The gut-heart axis

Cardiovascular diseases are the leading cause of death worldwide. They account for three out of every ten deaths globally, and there is growing scientific evidence that changes in the composition of gut bacteria can also affect the heart.¹

Much of this influence stems from the chemical compounds excreted by these microorganisms, called metabolites. Some of these metabolites, like short-chain fatty acids, have been shown to directly promote good physical and mental health. Others, however, are linked to damage in the arterial walls, increased cholesterol levels, and a higher risk of atherosclerosis—an inflammatory disease of the arterial walls that leads to fat accumulation in the form of plaques, which can rupture and form clots, causing severe complications like heart attacks or strokes.

Some bacterial metabolites are crucial

One of the most studied and well-supported factors is TMAO, or trimethylamine N-oxide². This molecule is produced by gut bacteria when diets are high in fats and proteins. Scientific studies and meta-analyses have found that elevated levels of this compound are associated with a 62% increased risk of major cardiovascular events, such as heart attacks, and a 63% higher risk of mortality from all causes.³

Where is this compound found? In red and processed meats, as well as in fish, which contain nutrients like choline, lecithin, carnitine, and betaine. Gut bacteria convert these nutrients into TMA (trimethylamine). Once this molecule enters the bloodstream and reaches the liver, it is transformed into TMAO. In moderate amounts, TMAO is eliminated from the body through urine. However, when present in high serum concentrations, it has been shown to damage blood vessel endothelium, promoting inflammation, atherosclerosis, and other cardiovascular events, such as heart attacks.³

Inflammation: a key factor in cardiovascular health

Another mechanism by which the gut microbiota influences cardiovascular disease is through inflammation. Some metabolites produced by bacteria, as well as the bacteria themselves, trigger the immune system’s response when they enter the bloodstream as foreign substances.

Seventy percent of immune cells are located in the gut. From there, they detect bacteria or molecules crossing the intestinal barrier into the bloodstream, triggering an inflammatory response to eliminate them before they cause harm. Once eliminated, the inflammatory response deactivates.

However, when inflammation becomes chronic, it can affect blood vessels, causing them to lose elasticity, harden, and narrow. This hinders proper blood flow, reducing the oxygen and nutrients delivered throughout the body.

Certain bacteria, such as those from the Clostridium or Eubacterium genera, play a harmful role in the progression of cardiovascular diseases by activating the immune system and provoking a pro-inflammatory state⁴, accelerating disease development. In fact, bacterial DNA has been found in plaques on arterial walls, reinforcing the idea of bacteria’s role in atherosclerosis progression.

Conversely, other bacteria, like those from the Bifidobacterium or Akkermansia genera, regulate the immune system toward an anti-inflammatory state, delaying cardiovascular disease progression.

Searching for new targeted therapies

David Sancho’s group at the Spanish National Center for Cardiovascular Research (CNIC) has identified a metabolite produced by the microbiota that is harmful because it contributes to atherosclerosis development. They are conducting experiments in animal models and humans to better understand this metabolite’s role in disease progression.

“By understanding how [this bacterial metabolite] causes atherosclerosis, we can develop targeted therapies,” Sancho explains in an interview with Gut Microbiota for Health. He adds that this metabolite is associated with inflammation and does not affect cholesterol levels, meaning it could be used alongside current therapies aimed at reducing cholesterol.

The relationship between bacteria and atherosclerosis also involves fat metabolism. Researchers from the University of Sheffield are studying in mice whether altering gut bacteria can influence atherosclerosis development and slow its progression.

A study by the Broad Institute at the Massachusetts Institute of Technology (MIT) and Harvard University, in collaboration with Massachusetts General Hospital, identified gut microbes affecting cardiovascular health. Published in Cell, the study identified gut bacterial species that consume cholesterol, reducing cardiovascular risk.⁵

By analyzing bacterial metabolites and genomes in over 1,400 people, they found that individuals with higher levels of Oscillibacter in their gut had lower cholesterol levels. The study also identified the mechanism these bacteria use to digest cholesterol, breaking it down so other bacteria can degrade and excrete it.

As with many other diseases, microbiota imbalances also influence cardiovascular health. Postdoctoral researcher Iñaki Robles at CNIC notes in an interview with Gut Microbiota for Health that various studies have linked these imbalances to hypertension. There are numerous studies in the past decade supporting a role for the gut bacteria in the regulation of blood pressure⁶ through several mechanisms, such as detrimental metabolites and inflammation. In this sense, as it has been already demonstrated, high salt intake impacts the gut microbiota⁷, particularly depleting Lactobacillus, and increases the levels of immune cells in the intestine, which contributes to higher blood pressure. On the other side, dietary fiber may help regulate blood pressure⁸ through gut microbiota-mediated metabolism.

What does the future hold?

In the future, understanding which metabolites contribute to cardiovascular disease will pave the way for new therapeutic strategies for both prevention and treatment. For instance, cardiovascular patients could be treated with high-fiber and fermented food diets to reduce bacterial imbalances and improve outcomes. Researchers are also studying probiotics as potential allies to enhance the presence of beneficial bacteria. Additionally, they are investigating bacteria that could serve as therapeutic targets for drug development.

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