Editor’s Note: This archived article was reviewed for accuracy, and minor corrections were made to clarify the study findings and avoid overstating results. The original publication date has been retained.
In a mouse study published in Nature Biotechnology, researchers reported that experimental cyclic peptides could selectively alter the gut microbiome, lower blood cholesterol and reduce atherosclerotic plaque. The findings suggested that targeted remodeling of gut bacteria could influence atherosclerosis, although the experiments did not show that the peptides could reverse atherosclerosis in humans.
Gut Bacteria
Atherosclerosis is a condition that involves the narrowing of arteries. It results from the buildup of plaque within blood vessels that carry oxygenated blood to different parts of the body. Narrowing stops the effective flow of blood to tissues and organs in need of it.
This disorder is a factor in the occurrence of two major causes of death: heart attacks and strokes.
For years now, scientists have been looking toward recruiting gut bacteria for the fight against medical disorders.
The study suggests that targeting the gut microbiome could offer a new way to influence cardiovascular risk factors. In the mice studied, remodeling the gut microbiome was associated with substantially lower cholesterol levels.
The team at Scripps Research developed cyclic peptides that selectively altered the gut microbiome in mice. Treatment shifted the animals’ gut bacteria toward a composition more similar to that seen in mice fed a low-fat diet and was associated with lower cholesterol levels and less atherosclerotic plaque.
Gut bacteria and health
The gut microbiome describes the super-abundant bacteria present in the digestive system. These microorganisms, that run into trillions, have a symbiotic relationship with humans or mammals. They get nutrients for their survival in the gut while also promoting the health of their hosts to an extent.
The evolution of the gut microbiome, which comprises several hundred bacterial species, took place long ago.
Scientists have taken more interest in understanding the microorganisms that are beneficial to their hosts in more recent decades. Their work shows that gut bacteria are helpful for digestion, metabolism, immune function, and brain health, among other functions.
At the same time, studies show that these microbes in the gut are a factor in health issues. They have been linked to disorders such as atherosclerosis, obesity, diabetes, and high blood pressure. Unfavorable changes to these bacteria play a role in these conditions.
Excessive use of antibiotics has been implicated in the disruption of the bacterial balance in the gut. Also, the consumption of Western diets that are high in calories and fats disrupts the gut microbiome.
Fighting atherosclerosis with peptides
Researchers in this study have been exploring the type of molecules used for years. They were hoping to use these to remodel the microbiome and so promote good health.
The Scripps Research team created a number of cyclic peptides with the aid of chemical methods. They then proceeded to put together a screening system to assess the potential ability of the molecules to remodel the microbiome.
The researchers aimed to identify molecules that could selectively alter bacterial growth and remodel the gut microbiome without broadly eliminating its microbial community. According to the scientists, nature inspired their use of small cyclic peptides.
“Our cells naturally use a diverse collection of molecules including antimicrobial peptides to regulate our gut microbe populations,” explained Luke Leman, Ph.D., co-senior author of the study and an assistant professor in Scripps Research’s Department of Chemistry.
For their experiments, the researchers used mice that were genetically engineered to be prone to high cholesterol and atherosclerosis. They then fed the animals a Western-style diet, which resulted in adverse changes in their balance of gut bacteria. The diet resulted in elevated cholesterol levels and promoted the development of atherosclerotic plaque.
Next, the scientists applied each of the peptides to samples from the gut of the mice. They examined the samples the following day to identify specific cyclic peptides that promoted positive shifts in bacterial balance.
From their investigations, the researchers identified two peptides that produced notable changes in the gut microbiome. These peptides were then used to treat mice fed a Western-style diet and prone to developing atherosclerosis.
Blood cholesterol levels in treated animals were significantly lower than in untreated mice. After two weeks, cholesterol levels were about 36% lower in the treated animals.
After 10 weeks, the area of atherosclerotic plaque in treated mice was about 40% lower than in untreated mice.
This comparison was between treated and untreated mice. It does not establish that existing atherosclerotic plaque shrank by 40% from its pretreatment level, and the findings should not be interpreted as evidence that the peptides reverse atherosclerosis in humans.
“It was surprising to us that simply remodeling the gut microbiome can have such an extensive effect,” said Professor Reza Ghadiri, Ph.D., a co-senior study author.
New investigation
For their experiments, the team used drinking water to deliver the molecules to mice’s guts. The peptides passed through the digestive system without appreciably entering the bloodstream.
No serious adverse effects were observed from the use of the peptides. Years of research revealed that the collection of molecules in this study is not toxic to cells in mammals.
The cyclic peptides appeared to interact with the outer membranes of susceptible bacterial cells, inhibiting or slowing their growth and thereby altering the composition of the gut microbiome.
Ghadiri, Leman, and their colleagues are now exploring the usefulness of the molecules for another disorder following their positive findings. They are studying in mice how the peptides could help combat diabetes, a condition also linked to an imbalance of gut bacteria.
The findings provide proof-of-concept that selectively remodeling the gut microbiome can influence cholesterol levels and atherosclerotic plaque development in a mouse model. Further research will be needed to determine whether this approach can be developed into a treatment that is safe and effective in humans.
References
Chen, P. B., Black, A. S., Sobel, A. L., Zhao, Y., Mukherjee, P., Molparia, B., Moore, N. E., Aleman Muench, G. R., Wu, J., Chen, W., Pinto, A. F. M., Maryanoff, B. E., Saghatelian, A., Soroosh, P., Torkamani, A., Leman, L. J., & Ghadiri, M. R. (2020). Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis. Nature Biotechnology, 38(11), 1288–1297. https://doi.org/10.1038/s41587-020-0549-5