Sodium butyrate alleviates chemotherapy induced gastrointestinal toxicity

Abstract ID 94122 Poster Board 062 Diarrhea is a prevalent side effect of chemotherapeutic treatment that can result in reduction of quality of life, dose limitation, and death. Irinotecan is a widely used chemotherapeutic in the treatment of unresectable colorectal and metastatic triple-negative breast cancer. The short chain fatty acid sodium butyrate is known to promote intestinal homeostasis and reduce inflammation. Additionally, sodium butyrate slows the proliferation and differentiation of colon cancer cells providing synergic treatment with conventional chemotherapeutic agents. Together sodium butyrate may serve as both a treatment for alleviating gastrointestinal distress produced by irinotecan treatment and synergistic compound for treatment of cancer. We hypothesize that inflammation produced by irinotecan treatment compromises epithelial membrane integrity and butyrate ameliorates. In this study we developed a model of irinotecan induced gastrointestinal toxicity that is ameliorated by once daily sodium butyrate administration. Male ICR mice were treated with either 60, 75, or 100 mg/kg irinotecan administered intra-peritoneally once daily for four consecutive days followed by monitoring and assessment of diarrhea for two additional days. Additionally, mice were co-treated with the sodium butyrate once daily (550 mg/kg) in vehicle and irinotecan (75 mg/kg) treated groups. Body weight, fecal water content, small intestinal transit, villi length, assessment of intestinal damage by H&E/AB-PAS in slices, and diarrhea scoring criteria were assessed over the six-day period. Mice treated with 60mg/kg irinotecan exhibited no production of diarrhea or bodyweight loss, mice treated with 75 mg/kg or 100 mg/kg irinotecan exhibited a decrease in body weight culminating in a 20% reduction on day 6 of treatment (Fig 1C). Animals treated with 75 mg/kg irinotecan exhibited increase in fecal water content on day 5 (N = 5, 54 [endif]--> 5.26%) and day 6 (N = 5, 58 [endif]--> 4.13%) (Fig 1D). There was a marked reduction in small intestine length (N = 40 t = 5.875, P<0.0001) and villi length (N = 10, t = 7.905, P<0.0001) (Fig 1A), when treated with irinotecan alone. However, in the presence of once daily sodium butyrate body weight reduction was ameliorated (two-way ANOVA, F (2.190, 48.17) = 26.82 P<0.0001) (Fig 1C). Interestingly damage to intestinal villi length was restored by sodium butyrate in irinotecan treated animals when compared to irinotecan administered alone (one-way ANOVA, N = 10, F (3,36) = .6343, P<0.0001) (Fig 1A) and produced no change in fecal water content (two-way ANOVA, N = 10, F (15, 130) = 2.383, P<0.873). Additionally, mice were assessed for diarrhea daily, however, in the presence of sodium butyrate increase in diarrhea scoring was alleviated (Fig 1B). Supported by NIH T32DA007027 and VCU Massey Cancer Center Innovation Pilot grant