The sex-related differences in gut microbiota characteristics and keystone species identification of lipid metabolism in dyslipidemia

Background Dyslipidemia exhibits pronounced sex-related differences, yet the integrated interactions among gut microbiota, host metabolism, and immune responses underlying these sex-related differences remain poorly understood. Methods We investigated sex-related alterations in gut microbiota composition, lipid metabolism, and inflammatory responses by integrating the re-analysis of a clinical cohort and mouse model in dyslipidemia, alongside isolation and identification of a keystone probiotic strain. Results High-fat diet (HFD) induced comparable hepatic steatosis and inflammation in both sexes. However, male mice exhibited earlier body weight gain and impaired intestinal barrier integrity (downregulated ZO-1/Occludin). Metabolomics analysis revealed distinct sex-related bile acid metabolic signatures, with females showing increased levels of several bile acids and enrichment of ascorbate and aldarate metabolism, while males exhibited reduced primary bile acids together with enrichment of bile acid biosynthesis and secretion pathways. Depletion of L. johnsonii observed in both clinical cohort and HFD mice was correlated with keystone taxa ( Lactobacillus ) and with lipid, inflammation, and bile acid markers. Moreover, the isolated L. johnsonii DM2420 strain exhibited cholesterol-lowering activity and BSH activity, harbored multiple genes associated with stress adaptation, and its supernatant metabolomics indicated bile acid remodeling in vitro . Conclusion Collectively, male mice exhibited greater susceptibility than females to HFD-induced dyslipidemia, which may be associated with the depletion of the candidate keystone taxon L. johnsonii in males and with related bile acid metabolic reprogramming. The isolated strain of L. johnsonii DM2420 exhibited a multifunctional profile that underscores its probiotic potential. Our findings preliminarily suggest a potential association between gut microbiota, bile acids, and immune responses in dyslipidemia and highlight the potential of keystone species-based precision strategies for sex-informed interventions.