Source: Thailand Medical News Jan 11, 2020 4 years, 11 months, 1 week, 3 days, 17 hours, 42 minutes ago
At times, 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.
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Medical scientists aren't sure exactly how this happens, but some think an infection may contribute to
IBS by damaging the gut nervous system. A new Rockefeller study takes a close look at why neurons in the gut die and how the immune system normally protects them. With research studies conducted on mice, the experiments described recently in
Cell offer insight on
IBS and could point toward potential new treatment approaches.
Normally, 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.
Dr Daniel Mucida, an Associate Professor and head of the Laboratory of Mucosal Immunology told
Thailand Medical News, "
Inflammation helps the gut ward off an
infection, but too much of it can cause lasting harm. Our work explores the complex mechanisms that prevent
inflammatory responses from destroying neurons."
To explore the effects of an
infection on the nervous system, Mucida and his colleagues gave mice a weakened form of
Salmonella, a bacterium that causes food poisoning, and analyzed neurons within the intestine. 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 biological 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.
Dr Fanny Matheis, a graduate student in the lab added, "This mechanism of cell death has been documented in other types of cells, but never before in neurons. We believe these gut neurons may be the only ones to die this way."
It is 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.
Past 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 an infection, a possible result is constipation, one of a number of unpleasant
-in-gut-bacteria-will-soon-result-in-a-database-that-can-distinguish-ibd-from-ibs">IBS symptoms. In their recent report, the team demonstrate how macrophages come to the neurons' aid during an
infection, ameliorating this aspect of the disorder.
Their research 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 scientists think might interfere with the cell death process.
The researchers found in other experiments, 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.
Dr Paul Muller, a postdoctoral fellow in the lab added, "Using what we learned about the macrophages, one could think about ways to disrupt the
inflammatory process that kills the neurons. For example, it might be possible to develop better treatments for
IBS that work by boosting polyamine production, perhaps through diet, or by restoring gut microbial communities. Since short-term stress responses also appear to have a protective effect, it may also be helpful to target that system.”
Reference : Fanny Matheis et al, Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss, Cell (2020). DOI: 10.1016/j.cell.2019.12.002
