Atherosclerosis, the main risk factor for cardiovascular disease, is characterized by cholesterol plaques in the arterial walls formed through a complex immune inflammatory response involving cholesterol-sequestering macrophages embedded in the arterial wall.
The hallmarks of atherosclerosis are:
- an association with the major metabolic syndrome disorders, Type 2 diabetes, obesity, and hypertension, all of which are associated with inflammation and all of which are affected by the gut microbiota.
The Gut Microbiota and Metabolic Syndrome Disorders
Atherosclerosis is associated with the metabolic syndrome disorders: Type 2 diabetes; obesity; and hypertension. Inflammatory response to an initial dysfunctional condition is common to all of them. Also common to all of them is an interplay with the gut microbiota, where the initial signs of the disorder modify the gut microbiota composition which then further develops the disorder. (The link between the gut microbiota and type 2 diabetes was discussed in a recent blog article).
The Gut Microbiota and Inflammation
As is the case for metabolic syndrome disorders, the development of atherosclerotic plaques is associated with changes in gut microbiota composition . In atherosclerotic subjects, there is a relative abundance of bacteria associated with inflammation, such as Enterobacteriaceae and Streptococcus, and a depletion of short chain fatty acid (SCFA) producing bacteria, such as Roseburia intestinalis. Amongst their other biological roles, SCFA’s, especially butyrate, help maintain the gut wall lining responsible for selective transfer of substances from the gut to the blood stream. In addition, the bacterium Akkermansia muciniphila, which is intimately associated with the epithelial cells and tight junctions between them in the gut wall lining, is also depleted in atherosclerosis.
Inflammation is central to the process of atherosclerotic plaque formation. Chronic excess cholesterol initiates an inflammatory response that starts the process of plaque formation. However, similar to what happens in Type 2 diabetes, the changes in gut microbiota composition that accompany the development of atherosclerosis (as described in the previous paragraph) boost the level of inflammation by causing the gut wall barrier to leak, allowing lipopolysaccharides (LPS’s) to pass into the blood. LPS molecules, which shed from the cell walls of certain bacteria in the gut, are potent initiators of inflammation.
The TMAO Hypothesis
In 2011, Stanley Hazen’s laboratory at the Cleveland Clinic developed an interesting hypothesis connecting a specific gut microbiota metabolite with atherosclerosis [1,4]. According to this hypothesis, choline from eggs and carnitine from meat, can be converted by some bacteria in the gut to the metabolite trimethylamine (TMA) which is subsequently taken up into the blood stream and transported to the liver where it is oxidized to trimethylamine oxide (TMAO). The hypothesis links TMAO to increased formation of atherosclerotic plaques though the mechanism is not known . If this hypothesis proves correct, it would provide a direct link between eggs and meat and atherosclerosis, carrying with it the suggestion of treatment by dietary restriction (not the first time that there has been a call for restricting eggs and meat to people with heart disease). The hypothesis has been received with enthusiasm by many in the field but there are critics who point out that fish, considered beneficial for atherosclerosis, contains high endogenous levels of TMAO. There is also evidence that carnitine is beneficial for atherosclerosis . Furthermore, choline is an essential nutrient which should not be overly restricted. So clearly, this matter requires further study.
Inflammation is central to atherosclerosis as well as to the metabolic syndrome disorders. The gut microbiota is not responsible for the initial inflammatory steps. Rather, it plays a secondary, though no less important, role in this process, transforming acute inflammation into chronic inflammation. This means that readjustment of the microbiota has the potential to wind back these disorders, once we have a more complete understanding of the processes involved.