Newly identified ‘metabolic signature’ can determine adherence to Mediterranean diet, help predict CVD risk

A newly identified “metabolic signature” can evaluate an individual’s adherence and metabolic response to the Mediterranean diet and help predict future risk of developing cardiovascular disease (CVD), according to new research led by Harvard T.H. Chan School of Public Health with collaborators from the Broad Institute of MIT and Harvard and Spain.

The metabolic signature consists of 67 metabolites—small chemicals produced in the processes of metabolism that circulate in the bloodstream—and can be measured through a blood sample.

The findings were published online in the European Heart Journal on May 14, 2020.

For the study, researchers used a machine-learning model to analyze hundreds of metabolites in blood samples from 1,859 participants from the Spanish PREDIMED study, the largest study of the Mediterranean diet’s ability to prevent CVD. The model identified 67 metabolites that when analyzed collectively indicated whether a person had followed the Mediterranean diet and showed how the person responded to the diet, which is high in unsaturated fats and emphasizes plant-based foods, fish, and olive oil, and has shown to be effective in reducing the risk of CVD and overall mortality. The study also showed that a higher level of the metabolic signature was associated with a lower long-term risk of CVD among PREDIMED study participants. Even after accounting for traditional CVD risk factors, the metabolic signature was effective at predicting long-term risk of CVD, the researchers said.

The researchers further tested and verified the metabolic signature in blood samples from 6,868 participants from the U.S.-based Nurses’ Health Study, Nurses’ Health Study II, and Health Professional’s Follow-Up Survey. They noted that ability for the signature to determine adherence and metabolic response to the Mediterranean diet, and to predict future CVD risk, were highly reproducible across all the study populations despite the fact that individuals living in Spain and in the U.S. have different dietary habits, lifestyles, and environmental exposures.

“This study is the first to develop a metabolic signature for the Mediterranean diet based on comprehensive metabolomic profiles. It demonstrates that the level of dietary adherence and individual’s response to diet can be objectively measured,” said Liming Liang, associate professor of epidemiology and biostatistics at Harvard Chan School and co-senior author of the paper. “The reproducibility of the findings in the U.S. and Spanish populations indicate the robustness of the approach.”

Assessing adherence to the Mediterranean diet has often relied on self-reported data obtained through questionnaires of study participants. The newly discovered metabolic signature could prove to be a potent and objective tool for the research community to further evaluate individuals’ adherence and metabolic response to the Mediterranean diet in various study populations and settings.

“The metabolic signature and metabolites included in the signature could also help researchers better understand how the Mediterranean diet can benefit people with complex metabolic diseases,” said Jun Li, research scientist of nutrition and epidemiology at Harvard Chan School and the first author of the paper. “Given that the metabolic signature is reflective of individuals’ metabolic response to diet and CVD risk, the signature has potential in the future to help facilitate personalized nutrition interventions.”

“From a public health perspective, our findings underscored the beneficial effects of the Mediterranean diet for the prevention of cardiovascular disease at a molecular level,” said Miguel A. Martinez-Gonzalez, Professor at the University of Navarra (Spain) and coauthor of this study.

Other Harvard Chan School authors include Jun Li, Marta Guasch-Ferré, Wonil Chung, Shilpa Bhupathiraju, Deirdre Tobias, Fred Tabung, Tong Zhao, Constance Turman, Yen-Chen Anne Feng, Lorelei Mucci, Heather Eliassen, Alberto Ascherio, Eric Rimm, JoAnn Manson, Lu Qi, and co-senior author Frank Hu.

Researchers from the Spanish PREDIMED study group, Brigham and Women’s Hospital, and the Broad Institute of MIT and Harvard were also co-authors of the paper.

The PREDIMED metabolomics studies were funded by National Institutes of Health (NIH) grants R01 HL118264 and R01 DK102896. The PREDIMED trial was funded by the Spanish Ministry of Health (Instituto de Salud Carlos III, The PREDIMED Network grant RD 06/0045, 2006–45 13, coordinated by M.A. Martinez-Gonzalez; and a previous network grant RTIC-G03/140, 2003–05, coordinated R. Estruch). Additional grants were received from the Ministerio de Economia y Competitividad-Fondo Europeo de Desarrollo Regional (Projects CNIC-06/2007, CIBER 06/03, PI06-1326, PI07-0954, PI11/02505, SAF2009-12304, and AGL2010–22319-C03-03) and by the Generalitat Valenciana (PROMETEO17/2017, 5 ACOMP2010-181, AP111/10, AP-042/11, ACOM2011/145, ACOMP/2012/190, ACOMP/2013/159 and ACOMP/213/165). The NHS, NHSII, and HPFS, and their metabolomics studies were supported by NIH grants U01 HL145386, UM1 CA186107, R01 CA49449, R01 HL034594, R01 HL088521, UM1 CA176726, R01 CA67262, UM1 CA167552, R0110 HL35464, HL60712, R01 CA50385, P01 CA87969, and R01 AR049880. J.L. was supported by 9-17-CMF-011 from the American Diabetes Association (ADA), K99 DK122128 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and a pilot and feasibility grant from the NIDDK-funded Boston Nutrition Obesity Research Center (P30 DK046200). M.G.-F. was supported by 1-18-PMF-029 from ADA. F.K.T was supported by R00 CA207736 from the National Cancer Institute. D.K.T is supported by 1-18-JDF-104977 from ADA.

“The Mediterranean diet, plasma metabolome, and cardiovascular disease risk,” Jun Li, Marta Guasch- Ferré, Wonil Chung, Miguel Ruiz-Canela, Estefanía Toledo, Dolores Corella, Shilpa N. Bhupathiraju, Deirdre K. Tobias, Fred K. Tabung, Jie Hu, Tong Zhao, Constance Turman, Yen-Chen Anne Feng, Clary B. Clish, Lorelei Mucci, A. Heather Eliassen, Karen H. Costenbader, Elizabeth W. Karlson, Brian M. Wolpin, Alberto Ascherio, Eric B. Rimm, JoAnn E. Manson, Lu Qi, Miguel Àngel Martínez-Gonzalez, Jordi Salas-Salvadó, Frank B. Hu, and Liming Liang, online May 14, 2020, European Heart Journal, doi: 10.1093/eurheartj/ehaa209

photo: Shutterstock/Foxys Forest Manufacture

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Harvard T.H. Chan School of Public Health brings together dedicated experts from many disciplines to educate new generations of global health leaders and produce powerful ideas that improve the lives and health of people everywhere. As a community of leading scientists, educators, and students, we work together to take innovative ideas from the laboratory to people’s lives—not only making scientific breakthroughs, but also working to change individual behaviors, public policies, and health care practices. Each year, more than 400 faculty members at Harvard Chan School teach 1,000-plus full-time students from around the world and train thousands more through online and executive education courses. Founded in 1913 as the Harvard-MIT School of Health Officers, the School is recognized as America’s oldest professional training program in public health.