$12 Million NIH Grant Aims to Drive Deeper Discovery of Heart Health/Gut Microbe Links

The National Institutes of Health (NIH) has awarded more than $12 million to Cleveland Clinic researchers to study the critical link between gut microbial pathways and the development of cardiometabolic diseases.

The researchers are led by Stanley Hazen, MD, PhD, Director of the Center for Microbiome and Human Health in Cleveland Clinic’s Lerner Research Institute and Co-Section Head of Preventive Cardiology and Rehabilitation in Cleveland Clinic’s Miller Family Heart & Vascular Institute.

He and his collaborators on this work — J. Mark Brown, PhD; Zeneng Wang, PhD; Adeline (Lynn) Hajjar, DVM, PhD; and Joseph DiDonato, PhD, all of Lerner Research Institute — will explore the concept that gut microbes act as a key endocrine “organ” that converts digested nutrients into chemical signals that function like hormones, creating physiological changes in humans. The researchers will focus on specific novel pathways linked to atherosclerosis, thrombosis and obesity, as well as the participation of specific gut microbe-driven pathways in increased susceptibility to cardiovascular and metabolic diseases.

3 related projects with 4 supporting cores

The new research program is the first “Program Project” grant funded by NIH focused on the gut microbiome and its links to human health and disease. The program will consist of three specialized projects and four supporting cores. The projects will:

• Explore in vivo how newly identified gut microbial pathways affect thrombosis and atherosclerosis
• Investigate how microbial metabolites act like hormones to drive disease in a high-fat environment
• Identify specific microbial genes and metabolites that are responsible for enhancing cardiovascular disease

The three projects will be led by Drs. Hazen and Brown from Cleveland Clinic along with Michael Fischbach, PhD, of Stanford University. The four supporting cores will be led by Drs. Hazen, Brown, Wang and Hajjar.

“We are only beginning to understand the critical links between the gut microbiome and heart disease,” says Dr. Hazen. “We are grateful to the NIH for this funding and excited about the potential of this research to open up new avenues for improving health and combating cardiovascular disease.”

Aiming to extend a track record of discovery

Dr. Hazen and his team have made pioneering discoveries in atherosclerosis and inflammatory disease research, including the seminal discovery linking gut microbial pathways to cardiovascular disease and metabolic diseases, including atherosclerosis, thrombosis, heart failure and chronic kidney disease. He and Cleveland Clinic cardiologist W.H. Wilson Tang, MD, together with two European colleagues, summarized these and related discoveries in a major “state-of-the-art review” earlier this year in the Journal of the American College of Cardiology (2019;73:2089-2105).

Central to those discoveries was the Hazen group’s demonstration that TMAO (trimethylamine N-oxide) — a byproduct of gut bacteria formed during digestion — contributes to the development of cardiovascular disease. High blood levels of TMAO have been shown to be a powerful tool for predicting future risk of heart attack, stroke and death, according to previous research initially spearheaded by Dr. Hazen and his team, and subsequently replicated around the world. TMAO testing is now widely available and in clinical use as a result.

The team also recently reported the development of a new class of drugs that target the TMAO pathway and reduce atherosclerosis and thrombosis potential in preclinical models. “As part of the Program Project, we are seeking to further develop therapeutics that leverage new insights into the mechanistic links between the gut microbiome and cardiometabolic diseases,” Dr. Hazen notes.