Published April 7, 2021
Editor’s note: This story first appeared on the IASP Pain Research Forum and has been edited for RELIEF.
Irritable bowel syndrome (IBS) is a mysterious condition that affects an estimated 11 percent of the global population and causes chronic abdominal pain, diarrhea and constipation. With IBS, nerve endings in the gut become hypersensitive, over-reacting to everyday stimuli and often causing debilitating pain. Some people have a “flare” – a painful episode that can last days or weeks – in response to eating certain foods, but researchers have been at a loss as to how foods can trigger IBS pain.
Now, a study in mice and people ties together years of work in the field, offering an elegant explanation for the mystery: an infection, such as food poisoning, can lay the foundation for IBS by causing an immune reaction in the gut, with lasting consequences.
The research team, headed by Guy Boeckxstaens at KU Leuven, Belgium, used a model of IBS in mice to show that painful sensitivity to foods can stem from a gastrointestinal (GI) infection. The immune system responds to foreign invaders and substances, known as antigens. In this case, mice exposed to the egg protein ovalbumin, a food antigen, during a gastrointestinal (GI) infection showed prolonged painful sensitivity to ovalbumin when they ate it later on, even long after the infection had been cleared.
Quite different from a food allergy, this phenomenon was strikingly localized to the colon (large intestine).
“I like this paper quite a lot,” said Karin Westlund High, a pain researcher at the University of New Mexico, Albuquerque, US, who was not involved in the work. “A lot of people have worked on this problem, and this study puts the pieces all in one place and nails down a mechanism. It’s a nice contribution to the field.”
In an accompanying News & Views, Stuart Brierly, a pain researcher at Flinders University, Adelaide, South Australia, wrote that the “study provides information on the mechanisms underlying abdominal pain, and gives added meaning to the saying, ‘you are what you eat.’”
Putting the clues together
Piecing together findings from previous research, Boeckxstaens hypothesized that under certain conditions, immune cells would mount a response to a common and normally harmless food antigen. He postulated that a bacterial infection could trigger such a reaction and that, upon re-exposure to the food, immune cell activation could lead to pain hypersensitivity.
A 2004 milestone study showed that there were more mast cells – a type of immune cell – in the innermost layer of the intestine, called the mucosa, of patients with IBS than in healthy control subjects.
“That set the stage that something is wrong with the mucosal immune system in these patients,” Boeckxstaens said.
Later work from his own group would show that visceral nerves (the nerves that innervate the gut) from IBS patients displayed heightened sensitivity in response to chemicals that activate them. “That was the first functional evidence that there was something different with the neuronal physiology in these patients,” he said.
Breaking oral tolerance
The mouse model of IBS developed by the team rests on the idea of breaking oral tolerance.
Oral tolerance is a phenomenon where the immune system recognizes potentially harmful antigens, in this case foods, but gives them a free pass so that they can be safely digested.
But harmful bacteria and other pathogens that make it down the GI tract don’t get this exception. When the immune system mounts a response to these invaders, it can also react to foods that happen to be present at the scene of the crime.
To model IBS, the researchers infected mice with the bacterium Citrobacter rodentium and also fed the animals drinking water containing ovalbumin (OVA), the egg protein. Five weeks later, after the infection had passed, feeding the mice OVA caused them to have diarrhea. The authors also detected a certain type of antibody, called IgE, specifically in the colon; antibodies are proteins made by immune cells to fight off or isolate antigens.
“In one of the most surprising findings, we found that IgE antibodies were involved,” Boeckxstaens said.
But they did not find IgE in the small intestine or circulating in the blood. “That’s an important finding; it’s a very localized phenomenon. This is what discriminates it from systemic [body-wide] food allergy.”
Following the infection, mice had increased GI pain responses for up to four weeks. When the mice were later fed OVA again, only the mice that had received OVA and the infection together displayed elevated pain responses.
All signs point to mast cells
What explains these findings?
It turned out the coincidence of the infection with OVA was what mattered.
“Oral tolerance was broken because of this ‘bystander’ effect,” Boeckxstaens said. “Because ovalbumin was present at the time of infection, by accident the immune system not only raised a response against the infectious agent – the bacterium – but also to the food antigen.”
The researchers found evidence that mast cells, which are immune cells that release inflammatory chemicals, played a central role in inciting the pain sensitivity.
For instance, when mast cells from mice that had been infected and exposed to OVA were incubated with a part of the egg protein, they degranulated. This is a process where the mast cells become activated and in this case release histamine, a chemical that can inflame the nerves.
Stop mast cells, prevent the pain
Certain drugs used to treat some inflammatory conditions in people work by stabilizing mast cells and preventing them from degranulating. When the researchers treated animals with a mast cell stabilizer, it returned the mice’s pain to a normal level.
Stopping mast cell degranulation could be a successful strategy for IBS treatment, said Richard Traub, who studies visceral pain at the University of Maryland, Baltimore, US, but was not involved in the new study.
“Once the barn door is open, it doesn’t matter if you close it, the horses are out,” referring to mast cell degranulation. “Once they [mast cells] degranulate, giving anything to block further degranulation doesn’t seem to make a difference. Once nerve hypersensitivity develops, it’s there. If you can block sensitization of afferents [sensory nerve fibers], that is going to be beneficial.”
From mice to people
Switching to humans, the researchers next examined fecal samples from IBS patients and healthy volunteers for levels of harmful bacteria. Nearly a quarter of the samples from the IBS patients contained the bacterium Staphyolococcus aureus, compared to only one in ten from the healthy controls.
In an effort to reproduce the mouse findings in people with IBS, the researchers then injected the intestinal mucosa of 12 IBS patients and eight healthy volunteers with a solution containing soy, wheat, gluten and milk – foods that commonly cause irritation in IBS patients in the absence of food allergy.
All of the patients, but only two of the healthy controls, showed an inflammatory gut reaction to the food antigens and had increased indicators of mast cell activity. Upon visual examination of biopsy samples from the volunteers’ guts, the researchers saw similar numbers of mast cells in patients and healthy controls. But those with IBS had more reactive mast cells in closer proximity to visceral nerves, which correlated with how severe the pain was in the patients.
“It’s showing up in a number of autoimmune and inflammatory conditions that immune cells are setting off the nerves,” Westlund High said. “Having these activated mast cells right at the nerve terminals all the time, aggravating them, poises them to explode, really. They’ve shown that again here.”
The work describes an elegant mechanism for how food-related abdominal pain could arise in IBS. It also suggests multiple possibilities for new treatment approaches.
“It seems like pharma could just go on this paper and come up with a whole lot of new treatments for people,” Westlund High said. “That struck me as why this paper is so important.”
The need is great, she added.
“This is such an important area for patients; it’s of broad relevance,” according to Westlund High. While some people have minor IBS symptoms, “there are others who are getting by day to day, hoping not to set off a flare. It’s very debilitating and frankly disabling for people who have true IBS.”
Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD