Ligilactobacillus salivarius Li01 enhances gut microbiota-derived indole-3-propionic acid to alleviate 5-fluorouracil-induced diarrhea in mice

Abstract

As a widely applied chemotherapeutic agent, 5-fluorouracil (5-FU) frequently causes significant gastrointestinal side effects, particularly diarrhea, a process in which the gut microbiome serves as a crucial mediator. In this study, we evaluated the effect of oral administration of Ligilactobacillus salivarius Li01 (Li01) on 5-FU-induced intestinal mucositis in mice. We discovered that intake of Li01 was associated with alleviated diarrheal symptoms by mitigating inflammation, reducing oxidative stress, and restoring intestinal barrier function. Moreover, transcriptome analysis revealed that the Th17 signaling pathway was significantly suppressed. We also confirmed the essential contribution of the gut microbiota in mediating these effects, since the protective benefits of Li01 were not observed when the gut microbiota was depleted by antibiotics. Furthermore, administration of Li01 markedly increased the production of indole-3-propionic acid (IPA) by the gut microbiota. This key molecule was shown to contribute to the protection against 5-FU-associated diarrhea by activating the pregnane X receptor (PXR). Additionally, a close correlation was identified between IPA levels and the abundance of two bacterial species that form a mutualistic relationship with strain Li01: Lactobacillus reuteri and Lactobacillus johnsonii. In conclusion, our study demonstrates that Li01 alleviates 5-FU-induced diarrhea and microbiota dysbiosis by enhancing gut microbiota-derived IPA, supporting its potential as a probiotic.