Cardiovascular disease: diet, microbiota and immunity are all linked!

Visualization of immune cell (lymphocyte) proliferation in mesenteric lymph node
Visualization of immune cell (lymphocyte) proliferation in mesenteric lymph nodes under the influence of microbiota modulated by fatty diet. Soraya Taleb/PARCC

While a high-fat, low-fiber diet is known to promote cardiovascular diseases such as atherosclerosis, the mechanisms involved are not yet fully understood. Researchers at Inserm and Université Paris Cité have now turned their attention to the role of intestinal microbiota in the development of atherosclerosis. Their work in mice shows that the low fiber content of the fatty diet leads to an imbalance in the intestinal microbiota, which in turn causes systemic inflammation that aggravates the development of atherosclerotic plaques in the arteries. These results, published in Cell Reports, provide further evidence of the importance of fiber in the diet, both for healthy intestinal function and for preventing the onset of cardiovascular disease.

Cardiovascular disease is one of the world’s leading causes of death. Among these diseases, atherosclerosis is characterized by the deposition of an "atheromatous" plaque, essentially composed of lipids, on artery walls. Eventually, these plaques can damage the arterial wall, obstruct the vessel or rupture, often with serious consequences. One of the major risk factors for atherosclerosis is obesity, particularly that induced by a diet too high in fat and low in fiber. Diet, but also its impact on the intestinal microbiota, is therefore a key area of interest in cardiovascular disease research.

A team led by Soraya Taleb, Inserm Research Director at the Paris Cardiovascular Research Center (Inserm/Université Paris Cité), has investigated the influence of a low-fiber, fatty diet on the intestinal microbiota in mice, and how this may contribute to the development of atherosclerosis.

The researchers used a mouse model of diet-induced atherosclerosis to compare the effects of different diets on metabolism, microbiota and the development of atherosclerosis.

Unsurprisingly, in mice fed a high-fat, low-fiber diet, their results showed an increase in metabolic risk factors linked to cardiovascular disease (significant weight gain, hyperglycemia, insulin resistance, increased liver weight and triglyceride content...).

But these are not the only effects observed with this diet, which also appears to be associated with an overall imbalance in the microbiota - both in its composition and in its immune response - resulting in altered production of metabolic by-products by the bacteria that make it up. In particular, short-chain fatty acids, derived from fiber fermentation and recognized for their positive impact on health, are produced in lower quantities.

This imbalance appears to be associated not only with metabolic risk factors, but also with a worsening of the vascular manifestations of atherosclerosis, with an increase in the size of atherosclerotic plaques in the aorta, and a systemic inflammatory phenomenon resulting in an increase in the number of immune cells in these plaques. However, fiber supplementation countered these effects.

These results indicate that, in mice fed a fatty diet, a pathological gut microbiota accelerates the development of atherosclerosis," comments Soraya Taleb. Our observations also show that, rather than the high fat content, it is the low fiber content of the diet that is responsible for the imbalance in the microbiota, and hence for the worsening of atherosclerosis. This lends further support to the idea that fiber plays a vital role in structuring a healthy microbiota and preventing systemic inflammatory diseases such as cardiovascular disease", she continues.

But how to explain the surprising link between the composition of the microbiota and the accumulation of immune cells in atherosclerotic plaques - In mice transplanted with an intestinal microbiota initially modulated by a fatty diet, the research team observed an increased proliferation of immune cells in the mesenteric ganglia [1] , the site of their activation in the gastrointestinal tract.

Tracing techniques that track the migration of immune cells have confirmed that it is indeed cells from the mesenteric lymph nodes that, having passed from the intestine into the bloodstream, accumulate in atherosclerotic plaques and thus contribute to the development of atherosclerosis.

The fact that we were able to observe that immune cells are able to migrate from the gut to the periphery, thereby generating systemic inflammation that aggravates atherosclerotic plaques, adds a new dimension to our understanding of the link between diet, gut, microbiota and atherosclerosis," explains Soraya Taleb. Further work is needed to identify which bacteria in the microbiota are involved in this mechanism, so that we can envisage targeted therapeutic approaches and study these mechanisms in humans", concludes the researcher.

[1] The mesenteric lymph nodes are located in the mesentery, a fold of peritoneum (the membrane lining the abdominal cavity and viscera) that connects the small intestine to the posterior wall of the abdomen.