Maslinic acid alleviates ulcerative colitis by inhibiting the colitis-aggravating pathogen Clostridium perfringens and modulating gut microbiota
Bailu Geng, Congmin Zhu, Zilu Cui, Yung‐Yi Chen, Qian Zhang, Haiyun Shi, Min Li, Shengtao Zhu, Weizhen Zhang, Mengran Zhao, Shutian Zhang, Junxuan Xu
Abstract
BACKGROUND: Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease, continues to pose therapeutic challenges due to the limitations of conventional drugs and their inability to prevent relapse. Emerging evidence highlights the crucial role of gut microbiota dysbiosis in UC pathogenesis, yet our understanding of specific harmful microbes and their contributions to disease development remains limited. PURPOSE: This study aims to (1) investigate the therapeutic potential of maslinic acid (MA), a food-derived natural compound, in colitis mice models; (2) elucidate the previously underestimated pathogenic role of Clostridium perfringens in UC development; and (3) reveal the molecular mechanisms underlying both C. perfringens pathogenesis and MA-mediated protection. METHODS: We examined the therapeutic effect of MA using DSS-induced colitis model and performing metagenomic sequencing; elucidated the pathogenic role of C. perfringens using GMrepo database, clinical stool samples, and in vivo infection models. Additionally, we revealed its mechanism using inhibitors and markers of various cell death and inflammation pathways. The bactericidal effect of MA on C. perfringens was studied through in vitro experiments and two in vivo colitis models. RESULTS: MA alleviates DSS-induced colitis and restores gut microbiota. C. perfringens is enriched following DSS administration while significantly decreased after treatment with MA. C. perfringens contributes to the development of colitis and induces ZBP1-mediated PANoptosis in intestinal epithelial cells, while stimulates inflammation through NOD2 activation. MA has direct bactericidal activity against C. perfringens through ROS induction. It can almost completely rescue the exacerbation of colitis-related pathological and physiological phenotypes caused by C. perfringens in two mice colitis models. CONCLUSIONS: Our study reveals that MA effectively mitigates DSS-induced colitis by inhibiting the colitis-aggravating pathogen C. perfringens and modulating gut microbiota. Furthermore, it elucidates the previously underestimated role and mechanism of C. perfringens in the development of UC. It also highlights the therapeutic potential of MA in preventing and treating UC, particularly in patients who are C. perfringens positive.