Erythrocyte very-long chain saturated fatty acids, gut microbiota-bile acid axis and incident coronary heart disease in adults: A prospective cohort study.

ABSTRACT

BACKGROUND: Prior researches have highlighted inverse associations between levels of circulating very-long chain saturated fatty acids (VLCSFAs) and coronary heart disease (CHD). However, the intricate links involving VLCSFAs, gut microbiota, and bile acids remain underexplored. OBJECTIVE: This study examined the association of erythrocyte VLCSFAs with CHD incidence, focusing on the mediating role of gut microbiota and fecal bile acids. METHODS: This 10-year prospective study included 2383 participants without CHD at baseline. Erythrocyte VLCSFAs (arachidic acid [C200], behenic acid [C220], and lignoceric acid [C240]) were measured using gas chromatography at baseline and 274 CHD incidents were documented in triennial follow-ups. Gut microbiota in 1744 participants and fecal bile acid metabolites in 945 participants were analyzed using 16S rRNA sequencing and UPLC-MS/MS at middle-term. RESULTS: The multivariable-adjusted HRs (95%CI) for CHD incidence in highest vs. lowest quartiles were 0.87 (0.61, 1.25) for C200, 0.63 (0.42,0.96) for C220, 0.59 (0.41,0.85) for C240, and 0.57 (0.39, 0.83) for total VLCSFAs. Participants with higher total VLCSFA levels exhibited increased abundances of Holdemanella, Coriobacteriales Incertae Sedis spp., Ruminococcaceae UCG-005 and UCG-010, and Lachnospiraceae ND3007 group. These five genera generated microbial score (ODMS) that accounted for 11.52% of the total VLCSFAs-CHD association (Pmediation =0.018). Bile acids tauro_α_ and tauro_ß_muricholic acid (T_α_ and T_ß_MCA) were inversely associated with ODMS and positively associated with incident CHD. Opposite associations were found for glycolithocholic acid (GLCA), glycodeoxycholic acid (GDCA). Mediation analyses indicated that GLCA, GDCA, and T_α_ and T_ß_MCA explained 56.40%, 35.19%, and 26.17% of the ODMS-CHD association, respectively (Pmediation =0.002, 0.008, and 0.020). CONCLUSIONS: Elevated erythrocyte VLCSFAs are inversely associated with CHD risk in the Chinese population, with gut microbiota and fecal bile acid profiles potentially mediating this association. The identified microbiota and bile acid metabolites may serve as potential intervention targets in future studies. CLINICAL TRIAL REGISTRY NUMBER NCT03179657.