A phytotherapeutic agent demonstrates clinical efficacy in amelioration of murine colitis through gut microbiota modulation: mechanistic link to Lactobacillus gasseri-dependent inhibition of ferroptotic pathways

Ulcerative colitis (UC), characterized by chronic intestinal inflammation and epithelial barrier dysfunction, remains a therapeutic challenge due to its complex etiology [1,2]. Among emerging mechanisms, ferroptosis—an iron-dependent form of regulated cell death driven by lipid peroxidation has recently been implicated in UC pathogenesis [3,4]. The gut microbiota plays a crucial role in maintaining intestinal homeostasis, and metabolism can result in pathological damage to the intestines [5, 6]. Metabolites act as important mediators of host-microbe interactions and are essential for the maintenance of the gut barrier [7, 8]. Targeting the microbiota-metabolic axis has emerged as a promising approach for managing UC. It has been demonstrated that QCHS significantly alleviated DSS-induced ferroptosis in the colon of UC mice, and that L. gasseri mediated this protective effect. For the first time, it was found that L. gasseri can act as a ferroptosis inhibitor, mitigating the progression of UC. In vitro, it was further demonstrated that L. gasseri inhibited RSL3-induced ferroptosis in NCM-460 cells, with the mechanism involving activation of the GSH/GPX4 signaling pathway. This work provides compelling evidence for the regulatory role of QCHS on the microbiota-metabolome axis and ferroptosis in UC mice, and uncovering a novel function of L. gasseri as an inhibitor of ferroptosis, offering new insights into potential therapeutic strategies for UC. These findings suggest that through the microbiota modulators or ferroptosis inhibitors targeting Lactobacillus, QCHS may be promising candidates for the treatment of UC.