Metabolomic profiling of a cholesterol lowering plant-based diet from two randomized controlled feeding trials

Andrea J Glenn^{1

2

3

4}, Anne-Julie Tessier^{5

6

7

8}, Meaghan E Kavanagh^{9

10}, Gloria A Morgan^{9

10

11}, Clary B Clish¹², Jordi Salas-Salvado^{13

14}, Vasanti S Malik^{5

9}, Anthony J Hanley⁹, Richard P Bazinet⁹, Elena M Comelli⁹, Ahmed El-Sohemy⁹, Simin Liu^{15

16

17

18}, Beatrice A Boucher⁹, Cyril W C Kendall^{9

10

19}, David J A Jenkins^{9

10

20

21

22}, Frank B Hu^{5

23

24}, John L Sievenpiper^{25

26

27

28

29}

Affiliations

¹ Department of Nutrition and Food Studies, New York University, New York, NY, USA. a.glenn@nyu.edu.
² Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. a.glenn@nyu.edu.
³ Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. a.glenn@nyu.edu.
⁴ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada. a.glenn@nyu.edu.
⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ Department of Nutrition, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
⁷ Montreal Heart Institute, Montreal, QC, Canada.
⁸ Institut de Valorisation des Données (IVADO), Montreal, QC, Canada.
⁹ Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁰ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada.
¹¹ School of Nutrition, Toronto Metropolitan University, Toronto, ON, Canada.
¹² Metabolomics Platform, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹³ CIBER Fisiopatologıa de la Obesidad y Nutricion (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain.
¹⁴ Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigacions Sanitàries Pere i Virgili, Universitat Rovira i Virgili, Reus, Spain.
¹⁵ Department of Epidemiology and Biostatistics, Joe C. Wen School of Population & Public Health, UC Irvine, Irvine, CA, USA.
¹⁶ Center for Global Cardiometabolic Health & Nutrition (CGCHN), Mary & Steve Wen Division of Cardiology, Department of Medicine, School of Medicine, UC Irvine, Irvine, CA, USA.
¹⁷ Division of Endocrinology Department of Medicine, and Division of Cardiothoracic Surgery Department of Surgery, Warren Alpert School of Medicine and Rhode Island Hospital, Providence, RI, USA.
¹⁸ Department of Epidemiology, Brown University, School of Public Health, Providence, RI, USA.
¹⁹ College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.
²⁰ Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
²¹ Division of Endocrinology and Metabolism, St. Michael's Hospital, Toronto, ON, Canada.
²² Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
²³ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁵ Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. john.sievenpiper@utoronto.ca.
²⁶ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada. john.sievenpiper@utoronto.ca.
²⁷ Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada. john.sievenpiper@utoronto.ca.
²⁸ Division of Endocrinology and Metabolism, St. Michael's Hospital, Toronto, ON, Canada. john.sievenpiper@utoronto.ca.
²⁹ Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. john.sievenpiper@utoronto.ca.

PMID: 40263496
DOI: 10.1038/s41430-025-01625-x

Randomized Controlled Trial

Metabolomic profiling of a cholesterol lowering plant-based diet from two randomized controlled feeding trials

Andrea J Glenn et al. Eur J Clin Nutr. 2025 Sep.

. 2025 Sep;79(9):863-875.

doi: 10.1038/s41430-025-01625-x. Epub 2025 Apr 22.

Authors

Affiliations

¹ Department of Nutrition and Food Studies, New York University, New York, NY, USA. a.glenn@nyu.edu.
² Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. a.glenn@nyu.edu.
³ Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. a.glenn@nyu.edu.
⁴ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada. a.glenn@nyu.edu.
⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ Department of Nutrition, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
⁷ Montreal Heart Institute, Montreal, QC, Canada.
⁸ Institut de Valorisation des Données (IVADO), Montreal, QC, Canada.
⁹ Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁰ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada.
¹¹ School of Nutrition, Toronto Metropolitan University, Toronto, ON, Canada.
¹² Metabolomics Platform, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹³ CIBER Fisiopatologıa de la Obesidad y Nutricion (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain.
¹⁴ Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigacions Sanitàries Pere i Virgili, Universitat Rovira i Virgili, Reus, Spain.
¹⁵ Department of Epidemiology and Biostatistics, Joe C. Wen School of Population & Public Health, UC Irvine, Irvine, CA, USA.
¹⁶ Center for Global Cardiometabolic Health & Nutrition (CGCHN), Mary & Steve Wen Division of Cardiology, Department of Medicine, School of Medicine, UC Irvine, Irvine, CA, USA.
¹⁷ Division of Endocrinology Department of Medicine, and Division of Cardiothoracic Surgery Department of Surgery, Warren Alpert School of Medicine and Rhode Island Hospital, Providence, RI, USA.
¹⁸ Department of Epidemiology, Brown University, School of Public Health, Providence, RI, USA.
¹⁹ College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.
²⁰ Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
²¹ Division of Endocrinology and Metabolism, St. Michael's Hospital, Toronto, ON, Canada.
²² Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
²³ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁵ Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. john.sievenpiper@utoronto.ca.
²⁶ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada. john.sievenpiper@utoronto.ca.
²⁷ Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada. john.sievenpiper@utoronto.ca.
²⁸ Division of Endocrinology and Metabolism, St. Michael's Hospital, Toronto, ON, Canada. john.sievenpiper@utoronto.ca.
²⁹ Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. john.sievenpiper@utoronto.ca.

PMID: 40263496
DOI: 10.1038/s41430-025-01625-x

Abstract

Background: Objective biomarkers of diet, such as metabolomics, may improve dietary assessment and provide additional insight into how diet influences disease risk. The portfolio diet, a cholesterol-lowering plant-based diet, is recommended for lowering low-density lipoprotein cholesterol (LDL-C). This diet is low in saturated fat and includes nuts, plant protein (legumes), viscous fiber, and phytosterols.

Objective: We examined metabolomic profiles in response to the portfolio diet in two randomized controlled trials (RCTs), where all foods were provided to the participants, compared to a control vegetarian diet and the same control diet with a statin.

Methods: The first RCT included 34 adults (age 58.4 ± 8.6 y) and the second RCT included 25 adults (age 61.0 ± 9.6 y), all with high LDL-C (>4.1 mmol/L). Plasma samples were obtained at baseline, week 2, and week 4 in both RCTs for metabolomics analysis using liquid chromatography-tandem mass spectrometry. Linear mixed models were used to examine effects of the interventions on the metabolites in each RCT, applying a Bonferroni correction.

Results: Of 496 known metabolites, 145 and 63 metabolites significantly changed within the portfolio diet interventions in the first and second RCT, respectively. The majority were glycerophosphocholines (32%), triacylglycerols (20%), glycerophosphoethanolamines (14%), sphingomyelins (8%), and amino acids and peptides (8%) in the first RCT, and glycerophosphocholines (48%), glycerophosphoethanolamines (17%), and amino acids and peptides (8%) in the second RCT. Fifty-two metabolites were consistently changed in the same direction with the portfolio diet intervention across both RCTs, after Bonferroni correction.

Conclusions: Many of these metabolites likely reflect the plant-based nature, low saturated fat content, and cholesterol-lowering effects of the diet, such as increased N2-acetylornithine, L-pipecolic acid, lenticin, and decreased C18:0 lipids and cholesteryl esters. Further research is needed to validate these metabolites as biomarkers of a plant-based dietary pattern.

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Conflict of interest statement

Competing interests: AJG has received travel support and/or honoraria from the Lawson Centre Nutrition Digital Series (University of Toronto), the Good Food Institute, Vinasoy, and the British Nutrition Society. AJH has received funding from the Dairy Farmers of Canada. EMC has received research support from Ocean Spray Cranberries and Lallemand Health Solutions (outside of this study). CWCK has received grants or research support from the Advanced Food Materials Network, Agriculture and Agri-Foods Canada (AAFC), Almond Board of California, Barilla, Canadian Institutes of Health Research (CIHR), Canola Council of Canada, International Nut and Dried Fruit Council, International Tree Nut Council Research and Education Foundation, Loblaw Brands Ltd, the Peanut Institute, Pulse Canada, and Unilever. He has received in-kind research support from the Almond Board of California, Barilla, California Walnut Commission, Kellogg Canada, Loblaw Companies, Nutrartis, Quaker (PepsiCo), the Peanut Institute, Primo, Unico, Unilever, and WhiteWave Foods/Danone. He has received travel support and/or honoraria from the Barilla, California Walnut Commission, Canola Council of Canada, General Mills, International Nut and Dried Fruit Council, International Pasta Organization, Lantmannen, Loblaw Brands Ltd., Nutrition Foundation of Italy, Oldways Preservation Trust, Paramount Farms, the Peanut Institute, Pulse Canada, Sun-Maid, Tate & Lyle, Unilever, and White Wave Foods/Danone. He has served on the scientific advisory board for the International Tree Nut Council, International Pasta Organization, McCormick Science Institute, and Oldways Preservation Trust. He is a founding member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD), is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of the EASD, and is a Director of the Toronto 3D Knowledge Synthesis and Clinical Trials. Foundation. DJAJ has received research grants from Saskatchewan & Alberta Pulse Growers Associations, the Agricultural Bioproducts Innovation Program through the Pulse Re-search Network, the Advanced Foods and Material Network, Loblaw Companies Ltd., Unilever Canada and Netherlands, Barilla, the Almond Board of California, Agriculture and Agri-food Canada, Pulse Canada, Kellogg’s Company, Canada, Quaker Oats, Canada, Procter & Gamble Technical Centre Ltd., Bayer Consumer Care, Springfield, NJ, Pepsi/Quaker, International Nut & Dried Fruit Council (INC), Soy Foods Association of North America, the Coca-Cola Company (investigator initiated, unrestricted grant), Solae, Haine Celestial, the Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Soy Nutrition Institute (SNI), the Canola and Flax Councils of Canada, the Calorie Control Council, the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI), and the Ontario Research Fund (ORF). He has received in-kind supplies formtrials as research support from the Almond Board of California,Walnut Council of California, the Peanut Institute, Barilla, Unilever, Unico, Primo, Loblaw Companies, Quaker (Pepsico), Pristine Gourmet, Bunge Limited, Kellogg Canada, WhiteWave Foods. He has been on the speaker’s panel, served on the scientific advisory board and/or received travel support and/or honoraria from the Lawson Centre Nutrition Digital Series, 19th Annual Stare-Hegsted Lecture, 2024 Diabetes Canada Conference, Nutritional Fundamentals for Health (NFH)-Nutramedica, Saint Barnabas Medical Center, The University of Chicago, 2020 China Glycemic Index (GI) International Conference, Atlantic Pain Conference, Academy of Life Long Learning, the Almond Board of California, Canadian Agriculture Policy Institute, Loblaw Companies Ltd, the Griffin Hospital (for the development of the NuVal scoring system), the Coca-Cola Company, Epicure, Danone, Diet Quality Photo Navigation (DQPN), Better Therapeutics (FareWell), Verywell, True Health Initiative (THI), Heali AI Corp, Institute of Food Technologists (IFT), Soy Nutrition Institute (SNI), Herbalife Nutrition Institute (HNI), Saskatchewan & Alberta Pulse Growers Associations, Sanitarium Company, Orafti, the International Tree Nut Council Nutrition Research and Education Foundation, the Peanut Institute, Herbalife International, Pacific Health Laboratories, Barilla, Metagenics, Bayer Consumer Care, Unilever Canada and Netherlands, Solae, Kellogg, Quaker Oats, Procter&Gamble, Abbott Laboratories, Dean Foods, the California Strawberry Commission, Haine Celestial, PepsiCo, the Alpro Foundation, Pioneer Hi-Bred International, DuPont Nutrition and Health, Spherix Consulting and WhiteWave Foods, the Advanced Foods and Material Network, the Canola and Flax Councils of Canada, Agri-Culture and Agri-Food Canada, the Canadian Agri-Food Policy Institute, Pulse Canada, the Soy Foods Association of North America, the Nutrition Foundation of Italy (NFI), Nutra-Source Diagnostics, the McDougall Program, the Toronto Knowledge Translation Group (St. Michael’s Hospital), the Canadian College of Naturopathic Medicine, The Hospital for Sick Children, the Canadian Nutrition Society (CNS), the American Society of Nutrition (ASN), Arizona State University, Paolo Sorbini Foundation, and the Institute of Nutrition, Metabolism and Diabetes. He received an honorarium from the United States Department of Agriculture to present the 2013W.O. Atwater Memorial Lecture. He received the 2013 Award for Excellence in Research from the International Nut and Dried Fruit Council. He received funding and travel support from the Canadian Society of Endocrinology and Metabolism to produce mini cases for the Canadian Diabetes Association (CDA). He is a member of the International Carbo-hydrate Quality Consortium (ICQC). His wife, Alexandra L Jenkins, is a director and partner of INQUIS Clinical Research for the Food Industry, his 2 daughters, Wendy Jenkins and Amy Jenkins, have published a vegetarian book that promotes the use of the foods described here, The Portfolio Diet for Cardiovascular RiskmReduction (Academic Press/Elsevier 2020 ISBN:978-0-12-810510-8) and his sister, Caroline Brydson, received funding through a grant from the St. Michael’s Hospital Foundation to develop a cookbook for one of his studies. He is also a vegan. JLS has received research support from the Canadian Foundation for Innovation, Ontario Research Fund, Province of Ontario Ministry of Research and Innovation and Science, Canadian Institutes of Health Research (CIHR), Diabetes Canada, American Society for Nutrition (ASN), International Nut and Dried Fruit Council (INC) Foundation, National Honey Board (U.S. Department of Agriculture [USDA] honey “Checkoff” program), Institute for the Advancement of Food and Nutrition Sciences (IAFNS; formerly ILSI North America), Pulse Canada, Quaker Oats Center of Excellence, The United Soybean Board (USDA soy “Checkoff” program), Protein Industries Canada (a Government of Canada Global Innovation Clusters), The Tate and Lyle Nutritional Research Fund at the University of Toronto, The Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers), The Plant Protein Fund at the University of Toronto (a fund which has received contributions from IFF), and The Nutrition Trialists Network Research Fund at the University of Toronto (a fund which has received donations from the Calorie Control Council, Physicians Committee for Responsible Medicine, and vegan grants through the Karuna Foundation). He has received food donations to support randomized controlled trials from the Almond Board of California, California Walnut Commission, Peanut Institute, Barilla, Unilever/Upfield, Unico/Primo, Loblaw Companies, Quaker, Kellogg Canada, Danone, Nutrartis, Soylent, and Dairy Farmers of Canada. He has received travel support, speaker fees and/or honoraria from ASN, Danone, Dairy Farmers of Canada, FoodMinds LLC, Nestlse, Abbott, General Mills, Nutrition Communications, International Food Information Council (IFIC), Calorie Control Council, International Sweeteners Association, International Glutamate Technical Committee, Arab Beverages Association, and Phynova. He has or has had ad hoc consulting arrangements with Perkins Coie LLP, Tate & Lyle, Inquis Clinical Research, Ingredion, and Brightseed. He is a former member of the European Fruit Juice Association Scientific Expert Panel and a former member of the Soy Nutrition Institute (SNI) Scientific Advisory Committee. He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the study of Diabetes (EASD), Canadian Cardiovascular Society (CCS), and Obesity Canada/Canadian Association of Bariatric Physicians and Surgeons. He serves as an unpaid member of the Board of Trustees of IAFNS and formerly served as an unpaid scientific advisor for the Carbohydrates Committee of IAFNS. He is a Director at Large of the Canadian Nutrition Society (CNS), a founding member of the International Carbohydrate Quality Consortium (ICQC), an Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and a director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His spouse is an employee of AB InBev. No other disclosures were reported.

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Metabolomic profiling of a cholesterol lowering plant-based diet from two randomized controlled feeding trials

Affiliations

Metabolomic profiling of a cholesterol lowering plant-based diet from two randomized controlled feeding trials

Authors

Affiliations

Abstract

Conflict of interest statement

References

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Medical