Gut Microbiome May Guide Personalized Heart Failure Therapy

Understanding more about the gut microbiome and how it may affect the development and treatment of heart failure could lead to a more personalized approach to managing the condition, a new review article suggests.

"The gut microbiome modulates heart failure pathophysiology, contributes to disease progression and therapeutic responses, and holds promise as a novel biomarker," the authors note. "Interactions among the gut microbiome, diet, and medications offer potentially innovative modalities for management of patients with heart failure," they add.

The review will be published in the May 2 issue of the Journal of the American College of Cardiology and has become available online on April 24.

"Over the past years we have gathered more understanding about how important the gut microbiome is in relation to how our bodies function overall and even though the cardiovascular system and the heart itself may appear to be quite distant from the gut, we know the gut microbiome affects the cardiovascular system and the physiology of heart failure," lead author, Petra Mamic, MD, Stanford University School of Medicine, told theheart.org | Medscape Cardiology.

"We've also learnt that the microbiome is very personalized. It seems to be affected by a lot of intrinsic and as well as extrinsic factors. For cardiovascular diseases in particular, we always knew that diet and lifestyle were part of the environmental risk, and we now believe that the gut microbiome may be one of the factors that mediates that risk," she said.

"Studies on the gut microbiome are difficult to do and we are right at the beginning of this type of research. But we have learned that the microbiome is altered or dysregulated in many diseases including many cardiovascular diseases, and many of the changes in the microbiome we see in different cardiovascular diseases seem to overlap," she added.

Mamic explained that patients with heart failure have a microbiome that appears different and dysregulated compared with the microbiome in healthy individuals.

"The difficulty is teasing out whether the microbiome changes are causing heart failure or if they are a consequence of the heart failure and all the medications and comorbidities associated with heart failure," she commented.

Animal studies have shown that many microbial products, small molecules made by the microbiome, seem to affect how the heart recovers from injury, for example after a myocardial infarction, and how much the heart scars and hypertrophies after an injury, Mamic reported. These microbiome-derived small molecules can also affect blood pressure, which is dysregulated in heart failure.

Other products of the microbiome can be pro-inflammatory or anti-inflammatory, which can again affect the cardiovascular physiology and the heart, she noted.

High-Fiber Diet May Be Beneficial

One area of particular interest at present involves the role of short-chain fatty acids, which are a byproduct of microbes in the gut that digest fiber.

"These short chain fatty acids seem to have positive effects on the host physiology. They are anti-inflammatory; they lower blood pressure; and they seem to protect the heart from scarring and hypertrophy after injury. In heart failure, the gut microbes that make these short-chain fatty acids are significantly depleted," Mamic explained.

They are an obvious focus of interest because these short-chain fatty acids are produced when gut bacteria break down dietary fiber, raising the possibility of beneficial effects from eating a high-fiber diet.

Another product of the gut microbiome of interest is trimethylamine N-oxide, formed when gut bacteria break down nutrients such as L-carnitine and phosphatidyl choline, nutrients abundant in foods of animal origin, especially red meat. This metabolite has proatherogenic and prothrombotic effects, and negatively affected cardiac remodeling in a mouse heart failure model, the review notes.

However, though it is too early to make specific dietary recommendations based on these findings, Mamic points out that a high-fiber diet is thought to be beneficial.

"Nutritional research is very hard to do and the data is limited, but as best as we can summarize things, we know that plant-based diets such as the Mediterranean and DASH diets seem to prevent some of the risk factors for the development of heart failure and seem to slow the progression of heart failure," she added.

One of the major recommendations in these diets is a high intake of fiber, including whole foods, vegetables, fruits, legumes, nuts, and less intake of processed food and red meat. "In general, I think everyone should eat like that, but I specifically recommend a plant-based diet with a high amount of fiber to my heart failure patients," Mamic said.

Large Variation in Microbiome Composition

The review also explores the idea of personalization of diet or specific treatments dependent on an individual's gut microbiome composition.

Mamic explains: "When we look at the microbiome composition between individuals, it is very different. There is very little overlap between individuals, even in people who are related. It seems to be more to do with the environment — people who are living together are more likely to have similarities in their microbiome. We are still trying to understand what drives these differences."

It is thought that these differences may affect the response to a specific diet or medication. Mamic gives the example of fiber. "Not all bacteria can digest the same types of fiber, so not everyone responds in the same way to a high-fiber diet. That's probably because of differences in their microbiome."

Another example is the response to the heart failure drug digoxin, which is metabolized by one particular strain of bacteria in the gut. The toxicity or effectiveness of digoxin seems to be influenced by levels of this bacterial strain, and this again can be influenced by diet, Mamic says.

Manipulating the Microbiome as a Therapeutic Strategy

Microbiome-targeting therapies may also become part of future treatment strategies for many conditions, including heart failure, the review authors say.

Probiotics (foods and dietary supplements that contain live microbes) interact with the gut microbiota to alter host physiology beneficially. Certain probiotics may specifically modulate processes dysregulated in heart failure, as was suggested in a rodent heart failure model in which supplementation with Lactobacillus-containing and Bifidobacterium-containing probiotics resulted in markedly improved cardiac function, the authors report.

However, a randomized trial (GutHeart) of probiotic yeast Saccharomyces boulardii in patients with heart failure found no improvement in cardiac function compared with standard care.

Commenting on this, Mamic suggested that a more specific approach may be needed.

"Some of our preliminary data have shown people who have heart failure have severely depleted B ifido bacteria," Mamic said. These bacteria are commercially available as a probiotic, and the researchers are planning a study to give patients with heart failure these specific probiotics. "We are trying to find practical ways forward and to be guided by the data. These people have very little Bifidobacteria, and we know that probiotics seem to be accepted best by the host where there is a specific need for them, so this seems like a sensible approach."

Mamic does not recommend that heart failure patients take general probiotic products at present, but she tells her patients about the study she is doing. "Probiotics are quite different from each other. It is a very unregulated market. A general probiotic product may not contain the specific bacteria needed."

Include Microbiome Data in Biobanks

The review calls for more research on the subject and a more systematic approach to collecting data on the microbiome.

"At present for medical research, blood samples are collected, stored, and analyzed routinely. I think we should also be collecting stool samples in the same way to analyze the microbiome," Mamic suggests.

"If we can combine that with data from blood tests on various metabolites/cytokines and look at how the microbiome changes over time or with medication, or with diet, and how the host responds including clinically relevant data, that would be really important. Given how quickly the field is growing I would think there would be biobanks including the microbiome in a few years' time."

"We need to gather this data. We would be looking for which bacteria are there, what their functionality is, how it changes over time, with diet or medication, and even whether we can use the microbiome data to predict who will respond to a specific drug."

Mamic believes that in future, analysis of the microbiome could be a routine part of deciding what people eat for good health and to characterize patients for personalized therapies.

"It is clear that the microbiome can influence health, and a dysregulated microbiome negatively affects the host, but there is lot of work to do. We need to learn a lot more about it, but we shouldn't miss the opportunity to do this," she concluded.

Mamic reports no disclosures.

J Am Coll Cardiol. Published online April 24, 2023. Abstract

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