Gut-bone Axis Research: Unveiling the Impact of Gut Microbiota on Postmenopausal Osteoporosis and Osteoclasts Through Mendelian Randomization

Background: Postmenopausal osteoporosis is a prevalent disease that affects the bone health of middle-aged and elderly women. The link between gut microbiota and bone health, known as the gut-bone axis, has garnered widespread attention.

Methods: We employed a two-sample Mendelian randomization approach to assess the associations between gut microbiota with osteoclasts and postmenopausal osteoporosis, respectively. Single nucleotide polymorphisms associated with the composition of gut microbiota were used as instrumental variables. By analyzing large-scale multi-ethnic GWAS data from the international MiBioGen consortium, and combining data from the eQTLGen consortium and the GEFOS consortium, we identified microbiota related to osteoclasts and postmenopausal osteoporosis. Key genes were further identified through MAGMA analysis, and validation was performed using single-cell data GSE147287.

Results: The outcomes of this study have uncovered significant associations within the gut microbiome community, particularly with the Burkholderiales order, which correlates with both an increase in osteoclasts and a reduced risk of postmenopausal osteoporosis. with an odds ratio (OR) of 0.400, and a P-value of 0.011. Further analysis using single-cell data allowed us to identify two key genes, FMNL2 and SRBD1, that are closely linked to both osteoclasts and osteoporosis.

Conclusion: This study utilizing Mendelian randomization and single-cell data analysis, provides new evidence of a causal relationship between gut microbiota and osteoclasts, as well as postmenopausal osteoporosis. It was discovered that the specific microbial group, the Burkholderiales order, significantly impacts both osteoporosis and osteoclasts. Additionally, key genes FMNL2 and SRBD1 were identified, offering new therapeutic strategies for the treatment of postmenopausal osteoporosis.