Remodeling Gut Microbiomes To Fight Disease

Scientists report that they have developed molecules that can change or remodel unhealthy gut microbiomes in mice to become more healthy ones, which may someday be applied to other diet related conditions; the scientists will be presenting their findings at the American Chemical Society Fall 2019 National Meeting & Exposition. 

"The gut microbiome contains hundreds of different species of bacteria and is where the largest concentration of bacteria living in us resides," says M. Reza Ghadiri, Ph.D. "If we all ate a healthy diet, exercised and didn't age, we wouldn't have problems with our gut microbiome and many diseases. But, that's not how all people live. Current methods aimed at improving the makeup of gut microbiomes have involved prebiotics, probiotics or drug therapies. Our goal was to take a totally new approach—to remodel the microbiome."

Self assembling cyclic D, L-a-peptides class of molecules were originally created to kill pathogenic bacteria, these molecules are not found in nature and they have highly specific modes of activity and selectivity against different bacterial species. 

"Our hypothesis was that instead of killing bacteria, if we could selectively modulate the growth of certain bacteria species in the gut microbiome using our peptides, more beneficial bacteria would grow to fill the niche, and the gut would be 'remodeled' into a healthful gut," Ghadiri explains. "Our theory was that process would prevent the onset or progression of certain chronic diseases."

To test their hypothesis LDL receptor knockout mice were used, "These mice have been bred to thrive on low-fat diets, but when they are fed a diet high in saturated fat—a so-called Western diet—they develop high plasma cholesterol, especially the LDL or 'bad' type," Ghadiri explains. "Within 10 to 12 weeks, they develop plaques in their arteries such as you would find in atherosclerosis patients." 

A mass screening assay was developed to find out which was the best peptide to test on mouse models. A microbiome was grown in the lab representative of mouse microbiome which was used to test with various peptides, and the 2 peptides that appeared to be the most effective for remodeling gut microbiome into states resembling more healthy mice gut microbiomes were selected. 

Three groups of mice were used in this study: those fed a Western diet; those fed a low fat diet; and another fed a Western diet plus oral doses of one or the other of the 2 selected peptides. Gut microbiome was sequenced from all 3 groups before and after dosing using fecal samples, as well as measuring for levels of molecules that affect the immune system, metabolism and inflammation, and the animal’s arteries were examined for plaques.

"Mice fed the Western diet with our peptides had a 50% reduction in total plasma cholesterol, and there was no significant plaque in the arteries, compared to the mice fed a Western diet and no peptides," Ghadiri says. "We also saw suppressed levels of molecules that increase inflammation and rebalanced levels of disease-relevant metabolites. These mice resembled those on a low-fat diet."

According to Ghadiri the mechanisms behind this most likely involve genes that affect bile acids, which then affect the metabolism of cholesterol as well as other genes that affect inflammatory processes. 

"This is the first time anyone has shown that there are molecules to purposefully remodel the gut microbiome and turn an unhealthful gut into a more healthful one," he says. "This opens up clear therapeutic possibilities. We can sequence the guts of individuals and eventually develop therapies."