Regulation of Peripheral Arterial Disease by Gut Microbes

There is a global epidemic of cardiovascular disease (CVD) caused by atherosclerosis, or “hardening of the arteries” which causes blockages in blood flow to tissue throughout the body. CVD is responsible for 30% of all deaths worldwide and leads to heart attacks, strokes, and peripheral arterial disease (PAD). Despite advances in antiplatelet and cholesterol-lowering drugs and identification of “traditional” risk factors for CVD such as smoking and diabetes mellitus, we are far from curing atherosclerosis because we still do not have the full picture of all the risk factors that lead to CVD. PAD, which affects the blood vessels to the limbs, is a particularly debilitating form of CVD. PAD patients have chronic pain, non-healing ulcers, and gangrene; often need surgical procedures to restore normal blood flow to treat these problems; and are at risk for losing limbs. Furthermore, unlike patients who have heart attacks but may not simultaneously have PAD, nearly all PAD patients are at greater risk for death from heart attacks than for losing limbs. Hence, it is critically important for PAD patients to be treated for overall CVD risk, not just blocked blood vessels in the limbs. However, there is no reliable molecular marker or blood test (“biomarker”) for PAD that can promote early treatment in patients who may not have symptoms, determine risk of disease progression, or help assess the response to therapy. Since current recognition of PAD is suboptimal (poor?) and there are effective therapies that improve the risk of death and morbidity for these patients, development of a biomarker for PAD is critically important. Recent evidence suggests that gut microbes may be part of the solution to the PAD? CVD? puzzle. The human intestinal tract is inhabited by trillions of microbes. Research by others has demonstrated that carnitine and phosphatidylcholine eaten in the diet is converted (or “metabolized”) to trimethylamine-N-oxide by gut microbes, which is then absorbed into the bloodstream and is associated with heart attacks, stroke, and death in humans. My laboratory demonstrated that tryptophan, a protein building block present in food, and specific small molecules, or metabolites, produced exclusively by gut microbes from tryptophan are associated with PAD in humans and with increased risk of death after vascular surgery. The next step is to take these novel observations back to the basic science laboratory to understand what is happening on a cellular and molecular level. My ultimate goal is to investigate if these metabolites can be new biomarkers for PAD. There is also the possibility that these metabolites and molecular pathways in microbes can be used as targets for new therapies that are much more specific than antibiotics or probiotics for the benefit of all patients with atherosclerosis. Approaching the prevention and treatment of atherosclerosis by targeting tryptophan metabolism in gut microbes has never been evaluated in the vascular research arena and is tremendously exciting. Therefore, this proposal advances The Woman’s Board mission to advance care through breakthrough discoveries and cutting-edge research. Furthermore, successful completion of this project’s objectives will provide critical preliminary data toward an NIH R01 grant by the applicant and would thus be invaluable in developing a springboard for the applicant’s independent research program, another goal of the Eleanor Wood-Prince Grants Initiative.