More than 10,000 different bacterial species occupy the human body, outnumbering human cells ten to one. At first glance, those numbers may seem alarming, but fear not, we need these bacteria to live normal, healthy lives. These bacteria—from the ones in our stomachs to those on our skin—have a symbiotic relationship with us: we provide them with the nutrients they need to survive, and they help us digest food and defend our body against disease-causing agents. Our lives are so intertwined with these helpful bacterial species that the bacteria have perhaps learned how to speak the language of human cells. Researchers at Rockefeller University have identified gut bacteria that produce signaling molecules that can interact with human cells, opening the door for a wide variety of medical treatments for various gastrointestinal disorders.
“The majority of FDA-approved drugs are either copies of, or inspired by, naturally-occurring compounds,” says Sean Brady, a professor at Rockefeller University whose lab conducted the study. According to Brady, bacteria are an incredibly common source for those compounds. “Most of our antibiotics and immunosuppressants come from looking at products produced by bacteria,” Brady said. Many of these drugs were found by searching soil bacteria to see if they produced molecules with antibiotic properties, which is one of the main focuses of Brady’s lab. However, in this project, the lab decided to screen the human microbiome—the set of bacteria that live within the human body—for molecules that might be able to interact directly with human cells. The crux of the idea is simple: these bacteria already live in our bodies, so researchers wanted to find out whether we can use these microbes to manipulate human physiology.
To get there, the scientists had a challenge to overcome: searching through the thousands of bacterial species living in the human body to find just one or two that can “talk” to human cells. A few decades ago, researchers would have had to do so by hand, culturing every bacterial strain individually and testing it for active molecules. In the twenty-first century, however, this task is much more feasible. The researchers had already identified one bacterial molecule, commendamide, that interacted with a class of human cell receptors called G-protein coupled receptors (GPCRs). Commendamide is an N-acyl amide, a type of biologically active organic molecule, that is often produced by bacteria. Taking advantage of this fact, the researchers used the Human Microbiome Project database to search for all of the bacterial genes in the human microbiome encoding proteins that can produce N-acyl amides like commendamide. They identified a total of 143 human microbial genes that code for such proteins, of which 44 were unique enough to merit testing in the lab for biological activity. The researchers determined that these 44 genes comprised six distinct classes of N-acyl amides that are naturally produced by bacteria, four of which are produced by gut bacteria.
The bacterial molecules identified by the researchers are quite similar to signaling molecules already produced by the human body; their structures mimic human signaling molecules incredibly closely. Furthermore, the bacterial molecules bind to the GPCR receptors just as well as the human signaling molecules do, such that the physiological result of GPCR activation is indiscernible between the human and bacterial molecules. Brady hypothesizes that as we learn more about the chemistry of the human microbiome, we’re going to find more cases of bacterial mimicry in the future. “More and more often you’re going to find molecules that maybe aren’t identical to, but resemble, the molecules that we as humans already make to target our own receptors,” Brady said.
Since the molecules these bacteria produce have such a strong effect on human physiology, the researchers decided to see if they can harness that ability for medical purposes. These commensal bacteria can interact with GPCRs, which is a lucky coincidence for researchers because GPCRs are implicated in a wide variety of metabolic disorders. These receptors are the largest and most diverse group of human cell receptors, and GPCRs make up about one third to one half of all drug targets are. Many GPCRs are located in the human gut as well, which is where the N-acyl-amide-producing bacteria were isolated from. In fact, GPCRs in the gut have been implicated in hunger, glucose absorption, and diabetes, which is exactly what the researchers decided to study.
The different N-acyl amide ligands were surveyed to see if they would bind to 240 different GPCRs. Of these, one GPCR in particular—denoted GPR119—bound the bacterial molecules particularly well. GPR119 is implicated in the regulation of glucose homeostasis, and has historically been a drug target for Type 2 Diabetes. Specifically, activation of GPR119 receptors in the gut can prevent the rapid change of blood sugar levels in hyperglycemic patients. Brady and his team wanted to see that activation of GPR119 with the bacterial N-acyl amides could produce the same effects as human signaling molecules.
To see if the bacterial molecules were capable of affecting GPR119 receptors strongly enough to regulate glucose levels, the researchers infected mice with E. coli engineered to produce the molecules of interest. They then measured the blood sugars of the mice. As predicted, the mice that were infected with N-acyl-amide-producing bacteria had lower blood sugar levels than mice that weren’t infected with the genetically engineered bacteria. This shows that some bacteria produce biologically active molecules that not only can interact with GPR119 in the gut, but can also regulate blood sugar in ways similar to many blood sugar medications.
Like any recently published study, these findings still have a long way to go from the lab to becoming viable medical treatments for diseases like diabetes. According to Brady, human physiology is incredibly complicated, and people are still working on how to apply these findings in mice and cell culture models to the human body. But that doesn’t stop Brady and his team from thinking about ways that these bacterial molecules could be harnessed as a drug. He suggests that perhaps people can ingest the pure molecule just like any other drug. “You could also imagine introducing the organism regularly, like in a yogurt,” Brady said. This is perhaps more enjoyable than taking a pill! Whatever the mode of action, these commensal bacteria provide us with ways to manipulate the human body in new, inventive, and potentially less invasive ways in the hopes of providing new treatments for common diseases.