Yiyi Fuzi Baijiang formula protects against DSS-induced colitis by orchestrating the gut barrier-microbiota-metabolism axis

BACKGROUND: Inflammatory bowel disease (IBD) is a relapsing inflammatory disorder of the gastrointestinal tract with increasing global incidence. Current therapies are often limited by side effects, loss of efficacy, and high cost, underscoring the need for safer and more effective alternatives, particularly multi-target agents derived from natural products. PURPOSE: This study aimed to elucidate the protective mechanisms of Yiyi Fuzi Baijiang formula (YFB), a traditional Chinese medicine (TCM) formulation, against dextran sulfate sodium (DSS)-induced acute colitis, focusing on its systemic regulation of the gut barrier-microbiota-metabolism axis. METHODS: We employed an integrated approach combining network pharmacology, UPLC-Q-TOF-MS/MS-based phytochemical analysis, in vivo evaluation in a DSS-induced colitis mouse model, 16S rRNA gene sequencing, and untargeted metabolomics to assess the effects of YFB and uncover its mechanisms of action. RESULTS: Network pharmacology predicted, and experiments confirmed, that core YFB components (e.g., quercetin, kaempferol) act via IL-17, TNF, and NF-κB pathways. YFB administration dose-dependently improved disease activity index, colon shortening, and histopathology in colitis mice. It restored intestinal barrier integrity by upregulating ZO-1, Occludin, and MUC2, while suppressing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-17A) and NF-κB activation. Critically, YFB promoted epithelial repair by restoring the expression of intestinal stem cell marker LGR5 and progenitor cell marker SOX9, and by normalizing the aberrant increase in endocrine cell marker CHGA. YFB treatment was associated with reversal of DSS-induced gut microbiota dysbiosis, restoration of diversity, enrichment of beneficial bacteria (e.g., Lachnospiraceae), and suppression of opportunistic pathogens (e.g., Enterobacteriaceae). Untargeted metabolomics showed that YFB treatment was associated with modulation of DSS-altered fecal metabolites (e.g., fatty acids, bile acids) and pathways such as "microbial metabolism in diverse environments". CONCLUSION: YFB, when administered concomitantly with DSS, protects against DSS-induced colitis via the synergistic effects of its multi-component system. Its mechanism entails systemic regulation of the gut barrier-microbiota-metabolism axis, involving suppression of NF-κB-driven inflammation, promotion of intestinal epithelial repair (via LGR5/SOX9/CHGA modulation), restoration of the intestinal barrier, alterations in gut microbiota, and modulation of host-microbial co-metabolism. These findings provide a scientific basis for YFB's clinical application and highlight the value of TCM formulations in managing complex multi-factorial diseases.