Causal link between gut microbiota and osteoporosis analyzed via Mendelian randomization.

ABSTRACT

OBJECTIVE: Osteoporosis (OP) is closely associated with gut microbiota (GM), yet the nature of their causal relationship remains elusive. Therefore, this study aims to reverse causality between GM and OP by using population cohorts and two-sample MR (TSMR) analysis. MATERIALS AND METHODS: In this study, we conducted an extensive genome-wide association study (GWAS) using publicly accessible summary statistics data for GM and OP. Employing rigorous criteria (p < 1*e-5), we identified independent genetic loci that exhibited significant associations with GM relative abundances as instrumental variables (IVs). A causal evaluation was primarily carried out using the inverse variance-weighted (IVW) method, supplemented by additional analyses such as MR-Egger, weighted median, simple mode, and weighted mode. RESULTS: We unveiled that increased abundances of the family Pasteurellaceae, order Pasteurellales, and genus Ruminococcaceae UCG004 were linked to an increased risk of OP. Conversely, the family Oxalobacteraceae, unknown family id.1000006161, genus Lachnospiraceae NK4A136 group, unknown genus id.1000006162, and order NB1n were associated with a reduced risk of OP. To ensure the reliability of our findings, we conducted quality assessments through Cochrane's Q test and a leave-one-out analysis. Furthermore, the stability and consistency of the results were confirmed by the MR-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test, and sensitivity analysis (p > 0.05). Our study reveals the causal relationships between 211 GM taxa and OP, pinpointing specific GM taxa associated with the risk of OP. This research sheds light on the genetic mechanisms that underlie GM-mediated OP and opens up promising avenues for identifying valuable biomarkers and potential therapeutic targets in future OP research. CONCLUSIONS: This study establishes a substantial GM-OP link with specific taxa being identified, offering biomarkers for early detection, tailored interventions, and improved patient education. These findings enhance OP diagnosis, prevention, and treatment, promising more effective, individualized care and inspiring future research.