Akkermansia-associated microbial modules and functional metabolic axes link gut microbiome to adiposity across humans and mice

Akkermansia muciniphila has been associated with metabolic health, but whether it reflects an isolated taxonomic marker or a broader functional microbiome state remains unclear. We integrated metagenomic profiles from three human cohorts with mouse multi-omics data to characterize Akkermansia -associated microbial and functional signatures linked to adiposity. In the discovery cohort, A. muciniphila was embedded within a co-occurring microbial module whose score was inversely associated with BMI. Functional profiling identified a reproducible energy/carbon metabolic axis, with additional amino acid–fermentation-related signals. Across two validation cohorts, module- and pathway-level features showed more consistent BMI associations than A. muciniphila abundance alone. In mouse models, high-fat diet reduced A. muciniphila abundance and the module score, whereas ketogenic diet increased A. muciniphila abundance and elevated the energy/carbon axis. Although human-derived module taxa were only partially transferable to mice, the energy/carbon axis showed functional convergence and diet responsiveness. Fecal metabolomics primarily revealed broad diet-associated metabolic remodeling, while microbiome–metabolome correlations provided exploratory links between the energy axis and lipid-related metabolites. Together, these findings support an ecosystem-level interpretation of A. muciniphila as part of a reproducible microbial module and functional metabolic axis that is associated with adiposity and responsive to dietary remodeling.