Causal relationship between Human Gut Microbiome and Bone Mineral Density: A Mendelian Randomization Study

Abstract Various recent studies have shown a link between the gut microbiome and bone mineral density (BMD). Whether the link represents a causative relationship, however, remains unclear. This study aims to thoroughly investigate the causal effects of the gut microbiome on BMD and pinpoint which particular gut microbe taxa have causal effects on BMDs at different specific skeletal sites. Based on summary statistics from genome-wide association studies (GWAS), a two-sample Mendelian randomization (MR) study was carried out to examine the effects of the gut microbiome at five taxonomic ranks (phylum, class, order, family, and genus) on BMDs at five skeletal sites (total body BMD [TB-BMD], femoral neck BMD [FN-BMD], forearm BMD [FA-BMD], heel BMD [H-BMD], lumbar spine BMD [LS-BMD]). After Bonferroni correction, a negative causal effect of the genus Eisenbergiella was shown exclusively on H-BMD (inverse variance weighted (IVW): β = -0.037, 95% confidence interval (CI) = -0.055, -0.018, P = 0.0001). On the contrary, the genus Oscillibacter had a positive causal effect exclusively on H-BMD (IVW: β = 0.029, 95% CI = 0.013, 0.044, P = 0.0003). At other skeletal sites, only nominal causal effects were observed. The reliability of these findings was strengthened by our following several sensitivity studies. A reverse MR analysis was conducted, which showed no reverse causation between H-BMD and the beforementioned two genera, Eisenbergiella and Oscillibacter . These findings show insights into the pathophysiology of low BMD and the association between the gut microbiome and bone health.