Bacteroides fragilis, bacteria known for their protective role in the gut, change their gene activity and behavior according to where in the gut they reside, a study in mice has found.
These findings suggest that understanding the mechanisms that allow bacteria to set up residency in a specific location in the gut may help develop strategies that promote those that benefit the gut while halting those that promote chronic conditions, such as inflammatory bowel disease (IBD).
The study, “Spatially distinct physiology of Bacteroides fragilis within the proximal colon of gnotobiotic mice,” was published in the journal Nature Microbiology.
The mammalian gut harbors bacteria, fungi, and viruses (collectively known as the gut microbiome) which perform key functions, including assisting in digestion and protecting the gut from harmful pathogens. However, the bacterial composition varies along the entire length of the gut, and it is still unknown whether bacteria behave differently based on their location.
In the study, researchers at the California Institute of Technology (Caltech) and colleagues at the Broad Institute of MIT and Harvard explored how Bacteroides fragilis (B. fragilis) — bacteria commonly found in the gut — change their behavior according to their location.
Previous studies have shown that B. fragilis produces protective molecules that halt the development of IBD.
B. fragilis is mostly present in the internal part of gut called the lumen, yet some of these bacteria have been found living within the surface lining that covers the gut, or the intestinal epithelia. These scarce colonies are covered by mucus that protects them from antibiotics. This finding led scientists to think that these colonies were responsible for re-populating the gut.
To better understand the roles of these two bacterial populations (in the gut lumen and in the intestinal epithelia), the researchers investigated the bacteria’s genetic activity by measuring the levels of RNA (the blueprint copy of DNA to convert messages contained in genes into proteins).
The team hypothesized that despite the fact that bacteria in the lumen and intestinal epithelia share the same DNA, they might activate genes differently depending on their location.
“For humans, where we live can dictate how we behave — for example, a person living in a city likely has a different everyday life than a person living in a small rural community,” Gregory Donaldson, PhD, one of the study’s co-leading authors, said in a Caltech news story.
“For the bacteria that we study, the intestines represent their entire world, so we wanted to know how differently they behave depending on how far away from the intestinal surface they are,” he said.
To test their hypothesis, the researchers used a mouse model colonized with B. fragilis only. Using an innovative genetic technique that allows the selection of bacterial RNA (which is generally limited compared to mammalian RNA), the researchers were able to study the bacteria’s gene activity. The genetic tool, called hybrid selection RNA-sequencing, was developed by a group led by Ashlee Earl, PhD, at the Broad Institute.
“Inspired by a previous approach to sequence small populations of parasites in human blood, we developed a technique that could boost the amount of bacterial RNA we could detect in these host-rich samples by orders of magnitude,” Earl said.
“This technique not only helped to reveal a new aspect of the Bacteroides-host relationship, but now provides us with a more general tool for listening in on conversations between humans and their rarest inhabitants,” she added.
The results showed that bacteria residing deep in the gut lumen are mainly dedicated to the digestion of food and nutrients, focusing more on surviving than growing. In contrast, bacteria found at the intestinal epithelia have an extremely active metabolism and are more focused on growing, despite their lower numbers.
In particular, the researchers found the sulfatase and glycosyl hydrolase genes seemed to be crucial for B. fragilis colonization of the intestinal epithelia. When they mutated these genes, bacteria were no longer able to grow and live close to the intestinal wall, at the intestinal epithelia.
These results suggest that B. fragilis is well-adapted to live at the epithelial surface, and that this is its preferred habitat.
“While we know a great deal about which bacteria reside in humans through DNA sequencing techniques and how microbial community membership changes as a result of disease or other factors, we know far less what bacteria are doing while living inside of us,” said Sarkis Mazmanian, PhD, co-lead author of the study.
“For the first time, this work gives us a glimpse into the lifestyle and behavior of an important human gut bacteria, while colonizing mice,” he said. “Knowing what key bacteria are actually doing in the gut may help develop rationale and robust therapies from the microbiome.”
As B. fragilis in the gut is known to have a protective effect, understanding how bacteria establish residency in the gut may help scientists to find ways to normalize gut equilibrium in diseases such as IBD.
The researchers may apply their strategy in the future to study other microorganisms, such as disease-causing bacteria that colonize the gut.
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