Bidirectional Association of Gut Microbiota-Derived Trimethylamine N-Oxide and its Precursors with Estimated Glomerular Filtration Rate: A Cross-Lagged Cohort Study

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BACKGROUND: It is unclear whether trimethylamine N-oxide (TMAO) and its precursors are bidirectionally associated with kidney dysfunction. OBJECTIVES: This study aims to investigate whether increased TMAO and its precursors are linked to decreased estimated glomerular filtration rate (eGFR) and whether reduced eGFR is associated with elevated TMAO and its precursors. METHODS: Our study consists of participants with creatinine, TMAO, and its precursors (choline, carnitine, and betaine) repeatedly measured from the Fuxin rural cohort. We utilized cross-lagged panel models to assess the potential bidirectional associations of TMAO and its precursors with eGFR. Age (≥60 and <60 y) and sex-specified associations and interaction effects were examined using multi-group cross-lagged panel models. The Bonferroni method was applied for multiple comparisons. RESULTS: Of 1746 participants [mean age 59.4 ± 9.3 y, 584 (33%) male], TMAO was inversely related to eGFR after 2 years [cross-lagged coefficient, 95% confidence interval: -0.030, -0.058, -0.002, P = 0.035], and eGFR was negatively associated with carnitine after 2 years (-0.138, -0.198, -0.078, P < 0.001). Subgroup analysis showed significant associations between baseline TMAO and eGFR after 2 years in individuals aged 60 and older (-0.061, -0.107, -0.014, P = 0.011) and between baseline eGFR and carnitine after 2 years in individuals aged 60 and older (-0.093, -0.164, -0.022, P = 0.010), in those under 60 (-0.153, -0.226, -0.079, P < 0.001), and in females (-0.154, -0.229, -0.079, P < 0.001). Additionally, baseline eGFR is nominally associated with choline after 2 years in those aged under 60 (0.092, 0.017, 0.167, P = 0.017) and in males (0.114, 0.015, 0.213, P = 0.025). CONCLUSIONS: Deceased eGFR is related to elevated serum carnitine concentrations and may be linked to choline. Conversely, elevated TMAO may be linked to reduced kidney function. This provides novel evidence that managing healthy kidney function helps keep TMAO and its precursors at optimal levels, whereas maintaining low TMAO concentrations reduces risk of kidney disease.

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