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

Area of Science:

• Gastroenterology
• Oncology
• Microbiome Research

Background:

• Chemotherapy, particularly irinotecan, causes significant gastrointestinal (GI) toxicity, limiting cancer treatment efficacy.
• GI epithelial barrier disruption leads to mucositis and diarrhea, impacting patient quality of life.
• Butyrate, a microbial metabolite, shows promise in maintaining epithelial barrier integrity.

Purpose of the Study:

• To investigate the therapeutic potential of oral butyrate in mitigating irinotecan-induced GI toxicity in a mouse model.
• To assess butyrate's effects on gut barrier function, motility, and microbiome composition following irinotecan treatment.

Main Methods:

• Mice were treated with irinotecan to induce GI toxicity, with some receiving oral butyrate supplementation.
• Assessed parameters included body weight, fecal water content, ileum myenteric neuron activity, epithelial permeability, and stem cell markers (Lgr5, Muc2).
• Fecal samples were analyzed for beta-glucuronidase activity and microbial community structure (beta diversity).

Main Results:

• Oral butyrate improved epithelial permeability, preserved Lgr5 and Muc2 expression, and reduced fecal water content in irinotecan-treated mice.
• Butyrate mitigated irinotecan-induced increases in GI motility and beta-glucuronidase activity.
• Butyrate treatment counteracted irinotecan-induced gut dysbiosis, reducing harmful bacteria like Akkermansia muciniphila and Desulfovibrio.

Conclusions:

• Oral butyrate effectively ameliorates irinotecan-induced gastrointestinal toxicity in mice.
• Butyrate's protective effects are linked to improved epithelial barrier function and restoration of gut microbiome balance.
• Butyrate represents a promising therapeutic agent for managing chemotherapy-related GI side effects.