The role of gut microbiota and plasma metabolites in osteoporosis: Insights from Mendelian randomization analysis

Studies have implicated the gut microbiota as significant in bone condition, influencing osteoporosis through immune modulation, endocrine regulation, and metabolite production. Our study explores the plasma metabolites' mediation effect between gut microbiomes and osteoporosis through Mendelian randomization (MR). Using publicly accessible GWAS data from 5959 individuals for gut microbiota and 8299 individuals for plasma metabolites, we employed MR analysis to explore their causal effects on osteoporosis. Osteoporosis outcome data were obtained from Pan-UKB, GERA, and FinnGen, covering 21,353 cases and 853,313 controls. Mediation effects of identified bacterial taxa on osteoporosis through plasma metabolites were computed using the product-of-coefficients approach. Our MR analysis identified several gut microbiomes and plasma metabolites potentially associated with osteoporosis. Notably, increased abundances of certain gut microbiomes like Desulfobacterota were linked with higher osteoporosis risk. Mediation analysis revealed that specific plasma metabolites like 5alpha-androstan-3alpha,17beta-diol monosulfate (3α-diol MS) levels significantly mediated the effects of these microbiomes on osteoporosis, explaining up to 9.15% of their effect. This study confirms the profound impact of gut microbiota on osteoporosis risk, mediated through specific plasma metabolites. These findings enhance our comprehension of the microbiota-bone health axis and could lead to new biomarkers or therapeutic targets for osteoporosis management, emphasizing the potential for modifying gut microbiota to mitigate disease risk.