Poster #103 - Mahshid Arastonejad

Butyrate Modulates Intestinal Microbiome and Epithelial Function to Attenuate Irinotecan-induced GI Toxicity

(Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, 23298, USA:)Stanley M Cheatham , Zayd Rehman , Mahshid Arastonejad , Yuesheng Zhang , David A Gewirtz , Hamid I Akbarali , Hisashi Harada:(Department of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond) , Natalie Luffman :Department of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond Katarzyna M Tyc :Department of Biostatistics, Virginia Commonwealth University, Richmond, 23298, USA

Chemotherapy-induced gastrointestinal (GI) toxicity is a significant dose-limiting complication in cancer treatment, often resulting from disruption of the epithelial barrier that leads to mucositis, diarrhea, and microbial dysbiosis. To investigate the mechanisms underlying these effects, we examined irinotecan-induced alterations in the gut microbiome and epithelial barrier function in mice. Using a web-based workflow, we characterized changes in microbiome composition and dynamics associated with irinotecan-mediated epithelial damage. Irinotecan treatment dose-dependently reduced body weight, increased fecal water content, and enhanced GI motility, consistent with clinical reports of refractory diarrhea. Loperamide temporarily reduced motility, but tolerance developed with chronic use. Oral butyrate supplementation improved epithelial permeability, preserved colonic crypt stem cell (lgr5) and mucin (muc2) expression, and prevented irinotecan-induced increases in fecal β-glucuronidase activity. Microbiome analyses revealed that irinotecan significantly shifted β diversity, with enrichment of mucin-degrading Akkermansia muciniphila and hydrogen sulfide-producing Desulfovibrio species, effects that were mitigated by butyrate treatment. Collectively, these studies identify molecular and microbial mechanisms by which chemotherapy disrupts gut barrier integrity and highlight the therapeutic potential of microbial metabolites such as butyrate to prevent chemotherapy-induced GI toxicity.