Gut microbiome associations in male reproductive endocrine-skeletal physiology: a taxonomic-resolution Mendelian...

The gut microbiome is increasingly linked to endocrine physiology, but human evidence that individual microbial traits contribute to male reproductive and skeletal phenotypes remains largely observational. We integrated MiBioGen genus-level and Dutch Microbiome Project species-level microbiome genome-wide association studies with sex-stratified steroid traits, sex hormone-binding globulin (SHBG), and heel estimated bone mineral density (eBMD) in a two-sample Mendelian randomization (MR) screen of 1204 microbe-outcome tests. The leading male endocrine association linked genetically proxied abundance of the MiBioGen-defined Eubacterium rectale group to greater odds of detectable male estradiol (odds ratio = 1.36; 95% CI, 1.12-1.65; P = 0.00246; eight instruments). This binary endpoint denotes assay detectability above 175 pmol/L, not circulating estradiol concentration. Independent GTEx V10/SuSiE fine-mapping of CYP19A1 expression in subcutaneous adipose provided aromatase-relevant tissue context but did not localize or mediate the microbial association. Complementary associations linked Roseburia hominis with SHBG and Alistipes finegoldii with heel eBMD; the latter was the only study-wide Bonferroni-significant result (P = 6.55 × 10^-8). A Bifidobacterium longum-female testosterone association attenuated after exclusion of the LCT/MCM6 region, indicating substantial host-diet genetic influence. Across 172 matched genus-species pairs, effect estimates showed little correlation, directional agreement was no better than chance, and no pair shared clumped instruments. These findings nominate the E. rectale group for targeted male endocrine follow-up and show that taxonomic resolution is part of the exposure definition in microbiome MR.