New York: For some people, a bout of intestinal distress like traveller's diarrhoea leads to irritable bowel syndrome (IBS). Recent discoveries have given researchers a better idea of how this happens, and potential leads for new treatments.
Scientists aren't sure exactly how this happens, but some think an infection may contribute to IBS by damaging the gut nervous system. The study, published in the journal Cell, takes a close look at why neurons in the gut die and how the immune system normally protects them.
The research from Rockefeller University on mice offers insight into IBS, a chronic inflammation of the intestinal tract and could point to potential new treatment approaches. According to the researchers, 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," said study researcher Daniel Mucida, Associate Professor at Rockefeller University in the US.
"Our work explores the complex mechanisms that prevent inflammatory responses from destroying neurons," Mucida added. To understand the effects of an infection on the nervous system, the research team gave mice a weakened form of Salmonella, a bacterium that causes food poisoning, and analysed neurons within the intestine.
They found that when an 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," said study researcher Fanny Matheis.
"We believe these gut neurons may be the only ones to die this way," Matheis added. It's not yet clear exactly how inflammation causes neurons to commit cell suicide, yet the researchers already have clues suggesting it might be possible to interfere with the process.
The key may be a specialised set of gut immune cells, known as muscularis macrophages. Previous work in Mucida's lab has shown that these cells express inflammation-fighting genes and collaborate with the neurons to keep food moving through the digestive tract.
If these neurons die off, as happens in infection, a possible result is constipation -- one of a number of unpleasant IBS symptoms. In their recent report, the team demonstrated how macrophages come to the neurons' aid during an infection, ameliorating this aspect of the disorder.
Their experiments revealed that macrophages possess a certain type of receptor molecule that receives stress signals released by another set of neurons in response to an infection. Once activated, this receptor prompts the macrophage to produce molecules called polyamines, which the researchers think might interfere with the cell death process.
In other experiments, the researchers 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.
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