we will prospectively assess coffee intake, fecal microbial features and metabolites in relation to CRC recurrence and survival in a cohort of 450 stage III CRC patients who provide detailed dietary data and stool specimens. Our ability to accomplish these aims is underscored by our experience with dietary intervention and biobanking studies in CRC; our multi’omic profiling effort to elucidate the interplay between diet, the gut microbiome, and host metabolism in CRC; as well as our experienced multidisciplinary team comprised of experts in nutrition, microbiome, epidemiology, oncology, and hepatology. The mechanistic insights provided by the project will not only help refine the recommendations for cancer survivorship for one of the most commonly consumed beverages worldwide, but also lead to discovery of novel adjuvant therapeutics and development of novel interventions based on manipulation of the diet, metabolome, and microbiome for improved CRC management.
