Genetically informed causal links between gut microbiota and bone mass: pleiotropy and metabolic mediation.

The interplay among host genetic architecture, gut microbiota, metabolites and bone metabolism remains poorly understood. This study aims to comprehensively investigate the shared genetic factors, causal relationships, and the involvement of blood metabolites between gut microbiota and bone mass, based on datasets from European populations. Here, we estimate the polygenic SNP heritability for 1104 gut microbiota taxa, only 96 (8.7%) showed significant polygenic heritability. We identify 14 distinct gut microbiota taxa with pleiotropic effects on estimated heel bone mineral density (eBMD), 11 of them are found to have a causal association with eBMD. Following sensitivity and validation analyses, we find that the gut microbiota taxa family Bifidobacteriaceae; genus Bifidobacterium and species Bifidobacterium adolescentis exert causal effects leading to decreased eBMD. Mediation analyses indicate that the impact of these taxa on eBMD may be driven by their influence on circulating stearidonate (18:4n-3) levels via n-3 pathway, with mediating proportion from 77.53% to 87.24%. In conclusion, the genetically informed negative association between bifidobacterial taxa and bone mass may reflect the host-microbe interactions at LCT/MCM6 locus and represent an adaptive microbial response to lactose intolerance, thus, it could potentially be mitigated through supplementation with bifidobacterial probiotics and n-3 polyunsaturated fatty acids.