Abstract Aging is associated with systemic low-grade inflammation (inflammaging) and increased susceptibility to infections, chronic diseases, and colorectal cancer (CRC). Age-associated gut dysbiosis contributes to a decline in beneficial microbial metabolites, particularly short-chain fatty acids (SCFAs), fostering a pro-inflammatory intestinal microenvironment that promotes tumorigenesis. Dietary strategies that restore microbial balance and enhance SCFA production could mitigate inflammaging and CRC risk. Fermentation of complex dietary polysaccharides (CDPs) by gut microbiota can generate host-beneficial metabolites, including SCFA, and help maintain epithelial barrier integrity and suppress aging-associated inflammation. In this study, using high-pure beta-glucans (BGs) from yeast (yeast beta-1,3/1,6-glucan; YBG) and microalgae (algal beta-1,3-glucan; paramylon, PM), we show that the CDP degradation process alters microbiota composition and metabolite profiles in vitro and in vivo, suppresses aging-associated inflammation and cancer susceptibility in the azoxymethane/dextran sulfate sodium (AOM/DSS) model of CRC. Dietary treatment using BGs significantly altered gut microbial composition, notably increasing the abundance of Akkermansia muciniphila, a mucin-degrading bacterium known to produce SCFAs. Fecal microbial cultures of aged mice with BGs showed elevated levels of anti-inflammatory metabolites and reduced levels of pro-inflammatory factors. Aged mice treated with BGs showed significantly lower colorectal tumor burden and disease severity. Bulk RNA sequencing of colon tissue of BG-treated mice revealed suppressed expression of oncogenes, metastasis-related genes, and pro-inflammatory cytokines, along with increased expression of anti-inflammatory cytokines and Muc2, a key gene involved in mucin production and gut barrier function. Our findings suggest that the CDP degradation process can rejuvenate the aging gut microbiota, restore host beneficial metabolite production and gut integrity, and suppress inflammaging. Ongoing studies using gnotobiotic animals and colonoid cultures aim to further elucidate the mechanisms by which CDP degradation by gut microbiota modulates gut integrity, inflammation, and CRC susceptibility. Collectively, this work demonstrates the potential of microbiota-targeted dietary strategies for promoting healthy aging, rejuvenating gut microbiota, and reducing CRC risk in elderly populations. Citation Format: Rekha Jalandra, Mousumi Bhattacharjee, Ruchika Maurya, Radhika R. Gudi, Jayda S. Gilliard, Caroline Westwater, Chenthamarakshan Vasu. Microbiota-dependent complex dietary polysaccharide degradation suppresses inflammaging and colorectal cancer susceptibility abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2463.
Jalandra et al. (Fri,) studied this question.