Polygenic risk for type 2 diabetes modulates gut microbiome associations across metabolic health traits

In this study, we integrated phenotype data, genotyping, and gut metagenomic data to investigate how genetic predisposition to T2D interacts with the gut microbiome, as well as attenuating lifestyle factors, across metabolic health traits in a cohort of 821 individuals of European ancestry. We evaluated increased BMI and waist circumference, hypertension, and hypercholesterolemia, which are established and interrelated risk factors for type 2 diabetes (T2D). Strongest microbiome differences overall were found in obese and hypertensive phenotypes. Among the most consistent findings was depletion of multiple Prevotella species in metabolically adverse phenotypes and individuals with elevated genetic risk. Microbiome differences in specific phenotypes were generally dependent on the genetic context. Analysis of the genetic risk and lifestyle confirmed that although high T2D PRS is associated with earlier manifestation of hypertension and excess weight, physical activity tends to weaken PRS–phenotype associations and attenuate the inherited susceptibility. Our findings suggest that genetic predisposition modifies microbiome–phenotype relationships in a trait- and context-dependent manner. Genetic risk may increase susceptibility to microbiome alterations, while environmental and lifestyle factors remain major contributors to microbiome variation and the phenotype. Our results underscore the importance of genetic stratification in the microbiome.