A Cross-Cohort Multi-Omics Study of Diet, Gut Microbiome, and Metabolomics in Type 2 Diabetes

The gut microbiome, interacting with dietary intake, modulates host metabolism and contributes to the pathogenesis of type 2 diabetes (T2D). Yet, large-scale multi-omics studies to examine these complex interactions are limited. Applying a validated data harmonization pipeline, we conducted a comprehensive study that integrates data on long-term habitual diet, gut microbiome, and circulating metabolomes from six studies of 4,929 participants with T2D, prediabetes, and normoglycemic status in the US, Europe, and Israel. Our analysis identified diet- and host-derived metabolites (e.g., quinate) and microbial-host co-metabolites (e.g., cinnamoylglycine and indole propionate) associated with T2D, independent of major risk factors. We also identified interactions between microbe and metabolite implicated in T2D risk. In addition, the inter-individual difference in the association of species (such as Roseburia inulinivorans) with T2D risk could potentially be explained by the strain-specific processing of metabolite implicated in the pathogenesis of T2D. Our study offers robust insights into the intricate interplay of diet, gut microbes, and their metabolites underlying the development of T2D in diverse populations.