Zhao_2025_Adv.Sci.(Weinh)__e17747

Aspirin provides long-term health benefits but can cause gastrointestinal toxicity, and the role of gut microbiota in aspirin metabolism and enterotoxicity remains unclear. In this study, the contribution and mechanisms of microbiota-aspirin interactions in intestinal injury are investigated. In a mouse model, aspirin-induced enteropathy is found to be more severe in microbiota-replete than in microbiota-depleted mice, implicating a detrimental role of gut microbiota. Co-cultivation experiments revealed that gut microbes facilitated the biotransformation of aspirin into salicylic acid, a metabolite more harmful than aspirin itself in disrupting epithelial cell integrity and renewal, both in vitro and in vivo. Through metagenomic screening, selective bacterial interrogation, and functional validation, Lysinibacillus sphaericus is identified as the culprit bacterium, and its secreted carboxylesterase EstB as the key enzyme catalyzing aspirin hydrolysis to salicylic acid. Importantly, inhibition of microbial EstB with the dietary compound flavanomarein abrogated aspirin biotransformation and prevented intestinal injury. Together, these findings reveal L. sphaericus and EstB as central drivers of aspirin enterotoxicity, highlight the functional importance of gut microbiota in drug metabolism, and suggest microbiota- and metabolite-guided precision prevention strategies.