Working on the premise that an intestinal infection may contribute to the development of irritable bowel syndrome (IBS) by damaging the gut nervous system, scientists at the Rockefeller University carried out a study (“Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss”), published in Cell, that takes a close look at why neurons in the gut die and how the immune system normally protects them.
Conducted with mice, the experiments offer insight on IBS and could point toward 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 Daniel Mucida, PhD, an associate professor and head of the Laboratory of Mucosal Immunology. “Our work explores the complex mechanisms that prevent inflammatory responses from destroying neurons.”
To understand 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 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.
“Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility and nutrient sensing. Bidirectional interactions between neuronal and immune cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated the effects of infection-induced inflammation on intrinsic EANs (iEANs) and the role of intestinal muscularis macrophages (MMs) in this context. Using murine models of enteric infections, we observed long-term gastrointestinal symptoms, including reduced motility and loss of excitatory iEANs, which was mediated by a Nlrp6- and Casp11-dependent mechanism, depended on infection history, and could be reversed by manipulation of the microbiota,” the investigators wrote.
“MMs responded to luminal infection by upregulating a neuroprotective program via β 2-adrenergic receptor (β 2-AR) signaling and mediated neuronal protection through an arginase 1-polyamine axis. Our results identify a mechanism of neuronal death post-infection and point to a role for tissue-resident MMs in limiting neuronal damage.”
“This mechanism of cell death has been documented in other types of cells, but never before in neurons,” said Fanny Matheis, a graduate student in the lab. “We 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.
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 an 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 scientists 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. When they restored the animals’ intestinal flora back to normal, the neurons recovered.
“Using what we learned about the macrophages, one could think about ways to disrupt the inflammatory process that kills the neurons,” said Paul Muller, PhD, a postdoctoral fellow in the lab.
For instance, 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, Muller thinks it may also be helpful to target that system.