What if something produced naturally by your gut bacteria could help fight a dangerous foodborne pathogen?
Researchers in Michigan State University's Department of Microbiology, Genetics, & Immunology may have found just such a substance. Academic Research Specialist Ritam Sinha and Rudolph Hugh Endowed Professor and Department Chair Victor DiRita and colleagues discovered that a molecule called indole can inhibit the growth of Campylobacter jejuni, a leading cause of food poisoning worldwide.
Their study, published in Science Advances, builds on years of research in the DiRita lab aimed at understanding how C. jejuni, known to researchers as Campy, manages to thrive in the gut and cause disease.
"Campylobacter is the most common cause of bacterial foodborne illness in the United States, but we still know much less about it than we do about other gut pathogens," DiRita said. "This study gives us a better understanding of the mechanisms that allow Campylobacter to cause disease, but what's particularly interesting is that we identified a molecule produced by the gut microbiome that can inhibit its growth. That opens up the possibility of finding creative new ways to limit infection."
When inflammation changes the gut
Previous research from the DiRita lab offered an important clue about the conditions Campy needs to succeed. Using a ferret model developed by Sinha, the researchers found that intestinal inflammation appears to help Campy grow during infection.
That presented an interesting puzzle. Inflammation is part of the body's response to infection, but in this case, it seemed to be creating an environment that benefited the pathogen. To understand why, the researchers developed a mouse model in which they could temporarily induce intestinal inflammation and study how it changed the conditions inside the gut.
One of the changes they found involved indole, a molecule produced when certain members of the gut microbiome break down tryptophan, an amino acid found in the diet. Indole is naturally present in the intestinal tract of both humans and mice.
When the researchers examined the microbial communities in the mice, one particular change caught their attention.
"We found a significant decrease in the bacteria that produce indole, so we wondered whether indole levels might be lower as well," Sinha said. "When we analyzed indole in the mouse gut, we confirmed this hypothesis."
The researchers then tested whether the loss of indole was simply a consequence of inflammation or whether it might be directly contributing to Campy's success. When they exposed Campy to concentrations of indole similar to those naturally found in the gut, its growth was inhibited. Further experiments showed that indole interferes with Campy's respiration and metabolism, making it more difficult for the bacterium to generate and use the energy it needs to grow.
In other words, inflammation appeared to be doing more than changing the gut environment. By reducing indole-producing microbes and consequently lowering indole levels, it was weakening one of the ways the gut microbiome helps keep Campy in check.
Harnessing a natural defense
Next, the researchers wanted to know if they could take advantage of the natural protection provided by indole.
When they increased indole levels in mice, Campy colonization decreased significantly. They also tested Escherichia coli Nissle 1917, a probiotic bacterium that naturally produces indole, and found that it also reduced Campy colonization. To determine whether indole was responsible for the effect, the researchers compared the probiotic with a version that could no longer produce indole. Lo and behold, that version did not provide the same protection against Campy.
The results raise the possibility that indole, indole-producing microbes or other approaches that support the microbiome's natural defenses could someday provide another way to limit Campy infection. That possibility is especially important as antibiotic resistance in Campy makes some infections increasingly difficult to treat.
The findings are pointing the researchers toward new questions. The team plans to explore whether dietary approaches could be used to influence the gut environment in ways that help control infection. They also want to understand an apparent contradiction at the heart of their discovery: If indole is already naturally present in the human gut and can inhibit Campy, how does the pathogen overcome that protection well enough to cause disease?
As a result, the researchers now plan to investigate how Campy interacts with indole during a more natural infection and whether the pathogen changes the gut environment in ways that help it overcome indole's effects.
"We're still doing a lot of basic research, but that is the foundation for any new therapeutic approaches that we or others might develop," DiRita said. "With increasing levels of antibiotic resistance in Campylobacter, this work is pointing us toward innovative, non-antibiotic ways of controlling infection."
This research was supported by the Michigan State University Rudolph Hugh Endowment.
By Debbie Walton
