Robust new research, published in the journal Science, has revealed a microbial mechanism connecting obesity with heart disease. The study describes how a high-fat diet damages intestinal cells, leading to an imbalance of bad bacteria that produce metabolites known to contribute to cardiovascular disease.
The new findings build on several previous studies to finally present a complete picture of the relationship between diet, gut bacteria and heart disease. Prior research has shown gut bacteria and the health of intestinal tissue share a close relationship.
When the epithelial cells that line our intestines are inflamed, our gut microbial populations can fall out of balance. And this microbiome imbalance, known as dysbiosis, leads to excessive production of certain metabolites that increase one’s risk of atherosclerosis. But there was still one missing link in that chain reaction researchers had not fully uncovered.
"It was known that exposure to a high-fat diet causes dysbiosis – an imbalance in the microbiota favoring harmful microbes, but we didn't know why or how this was happening," explains Mariana Byndloss, a researcher from Vanderbilt University Medical Center working on the new study. "We show one way that diet directly affects the host and promotes the growth of bad microbes."
Using mouse models the new research showed how a high-fat diet impairs the activity of mitochondria in intestinal epithelial cells. This diet-induced damage leads to those cells producing excessive volumes of oxygen and nitrate.
Certain harmful gut microbes such as E. coli thrive in high oxygen and nitrate environments, so this helps them increase in numbers and intensify production of a metabolite called trimethylamine (TMA). The liver then oxidizes TMA, converting it into trimethylamine-N-oxide (TMAO), a compound increasingly implicated in cardiovascular disease.
The researchers then went one step further, investigating whether protecting those intestinal epithelial cells could stop this entire high-fat diet-induced chain of events. They turned to a drug called 5-aminosalicylic acid (5-ASA), used for over 30 years to help reduce intestinal inflammation in subjects with inflammatory bowel disease.
In mouse models 5-ASA helped restore normal mitochondrial function in intestinal cells. This then lowered the downstream increase in TMAO previously triggered by a high-fat diet.
Byndloss says this is compelling proof-of-concept evidence showing it is possible some of the negative outcomes of a high-fat diet can be prevented. In the future, Byndloss notes, it could be possible to use drugs like 5-ASA alongside probiotics to help maintain healthy gut bacterial populations and limit the negative effect of high-fat diets on the heart.
"Only by fully understanding the relationship between the host – us – and gut microbes during health and disease are we going to be able to design therapies that will be effective in controlling obesity and obesity-associated outcomes like cardiovascular disease,” says Byndloss.
The new study was published in the journal Science.
