Abstract
Comparative analyses of the human microbiome have identified both taxonomic and functional shifts that are associated with numerous diseases. To date, however, microbiome taxonomy and function have mostly been studied independently and the taxonomic drivers of functional imbalances have not been systematically identified. Here, we present FishTaco, an analytical and computational framework that integrates taxonomic and functional comparative analyses to accurately quantify taxon-level contributions to disease-associated functional shifts. Applying FishTaco to several large-scale metagenomic cohorts, we show that shifts in the microbiome's functional capacity can be traced back to specific taxa. Furthermore, the set of taxa driving functional shifts and their contribution levels vary markedly between functions. We additionally find that similar functional imbalances in different diseases are driven by both disease-specific and shared taxa. Such integrated analysis of microbiome ecological and functional dynamics can inform future microbiome-based therapy, pinpointing putative intervention targets for manipulating the microbiome's functional capacity.