Abstract
OBJECTIVES: Limited evidence exists on the association between dietary phytosterol intake and the risk of type 2 diabetes (T2D). We aimed to investigate this association and identify the underlying plasma metabolic, metabolomic, and gut microbial features. METHODS: We followed 204,633 participants (79% women) from three large US prospective cohorts for up to 36 years. Validated food-frequency questionnaires were used to estimate dietary intake of total phytosterol and three subtypes: β-sitosterol, campesterol, and stigmasterol. We applied Cox proportional hazards models to evaluate their associations with T2D risk. In a subset of 39,879 participants with plasma metabolic biomarkers and 9,528 participants with plasma metabolomics data, we examined the association between phytosterol intake and metabolic biomarkers related to insulinemia, glycemia, lipids, and inflammation, as well as T2D-related metabolomic profiles. Additionally, we explored the gut microbial species and enzymes involved in these associations in a subset of 465 participants with gut microbiome data. RESULTS: During follow-up, we documented 20,708 incident T2D cases. After adjustment for covariates, higher intake of total phytosterol was associated with a lower T2D risk (HR comparing extreme quintiles = 0.87, 95% CI: 0.82, 0.92; P trend<0.001). Similar associations were observed for β-sitosterol (HR=0.86, 95% CI: 0.81, 0.91; P trend<0.001) and campestrol (HR=0.89, 95% CI: 0.84, 0.94; P trend<0.001), but not for stigmasterol.β-sitosterol and campestrol were also associated with favorable plasma metabolic profiles, such as lower levels of C-reactive protein, leptin, and C-peptide, as well as beneficial T2D-relevant metabolomic profiles. Moreover, we identified several gut microbial species, and their enzymes involved in these associations. For example, Faecalibacterium prausnitzii and its β-sitosterol-degrading enzyme 3-oxosteroid 1-dehydrogenase (EC1.3.99.4) were associated with higher β-sitosterol intake and a metabolomic profile indicative of lower T2D risk. CONCLUSIONS: A higher intake of phytosterols, particularly β-sitosterol and campesterol, was associated with a lower risk of T2D, with consistent findings across epidemiological and multi-omics analyses. These findings support the role of a healthy plant-based dietary pattern rich in phytosterol-containing foods such as whole grains, nuts, seeds, fruits, vegetables, and vegetable oils in lowering T2D risk.