Gut microbiome composition and functional potential associate with incident type 2 diabetes in 4,685 adults from a Swedish prospective cohort

Cross-sectional studies link gut microbiome alterations to type 2 diabetes (T2D), but prospective evidence remains limited. We aim to identify taxonomic and functional features associated with future T2D risk. We analyze shotgun metagenomic data from 4,685 participants (mean age, 73.9 years; 49.0% women) in the Swedish SIMPLER cohort, followed for a median 5.3 years, during which 383 developed T2D. Six species are associated with increased T2D risk: Desulfovibrio piger, Alistipes communis, Alistipes finegoldii, Akkermansia muciniphila, Ruminococcus gnavus, and GGB3614_SGB4886 (Lachnospiraceae), while three are protective: Erysipelotrichaceae bacterium, Coprococcus catus, and Clostridia unclassified SGB6317. We observe context-specific associations, including a dietary fiber-modified effect for A. muciniphila indicative of diet-dependent patterns. Three gut metabolic modules are associated with incident T2D: asparagine degradation (higher risk), mannose degradation, and the non-oxidative pentose phosphate pathway (lower risk). These prospective findings offer insights into T2D etiology and may support microbiome-informed strategies for risk prediction and prevention.