Longevity Briefs: Some Gut Bacteria May Drive Heart Disease

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Atherosclerosis – the hardening and narrowing of arteries – is one of the primary age-related causes of death worldwide. Atherosclerosis occurs when oxidised cholesterol becomes trapped within the walls of the arteries, a process that is believed to be driven by inflammation involving white blood cells called macrophages. The development of atherosclerosis can be slowed by lowering low density lipoprotein (LDL, the particle that delivers cholesterol to the plaque) and by controlling blood pressure, since high blood pressure can damage the lining of the arteries and trigger inflammation.

While there are ways to lower risk, the unfortunate fact is that healthy lifestyle practices will not fully prevent atherosclerosis, and some people with normal blood pressure and LDL can still develop early vascular disease. This is partly because of an increase in chronic inflammation due to the ageing of the immune system. However, scientists also think that there are many other drivers of atherosclerosis that remain unaccounted for. In this study, researchers discover a new link between atherosclerosis and a molecule produced by gut bacteria.

The discovery:

Researchers began by searching for gut bacterial products that might be associated with atherosclerosis. To do this, they fed mice that were genetically susceptible to atherosclerosis a range of different diets. Some mice were also given an antibiotic treatment to deplete the mices’ gut microbes. By collecting blood samples, analysing the gut bacterial metabolites in these samples, and studying the extent of atherosclerosis, researchers were able to use statistical analysis to identify a bacterial product called imidazole propionate (ImP) as being strongly associated with atherosclerosis in mice.

Having singled out ImP as potentially important, the next step was to see if its presence correlated with atherosclerosis in humans. They analysed plasma samples from around 3850 individuals from two separate study cohorts. Around half of these participants had subclinical atherosclerosis (the disease is present but hasn’t yet caused noticeable symptoms) as assessed by imaging techniques (ultrasound and CT scans). The remainder were asymptomatic volunteers without atherosclerosis to serve as controls. They found that higher ImP levels were strongly associated with atherosclerosis after accounting for confounding risk factors like age, smoking and LDL.

Correlation doesn’t necessarily mean causation, so to test whether ImP could cause atherosclerosis, researchers gave it to atherosclerosis-prone mice in their drinking water for 8-12 weeks. They found that ImP significantly increased atherosclerosis in these mice compared to control mice. However, ImP did not significantly alter the mices’ cholesterol levels. Further cell culture experiments suggested that instead, ImP triggers inflammation by binding to a specific receptor (called I1R) on the surface of immune cells of the type present in the fatty plaque. Finally and perhaps most importantly, they treated mice fed a high-cholesterol diet with a molecule that blocks this receptor, and found that this significantly slowed atherosclerosis progression.

The implications:

This research opens exciting new avenues for preventing and treating atherosclerosis. The strong association between ImP and atherosclerosis suggests ImP could be a used as a means to detect the disease earlier or identify those most at risk, allowing for earlier interventions. The discovery could also lead to the development of new therapies that work by blocking the actions of ImP, or potentially by targeting the gut bacteria that produce it. This could be a way of reducing inflammation in the walls of the arteries without compromising immune function elsewhere.

Unfortunately, more work is required to identify which specific bacterial strains are responsible for ImP production and what dietary interventions can reduce the presence of these strains. This study does remind us of the importance of inflammation in atherosclerosis, a fact that is now widely acknowledged even if current treatments still focus on blood pressure and cholesterol. Fortunately there are many ways of limiting inflammation naturally, including the consumption of anti-inflammatory foods such as plants rich in antioxidants, engaging in regular exercise, improving sleep quality and avoidance of environmental toxins.