Impact of Ruminococcus gnavus on lipid metabolism via isoCDCA

The gut microbiota is increasingly recognized as a regulator of host lipid metabolism, yet the specific strains and effector metabolites driving hyperlipidemia remain poorly defined. Here, we identified Ruminococcus gnavus (R. gnavus) as a candidate contributor to cholesterol-related dyslipidemia and delineated its metabolic mechanism. Comparing individuals with high versus normal TC/LDL-C (HTL vs NTL) in both normal-weight and overweight populations, we found that fecal R. gnavus was enriched in HTL individuals regardless of BMI stratum, a finding validated by species-specific qPCR in an independent cohort (n = 488). Administering R. gnavus to mice fed a normal or high-fat diet induced alterations in circulating lipids and liver function markers, accompanied by hepatic steatosis. Hepatic transcriptomics and targeted bile acid profiling converged on bile acid metabolism: R. gnavus downregulated key hepatic genes (Cyp7a1, Cyp8b1, Ldlr, and Ppara) and elevated isochenodeoxycholic acid (isoCDCA) levels both in vivo and in vitro. In vitro, R. gnavus directly converted chenodeoxycholic acid (CDCA) to isoCDCA. Clinically, serum isoCDCA was elevated in HTL individuals in an independent cohort (n = 1,137) and was positively associated with TC, TG, and LDL-C. Functionally, oral isoCDCA supplementation reproduced key lipid disturbances in mice, and isoCDCA downregulated lipid metabolism genes and promoted lipid accumulation in hepatocytes; heterologous expression of R. gnavus hydroxysteroid dehydrogenases conferred isoCDCA-producing capacity on E. coli and elevated circulating TC and LDL-C in colonized mice. These findings nominate isoCDCA as a microbial effector metabolite linking R. gnavus to hepatic lipid dysregulation and identify the R. gnavus–isoCDCA axis as a potential target for the prevention and treatment of hyperlipidemia.