Effects of Green-MED Diet Via the Gut-fat-brain Axis

NCT03020186 | Completed DMC

• 1 other identifier: BGU
• Study Type: interventional
• Target: 294
• Locations: 1 country
• Sites: 1

Brief Summary

Mediterranean (MED) diet, richer in plants/seeds (and dietary polyphenols) and low in processed meat (green-MED diet) may have a pronounced beneficial effect on age-related declines that begin in middle age, reflected by changes in adiposity, cognitive function, and cardiometabolic risk. The investigators hypothesize that long-term intake of this diet will significantly potentiate the effects of a healthy lifestyle (physical activity and Mediterranean diet), constituting a powerful strategy to halt or even reverse the progression of several age-related processes related to adiposity, cardiometabolic health and cognition. The investigators further hypothesize that lifestyle intervention might modify the gut microbiota profile and that autologous fecal microbiota supplement derived from the time of maximal weight loss might halt the expected subsequent regain phase.

Conditions

Abdominal Obesity Metabolic Syndrome

Outcome Measures

Primary Outcomes (3)

• Abdominal fat

  Changes in visceral fat (MRI)

  18 months

• Hepatic fat

  Changes in hepatic fat (MRI)

  18 months

• Obesity

  Changes in body weight and waist circumference

  6, 14, 18 months

Secondary Outcomes (18)

• Brain anatomy

  18 months

• Cognitive function-MRI

  18 months

• Cognitive function

  18 months

• Cardiac state

  18 months

• Cardiac state

  18 months

Study Arms (3)

Physical activity

PLACEBO COMPARATOR

Physical activity (PA) group will receive free gym memberships and the instruction necessary to engage in moderate-intensity physical activity, \~80% of which will have an aerobic component. The participants will get basic health promoting guideline for healthy diet .

Other: Physical activity

Physical activity+ MED diet

EXPERIMENTAL

On top of the PA intervention described in Arm 1, the participants will be guided for moderate weight loss with a traditional Mediterranean (MED) diet, low in simple carbohydrates. The diet will include 1oz/day of walnuts that will be provided free of charge.

Other: Physical activity+ MED diet

Physical activity+ green-MED diet

EXPERIMENTAL

On top of the PA intervention described in Arm 1, the participants will guided for moderate weight loss with a MED diet, low in simple carbohydrates that will be rich in plants and polyphenols and low in processed meat. The diet will include 1oz/day of walnuts, 3-4 cups/day of green tea and \~500cc green shake/dinner based on specific strain of duckweed \[Wolffia globose, "Mankai"\], an aquatic plant, which might serve as a plant protein source. All the above will be provided free of charge.

Other: Physical activity+green MED diet

Interventions

Physical activity OTHER

Physical activity

Physical activity+ MED diet OTHER

Physical activity+ MED diet

Physical activity+green MED diet OTHER

\*\*\*\*Sub-study from all 3 main arms: Autologous fecal microbiota supplement intervention derived from the time of maximal weight loss: At the 6-month time period, the time of anticipated greatest weight reduction, participants's feces samples will be processed to capsulized inocula. Samples will be frozen within 2 hours and will be kept at -80c pending analysis. Participants will be randomized to receive either research capsules or identical placebo capsules between 8 and 14 months time period. Placebo capsules will consist of a combination of powdered cocoa and vegetable gelatin in normal saline/glycerol and will be identical in appearance to research capsules.

Physical activity+ green-MED diet

Eligibility Criteria

• Age: 30 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• age \>30 years with abdominal adiposity (waist circumference: men \> 102 cm, women \> 88 cm) or dyslipidemia (TG\>150mg/dl and HDL-c \<40mg/dL for men and \<50mg/dL for women)

You may not qualify if:

• Individuals who may not be able to partake in PA in the gym; TGs\>400 mg/dL; serum creatinine\>2 mg/dL; disturbed liver function; major illness that might require hospitalization; pregnant or lactating women; presence of active cancer, is receiving or received chemotherapy in the last three years; participation in another trial; participants who are treated with Coumadin (warfarin) - given its interaction with vitamin K and high level of this vitamin in "Mankai" green shake; pacemaker or platinum implant, because of the impossibility of MRI screening.

Sponsors & Collaborators

• Ben-Gurion University of the Negev: lead
• Harvard School of Public Health (HSPH): collaborator
• University of Leipzig: collaborator

Study Sites (1)

Nuclear research center Negev

Dimona, Israel

Location

Related Publications (16)

• Klein H, Pachter D, Goldberg Toren DT, Kamer O, Alufer L, Ebstein Karamani N, Chassidim Y, Shelef I, Rudich A, Yoel U, Ben-Arie G, Zelicha H, Yaskolka Meir A, Tsaban G, Bartal C, Bluher M, Stumvoll M, Ceglarek U, Isermann B, Qi L, Stampfer MJ, Hu FB, Shai I. How effective is rejoining a long-term weight loss program? The 5- and 10-year MRI-assessed Follow Interventions Trial (FIT) project. BMC Med. 2026 Jan 30. doi: 10.1186/s12916-026-04663-9. Online ahead of print.

  PMID: 41612310 DERIVED

• Pachter D, Yaskolka Meir A, Kaplan A, Tsaban G, Zelicha H, Rinott E, Levakov G, Finkelstein O, Shelef I, Salti M, Beyer F, Witte V, Kloting N, Isermann B, Ceglarek U, Riklin Raviv T, Bluher M, Stumvoll M, Wang DD, Hu FB, Stampfer MJ, Avidan G, Shai I. Serum Galectin-9 and Decorin in relation to brain aging and the green-Mediterranean diet: A secondary analysis of the DIRECT PLUS randomized trial. Clin Nutr. 2025 Oct;53:99-108. doi: 10.1016/j.clnu.2025.08.021. Epub 2025 Aug 23.

  PMID: 40897150 DERIVED

• Yaskolka Meir A, Tsaban G, Rinott E, Zelicha H, Schwarzfuchs D, Gepner Y, Rudich A, Shelef I, Bluher M, Stumvoll M, Ceglarek U, Isermann B, Kloting N, Keller M, Kovacs P, Qi L, Wang DD, Liang L, Hu FB, Stampfer MJ, Shai I. Individual response to lifestyle interventions: a pooled analysis of three long-term weight loss trials. Eur J Prev Cardiol. 2025 Nov 11;32(16):1660-1670. doi: 10.1093/eurjpc/zwaf308.

  PMID: 40472282 DERIVED

• Klein H, Zelicha H, Yaskolka Meir A, Rinott E, Tsaban G, Kaplan A, Chassidim Y, Gepner Y, Bluher M, Ceglarek U, Isermann B, Stumvoll M, Shelef I, Qi L, Li J, Hu FB, Stampfer MJ, Shai I. Visceral adipose tissue area and proportion provide distinct reflections of cardiometabolic outcomes in weight loss; pooled analysis of MRI-assessed CENTRAL and DIRECT PLUS dietary randomized controlled trials. BMC Med. 2025 Feb 4;23(1):57. doi: 10.1186/s12916-025-03891-9.

  PMID: 39901232 DERIVED

• Pachter D, Kaplan A, Tsaban G, Zelicha H, Meir AY, Rinott E, Levakov G, Salti M, Yovell Y, Huhn S, Beyer F, Witte V, Kovacs P, von Bergen M, Ceglarek U, Bluher M, Stumvoll M, Hu FB, Stampfer MJ, Friedman A, Shelef I, Avidan G, Shai I. Glycemic control contributes to the neuroprotective effects of Mediterranean and green-Mediterranean diets on brain age: the DIRECT PLUS brain-magnetic resonance imaging randomized controlled trial. Am J Clin Nutr. 2024 Nov;120(5):1029-1036. doi: 10.1016/j.ajcnut.2024.09.013. Epub 2024 Sep 14.

  PMID: 39284453 DERIVED

• Alufer L, Tsaban G, Rinott E, Kaplan A, Meir AY, Zelicha H, Ceglarek U, Isermann B, Bluher M, Stumvoll M, Stampfer MJ, Shai I. Long-term green-Mediterranean diet may favor fasting morning cortisol stress hormone; the DIRECT-PLUS clinical trial. Front Endocrinol (Lausanne). 2023 Nov 14;14:1243910. doi: 10.3389/fendo.2023.1243910. eCollection 2023.

  PMID: 38034010 DERIVED

• Kamer O, Rinott E, Tsaban G, Kaplan A, Yaskolka Meir A, Zelicha H, Knights D, Tuohy K, Fava F, Uwe Scholz M, Ziv O, Rubin E, Bluher M, Stumvoll M, Ceglarek U, Clement K, Koren O, Hu FB, Stampfer MJ, Wang DD, Youngster I, Shai I. Successful weight regain attenuation by autologous fecal microbiota transplantation is associated with non-core gut microbiota changes during weight loss; randomized controlled trial. Gut Microbes. 2023 Dec;15(2):2264457. doi: 10.1080/19490976.2023.2264457. Epub 2023 Oct 5.

  PMID: 37796016 DERIVED

• Yaskolka Meir A, Keller M, Hoffmann A, Rinott E, Tsaban G, Kaplan A, Zelicha H, Hagemann T, Ceglarek U, Isermann B, Shelef I, Bluher M, Stumvoll M, Li J, Haange SB, Engelmann B, Rolle-Kampczyk U, von Bergen M, Hu FB, Stampfer MJ, Kovacs P, Liang L, Shai I. The effect of polyphenols on DNA methylation-assessed biological age attenuation: the DIRECT PLUS randomized controlled trial. BMC Med. 2023 Sep 25;21(1):364. doi: 10.1186/s12916-023-03067-3.

  PMID: 37743489 DERIVED

• Zelicha H, Kloting N, Kaplan A, Yaskolka Meir A, Rinott E, Tsaban G, Chassidim Y, Bluher M, Ceglarek U, Isermann B, Stumvoll M, Quayson RN, von Bergen M, Engelmann B, Rolle-Kampczyk UE, Haange SB, Tuohy KM, Diotallevi C, Shelef I, Hu FB, Stampfer MJ, Shai I. The effect of high-polyphenol Mediterranean diet on visceral adiposity: the DIRECT PLUS randomized controlled trial. BMC Med. 2022 Sep 30;20(1):327. doi: 10.1186/s12916-022-02525-8.

  PMID: 36175997 DERIVED

• Rinott E, Meir AY, Tsaban G, Zelicha H, Kaplan A, Knights D, Tuohy K, Scholz MU, Koren O, Stampfer MJ, Wang DD, Shai I, Youngster I. The effects of the Green-Mediterranean diet on cardiometabolic health are linked to gut microbiome modifications: a randomized controlled trial. Genome Med. 2022 Mar 10;14(1):29. doi: 10.1186/s13073-022-01015-z.

  PMID: 35264213 DERIVED

• Kaplan A, Zelicha H, Yaskolka Meir A, Rinott E, Tsaban G, Levakov G, Prager O, Salti M, Yovell Y, Ofer J, Huhn S, Beyer F, Witte V, Villringer A, Meiran N, B Emesh T, Kovacs P, von Bergen M, Ceglarek U, Bluher M, Stumvoll M, Hu FB, Stampfer MJ, Friedman A, Shelef I, Avidan G, Shai I. The effect of a high-polyphenol Mediterranean diet (Green-MED) combined with physical activity on age-related brain atrophy: the Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT PLUS). Am J Clin Nutr. 2022 May 1;115(5):1270-1281. doi: 10.1093/ajcn/nqac001.

  PMID: 35021194 DERIVED

• Tsaban G, Yaskolka Meir A, Zelicha H, Rinott E, Kaplan A, Shalev A, Katz A, Brikner D, Bluher M, Ceglarek U, Stumvoll M, Stampfer MJ, Shai I. Diet-induced Fasting Ghrelin Elevation Reflects the Recovery of Insulin Sensitivity and Visceral Adiposity Regression. J Clin Endocrinol Metab. 2022 Jan 18;107(2):336-345. doi: 10.1210/clinem/dgab681.

  PMID: 34643713 DERIVED

• Yaskolka Meir A, Rinott E, Tsaban G, Zelicha H, Kaplan A, Rosen P, Shelef I, Youngster I, Shalev A, Bluher M, Ceglarek U, Stumvoll M, Tuohy K, Diotallevi C, Vrhovsek U, Hu F, Stampfer M, Shai I. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. Gut. 2021 Nov;70(11):2085-2095. doi: 10.1136/gutjnl-2020-323106. Epub 2021 Jan 18.

  PMID: 33461965 DERIVED

• Tsaban G, Yaskolka Meir A, Rinott E, Zelicha H, Kaplan A, Shalev A, Katz A, Rudich A, Tirosh A, Shelef I, Youngster I, Lebovitz S, Israeli N, Shabat M, Brikner D, Pupkin E, Stumvoll M, Thiery J, Ceglarek U, Heiker JT, Korner A, Landgraf K, von Bergen M, Bluher M, Stampfer MJ, Shai I. The effect of green Mediterranean diet on cardiometabolic risk; a randomised controlled trial. Heart. 2021 Jun 11;107(13):1054-1061. doi: 10.1136/heartjnl-2020-317802.

  PMID: 33234670 DERIVED

• Rinott E, Youngster I, Yaskolka Meir A, Tsaban G, Zelicha H, Kaplan A, Knights D, Tuohy K, Fava F, Scholz MU, Ziv O, Rubin E, Tirosh A, Rudich A, Bluher M, Stumvoll M, Ceglarek U, Clement K, Koren O, Wang DD, Hu FB, Stampfer MJ, Shai I. Effects of Diet-Modulated Autologous Fecal Microbiota Transplantation on Weight Regain. Gastroenterology. 2021 Jan;160(1):158-173.e10. doi: 10.1053/j.gastro.2020.08.041. Epub 2020 Aug 26.

  PMID: 32860791 DERIVED

• Yaskolka Meir A, Tsaban G, Zelicha H, Rinott E, Kaplan A, Youngster I, Rudich A, Shelef I, Tirosh A, Brikner D, Pupkin E, Sarusi B, Bluher M, Stumvoll M, Thiery J, Ceglarek U, Stampfer MJ, Shai I. A Green-Mediterranean Diet, Supplemented with Mankai Duckweed, Preserves Iron-Homeostasis in Humans and Is Efficient in Reversal of Anemia in Rats. J Nutr. 2019 Jun 1;149(6):1004-1011. doi: 10.1093/jn/nxy321.

  PMID: 30915471 DERIVED

MeSH Terms

Conditions

Abdominal obesity metabolic syndrome

Interventions

Exercise

Intervention Hierarchy (Ancestors)

Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Iris Shai, PhD

  Ben-Gurion University of the Negev

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle investigator

Study Record Dates

• First Submitted: January 9, 2017
• First Posted: January 13, 2017
• Study Start: January 1, 2017
• Primary Completion: March 1, 2019
• Study Completion: March 1, 2019
• Last Updated: July 15, 2019

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)