Mediterranean diet and exercise reshape gut microbiome, aiding weight loss

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In a recent study published in The American Journal of Clinical Nutrition, researchers investigate the health benefits of the Mediterranean diet (MedDiet) and physical activity interventions on overweight and obese participants by measuring changes in fecal metabolomic- and gut microbiota.

Study: 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. Image Credit: Valentyn Volkov / Shutterstock.comStudy: 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. Image Credit: Valentyn Volkov /

Health benefits of the MedDiet

Characterized by a high intake of healthy vegetables, legumes, fruits, whole cereals, and nuts, moderate intake of seafood, low intake of dairy products and processed meats, as well as olive oil comprising the primary fat source, the traditional MedDiet has been growing in global popularity.

Previous studies have investigated the health benefits of the MedDiet, which include significant cardiovascular disease (CVD), obesity, neurological, and all-cause mortality risk reductions as compared to suboptimal dietary patterns like the Western diet.

The high concentrations of dietary fiber and anti-inflammatory nutraceuticals in the MedDiet have also been associated with promoting and persisting beneficial gut microbiota. To date, the metabolomic consequences of these associations remain unknown.

Exploring the blood metabolome provides important insights into how gut microbiota-derived metabolites correlate with cardiometabolic diseases. Through the use of plasma metabolomics and 16S sequencing, researchers can elucidate how diet, circulating metabolites, and gut microbiota impact cardiovascular health.

Understanding the influence of dietary interventions on both gut microbial composition and metabolomic profiles can support clinical recommendations to follow the MedDiet and other healthy diets, particularly in high-risk patients. Furthermore, these data can provide foundational insights for future studies investigating the indirect effects of diet on other non-cardiovascular somatic systems.

About the study

In the present study, researchers used data from the PREvención con DIeta MEDiterránea (PREDIMED)-Plus randomized trial to investigate the effects of one year of intensive lifestyle intervention on fecal metabolites, gut microbiota, and cardiovascular risk factors, particularly in overweight and obese patients. The study comprised 400 individuals between the ages of 55 and 75 years from Alicante, Barcelona, Reus, and Valencia who were randomly divided between the intervention group (IG) and control group (CG).

Data collection included dietary and lifestyle information obtained through the er-MedDiet questionnaire, a 17-item derivation of the 14-item Mediterranean Diet Adherence Screener (MEDAS) questionnaire. Blood and stool samples were also collected during baseline assessments and routine follow-up. Anthropometric measurements and demographic data were further obtained from medical and government records.

The researchers encouraged all study participants to increase their usual physical activity levels to include at least 45 minutes daily of brisk walking or an equivalent activity. All study participants were also encouraged to perform specific exercises that increase their balance, strength, and flexibility to ultimately complete 150 minutes or more of moderate-to-vigorous physical activity each week.

Changes in physical activity levels were quantified using questionnaires that assigned the metabolic equivalent of tasks (MET) min/week metrics to physical activity status and MET h/day for sedentary behaviors. The study intervention included lifestyle recommendations for physical activity and diet and in-person behavioral support from a licensed dietitian for the IG group. In contrast, CG was treated ad libitum with a regular MedDiet, which was the only intervention.

Outcomes of interest were measured using liquid chromatography-tandem mass spectrometry (LC-MS) for metabolomics identification, characterization, and quantification and 16S amplicon sequencing for gut microbiome evaluations. Linear regression models and weighted gene co-expression network analysis (WGCNA) were used to identify between-group differences and metabolomic sub-networks, respectively.

Study findings

The present study highlights the combined health benefits of a dietitian-guided MedDiet alongside physical activity compared to an ad libitum MedDiet.

Overweight and obese participants in the IG cohort exhibited a mean weight reduction of 4.2 kg and 4.4 cm lower waist circumference than their CG counterparts. The body mass index (BMI) and total energy intake estimates of the IG group were 1.5 kg/m2 and 113.9 kcal lower than controls, thus explaining the 0.1% observed reductions in glycated hemoglobin values as compared to controls.

Fecal metabolomic analysis revealed a total of 532 fecal metabolites, four of which were significantly different between IG and CG following one year. These four metabolites included 4,7,10,13,16-docosapentaenoic acid (DPA) and adrenic acid, both of which decreased following the intervention, as well as oleic acid and 3-methyl-adipic acid (3-MAA), both of which increased following intervention. While preliminary analyses suggested an additional 56 metabolites of interest, these were non-significant following false discovery rate (FDR) corrections.

Network analyses grouped the 532 identified metabolites into 16 subnetworks ranging in size from Grey60 to brown. The Black, Midnight Blue, Pink, and Salmon subnetworks significantly differed between IG and CG cohorts following one year of the study.

The Black subnetwork comprised ceramides and spingosines, whereas the Midnight blue subnetwork consists of purines. The Pink subnetwork metabolites included fatty acids and carnitines, whereas the Salmon network comprised bile acids.

Compared to the CG, the IG exhibited reduced levels of the Black, Midnight Blue, and Pink subnetworks. Comparatively, the IG exhibited increased levels of the Salmon subnetwork compared to the CG.  

Gut microbial analysis determined that IG Shannon and Chao1 alpha diversity indices were significantly higher than CG indices by the end of the study, with the top two axes of the principal coordinate analysis (PCoA) explaining 36% of the observed differences. 

The Eubacterium hallii group exhibited a significant reduction in population size in the IG compared to the CG. A reduced abundance of Dorea was also observed but to a lesser extent than in the Eubacterium hallii group.


The present lifestyle intervention-based clinical trial highlights the benefits of stringent dietary supervision and physical activity engagement for at-risk overweight and obese individuals, even when compared to equal-risk subjects consuming a similarly healthy diet. The energy-reduced MedDiet and physical activity intervention in the IG, when compared with an ad libitum MedDiet for the CG, significantly reduced weight metrics, including waist circumference and BMI.

Even with similar healthy dietary patterns, the high intensity of the dietary intervention and weight-loss intervention components, such as caloric restriction and physical activity, could have significant benefits on CVD risk factors, potentially through modulation of the fecal microbiota and metabolome. Public health policies and interventions can be tailored to individual microbiome profiles, allowing for more precise and effective strategies for preventing and managing cardiometabolic diseases.”

Journal reference:
  • García-Gavilán, J. F., Atzeni, A., Babio, N., et al. (2024). 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 American Journal of Clinical Nutrition. doi:10.1016/j.ajcnut.2024.02.021
Hugo Francisco de Souza

Written by

Hugo Francisco de Souza

Hugo Francisco de Souza is a scientific writer based in Bangalore, Karnataka, India. His academic passions lie in biogeography, evolutionary biology, and herpetology. He is currently pursuing his Ph.D. from the Centre for Ecological Sciences, Indian Institute of Science, where he studies the origins, dispersal, and speciation of wetland-associated snakes. Hugo has received, amongst others, the DST-INSPIRE fellowship for his doctoral research and the Gold Medal from Pondicherry University for academic excellence during his Masters. His research has been published in high-impact peer-reviewed journals, including PLOS Neglected Tropical Diseases and Systematic Biology. When not working or writing, Hugo can be found consuming copious amounts of anime and manga, composing and making music with his bass guitar, shredding trails on his MTB, playing video games (he prefers the term ‘gaming’), or tinkering with all things tech.


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