Research into the effects of the gut microbiome on health and aging is presently flourishing. Scientists are identifying meaningful changes in microbial populations that take place with age, as well as metabolites generated by gut microbes that favorably influence health, such as indoles, butyrate, propionate, and so forth. With advancing age, the balance of microbial populations shifts from beneficial to harmful. The production of beneficial metabolites decreases. Microbes invade gut tissue to produce a state of chronic inflammation that spreads to accelerate the onset and progression of age-related disease throughout the body. The size of the contribution of the gut microbiome to the progression of aging is up for debate, but based on evidence from animal models it isn’t unreasonable to guess at it being in the same ballpark as the effects of exercise.
There are many possible causes of the age-related deterioration of the gut microbiome. Dietary changes, lesser degrees of exercise, dysfunction in intestinal tissues, the decline of immune function. The immune system plays a role in gardening the microbes of the gut, as illustrated by the fact that beneficial changes in the gut microbe can be produced via forms of immunization against bacterial proteins.
Regardless of cause, a range of strategies might be employed to readjust a dysfunctional gut microbiome to produce a better outcome for the individual. For example, fecal microbiata transplantation from young to old has been shown to extend life in short lived killifish. In principle similar effects could be achieved with aggressive use of probiotics, or methods of selective destruction of harmful microbes. The approach noted in today’s research materials is an example of the latter approach. Researchers have identified molecules that are harmless to cells, but suppress growth in some species of harmful gut microbes. The result is improved health in an animal model of a poor diet.
The gut microbiome, which includes hundreds of bacterial species, evolved long ago as part of a fundamental symbiosis: The bacteria get a place to live and plenty to eat, and in return they assist their animal hosts, largely by helping them digest food. Scientists have learned that this symbiosis can have a downside for the bacteria’s human hosts. When people overuse antibiotics or consume “Western” diets rich in carbs, fats and sugar, the gut microbiome can be altered in ways that promote disease. Indeed, it now appears that the increased risks of obesity, diabetes, hypertension, and atherosclerosis that are conferred by the Western diet are due in part to adverse changes in the microbiome.
That recognition has led researchers to look for ways to remodel the microbiome. “Our approach, using small molecules called cyclic peptides, is inspired by nature. Our cells naturally use a diverse collection of molecules including antimicrobial peptides to regulate our gut microbe populations.” the team already had a small collection of cyclic peptides that had been made using chemistry techniques. For the study, they set up a screening system to determine if any of those peptides could beneficially remodel the mammalian gut microbiome by suppressing undesirable gut bacterial species.
Using mice that are genetically susceptible to high cholesterol, they fed the animals a Western-type diet that swiftly and reliably produces high blood cholesterol and atherosclerosis, as well as adverse shifts in the gut microbiome. The researchers then sampled the animals’ gut contents and applied a different cyclic peptide to each sample. A day later, they sequenced the bacterial DNA in the samples to determine which peptides had shifted the gut microbiome in the desired direction.
The scientists soon identified two peptides that had significantly slowed the growth of undesirable gut bacteria, shifting the species balance closer to what is seen in mice that are fed a healthier diet. Using these peptides to treat atherosclerosis-prone mice that were eating a high-fat Western diet, they found striking reductions in the animals’ blood levels of cholesterol compared to untreated mice – about 36 percent after two weeks of treatment. They also found that after 10 weeks, the atherosclerotic plaques in the arteries of the treated mice were about 40 percent reduced in area, compared to those in untreated mice.
The gut microbiome is a malleable microbial community that can remodel in response to various factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic d,l-α-peptides that remodeled the Western diet (WD) gut microbiome toward the low-fat-diet microbiome state.
Daily oral administration of the peptides in WD-fed LDLr-/- mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including interleukin-6, tumor necrosis factor-α, and interleukin-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.