Table 2.

Summary of the main findings of randomized controlled trials testing the effects of Mediterranean diet on gut microbiome in subjects with chronic illness

Reference	Participants	Study arm	Comparison arm	Duration of intervention	Effects on gut microbiome	Effects on other physiologic parameters	Other key findings
Haro 2016 [46]	Twenty obese subjects	MD	LFHCC diet	1 year	↑ Roseburia, Oscillospira, Parabacteroides distasonis ↓ Prevotella, Faecalibacterium prausnitzii	↑ Insulin sensitivity index Different urinary metabolomic profile	LFHCC diet also induced favorable changes in gut microbiome composition
Meslier 2020 [47]	Eighty-two overweight and obese subjects with low fruit and vegetable intake	MD	Habitual diet	8 weeks	↑ Faecalibacterium prausnitzii ↓ Ruminococcus gnavus ↑ representation of genes involved in carbohydrate metabolism and SCFA synthesis	↓ plasma cholesterol ↑ Insulin sensitivity ↓ fecal bile acids	MD resulted into increased levels of urinary urolithins, proportionate to plant food intake
Pagliai 2020 [48]	Twenty-three overweight subjects with low/moderate cardiovascular risk	Low-calorie MD	Vegetarian diet	3 + 3 months (cross-over design)	↑ Enterohabdus, Lachnoclostridium, Parabacteroides ↑ synthesis of propionic acid	↓ inflammatory cytokines	No major changes in microbiome composition with either dietary pattern
Rinott 2022 [49]	Two hundred and forty-nine subjects with abdominal obesity/dyslipidemia	MD or Green MD plus walnuts	Standard guideline-based healthy diet	6 months	↑ Prevotella ↓ Bifidobacterium ↑ representation of genes involved in branched-chain amino acid metabolism	↓ Body weight, blood pressure, blood lipids ↑ Insulin sensitivity	The beneficial effects of MD are mediated by specific changes in gut microbiome, that are emphasized in green MD
Calabrese 2022 [50]	One hundred and nine patients with NAFLD	LGIMD with or without aerobic activity	Standard guideline-based healthy diet	3 months	Changes in overall composition ↑ Ruminococcus, Enterohabdus, Coprobacter, Lachnospiraceae	↓ elastosonographic index of liver fibrosis	The effects of MD on gut microbiome are emphasized when MD is associated with physical activity
Ben-Yacov 2023 [53]	Two hundred adults with pre-diabetes	MD	PPT diet based on machine-learning	6 months	↑ Bifidobacterium adolescentis and other taxa	↓ plasma cholesterol ↑ Insulin sensitivity	PPT diet was more effective in driving changes in gut microbiome composition
Haro 2016 [54]	Two hundred and thirty-nine patients with CHD (with or without metabolic syndrome)	MD	Low-fat diet	2 years	↑ Parabacteroides distasonis, Bacteroides thetaiotamicron, Faecalibacterium prausnitzii, Bifidobacterium adolescentis in patients with metabolic syndrome	↓ waist circumference ↓ glucose plasma levels ↓ triglycerides ↑ HDL	Mediterranean diet-induced marked changes in fecal microbiome composition only in subjects with metabolic syndrome
Galié 2021 [55, 56]	Thirty-eight overweight patients with metabolic syndrome	MD	Free diet with 50 g/day nut supplement	2 + 2 months (cross-over design)	↑ Lachnospiraceae, Ruminococcaceae	↓ glucose, insulin, HOMA-IR	MD-induced changes in microbiome were associated with positive changes in fecal acetate and with changes in 65 serum metabolites
Lewis 2021 [57]	One hundred and ninety-one patients with Crohn’s disease	MD	Carbohydrate diet tailored to Chron’s disease	6 weeks	No major differences in microbiome composition	Improvement of parameters of inflammation in both diets	Two distinct clusters of microbiome response to diet were identified, one with increasing abundance of Bacteroides vulgatus and the other with decreasing abundance of Faecalibacterium prausnitzii

MD Mediterranean Diet; LFHCC Low-Fat High-Complex Carbohydrate; LGIMD Low-Glycemic Index Mediterranean Diet; PPT Personalized Postprandial Targeting; CHD Coronary Heart Disease; HDL High-Density Lipoprotein; HOMA-IR Homeostatic Model Assessment of Insulin Resistance; NAFLD Non-Alcoholic Fatty Liver Disease