Abstract 4243: Dietary flavonoids prevent colon tumor formation in ApcMin/+ mice in a microbiome- and sex-dependent manner

Abstract

Abstract Background: A diet rich in colorful fruits and vegetables is effective for the prevention of various inflammation-induced cancer types. Mechanistically, this effect has been attributed to the potent antioxidant properties of flavonoid molecules. However, contrary to observations in mice, the success of flavonoids in human dietary cancer prevention trials is often dampened due to large interpersonal variation. Antioxidant activity alone does not explain this variability, suggesting there is an additional important variable that has not been accounted for. Since flavonoids have a poor bioavailability and predominantly passage into the large intestine, we hypothesize that gut microbial metabolism is essential for flavonoid bioactivity in colon cancer prevention. Goals and Objectives: The goal of this study was to evaluate the impact of microbiota composition on the efficacy of dietary flavonoids in preventing intestinal tumorigenesis. Methods: We used the adenomatous polyposis coli - multiple intestinal neoplasia (ApcMin/+) mouse model, which is genetically predisposed to develop adenomas along its gastrointestinal tract. Development of these adenomas and eventual adenocarcinoma formation is further influenced by factors such as inflammation, dietary input and the gut microbiota. Animals were fed a control high fat diet (HFD) or prevention diets consisting of 1% berry extract, 1% purified flavonoid or 1% microbial catabolite, all on the HFD background. The contribution of the microbiota was modelled by including experimental groups that received an antibiotic cocktail in their drinking water throughout the course of the experiment. For these animals, microbiota community composition was determined by 16S rRNA sequencing, plasma was collected for histological profiling and metabolomics analysis and end-point measurements of intestinal tumor numbers and size were performed. Results: Supplementation with berry extract significantly reduced colon tumor numbers and incidence in male, but not in female mice. This effect was negated in mice on antibiotic drinking water, implicating the involvement of the gut microbiota. Community analysis revealed a relative increase in Erysipelotrichaceae, Clostridia and Akkermansia in the berry supplemented versus HFD control mice. In addition, their systemic monocyte counts were reduced. Dietary supplementation with a major gut microbial flavonoid catabolite, did not reduce colon tumor formation, suggesting the functional involvement of different microbial metabolites. Conclusions: Our study demonstrates the involvement of the mouse gut microbiota in dietary prevention of colon tumor formation. These effects impact circulating monocytes and are linked to changes in the plasma metabolome. We are currently elucidating the microbial actors and associated molecular pathways involved. Citation Format: Beckey DeLucia, Jan Claesen. Dietary flavonoids prevent colon tumor formation in ApcMin/+ mice in a microbiome- and sex-dependent manner. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4243.