Irritable bowel: discovery of the underlying mechanism potentially underlying the disorder

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Researchers from the University of California, San Francisco have uncovered a mechanism that may underlie irritable bowel syndrome, a benign disorder that greatly affects the quality of life of sufferers and affects at least 5% of the French population. (often women). Their experiments in mice revealed the presence of certain intestinal cells whose activity may be responsible for chronic intestinal pain and transit disorders that characterize the disease.

Irritable bowel syndrome (or IBS) is a common gastrointestinal disorder that affects normal bowel function. This causes recurrent abdominal pain (cramps, burning, bloating), diarrhea and/or constipation. People with IBS have more sensitive guts and therefore react poorly to foods that do not cause discomfort to others. High-fat foods, high-fiber foods, alcohol, caffeine, and certain medications or stress are known to cause seizures.

To date, there is no specific treatment for IBS, as its origin remains poorly understood. Treatment of the disease is to reduce the pain and discomfort of patients. Some studies have shown that some patients have increased intestinal permeability, which allows the passage of pro-inflammatory molecules in the body, which may be the cause of a diffuse inflammatory response. Another suggestion suggests that IBS may be the result of an imbalance in the gut microbiota. In the new study, researchers point to enterochromaffin cells that line the gut and become activated when exposed to stimuli.

Cell hyperactivation causing pain

Sensitive signals from the intestine are transmitted to the CNS by primary afferent nerve fibers, including those innervating the intestinal mucosa, where they interact with epithelial cells; the latter include enteroendocrine cells that play a crucial role in the regulation of the gastrointestinal tract, in particular intestinal motility and secretion: they detect various physiological signals and therefore release hormones and neurotransmitters to regulate nutrient absorption and digestion, motility, eating behavior and sensory perception.

Enterochromaffin (EC) cells are an extremely small subpopulation of enteroendocrine cells; they detect environmental and endogenous stimuli that can cause or exacerbate pain, including food irritants, microbial metabolites, inflammatory agents, mechanical swelling, hormones, and stress-related neurotransmitters. When they are activated, they release serotonin. The researchers examined mouse EC cells to determine how much they contribute to visceral pain.

Their experiment consisted of inhibition or activation of rodent EC cells, followed by evaluation of the consequences for the activity, neuroanatomy, and behavior of sensory nerve fibers in the colon. Short chain fatty acids of bacterial origin are known enteroendocrine cell activators; Therefore, EC cells were activated by coating the intestines of mice with isovalerate. The researchers then performed a series of colorectal blistering (to mimic intestinal gas and bloating) and then compared the behavior of the isovalerate-treated animals with the behavior of control animals in the face of the induced pain.

After chemical activation of enterochromaffin cells, male mice were significantly more sensitive to colorectal distension than control animals. In females, susceptibility differed little, regardless of whether they were exposed to the activating agent or not. © J. Byrer et al.

The team was able to observe that male mice that received isovalerate were much more sensitive to stretch (they folded more often under the action of abdominal contractions) than male mice whose intestines were not coated with this fatty acid. On the other hand, female mice showed the same hypersensitivity whether they were exposed to isovalerate or not.

Appropriate therapeutic goal

At the same time, the researchers confirmed that the sensitizing effect of isovalerate is indeed mediated by EC cells: chemical inhibition of the activity of these cells reduces the response of sensory nerves to mechanical irritation of the mucous membrane. “Suppression of EC cell activity has a proportionally greater effect in women. This, and the greater sensitivity of males to isovalerate, suggests that female EC cells have higher basal activity,” the researchers note in their study. This explains why IBS mostly affects women.

Having shown that stimulation of EC cells is sufficient to cause acute visceral hypersensitivity, the researchers investigated whether the chronic pain seen in IBS could be due to long-term activation of EC cells. After administering a EC cell-activating agent to mice for three weeks, they assessed their sensitivity to colorectal distension 72 hours after the cessation of this “treatment”. Result: These mice remained much more sensitive than control mice.

In other words, EC cells can remain active even after irritants have left the gut, which may be one reason why chronic gastrointestinal disorders often develop after food poisoning or infections. It remains to be seen how long this hypersensitivity will last once the irritant is removed, which the team has not yet determined.

Meanwhile, these results suggest that chronic EC cell activation alone is sufficient to cause acute and persistent visceral hypersensitivity and has helped to partially explain the gender disparity observed in IBS. Thus, these intestinal cells may become a new topical therapeutic target for the treatment of chronic visceral pain.

J. Byrer et al., bioRxiv.

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