Association of Gut Microbiota-Related Metabolites and Type 2 Diabetes in Two Puerto Rican Cohorts.

(1) Aims: Gut microbiota metabolites may play integral roles in human metabolism and disease progression. However, evidence for associations between metabolites and cardiometabolic risk factors is sparse, especially in high-risk Hispanic populations. We aimed to evaluate the cross-sectional and longitudinal relationships between gut microbiota related metabolites and measures of glycemia, dyslipidemia, adiposity, and incident type 2 diabetes in two Hispanic observational cohorts. (2) Methods: We included data from 670 participants of the Boston Puerto Rican Health Study (BPRHS) and 999 participants of the San Juan Overweight Adult Longitudinal Study (SOALS). Questionnaires and clinical examinations were conducted over 3 years of follow-up for SOALS and 6 years of follow-up for BPRHS. Plasma metabolites, including L-carnitine, betaine, choline, and trimethylamine N -oxide (TMAO), were measured at baseline in both studies. We used multivariable linear models to evaluate the associations between metabolites and cardiometabolic risk factors and multivariable logistic and Poisson regressions to assess associations with prevalent and incident type 2 diabetes, adjusted for potential confounding factors. Cohort-specific analyses were combined using a fixed-effects meta-analysis. (3) Results: Higher plasma betaine was prospectively associated with lower fasting glucose [-0.97 mg/dL (95% CI: -1.59, -0.34), p = 0.002], lower HbA1c [-0.02% (95% CI: -0.04, -0.01), p = 0.01], lower HOMA-IR [-0.14 (95% CI: -0.23, -0.05), p = 0.003], and lower fasting insulin [-0.27 mcU/mL (95% CI: -0.51, -0.03), p = 0.02]. Betaine was also associated with a 22% lower incidence of type 2 diabetes (IRR: 0.78, 95% CI: 0.65, 0.95). L-carnitine was associated with lower fasting glucose [-0.68 mg/dL (95% CI: -1.29, -0.07), p = 0.03] and lower HbA1c at follow-up [-0.03% (95% CI: -0.05, -0.01), p < 0.001], while TMAO was associated with higher fasting glucose [0.83 mg/dL (95% CI: 0.22, 1.44), p = 0.01] and higher triglycerides [3.52 mg/dL (95% CI: 1.83, 5.20), p < 0.0001]. Neither choline nor TMAO were associated with incident type 2 diabetes. (4) Conclusions: Higher plasma betaine showed consistent associations with a lower risk of glycemia, insulinemia, and type 2 diabetes. However, TMAO, a metabolite of betaine, was associated with higher glucose and lipid concentrations. These observations demonstrate the importance of gut microbiota metabolites for human cardiometabolic health.