The Association between Circulating 25‐Hydroxyvitamin D and Carotid Intima‐Media Thickness Is Mediated by Gut Microbiota and Fecal and Serum Metabolites in Adults

Scope Vitamin D is vital to cardiovascular health. This study examines the association between plasma 25‐hydroxyvitamin D (25[OH]D) and the progression of carotid intima‐media thickness (cIMT) and identifies the potential mediating biomarkers of gut microbiota and metabolites in adults. Methods and Results This 9‐year prospective study includes 2975 subjects with plasma 25(OH)D at baseline and determined cIMT every 3 years. Higher circulating 25(OH)D is associated with decreased odds of higher (≥median) 9‐year cIMT changes at the common carotid artery (hΔCCA‐cIMT) ( p ‐trend < 0.001). Multivariable‐adjusted OR (95%CI) of hΔCCA‐cIMT for tertiles 2 and 3 (vs. 1) of 25(OH)D is 0.87 (0.73–1.04) and 0.68 (0.57–0.82). Gut microbiome and metabolome analysis identify 18 biomarkers significantly associated with both 25(OH)D and hΔCCA‐cIMT, including three microbial genera, seven fecal metabolites, eight serum metabolites, and pathway of synthesis and degradation of ketone bodies. Mediation/path analyses show the scores generated from the overlapped differential gut microbiota, fecal and serum metabolites, and serum acetoacetic acid alone could mediate the beneficial association between 25(OH)D and hΔCCA‐cIMT by 10.8%, 23.1%, 59.2%, and 62.0% (all p < 0.05), respectively. Conclusions These findings show a beneficial association between plasma 25(OH)D and the CCA‐cIMT progression. The identified multi‐omics biomarkers provide novel mechanistic insights for the epidemiological association.