Mediating Role of Gut Microbiota in the Regulation of Colorectal Cancer Risk in the Context of Time-restricted Eating and Calorie Restriction

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PROJECT ABSTRACT The goal of this Diversity Supplement is to extend the significance and innovation of the Parent grant by examining the effect of time-restricted eating (TRE) and daily calorie restriction (CR) on the gut microbiota (GM) and host-microbial interactions relevant to the prevention of colorectal cancer (CRC), the third most incident cancer in the United States. The Diversity Supplement will also provide essential training in cancer prevention to a promising Hispanic woman and Early-Stage Career Investigator, Dr. Beatriz Peñalver Bernabé. Obesity is a major modifiable lifestyle risk factor for CRC. TRE is emerging as an alternative approach to managing weight that involves simply watching the clock and eating for 4-10 hours daily, thus restricting the body’s exposure to nutrients for extended periods of time. TRE demonstrates excellent adherence as it is simple and omits burdensome calorie counting, a hallmark of traditional daily CR. The GM can produce beneficial metabolites, such anti-inflammatory butyrate, or improve gut integrity by promoting mucus production, but a dysregulated GM can lead to increase colonic levels of pro-inflammatory and cancer-promoting metabolites. Existing studies on the effects of TRE on the GM are limited in scope and methodology due to small samples sizes, short duration, use of low-resolution methods that fail to examine changes in microbial metabolic function, and lack of a robust assessment of host-microbial interactions in response to TRE. Further, the differential effects of TRE versus CR on the GM and the relevance to colonic carcinogenesis remains unknown. We hypothesize that both TRE and CR will promote a GM environment less permissive of colonic carcinogenesis and that TRE will be superior due to differences in nutrient exposures, a downstream effect of the shortened eating window. Further, we surmise that systems-level approaches, such as network analysis, can identify the key communications between the host and microbial metabolic and colon genetic networks that play mechanistic roles in CRC risk and prevention. Levering the infrastructure of the Parent grant, the proposed Diversity Supplement will use high-resolution methods, such as metagenomics and metabolomics, to characterize GM composition and metabolic function and host systemic metabolism. Statistical and network approaches will be employed to integrate these multi- omics data and colonic transcriptional profiles to determine the effect of TRE and CR on GM and host-microbial interactions. We aim to examine the microbial-regulated metabolite signatures and host-microbial interactions in response to TRE and daily CR while promoting and enhancing diversity among cancer prevention researchers. The Diversity Supplement will provide needed insight into the modulation of the GM and host-microbial interactions in response to TRE and CR and its relevance to the prevention of colorectal carcinogenesis.