A function-guided multi-omics integrated strategy to reveal the effective chemicalome and mechanisms of the 50% ethanol extract of Eucommia ulmoides leaf in alleviating osteoarthritis.
Abstract
Conventional multi-omics integration in herbal medicine research relies mainly on statistical correlations and pathway analyses, potentially overlooking key bioactive metabolites and their associated enzyme targets. To address this, we developed an enzyme function-guided strategy integrating chemomics, metabolomics, and microbiomics to reveal the potential mechanism of the 50% ethanol extract of Eucommia ulmoides leaf (EEUL) against osteoarthritis (OA). The anti-inflammatory, cartilage-repairing, and analgesic effects of EEUL were confirmed in zebrafish phenotypic screening models and in the mouse OA model induced by the high-cholesterol diet (HCD) combined with anterior cruciate ligament transection (ACLT). Integrated metabolomic and microbiomic analyses further showed that OA-associated metabolic dysregulation and gut microbial dysbiosis were significantly reversed by EEUL. Remarkably, gut microbiota-derived bile salt hydrolase (BSH) was prioritized by enzyme function-guided analysis as a functional bridge linking the EEUL chemicalome to the altered metabolome. Meanwhile, the bioactive chemical constituents of EEUL, such as quercetin and kaempferol, exhibited high binding affinity to BSH. Consistently, BSH activity was reduced and the bile acid pool was modified by EEUL, accompanied by decreased intestinal farnesoid X receptor (FXR) expression, increased circulating glucagon-like peptide-1 (GLP-1) levels, and upregulated articular GLP-1 receptor (GLP-1R) expression. Collectively, these findings suggest that the ameliorative effect of EEUL on osteoarthritis may be mediated via the putative gut FXR-joint GLP-1R axis. By establishing enzyme-level functional connections among multi-omics, this study provides a novel framework for elucidating the mechanisms of herbal medicine and explores a promising strategy for developing long-term and safe OA interventions.
Abstract as supplied by the indexing source. © the authors / publisher.