Researchers at KU Leuven in Belgium have found a potential mechanism underlying irritable bowel syndrome (IBS) that involves activation of immune cells primed by past gastrointestinal infections.
Approximately 20 percent of people in the world experience some form of pain or discomfort after a meal. However, IBS patients do not have allergies to any given foods, nor any gastrointestinal conditions, such as celiac disease. Despite this, gluten-free and other diets offer some relief, but it has never been clearly understood why.
Now, new research shows that the immune system may be aberrantly activated in response to certain foods, and that the response may be caused by bacterial infections or bacterial toxins that the intestine was exposed to. The research findings were published in the journal Nature.
The Belgian researchers specifically found that some foods could trigger the activation of mast cells, which in turn release histamine to cause IBS pain. Through laboratory and clinical studies, the scientists discovered that blockade of histamine could help alleviate IBS symptoms.
The new findings unravel a causal, biological mechanism underlying IBS, helping classify it as an actual disease rather than a condition of unknown or vague etiology.
“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 Professor Guy Boeckxstaens, a gastroenterologist at KU Leuven and lead author of the new research, in a statement from KU Leuven regarding the findings. “With these new insights, we provide further evidence that we are dealing with a real disease.”
While diseases like celiac are associated with inappropriate activation of the immune system triggered by food antigens, this is not the case in IBS. In a normal, healthy intestine, foods do not trigger immune responses and so in a patient with IBS, something else must activate the response.
Mouse and Human Studies
The investigators began with the observation that people with IBS often cite that symptoms of the condition arise after a recent bout of a gastrointestinal infection, such as food poisoning. They hypothesized that an infection may sensitize the immune system to a particular food(s) to trigger an immune response against it.
To test their hypothesis in the lab, the researchers infected mice with a stomach bacterium and fed them a protein found in egg white called ovalbumin at the same time (this protein is commonly used as a typical model food antigen in experiments). The mice were fed the protein again after the infection had been cleared, to see whether the infection had sensitized the immune system. Another set of mice were fed just the ovalbumin without being infected.
The results confirmed their hypothesis as the mice that were infected with the stomach bug experienced digestive intolerance along with increased visceral abdominal pain (assessed by abdominal muscle contractions) after being given ovalbumin. Mice that had not been infected did not experience any intestinal issues after ingesting ovalbumin.
Mast Cell Activation
The ovalbumin induced mast cell activation and histamine release, leading to the observed gastrointestinal symptoms. Ovalbumin led to increased dietary-antigen-specific IgE antibodies in the mice that were limited to the intestine.
The researchers pieced together the events and were able to link the observed upregulation of IgE antibodies, activation of mast cells and histamine release to ingestion of the ovalbumin to an increase visceral pain. Importantly, the immune response was only triggered in the portion of the intestine that had been infected by the bacteria. Moreover, the response did not induce symptoms typical of a food allergy.
Professor Boeckxstaens speculated that the findings may be indicative of broader, 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 research team also conducted some clinical studies to see whether the results translated to humans. They injected food antigens associated with IBS (gluten, wheat, soy and cow’s milk) into the intestinal mucosa of 12 IBS patients; this generated localized immune reactions similar to those seen in the mice. No reaction occurred in healthy volunteers.
The researchers say that the findings need further confirmation as the study involved a relatively small number of people.
Nevertheless, the results appear significant, particularly when coupled with previous clinical trial studies that have shown improvements in IBS symptoms when patients are treated with anti-histaminics. “This is further proof that the mechanism we have unraveled has clinical relevance,” said Professor Boeckxstaens.
The antihistamine treatment is currently being evaluated in larger clinical trials. In addition to histamine, mast cells release other immune mediators including various cytokines, proteases and metabolites of arachidonic acid, which could also be therapeutically targeted.
Professor Boeckxstaens said, “But knowing the mechanism that leads to mast cell activation is crucial, and will lead to novel therapies for these patients, [as] 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.”