The Linkage Among Gut Microbiota, Inflammatory Cytokines, and Immune Cell Dynamics in Osteoporosis: A Mendelian Randomization Study.

This investigation attempted to discern the causal link of gut microbiota with osteoporosis, examining potential mediating factors, involving inflammatory markers and immune cell activity. Bidirectional two-sample univariable Mendelian randomization (UVMR) was used to decipher the causal link of gut microbiota with osteoporosis, verifying three core assumptions. External datasets were utilized to validate UVMR outcomes and implemented reverse analyses to identify potential reverse causality. Additionally, mediation effects were figured out through UVMR, estimating effect sizes and proportions for every qualifying mediator. It was attempted to precisely select instrumental variables (IVs), ensuring that those influenced by linkage disequilibrium (LD) or demonstrating weak correlations were excluded. The inverse-variance weighted (IVW) analysis unveiled 12 gut microbiota species that were remarkably linked with osteoporosis risk. Specifically, five families, involving Pasteurellaceae, could elevate the risk of osteoporosis, while another five, such as Oxalobacteraceae, were protective. Additionally, two inflammatory markers exhibited a remarkable linkage with osteoporosis following heterogeneity testing, and 37 distinct immune cell types were recognized as being relevant to the disease after adjusting for heterogeneity and pleiotropy. Reverse MR analysis confirmed the absence of reverse causality among gut microbiota, inflammatory factors, immune cells, and osteoporosis. Notably, mediation analysis unveiled that Cyanobacteria influenced HLA DR++ monocytes' percentage in leukocytes, contributing to osteoporosis's pathogenesis. The outcomes highlighted specific gut microbiota, inflammatory factors, and immune cells, noticeably contributing to osteoporosis's pathogenesis. The identified mediating pathways provided innovative insights into disease mechanisms and potential therapeutic targets. Key words Gut Microbiota " Inflammatory cytokines " Immune cell dynamics " Osteoporosis " Mendelian randomization.