Effect of 1-year lifestyle intervention with energy-reduced Mediterranean diet and physical activity promotion on the gut metabolome and microbiota: a randomized clinical trial

The health benefits of the Mediterranean diet (MedDiet) have been linked to the presence of beneficial gut microbes and related metabolites. However, its impact on the fecal metabolome remains poorly understood. Our goal was to investigate the weight loss effects of a 1-year lifestyle intervention based on an energy-reduced MedDiet coupled with physical activity (intervention group), compared to an ad libitum MedDiet (control group), on fecal metabolites, fecal microbiota, and their potential association with cardiovascular risk factors A total of 400 participants (200 from each study group), aged 55-75 years, and at high cardiovascular risk, were included. Dietary and lifestyle information, anthropometric measurements, blood biochemical parameters, and stool samples were collected at baseline and after 1 year of follow-up. Liquid chromatography-tandem mass spectrometry was used to profile endogenous fecal metabolites, and 16S amplicon sequencing was employed to profile the fecal microbiota. Compared to the control group, the intervention group exhibited greater weight loss and improvement in various cardiovascular risk factors. We identified intervention effects on four stool metabolites and subnetworks primarily composed of bile acids, ceramides, and sphingosines, fatty acids, carnitines, nucleotides, and metabolites of purine and the Krebs cycle. Some of these were associated with changes in several cardiovascular risk factors. Additionally, we observed a reduction in the abundance of the genera Eubacterium Hallii group and Dorea, and an increase in alpha diversity in the intervention group after 1 year of follow-up. Changes in the intervention-related microbiota profiles were also associated with alterations in different fecal metabolite subnetworks and some cardiovascular risk factors. An intervention based on an energy-reduced MedDiet and physical activity promotion, compared with an ad libitum MedDiet, was associated with improvements in cardiometabolic risk factors, potentially through modulation of the fecal microbiota and metabolome. ISRCTN89898870 (https://doi.org/10.1186/ISRCTN89898870)