Bairui granules attenuate ulcerative colitis via microbial-metabolite crosstalk and Isorhamnetin-3-O-glucoside-mediated JAK2/STAT3 suppression.

BACKGROUD: Bairui Granules (BRKL), a standardized botanical drug derived from Thesium chinense Turcz., has been clinically used for respiratory infections. However, its potential in ulcerative colitis (UC) and underlying mechanisms remain unexplored. This study elucidated the therapeutic effects and mechanisms of BRKL against UC through integrated phytochemistry, multi-omics, and pharmacological approaches.

METHODS

We investigated the protective effects of BRKL on DSS-induced colitis in mice. Pathological characteristics and oxidative stress of the distal colon were assessed. The impact of BRKL on gut microbiota was analyzed using 16S rRNA sequencing, while metabolomics explored changes in small molecular metabolites. UPLC-QE-MS validated BRKL's prototype compounds in the bloodstream, and network pharmacology predicted its targets and pathways. Molecular docking/dynamics validated target engaagement, followed by experimental validation in vitro and in vivo.

RESULTS

BRKL significantly alleviated colitis symptoms, restored gut barrier integrity, and reduced oxidative stress. It reshaped gut microbiota composition (Akkermansia, Lachnospiraceae; Escherichia-Shigella) and modulated 22 colon metabolites linked to histidine and JAK-STAT pathways. Network pharmacology identified JAK2 as a core target, corroborated by molecular dynamics showing stable binding of BRKL-derived Withalongolide L to JAK2. BRKL and its active component Isorhamnetin-3-O-glucoside (0.1 mg/g crude drug) suppressed IL-6/JAK2/STAT3 phosphorylation, reduced apoptosis, and inhibited pro-inflammatory cytokines . Structural analysis confirmed Isorhamnetin-3-O-glucoside as a novel JAK2 inhibitor scaffold (Tanimoto index <0.3 vs. clinical inhibitors).

CONCLUSION

BRKL ameliorates UC by synchronously modulating gut microbiota-metabolite interactions and blocking the JAK2/STAT3 pathway. Isorhamnetin-3-O-glucoside are identified as key bioactive compounds, positioning BRKL as a promising phytotherapeutic for inflammatory bowel disease.