Microbiota-Mediated Conversion of Asiaticoside to Asiatic Acid Restores Intestinal Homeostasis in Mice with Chronic Intestinal Inflammation

Abstract

Asiaticoside, a triterpenoid saponin abundant in Centella asiatica, exhibits notable anti-inflammatory activity but suffers from poor oral bioavailability. Here, we reveal a gut microbiota-dependent mechanism underlying its therapeutic efficacy against chronic intestinal inflammation. Using a DSS-induced mouse model and antibiotic-mediated microbiota depletion, we demonstrate that asiaticoside requires microbial metabolism to alleviate epithelial injury, oxidative stress, and inflammatory cytokine production. HPLC analysis showed that asiaticoside is hydrolyzed by gut microbes into asiatic acid, which accumulates in colonic tissues and suppresses IL-17 signaling, NF-κB, and JAK2/STAT3 activation while restoring Nrf2-mediated antioxidant responses. The released glycosides are further fermented into butyrate and other short-chain fatty acids, supporting colonocyte metabolism and intestinal barrier function. Antibiotic treatment abolishes asiaticoside conversion, SCFA production, and therapeutic efficacy. These findings establish microbial biotransformation as a critical determinant of asiaticoside activity and a key mechanism governing natural glycoside pharmacology.