Gut neurons help prevent tissue over-inflammation

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As the guardian of our health, the immune system has to sense and react to pathogens to eliminate them, but not so fiercely as to over-inflame and damage tissue. The need for this balance is most apparent in the gut - which is continually under threat from bacteria like Salmonella that could be lurking in the food and drink that we ingest.

 The researchers say they now have a much better idea of how neurons and macrophages in the gut work together to help prevent damage from inflammation.
 
Now, a new study - by researchers at Rockefeller University, New York, NY, and published in Cell - shows that neurons in the gut appear to work with cells of the immune system to fine-tune this balance and prevent over-inflammation of intestinal tissue.

Senior author Daniel Mucida, an assistant professor and head of Rockefeller's mucosal immunology lab, says:
"Resistance to infections needs to be coupled with tolerance to the delicacy of the system. Our work identifies a mechanism by which neurons work with immune cells to help intestinal tissue respond to perturbations without going too far."

 He and his colleagues believe their findings could help develop new treatments for gastrointestinal diseases, such as irritable bowel syndrome (IBS).

Prof. Mucida explains that the lining of the human gut - known as the human intestinal mucosae - has a total surface area of about 300 m² and is the largest surface of the body that is exposed to potential pathogens from the environment. The gut absorbs around 100 g of dietary proteins a day and is home to around 100 trillion "friendly" bacteria.

To maintain immune protection over such a large area, there are more white blood cells in the gut than in the whole of the rest of the human body.

The study concerns itself with two types of large white blood cell known as macrophages: lamina propria macrophages (found close to the lining of the gut and thus close to the food as it is digested) and muscularis macrophages (found in much deeper-sited tissue, further away from food as it digests).

Muscularis macrophages 'almost hug the neurons'

Using a 3D imaging system, the researchers looked for differences in the cell structures of the two types of macrophage. As well as noticing differences in the structure and movement of the cells, the team found they surround neurons in the gut wall.

With the help of "transcriptional profiling tools," the researchers also found the different types of macrophage had different groups of genes switched on and off - they had different gene expression profiles - in the presence of an infection.

The lamina propria macrophages appeared to express more pro-inflammatory genes, while the muscularis macrophages favored anti-inflammatory genes.

Prof. Mucida says they wanted to know what was telling the macrophage genes to have these different responses to infection and explains:
"We came to the conclusion that one of the main signals seems to come from neurons, which appear in our imaging to almost be hugged by the muscularis macrophages."


In further tests, the team found that receptors on the surface of the muscularis macrophages respond to norepinephrine, a signaling chemical or neurotransmitter that is released by neurons. They suggest this be could a route through which gut neurons control inflammation.

The team also found the muscularis macrophages are activated much faster via the neuron route than when summoned by other immune cells. They suggest this is how the cells are able to respond to infection very quickly - within 1 or 2 hours - despite being deeply embedded in the gut wall and far away from the source of infection.

Prof. Mucida says they now have a much better idea of how neurons and macrophages in the gut work together to help prevent damage from inflammation, and he concludes:

"It's plausible that a severe infection could disrupt this pathway, leading to the tissue damage and permanent gastrointestinal changes that are seen in diseases like irritable bowel syndrome. These findings could be harnessed in the future to develop treatments for such diseases."

New studies are also uncovering that the friendly bacteria that live in and on our bodies help regulate immunity. For instance, Medical News Today recently learned of a study that shows how - once considered as sterile - the lungs are home to bacteria that help regulate the immune system through interaction with specialized cells called dendritic cells.