Bacteroides gut bacteria may ease inflammation in CF lungs

Anti-inflammatory effects observed in blood, airways of mouse model

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Gut bacteria called Bacteroides had anti-inflammatory effects in the blood and airways of a mouse model of cystic fibrosis (CF) via its production of an immune-modulating metabolite called propionate, a study finds.

The findings add to evidence of a so-called gut-lung axis, where microbes in the gut can influence lung health. They also suggest that supplementing the body with Bacteroides could have clinical benefits for CF patients.

“We think this establishes the idea that changes in the gut are causing a reprogramming of the immune system in such a way that the body isn’t as sensitive to subsequent airway infections, so you don’t have as much disease burden,” George O’Toole, PhD, professor at Dartmouth University’s Geisel School of Medicine and the study’s senior author, said in a press release.

The study, “Intestinal Bacteroides modulates inflammation, systemic cytokines, and microbial ecology via propionate in a mouse model of cystic fibrosis,” was published in mBio.

In CF, the CFTR protein that helps move salt into and out of cells is missing or dysfunctional, leaving them unable to properly regulate the flow of salt and water, and leading to thick, sticky mucus building up, which offers a fertile breeding ground for harmful bacteria, called opportunistic pathogens. In the lungs, these illness-causing microbes outnumber healthy bacteria that normally live there and lead to chronic infections that contribute to declines in lung function.

It’s been recently recognized that the collection of microbes in the gastrointestinal tract, called the gut microbiome, is also impaired in CF and the CF gut shows evidence of increased inflammation.

In more than a decade of research, O’Toole and his colleagues discovered that an altered gut microbiome in CF affects more than the intestines. Microbial changes there correlate with lung function outcomes, a connection known as the gut-lung axis.

“Surprisingly, the best predictor of how a kid’s airway would function actually turned out to be the microbes in their gut rather than the microbes in their airway,” O’Toole said. “We also had noticed that kids with CF were depleted for Bacteroides, a microbe known to be important in programming gut function and the immune system early in life.”

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This led the researchers to explore whether a lack of Bacteroides, which generally plays a beneficial role, might lead to immune alterations that promote inflammation and clinical worsening in CF.

Intestinal cells engineered to be without CFTR were grown in the lab and treated with Bacteroides that had been isolated from the stool of children with or without CF. From this, the researchers found that bacteria from either source were able to dampen production of an inflammatory molecule called IL-8 that’s been linked to worse lung function in CF, and that its ability to do so was dependent on a molecule called propionate.

Propionate is a type of short-chain fatty acid, a family of metabolites generated by bacteria in the gut during chemical reactions. These molecules play an important role in the microbiome and are involved in regulating inflammatory responses.

The researchers then experimented with a mouse model of CF where the natural microbiome was depleted with antibiotics and then repopulated using stool samples from children with CF, some of which had been supplemented with Bacteroides.

As expected, introducing Bacteroides led to increased propionate levels in the stool.

All the mice were then exposed to an inflammation-stimulating molecule produced by Pseudomonas aeruginosa, the bacteria that most commonly causes CF lung infections.

Bacteroides-supplemented mice had lower levels of a number of pro-inflammatory molecules called cytokines in their bloodstream after the inflammatory challenge.

Again, the anti-inflammatory effects of Bacteroides appeared dependent on propionate. Mice exposed to the strain of the bacteria that can’t produce propionate had higher levels of certain inflammatory molecules in their blood and lungs than mice exposed to a standard propionate-producing strain.

Propionate is likely not the only metabolite having anti-inflammatory effects, the researchers said. “It may be a suite of metabolites produced by Bacteroides … that together most effectively modulate systemic production of cytokines,” they wrote.

The scientists believe their findings suggest that Bacteroides-containing probiotics — supplements of live beneficial bacteria — could modulate lung inflammation and influence clinical outcomes in CF patients.

“This actually provides, we think, a proof of concept that probiotics could be beneficial to kids with CF, so it could have important implications for treatments,” O’Toole said.