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Background: Fasting morning cortisol (FMC) stress hormone levels, are suggested to reflect increased cardiometabolic risk. Acute response to weight loss diet could elevate FMC. Richer Polyphenols and lower carbohydrates diets could favor FMC levels. We aimed to explore the effect of long-term high polyphenol Mediterranean diet (green-MED) on FMC and its relation to metabolic health., Methods: We randomized 294 participants into one of three dietary interventions for 18-months: healthy dietary guidelines (HDG), Mediterranean (MED) diet, and Green-MED diet. Both MED diets were similarly hypocaloric and lower in carbohydrates and included walnuts (28 g/day). The high-polyphenols/low-meat Green-MED group further included green tea (3-4 cups/day) and a Wolffia-globosa Mankai plant 1-cup green shakeFMC was obtained between 07:00-07:30AM at baseline, six, and eighteen-months., Results: Participants (age=51.1years, 88% men) had a mean BMI of 31.3kg/m 2 , FMC=304.07nmol\L, and glycated-hemoglobin-A1c (HbA1c)=5.5%; 11% had type 2 diabetes and 38% were prediabetes. Baseline FMC was higher among men (308.6 ± 90.05nmol\L) than women (269.6± 83.9nmol\L;p=0.02). Higher baseline FMC was directly associated with age, dysglycemia, MRI-assessed visceral adiposity, fasting plasma glucose (FPG), high-sensitivity C-reactive-protein (hsCRP), testosterone, Progesterone and TSH levels (p ≤ 0.05 for all). The 18-month retention was 89%. After 6 months, there were no significant changes in FMC among all intervention groups. However, after 18-months, both MED groups significantly reduced FMC (MED=-1.6%[-21.45 nmol/L]; Green-MED=-1.8%[-26.67 nmol/L]; p<0.05 vs. baseline), as opposed to HDG dieters (+4%[-12 nmol/L], p=0.28 vs. baseline), whereas Green-MED diet FMC change was significant as compared to HDG diet group (p=0.048 multivariable models). Overall, 18-month decrease in FMC levels was associated with favorable changes in FPG, HbA1c, hsCRP, TSH, testosterone and MRI-assessed hepatosteatosis, and with unfavorable changes of HDLc (p<0.05 for all, weight loss adjusted, multivariable models)., Conclusion: Long-term adherence to MED diets, and mainly green-MED/high polyphenols diet, may lower FMC, stress hormone, levels,. Lifestyle-induced FMC decrease may have potential benefits related to cardiometabolic health, irrespective of weight loss., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03020186., Competing Interests: IS advises the nutritional committee of Hinoman, Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alufer, Tsaban, Rinott, Kaplan, Meir, Zelicha, Ceglarek, Isermann, Blüher, Stumvoll, Stampfer and Shai.)

Background: Previous studies have linked the Mediterranean diet (MED) with improved cardiometabolic health, showing preliminary evidence for a mediating role of the gut microbiome. We recently suggested the Green-Mediterranean (Green-MED) diet as an improved version of the healthy MED diet, with increased consumption of plant-based foods and reduced meat intake. Here, we investigated the effects of MED interventions on the gut microbiota and cardiometabolic markers, and the interplay between the two, during the initial weight loss phase of the DIRECT-PLUS trial., Methods: In the DIRECT-PLUS study, 294 participants with abdominal obesity/dyslipidemia were prospectively randomized to one of three intervention groups: healthy dietary guidelines (standard science-based nutritional counseling), MED, and Green-MED. Both isocaloric MED and Green-MED groups were supplemented with 28g/day walnuts. The Green-MED group was further provided with daily polyphenol-rich green tea and Mankai aquatic plant (new plant introduced to a western population). Gut microbiota was profiled by 16S rRNA for all stool samples and shotgun sequencing for a select subset of samples., Results: Both MED diets induced substantial changes in the community structure of the gut microbiome, with the Green-MED diet leading to more prominent compositional changes, largely driven by the low abundant, "non-core," microorganisms. The Green-MED diet was associated with specific microbial changes, including enrichments in the genus Prevotella and enzymatic functions involved in branched-chain amino acid degradation, and reductions in the genus Bifidobacterium and enzymatic functions responsible for branched-chain amino acid biosynthesis. The MED and Green-MED diets were also associated with stepwise beneficial changes in body weight and cardiometabolic biomarkers, concomitantly with the increased plant intake and reduced meat intake. Furthermore, while the level of adherence to the Green-MED diet and its specific green dietary components was associated with the magnitude of changes in microbiome composition, changes in gut microbial features appeared to mediate the association between adherence to the Green-MED and body weight and cardiometabolic risk reduction., Conclusions: Our findings support a mediating role of the gut microbiome in the beneficial effects of the Green-MED diet enriched with Mankai and green tea on cardiometabolic risk factors., Trial Registration: The study was registered on ClinicalTrial.gov ( NCT03020186 ) on January 13, 2017., (© 2022. The Author(s).)

To address how the microbiome might modify the interaction between diet and cardiometabolic health, we analyzed longitudinal microbiome data from 307 male participants in the Health Professionals Follow-Up Study, together with long-term dietary information and measurements of biomarkers of glucose homeostasis, lipid metabolism and inflammation from blood samples. Here, we demonstrate that a healthy Mediterranean-style dietary pattern is associated with specific functional and taxonomic components of the gut microbiome, and that its protective associations with cardiometabolic health vary depending on microbial composition. In particular, the protective association between adherence to the Mediterranean diet and cardiometabolic disease risk was significantly stronger among participants with decreased abundance of Prevotella copri. Our findings advance the concept of precision nutrition and have the potential to inform more effective and precise dietary approaches for the prevention of cardiometabolic disease mediated through alterations in the gut microbiome.