The report describes how the scientists created a set of peptide molecules that are able to slow the growth of less desirable species of gut bacteria; in mice that develop high cholesterol and atherosclerosis from being fed a high fat diet the peptides shifted the balance of species in gut microbiome to be more beneficial, and this shift was observed to reduce cholesterol levels while dramatically slowing the buildup of fatty deposits in the arteries.
“It was surprising to us that simply remodeling the gut microbiome can have such an extensive effect,” says study co-senior author Reza Ghadiri, Ph.D., professor in the Department of Chemistry at Scripps Research.
Symbiotic bacteria have become the focus of study around the globe as scientists have discovered that these microbes/metabolites help to digest food as well as playing roles in metabolism, immunity, and many other important functions within the body. This symbiosis also has a down side, as when antibiotics are overused or diets rich in sugar, salt, carbs and fats are followed the gut microbiome can be altered in ways that are not beneficial to promote disease.
Some scientists now believe that the increased risk for obesity, diabetes hypertension, and atherosclerosis conferred by a Western style diet are due in part to the adverse changes in the microbiome. This has led to the search for ways to remodel the microbiome to reverse those changes to be more beneficial. As such this group of researchers are working on developing a method that involves delivering small molecules to slow and/or kill the growth of bad gut bacteria without adversely affecting the populations of good gut bacteria.
“Our approach, using small molecules called cyclic peptides, is inspired by nature,” says co-senior author Luke Leman, Ph.D., an assistant professor in the Department of Chemistry at Scripps Research. “Our cells naturally use a diverse collection of molecules including antimicrobial peptides to regulate our gut microbe populations.”
The team set up a screening system to determine if any peptides from a collection of cyclic peptides could beneficially remodel mammalian gut microbiome by suppressing undesirable gut bacterial species in mice that were genetically susceptible to high cholesterol. The animals were fed a typical Western style diet that swifty produces high blood cholesterol and atherosclerosis along with adverse changes in the gut microbiome. Samples from the animals’ gut contents were taken and a different cyclic peptide was applied to each sample, and a day later the samples were sequenced for bacterial DNA to determine which of the peptides had shifted the gut bacteriome to the positive desired direction.
Two peptides were identified that had significantly slowed the growth of undesirable gut bacteria to shift the balance of species to be more closer to what would typically be seen in animals that had been fed a healthier diet. These peptides were used to treat the atherosclerosis prone animals on the high fat diet which was found to promote striking reductions in the blood levels of cholesterol compared to those that were untreated to about 36% after two weeks of treatment. After 10 weeks of treatment atherosclerotic plaques in the arteries of the treated mice were also found to be about 40% reduced in the area compared to those that were untreated.
“These were really remarkable effects,” Ghadiri says.
According to Ghadiri these cyclic peptides interacted with the outer membranes of certain bacterial cells in a manner that slowed or stopped the cells’ growth, as well as transiting through the gut without entering the bloodstream. During this study these peptides were delivered to the animals in drinking water, and this was not associated with any adverse side effects.
Inspired by their proof of principle demonstration the researchers are moving on to test these peptides in mice that are models of diabetes, which is another common condition that has been linked to an unhealthy microbiome, in hopes of replicating similar positive results.
