KU Leuven researchers have identified the biological mechanism that could explain why some people experience abdominal pain when they eat certain foods. Their studies, carried out in mice and in humans, suggest a mechanism that links certain foods with a local immune response, the activation of mast cells—which release histamine—and subsequent pain and discomfort. The findings could pave the way to the development of more efficient treatments for irritable bowel syndrome (IBS) and other food intolerances.

“Very often these patients are not taken seriously by physicians, and the lack of an allergic response is used as an argument that this is all in the mind, and that they don’t have a problem with their gut physiology,” said research lead Guy Boeckxstaens, MD, PhD, a gastroenterologist at KU Leuven. “With these new insights, we provide further evidence that we are dealing with a real disease.” Boeckxstaens and colleagues reported on their findings in Nature, in a paper titled, “Local immune response to food antigens drives meal-induced abdominal pain.”

Up to 20% of the world’s population suffers from IBS, which causes stomach pain or severe discomfort after eating, and can affect quality of life. Gluten-free and other diets can provide some relief, but why this works is a mystery, since IBS patients are not allergic to the foods in question, nor do they have other known conditions such as celiac disease. “IBS is a debilitating and difficult-to-treat condition for which no curative therapies are currently available,” the investigators stated. “Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown.”

Abnormal intestinal pain, or visceral hypersensitivity (VHS), is a hallmark symptom of IBS, and it has been proposed that an increase in the numbers of mast cells and release of mast cell mediators, underlies this VHS, the team further noted. Interestingly, earlier work by Boeckxstaens and his colleagues had shown that blocking histamine, an important component of the immune system, can help to improve IBS in patients with the condition.

In a healthy intestine, the immune system does not react to foods, so the first step for the KU Leuven team in their latest studies was to find out what might cause this tolerance to break down. It has been reported that gastrointestinal infections can represent a significant risk factor for subsequent development of IBS, and people with IBS often report that their symptoms started after a gastrointestinal infection, such as food poisoning. “Between 3 and 36% of enteric infections lead to new-onset IBS, and up to 17% of patients with IBS report that their symptoms started upon gastrointestinal infection,” the scientists commented.

This gave the researchers the idea that an infection while a particular food is present in the gut might sensitize the immune system to that food. To investigate this they infected mice with the intestinal pathogen Citrobacter rodentium, and at the same time fed the animals ovalbumin (OVA), a protein found in egg white that is commonly used in experiments as a model food antigen. Once the infection had cleared, the mice were given ovalbumin again, to see if their immune systems had become sensitized to it. The investigators found that in mice that had previously been given ovalbumin and infected with the stomach bug, subsequent administration of ovalbumin on its own provoked mast cell activation, histamine release, and digestive intolerance, with increased abdominal pain. These animals also exhibited a leaky gut. In contrast, the control animals that had previously been given ovalbumin without the stomach infection weren’t affected by subsequent ovalbumin administration.

The researchers were then able to unpick the series of events in the immune response that connected the ingestion of ovalbumin to activation of the mast cells. Significantly, this immune response only occurred in the part of the intestine infected by the C. rodentium bacteria, and did not produce more general symptoms of a food allergy. “Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain,” the authors wrote. “ … we show that bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine.”

Interestingly, the immune response could be inhibited by either treating the animals with an antibody against IgE, or by genetically knocking down IgE. “To further investigate the role of the antigen-specific immune response to OVA in VHS, we treated mice with a monoclonal anti-IgE antibody,” they explained. “This treatment prevented the development of VHS and the increase in colonic permeability upon re-exposure to OVA. We confirmed these results in IgE-deficient (Igh7-/-) mice.” Inhibiting mast cell activation also prevented VHS, the team further demonstrated. “Notably, treatment with the mast cell stabilizer doxantrazole and genetic ablation of mast cells normalized and prevented, respectively, VHS and decreased colonic permeability.”

The researchers next wanted to investigate if the immune systems of people with IBS reacted in the same way. They injected food antigens associated with IBS (gluten, wheat, soy, and cow milk) into the intestine wall of 12 volunteers with IBS, and another 8 healthy controls. The injections resulted in all of the IBS group generating localised immune reactions similar to that seen in the mice, to at least one of the food antigens. No reaction was seen in healthy volunteers.

“A key breakthrough proposed here is the understanding of how oral tolerance to food antigens, a pivotal regulatory process in homeostasis, can be lost in IBS and lead to aberrant pain signaling,” the team stated. “A fundamental difference from food allergy is that OVA-specific IgE antibodies were detected only in colonic tissue, indicating a local rather than systemic immune response against dietary antigens.”

Boeckxstaens speculated that the findings point to a potential spectrum of food-related immune diseases. “At one end of the spectrum, the immune response to a food antigen is very local, as in IBS. At the other end of the spectrum is food allergy, comprising a generalized condition of severe mast cell activation, with an impact on breathing, blood pressure, and so on.”

The reported study involved a relatively small number of people, and so the findings will need to supported by additional research, but the results do appear significant when considered alongside earlier clinical trials showing improvement during treatment of IBS patients with antihistaminics. “This is further proof that the mechanism we have unraveled has clinical relevance,” Boeckxstaens said. A larger clinical trial of the antihistamine treatment is currently underway. “But knowing the mechanism that leads to mast cell activation is crucial, and will lead to novel therapies for these patients,” Boeckxstaens continued. “Mast cells release many more compounds and mediators than just histamine, so if you can block the activation of these cells, I believe you will have a much more efficient therapy.”

The authors concluded, “Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorder … “IgE-mediated activation of mast cells could be of interest as a prognostic biomarker as well as a therapeutic target in patients with IBS.”

They point out that improvement of IBS symptoms has been reported in patients with severe asthma, who were treated with omalizumab, a monoclonal antibody against IgE. “Therefore, our findings set the stage for further studies of the potential of therapies that target upstream mechanisms of mast cell sensitization and/or activation ….”

Writing in an accompanying News & Views article in Nature, titled, “Food for Thought about the immune drivers of gut pain,” Stuart M. Brierley, PhD, professor at the College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, said the study adds new meaning to the saying “you are what you eat.’ The KU Leuven team’s results present different potential options for treatment, he commented. “These include: improving intestinal-barrier function to reduce gut access to the intestinal immune system; targeting IgE antibodies that are specific to the food substance of interest; reducing mast-cell degranulation; targeting molecules released by mast cells or the receptors on which they act; and blocking the colonic sensory nerves that transmit the noxious information and cause pain.”

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