Betulin Alleviates 5-Fluorouracil-Induced Intestinal Mucositis in Mice.

Background

Chemotherapy-induced intestinal mucositis (CIM) is a common gastrointestinal complication of anticancer therapy, and 5-fluorouracil (5-FU) is among the agents most frequently implicated. Betulin (BE), a lupane-type pentacyclic triterpenoid with anti-inflammatory and cytoprotective activities, has not been systematically evaluated in 5-FU-induced CIM. Purpose: This study evaluated the therapeutic effects of BE in a mouse model of 5-FU-induced CIM and examined associated histopathological, apoptotic, inflammatory, and gut microbiota changes.

Methods

BALB/c mice received intraperitoneal 5-FU (30 mg/kg/day) for four consecutive days, followed by oral BE at 0, 50, 100, 200, or 400 mg/kg/day for another four days. Clinical manifestations, colon morphometry, blinded descriptive histopathological assessment, apoptosis- and inflammation-related markers, and gut microbiota were assessed.

Results

BE treatment alleviated body weight loss, diarrhea, and reduced food intake and was associated with improved colon morphometry and less severe histological injury. At 200 mg/kg, BE treatment was associated with lower Tnf and Nos2 mRNA expression, lower Bax and total caspase-3 protein abundance, higher Bcl-2 protein abundance, and lower iNOS protein abundance. Microbiota analysis of the 200 mg/kg group showed treatment-associated differences in microbial diversity and community composition; these findings were considered exploratory because of the small sample size.

Conclusions

BE showed therapeutic potential in 5-FU-induced intestinal mucositis. The molecular and microbiota findings obtained at 200 mg/kg support associations with apoptosis-, inflammation-, and microbiota-related changes but do not establish a definitive mechanism.