Large-scale metaproteomics of human gut microbiota reveals microbial functions in metabolic diseases and aging.

Abstract

The protein-level functionalities of the human gut microbiota in large populations, and their associations with host factors, remain unexplored. This study reports a metaproteomic study of 1,967 fecal samples from 1,399 middle-aged and elderly Chinese individuals, identifying microbial functions linked to 44 phenotypes. We uncover aging-associated functional shifts in carbon metabolism and energy production driven by species within the Bacillota, Bacteroidota, Actinomycetota, and Pseudomonadota. Across metabolic diseases, we observe the consistent depletion of Bacillota species and their proteins involved in carbohydrate, energy, amino acid metabolism, and short-chain fatty acid production. We also identify medication-associated features across diabetes, hypertension, and dyslipidemia. Validated in an independent cohort, Megasphaera elsdenii emerged as a hub species in type 2 diabetes. Experimental validation indicates that M. elsdenii is promoted by antidiabetic drugs and may regulate glucose homeostasis through butyrate production. This study provides protein-level evidence of microbial functions in health and disease, highlighting potential therapeutic targets.