How a gut infection may cause chronic symptoms

Sometimes the end of an intestinal infection is just the beginning of more misery.

Of those who contract traveler’s diarrhea, for example, an unlucky few go on to develop irritable bowel syndrome (IBS), a chronic inflammation of the intestinal tract.

Scientists aren’t sure exactly how this happens, but some think an infection may contribute to IBS by damaging the gut nervous system.

In a new study, researchers looked at why neurons in the gut die and how the immune system normally protects them.

Their findings may offer insight on IBS and could point toward potential new treatment approaches.

The research was conducted by a team at Rockefeller University.

In a healthy gut, the immune system must strike a careful balance between responding to threats and keeping that response in check to avoid damage.

Inflammation helps the gut ward off an infection, but too much of it can cause lasting harm.

In the study, the team examined the complex mechanisms that prevent inflammatory responses from destroying neurons.

To understand the effects of an infection on the nervous system, they analyzed neurons within the intestine in mice with a weakened form of Salmonella.

They found that infection-induced a long-lasting reduction of neurons, an effect they attributed to the fact these cells express two genes, Nlrp6 and Caspase 11, which can contribute to a specific type of inflammatory response.

This response, in turn, can ultimately prompt the cells to undergo a form of programmed cell death.

When the researchers manipulated mice to eliminate these genes specifically in neurons, they saw a decrease in the number of neurons expiring.

This mechanism of cell death has been documented in other types of cells, but never before in neurons. The researchers believe these gut neurons may be the only ones to die this way.

It’s not yet clear exactly how inflammation causes neurons to commit cell suicide, yet the scientists already have clues suggesting it might be possible to interfere with the process.

The key may be a specialized set of gut immune cells, known as muscularis macrophages.

The researchers also found that Salmonella infection alters the community of microbes within the guts of mice—and when they restored the animals’ intestinal flora back to normal, the neurons recovered.

They say it is possible to develop better treatments for IBS that work by boosting polyamine production, perhaps through diet, or by restoring gut microbial communities.

The lead author of the study is Daniel Mucida, an associate professor and head of the Laboratory of Mucosal Immunology.

The study is published in Cell.

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