Systematic Metaproteomics Mapping Reveals Functional and Ecological Landscapes of Human Gut Microbiota Responses to Therapeutic Drugs

Therapeutic compounds significantly alter the composition of the gut microbiota, yet their functional and ecological impacts, particularly at the protein level, remain largely unexplored. In this study, we systematically mapped metaproteomic responses ofex vivohuman gut microbiota to 312 compounds, generating 4.6 million microbial protein responses, available as an interactive resource (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://shiny.imetalab.ca/MPR_Viz/">https://shiny.imetalab.ca/MPR_Viz/</ext-link>). Across protein-level, taxonomic composition-level, and ecosystem-level analyses, we simultaneously identified metaproteomic shifts in 47 compounds, a tri-stability taxonomic landscape, and, using our PhyloFunc beta-diversity metric, three distinct functional community state types with cross-individual ecological consistency. Notably, neuropharmaceuticals triggered profound metaproteomic alterations, marked by a decline in functional redundancy (FR) and an increase in antimicrobial resistance proteins (ARPs), shifting the community to alternative functional state on the functional landscape. We validated that enhancing FR maintained a microbiota’s resilience against neuropharmaceutical-induced ARP increase. These findings establish a novel landscape-based framework for understanding microbiome resilience and advancing targeted therapeutic interventions.