Gut microbial metabolism of bile acids modifies the effect of Mediterranean diet interventions on cardiometabolic risk in a randomized controlled trial

Bile acids (BAs) undergo extensive microbial metabolism in the gut and exert hormone-like functions on physiological processes underlying metabolic risk. However, the extent to which gut BA profiles predict cardiometabolic risk and explain individual responses to dietary interventions in humans is still unclear. In the DIRECT-PLUS Trial, we conducted a multi-omics analysis of 284 participants randomized into three groups: healthy dietary guidelines and two Mediterranean diet (MedDiet) groups. We longitudinally measured 44 fecal BAs using liquid chromatography-mass spectrometry, the gut microbiome through shotgun metagenomic sequencing, and body adiposity and serum lipids at baseline, 6, and 18 months. Fecal levels of 14 BAs, such as lithocholic acid and ursodeoxycholic acid, were prospectively associated with body mass index (BMI) and serum lipid profiles (false discovery rate [<i>q</i>]<0.05). Baseline fecal BA levels significantly modified the beneficial effects of the MedDiet; for example, BMI reduction induced by MedDiet interventions was more pronounced in individuals with lower 12-dehydrocholic acid levels (<i>q</i>-interaction <0.001). We confirmed that the gut microbiome is a major modifier of the secondary BA pool in humans. Furthermore, the association of fecal BAs with body adiposity and serum lipids varied significantly in individuals with different abundances of gut microbes carrying BA metabolism enzymes, e.g. several <i>Ruminococcus</i> spp. In summary, our study identifies novel predictive biomarkers for cardiometabolic risk and offers new mechanistic insights to guide personalized dietary interventions.