Effects of psychological stress on inflammatory bowel disease via affecting the microbiota–gut–brain axis

Abstract

Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory condition with chronic and relapsing manifestations and is characterized by a disturbance in the interplay between the intestinal microbiota, the gut, and the brain. The microbiota–gut–brain axis involves interactions among the nervous system, the neuroendocrine system, the gut microbiota, and the host immune system. Increasing published data indicate that psychological stress exacerbates the severity of IBD due to its negative effects on the microbiota–gut–brain axis, including alterations in the stress response of the hypothalamic–pituitary–adrenal (HPA) axis, the balance between the sympathetic nervous system and vagus nerves, the homeostasis of the intestinal flora and metabolites, and normal intestinal immunity and permeability. Although the current evidence is insufficient, psychotropic agents, psychotherapies, and interventions targeting the microbiota–gut–brain axis show the potential to improve symptoms and quality of life in IBD patients. Therefore, further studies that translate recent findings into therapeutic approaches that improve both physical and psychological well-being are needed.

Introduction

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic idiopathic inflammatory disorder of the gastrointestinal tract in which symptoms develop in a relapsing and remitting pattern. UC is characterized by diffuse mucosal inflammation, usually involving the rectum as the first site and extending continuously to proximal segments of the large intestine. The main feature of Crohn’s disease is segmental, asymmetric, and transmural inflammation that can cause lesions in any region of the gastrointestinal tract, and the most common segments are the terminal ileum and the ileocecum.^[1,2] In addition to classic hallmarks such as abdominal pain, bloody diarrhea, watery stool, and weight loss, extraintestinal manifestations involving the eyes, joints, liver, biliary tract, and skin are also frequently observed in IBD patients.^[3] As the disease progresses, surgery is required for 10–20% of patients with UC,^[2] and more than half of patients with CD will develop complications, such as stenosis, abscess, or fistula, requiring surgery.^[4] In China, the prevalence and incidence of IBD had risen significantly. In 2021, the number of IBD patients in China reached 168,077 and it was projected that by 2035, the number of new cases of IBD in China will reach 41,901.^[5] According to a recent study in the United States, the prevalence of IBD exceeds 0.7%.^[6] Moreover, the incidence in newly industrialized countries with gradually increasing Westernized societies is accelerating, imposing a heavy burden on health care systems and societies.^[7]

As a systemic disease, IBD is often associated with comorbidities such as mood disorders, and there is supposed to be a two-way relationship between psychological comorbidities and IBD.^[8] Communication between the gut and the brain is regulated by multiple pathways, including neural, hormonal, immune, metabolic, and microbial signals. Dysregulation of the gut–brain axis serves as a crucial link between gastrointestinal and neurological diseases.^[9] This review aims to discuss how psychological stress affects IBD through the gut–brain axis.

Gut–Brain Communication

The close relationship between the gut and the brain, which is termed the “gut–brain axis”, was discovered in the 21st century.^[9] It is recognized as a link between the cognitive and emotional centers of the brain and intestinal functions.

There are different levels of gut–brain communication [Figure 1].

Figure 1.

Effects of psychological stress on the gut–brain axis in IBD. ACTH: Adrenocorticotropic hormone; CA: Catecholamines; CRH: Corticotropin-releasing hormone; CRHR1: Corticotropin-releasing hormone receptor 1; Foxp3: Forkhead box protein P3; GC: Glucocorticoids; IBD: Inflammatory bowel disease; IL-6: Interleukin-6; IL-10: Interleukin-10; IL-17: Interleukin-17; IL-18: Interleukin-18; IL-22: Interleukin-22; iNOS: Inducible nitric oxide synthase; MCC: Middle cingulate cortex; mesLNCs: Mesenteric lymph node cells; SNS: Sympathetic nervous system; TNF-α: Tumor necrosis factor-α; Treg: Regulatory T cell; VN: Vagus nerve. This figure was created with BioRender.com (https://biorender.com/).

Neuronal communication

The autonomic nervous system (ANS), a neural relay network, is composed of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS, including the vagus nerve). Stress can stimulate sympathetic nerve branches and activate the sympatho–adreno–medullary (SAM) axis, resulting in the release of catecholamines (epinephrine and norepinephrine) from the adrenal gland medulla. In contrast, during “quiet conditions” (such as rest and digestion), the PNS, with acetylcholine as its main neurotransmitter and presenting counteractivity on the SNS, is predominant.^[10,11]

The enteric nervous system (ENS) is an independent nervous system in the gastrointestinal tract and is mainly responsible for coordinating gut functions, including bowel motility, blood flow regulation, and epithelial secretion.^[12]

By integrating signals from the ENS and the central nervous system (CNS), the ANS maintains physiological homeostasis and responses to endocrine, autonomic, motor, and behavioral factors. ANS controls key functions of the gastrointestinal tract, including gut motility and permeability, osmolarity, bile secretion, mucosal mechanical deformation, bicarbonate and mucus production, and the mucosal immune response. Afferent nerves from the intestinal cavity, such as hormones, neurotransmitters, and immune factors, can send signals to the brain through autonomic neurons to regulate sleep, behavior, and stress reactivity.^[13]

Neuroendocrine communication

The hypothalamic–pituitary–adrenal (HPA) axis is an important part of the neuroendocrine system in the human body and participates in the non-neuronal communication pathway in the gut–brain axis.^[14] When a stress response occurs, corticotropin-releasing hormone (CRH) released from the hypothalamic paraventricular nucleus promotes the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. Then, ACTH enters the systemic circulation and targets the adrenal cortex, eventually leading to the release of glucocorticoids, which are subsequently distributed throughout the body to prepare for the body’s “fight or flight” response.^[15]

Microbial communication

The gut microbiota is a relatively newly discovered component of the gut–brain axis, and changes in its composition have been suggested to alter brain function. A recent preclinical study reported that receiving fecal microbiota from mice that sustained unpredictable chronic mild stress triggered depression-like behavior and early and sustained neuroinflammatory responses in healthy mice,^[16] suggesting a causal link between the gut microbiota and depression. In addition to the composition of the gut microbiota, microbial metabolites are also sufficient to affect the central nervous system. Another study showed that the oral administration of short-chain fatty acids exerted significant antidepressant and antianxiety effects by modulating tryptophan metabolism and the levels of inflammation and neurotransmitters in a treatment-resistant depression rat model.^[17]

Involvement of the immune system

Recent studies have demonstrated that peripheral interleukin-17-producing T cells induce neuronal death and accelerate Parkinson’s disease-related neurodegeneration in a human autologous stem cell-based model.^[18] Another study suggested that the gut microbiome and microbial metabolites contributed to the transformation of mucosal T cells to the T helper 17 (Th17) phenotype, thereby aggravating neuroinflammation in experimental autoimmune encephalomyelitis.^[19] These findings highlighted the critical role of the mucosal immune system as a regulator of gut–brain communication.

Gut Microbiota

The microbiota in the normal human gut is divided into two main phyla, namely, Firmicutes and Bacteroidetes.^[20] The gut microbiota coexists with the intestinal mucosa and endows healthy individuals with metabolic, immune, and intestinal protective functions. The gut microbiota is involved in many metabolic processes in the gastrointestinal tract, including the metabolism of diet fibers, protein, amino acids, lipids, bile salt, choline, and polyphenols.^[21] The symbiotic balance between the gut microbiota and the host is mainly mediated by the binding of secreted immunoglobulin A (sIgA), which is present on the surface of the gut mucosa, to microorganisms.^[22] In addition, specific gut bacteria, especially Clostridia species, reportedly modulate immune responses mediated by regulatory T cells (Tregs) to promote broad immunological tolerance by the immune system and benefit the rest of the microbiota.^[23] The protective functions of the microbiota include promoting the restoration of mucosal integrity^[24] and restraining pathogen growth via competitive metabolic interactions, localization to intestinal niches, and induction of host immune responses.^[25] In addition, the adhesion of certain microbes (such as Citrobacter rodentium and Escherichia coli O157) to intestinal epithelial cells plays an important role in inducing intestinal Th17 cells and triggering Th17 cell responses.^[26]

Recently, the relationship between the gut microbiota and chronic inflammatory disorders, such as IBD, has become a research hot spot. Several studies have documented a taxonomic shift, with a reduced abundance of the phylum Firmicutes, particularly Faecailbacterium prausnitzii, a beneficial bacterium with anti-inflammatory properties,^[27] both in fecal^[28,29] and biopsy^[30] samples of patients with IBD compared to healthy individuals. Conversely, the abundance of potential opportunistic pathogens Bacteroides species, such as Bacteroides fragilis, was reported to increase in fecal samples of IBD patients.^[27] Moreover, the abundance of Enterobacteriaceae, a member of the Proteobacteria phylum, is relatively increased in patients with CD.^[31] Overall, it is agreed that the number of species and the diversity of the gut microbiota are reduced in IBD patients.

Changes in the gut microbiota composition are accompanied by alterations in microbial metabolites, which might affect the host in a manner that is associated with IBD pathogenesis or neuroimmune mechanisms that influence mood and behavior. Short-chain fatty acids (SCFAs) produced by specific Clostridia species (spp.) reportedly protect against colitis in mouse models by enhancing the function of intestinal Tregs.^[32] This result is consistent with the finding of a reduction in SCFAs in the mucosa and feces of patients with IBD.^[33] Tryptophan is an essential amino acid that can cross the blood–brain barrier and participate in the synthesis of serotonin after being absorbed by the intestine. However, the ability of tryptophan to cross the blood–brain barrier is affected by intestinal metabolic pathways. Therefore, by affecting intestinal metabolic processes and regulating tryptophan levels, the gut microbiota can affect the brain, leading to behavioral changes.^[34]

Stress and the Gut–Brain Axis in IBD

HPA axis

The HPA axis is the core regulator of the stress response and significantly influences the brain–gut–microbiota axis. As mentioned above, during the stress response, the secretion of the immunosuppressive hormone cortisol is increased due to the activation of the HPA axis, which commonly promotes the synthesis of anti-inflammatory cytokines. However, several studies have demonstrated the promoting role of HPA axis activation under stress in increasing intestinal permeability and triggering inflammation. Peripheral CRH reproduces the effect of acute psychological stress on increasing intestinal permeability via a mast cell-dependent mechanism, thus promoting the onset and development of IBD.^[35] In the neonatal maternal separation (MS) model, a model of stress in early life for IBD and irritable bowel syndrome (IBS), CRH receptor 1 (CRHR1) mediates intestinal injury through mechanisms, including increased intestinal permeability and intestinal inflammation.^[36] In another early-life stress mouse model, prenatal maternal stress reportedly impaired intestinal epithelial cell proliferation, Paneth cell and goblet cell differentiation, and mucosal barrier function.^[37] Zheng et al^[38] revealed that chronic stress and high level of glucocorticoid hormone impaired the homeostasis and barrier function of the colonic epithelium in mouse models. Another relevant study reported that the stress-related HPA axis response triggered reversible inflammation and persistent epithelial dysfunction.^[39] A correlation between the activation of the HPA axis and intestinal permeability has also been confirmed in humans. As Vanuytsel et al^[40] reported, the effect of public speech stressors increasing intestinal permeability appears only in men with significantly high cortisol levels.

In addition to affecting intestinal permeability, the activation of the HPA axis also impacts the colonization and composition of the intestinal flora. Abnormal solicitation of the HPA axis during the process of brain development has been proven to influence microbial colonization.^[41] Peripheral CRH administration affects the gut microbiota composition in both MS model rats and control rats^[42] and deteriorates gut microflora homeostasis in IBD mice.^[43] Petrosus et al^[44] revealed that the administration of cortisol led to a shift in microbiota composition in a porcine model. CRHR, particularly CRHR1, is involved in MS-induced microbiome alterations.^[36] Conversely, the HPA axis is also affected by the intestinal flora. It has been reported that probiotics can correct stress-induced abnormalities in the colonic flora and improve intestinal barrier function by normalizing the function of the HPA axis.^[45,46] These studies suggest that the interaction between the HPA axis and intestinal flora is involved in the effect of stress on colitis in the IBD model.

ANS

In addition to the HPA axis, the ANS is also associated with stress and acts as an important target of the stress response. Stress can result in long-term changes in the balance of the sympathetic and vagus nerves. More specifically, stress promotes the inflammatory response by inhibiting the vagus nerve, which has dual anti-inflammatory effects via its afferent and efferent fibers,^[47] and stimulating the sympathetic nervous system via autonomic-related projection neurons of the paraventricular nucleus to the dorsal motor nucleus of the vagus nerve and sympathetic preganglionic neurons of the spinal cord.^[48]

The protective effect of vagus nerve function on IBD has been demonstrated by multiple studies. A significant decrease in vagal tone was observed in patients with IBD,^[49] and low resting vagal tone was associated with increased circulating tumor necrosis factor (TNF) in patients with CD in remission.^[50] A matched cohort study, involving 15,637 patients who underwent vagotomy, revealed a positive correlation between vagotomy and subsequent IBD, especially CD, which indirectly emphasizes the beneficial role of vagal tension in IBD.^[51] The alleviating effect of vagus nerve stimulation (VNS) on IBD has been preliminarily verified in animal models and CD patients. Chronic VNS reduced the degree of weight loss and the levels of inflammatory markers in rats with experimental colitis.^[52] Electrical stimulation of the splenic nerve bundle, downstream of the vagus nerve cholinergic anti-inflammatory pathway, also reduced the severity of colonic inflammation in mice with experimental colitis.^[53] A 6-month follow-up pilot study of patients with active CD who received VNS revealed that among the seven patients, two withdrew from the study due to clinical deterioration at 3 months, and five achieved clinical, biological (C-reactive protein and/or fecal calprotectin), and endoscopic remission with a recovery of the vagus nerve tone (heart rate variability, HRV).^[54] Two other studies reported similar results. VNS restored homeostatic vagal tone, reduced inflammatory status, and improved quality of life (QOL) in CD patients.^[55,56] Moreover, VNS was feasible, generally safe, and well tolerated in patients involved in these studies, suggesting that VNS may be an effective method for the treatment of active CD.

In contrast to the protective effect of the vagus nerve, the activation of the sympathetic nervous system under stress is considered to exacerbate the deterioration of IBD. A prospective cohort study reported that a high level of perceived stress was related to tonic sympathetic activation and an increased risk of clinical flares in UC patients.^[57] Psychological stress can promote the expression of dopamine β-hydroxylase and the potential synthesis of catecholamines, which are involved in the pathogenesis of psychological stress-induced colitis through α2-adrenoreceptors (α2-ARs).^[58] Another preclinical study performed by Deng et al^[59] revealed that isoproterenol, a β-AR agonist, simulated the effects of psychological stress on neutrophilia, neutrophil infiltration, and colon injury in dextran sulfate sodium (DSS)-induced colitis, and these effects were attenuated by the β1-AR/β2-AR inhibitor propranolol, suggesting that psychological stress promoted neutrophil infiltration into colon tissue via activation of the adrenergic nervous system in a colitis model. A recent study revealed that sympathetic output triggered by psychological stress enriched the gut commensal Lactobacillus murinus and increased the production of indole-3-acetate, a microbial metabolite that contributes to the loss of intestinal secretory cells.^[60]

Through in-depth research, the critical role of the ENS in mediating the aggravating effect of chronic psychological stress on gut inflammation was revealed. Long-term elevated glucocorticoid levels resulting from chronic stress allow the generation of an inflammatory subset of enteric glia, which promotes inflammation mediated by monocytes and TNF.^[61]

CNS

Neuroimaging has developed rapidly in recent years and has been widely used in research on nervous system diseases and mental disorders. This series of technologies made it possible to explore the complex interaction between the brain and the gut in intestinal diseases. Recently, several studies have revealed that psychological stress-induced morphological, functional, and metabolic changes in specific brain regions are associated with disease severity in patients with IBD.

Two observational studies revealed that the gray matter structure of specific brain regions and white matter microstructural properties in CD patients were significantly different from those in healthy controls and that these characteristic changes were correlated with disease duration.^[62,63] Furthermore, alterations in white matter microstructure are related to anxiety levels in CD patients.^[63] Resting-state functional magnetic resonance imaging (MRI) and multimodal MRI studies have shown that IBD patients present with abnormal neural activity and functional connectivity in various brain regions that are mainly related to pain, emotion, and cognitive-related functions.^[64,65,66] Another study involved a dynamic functional connectome analysis to capture inflammation-associated brain alterations and revealed that enhanced cortical stability in the medial prefrontal cortex was associated with severe depression and in patients with UC.^[67] A proton magnetic resonance spectroscopy (¹H-MRS) study conducted by Lv et al^[68] reported increased glutamate (Glu)/total creatine (tCr) levels and decreased γ-aminobutyric acid (GABA+)/tCr levels in the bilateral anterior cingulate cortex in CD patients with abdominal pain. They also found that the Glu/tCr level was positively correlated with the VAS score of pain and that the GABA+/tCr level was negatively correlated with disease activity. A stress-evoking task elicited differences in neural activity in various brain regions, including the amygdala, hippocampus, and insula, between CD patients and controls, suggesting altered habituation to stress in patients.^[69] Recent studies have focused on the role of the middle cingulate cortex (MCC) in IBD under stress. In CD patients, stress increases blood oxygen level-dependent (BOLD) signals in the MCC, suggesting that stress-induced MCC hyperactivity may aggravate disease symptoms via the regulation of intestinal motility and the promotion of inflammatory activity through autonomic and neuroendocrine regulation.^[70] In an acute experimental colitis model, the MCC was highly activated in response to mechanical stimulation of the colon, and attenuation of MCC activity alleviated anxiety-like behaviors, visceral hypersensitivity, and visceromotor responses to colorectal distensions.^[71] These findings suggested that the MCC is a potential target for the treatment of cingulate gyrus-mediated intestinal diseases.

Most of the above studies focused on the structural, functional, and molecular changes in specific brain regions in CD patients under stress. However, more neuroimaging changes and the mechanism underlying their impact on this disease remain to be explored.

Stress and the Intestinal Microbiota in IBD

Several studies on the effects of stressor exposure on the intestinal flora have reported consistent findings of decreased relative abundances of populations of the genera Bacteroides and Lactobacillus and increased relative abundances of bacteria of the genus Clostridium in mouse models exposed to different stressors, including material separation, social disruption, and restraint stress.^{[42,72,73,74]} Similar results have been obtained in human studies. In pediatric patients with CD, a higher level of perceived stress was correlated with lower relative abundances of Firmicutes and Anaerostipes, as well as higher relative abundances of Parabacteroides.^[75] Infants of mothers with high reporting pressure and high cortisol concentrations during pregnancy presented significantly greater relative abundances of Proteobacteria groups containing pathogens such as Escherichia, Serratia, and Enterobacter and lower relative abundances of Lactobacillus, Aerococcus, Lactococcus, and Bifidobacteria, which was proven to be a common feature of increased levels of potential inflammation.^[76] Alterations in the intestinal flora, especially the relative abundance of Lactobacillus, are related to the severity of IBD. Maltz and colleagues reported that the relative abundance of Lactobacillus was negatively correlated with interleukin (IL)-1β and inducible nitric oxide synthase (iNOS), suggesting that Lactobacillus abundance is inversely correlated with colonic inflammation and that Lactobacillus might play an important role in the regulation of mucosal inflammation.^[74] In addition, the administration of Lactobacillus to mice with experimental colitis resulted in decreased disease activity indices, histological scores, and levels of the inflammatory cytokines like interferon γ (IFN-γ), TNF-α, IL-6, and IL-1β.^[77]

In addition to changing the composition of the gut microbiota, stress exposure also leads to alterations in the levels of bacterial metabolites, especially SCFAs, which play important roles in metabolic and immune homeostasis and intestinal barrier integrity.^[78] Prolonged restraint stress or social disruption stress significantly reduced the production of SCFAs (acetic acid, butyric acid, and propionic acid) in mice.^[74] Conversely, the administration of acetic and butyric acids to germ-free mice significantly improved disease indices, with an increase in colon length and a decrease in the disease activity index and the level of myeloperoxidase (an inflammatory mediator).^[79] These results suggested that a decrease in SCFA levels may be one of the important targets by which stress aggravates colitis. However, another study reported no association between SCFA levels and the severity of colonic inflammation, but the expression of G protein-coupled receptor 41 (GPR41, the SCFA receptor) in colonic tissue was positively correlated with inflammatory cytokines and colonic histopathology scores.^[74] These results suggest that the role of SCFAs and their receptors in colitis is complex and that the specific mechanism involved remains to be studied.

Stress and Intestinal Immunity in IBD

A prospective population-based study conducted by Bernstein and colleagues revealed that negative affect, perceived stress, and major life events were the trigger variables exhibiting a significant association with IBD symptom flares.^[80] Similarly, another prospective study reported that general stress was related to IBD symptom activity.^[81] The relationship between psychological stress and inflammation was also confirmed by experimental studies on patients with UC. Experimental stress testing in patients with inactive UC revealed that acute psychological stress caused systemic and rectal mucosal proinflammatory responses.^[82] The use of a rodent model of stress has supplemented these findings and deepened the research at the molecular mechanism level. Psychological stress enhanced the inflammatory response in DSS-induced chronic colitis mice model. Chronic stress affects the immune system by increasing the infiltration of neutrophils, B cells, and proinflammatory ly6Chi macrophages in the colonic lamina propria; compromising the thymus; decreasing the proportions of B cells and CD4⁺ T cells in mesenteric lymph node;^[83] and increasing the formation of colonic tertiary lymphoid organs.^[84]

The intestinal immune mechanisms underlying the stress-induced aggravation of colitis are listed below.

Expression of cytokines

IL-10

IL-10 suppresses the functions of macrophages and T cells and regulates the immune response by inhibiting the production of inflammatory cytokines, including IL-1, IL-6, and TNF-α. IL-10-deficient mice exhibit normal lymphocyte development and antibody responses but suffer from chronic enterocolitis. Therefore, the IL-10-deficient mouse model is one of the oldest models of colitis.^[85] Relevant studies have reported that psychological stress can aggravate colitis in IL-10 (−/−) mice^[86,87] and might be associated with long-term defects in intestinal barrier function.^[86] Both stress and DSS treatment can also reduce the expression of IL-10 messenger RNA (mRNA) in mouse models.^[83] However, the precise role of IL-10 in the stress-induced exacerbation of colitis remains unclear.

IL-18

Studies have indicated that IL-18 promotes intestinal autoinflammation and impairs mucosal barrier integrity in a colitis model by inhibiting the maturation of goblet cells^[88,89] and that the severity of colitis is under the control of epithelial IL-18 signaling.^[88] Many studies have confirmed that IL-18 is involved in the stress response. The level of IL-18 could increase during stress without an exogenous stimulus. The increased synthesis of IL-18 in the adrenal gland is a response to stress-induced activation of the HPA axis.^[90,91] Stress-induced IL-18 elevates the level of IL-6, a proinflammatory cytokine.^[92] Deletion of IL-18 or an IL-18 neutralizing antibody blocked the increase in TNF-α and IL-6 expression induced by stress and ameliorated the exacerbation of colitis resulting from stress, suggesting that psychological stress exacerbates colitis in mice by enhancing the expression of IL-18-dependent proinflammatory cytokines.^[93] Nishida et al^[94] reported that the deletion of IL-18 in mice completely blocked the stress-induced reduction in the mucosal defense factors, namely, mucin 2 (MUC2) and trefoil factor 3 (TFF3), and in the number of rectal goblet cells, suggesting that IL-18 might be a critical determinant of rectal vulnerability to psychosocial stress.

IL-22

IL-22 is considered a tissue-protective cytokine that targets epithelial lineages, preserves epithelial barrier integrity, and promotes epithelial regeneration and mucosal healing by stimulating the production of antibacterial mediators and mucins. IL-22 has clinical relevance to IBD because of its capacity to stimulate mucosal healing, its involvement in susceptibility gene networks of IBD, and its ability to promote the expression of calprotectin, a biomarker of IBD.^[95] Moreover, a recent study revealed that the therapeutic effect of indigo naturalis on DSS-induced colitis is mediated by activation of the IL-22 pathway.^[96] IL-22 enhanced crypt immunity and improved anti-microbial response both through inducing the binding of phospho-signal transducer and activator of transcription 3 (Stat3) to the IL-18 gene promoter and through IL-18-independent mechanisms. IL-22-dependent activation of the IL-18 response circuit maintained the homeostasis of the epithelial barrier and enhanced host defense against adherent-invasive Escherichia coli (AIEC).^[97] The relationship between IL-22 and stress-mediated exacerbation of colitis is a novel research topic. Psychological stress impairs IL-22-driven protective mucosal immunity against AIEC by promoting glucocorticoid-mediated apoptosis of CD45⁺ CD90⁺ cells, the major IL-22 producers in the gut.^[98]

Involvement of CD4⁺ T cells and Tregs

Previous studies have suggested that CD4⁺ T cells are involved in mediating IBD. Adoptive transfer of CD4⁺ T cells isolated from healthy donor mouse spleens to immunodeficient severe combined immunodeficiency (SCID) recipients causes chronic intestinal inflammation that shares similar characteristics with human IBD,^[99] and the transfer of bacterially reactive CD4⁺ T cells from colitis mice induces colitis in SCID recipient mice.^[100] In addition, it was demonstrated that stress-induced reactivation of experimental colitis requires the mediation of CD4⁺ T cells, which can be adoptively transferred.^[101] Recently, Amoroso et al^[102] reported that the transfer of CD4⁺ mesenteric lymph node cells (mesLNCs) from donor mice subjected to chronic psychological stress induced systemic inflammation and local intestinal inflammation characterized by chronic stress in healthy recipient mice and increased the adrenal weight and secretion of IL-6 from in vitro anti-CD3-stimulated mesLNCs in recipient mice treated with DSS. This study suggested that CD4⁺ T cells are involved in the physiological and immunological effects of chronic stress and might participate in the stress-induced progression of colitis.

Tregs characterized by their immunosuppressive nature and the expression of the transcription factor foxhead box P3 (Foxp3) play a vital role in the promotion of immunological self-tolerance and the maintenance of immune homeostasis. Tregs suppress effector cell activities via multiple mechanisms, such as cytokine secretion, metabolic disruption, cytolysis, and inhibition of dendritic cells (DCs), to exert protective effects and prevent intestinal inflammation.^[103] Maul et al^[104] reported a decrease in the Treg pool in the intestinal lamina propria and an abnormal distribution of Tregs in patients with active IBD. Moreover, published data indicate that Tregs are also involved in the regulation of psychological stress. Tregs expansion depending on ileal innate lymphoid cell 3 (ILC3) activity was involved in the mechanism by which synbiotics attenuate depressive- and anxiety-like behaviors and enhance resilience to chronic and recurrent stress.^[105] A previous study in mouse colitis models revealed that prolactin (PRL) induced by psychological stress stimulates DCs to increase the production of IL-6 and IL-23, which results in the differentiation of Tregs into IL-17⁺ Foxp3⁺ T cells that barely exhibit immunosuppressive functions and even express high levels of the proinflammatory cytokine TNF-α.^[106] This discovery suggested that Tregs are involved in the mechanism by which psychological stress-derived PRL promotes the induction of IBD-like inflammation in the intestine.

Stress-induced intestinal autophagy

Autophagy is an essential and fundamental metabolic mechanism in cells. The significance of autophagy is to preserve cellular and organismal homeostasis via the degradation of long-lived and misfolded proteins as well as damaged cellular organelles in lysosomes into basal nutrient elements for subsequent recycling. Autophagy is indispensable for the maintenance of intestinal barrier integrity, antimicrobial defense, and mucosal immunity.^[107] Knocking out the autophagy gene Atg16l1 in T cells led to spontaneous intestinal inflammation with a loss of Foxp3(+) Tregs in mice, suggesting the vital role of baseline autophagy in the maintenance of intestinal immune homeostasis.^[108] However, abnormal or over-induced intestinal autophagy has been reported to be associated with an excessive intestinal inflammatory response and epithelial lesions and to contribute to the exacerbation of IBD.^[109,110]

Recent studies have reported the relationship between psychological stress and intestinal autophagy in IBD patients. Giannogonas et al^[43] observed that biopsy specimens from IBD patients with greater psychosocial stress showed a significant increase in light chain 3 (LC3, a molecular marker of autophagy) staining, suggesting an association between high psychosocial stress and enhanced intestinal autophagy. Preclinical studies have revealed the detrimental effect of psychosocial stress on DSS-induced IBD through the induction of intestinal autophagy. Peripheral CRH-induced psychosocial stress in IBD model mice further increased the level of intestinal macrophage autophagy. In addition, the autophagy inducer rapamycin exacerbated CRH-induced colonic injury, while the inhibition of autophagy with chloroquine attenuated the aggravating effects of CRH on the severity of IBD and inflammation under lipopolysaccharide (LPS) challenge.^[111] In agreement with these results, Wang et al^[43] concluded that autophagy was involved in the pathophysiology of stress-induced aggravation of IBD via the regulation of the interaction between the intestinal barrier and microbiota and the promotion of macrophage M1/M2 polarization.

Interactions among Brain, Gut, and Microbiota

Generally, psychological stress activates the HPA axis and the sympathetic nervous system, and inhibits the vagus nerve, thereby increasing the production of inflammatory mediators and the infiltration of inflammatory cells into the intestine, altering the composition and metabolites of the gut microbiota, leading to increased intestinal permeability and dysfunction of the intestinal barrier. In addition, stress also directly affects the CNS, leading to anxiety-like behavior, visceral hypersensitivity, and visceromotor responses. HPA axis activation also induces abnormal autophagy and generation of inflammation-associated glial cells in ENS, thereby contributing to the exacerbation of IBD.

The mechanism by which the microbiota-gut–brain axis in turn affects mental health is through increasing the release of pro-inflammatory cytokines, including IL-6 and TNF-α, into the systemic circulation and across the blood-brain barrier, while activating the ENS and inhibiting vagus nerve transmission. These bodily fluids and neural pathways activate the HPA axis, leading to increased production of corticosteroids and playing an anti-inflammatory role, while also participating in the onset of depression,^[112] thus forming a vicious cycle.

Managing Stress in Patients with IBD

According to the recent clinical practice guidelines, therapeutic interventions for IBD mainly include 5-aminosalicylic acid (ASA), enteral nutrition, corticosteroids, immunomodulators, anti-TNF-α agents, immunosuppressive drugs, and biologics. These traditional medical therapies are conducive to early induction of clinical remission and long-term maintenance.^[113] However, a curative treatment strategy for IBD has not been established. Moreover, increased psychosocial burdens and a high rate of comorbidity with psychological disorders also affect patients’ QOL. Fortunately, the mechanism of psychosocial stress in IBD has gradually been clarified by mounting evidence. Relieving psychological stress, a potential IBD therapeutic option, is highly beneficial for ameliorating symptoms and improving QOL.

Psychotropic agents and psychotherapies

Increased awareness about the effects of gut–brain dysregulation in chronic gastrointestinal conditions has given rise to a newly established discipline, psychogastroenterology, which focuses on treating gastrointestinal symptoms and associated mental problems with gut–brain therapies, including psychotropic agents and psychotherapy.^[114]

Psychotropic agents

The efficacy of antidepressants in disorders of the gut–brain interaction has been confirmed. Antidepressants are reported to alleviate gastrointestinal symptoms by regulating neurotransmitters involved in the regulation of motility and sensation of the gut,^[115] exerting analgesic effects by blocking the receptors of relevant neurotransmitters,^[116] reducing gastrointestinal afferent signals,^[117] and downregulating visceral signals by affecting the functions of the anterior cingulate cortex.^[118] In patients with functional gastrointestinal disorders, antidepressants are used to treat comorbid psychological disorders such as depression, anxiety, and pain, as well as to ameliorate diarrhea, constipation, nausea, and sleep disorders.^[119] Antidepressants are also commonly used in patients with IBD. It was reported that up to 30% of IBD patients in Western countries take antidepressants.^[120] However, high-quality evidence for the role of antidepressants in the management of IBD is limited. Two observational studies reported that IBD patients who used antidepressants had lower disease activity^[121] and medical therapy escalation rates^[122] than non-users. In another large-scale follow-up study, the use of antidepressants appeared to reduce the increased risk of new-onset IBD among patients with depression at baseline.^[123] To date, only three randomized, double-blind, placebo-controlled trials have examined the use of antidepressants for the treatment of IBD. The serotonin and norepinephrine reuptake inhibitors (SNRIs), namely, duloxetine^[124] and venlafaxine,^[125] were reported to reduce the severity of anxiety, depression, and physical symptoms and improve QOL in patients with IBD compared with those in the placebo group. In IBD model C56BL/6 mice, fluoxetine, a selective serotonin reuptake inhibitor (SSRI), exhibited anti-inflammatory effects on the intestinal mucosa by remodeling intestinal cells and macrophages.^[126] However, another randomized controlled trial (RCT) showed no effect of fluoxetine on improving patients’ QOL or relieving anxiety or depression compared to placebo.^[127] Due to limited and low-quality evidence, recent systematic reviews have failed to draw firm conclusions about the safety and efficacy of antidepressants for IBD treatment.^[120,128] In addition, a recent population-based study revealed that the risk of corticosteroid dependency in UC patients who continuously use antidepressants was significantly greater than that in non-users,^[129] suggesting that long-term use of antidepressants has no protective effect on patients with UC in routine clinical practice and even leads to worse clinical outcomes.

Several studies have explored the application of other psychotropic drugs, such as mood stabilizers and opioids, in IBD treatment. The mood stabilizers, namely, gabapentin and topiramate, were shown to have protective effects on colonic tissue in rodent models of IBD.^[130,131] However, clinical studies have denied the correlation between the use of these two drugs and the clinical benefits of these drugs in IBD patients.^[132,133] Opioids are frequently used in the treatment of abdominal pain in patients with IBD, but heavy opioid use is related to opioid dependency and increased all-cause premature mortality.^[134] Another clinical trial showed that low-dose naltrexone was effective and safe for improving clinical symptoms and inducing remission in patients with IBD.^[135] Notably, patients with IBD are usually excluded from randomized controlled trials of psychotropic drugs; therefore, doctors should rely more on their clinical experience and study findings based on other patient populations when prescribing psychotropic agents to IBD patients.

Psychotherapies

In terms of psychotherapies for patients with IBD, there have been several examinations of stress management: cognitive behavioral therapy (CBT), mindfulness-based interventions (MBI), multi-convergent therapy (MCT), hypnosis, and short-term psychoanalytic psychotherapy (STPP) [Table 1].^{[136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158]} Stress management educates patients on stress coping, or relaxation techniques. There is evidence that stress management has a positive effect on psychological and physical health in patients with IBD, especially in terms of improving QOL and mood,^[136,137] relieving anxiety and stress,^[137] alleviating fatigue, constipation, abdominal pain, and distended abdomen,^[138] and reducing relapse.^[139] CBT is a goal-focused approach that aims to collaboratively identify patients’ maladaptive thoughts and create functional and balanced cognitive patterns to reduce emotional distress and create helpful behaviors. Several studies have demonstrated that the major benefits of CBT for IBD patients include reducing psychological symptoms such as disease-related worries and concerns, anxiety, and depression and improving QOL.^{[140,141,142,143,144,145]} Although one pilot feasibility study reported that CBT attenuated IBD disease activity,^[146] another RCT involving 176 patients suggested that CBT did not affect the course of IBD.^[147] In addition, a recent RCT concluded that group multicomponent CBT also decreased the number of relapses self-reported by patients.^[148] Mindfulness is the practice of purposefully and non-judgmentally focusing on the present moment. Several RCTs have examined mindfulness-based interventions that help relieve psychological and somatic symptoms, improve QOL, and reduce inflammatory indices such as C-reactive protein.^{[149,150,151]} MCT, a form of psychotherapy combining mindfulness meditation with CBT, reportedly improves the Inflammatory Bowel Disease Questionnaire (IBDQ) score in IBD patients with IBS symptoms.^[152] Medical hypnosis is an approach for alleviating physical symptoms, relieving distress, and influencing physiological processes. Studies on the application of hypnosis in IBD treatment have also shown promise for improving patients’ physical health.^{[153,154,155,156]} STPP, a treatment for depression in adolescents focused on emotional awareness and defense analysis, has been shown to increase the rate of steroid-free remission in adolescents and young adults with quiescent IBD receiving standard medical therapy.^[157]

Table 1.

Summary of evidence for the use of psychotherapies in patients with inflammatory bowel disease.

Psychotherapy	Type of study	N	Outcome in patients	Reference
Stress management	RCT	58	Improved QOL in UC patients.	Boye et al[136]
	RCT	39	Decreased levels of anxiety, pain, and stress as well as improved QOL and mood.	Mizrahi et al[137]
	Clinical study	45	Alleviated fatigue, constipation, abdominal pain, and distended abdomen.	García-Vega and Fernandez-Rodriguez[138]
	Clinical study	36	Reduced the relapse rate of IBD in the next 12 months.	Keefer et al[139]
CBT	RCT	57	Continuously improved anxiety and depression.	Díaz Sibaja et al[141]
	RCT	199	Improved health-related QOL at 12 weeks after baseline but did not maintain at 6 months.	McCombie et al[142]
	RCT	176	No changes in the course of IBD in 24 months.	Mikocka-Walus et al[147]
	RCT	174	Did not affect the remission rate, anxiety, depression, or coping but improved the QOL in patients with high mental health needs.	Mikocka-Walus et al[143]
	RCT	120	Reduced stress and the number of relapses self-reported by patients, and improved QOL.	Bernabeu et al[148]
	Pilot feasibility study	20	Improved sleep continuity, dysfunctional sleep-related beliefs, and reduced IBD disease activity.	Salwen-Deremer et al[146]
	Pilot feasibility study	22	Alleviated fatigue and increased QOL.	Artom et al[144]
	Clinical study	20	Improved pain self-efficacy and QOL, as well as reduced depression, anxiety, and pain catastrophizing and avoidance resting behavior.	Sweeney et al[145]
	Clinical study	28	Decreased disease-related worries and concerns.	Mussell et al[140]
MBI	RCT	55	Relieved stress in patients who flared but had no effect on flare-ups in UC patients in remission.	Jedel et al[149]
	RCT	44	Improved score of depression, trait anxiety, and dispositional mindfulness.	Schoultz et al[150]
	RCT	29	Improved psychological and physical symptoms, QOL, and C-reactive protein.	Gerbarg et al[151]
MCT	RCT	66	Improved IBDQ scores in patients with IBS-type symptoms but did not affect the relapse rate.	Berrill et al[152]
	RCT	116	Significantly reduced disease activity, improved QOL, alleviated psychological symptoms and fatigue, and increased mindfulness disposition.	Goren et al[158]
Hypnosis	RCT	54	Prolonged remission in patients with quiescent ulcerative colitis.	Keefer et al[153]
	Clinical study	15	Reduced corticosteroid requirements in patients on corticosteroids but not responding to medication at baseline.	Miller and Whorwell[154]
	RCT	17	Decreased pulse and median serum IL-6 concentration as well as the rectal mucosal release of substance P, histamine, IL-13, and blood flow.	Mawdsley et al[155]
	RCT	63	Relieved IBS-type symptoms in patients with quiescent IBD but was not superior to standard medical treatment.	Hoekman et al[156]
STPP	RCT	60	8-week STPP + standard medical therapy effectively increased the steroid-free remission rates compared to standard medical therapy alone.	Milo et al[157]

CBT: Cognitive behavioral therapy; IBD: Inflammatory bowel disease; IBDQ: Inflammatory Bowel Disease Questionnaire; IBS: Irritable bowel syndrome; IL-6: Interleukin-6; IL-13: Interleukin-13; MBI: Mindfulness-based interventions; MCT: Multi-convergent therapy; QOL: Quality of life; RCT: Randomized controlled trial; STPP: Short-term psychoanalytic psychotherapy; UC: Ulcerative colitis.

Interventions targeting the brain–gut–microbiota axis

Given that stress plays an important role in disturbing the balance of the microbiota–gut–brain axis, multiple studies have also explored potential interventions targeting the microbiota–gut–brain axis that might help benefit IBD patients with psychological comorbidities. However, most of these studies focused on modulating the gut microbiota instead of targeting other aspects of the axis to ameliorate the effects of stress on IBD.

A probiotic mixture containing Lactobacillus rhamnosus strain R0011 (95%) and L. helveticus strain R0052 (5%) was shown to ameliorate gut functional abnormalities and reduce the elevated blood corticosterone levels induced by stress in rats.^[46] Eutamene et al^[159] reported that the administration of Lactobacillus paracasei NCC2461 to rats alleviated stress-induced visceral pain and corrected gut permeability disturbances. In other animal studies, long-term stressor exposure exacerbated Citrobacter rodentium-induced infectious colitis in mice, while the probiotic Lactobacillus reuteri prevented the aggravating effect of stressor exposure on pathogen-induced colitis^[160] and reduced the transfer of pathogens from the colon to the spleen,^[161] but did not attenuate the alteration of the colonic microbiota.^[162] Notably, Anaerostipes hadrus BPB5, a potential probiotic candidate for IBD, was found to increase the disease activity index and mortality in DSS-treated mice but had no negative effect on healthy mice.^[163] This suggests that probiotic candidates that are beneficial to healthy populations may not necessarily improve the health of IBD patients and might even increase the severity of the disease. In addition, the total flavone of Abelmoschus manihot (TFA), which is extracted from the traditional Chinese medicine Flos Abelmoschus manihot, was demonstrated to exert protective effects on UC aggravated by chronic stress in mice. In this study, TFA was also observed to rescue the depression-like phenotype, improve gut barrier function, and attenuate intestinal microbial dysbiosis in a chronic stress-induced depression model.^[164]

In addition, oxytocin, a nonapeptide hormone that has been reported to attenuate the stress response of the HPA axis and relieve anxiety by increasing vagal nerve tone as well as decreasing sympathoadrenal and HPA tone, was shown to exert protective effects (decreasing anxiety, colonic myeloperoxidase and malondialdehyde levels, infiltration of inflammatory cells, and submucosal edema) in a stress-aggravated colitis rat model.^[165]

Most of the existing studies are carried out in animal models and focus on targeting the intestinal microbiota. Intervention methods to alleviate the stress of IBD patients and improve mental health by targeting the gut–brain axis remain to be explored.

In conclusion, this article reviews the connections and interactions among the microbiota, gut, and brain, the impact of psychological stress on the microbiota–gut–brain axis, and the existing and potential interventions for the management of stress in individuals with IBD. According to recent evidence, patients with IBD have a high incidence of psychiatric complications, which in turn exacerbates the severity of IBD. The underlying mechanisms might involve alterations in the functions of the microbiota–gut–brain axis, especially the HPA axis, the sympathetic and vagus nerves, the intestinal flora and metabolites, as well as intestinal immunity and permeability. However, most of these findings are obtained from animal experiments and preclinical studies. Changing these research findings into therapeutic approaches that improved both somatic and psychological symptoms in patients with IBD might be a direction of great interest for large-scale clinical research in the future.

Funding

This study was supported by grants from the Science and Technology Program of Qinghai (No. 2023-ZJ-936M), the Science and Technology Program of Xining (No. 2022-M-19), the Science and Technology Program of Guangzhou (No. 2021020800007), and Guangdong Provincial People’s Hospital Self Funded Project (No. 8207104096).

Conflicts of interest

None.