The gut microbiota-bile acid axis mediates the beneficial associations between plasma vitamin D and metabolic syndrome in Chinese adults: A prospective study

Background & aims: Previous studies have suggested that circulating 25-hydroxyvitamin D (25 [OH]D, VD) and the gut microbiota-bile acid axis play crucial roles in metabolic health. Exploring the mediating role of the gut microbiota-bile acid axis would improve our understanding of the mechanisms underlying the effects of VD on human metabolic health. This study examined the association between plasma 25(OH)D and the prevalence/incidence of metabolic syndrome (MetS) and the mediating role of the gut microbiota-bile acid axis.Methods: This prospective study included 3180 participants with plasma 25(OH)D data at baseline and 2966 participants with a 9-year follow-up. MetS was determined every three years. The gut microbiota was analyzed by 16S rRNA sequencing in 1752 participants, and targeted bile acid metabolites in feces were further determined in 974 participants using UPLC-MS/MS at the middle of the study. Mediating roles of microbiota and bile acids in the VD-Met S associations were analyzed using mediation/path analyses adjusted for potential confounders.Results: Among the 2966 participants who were followed-up, 1520, 193, 647, and 606 were Met S-free (normal), recovered, had incident MetS, and had persistent MetS, respectively. The multivariableadjusted ORs (95% CIs) of MetS prevalence were 0.65 (0.50, 0.84) for baseline MetS and 0.46 (0.33, 0.65) for 9-year persistent MetS in quartile 4 (compared to quartile 1) of plasma 25(OH)D (median: 37.7 vs. 19.6, ng/ml). The corresponding HR (95% CI) of 9-year MetS incidence was 0.71 (0.56, 0.90) (all P-trend < 0.05). Higher VD concentrations were associated with greater a-diversity of the gut microbiota, which was inversely correlated with MetS risk. The groups classified by VD and MetS status had significantly different b-diversity. Ruminiclostridium-6 and Christensenellaceae R-7 group were enriched in the high-VD group and were inversely associated with MetS. However, opposite associations were observed for Lachnoclostridium and Acidaminococcus. The overlapping differential microbial score (ODMS) developed from the four differential genera explained 12.2% of the VD-MetS associations (Pmediation = 0.015). Furthermore, the fecal bile acid score created from 11 differential bile acids related to ODMS and MetS mediated 34.2% of the association between ODMS and MetS (Pmediation = 0.029). Path analyses showed that the inverse association between plasma 25(OH)D and MetS could be mediated by the gut microbiota-bile acid axis.