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

Chemotherapy-induced gastrointestinal toxicity is a significant dose-limiting complication for cancer treatment. Disruption of the gastrointestinal (GI) epithelial barrier function by several chemotherapeutic agents results in development of mucositis and diarrhea. Thus, maintaining barrier integrity may be of therapeutic benefit. Recent studies have shown the beneficial effects of the microbial metabolite butyrate, a short chain fatty acid (SCFA), on epithelial barrier integrity. In this current study, we tested the effect of oral butyrate on irinotecan-induced gastrointestinal (GI) toxicity in mice. Irinotecan dose-dependently reduced body weight and increased fecal water content. Nicotine-induced inward currents in ileum myenteric neurons were significantly increased in irinotecan treated mice consistent with enhanced GI motility. Loperamide reduced GI motility of irinotecan treated mice, however tolerance developed with chronic use, consistent with clinical findings of loperamide refractory diarrhea in patients. Oral butyrate improved epithelial permeability, prevented loss in stem cell marker, lgr5 in colonic crypts and muc2 expression in ileum. Butyrate also prevented irinotecan-induced increase in β-glucuronidase activity in fecal samples. Irinotecan treatment produced a significant shift in the β diversity of the fecal microbiome that was mitigated by butyrate. The microbial dysbiosis was associated with increases in the mucin degrading bacteria Akkermansia muciniphilia and the hydrogen sulfide producing Desulfovibrio sp10575755 that was reduced with butyrate treatment.