New Approaches Targeting the Microbiome in CV Disease

April 25, 2019

New findings are providing an excellent opportunity for the development of novel therapeutic strategies that target the intestinal microbiome for prevention and treatment of cardiovascular disease, a review of the field suggests.

The "State-of-the-Art Review" is published online in the April 30 issue of the Journal of the American College of Cardiology.

Detailed mechanistic studies have strongly implicated the key role of the gut microbiome in mediating cardiovascular disease processes or risk factors, but most previous studies have focused on characterizing the microbial composition rather than its functional alterations and downstream consequences, the review states.

"While previous studies have focused on what specific organisms are implicated, we are beginning to realize that it is their balance of the ecosystem within the body that creates an environment that protects or promotes various cardiovascular diseases," lead author W.H. Wilson Tang, MD, of the Cleveland Clinic in Ohio, told Medscape Medical News.

"Therefore, a more holistic concept has evolved based on how gut bacteria can generate metabolites from the nutrients ingested and how these may affect different human organs," Tang said.

Tang explained that prior studies have hypothesized that specific bacteria may directly promote pathophysiologic processes, and that by eliminating them with antibiotics, might lead to fewer adverse events. 

"This approach has not worked because the underlying mechanisms were poorly understood, and there is an assumption of 'one-size-fits-all,' " Tang said. "Now we appreciate that much of our gut bacteria are likely beneficial and their compositions in our healthy gut are often difficult to alter, yet their metabolism can be modulated by dietary exposures that are unique across individuals." 

The review notes that in the latest studies, researchers have identified new mechanisms that can explain why some gut bacteria metabolites from dietary nutrients can be potentially beneficial (such as short-chain fatty acids modulating blood pressure) while others may be potentially harmful, such as trimethylamine N-oxide (TMAO) that can affect cholesterol metabolism, promote atherosclerosis, and increase thrombosis risks.

Conflicting Results

Tang reported that, thus far, studies on the effects of various different diets on the microbiome have produced conflicting results. 

"What is clear is that dietary patterns represent one of the biggest environmental exposures to our gut bacteria, and so altering diet may indeed play some role in reshaping our gut microbial metabolism and overall health.  However, the concept of classifying food groups or diets as 'good' or 'bad' for health is somewhat outdated, since it depends largely on how nutrients are digested and interact with the body's gut bacteria," he said.

"Individuals can have vastly different gut bacterial compositions, so the same food may have different short- and long-term effects in different persons," he added. "This is further complicated by the fact that we all have our own unique physiological response to nutrients and metabolites independent of our gut microbiome."

Tang believes that this may explain why many studies have contrasting results — they did not take into account interpersonal individuality that is dependent on gut bacteria function.

More promising future approaches, the review suggests, may include personalized dietary interventions, probiotics and/or prebiotics, or nonlethal microbial inhibitors that target specific pathways once they are identified, such as TMAO production.

TMAO Inhibitors — A Novel Approach

The review notes that agents targeting the TMAO pathway "would also be expected to have multiple additional potential therapeutic benefits," including reducing the progression of renal functional decline, heart failure progression, and adverse outcomes in numerous high-risk cohorts (those with type 2 diabetes, chronic kidney disease, and heart failure).  "However, well-powered prospective intervention studies are needed to validate this novel therapeutic approach," the authors write.

"The concept of 'drugging' the microbiome to alter a disease process instead of eliminating the bacteria paves a completely new approach to prevent diseases," Tang commented.  "In this way, specific enzymes making metabolites that are potentially harmful to the human host can be inhibited by designer drugs without killing the bacteria itself, thus limiting unwanted side effects to the human host. This approach can be complementary to traditional medications and potentially lead to better management of cardiovascular disease risk."

Whether current dietary recommendations that promote cardiovascular health have potential beneficial impact on the intestinal microbiome in general, or TMAO specifically, remains to be determined, the review states.

"It is important to recognize that most dietary advice recommends approaches that would be expected to lower TMAO, including lowering of caloric and fat consumption," the authors note.

Approaches that aim to manipulate the intestinal microbiome and its metabolic pathways hold some promise, although they have yet to be realized in clinical practice, the authors add.

They report that a TMA lyase inhibitor, 3,3-dimethyl-1-butanol, has been shown to lower TMA/TMAO production without compromising microbial cell survival, and was associated with reduced atherosclerotic burden, lower macrophage foam cell formation, and attenuated cardiorenal disease progression in mice.

This substance has been identified in some samples of cold-pressed, extra-virgin olive oil, a major component of the Mediterranean diet that has been associated with improvement in cardiovascular health. However, the impact of Mediterranean diet on changes in TMAO has been somewhat mixed.

Next-generation TMA lyase inhibitors have recently been reported to be highly potent, suppressing TMAO levels in animal models. These agents have also "shown the potential to selectively target and accumulate within intestinal microbiota, which permits sustained inhibition of TMA-producing microbial enzymes with limited systemic exposure within the host," the review notes.

However, the authors stress that cardiometabolic diseases likely result from several metabolites, which may contribute to a variable extent in different individuals with high or low susceptibility, and that TMAO is likely only the "tip of the iceberg."

"Future identification of microbially produced metabolites and investigation of whether they are causally linked to cardiometabolic disease will provide exciting potential novel opportunities to improve cardiovascular health and prevention," they conclude.

Asked what advice clinicians should be giving to patients about diet and probiotics based on this research, Tang said this was beyond the scope of the current review. However, he added: "The evidence for probiotics for cardiovascular health is sparse. The American Heart Association continues to have broad recommendations on healthy diet choices, and there is clinical trial data supporting potential cardiovascular benefits of [a] Mediterranean diet — whether they are linked to microbiome function is unclear."

This review was supported by grants from the National Institutes of Health (NIH), the Of fi ce of Dietary Supplements, and the Fondation Leducq. Tang has served as a consultant for The Advisory Board Company. Coauthors include the founder and a shareholder of Metabogen AB (a Swedish company developing therapeutics based on the microbiome), and a co-inventor on patents held by the Cleveland Clinic related to cardiovascular diagnostics and therapeutics.

J Am Coll Cardiol. Published online April 22, 2019. Abstract

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