Multi-omics reveal mechanisms of <em>L. bacterium</em> mediated intestinal protective effect of paeoniflorin in diarrhea-predominant irritable bowel syndrome

Irritable bowel syndrome (IBS), a functional gastrointestinal disorder characterized by impaired digestive function, predominantly presents as the diarrhea-predominant subtype (IBS-D). Current therapeutic strategies for IBS-D primarily aim to restore intestinal barrier integrity and regulate secretory homeostasis. However, progress in therapeutic development has been limited by an incomplete understanding of the microbial sensing mechanisms that govern intestinal barrier dynamics. This study investigates the therapeutic efficacy of paeoniflorin (PF) in IBS-D treatment and elucidates its underlying mechanisms. Through comprehensive preclinical evaluation, PF administration significantly ameliorated diarrheal symptoms and psychiatric comorbidities in IBS-D rats, concomitant with structural restoration of intestinal villi and functional recovery of secretory regulation. Mechanistically, PF exerted its therapeutic effects through gut microbiota-dependent attenuation of sIgA hypersecretion. Notably, fecal microbiota transplantation and depletion experiments revealed that PF-mediated intestinal barrier repair and secretory normalization were operated through <em>s_Lachnospiraceae_bacterium</em> (<em>L. bacterium</em>) modulation. Functional characterization demonstrated that <em>L. bacterium</em> alleviated IBS-D pathophysiology by enhancing tight junction assembly and facilitating mucin maturation. Furthermore, mechanistic analysis identified FoxO3a signaling as a pivotal mediator of the intestinal protection conferred by<em> L. bacterium</em>. Collectively, this study not only establishes PF as a promising therapeutic candidate but also uncovers novel microbial-epithelial crosstalk mechanisms, highlighting the translational potential of probiotic-based interventions and bioactive compounds for intestinal disorders. These findings provide clinically relevant insights for the development of targeted therapeutics for IBS-D.