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A number of gastrointestinal diseases, GI diseases, are believed to be caused by intestinal barrier dysfunction, predisposing the gastrointestinal tract, or GI tract, to inflammation, including the development of inflammatory bowel disease, or IBD. While increased intestinal permeability is often considered to be a worsening symptom associated with GI disease, or gastrointestinal disease, clinical and experimental evidence has found that it may in fact be a factor to the development of digestive health issues.
Similar to IBD, food allergies are also believed to develop due to increased intestinal permeability. Food allergies are adverse, often dangerous immune system reactions which occur after certain food proteins/antigens are consumed. Food allergies are most common in babies and children, however, they can develop at any age. In this article, experimental and clinical data is summarized with current evidence relevant to intestinal permeability and intestinal barrier dysfunction in gastrointestinal diseases, GI diseases, and describe the potential implications of these research studies in disease pathogenesis.
It is believed that intestinal barrier dysfunction can lead to both antigen sensitization in addition to the IgE/mast cell-mediated anaphylactic effector stage of disease. The development of food allergies is directly determined by the exposure of the food antigen to the mucosal immune system, which may be the cause for antigen sensitization as well as the production of dietary antigen-specific CD4+ Th2 cells and IgE. It is also believed that changes in intestinal barrier function allows increased amounts of dietary antigen to move across the intestinal barrier, exposing dietary antigens to the mucosal immune system, which can then lead to the development of the dietary antigen-specific reactions. Consistent with this concept, intestinal permeability in children with food allergies evaluated by a lactulose/mannitol ratio found in the urine, was significantly higher compared to that of healthy young children. To determine whether the changes in intestinal barrier function was a result of an adverse allergic reaction to dietary antigen, lactulose/mannitol ratios were analyzed in patients who had been on an allergen-free diet for a minimum of six months. Intestinal permeability remained elevated in these individuals, indicating that increased intestinal permeability continued even in the absence of food antigen stimulation.
Further information supporting a role for increased intestinal permeability in the development of food allergies and food antigen sensitization has been determined by current clinical and experimental research studies which have demonstrated a connection between increased intestinal permeability and the development of new-onset food allergies in patients after liver and heart transplants. Patients treated with the immunosuppressant tacrolimus, FK506 have demonstrated to have increased intestinal permeability as well as increased levels of food antigen-specific IgE. Several of these patients developed new-onset food allergies. The development of food allergies by immunosuppressed post-transplant patients was originally believed to be a result of the passive transfer of food antigen-specific IgE or lymphocytes from food-allergic donors to formerly non-allergic recipients. However, research studies have reported the development of food allergies in patients where the donor had no history of allergies. Interestingly, in vitro and in vivo experiments with rats have shown that tacrolimus triggers a dose-dependent growth in intestinal permeability demonstrating that tacrolimus-induced changes in intestinal barrier function might be a possible explanation for the new-onset food allergies in immunosuppressed post-transplant patients.
Tacrolimus has been demonstrated to detach mitochondrial oxidative phosphorylation, resulting in impaired mitochondrial energy production and a significant decrease in cellular ATP. Essentially, the formation of the intestinal barrier and also the maintenance of intercellular junctional complexes are energy-dependent processes and decreased cellular ATP is responsible for causing a breakdown in TJ complexes as well as intestinal barrier dysfunction. Consistent with this, rats treated with tacrolimus were demonstrated to have a dose-dependent growth in intestinal permeability that correlated with decreased intracellular ATP levels and CO2 release. In the same manner, liver transplant patients treated with tacrolimus were discovered to have decreased mitochondrial energy production associated with increased intestinal permeability and an increase in serum endotoxin levels.
The immunosuppressive activity of tacrolimus is through the inhibition of calcineurin, which is essential for IL-2 triggered T-cell activation Inhibition of IL-2 was demonstrated to promote T-helper 2 immune reactions. Th2 cells secrete IL-4, IL-5 and IL-13, which promote IgE-mediated allergic inflammation and set the stage for food antigen sensitization as well as the development of food allergies. There are probably several mechanisms involved in the pathogenesis of food allergies by tacrolimus-immunosuppressed patients and increased intestinal permeability is seemingly a significant mediator to help with the introduction of food antigens to the immune system and oral antigen sensitization.
Researchers provided experimental evidence supporting a role for intestinal permeability in oral antigen sensitization and the development of food allergies in mice. Researchers created a transgenic mouse that overexpresses the cytokine interleukin-9 specifically from the enterocytes of the small intestine (iIL-9Tg). A result of transgenic overexpression of IL-9 was a pronounced intestinal mastocytosis and changes in intestinal permeability. Repeated oral administration of OVA into iIL-9Tg BALB/c mice instead of WT mice boosted the development of antigen-specific IgE, CD4+ IL-4+ T-cells and symptoms of a food allergy reaction in the absence of preceding systemic sensitization or the utilization of adjuvant. Pharmacological mast cell depletion in iIL-9Tg mice has been found to restore intestinal permeability to levels similar to WT mice. Unexpectedly, regulating intestinal barrier function and decreased intestinal permeability in iIL-9Tg mice prevented orally-induced antigen sensitization. These findings indicate that increased intestinal permeability helps improve antigen uptake as well as the oral introduction of food antigen sensitization.
Intestinal barrier dysfunction is believed to add to the severity of food allergen-induced clinical and experimental symptoms. Oral challenge of food allergic individuals with food allergies developed a rise in lactulose/mannitol ratio in the urine. The level of intestinal barrier dysfunction positively connected to the severity of symptoms. Treatment of this food allergic group with sodium cromoglycate a mast cell stabilizer before ingestion of food allergen, significantly decreased lactulose permeability compared to food allergen-challenged individuals not becoming sodium cromoglycate demonstrating a role for mast cells in dietary antigen-induced intestinal epithelial barrier dysfunction.
Consistent with clinical observations animal variations of GI anaphylaxis and food allergy symptoms also have demonstrated increased intestinal permeability after oral antigen challenge. Intraluminal battle of egg-sensitized rats using egg albumin triggered a 15 times growth in uptake of 51cr-labelled EDTA as compared to rats treated with unrelated protein. Research studies using mast cell-deficient animals or pharmacological agents to deplete mast cells also have provided evidence demonstrating that mast cells are essential for changes to intestinal barrier function through food allergic reactions. Increased permeability after antigen challenge was shown to originally be the result of increased antigen uptake and translocation from the transcellular route, as evidenced by an increase in HRP-containing endosomes within minutes of HRP challenge in rats that were sensitized. The next phase, which occurs after sensitization and is mast cell-dependent, was associated with a disturbance in the TJs and an increase in paracellular permeability. Together, these research studies suggest a role for changes to intestinal barrier function in food allergy.
What’s more, these research studies suggest a role for mast cells in the regulation of intestinal barrier dysfunction in food allergy. Information referenced from the National Center for Biotechnology Information (NCBI) and the National University of Health Sciences. The scope of our information is limited to chiropractic and spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .
By Dr. Alex Jimenez
Overall health and wellness are essential towards maintaining the proper mental and physical balance in the body. From eating a balanced nutrition as well as exercising and participating in physical activities, to sleeping a healthy amount of time on a regular basis, following the best health and wellness tips can ultimately help maintain overall well-being. Eating plenty of fruits and vegetables can go a long way towards helping people become healthy.
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