Chronic Psychological Stress in Rats Induces Intestinal Sensitization to Luminal Antigens

Abstract

There is increasing evidence that stress plays a role in the pathophysiology of chronic intestinal disorders, but the mechanisms remain unclear. Previous studies in rats have revealed that stress decreases gut barrier function and allows excessive uptake of luminal material. Here, we investigated whether chronic psychological stress acts to induce sensitization of intestinal tissues to oral antigens. Rats were subjected to 1 hour per day of water avoidance stress or sham stress daily for 10 days, and horseradish peroxidase (HRP) was delivered by gavage on day 5. Studies to determine sensitization were conducted on day 20. All stressed rats developed HRP-specific IgE antibodies, antigeninduced intestinal secretion, and increased numbers of inflammatory cells in gut mucosa. Luminal HRP was absorbed more readily by enterocytes of stressed animals. In addition, stressed rats had increased expression of interleukin-4 and decreased expression of interferon-␥ in gut mucosa, a cytokine profile that is typical of allergic conditions. Treatment of stressed rats with an antagonist to corticotropin-releasing hormone (previously shown to inhibit stress-enhanced gut permeability) eliminated the manifestations of intestinal hypersensitivity. Our results indicate that the presence of oral antigen during chronic psychological stress alters the immune response (to sensitization rather than oral tolerance) and causes subsequent antigen-induced gut pathophysiology. A number of publications 1-4 in recent years indicate that stress plays a role in gastrointestinal pathophysiology in conditions such as inflammatory bowel disease, irritable bowel syndrome (IBS), and food allergies. In inflammatory bowel disease and perhaps IBS, there is evidence that intestinal tissues may become sensitized to a luminal antigen and that subsequent encounter with the antigen initiates an inflammatory response that is involved in the pathophysiology of disease. [5][6][7][8][9] Although this theory remains controversial, it is clear that sensitization of intestinal tissues is a feature of food allergy. There is little information on the relationship between stress and intestinal anaphylaxis, although several reports indicate that psychological stress triggers allergic reactions in other organ systems.10 -12 With respect to detrimental reactions to oral antigens, immunogenic material must penetrate the intestinal epithelial barrier to contact and activate immune cells in the lamina propria. 13 In a sensitized host, immediate hypersensitivity reactions are initiated by antigen cross-linking of specific IgE antibodies bound to the surface of mucosal mast cells located in close proximity beneath the gut epithelium. Released mediators then act on nearby cells to induce both rapid (within minutes) changes in physiology and delayed (within hours to days) effects. 13,14 In allergic conditions in general, it is not clear how an individual develops sensitivity to a particular antigen. Genetic factors play a role, but persons can develop a hypersensitivity reaction ...

How Stress Induces Intestinal Hypersensitivity

“…1 In an elegant series of experiments presented in this issue of The American Journal of Pathology, Yang and colleagues demonstrate that, in a genetically susceptible host, stress contributes to the development of food allergies by increasing transepithelial permeability in a corticotropinreleasing hormone (CRH)-dependent fashion. 5 Their report offers convincing data to support their earlier groundbreaking observations that stress may alter epithelial function. Using a model of water-avoidance-stress in rats, the authors observed that during chronic stress intestinal antigen uptake is increased, which in turn sensitizes the host to mast cell-induced enteropathy on secondary exposure to the same antigen.…”

Regulation of TWIK-related potassium channel-1 (Trek1) restitutes intestinal epithelial barrier function

“…HRP flux was performed with established procedures that were published elsewhere. 13 In separate experiments, FITC-dextran (10 mg/ml; 1, MW54000; 2, MW570 000) was added to the (e) HRP flux was performed with the T84 monolayers at time points as denoted on the X axis of the bar graphs. Each Transwell was only used for one permeability experiment.…”

Hodgkin's lymphoma and late onset egg allergy: is there a causal relationship?

“…Some studies in mice models proved that physical and psychological stress can induce intestinal sensitisation to luminal antigens and oral tolerance disruption by inducing alterations in colonocyte differentiation and decreased expression of RNAm encoding tight junction proteins, with a consequent increase in paracellular permeability and excessive uptake of luminal material. 8,9 Stress is also associated to gut flora changes, with the possible consequences already discussed above.…”