Abstract 6031: Fasting associated microbiota contributes to small intestinal radioprotection by modulating the epigenome

Abstract

Abstract Normal tissue toxicity often restricts the administration of effective radiation doses for optimal tumor cell elimination. We identified a novel host-protective effect conferred by short-term fasting when treating mice with high dose radiation. We showed that fasting mice for 24h induces epigenetic and transcriptional changes in small intestinal epithelial cells (siECs) and confers protection to small intestinal stem cells from high dose radiation. Here we report that fasting induces changes in the gut microbiome favoring bacteria producing metabolites, specifically short-chain fatty acids, that induce epigenetic changes in siECs. 16S rRNA sequencing of feces isolated from the small intestines of fed and fasted mice revealed a marked enrichment of Akkermansia muciniphila (AKK) in fasted relative to fed mice. Specific depletion of AKK through antibiotic treatment impaired the ability of fasting to provide organismal radioprotection whereas both organismal and OLFM4+ stem cell protection was restored in fasted animals upon reintroduction of AKK. AKK produces short chain fatty acids (SCFAs) including propionate which is able to induce histone modifications and our metabolomic analysis of feces isolated from the ileums of mice demonstrated a significant increase in propionic acid levels in fasted mice compared to fed mice. Importantly, we showed that AKK conditioned medium as well as its metabolite (propionate) are able to induce histone acetylation in Lgr5+ stem cell enriched epithelial spheroids cultured in vitro. We are currently employing high-dimensional analysis techniques, including single cell analysis, Cut&Tag and RNAseq to determine how the epigenetic and transcriptional changes induced by fasting provide organismal and SI radioprotection. Citation Format: Praveen Barrodia, Emre Arslan, Sabrina Jeter-Jones, Robert R. Jenq, Kunal Rai, Helen Piwnica-Worms. Fasting associated microbiota contributes to small intestinal radioprotection by modulating the epigenome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6031.