“Before COVID, obesity and metabolic syndrome were considered the pandemic of the 21st century. Right now, roughly 40% of the U.S. population is obese, and that percentage is predicted to climb,” Byndloss said. “Our research has revealed a previously unexplored mechanism for how diet and obesity can increase risk of cardiovascular disease — by affecting the relationship between our intestines and the microbes that live in our gut.”

In previous studies, Byndloss and Andreas Bäumler, PhD, at the University of California at Davis, found that the epithelial cells lining the intestines and gut microbes share a mutually beneficial relationship that promotes a healthy gut environment. They wondered if diseases like obesity affect this relationship.

The collaborating research teams found that a high-fat diet causes inflammation and damages intestinal epithelial cells in animal models. The high-fat diet impairs the function of energy-generating mitochondria, Byndloss explained, causing the intestinal cells to produce more oxygen and nitrate.

These factors, in turn, stimulate the growth of harmful Enterobacteriaceae microbes, such as E. coli, and boost bacterial production of a metabolite called TMA (trimethylamine). The liver converts TMA to TMAO (trimethylamine-N-oxide), which has been implicated in promoting atherosclerosis and increasing the relative risk for all-cause mortality in patients.

“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,” Byndloss said. “We show one way that diet directly affects the host and promotes the growth of bad microbes.”

The researchers demonstrated that a drug currently approved for treatment of inflammatory bowel disease restored the function of intestinal epithelial cells and blunted the increase in TMAO in the animal models. The drug, called 5-aminosalicylic acid, activates mitochondrial bioenergetics in the intestinal epithelium.

“This is evidence that it’s possible to prevent the negative outcomes associated with a high-fat diet,” Byndloss said. A drug such as 5-aminosalicylic acid might be used in conjunction with a probiotic to both restore a healthy intestinal environment and boost beneficial microbe levels, she added.

“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.”

Byndloss and her team plan to extend their studies into animal models of cardiovascular disease. They also are exploring the role of the host-microbe relationship in the development of other diseases including colorectal cancer.

Woongjae Yoo, PhD, a postdoctoral fellow in Pathology, Microbiology and Immunology at VUMC, is the first author of the Science paper.

Byndloss and Bäumler are co-corresponding authors. The research was supported by the V Foundation for Cancer Research, American Cancer Society, United States-Israel Binational Science Foundation, USDA/NIFA, Crohn’s and Colitis Foundation, and the National Institutes of Health.

Source: Eurekalert