KU Leuven researchers have identified the biological mechanism that explains why some people experience abdominal pain when they eat certain foods.
The finding paves the way for more efficient treatment of irritable bowel syndrome and other food intolerances. The study, carried out in mice and humans, was published in Nature.
Up to 20% of the world’s population suffers from the irritable bowel syndrome (IBS), which causes stomach pain or severe discomfort after eating.
This affects their quality of life. Gluten-free and other diets can provide some relief, but why this works is a mystery, since the patients are not allergic to the foods in question, nor do they have known conditions such as coeliac disease.
“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,” says Professor Guy Boeckxstaens, a gastroenterologist at KU Leuven and lead author of the new research. “With these new insights, we provide further evidence that we are dealing with a real disease.”
His team’s laboratory and clinical studies reveal a mechanism that connects certain foods with activation of the cells that release histamine (called mast cells), and subsequent pain and discomfort.
Earlier work by Professor Boeckxstaens and his colleagues showed that blocking histamine, an important component of the immune system, improves the condition of people with IBS.
In a healthy intestine, the immune system does not react to foods, so the first step was to find out what might cause this tolerance to break down.
Since people with IBS often report that their symptoms began after a gastrointestinal infection, such as food poisoning, the researchers started with the idea that an infection while a particular food is present in the gut might sensitize the immune system to that food.
They infected mice with a stomach bug, and at the same time fed them ovalbumin, a protein found in egg white that is commonly used in experiments as a model food antigen. An antigen is any molecule that provokes an immune response.
Once the infection cleared, the mice were given ovalbumin again, to see if their immune systems had become sensitized to it.
The results were affirmative: the ovalbumin on its own provoked mast cell activation, histamine release, and digestive intolerance with increased abdominal pain.
This was not the case in mice that had not been infected with the bug and received ovalbumin.
A spectrum of food-related immune diseases
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 disruptive bacteria. It did not produce more general symptoms of a food allergy.
Professor Boeckxstaens speculates that this points to a 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 researchers then went on to see if people with IBS reacted in the same way. When food antigens associated with IBS (gluten, wheat, soy and cow milk) were injected into the intestine wall of 12 IBS patients, they produced localized immune reactions similar to that seen in the mice. No reaction was seen in healthy volunteers.
The relatively small number of people involved means this finding needs further confirmation, but it appears significant when considered alongside the earlier clinical trial showing improvement during treatment of IBS patients with anti-histaminics.
“This is further proof that the mechanism we have unraveled has clinical relevance,” Professor Boeckxstaens says.
A larger clinical trial of the antihistamine treatment is currently under way.
“But knowing the mechanism that leads to mast cell activation is crucial, and will lead to novel therapies for these patients,” he goes on.
“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.”
Cytokines play a crucial role in the pathogenesis of inflammatory bowel diseases (IBD), such as Crohn’s disease, regulating diverse aspects of the inflammatory reaction (1). IFN-γ is a primary proinflammatory cytokine involved in Crohn’s disease pathogenesis (2).
IFN-γ is critical in the regulation of multiple immune functions, such as antigen presentation, cellular proliferation, leukocyte trafficking, microbicide effector activation, and pathogen recognition (3).
However, overproduction of IFN-γ is implicated in many gastrointestinal disorders, including Crohn’s disease, celiac disease, and autoimmune gastritis (4–6), and also plays a role in pulmonary inflammation (7).
Several recent studies have reported a link between inflammatory bowel disease and pulmonary inflammation (8–11) Incidence of IBD is significantly increased among patients with lung disorders (12). Despite these epidemiological and clinical observations, few experimental studies have investigated the role of airway allergic responses in the development of IBD.
To reveal the mechanisms underlying the effects of allergic airway inflammation on IBD pathogenesis, we hypothesized that intratracheal ovalbumin (OVA) exposure would induce inflammation in both the lung and the colon, as it is well-known that OVA exposure causes Th2- and Th1-mediated airway inflammation responses (13).
Notably, we observed that intratracheal OVA exposure is sufficient to induce colitis mediated by Th1 responses, not Th2 responses. Based on these results, we investigated the role of Th1 responses in OVA exposure induced colitis using T-bet or IFN-γ deficient mice. In this study, we demonstrate that IFN-γ plays a key role in colitis induced by intratracheal exposure to OVA.
Recently, the link between colitis and pulmonary diseases has been discussed in the literature. Several cross-sectional studies reported an increased risk of colitis in patients with allergic disorders (12, 22, 27). While it is well-known that pathogen exposure of the lungs leads to development of allergic responses in the lung, the effects on a remote site such as in the colon still remained uncertain (22).
We demonstrated that cigarette smoke induced colitis via IFN- γ (28) whilst another group showed that impaired gas exchange associated with cigarette smoke caused systemic and intestinal ischemia, driving angiogenesis and gastrointestinal tract epithelial barrier dysfunction, and resulting in the increased risk and severity of Crohn’s disease (29).
This study confirmed that colitis is mediated by the Th1 response, in particular IFN-γ-producing CD4 T cells. Based on our previous study, we confirmed the induction of colitis by exposing the airway to an allergen (OVA) and clarified the mechanism of this induction.
Our experiments demonstrate that the Th1 cell-specific transcription factor T-bet is robustly involved in OVA-induced colitis. Intratracheal OVA-induced colitis resulted in production of T-bet mediated cytokines, including TNF-α, IL-6, and IFN-γ in normal mice, while OVA exposure of T-bet deficient mice failed to result in induction of colitis.
Furthermore, experimentation using IFN-γ deficient mice confirmed that IFN-γ mediates airway allergic response induced colitis. In fact, our results support the general notion that pathogenesis of Crohn’s disease is predominantly associated with a Th1 response, but not with Th2 response (30).
As IFN-γ plays a necessary role in the development of colitis (31), anti-IFN-γ has been applied as a targeted therapy in the treatment of Crohn’s disease (32). Recently, involvement of the Th17 response in the pathogenesis of colitis has been reported (33). In our experiment, intratracheal administration of OVA caused a stronger Th17 response in the lungs of T-bet deficient mice than in WT mice.
This agrees with previous studies, which have demonstrated that T-bet suppresses Th17 differentiation, consequently leading to higher levels of IL-17A in T-bet KO mice than in WT mice (34). However, intratracheal administration of OVA did not alter IL-17A levels in the colons of WT, T-bet deficient, or IFN-γ deficient mice.
The IFN-γ pathway is not the only mechanism linking inflammatory bowel disease and pulmonary inflammation; a recent study demonstrated the role of macrophages in cigarette smoke-induced colitis (35). Indeed, we also observed an increase in the number of macrophages in the colonic laminar propria after OVA sensitization (Supplementary Figure 1), thus detailed mechanisms need to be identified in subsequent studies.
FTY720 treatment can influence the development of asthma, however the effects may differ depending on the mode of administration. Sawicka et al. used the adoptive transfer model for Th1 and Th2 cells in asthma development. In their model, FTY720 inhibited the migration of Th1 and Th2 cells to the lungs, resulting in attenuated asthma as FTY720 also prevents the migration of lymphocytes to inflammatory sites (13).
Idzko et al. applied FTY720 locally via inhalation, which inhibited the migration of lung DCs to the mediastinal lymph nodes and blocked the formation of Th2 cells in the lymph nodes (36). In our experiments, we i.p. injected FTY720 to block the migration of inflammatory cells to the colon. Systemic FTY720 treatment may have less of an effect on the primary site of inflammation than local treatment, and may explain why our FTY720 treatment did not affect the development of asthma.
This initial study indicates a promising future of potential therapeutic discovery and subsequent treatment of colitis in patients with allergic airway inflammation, including asthma. We found a circulating CD4 T cell mediated mechanism for interaction between the gastrointestinal and respiratory systems. It, however is still remained a lack of understanding of the cross-talk between lung and colon. Further studies are needed to broaden our knowledge of the cross-talk between lung and colon.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437076/