While our rapidly evolving knowledge of the gut microbiome, and its intrinsic connection with general health, is offering incredible insights into many different kinds of disease, exactly how to translate these findings into clinical treatments is still unclear. Fecal transplants seem like an almost primitive, brute-force technique, and pre or pro-biotics only really focus on one or two single bacterial species.
Reza Ghadiri, from the Scripps Research Institute, has recently developed a new kind of microbiome-modulating treatment. In a presentation at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition, Ghadiri suggests novel peptides can be designed to remodel the microbiome to resemble a bacterial population seen in healthy individuals.
“The gut microbiome contains hundreds of different species of bacteria and is where the largest concentration of bacteria living in us resides,” says Ghadiri. “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.”
The strategy was not to kill harmful bacteria, or transplant beneficial bacteria, but rather remodel a dysfunctional microbiome into a healthy one, using a novel set of peptides designed by his laboratory. Called self-assembling cyclic D, L-α-peptides, these molecules can be specifically engineered to modulate the growth of different bacterial species.
The initial proof-of-concept tests used a classic mouse model for cardiovascular disease. Called LDL receptor knockout mice, these animals remain healthy when fed low-fat diets, but rapidly develop high blood cholesterol and arterial plaques when eating high-saturated fat, or Western diets. The blueprint for a healthy microbiome in the study was the bacterial make-up in the animals when fed a low-fat diet. Using mass screening assay techniques the researchers tested a number of different peptides to discover which molecules most effectively turned an unhealthy microbiome into one resembling those seen in the low-fat eating animals.
After two specific peptides were isolated, the researchers tested the new molecular treatment. Alongside a duo of mouse control groups – one eating a low-fat diet, and one eating a Western-style diet – a third group of animals was fed the peptide treatment with a fatty Western diet. The results were undeniably impressive, with the peptide treatment effectively remodeling the animals’ microbiome to resemble the low-fat eating cohort, as well as significantly improving the animals’ health.
“Mice fed the Western diet with our peptides had a 50 percent 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,” says Ghadiri. “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.”
It is important to note Ghadiri’s research has yet to be peer-reviewed and published in a journal, so plenty of questions do remain regarding the technique’s ultimate safety and efficacy. However, the general concept behind the research is compelling. Instead of trying to kill harmful bacteria, or transplant beneficial bacteria, this hypothesis imagines remodeling, or reconstructing, a dysfunctional microbiome into a healthy one by using highly targeted peptides that can affect a broad number of different bacteria in very specific ways. It may be several years before this kind of work achieves human clinical outcomes but it certainly appears to have the potential to make fecal transplants look like a brutally archaic way of modulating a person’s microbiome.
“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,” says Ghadiri. “This opens up clear therapeutic possibilities. We can sequence the guts of individuals and eventually develop therapies.”
The research was presented at the American Chemical Society Fall 2019 National Meeting & Exposition.
Source: American Chemical Society