New Study Provides Evidence That Food Sensitivities Are Real
Research demonstrates the role of localized mast cell activation in meal-induced abdominal pain
Up to 20 percent of the world’s population reports having food allergies or intolerances, which can substantially reduce quality of life and contribute to financial burden. Food intolerances, in particular, are especially common among patients with irritable bowel syndrome (IBS), with 84 percent reporting more pronounced symptoms with certain foods.
Food Allergies vs Food Intolerances
Traditionally, allergies have been considered distinct from food intolerances since the former comprise an immunological reaction while the latter involve the digestive system. However, this method of differentiating between the two is illogical. For one, gastrointestinal involvement does not preclude an immune system response, as the gut lining is home to 70% percent of the immune system in the form of GALT, or gut-associated lymphoid tissue.
The immune cells that comprise GALT are far more numerous than those associated with other secondary lymphoid tissues and interact with trillions of gut microbiota community members, including bacteria, archaea, and eukaryotes. Interfacing between the host immune system and the digestive tract, GALT plays a crucial role in promoting oral tolerance, the ability to discriminate between friend and foe, and determines whether an individual will experience food allergies or sensitivities.
A 2015 review article in Frontiers of Microbiology summarizes, “GALT is necessary for preventing acute proinflammatory immune responses against the microbiota resulting in inflammatory bowel diseases or against food protein causing food allergy and celiac disease.” In other words, the superficial distinction between the digestive and immune systems is inaccurate and unnecessary, as the two are inextricably linked.
Still, one might argue that food allergies are still distinct from food intolerances because, in contrast to the latter, the former are mediated by immunoglobulin E (IgE) antibodies, which play an important role in hypersensitivity reactions and response to parasitic infection. But as we’re about to discover, even this assumption may be incorrect.
Many patients with IBS report developing long-term symptoms after gastrointestinal infection, which can certainly disrupt gut homeostasis and interfere with oral tolerance. Postprandial abdominal pain and discomfort, or visceral hypersensitivity (VHS), is a hallmark symptom that may be mediated by mast cells. A recent study published in Nature examined possible post-infectious consequences of gut infection more closely in both mice and humans.
Gut Infection Predisposes Mice to Food Sensitivity Reactions
Researchers at KU Leuven first infected mice with the intestinal pathogen Citrobacter rodentium while simultaneously exposing them to ovalbumin (OVA), a protein that is found in egg whites and commonly used as a model antigen in experiments. Even after the enteric infection had been cleared, repeated exposure to ovalbumin triggered mast cell activation, histamine release, and visceral hypersensitivity. The rise in OVA-specific IgE antibodies in the colon was also accompanied by increased mucosal permeability, a phenomenon commonly referred to as “leaky gut.”
In contrast, the control mice who first received ovalbumin in the absence of C. rodentium infection remained unaffected by subsequent OVA administration. The researchers discovered that treating infected mice with antibodies that neutralize IgE prevented the development of visceral hypersensitivity and intestinal hyperpermeability upon re-exposure to the allergen. Treatment with the mast cell stabilizer doxantrazole was also effective.
Of note, the mast cell activation that occurred in response to ingestion of ovalbumin was localized to the area of the intestine affected by the C. rodentium infection. “Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain,” the authors explained. “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.”
Evidence of Localized Mast Cell Activation in Patients with IBS
Next, researchers shifted their focus to patients with IBS to determine whether localized immune activation occurs in humans. Solutions of soy, wheat, gluten, and milk were injected into the colonic mucosa of 12 individuals with IBS and 8 healthy volunteers. All twelve individuals in the IBS group demonstrated colonic mucosal reactions to at least one of the foods tested, compared to only two of the healthy controls. While total numbers of mast cells did not differ between the two groups, patients with IBS had more IgE positive mast cells in close proximity to nerve fibers than healthy controls.
In line with the team’s findings, a case report from 2015 described a patient with severe asthma whose IBS symptoms were almost completely resolved after treatment with omalizumab, a monoclonal antibody against IgE. The paper noted, “This observation suggests that some form of allergic process, which may be mediated by IgE, might be driving IBS in some patients and there is evidence from the literature that atopy is more common in this condition.”
The study authors also hypothesized that superantigens (SAgs), microbial antigens that cause activation of T cells, play a role in IBS pathology by triggering an immune response that results in a similar loss of oral tolerance as bacterial gastroenteritis. Researchers discovered that 47 percent of samples from patients with IBS were positive for one or more superantigens compared to just 17 percent of those from healthy volunteers.
This study supports the role of localized mast cell activation in IBS and suggests that food sensitivities occur through a physiological mechanism distinct from food allergies. Many patients report anecdotal improvement in their disease symptoms while following an elimination diet, and these results provide a possible explanation for why that may be the case.
Highlighting Real-World Patient Experiences
For patients like 30-year-old Mark (pseudonym used to maintain anonymity), solutions can’t come quickly enough. Diagnosed with irritable bowel syndrome and adrenal insufficiency, Mark experiences a host of disabling symptoms upon consuming many different foods, including poultry, rice, beans, potatoes, wheat, corn, and peas.
Although his doctors placed him on hydrocortisone, a corticosteroid, and cromolyn, a mast cell stabilizer, he still continues to experience chest tightness, throat swelling, tachycardia, and diarrhea shortly after eating. His serum immunology panels, checking for IgA, IgG, IgM, IgE antibodies and complement levels, have been unrevealing so far.
Serum levels of tryptase, a marker for mast cell activation, are normal even when Mark is having a reaction. Localization of mast cell activation may explain the inability of blood testing to corroborate patient symptoms. Principal investigator Guy Boeckxstaens, MD, PhD, a gastroenterologist at KU Leuven, speculates that his team’s findings suggest the existence of a potential spectrum of food-related immune diseases.
Non-celiac gluten sensitivity, for example, is a controversial diagnosis among physicians whose attitudes may range from downright dismissive to sympathetic. “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,” explains Boeckxstaens. Patients like Mark may fall somewhere between either ends of that spectrum.
“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. With these new insights, we provide further evidence that we are dealing with a real disease.”
Further Routes of Scientific Inquiry and Clinical Investigation
The paper raises several additional points for consideration. Since the study involved a relatively small number of people, further investigations will be necessary to validate findings, and a larger clinical trial of antihistamine treatment is already underway. Since the investigators discovered the mechanism responsible for postprandial abdominal pain using ingested food antigens in mice but directly injected food solutions into the gut mucosa in humans, it may be of clinical interest to determine whether orally consumed food antigens in humans produce the same effects.
The study authors used C. rodentium to replicate a mouse model of gastroenteritis, but other pathobionts, such as Escherichia coli, Salmonella, Giardia and Shigella, can also precede the onset of IBS. This research also raises the question of whether localized mast cell activation can occur in other regions such as the stomach or small intestine. Could activation of sensory nerves in the upper GI tract explain conditions such as dyspepsia or acid reflux disease?
Obtaining definitive answers to all of these questions may prove a time-consuming endeavor. For now, therapeutic strategies that remove offending foods, improve gut barrier function, stabilize mast cells, and block colonic sensory nerves can all help relieve symptoms in patients who experience meal-induced abdominal pain and indigestion. Boeckxstaens summarizes,
“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.”
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