Psychological stress and food-induced abdominal pain: Unraveling the gut-brain axis in irritable bowel syndrome (IBS)
Irritable bowel syndrome (IBS) is a complex disorder characterized by chronic abdominal pain, bloating, and altered bowel habits. Among the myriad triggers of IBS symptoms, food is one of the most frequently reported culprits. While systemic food allergies have been ruled out as a cause of IBS, emerging research suggests that localized immune responses to food antigens, particularly in the gut, may play a critical role in symptom development. A groundbreaking study has now uncovered a novel mechanism by which psychological stress can disrupt oral tolerance to food, leading to immune activation, mast cell sensitization, and subsequent abdominal pain in IBS patients.
The role of food antigens in IBS
Food is a well-known trigger of abdominal pain in IBS patients. However, the mechanisms underlying food-induced symptoms remain poorly understood. Recent research in mice has revealed that an enteric bacterial infection can break oral tolerance to food, resulting in IgE-dependent mast cell activation and food-induced abdominal pain. Building on these findings, the current study demonstrates that psychological stress, a well-established risk factor for IBS, can similarly disrupt oral tolerance to food antigens. This disruption triggers a localized neuroimmune response, leading to visceral hypersensitivity—a hallmark of IBS.
Psychological stress and gut immunity
Psychological stress is a key contributor to gastrointestinal (GI) symptoms in many IBS patients. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which governs the body’s response to stress, has been implicated in IBS pathophysiology. In rodent models, stress-induced activation of the HPA axis increases gut permeability, allowing luminal antigens to pass into the lamina propria and interact with the intestinal immune system. This process can facilitate immune responses to food antigens, even in the absence of systemic allergy.
The study found that water avoidance stress (WAS), a model of psychological stress in rodents, increased visceral pain responses in mice. Notably, this effect was not sustained after the stressor was removed, but mice exposed to a food antigen (ovalbumin, OVA) during stress exhibited heightened pain signaling upon re-exposure to OVA. This suggests that psychological stress promotes aberrant immune processing of food antigens in the gut, leading to localized hypersensitivity.
Mast cells: Key players in stress-induced pain
Mast cells, which are abundant in the gut, play a central role in this stress-induced immune response. The study observed increased expression of mast cell mediators, such as tryptase α/β-1, in the colon of stressed mice re-exposed to OVA. Importantly, the number of mast cells did not increase, indicating that their activation—rather than their proliferation—was responsible for the heightened pain signaling. Mast cell stabilizers, such as doxantrazole, normalized visceral pain perception, further underscoring the critical role of mast cells in this process.
Mast cell activation is a hallmark of type 2 immunity, which is associated with allergic diseases like asthma and atopy. The study found that stress-induced immune responses to food antigens were mediated by type 2 cytokines, such as IL-13 and IL-4. Mice deficient in Stat6, a transcription factor essential for type 2 immunity, exhibited reduced pain signaling upon OVA re-exposure, highlighting the importance of this immune pathway in stress-induced gut hypersensitivity.
Stress, T regulatory cells, and oral tolerance
Psychological stress has also been shown to alter the function of T regulatory cells (Tregs), which are critical for maintaining immune tolerance in the gut. Stress reduces the levels and function of Tregs, potentially disrupting oral tolerance to food antigens. This disruption may allow luminal antigens to trigger immune responses, leading to mast cell activation and visceral pain. Future studies are needed to explore how stress-induced changes in Treg function contribute to the loss of oral tolerance and the development of food-induced abdominal pain.
Gut microbiota: A potential modulator of stress-induced symptoms
The gut microbiota, which plays a crucial role in gut-brain communication, may also contribute to stress-induced immune responses. Certain bacteria, such as Klebsiella aerogenes, can produce histamine, which recruits mast cells and exacerbates visceral hypersensitivity. While the current study did not find evidence of increased mast cell recruitment in stressed mice, the role of the gut microbiota in stress-induced loss of oral tolerance warrants further investigation.
Implications for IBS
The findings of this study provide novel insights into the mechanisms underlying food-induced abdominal pain in IBS. By demonstrating that psychological stress can disrupt oral tolerance and trigger localized immune responses to food antigens, the research sheds light on the gut-brain interactions that drive IBS symptoms. These findings may have broader implications for other disorders of gut-brain interaction, such as functional dyspepsia and inflammatory bowel disease.
Future directions
Many questions remain unanswered. For instance, why do some IBS patients report inconsistent responses to the same foods? Factors such as the dose of food antigens, gut permeability, and episodic changes in the gut microbiota may play a role. Additionally, the impact of food processing on the immunogenicity of antigens and their ability to trigger immune responses requires further exploration.
Conclusion
In summary, this study reveals that psychological stress can trigger a type 2 immune response to food antigens, leading to mast cell sensitization and increased pain signaling in the gut. These findings deepen our understanding of the gut-brain axis in IBS and highlight the importance of stress management in alleviating food-induced symptoms.
Reference
- Aguilera-Lizarraga J, Lopez-Lopez C, Jaramillo-Polanco J, et al. Psychological stress-induced local immune response to food antigens increases pain signaling across the gut in mice. Gastroenterology 2025 Feb 18:S0016-5085(25)00371-3.