Functionally declining microbiota in chronic disease: beyond taxonomic loss

Microbiota deterioration in modern human populations has been linked to chronic disease, and taxonomic profiling is increasingly used to understand, diagnose, and guide treatment. Yet such profiles do not fully capture disease-relevant microbiota states. I propose functional decline within retained taxa as a distinct axis of microbiota deterioration, complementary to taxonomic loss. Modern environmental pressures can drive not only taxonomic loss but also directional selection toward variants or lineages with reduced host-beneficial function or increased harmful activity. Two mechanistically characterized systems from studies by my group illustrate this process: antibiotic-selected Akkermansia variants with diminished metabolic benefits, and Faecalibacterium pathobionts that promote disease when dominant over beneficial strains, with supporting evidence from atopic dermatitis and pediatric inflammatory bowel disease. Evidence from additional gut taxa suggests that this pattern may extend beyond these two examples. By integrating this hidden axis of functional decline with the well-established axis of taxonomic loss, the proposed two-axis framework could help clarify inconsistent microbiota-disease associations and guide strain-resolved, function-first approaches to microbiota analysis and intervention.