Low plasma trimethylamine N-oxide is associated with vitamin D deficiency: toward a U-shaped TMAO–health hypothesis

Abstract Background & aims: Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been studied predominantly in relation to adverse outcomes at high concentrations, whereas the health relevance of low circulating TMAO remains largely unexplored. Because fatty fish provides both preformed TMAO and vitamin D, we postulated that plasma TMAO is positively associated with circulating 25-hydroxyvitamin D [25(OH)D]. Methods: We cross-sectionally analyzed 621 adults undergoing health examinations (median age 52.0 years; 52.7% men), using multivariable linear regression of serum 25(OH)D on plasma TMAO (per 1-SD logTMAO; quartiles), restricted cubic splines for dose–response, and likelihood ratio tests for BMI effect modification. Results: Median TMAO was 170.3 ng/mL (IQR 116.1–247.1); mean 25(OH)D was 22.1 ± 11.7 ng/mL. Adjusted for age, sex, BMI, and season, each 1-SD higher logTMAO was associated with 2.18 ng/mL higher 25(OH)D (95% CI 1.29–3.07), and Q4 vs Q1 differed by 4.56 ng/mL (2.05–7.07; both P < 0.001); across TMAO percentile bands, mean 25(OH)D rose from 20.1 to 29.8 ng/mL and deficiency prevalence fell from 60.3% to 33.9%. The association was nonlinear ( P for nonlinearity = 0.018) and modified by BMI ( P for interaction = 0.018): positive in normal-weight and overweight participants but attenuated, with a reversed point estimate, in obesity. It remained positive after excluding participants with obesity, high-leverage observations, and renal impairment. Conclusions: In Chinese adults, lower plasma TMAO was associated with lower circulating 25(OH)D, with BMI-dependent effect modification. Together with the established harms of high TMAO concentrations, these findings motivate a U-shaped TMAO–health hypothesis that awaits prospective confirmation.