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The pain of irritable bowel syndrome may be caused by an immune reaction to food in the gut. 

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What causes irritable bowel syndrome pain? It may be a local immune reaction

For the millions of people with irritable bowel syndrome (IBS), the condition’s cramping, diarrhea, and constipation are frustrating and distressing. And it’s made worse when doctors sometimes dismiss the symptoms, attributing them to anxiety or even the imagination—“all in the mind or between the ears,” says Guy Boeckxstaens, a gastroenterologist at KU Leuven.

It’s an argument Boeckxstaens rejects, and for years he’s sought to understand one hallmark of IBS: abdominal pain brought on by eating. This week, he and more than 40 colleagues present data to support a new hypothesis, that this pain is caused by a kind of localized allergic reaction to food in the gut.

“Many patients believe they are allergic to something,” but food allergy tests of the blood find no evidence of that, says Robin Spiller, a gastroenterologist at the University of Nottingham who was not involved in the research. “The idea that you can have a specific allergic response going on in the gut” is “a really new concept.”

One of the first clues to explain the pain emerged about 15 years ago, when researchers uncovered something intriguing in IBS patients. “The immune system was different,” says Giovanni Barbara, a gastroenterologist at the University of Bologna who led the work. In biopsies of intestinal tissue from patients, immune cells called mast cells were activated; normally, mast cells act as a sort of alert system for the body, spewing out chemicals such as histamine when threatened with infection or other threats, like parasites. But in these IBS patients—who had no active infections—not only were mast cells activated, they were in unusually close proximity to nerve cells and caused them to fire excessively. “I remember when I started showing this data, everybody was smiling and laughing,” Barbara says. “Nobody believed me,” he adds, because many physicians and researchers doubted that the pain of IBS was rooted in gut biology.

But Boeckxstaens was intrigued and set out to learn more. His team started with a known trigger of IBS, intestinal infections, which can range from acute food poisoning to mild disease with few symptoms. Studies suggest about 10% of previously healthy people recover from their infections but are left with IBS. One hypothesis suggests that after infection, low-grade inflammation can persist in the gut, leading to chronic pain. Yet Boeckxstaens had previously examined intestinal biopsies of IBS patients and hadn’t found inflammation.

Instead, he had another idea: A gut infection disrupts how the organ tolerates protein fragments called antigens, which are present in many foods. When battling an infection, the intestine’s immune system is revved up and may mistakenly perceive food antigens as enemy forces. And if a gut reaction to food antigens persists after infection abates, that could explain the pain and cramping that often accompany a meal.

To test this, Boeckxstaens and colleagues infected mice with harmful gut bacteria, and at the same time fed them antigens from egg whites. After the gut infection cleared, the mice ingested the antigens again—and this time, they seemed to experience abdominal pain, as measured by stomach muscle contractions. Mice that didn’t get egg white protein while they were infected had no trouble.

Probing further, the researchers found that after an infection, the egg white protein set off a chain reaction similar to what happens in food allergies. The egg white protein anchored itself to antibodies called immunoglobulin E (IgE), which are bound to mast cells. In the mice—as in people with food allergies—this caused mast cells to become activated and release their chemicals. The reaction to egg protein persisted for the 4 weeks the researchers followed the mice. And it also underscored the interplay between mast cells and nearby gut neurons that Barbara had observed years earlier: If mast cells were shooting out chemicals, that could cause neurons to become hypersensitive and more excitable, which the body would interpret as pain.

“This can open people’s minds” to the idea that IBS pain is rooted in biology, says Bana Jabri, a pediatric gastroenterologist and mucosal immunologist at the University of Chicago. Jabri has pursued a similar line of inquiry into celiac disease, in which patients can’t tolerate gluten, and reported with colleagues in 2019 that ingesting gluten causes a strong immune reaction specific to the substance, which in turn drives abdominal symptoms such as pain and nausea.

Boeckxstaens cautions that what his mice experienced isn’t a food allergy because of one key difference: The immune reaction was localized to the gut. In people allergic to, say, peanuts or cow’s milk, IgE antibodies circulate in blood, and an allergic reaction can cause symptoms all over the body. In these mice, blood tests didn’t detect IgE suggesting an egg white allergy.

Was the same true in people with IBS? Boeckxstaens’s group tested 12 people with the condition for four common food allergies: to cow’s milk, gluten, wheat, and soy. All were negative. Then the researchers injected these potential allergens rectally. Subsequent tests found every volunteer had a localized reaction to at least one of the antigens. The same tests on eight healthy volunteers turned up only two people who each had a borderline gut reaction to either soy or gluten, they report today in Nature. (Boeckxstaens suspects some unaffected people may have mild reactions, too, which their gut can tolerate; these two volunteers had no symptoms.)

“It’s pretty novel and thought-provoking,” says Daniel Mucida, an immunologist at Rockefeller University, who says the findings raise many new questions. If the mouse’s localized IgE reaction also happens in people with IBS, he wonders whether it is specific to certain foods—as the study in mice was structured to test—or is more general. Another line of inquiry involves treatment. Currently, IBS treatments focus on allaying symptoms, because the condition’s causes have been murky. But if mast cells and IgE are driving symptoms, at least in some cases, immune therapies targeting them could prove useful.

Finally, Mucida wonders whether this immune reaction appears in different types of IBS. Infection-induced IBS is just one category, but there are others, including IBS linked to stress. Boeckxstaens is exploring that question now, studying whether in mice, stress alone can induce a similar immune cascade in the gut.