Lower Thyroid Function and Higher Plasma Choline: Effect Modification by Metabolic Dysfunction-Associated Steatotic Liver Disease

Evidence is accumulating that there is a bidirectional relationship between thyroid function and the gut microbiome. We assessed associations of gut microbiome-derived circulating metabolites, choline, trimethylamine N-oxide (TMAO), and betaine with thyroid function status. Among 4771 euthyroid participants of the community-dwelling PREVEND cohort study (thyroid stimulating hormone (TSH), free thyroxine, and free triiodothyronine levels within the reference range; no use of thyroid function altering medication), associations of TSH (higher levels indicating low-normal thyroid function) with choline, TMAO, and betaine (determined by nuclear magnetic resonance spectroscopy) were assessed. Plasma choline varied by TSH category with the highest values observed in the highest TSH quartile (<i>p</i> < 0.001). Such a trend was also found for TMAO (<i>p</i> = 0.10) but not for betaine (<i>p</i> = 0.68). Linear regression analysis showed a positive association of choline with TSH in fully adjusted analysis (std β: 0.04 (95% CI, 0.01; 0.07; <i>p</i> = 0.012)). TMAO was associated with TSH in unadjusted analysis (std β: 0.03 (95% CI, 0.01; 0.06; <i>p</i> = 0.031)), but not in a fully adjusted model (0.03 (95% CI, -0.01; 0.06; <i>p</i> = 0.094)). Betaine was not associated with TSH. The association of choline with TSH was more pronounced in participants with an elevated fatty liver index, a proxy of metabolic dysfunction-associated steatotic liver disease (fully adjusted std β: 0.08; 95% CI, 0.03; 0.13; <i>p</i> = 0.003). Given associations of higher plasma choline and TMAO with cardiovascular disease and mortality, low-normal thyroid function could influence cardiometabolic health via effects on gut microbiome-derived circulating metabolites.