Guild-based microbial network links gut microbiota, serum metabolites, and bone mineral density

Although associations between the gut microbiota and bone mineral density (BMD) are increasingly recognized, existing evidence largely relies on taxonomic rather than ecological perspectives. How microbial communities function as integrated systems to influence BMD, and the role of serum metabolites, remain unclear. This study integrates gut metagenomic, serum metabolomic, and BMD data from 577 participants in the Taizhou Imaging Study. Employing a guild-based framework, we clustered gut microbiota into putative ecological units (guilds), identified BMD-associated guilds and serum metabolites, and explored mediating effects. Gut microbial diversity did not differ significantly among BMD groups, whereas co-occurrence networks showed different topological patterns: the osteoporotic network exhibited higher connectivity yet lower modularity, suggesting a less organized state. Guild-based analysis identified three candidate BMD-related guilds, and 15 serum metabolites, including amino acids and lipoprotein subfractions, were associated with BMD. Mediation analysis observed a statistical suppression effect in females, where very-low-density lipoprotein-1 triglycerides attenuated the observed positive correlation between a key guild (Guild_17) and its constituent species UBA11524_sp000437595 and BMD (Prop. mediated: − 25.48% and −30.39% at guild and species level). Our findings suggest that BMD is associated with altered gut microbial networks and lipoprotein profiles, providing observational evidence that may inform understanding of osteoporosis.