Causal Gut Microbiota-Bone Links: Pleiotropic Effects and Stearidonate Mediation

Accumulating evidence implicates gut microbiota play a pivotal role in influencing bone metabolism and contribute to the development of osteoporosis (OP). This study aimed to comprehensively investigate the pleiotropic effects between the gut microbiota taxa and bone density, with consideration of shared genetic factors, causal relationships, and the involvement of blood metabolites stearidonate in this complex interplay. We estimate the polygenic SNP heritability (h ² SNP) for 1104 gut microbiota (GM) taxa GWASs, and identify 97 unique GM taxa with a significant polygenic heritability for further investigation. We identified 14 distinct GM taxa with horizontal pleiotropic effects on heel bone mineral density (eBMD), 11 of them were found to have a causal association with eBMD. GM taxa family Bifidobacteriaceae and its child taxa, genus Bifidobacterium and species Bifidobacterium adolescentis exert causal effects leading to decreased bone mineral density. The mediating effect of these three gut taxa on eBMD was traced back to their influence on blood stearidonate (18:4n3) levels. These findings enhance our understanding of stearidonate's role as a modifiable link in the multifaceted relationship between gut microbiota and bone health.