Impact of different stress paradigms on irritable bowel syndrome: Evidence from clinical and animal studies

Abstract

Irritable bowel syndrome is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain and altered bowel habits, a condition significantly influenced by stress. Based on the brain’s perception and response to stressors, stress can be categorized into physical stress and psychological stress. Accordingly, this narrative review focuses on elucidating the effects of different stress paradigms on irritable bowel syndrome. Stress activates the locus coeruleus–norepinephrine system and hypothalamic–pituitary–adrenal axis, contributing to symptom onset and progression. Physically, stress disrupts intestinal homeostasis and promotes low-grade inflammation, leading to the emergence of gastrointestinal symptoms, which typically occur following intestinal infection or in the context of inflammatory bowel disease. Psychologically, stress can trigger mental symptoms such as anxiety and depression, which share a bidirectional causal relationship with irritable bowel syndrome; antidepressants and cognitive behavioral therapy have been shown to be effective in managing irritable bowel syndrome. Early adverse life events may heighten stress sensitivity and increase irritable bowel syndrome risk. Animal models employing psychosocial or physical stressors have demonstrated that stress induces visceral hypersensitivity and brain–gut axis dysregulation through mechanisms including intestinal barrier impairment, mild inflammation, microbiota disruption, and altered neural signaling. These insights support integrated strategies for the prevention and management of irritable bowel syndrome.

Keywords

Stress irritable bowel syndrome physical stress psychological stress psychosomatic disorders

Introduction

Irritable bowel syndrome is a prevalent functional gastrointestinal disorder characterized by chronic abdominal pain or discomfort accompanied with altered bowel consistency and frequency, along with concurrent physical and psychological comorbidities.¹ According to stool characteristics, patients can be categorized into IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), IBS with mixed stool pattern (IBS-M), and IBS unclassified (IBS-U).² Although not life-threatening, IBS considerably impairs patients’ quality of life (QOL) due to its chronic and relapsing nature, frequently prompting repeated medical treatment and consequently straining healthcare resources.³ During the chronic course of IBS, although there are no organic lesions, stress can mediate the onset and progression of the condition through the involvement of multiple pathways.

The concept of “stress” was first introduced by Selye,⁴ defined as a nonspecific physiological response mediated through neuro–endocrine–immune system interactions when an organism encounters threatening stimuli (also known as “stressors”) from internal or external environments.⁵ Based on temporal characteristics, stress can be categorized into acute and chronic types. Acute stress manifests as the “fight-or-flight” response when confronting sudden or short-term stressors, characterized by the rapid mobilization of energy reserves to ensure survival. However, when acute stressors persist and evolve into chronic stress, the homeostatic regulatory mechanisms become progressively compromised, leading to increased sensitivity to stressor exposure and heightened vulnerability to stress-related pathologies.^6,7

As previously discussed, stress is a physiological response that relies on the brain’s perception and reaction to stressors, which may be real (physical) or perceived (psychological). These two types of stressors elicit stress responses through the activation of distinct brain regions, thereby differentiating them.^8,9 The brain distinguishes between the following two categories: (a) stimuli that produce actual disturbances in the physiological state, overwhelming specific homeostatic mechanisms, such as pathogenic infections¹⁰ and homeostatic imbalance¹¹ and (b) stimuli that threaten the individual’s current or anticipated state, leading to negative affective states.¹² The former is described in terms such as physical stress, while the latter is commonly labeled as psychological stress.⁸

Alternatively, from the perspective of the outcomes caused by stress, it can be differentiated as physiological (eustress) and pathological (distress). Physiological stress, characterized by moderate intensity and limited duration, activates metabolic regulatory pathways to enhance energy metabolism and improve environmental adaptability, demonstrating beneficial biological effects. Conversely, pathological stress induced by excessive intensity or prolonged exposure disrupts these regulatory pathways, resulting in metabolic dysregulation and organ dysfunction that ultimately culminate in disease manifestation.^13,14

The pathogenesis of IBS involves multiple interrelated mechanisms, with key contributing factors including visceral hypersensitivity, low-grade inflammation, impaired intestinal barrier function, gastrointestinal motility disorders, psychological disturbances, brain–gut axis (BGA) dysregulation, and gut microbiota dysbiosis.¹⁵ Stress may influence IBS pathogenesis and progression through the modulation of these pathways, either individually or in combination. A recent study analyzing the content of TikTok videos related to IBS has revealed that the majority of these videos were predominantly patient-driven and frequently contained misinformation, with evidence-based treatments being underrepresented.¹⁶ This highlights an urgent need to enhance healthcare engagement and content oversight as well as to actively participate in health education and promotional efforts to improve public awareness of diseases. Previous research has predominantly focused on therapeutic efficacy and pathogenic mechanisms, with limited discussion regarding the etiology of IBS. Therefore, to better understand how various stressors in daily life contribute to the onset and progression of IBS, this review focuses on the clinical outcomes associated with these stress paradigms in patients with IBS. Additionally, it incorporates findings from animal studies to shed light on the potential mechanisms through which stress mediates the pathogenesis of IBS, aiming to provide insights for patient education as well as for the prevention and treatment of the condition (Figure 1).

Figure 1.

Different stress paradigms on irritable bowel syndrome. Stress can induce the onset and progression of IBS. Based on the brain’s perception and response to stressors, stress can be categorized as physical stress and psychological stress. In clinical research, physical stress such as intestinal infection or the remission phase of IBD are associated with an increased risk of developing IBS-like symptoms, whereas anxiety, depression, and EALs represent common psychosocial stresses. In animal studies, post-stress animal models based on these two categories of stressors are widely employed to simulate the underlying mechanisms of stress-induced IBS in humans. Regarding physical stressors, animal models are often established by inducing intestinal inflammation in experimental participants. These include post-intestinal infection IBS models to simulate post-infectious IBS and post-noninfectious intestinal inflammation IBS models to mimic the comorbid condition of IBD–IBS. In terms of psychosocial stressors, approaches such as WAS, restraint stress, maternal separation, and CUMS are utilized to replicate the pathophysiological changes observed in humans following chronic stress exposure. IBS: irritable bowel syndrome; IBD: inflammatory bowel disease; EALs: early adverse life events; WAS: water avoidance stress; CUMS: chronic unpredictable mild stress.

Methods

This review is a narrative review and it is guided by the Scale for the Assessment of narrative review articles (SANRA).¹⁷ We conducted a search in the PubMed and Web of Science databases up to March 2026 for published literature. The search strategy combined keywords related to “irritable bowel syndrome” (e.g. “IBS”), “stress” (e.g. “physical stress,” “psychological stress,” “infection,” and “anxiety and depression”), and “mechanisms” (e.g. “brain–gut axis,” “HPA axis,” and “visceral hypersensitivity”). The reference lists of retrieved articles were also manually screened to identify additional relevant studies.

We included original research articles (both clinical studies and animal experiments) and peer-reviewed reviews published in English. Case reports, conference abstracts, and opinion pieces were excluded. The initial screening was performed based on titles and abstracts, followed by a full-text assessment to determine eligibility.

The key data extracted from the included studies included the study design, population/animal model characteristics, type of stressor, main findings regarding the pathophysiology of IBS, and proposed mechanisms. The findings were synthesized narratively and structured around the identified main themes, such as clinical evidence, preclinical evidence, and the interplay between different stress paradigms.

Stress response and stress-activated pathways

The neuroendocrine regulation of stress responses primarily involves two principal pathways: the locus coeruleus–norepinephrine (LC–NE) system and the hypothalamic–pituitary–adrenal (HPA) axis. These systems mediate adaptive physiological responses to stressors through coordinated interactions.

The LC–NE system initiates rapid physiological adjustments through noradrenergic signaling. When peripheral receptors detect stressors, neural signals are first integrated in the LC, which subsequently transmits impulses via descending fibers to the lateral horn of the spinal cord. This activation stimulates the sympathetic nervous system, triggering catecholamine release.¹⁸ The subsequent binding of catecholamines to α- and β-adrenergic receptors induces compensatory physiological changes, including increased heart rate, vasoconstriction, and accelerated hepatic glycogenolysis. These coordinated responses collectively enhance organismal adaptation to acute stressors.

Concurrently, the HPA axis orchestrates a more sustained hormonal response through its three principal components: the paraventricular nucleus (PVN) of the hypothalamus, anterior pituitary gland, and adrenal cortex. Corticotropin-releasing factor (CRF), a critical neuropeptide synthesized in the PVN, serves as the primary signaling molecule in stress transduction.¹⁹ Stressor exposure induces CRF hypersecretion, which activates the HPA axis—a hallmark event in stress pathophysiology. This activation cascade culminates in adrenal glucocorticoid (GC) secretion, which exerts peripheral effects including blood pressure regulation, glycemic control, and anti-inflammatory actions. Furthermore, GCs interact with glucocorticoid receptors in limbic structures (e.g. hippocampus), PVN, and anterior pituitary, establishing a negative feedback loop that tightly regulates HPA axis activity.⁶

Notably, functional crosstalk exists between these systems: LC-derived norepinephrine directly modulates CRF synthesis and release through α1-adrenergic receptors. This interactive regulation holds significant physiological implications. During acute stress, coordinated signaling from both pathways induces adaptive gastrointestinal modifications via enteric nervous system modulation. However, chronic stress exposure disrupts this equilibrium. Sustained neural activation promotes gut dyshomeostasis, enabling abnormal visceral afferents to ascend through spinothalamic and spinomesencephalic tracts to central networks, ultimately establishing visceral hypersensitivity and associated gastrointestinal dysfunctions.²⁰

Evidence from clinical research

Intestinal infection

As a critical site for microbial colonization, dysregulation of gut microbiota may contribute to intestinal dysfunction and lead to post-infectious irritable bowel syndrome (PI–IBS) through multiple mechanisms.²¹ A prospective cohort study following the new Shiga-like toxin-producing Escherichia coli (STEC) strain O104:H4 outbreak demonstrated that the prevalence of IBS, according to the Rome III diagnostic criteria, increased from 9.8% pre-infection to 25.3% at the 1-year follow-up, while 16.9% of new cases occurred among those infected with no symptoms of IBS at baseline.²² Similarly, Scalan Walter et al.²³ and Donashitch et al.²⁴ conducted retrospective studies, indicating that individuals infected with Campylobacter and Escherichia coli, respectively, had a significantly increased risk of developing IBS. However, it should be noted that both of these studies relied on medical diagnosis results derived from the medical insurance database based on international classification of diseases (ICD) codes, rather than on clinical symptom questionnaires consistent with the Rome III/IV criteria for IBS diagnosis. Therefore, the findings may have been influenced by the accuracy of ICD codes. In contrast to the above findings, a multicenter prospective study conducted in South Korea, which enrolled 354 patients with infectious enteritis, identified only 7 individuals meeting the Rome IV criteria for PI–IBS at the 3-month follow-up and only 1 patient fulfilling the diagnostic criteria after 1 year.²⁵ Several factors may account for these differences. First, this study employed telephone-based follow-up assessments and did not include outpatients. Second, the diagnostic criteria for IBS differ between the Rome IV and Rome III frameworks.²⁶ Third, there exist inherent epidemiological differences in IBS prevalence between Asian and Western populations.²⁷ Nevertheless, epidemiological evidence indicates that the global prevalence of IBS is higher in women than in men,²⁸ and the aforementioned studies also suggest that women are at higher risk of developing PI–IBS.^24,25 This discovery is consistent with the results of another study that enrolled 51 Rome III Campylobacter PI–IBS patients and 39 healthy volunteers.²⁹ Increased colonic permeability in Campylobacteri-associated PI–IBS was confirmed using 2–24 h lactulose excretion. On this basis, after multiple omics analyses, the present study found that higher colonic permeability was related to the changes in polyamine and histamine metabolites, and women showed greater molecular changes. Regarding the underlying mechanisms of PI–IBS, another study conducted sigmoidoscopy biopsies on 7 patients who met the Rome IV criteria for PI–IBS following Campylobacter jejuni infection.³⁰ The results revealed that the pathological basis of PI–IBS involves antigen overload, which is caused by enhanced transcellular uptake, rather than disruption of tight junctions, thereby contributing to low-grade intestinal inflammation. These findings highlight potential targets for reducing the incidence of PI–IBS as a long-term sequela.

In addition to bacterial gastroenteritis, viral infections are similarly associated with an increased risk of developing PI–IBS. A 1-year prospective cohort study evaluated the outbreak of norovirus gastroenteritis in Italy using a standardized questionnaire.³¹ The symptoms were assessed utilizing the Rome III criteria and the Gastrointestinal Symptom Rating Scale (GSRS). The findings revealed that among 313 exposed individuals, 40 were newly diagnosed with PI–IBS, compared with only 3 of the 321 controls. Furthermore, GSRS scores remained significantly higher in the exposed group than in the control group at both 6- and 12-month follow-ups. However, the severity of acute-phase symptoms showed no significant correlation with the subsequent development of PI–IBS. These results confirm that viral gastroenteritis confers a risk of PI–IBS comparable to that of bacterial infections, although the severity of acute symptoms does not predict long-term outcomes. Notably, in the aftermath of the coronavirus disease 2019 (COVID-19) pandemic, an increasing body of evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel virus, has the potential to induce long-term gastrointestinal sequelae. A prospective multicenter controlled study involving 614 COVID-19 patients and 269 controls, conducted over a 1-year follow-up period, has shown that the incidence of IBS, according to the Rome IV diagnostic criteria, was significantly higher among individuals with prior (SARS-CoV-2) infection.³² A North American observational cohort study has further identified elevated disorders of gut–brain interaction (DGBI) in patients with COVID-19 after 12–18 months, with gastrointestinal symptom persistence correlating with acute-phase severity.³³

In addition to bacterial and viral infections, parasitic infections are one of the pathogenic factors of PI–IBS. Jadallah et al. examined fresh stool samples from 109 IBS patients meeting the Rome III criteria and 100 healthy controls using a combination of microscopy, polymerase chain reaction, and enzyme-linked immunosorbent assay.³⁴ They found that Blastocystis, Cryptosporidium, and Giardia were detected at significantly higher rates in IBS patients. Multiple meta-analyses have indicated that parasitic infections confer the highest risk for developing PI–IBS; however, these findings should be interpreted with caution due to the limited number of included studies.^35,36 Nonetheless, these results hold important implications for public health management.

Inflammatory bowel disease (IBD)

IBD is a common chronic inflammatory disorder among gastrointestinal diseases. Clinical observations have shown that IBD patients in remission continue to experience abdominal pain, altered bowel habits, and other gastrointestinal symptoms consistent with the diagnostic criteria for IBS.³⁷ Although IBD and IBS present distinct intestinal mucosal characteristics macroscopically, histopathological evidence reveals similar pathophysiological features, including immune activation, impaired intestinal permeability, enteric neuropathy, and gut dysbiosis.³⁸ Brzozowski et al. previously proposed a mechanistic model to elucidate this phenomenon, suggesting that the chronic intestinal inflammation characteristic of IBD leads to the persistent release of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α). This, in turn, activates the autonomic nervous system (ANS) via CRF and adrenocorticotropic hormone (ACTH)–dependent pathways. The resulting neuroendocrine cascade culminates in the release of GCs and catecholamines, thereby establishing a sustained stress response pathway.¹⁸

The overlap between IBD and IBS is substantiated by numerous clinical studies. A 3-year prospective cohort study by Jonefjäll et al. demonstrated that among 87 patients with ulcerative colitis (UC) who met clinical remission criteria, 25 exhibited IBS-like symptoms and experienced more severe gastrointestinal manifestations during their primary flare.³⁹ This suggests heightened intestinal sensitivity in these patients. Long-term follow-up data corroborate these findings; a 20-year cohort study involving 260 UC patients reported a 27% overall prevalence of IBS-like symptoms, with 29% persistence even in endoscopy-confirmed deep remission.⁴⁰ Furthermore, Halpin et al. demonstrated through a meta-analysis that IBD patients have a higher risk of developing IBS-like symptoms compared with healthy controls, with a higher risk of Crohn’s disease than that of UC.⁴¹

In terms of treatment, IBD in remission with IBS-like symptoms requires a stepwise approach, beginning with the exclusion of active inflammation through fecal calprotectin and endoscopic evaluation, followed by symptom-targeted interventions. However, current evidence remains limited by the paucity of high-quality clinical trials, leading to significant evidence gaps in guideline development.⁴² Therefore, pharmacological strategies adapted from IBS protocols for patients with IBD–IBS overlap include antispasmodics (e.g. pinaverium bromide), gut motility modulators (peppermint oil), antidiarrheals (loperamide), and novel histamine H1-receptor antagonists (Ebastine).^43,44

Anxiety and depression

Anxiety and depression, as prevalent psychological stressors, play an important regulatory role in the pathogenesis and progression of IBS. They exacerbate visceral hypersensitivity through activation of the CRF system, dysregulation of ANS balance, and alterations in neuroplasticity.⁴⁵ A cross-sectional study involving 314 IBS patients revealed significant associations between QOL and multiple factors.⁴⁶ By using a generalized linear model, the study identified gastrointestinal-specific anxiety as the strongest predictor of reduced IBS-QOL, suggesting that psychological interventions substantially improve patients’ QOL. Building on these findings, Ruan et al. employed Mendelian randomization (MR) analysis and demonstrated that depression significantly increases the risk of developing IBS.⁴⁷

Notably, not only do psychological disorders predict the risk of IBS but gastrointestinal symptoms of IBS may precede the onset of psychological symptoms, highlighting a bidirectional causal relationship between the two. A 1-year prospective study involving 1900 participants has demonstrated that individuals with elevated baseline levels of anxiety and depression had a significantly increased risk of developing IBS 1 year later, whereas IBS patients without initial psychological symptoms showed a significant increase in anxiety and depression levels at the 1-year follow-up.⁴⁸ Using a two-sample MR approach, Chen et al. identified a bidirectional causal link between IBS and major depressive disorder.⁴⁹ Further supporting this, Luo et al., using two-sample MR, found that mood instability (extending beyond anxiety and depression alone) is an independent risk factor for IBS and shares a bidirectional causal relationship with it.⁵⁰ A meta-analysis incorporating 24 studies (IBS group: n = 1775 vs. healthy controls: n = 1062) has shown that the risk of depressive symptoms and severity in IBS patients were significantly higher than those in healthy controls. Subgroup analysis further confirmed that all IBS subtypes had more severe depressive symptoms than the control group. In addition, the Hamilton Depression Rating Scale (HAM-D) and IBS diagnostic criteria were significantly associated with the severity of depressive symptoms.⁵¹

Neuroimaging studies have additionally provided neurobiological evidence for the pathophysiological link between psychological comorbidities and IBS. Li et al. employed resting-state functional magnetic resonance imaging (fMRI) and found that IBS patients with depressive symptoms (DEP-IBS) had abnormal functional connectivity in brain regions related to the frontal-limbic system and somatosensory network.⁵² These alterations were most pronounced in the insula and supplementary motor area, suggesting that neural network reorganization underlies the interaction between negative emotion and gastrointestinal symptoms, thereby maintaining the vicious cycle of symptoms.

Building on these findings, a retrospective cohort study utilizing data from the UK Biobank, comprising a large sample of 171,104 participants, integrated neuroimaging, cognitive function, biochemical markers, and genetic data to explore the relationship between IBS and brain health.⁵³ The study has revealed that the severity of IBS symptoms is positively correlated with depression and anxiety and negatively correlated with well-being. Neuroimaging analyses have demonstrated that symptom severity is negatively associated with the volume of brain regions involved in emotional regulation and higher cognition. Biochemical findings have suggested elevated triglyceride levels and immunometabolic dysregulation in individuals with IBS. MR analyses have confirmed a bidirectional causal relationship between depression and IBS, with abnormalities in biochemical markers serving as key mediators in the influence of depression on IBS. This study provides evidence supporting brain health interventions—such as antidepressant therapy—and metabolic-targeted strategies—such as lipid management—in patients with IBS.

Given the widespread bidirectional association between psychological disorders and IBS, numerous previous studies have incorporated mental health outcomes when evaluating the efficacy of IBS treatments. A meta-analysis assessing the effects of stress-management interventions in patients with IBS found no significant differences in the severity of IBS symptoms in either the short or long term; additionally, there were no sustained benefits in the QOL or mental health.⁵⁴ Another prospective cohort study, which included 448 patients meeting the Rome IV criteria for IBS, has revealed that depressive symptoms significantly diminish the efficacy of dietary interventions in patients with mild to moderate IBS.⁵⁵ This highlights the importance of evaluating psychological status when formulating individualized IBS treatment strategies, including the selection of dietary interventions.

Therefore, maintenance of psychological health may offer benefits to patients with IBS. In terms of nonpharmacological interventions, numerous studies have shown that cognitive behavioral therapy can improve both symptoms and QOL in patients with IBS, with sustained benefits observed during long-term follow-up.^56,57 Regarding conventional pharmacological treatments, multiple clinical studies have demonstrated that antidepressants alleviate IBS symptoms.^12,58,59 Tricyclic antidepressants (TCAs), as the first-line medication for abdominal pain management, alleviate symptoms through norepinephrine reuptake inhibition. However, they may induce constipation; therefore, they are more suitable for use in diarrhea-predominant IBS.⁶⁰ Another treatment option for abdominal pain management involves the use of selective serotonin reuptake inhibitors (SSRIs). Their analgesic effect may not be as strong as that of TCAs; however, they demonstrate synergistic effects when combined with TCAs. Moreover, they exhibit superior efficacy in managing psychiatric symptoms such as anxiety and depression, rendering them preferable for IBS patients with significant psychological distress.^58,59 Notably, TCAs are beneficial for diarrhea but may cause constipation; SSRIs help with constipation but may cause diarrhea. Therefore, it is necessary to establish an individualized medication regimen and implement dynamic monitoring in clinical practice to achieve the optimal balance between maximizing efficacy and minimizing adverse effects.

Early adverse life events (EALs)

EALs are defined as traumatic experiences or major disruptions occurring before the age of 14 years that impair the stability of family environment or the relationship between the primary caregiver and the child. It covers injuries ranging from physical abuse, sexual abuse, emotional neglect, and parental loss or dysfunctional parent–child relationships.^61,62 To investigate the impact of EALs on HPA axis-mediated visceral stress responses, Videlock et al. conducted a cross-sectional study using the Trauma History Questionnaire (THQ) involving 44 IBS patients and 39 healthy controls.⁶³ The THQ assessed the presence and age of occurrence of traumatic events, including crime, general trauma and disaster, and physical and sexual abuse. The results showed that there were 21 patients in the IBS group and 18 in the healthy control group who met the criteria for EALs. Additionally, the study used sigmoidoscopy as a visceral stressor and analyzed salivary cortisol levels pre- and post-stress via time-series analysis. Individuals with a history of EALs exhibited significantly higher mean cortisol levels and larger area under the curve compared with non-EALs participants. Notably, the rate of cortisol recovery observed in IBS patients was negatively correlated with symptom severity, and positively correlated with disease-specific QOL.⁶³ These findings suggest that HPA axis hyperreactivity to visceral stress is more strongly associated with history of EALs than with IBS alone, while HPA axis responsiveness to stress may modulate IBS symptoms.

The long-term psychological effects of EALs on individuals are also supported by research. A case–control study by Rahal et al. has demonstrated higher incidence of fearful experiences during EALs in IBS patients compared with controls, and the emotion of fear could significantly predict the number of EALs encountered by IBS patients.⁶⁴ The results indicate that childhood adversities such as neglect, abuse, caregiver loss, and life-threatening events may enhance the vulnerability to emotional disorders (depression, anxiety) in later life, thereby increasing the risk of IBS. Parker et al. extended these findings through assessment of IBS symptom severity, psychological symptoms, resilience (defined as adaptive recovery from adversity while maintaining functionality), and EALs exposure to find that the resilience level of IBS patients was significantly lower than that of the general population and was related to the severity of IBS symptoms. Reduced resilience can aggravate the severity of IBS symptoms and worsen psychological health.⁶⁵ This suggests that EALs mediate IBS pathogenesis and development through compromised psychological adaptation mechanisms.

Interplay of stress paradigms in clinical research

It is important to note that in real‑world clinical settings, individuals are seldom exposed to only one type of stress paradigm; these paradigms often interact with one another. Most stress paradigms can indirectly increase the risk of developing IBS by impairing psychological health (Figure 2). A growing body of research indicates a potential correlation between the gastrointestinal symptoms of PI–IBS and compromised mental health. A prospective cohort study that followed up patients with infectious gastroenteritis outbreaks due to exposure to contaminated drinking water found that patients with psychological comorbidity had an increased risk of PI–IBS.⁶⁶ Blackett et al. conducted a 6-month follow-up investigation involving 749 individuals who had recovered from COVID-19 and found that among 33 patients who developed abdominal pain after infection, 13 met the Rome IV diagnostic criteria. Furthermore, symptom severity was positively correlated with psychological distress.⁶⁷ Similarly, an observational cohort study in North America assessed COVID-19 patients’ subjective distress caused by potentially traumatic events using the Impact of Events-Revised (IES-R) instrument. Regression analysis identified high psychological trauma scores as the strongest predictor of gastrointestinal symptom severity.³³ These findings suggest that impaired mental health is involved to a certain extent in the occurrence of gastrointestinal symptoms in PI–IBS.

Figure 2.

Interplay of stress paradigms in clinical research. In clinical settings, different stress paradigms interact, with most capable of indirectly elevating IBS risk by affecting mental health. The red lines represent enhancing effects, while the blue lines indicate suppressing effects. IBS: irritable bowel syndrome; IBD: inflammatory bowel disease; EALs: early adverse life events; TCAs: tricyclic antidepressants; SSRIs: selective serotonin reuptake inhibitors. The copyright of the above image belongs to Figdraw.

Consistent with these results, a meta-analysis has revealed the important role of psychological states in patients with overlapping IBD–IBS.⁶⁸ The authors used weighted mean difference and standardized mean difference to evaluate the psychological status of IBD patients with IBS-like symptoms. The results showed that the scores of anxiety and depression were significantly higher among IBD–IBS patients than among those with IBD without IBS-like symptoms, suggesting that psychological factors are involved in the occurrence of symptoms. The study by Wileman et al. also reported similar findings; their study found through latent profile analysis that depression, anxiety, negative symptom perceptions, all-or-nothing and avoidance behaviors significantly increase the relative risk of patients with overlapping IBD–IBS.⁶⁹ These results provide an important theoretical basis for recognizing the potential impact of cognitive behavioral factors in exacerbating symptoms, early identification of patients who require support, and formulation of more precise treatment plans. Furthermore, existing studies have confirmed that cognitive behavioral therapy has definite therapeutic effects on such patients.⁷⁰ A randomized controlled trial has confirmed that hypnotherapy is as effective in improving abdominal symptoms and QOL in such patients as traditional treatments (dietary modification/pharmacotherapy).⁷¹

Evidence from animal experiments

The research on the stress regulation mechanism of IBS has led to the systematic development of various animal models following stress exposure. These models can be broadly categorized into two types: (a) those based on psychosocial stressors and (b) those based on physical stressors.⁷² Both categories of stress-induced animal models primarily utilize visceral sensitivity in experimental animals as the main outcome measure to evaluate the effectiveness of the modeling approach, thereby simulating the process of stress-induced onset and progression of IBS in humans. In animal experiments, the quantification of visceral sensitivity primarily relies on two key parameters, including the abdominal withdrawal reflex (AWR) score and number of mast cells (MCs) in intestinal tissues.

The AWR scoring system (0–4 scale) assesses behavioral responses in experimental animals to colorectal distension induced by graded balloon inflation.⁷³ Notably, MCs are activated by stress conditions and degranulated to release bioactive substances, including biogenic amines such as bradykinin and 5-hydroxytryptamine (5-HT), arachidonic acid metabolites, and mediators such as neuropeptide substances (SP) and proinflammatory cytokines. These effector molecules induce visceral nociceptive hypersensitivity by activating submucosal neurons, thereby contributing to visceral hyperalgesia pathogenesis. Therefore, MCs may modulate the BGA in IBS through interaction between central and peripheral nervous systems, ultimately promoting IBS progression.

Regarding BGA mechanisms, microglia have also emerged as an observational target. As immune cells in the central nervous system, they are essentially macrophages, which can be activated by pathological events such as chronic stress, thus releasing abundant proinflammatory cytokines that induce neuroinflammation⁷⁴ and inducing the occurrence of visceral hypersensitivity together with MCs.⁷⁵ This interaction between nervous and immune system may be a potential mechanism for the pathogenesis and progression of IBS.

Psychosocial stress-induced post-stress animal models

Water avoidance stress

The water avoidance stress (WAS) model represents a well-established experimental paradigm for inducing stress responses in rodents. This protocol involves placing experimental animals on a small platform floating on water, creating a sustained water-avoiding aversive environment to induce stress. Emerging evidence demonstrates that WAS significantly affects the interaction of the neuroimmune interactions. Xia et al. found a marked activation of intestinal mucosal MCs in rats after WAS, suggesting an increase in visceral sensitivity.⁷⁶ Notably, immunofluorescence analysis revealed spatial colocalization between activated MCs and Tuj-1 (a neuronal-specific β-tubulin marker) positive nerve fibers. Concurrently, microglial proliferation was also observed in the amygdala of stressed animals. These findings are consistent with those reported by Zhang et al., which demonstrated a significant increase in MCs in the distal colonic mucosa and microglia in the amygdala and lumbar spinal cord in WAS rats.⁷⁷

From a neuroplasticity perspective, Duan et al. identified a molecular mechanism underlying chronic WAS effects.⁷⁸ They found upregulated expression of EphB2 receptors, N-methyl-D-aspartate receptors (NMDARs), and postsynaptic density protein 95 (PSD95) in the basolateral amygdala (BLA) following chronic WAS exposure, while suppression of EphB2 expression significantly reduced NMDAR and PSD95 levels. Behavioral assessments demonstrated that either BLA inactivation or downregulation of EphB2 in the BLA alleviated anxiety-like behaviors during the maintenance phase of visceral pain. However, NMDAR activation after EphB2 downregulation still triggered visceral hypersensitivity and anxiety-like behaviors. These findings suggest that WAS enhances synaptic plasticity of the BLA by up-regulating EphB2 levels in the BLA, which in turn increases NMDAR expression, and ultimately causes IBS-like symptoms.

Notably, Xia et al. observed significant downregulation of tight junction proteins (occludin and ZO-1) in the colon of WAS-treated rats, accompanied with reduced α-diversity of gut microbiota.⁷⁶ Similarly, Creekmore et al. reported decreased occludin levels in the intestinal epithelium of rats following WAS-induced stress and found a positive correlation between visceral pain and increased colonic permeability.⁷⁹ Building on this observation, their intervention using occludin siRNA demonstrated that knockdown of the occludin protein was negatively correlated with increased paracellular permeability and exacerbated visceral pain, reaching levels similar to those observed in WAS rats. This suggests that chronic stress-induced visceral hypersensitivity is directly related to the degree of alteration in colonic epithelial paracellular permeability.⁷⁹ Furthermore, Wiley et al. conducted RNA sequencing to analyze transcriptomic changes in the colonic epithelium of the WAS rat model. Their findings revealed that the most significantly downregulated biological processes were related to digestive system development and function, while the most significantly upregulated processes involved inflammatory responses, tissue damage, and H3K9 methylation-mediated chromatin remodeling. This indicates that chronic stress is associated with elevated levels of cytokines and chemokines, whose downstream signaling pathways are linked to dysfunctional enterocyte development and function. Epigenetic regulation via chromatin remodeling may play a crucial role in this process.⁸⁰ Collectively, these multidimensional findings, including intestinal barrier integrity, intestinal microecology, and neural plasticity, provide compelling experimental evidence for the mechanism of stress-induced BGA dysregulation in IBS.

Restraint stress

Restraint stress, another classical experimental animal stress model, activates stress responses by physically restricting the participants’ freedom of movement. Accumulating evidence has shown that the visceral sensitivity of experimental animals increased after restraint stress. Taguchi et al. demonstrated that restraint stress significantly increased visceral sensitivity in rats, assessed using AWR scores.⁸¹

It is noteworthy that neuroimaging studies provide further evidence for the regulatory mechanism of restraint stress. Da Silva et al. used fMRI to scan the brain of restraint stress rats.⁸² The results revealed heightened neural activity in the insular cortex, limbic system, and reward-related nuclei. This neural hyperactivity was correlated with amplified amplitudes of visceromotor response (VMR), suggesting the enhanced neural activities of these brain areas are involved in the increase in visceral sensitivity through neural regulation. Their fMRI findings revealed that there were neuroplastic changes in the insular cortex after stress, which provided crucial imaging evidence for elucidating the mechanism of IBS induced by stress through the BGA.

Maternal separation (MS)

The establishment of animal models for early life stress demonstrates significant homology with clinical research. In rodent studies, MS can be used to simulate human EALs, which is induced by separating newborn pups from their mothers for 3 h daily over 12 consecutive days. Wong et al. demonstrated that this MS paradigm can significantly enhance visceral sensitivity in mice.⁸³ Additionally, Yang et al. found that MS intervention induced marked upregulation of 5-HT expression accompanied with intestinal structural and functional disturbances, while specific inhibition of 5-HT effectively reversed these alterations.⁸⁴ These experimental findings align with clinical observations, thereby validating the reliability of MS models in visceral hypersensitivity research.

Chronic unpredictable mild stress (CUMS)

CUMS, originally developed to study the underlying mechanisms of depressive symptoms,^85,86 is increasingly used to establish IBS animal models due to its combination of physiological and psychosocial stressors. This model construction involves exposure of animals to a different, randomly ordered stressor each day for 3 consecutive weeks. Common stressors include the following: (a) 24-hour food deprivation; (b) 24-hour water deprivation; (c) 24-hour housing on wet bedding; (d) cage tilting at a 30° angle for 24 h; (e) swimming in water at 30°C for 1 h; (f) swimming in water at 8°C–10°C for 5 min; (g) tail clipping for 1 min; (h) overnight illumination or constant darkness; (i) empty cage; and (j) restraint stress for 1 h. These stressors are combined according to specific laboratory protocols. This systematic approach successfully simulates the physiological and psychological changes in humans under chronic stress, enhancing the persuasiveness of mechanistic explorations. For instance, Luo et al. found that CUMS induces a Th1/Th2 immune imbalance,⁸⁷ while He et al. observed gut microbiota dysbiosis in CUMS-exposed mice, which was significantly correlated with depressive-like behaviors. Furthermore, they demonstrated that the gut microbiota from CUMS mice could prime microglia in the hippocampal dentate gyrus, promoting excessive inflammatory responses and impairing neurogenesis, thereby increasing stress sensitivity.⁸⁸ Their findings offer a new perspective on the pathogenesis of chronic stress-induced disorders. In IBS research, the CUMS model is primarily used to establish IBS-D animal models. Experimental animals typically exhibit symptoms consistent with IBS-D, such as enhanced visceral hypersensitivity and altered stool characteristics,^89,90 confirming the validity of this modeling approach for investigating IBS related mechanisms.

Physical stress-induced post-stress animal models

Post-intestinal infection IBS models

Intestinal infections can lead to PI–IBS, and as a common intestinal stressor, similar modeling approaches have been established in experimental animals. Du et al. developed a PI–IBS mouse model using Trichinella spiralis infection and observed increased visceral hypersensitivity, accompanied with gut microbiota dysbiosis and central nervous system hyperfunction of NMDARs, offering novel potential targets for BGA intervention.⁹¹ Similarly, Zhang et al. used Trichinella spiralis infection to develop a PI–IBS rat model, in which the rats exhibited diarrhea symptoms and heightened visceral sensitivity, consistent with IBS-D.⁹² Kotani et al. developed a PI–IBS mouse model using Citrobacter rodentium infection and found that only Toll-like receptor (TLR) 9 knockout (KO) mice displayed significant visceral hypersensitivity without accompanying low-grade intestinal inflammation or increased intestinal permeability. They further revealed that TLR9 KO mice showed significantly elevated expression of bradykinin receptors in the colonic mucosal epithelium, elucidating a mechanism through which TLR9 signaling deficiency induces PI–IBS via upregulation of bradykinin receptors.⁹³ In contrast to the above findings, a study reported that chronic Toxoplasma gondii infection can reduce visceral sensitivity in mice by suppressing nociception via opioid receptors.⁹⁴ This divergent experimental result provides new evidence for understanding the relationship between chronic infection and PI–IBS.

Post-noninfectious intestinal inflammation IBS models

Consistent with clinical observations of IBS-like symptoms in IBD patients during remission, inducing experimental colitis in animals can elicit IBS-like manifestations. Several chemical stimulants have been used to induce experimental colitis and increase the visceral sensitivity in rodents. The acetic acid enema model, which triggers intestinal inflammation, is frequently combined with restraint stress to establish IBS animal models. Li et al. observed that after the model was established, the AWR score of rats increased, and the number of MCs in the colon increased, indicating increased visceral sensitivity in rats.⁹⁵ Similarly, Zeng et al. constructed the IBS-D model by administering 4% acetic acid by enema combined with restraint stress. They found that the intestinal barrier function of the mice in this model was impaired, accompanied with local intestinal inflammation and depressive-like behaviors.⁹⁶ Employing this same modeling approach, both Fan et al. and Sun et al. have documented increased visceral sensitivity, reduced levels of tight junction proteins, elevated proinflammatory cytokines, and gut microbiota dysbiosis in rats.^97,98 Zhang et al. further noted an increased MC count in the colon, abnormal intestinal motility, altered stool characteristics, and elevated 5-HT levels in model rats.⁹⁹

The trinitrobenzene–sulfonic acid (TNBS)-induced model, extensively validated in IBD research, is also utilized to study IBS mechanisms via the examination of the visceral hypersensitivity that persists during colitis remission. Previous research has shown that post-colitis rats exhibited increased colonic MCs, excessive histamine release, and significantly enhanced visceral sensitivity. Studies have also demonstrated that histamine H4 receptors (H4Rs) induce post-inflammatory visceral hypersensitivity via MC activation and histamine release, while histamine H1 receptors (H1Rs) contribute to its development by mediating nociceptive signaling in the dorsal root ganglia and enteric nerves, suggesting novel therapeutic strategies for IBS.¹⁰⁰ Zheng et al. demonstrated through TNBS model mice that intestinal fungal dysbiosis is involved in the formation of visceral hypersensitivity in IBS.¹⁰¹ These comprehensive findings, spanning molecular biology, histopathology, and neuroendocrinology, substantiate that such chemical-induced models effectively simulate stress-associated physiological alterations and provide a reliable experimental basis for translational medical research.

Discussion

Stress is a significant contributing factor to IBS; however, its definition remains ambiguous, with varying interpretations, depending on disciplinary perspectives. Epidemiology focuses on the stress events themselves, psychology emphasizes the assessment of the individual, whereas biology pays attention to the physiological responses.¹⁰² However, IBS is not purely an organic or psychiatric disorder; as a psychosomatic disease, it exhibits a continuum of features, ranging from isolated physical or psychological symptoms to multisymptomatic comorbidity.¹⁰³ Previous reviews have predominantly focused on exploring the mechanism of IBS, characterizing it as a disorder in which stress acts as a key trigger leading to BGA dysfunction.^104,105 Based on these findings, first-line treatment for IBS typically consists of symptomatic pharmacotherapy combined with lifestyle modifications, such as dietary interventions.^106,107 However, for a patient-centered individualized treatment approach, it is essential to clearly recognize the distinct clinical outcomes associated with different stress paradigms. Thus, this review attempted to categorize common stressors into physical and psychological stress types based on the brain’s perception and response to stressors, thereby offering a novel etiological perspective to inform the prevention and management of IBS. However, it should be noted that this review only encompasses stress paradigms commonly encountered in daily life and does not provide a detailed account of other stressors. Furthermore, the mechanism explorations discussed herein are mainly derived from animal studies; whether these findings can be effectively translated into clinical practice remains to be further investigated.

Conclusion

Stress response represents a nonspecific physiological adaptation mechanism to external challenges, coordinating the adjustment of multiple systems to maintain organismal homeostasis. Under normal circumstances, it can ensure that individuals can better adapt to changes in the situation and promote survival advantage. However, in response to chronic or severe and uncontrollable stressors, the disorder of stress response will induce maladaptive changes in both structural and functional brain networks, which will lead to disease occurrence. Future studies should further clarify the interaction mechanism of different stressors, especially the dynamic regulation of BGA during stress intervention. In clinical practice, clinicians should incorporate an assessment of stressors experienced by IBS patients to better formulate individualized management strategies. Through the integration of basic research and clinical practice, it is expected to provide more comprehensive prevention and treatment strategies for this typical psychosomatic disease.

Footnotes

Author contributions

Mingxu Zheng: Writing—Original Draft

Shaopeng Sun: Writing—Review & Editing

Bin Lv: Writing—Review & Editing

The authors declare that no AI tools were used in this review.

Availability of data and materials

Not applicable.

Consent for publication

Not applicable.

Clinical trial number

Not applicable.

Declaration of conflicting interests

The authors have no relevant financial or nonfinancial interests to disclose.

Ethics approval and consent to participate

Not applicable.

Funding

No funding was received to assist with the preparation of this manuscript.

ORCID iD

Mingxu Zheng

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