Microbial Influences on Calcium‐Phosphorus Homeostasis and Metabolic Bone Diseases: A Bidirectional Mendelian Randomisation Study on the Gut–Bone Axis

Observational studies have shown that the gut microbiota (GM) is associated with bone diseases, particularly calcium-phosphorus metabolic bone diseases, demonstrating the existence of a gut-bone axis. However, whether these associations are causal effects remains to be determined. This study employed bidirectional two-sample Mendelian randomisation (MR) using summary data from Genome-Wide Association Studies (GWAS) of 211 gut microbial taxa and six metabolic bone diseases (osteoporosis, Osteopenia, osteonecrosis, osteomyelitis, hypoparathyroidism and hyperparathyroidism) to explore causal relationships and their directionality. Comprehensive sensitivity analyses were conducted to ensure the robustness of the results, and a false discovery rate-corrected p_FDR of < 0.05 was used as a threshold to support strong associations. Additionally, co-localisation analysis was conducted to consolidate the findings. We identified 35 causal relationships between GM and metabolic bone diseases, with 17 exhibiting positive and 18 negative correlations. Furthermore, reverse MR analysis indicated that osteomyelitis was associated with elevated abundance of two GMs (p_FDR < 0.05, PP.H4 < 75%). No evidence of horizontal pleiotropy or heterogeneity was observed, and co-localisation analysis further strengthened the evidence for these causal relationships. The study underscores the critical role of GM in influencing bone health through the gut-bone axis, paving the way for future therapeutic interventions targeting the gut-bone axis and offering new directions for research in bone metabolism and diseases.