Population-based metaproteomics reveals functional associations between gut microbiota and phenotypes

The association of the gut microbial community with various physiological disorders underscores the significance of understanding its biological functions, which have yet to be fully explored. In this study, we characterized 86,876 microbial proteins and 1,277 human proteins in 1,967 Chinese stool specimens of GNHS cohort. Our findings demonstrate that, compared to metagenomic data, metaproteomic data can effectively capture the microbial biodiversity of an entire population using about 500 individuals. Additionally, it reveals greater inter-individual variability in microbial functions and serves as a more reliable indicator for assessing the temporal stability of the microbiota. We delineated the highly expressed functions of microbes among population and identified the core microbes across individuals that are likely to contribute to SCFA and vitamin B production. Moreover, our analysis discovered 10,714 associations between metaproteomic taxon, microbial function, or human proteins with 39 phenotypes, uncovering 1,381 microbial taxa, functions, and host proteins that related to Type 2 Diabetes (T2D). Among them, five features exhibited consistent and significant associations with T2D in both the GNHS cohort and an independent cohort. Finally, we demonstrated that Megasphaera elsdenii could mitigate elevated blood glucose levels in the host by metabolizing lactate to produce butyric acid, suggesting a protective mechanism against T2D. Our study underscores the power of population-based metaproteomics to offer unique functional insights into the gut microbiota.