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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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Research Progress of Central and Peripheral Corticotropin-Releasing Hormone in Irritable Bowel Syndrome with Comorbid Dysthymic Disorders

Yi Feng Liang1 , Xiao Qi Chen1 , Meng Ting Zhang2 , He Yong Tang2 , Guo Ming Shen2

1College of Acupuncture and Massage and 2College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China

Correspondence to: Guo Ming Shen
ORCID https://orcid.org/0000-0002-3456-9946
E-mail guomings_66@163.com

Yi Feng Liang, Xiao Qi Chen, and Meng Ting Zhang contributed equally to this work as first authors.

Received: August 5, 2022; Revised: April 26, 2023; Accepted: May 22, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver.

Published online August 8, 2023

Copyright © Gut and Liver.

Irritable bowel syndrome (IBS) is considered a stress disorder characterized by psychological and gastrointestinal dysfunction. IBS patients not only suffer from intestinal symptoms such as abdominal pain, diarrhea, or constipation but also, experience dysthymic disorders such as anxiety and depression. Studies have found that corticotropin-releasing hormone plays a key role in IBS with comorbid dysthymic disorders. Next, we will summarize the effects of corticotropin-releasing hormone from the central nervous system and periphery on IBS with comorbid dysthymic disorders and relevant treatments based on published literatures in recent years.

Keywords: Irritable bowel syndrome, Dysthymic disorder, Corticotropin-releasing hormone, Review

Irritable bowel syndrome (IBS) is a group of functional gastrointestinal diseases characterized by abdominal pain and/or abdominal discomfort accompanied by changes in defecation behavior without obvious biochemical abnormalities and organic changes, which is associated with various pathophysiological mechanisms such as genetic factors, abnormal colonic movement, visceral hypersensitivity, psychological distress, and intestinal microflora disorder.1,2 In addition to its own digestive tract symptoms, IBS is often merged by mental symptoms such as anxiety and depression, as well as physical symptoms such as migraine, fatigue, and sleeping disturbances.3-5 A hospital in Bangladesh evaluated the incidence of mental illness among 110 IBS patients and revealed that the most common dysthymic disorder was anxiety (22.7%), followed by major depression (19.1%) and somatization disorder (14.5%).6 The clinical manifestations of each individual are quite different, and some patients' mental symptoms are even more serious than those of gastrointestinal, which brings great difficulties to treatment and makes the patient's condition protracted. Therefore, it is of great clinical value to provide psychiatric intervention for patients with IBS. Clinical evidence has suggested that IBS is a stress-sensitive disorder, of which chronic psychological stress is considered to be one of the main causes.7 For instance, abuse in childhood, divorce of parents and long-term pressure from work and study may induce or aggravate the symptoms of IBS.8,9 Similarly, chronic stress is one of the major causes of the development and persistence of depressive behavioral phenotypes.10 It can be seen that stress is a common pathogenic factor of IBS and mood disorders, and under the stimulation of stress, the body will release corticotropin-releasing hormone (CRH) for coping and adjusting.11

CRH, also known as corticotropin-releasing factor, was isolated from sheep hypothalamus by Vale et al. in 1981.12 CRH is an important neuroendocrine peptide, a 41-amino acid peptide produced by neuroendocrine cells in the central nervous system (CNS) and the periphery, which plays a key role in the pathogenesis of stress-induced intestinal diseases. CRH is mainly synthesized and released from the paraventricular nucleus (PVN) of hypothalamus to regulate various systems of the body in response to normal stress. There are two kinds of receptors of CRH, CRH receptor (CRHR) 1 and CRHR2, and the affinity of the former to CRH is 10 to 40 times higher than that of the latter.13 CRHR1 is widely expressed in the central and peripheral nervous system as well as immune cells and is a pivotal mediator causing endocrine, autonomic and immune reactions in response to stress, modulating the "fight or flight" through the CRH-adrenocorticotropic hormone-glucocorticoid axis. In addition to being expressed in the brain, CRHR2 is also highly expressed in peripheral tissues such as gastrointestinal tract and cardiac smooth muscle, and is involved in regulating metabolism, blood pressure, immune cell signal transduction, and stress processing responses through urocortin II and urocortin III.14,15 Under normal circumstances, the body will rapidly release CRH when stressed, resulting in an increase in energy consumption and enhancement of cardiac function. After that, the body needs to recover from the enhanced state to homeostasis through the negative feedback regulation of glucocorticoid in a long process. If this balance is broken, uncontrolled CRH will cause damage to nervous, digestive, cardiovascular, and other systems.16 CRH is a pivotal mediator of stress-induced IBS and dysthymic disorders within both CNS and periphery: Studies have found that water avoidance stress and wrap restraint stress can lead to intestinal dysmotility and visceral hypersensitivity in mice, and peripheral CRH and CRHR1 are increased in colon tissues.17,18 CRHR1 agonists could reduce distal colon transport time, increase distal and transverse colon contractility, and induce watery diarrhea in rats.19 On the contrary, CRHR2 agonists could reduce visceral pain hypersensitivity in colorectal dilatation rats.20 Clinically, it has been shown that the concentration of CRH in the plasma and cerebrospinal fluid of depressed patients markedly rises, related to CRH-induced increased releasing of cortisol through the hypothalamic-pituitary-adrenal (HPA) axis.10,21 Accordingly, IBS and dysthymic disorders may share a common pathophysiological basis, namely, abnormal CRH function.22 The mechanism of CRH is shown in Fig. 1.

Figure 1.Effect of CRH on irritable bowel syndrome with comorbid dysthymic disorders.
CNS, central nervous system; PVN, paraventricular nucleus; CRH, corticotropin-releasing hormone; CeA, central amygdala; CRHR1, corticotropin-releasing hormone receptor 1; LC, locus coeruleus; NE, norepinephrine; DRN, dorsal raphe nucleus; 5-HT, 5-hydroxytryptamine; MC, mast cell; IL-6, interleukin-6; EC, entero-chromaffin cell; PG, prostaglandin; EG, eosinophilic granulocyte.

CRH widely spreads over CNS, such as PVN, central amygdala (CeA), bed nucleus of the stria terminalis (BNST), cerebral cortex, pituitary, hippocampus, locus coeruleus (LC), spinal cord, involved in endocrine, stress response, regulation of vagus, and so on.23 Researches have shown that IBS patients have abnormal spontaneous activity in brain regions associated with pain processing (such as amygdala, anterior cingulate cortex [ACC], lobus insularis, and thalamus) and emotion regulation (such as amygdala, LC, hippocampus, hypothalamus).7,24,25 The parts of the brain where CRH changes the intestinal movement include PVN, LC complex, and dorsal motor nucleus, while the parts of the brain that regulate visceral pain are located in the CeA, hippocampus, BNST and LC, and the brain regions that affect psychological state are located in hypothalamus, amygdala, and dorsal raphe nucleus (DRN). For example, intra-cerebroventricular injection of CRH may cause increased colon movement, decreased absorption of intestinal fluid, enhanced algesia to colorectal distension (CRD), impaired colon secretion and barrier function, abdominal pain and diarrhea.7 Moreover, the stereoscopic injection of CRH into the hippocampus could lead to depressive symptom.26 As follows, we will discuss the role of CRH within hypothalamus, amygdala, DRN, LC as well as spinal cord and how it is involved in IBS with comorbid dysthymic disorders.

1. Hypothalamus

Hypothalamus, a high-level nerve center regulating visceral and endocrine activities, releases CRH when stress induces intestinal disorder and activates HPA axis, which promotes the release of corticosteroid, thus becoming a key mediator of immune stress. As a starting point for the HPA axis, the hypothalamus connects the emotional, limbic, cortical center in the brain (such as hippocampus, amygdala, and ACC) to the peripheral pressure system (such as pituitary, adrenal cortex).27 By means of visceral hypersensitivity rat models, it has been discovered that the expression of c-fos and CRH is significantly increased in hypothalamus, diacele, and spinal cord.28,29 CRD or maternal separation stress to neonatal rats can induce the disinhibition of PVN-projecting gamma-aminobutyric acid positive (GABA-ergic) neurons in the anterior ventral region of BNST, resulting in continuous sensitization of CRH neurons in PVN and visceral hypersensitivity, which can be prevented via injecting lidocaine or small interfering RNA that targeting CRH to PVN.30,31 Previous study has found increasing concentration of CRH in cerebrospinal fluid and growing expression of CRH messenger RNA (mRNA) within PVN in depressed patients.21 Likewise, the levels of CRH and CRHR1 in PVN of male rats rise after experiencing gestational intermittent hypoxia, leading to persistent anxiety and depression during adulthood, while knock-out of CRHR1 decreases their anxiety-like behavior.32,33 Also, the excitatory postsynaptic protein-93 could increase depression-like behavior by activating CRH neurons in PVN, and its effect would be reduced by gene knock-out.34 In addition, specific CRH knock-out of PVN can produce anti-anxiety function: When exposed to a variety of pressure source (including open field, elevated plus maze, hole-board, and light-dark box), the original anxiety-like behavior of mice is significantly reduced, while plasma administration of exogenous corticosterone cannot reverse this anti-anxiety effect.35 To sum up, PVN-CRH neurons are closely associated with both visceral hypersensitivity and mood disorders.

2. Amygdala

As one part of the limbic system, the amygdala is related to generating, recognizing and adjusting emotion, and plays a crucial role in the integration of the body's neurophysiological response to stress and the regulation of anxiety.11,36 It has been discovered that amygdala always shows an activation state for visceral stimulation in patients with IBS.37 CeA, one of the main nuclei of amygdala, plays an important role in regulating the generation of chronic pain and negative emotional state, and widely projects to BNST, ventral tegmental area, periaqueductal gray, LC, parabrachial nucleus and dorsal nucleus of vagus.38 Stresses like CRD could increase the expression of CRH and immune response within CeA, thus activating LC to up-regulate the norepinephrine (NE) system and eventually resulting in anxiety and visceral hypersensitivity.39-42 Similarly, water avoidance stress and maternal separation could lead to visceral hypersensitivity, which is associated with decreased methylation of CRH promoter, increased acetylation of histone and expression of CRH mRNA within CeA.43 As is well known that CRH released by hypothalamus combines with receptors in the anterior pituitary, which secretes adrenocorticotropic hormone into the peripheral blood circulation, resulting in increased cortisol in human or corticosterone in rodent, while the latter binds to glucocorticoid receptor, initiating negative feedback regulation of HPA axis at hypothalamus and hippocampus level, and reducing CRH secretion. On the contrary, the binding of corticosterone to glucocorticoid receptor in amygdala would promote the HPA axis and increase the expression of CRH, thus stimulating the stress-induced colonic hypersensitivity response, which can be inhibited by gene knock-out of CeA-CRH.11 Via chemical genetic and fluorescent labeling technology, anxiety-like behavior has been proved to be caused by dorsolateral BNST-projecting CRH from CeA that combines with CRHR1.44 Also, basolateral amygdala (BLA) is an important nucleus of amygdala, playing a key role in processing stressful events and emotional disorders. CRH could mediate depression and anxiety through BLA. Activation of CRH-CRHR1 signaling enhances synaptic efficiency of the outer vesicle-BLA pathway, sensitizes BLA neurons, and promotes depression-like behavior in rats induced by chronic forced swimming (a valid stress model used to test the clinical efficacy of antidepressants).45 Additionally, increased level of CRH in BLA of male rats treated with oral perfluorooctanoic acid-a hazardous environmental pollutant-induces anxiety-like behavior, which can be alleviated by injection of CRHR1 antagonists into BLA.46

3. Locus coeruleus

LC is located in the pons, and its neurons extensively innervate the brain and release neuromodulator NE in its terminal regions. LC-NE system is thought to be involved in the global regulation of behavior, wakefulness, physical and emotional responses to stress.33,47 Clinical studies have found that LC-NE system of IBS patients is usually in active state, and the NE efferent projection from LC cortex and corneal edge may cause anxiety as well as visceral hypersensitivity.7,48,49 CRH neurons from hypothalamus, CeA can project to LC, promoting LC to discharge and release NE, while NE can in turn activate HPA axis and prompt the secretion of CRH.47,50-52

4. Dorsal raphe nucleus

DRN, a vital nucleus of 5-hydroxytryptamine (5-HT) neurons CNS-including about 35% of the 26,000 neurons producing 5-HT in brain, is involved in pressure response, sleep, and temperature regulation.53 The 5-HT system plays an important role in stress-related mental diseases and is considered as a major neurotransmitter for depression, anxiety, bipolar disorder, obsessive-compulsive disorder and other psychiatric disorders.54,55 For example, low expression of 5-HT within CNS accounts for depression. Stressors could inhibit 5-HT neuron activity by stimulating the release of CRH in DRN, which is mediated by CRHR1 located on GABA afferent neurons, whereas CRHR2 mediates an opposite effect, promoting the release of 5-HT.56-59 Another study has shown that low-dose CRH binds to CRHR1 while high-dose CRH combines with CRHR2.60 In addition, inhibition of DRN 5-HT by CRH may lead to visceral hyperalgesia, for the reason that 5-HT is also a main factor of central descending pain-inhibiting system, however, this response can be inhibited by lateral ventricular injection of CRHR1 antagonists or CRHR2 agonists.61

5. Spinal cord

The spinal cord is the first position in CNS to perceive and regulate the signal of visceral hypersensitivity, and also the transfer station of information between intestine and the higher center. As is known that the mechanisms of visceral hypersensitivity include peripheral sensitization and central sensitization: Enhanced excitability of primary sensory neurons within intestinal tract could cause central sensitization state and heighten the response of spinal neurons to visceral harmful information, thus leading to more sustained visceral hypersensitivity.62-64 Researches have shown that 5-HT-ergic neurons in DRN can project to spinal cord, and the binding of 5-HT to 5-HT type 2 or 3 receptors released after stress would promote colorectal motility, while the binding of 5-HT to type 2C or 3 receptors could inhibit or promote visceral hypersensitivity respectively.65-67 The mouse model of visceral hypersensitivity induced by CRD has shown that the expression of CRH mRNA in spinal cord is significantly increased, especially in the lumbar swelling.28,68 CRHR2 is mainly distributed within the parasympathetic nucleus, central canal, layers I and II of the spinal dorsal horn, and is mainly expressed in inhibitory enkephalinergic intermediate neurons, which mediate abirritation and could raise the pain threshold of spinal secondary neurons and so inhibit visceral pain.69,70 By contrast, CRHR1 is low-expressed in spinal cord, and its combination with CRH would aggravate pain sensitivity.71

CRH is diffusely expressed in peripheral tissues, such as heart, blood vessel, gastrointestinal tract, lung, kidney, pancreas, fat, testis, ovary, placenta, and so on.72 Peripheral CRH-CRHR1 binding mediates gastric mucosal protection and reduces sperm quantity and quality.73,74 However, CRH-CRHR2 signaling can dilate blood vessel, significantly increase the contractility of cardiac myocytes, induce arrhythmias, decrease food intake and delay gastric emptying via enhancing the mechanical sensitivity of vagal afferent nerves.75,76 CRH is commonly expressed in human intestine, and by means of immunohistochemistry, CRH mRNA expression is detected in lamina propria cells, submucosa, and intramuscular nerve plexus.77 Different from central CRH, the one secreted by neuroendocrine cells and immune cells in intestine could affect the contractility of smooth muscles, visceral sensitivity, mucosal permeability and transport capacity, which are strongly related to the colonic manifestations of IBS patients.78 CRHR1 and CRHR2 are located throughout the intestinal tract in a variety of cells, including the enteric nerve cell, endocrine cell (entero-chromaffin cell, EC) and immune cell (mast cell [MC], eosinophilic granulocyte [EG], and T-helper lymphocyte).7 CRHR2 antagonizes CRHR1 in the regulation of visceral sensation and intestinal motility: CRHR1 mediates intestinal injury by promoting intestinal inflammation, enhancing colonic motility, increasing intestinal permeability, changing intestinal morphology and regulating intestinal microbes. On the contrary, CRHR2 activates intestinal stem cell and repairs the injured intestine.13,78,79 Next, we will discuss how peripheral CRH is involved in IBS with comorbid dysthymic disorders through the mediating of MC, EC, macrophage, EG, and enteric nervous system (ENS).

1. Mast cell

MC is recognized as an important early immune effector cell in stress response and stress-related pathophysiology, which is widely distributed around the micro vessel beneath gut submucosa and meanwhile plays an important role in regulating intestinal barrier function, secretory function of epithelial cell, intestinal blood supply, neuro-immune system interaction, visceral sensitivity and intestinal motor function. The immunoglobulin E exists on MC surface, which tends to degranulate when sensitized by external factors (parasite, virus, bacterium, and food) or internal factors (neurotransmitter, hormone from CNS) and release intracellular histamine, protease, serotonin, prostaglandin, cytokine, which represent a defense mechanism that mobilizes pivotal resources for the host's “fight-or-flight” response and enhances immune function. Nevertheless, uncontrolled activation of MC can be harmful and associated with the onset and severity of diseases like allergy, asthma as well as IBS.80 The number of MC within colon usually increases in IBS patients or animal models, which is positively correlated not only with the severity of IBS, especially the level of abdominal pain, but also with depression scores.81,82 Hence, MC and its mediators are considered to be key components of the pathological factors of IBS.83 CRH could activate MC degranulation to release various mediators, which would promote colonic secretion and enhance the excitability of enteric neurons, leading to visceral allergy and increased intestinal permeability in IBS patients.84 For example, histamine and protease create prostaglandin-mediated pain-promoting effects, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and protease destroy intercellular tight junction protein and its component zonula occludens-1, inhibit the weakly inward rectifying K+ channel-related potassium channel-1 expression within colon epithelial cells, increase intestinal mucosal permeability and promote inflammation.85-89 Via immunohistochemical staining, a large proportion of CRHR1 and MC have been found labeled together in colonic mucosa, and the concentration of CRHR1 and MC increases in IBS model rats.90 Confocal microscopy has shown that CRHR1 is mainly distributed on MC cell membrane while CRHR2 is located on MC surface or inside it.80 Moreover, MC degranulation is mediated by CRHR1, and CRHR1 antagonists could prevent visceral hypersensitivity but could not reverse it after MC degranulation.91,92 By contrast, CRHR2 has been proved to be a negative regulator for MC degranulation, and its activation would reduce the severity of immunoglobulin E-mediated anaphylaxis and stress-induced intestinal hyperpermeability.93 Besides, it has been demonstrated that public speech, as a psychosocial stressor, mediates an increase of intestinal permeability of healthy volunteers via the activation of HPA axis, while this response can be blocked by preconditioning with MC stabilizer disodium cromoglycate.93,94

2. Entero-chromaffin cell

EC is the main cell type for the synthesis, storage and release of 5-HT within intestine: 95% of 5-HT comes from the intestine, in which 90% of 5-HT is derived from EC.95 Enteric 5-HT plays a key role in regulating visceral sensation, intestinal motility and permeability: It mainly binds to 5-HT3 receptors at the terminal of primary afferent neurons, leading to abdominal pain and diarrhea.96,97 Clinical data has indicated that EC density in rectum and plasma 5-HT level increase in IBS-diarrhea patients, while the latter decreases in IBS-constipation patients.96,98 Stress can activate the CRHR1 signaling pathway, which leads to EC hyperplasia and increased 5-HT secretion, thus stimulating enteric neurons to produce acetylcholine, which further excites sensory afferent nerves of spinal cord to amplify and project harmful signals from intestinal tract to CNS, resulting in visceral hypersensitivity and strengthened intestinal motility.99,100

3. Macrophage

Macrophage is also one kind of immune cells, and can be divided into M1 and M2 types. M1 type releases pro-inflammatory cytokines, such as tumor necrosis factor-α, IL-1β, and IL-6, which could be promoted by CRH-CRHR1.79 On the contrary, M2 type inhibits the function of M1 by producing anti-inflammatory factors such as IL-10.101 Additionally, macrophage plays an important role in intestinal motility by acting on the muscular plexus: M2 type infiltration is enhanced in the colon tissues of IBS patients, thus accelerating intestinal motility.101 There are also a large number of CRHRs on the surface of enteric macrophage: The combination of CRH and CRHR1 could induce macrophage to degranulate and release a series of active substances such as prostaglandin, cytokines, then activating afferent nerves or dorsal root ganglions, and forming visceral hypersensitivity,13 while the activation of CRHR2 may inhibit this effect.102 In addition to mediating intestinal symptoms, macrophage is implicated in mood disorders: Toll-like receptor 4 expressed on macrophage is an independent risk factor associated with the severity of major depression.103 CRH could activate Toll-like receptor 4, aggravating the psychiatric symptoms of IBS patients.104

4. Eosinophilic granulocyte

EG is widely distributed in the gastrointestinal tract, responsible for maintaining gastrointestinal homeostasis, and is also one of the main sources of CRH within intestine.81 Studies have found that increased EG in sigmoid colon is associated with higher anxiety scores, while psychological stress could stimulate EG, leading to the release of CRH and activation of MC, thus increasing intestinal permeability.82,105,106 Clinical tests have shown that the number of intestinal mucosa EG in IBS patients rises, and intracellular CRH expression increases, which is positively correlated with intestinal symptoms and depression.107-109

5. Enteric nervous system

ENS, a network of neurons and glial cells located within the intestinal wall, includes two major nerve plexus: the submucosal plexus (SMP), which regulates the absorption and secretion functions of mucosal epithelial cells, intramural blood flow, and neuroimmune interactions, and the myenteric plexus (MP), while the MP modulates intestinal movement. ENS provides intrinsic neurological control of almost all gastrointestinal functions, such as gastrointestinal motility and homeostasis, and is thought to underlie a range of gastrointestinal diseases, including IBS. Secretory motor neurons in SMP promote gastrointestinal secretory function by releasing acetylcholine or vasoactive intestinal peptide, while the increase of choline acetyltransferase and vasoactive intestinal peptide neurons in the ileum SMP of IBS-D rats may be related to the increase of intestinal secretion and the appearance of diarrhea symptoms. In addition, the decreased release of nitric oxide by inhibitory muscle motor neurons in MP may be the cause of the enhanced intestinal motility of IBS.110 According to research, the excitatory effect of CRH on the ENS is mediated by CRHR1, but not CRHR2: wrap restraint stress induces increased expression of CRHR1 in the MP and SMP of rats, especially in the SMP, which is associated with visceral hypersensitivity and high intestinal motility.111 Excitatory muscle motor neurons in the MP express CRHR1 receptors, explaining the activation effect of CRH on intestinal motility. Besides, CRH binds to CRHR1 expressed by secretomotor neurons in the SMP, inducing the secretion of water, electrolytes, and mucus.112 CRHR1 antagonists could block the neuronal activation of colon induced by IBS plasma, while CRHR2 antagonists exert no such effect.113

In general, the guideline recommends the use of spasmolytic as the first-line therapy to relieve the overall symptoms of IBS. It alleviates abdominal pain and diarrhea via inhibiting the effect of acetylcholine on muscarinic or tachykinin neurokinin 2 receptors or blocking calcium channels in the enteric smooth muscle. However, it is also associated with a series of side effects, including dry mouth, dizziness, blurred vision, and constipation.1 At the same time, for patients with comorbid mood disorders, spasmolytic can not relieve their mental symptoms well. Therefore, we need a class of drugs that could both ease patients' intestinal symptoms and improve their dysthymic disorders, and CRH-related therapies may be able to resolve these problems.

Given that CRH-CRHR1 produces an effect that promoting intestinal and psychiatric symptoms, while CRH-CRHR2 generates an opposite effect, treatment with CRHR1 antagonists or CRHR2 agonists should be taken into account. Selective CRHR1 antagonists currently developed include antalarmin, pexacerfont, NBI-30775 (R121919), CP-376, JTC-017, NGD9002, and so on, and the combination of CRHR1 antagonists with CRHR1 in different parts of the body could create diverse effects.114 For example, R121919 has been successfully used in clinical treatment of depression and anxiety, which is associated with decreased blood oxygen level-dependent signal in brain regions related to emotional arousal circuit (amygdala, hippocampus, and ACC).115-117 JTC-017 could reduce the release of hippocampus NE after acute CRD stress in rats, and relieve visceral hypersensitivity as well as anxiety-like behavior.118 However, the clinical results of many CRHR1 antagonists are not satisfactory. They have yet brought plenty of problems, such as high affinity, long elimination half-life, active metabolites, high protein binding, pre-clinical screening, mismatch between dynamic characteristics of CRHR function and subject patients, acute versus advanced manifestations of the disease; NBI-77860 has the side effect of headache; R121919 significantly reduces the score of depressive patients, but the relevant study lacks blind, randomized, or placebo-controlled controls and causes elevated liver enzymes; there was no significant difference between CP-316,311 and placebo treatment.119-121 In addition, the balance between receptor affinity and the pharmacokinetic property of CRHR1 antagonists remains the focus of the pharmaceutical industry.114 Besides, CRHR2 agonists have an anti-anxiety effect in CNS, but can delay gastric empty, therefore, organ-selective CRHR2 agonists should be chosen in clinic.13

In addition to directly acting on the CRH-CRHR signaling pathway with CRHR1 antagonists or CRHR2 agonists, we can modulate CRH indirectly via brain neuromediators. Calcium imaging has shown that 12 kinds of substances (such as glutamic acid, serotonin, NE, dopamine, and neuromedin C) can activate PVN-CRH, while three kinds of substances (GABA, glycine, and nociceptin) can inhibit PVN-CRH, which can be used as the direction of CRH targeted therapy in the future.122 For example, GABA-ergic neurons from BNST, dorsomedial hypothalamus, arcuate nucleus, medial preoptic nucleus, and glutamic acid positive neurons from periaqueductal gray matter, zona incerta, PBN, raphe nucleus, nucleus tractus solitarius all project to PVN and regulate the function of HPA axis: GABA-ergic neurons inhibit the release of CRH, while glutamic acid positive neurons promote the secretion of CRH.31,123 Therefore, the excitatory/inhibitory balance mediated by rapid ion transfer is a key regulator of PVN-CRH neuron excitability, and the release of CRH can be effectively inhibited by the activation of GABA receptors or antagonism of glutamic acid receptors on PVN, thus improving splanchnic hypersensitivity.124 Besides, injection of the histone deacetylase inhibitor trichostatin A into CeA could hold back the activation of the CRH promoter, thereby preventing stress-induced visceral hypersensitivity.39

Furthermore, commonly used IBS treatments are increasingly shown to be involved in regulating CRH. Benzodiazepines, traditional anti-anxiety drugs, including clonazepam and alprazolam, have been proven to reduce the activity of CRH neurons within hypothalamus; selective serotonin reuptake inhibitors such as escitalopram can inhibit CeA-CRH release and increase glucocorticoid receptor density in hippocampus and hypothalamus, promoting negative feedback regulation of HPA axis; prophylactic use of tricyclic antidepressants, such as amitriptyline, can improve intestinal symptoms in IBS model rats and reduce the expression of CRH in hypothalamus and colon.41,125 Environmental enrichment, one novel kind of behavioral therapies, can prevent IBS through three approaches: preventing stress-induced increase of colon permeability, activating phosphorylation of extracellular signal-regulated kinases in spinal cord, restraining the activity of CRH promoter within CeA, and these effects would last long after environmental enrichment.126 In addition, Chinese traditional therapeutic methods such as acupuncture and moxibustion can not only improve intestine symptoms, but also has unique psychological and psychiatric therapeutic effects, such as reducing the expression of CRH and CRHR1 in hypothalamus to relieve anxiety and depression, decreasing the level of CRH, CRHR1, MC and 5-HT in colon to alleviate visceral hypersensitivity, increasing the expression of zonula occludens-1 to repair the intestine mucosal barrier, or reduce the expression of central and peripheral CRHR2 to improve jejunal dyskinesia, ultimately achieve the effect of simultaneous treatment to both body and mind.90,127-133

The latest standard of Rome IV highlights the importance of the brain-gut axis dysfunction in the pathogenesis of IBS, and names functional gastrointestinal disorders as disorders of brain-gut interaction. The brain-gut axis consists of CNS, autonomic nervous system, ENS, and HPA axis. The ACC of brain receives exogenous stimulation, while the ENS receives endogenous stimulation, which are transmitted to enteric nerve plexus or directly act on intestinal cells after integration by autonomic nerve or HPA axis. When emotional stress changes, sympathetic nerve excitation would cause intestinal vasoconstriction, and vagal nerve hyperfunction would lead to increased enteric secretion or movement. Epidemiological surveys have shown that many IBS patients have got depression or anxiety, and patients with pre-existing dysthymic disorders are more likely to suffer from IBS, which is also evidence for brain-gut interaction. So far, IBS still remains a challenge. Patients suffer from recurrent abdominal pain and diarrhea, and over a long period of time, they would develop varying degrees of anxiety or depression, which may more aggravate intestinal symptoms, the reason why IBS is hard to cure.

Recently, researchers have discovered that a variety of neuropeptides co-express in both the brain and intestine, such as serotonin, vasoactive intestinal peptide, substance P, neuropeptide Y, CRH, motilin, playing different roles in the pathogenesis of IBS, among which CRH is the key driver in IBS with comorbid dysthymic disorders. CRH is a vital neurotransmitter of HPA axis. When the body is under physiological or psychological stress, the HPA axis is activated and CRH is released to regulate the body and restore stability. However, the disordered CRH system would cause stress-related diseases, such as IBS and mood disorders. The hyperactivity of HPA axis is one of the common pathological mechanisms of mental diseases including depression: Clinically, it has been found that the concentration of CRH within plasma and cerebrospinal fluid of depressive patients rises; the prevalence of depression in females is several times higher than that in males, and animal experiments have shown that the binding rate of CRH-CRHR1 in females is generally higher than that in males.10,21 Similarly, increased CRH expression in colon of IBS patients is positively correlated with intestinal symptoms. CRH produced in CNS and intestine under stress would be combined with different CRHRs (mainly CRHR1) in different parts of the body, causing a variety of effects: CRH binding to receptors within DRN could inhibit the release of 5-HT, and then lead to visceral hypersensitivity or depression-like behavior; CRH-CRHR1 signaling would activate the LC-NE system, causing anxiety and visceral allergy; CRHR1 mediates MC degranulation, then leads to increased intestinal permeability, while CRHR2 acts as a negative regulator of this effect and improves symptoms of IBS patients.

Based on the understanding of the role of CRH in regulating IBS with comorbid dysthymic disorders, we may be able to use more precise treatment to help IBS patients relieve symptoms, improve living quality, and even get cured one day. The most targeted treatment for CRH is the use of CRHR1 antagonists or CRHR2 agonists. At present, a variety of drugs have been available, but due to the problems of long half-life and high affinity, related researches are still in the stage of animal experiments and clinical trials, and they have not been widely used in clinic. Besides, as researches progress, we have also found that some commonly used treatment, such as tricyclic antidepressants, benzodiazepines anti-anxiety agents, behavioral therapies, acupuncture, and moxibustion, could adjust CRH expression or change the combination of CRH with its receptors, to improve both physical and mental symptoms, which can better guide the clinical application. In the future, we need to focus on studying more about the working mechanisms of central and peripheral CRH in IBS with comorbid dysthymic disorders, developing relevant targeted drugs and gradually applying them to the clinic.

This study was supported by the National Natural Science Foundation of China (No.81904095 and No.81973936), Anhui University of Chinese Medicine 2018-2019 High-level Talents Introduction Support Plan (No.2019rcyb002).

No potential conflict of interest relevant to this article was reported.

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Article

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Gut and Liver

Published online August 8, 2023

Copyright © Gut and Liver.

Research Progress of Central and Peripheral Corticotropin-Releasing Hormone in Irritable Bowel Syndrome with Comorbid Dysthymic Disorders

Yi Feng Liang1 , Xiao Qi Chen1 , Meng Ting Zhang2 , He Yong Tang2 , Guo Ming Shen2

1College of Acupuncture and Massage and 2College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China

Correspondence to:Guo Ming Shen
ORCID https://orcid.org/0000-0002-3456-9946
E-mail guomings_66@163.com

Yi Feng Liang, Xiao Qi Chen, and Meng Ting Zhang contributed equally to this work as first authors.

Received: August 5, 2022; Revised: April 26, 2023; Accepted: May 22, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Irritable bowel syndrome (IBS) is considered a stress disorder characterized by psychological and gastrointestinal dysfunction. IBS patients not only suffer from intestinal symptoms such as abdominal pain, diarrhea, or constipation but also, experience dysthymic disorders such as anxiety and depression. Studies have found that corticotropin-releasing hormone plays a key role in IBS with comorbid dysthymic disorders. Next, we will summarize the effects of corticotropin-releasing hormone from the central nervous system and periphery on IBS with comorbid dysthymic disorders and relevant treatments based on published literatures in recent years.

Keywords: Irritable bowel syndrome, Dysthymic disorder, Corticotropin-releasing hormone, Review

INTRODUCTION

Irritable bowel syndrome (IBS) is a group of functional gastrointestinal diseases characterized by abdominal pain and/or abdominal discomfort accompanied by changes in defecation behavior without obvious biochemical abnormalities and organic changes, which is associated with various pathophysiological mechanisms such as genetic factors, abnormal colonic movement, visceral hypersensitivity, psychological distress, and intestinal microflora disorder.1,2 In addition to its own digestive tract symptoms, IBS is often merged by mental symptoms such as anxiety and depression, as well as physical symptoms such as migraine, fatigue, and sleeping disturbances.3-5 A hospital in Bangladesh evaluated the incidence of mental illness among 110 IBS patients and revealed that the most common dysthymic disorder was anxiety (22.7%), followed by major depression (19.1%) and somatization disorder (14.5%).6 The clinical manifestations of each individual are quite different, and some patients' mental symptoms are even more serious than those of gastrointestinal, which brings great difficulties to treatment and makes the patient's condition protracted. Therefore, it is of great clinical value to provide psychiatric intervention for patients with IBS. Clinical evidence has suggested that IBS is a stress-sensitive disorder, of which chronic psychological stress is considered to be one of the main causes.7 For instance, abuse in childhood, divorce of parents and long-term pressure from work and study may induce or aggravate the symptoms of IBS.8,9 Similarly, chronic stress is one of the major causes of the development and persistence of depressive behavioral phenotypes.10 It can be seen that stress is a common pathogenic factor of IBS and mood disorders, and under the stimulation of stress, the body will release corticotropin-releasing hormone (CRH) for coping and adjusting.11

CRH, also known as corticotropin-releasing factor, was isolated from sheep hypothalamus by Vale et al. in 1981.12 CRH is an important neuroendocrine peptide, a 41-amino acid peptide produced by neuroendocrine cells in the central nervous system (CNS) and the periphery, which plays a key role in the pathogenesis of stress-induced intestinal diseases. CRH is mainly synthesized and released from the paraventricular nucleus (PVN) of hypothalamus to regulate various systems of the body in response to normal stress. There are two kinds of receptors of CRH, CRH receptor (CRHR) 1 and CRHR2, and the affinity of the former to CRH is 10 to 40 times higher than that of the latter.13 CRHR1 is widely expressed in the central and peripheral nervous system as well as immune cells and is a pivotal mediator causing endocrine, autonomic and immune reactions in response to stress, modulating the "fight or flight" through the CRH-adrenocorticotropic hormone-glucocorticoid axis. In addition to being expressed in the brain, CRHR2 is also highly expressed in peripheral tissues such as gastrointestinal tract and cardiac smooth muscle, and is involved in regulating metabolism, blood pressure, immune cell signal transduction, and stress processing responses through urocortin II and urocortin III.14,15 Under normal circumstances, the body will rapidly release CRH when stressed, resulting in an increase in energy consumption and enhancement of cardiac function. After that, the body needs to recover from the enhanced state to homeostasis through the negative feedback regulation of glucocorticoid in a long process. If this balance is broken, uncontrolled CRH will cause damage to nervous, digestive, cardiovascular, and other systems.16 CRH is a pivotal mediator of stress-induced IBS and dysthymic disorders within both CNS and periphery: Studies have found that water avoidance stress and wrap restraint stress can lead to intestinal dysmotility and visceral hypersensitivity in mice, and peripheral CRH and CRHR1 are increased in colon tissues.17,18 CRHR1 agonists could reduce distal colon transport time, increase distal and transverse colon contractility, and induce watery diarrhea in rats.19 On the contrary, CRHR2 agonists could reduce visceral pain hypersensitivity in colorectal dilatation rats.20 Clinically, it has been shown that the concentration of CRH in the plasma and cerebrospinal fluid of depressed patients markedly rises, related to CRH-induced increased releasing of cortisol through the hypothalamic-pituitary-adrenal (HPA) axis.10,21 Accordingly, IBS and dysthymic disorders may share a common pathophysiological basis, namely, abnormal CRH function.22 The mechanism of CRH is shown in Fig. 1.

Figure 1. Effect of CRH on irritable bowel syndrome with comorbid dysthymic disorders.
CNS, central nervous system; PVN, paraventricular nucleus; CRH, corticotropin-releasing hormone; CeA, central amygdala; CRHR1, corticotropin-releasing hormone receptor 1; LC, locus coeruleus; NE, norepinephrine; DRN, dorsal raphe nucleus; 5-HT, 5-hydroxytryptamine; MC, mast cell; IL-6, interleukin-6; EC, entero-chromaffin cell; PG, prostaglandin; EG, eosinophilic granulocyte.

CRH IN CNS

CRH widely spreads over CNS, such as PVN, central amygdala (CeA), bed nucleus of the stria terminalis (BNST), cerebral cortex, pituitary, hippocampus, locus coeruleus (LC), spinal cord, involved in endocrine, stress response, regulation of vagus, and so on.23 Researches have shown that IBS patients have abnormal spontaneous activity in brain regions associated with pain processing (such as amygdala, anterior cingulate cortex [ACC], lobus insularis, and thalamus) and emotion regulation (such as amygdala, LC, hippocampus, hypothalamus).7,24,25 The parts of the brain where CRH changes the intestinal movement include PVN, LC complex, and dorsal motor nucleus, while the parts of the brain that regulate visceral pain are located in the CeA, hippocampus, BNST and LC, and the brain regions that affect psychological state are located in hypothalamus, amygdala, and dorsal raphe nucleus (DRN). For example, intra-cerebroventricular injection of CRH may cause increased colon movement, decreased absorption of intestinal fluid, enhanced algesia to colorectal distension (CRD), impaired colon secretion and barrier function, abdominal pain and diarrhea.7 Moreover, the stereoscopic injection of CRH into the hippocampus could lead to depressive symptom.26 As follows, we will discuss the role of CRH within hypothalamus, amygdala, DRN, LC as well as spinal cord and how it is involved in IBS with comorbid dysthymic disorders.

1. Hypothalamus

Hypothalamus, a high-level nerve center regulating visceral and endocrine activities, releases CRH when stress induces intestinal disorder and activates HPA axis, which promotes the release of corticosteroid, thus becoming a key mediator of immune stress. As a starting point for the HPA axis, the hypothalamus connects the emotional, limbic, cortical center in the brain (such as hippocampus, amygdala, and ACC) to the peripheral pressure system (such as pituitary, adrenal cortex).27 By means of visceral hypersensitivity rat models, it has been discovered that the expression of c-fos and CRH is significantly increased in hypothalamus, diacele, and spinal cord.28,29 CRD or maternal separation stress to neonatal rats can induce the disinhibition of PVN-projecting gamma-aminobutyric acid positive (GABA-ergic) neurons in the anterior ventral region of BNST, resulting in continuous sensitization of CRH neurons in PVN and visceral hypersensitivity, which can be prevented via injecting lidocaine or small interfering RNA that targeting CRH to PVN.30,31 Previous study has found increasing concentration of CRH in cerebrospinal fluid and growing expression of CRH messenger RNA (mRNA) within PVN in depressed patients.21 Likewise, the levels of CRH and CRHR1 in PVN of male rats rise after experiencing gestational intermittent hypoxia, leading to persistent anxiety and depression during adulthood, while knock-out of CRHR1 decreases their anxiety-like behavior.32,33 Also, the excitatory postsynaptic protein-93 could increase depression-like behavior by activating CRH neurons in PVN, and its effect would be reduced by gene knock-out.34 In addition, specific CRH knock-out of PVN can produce anti-anxiety function: When exposed to a variety of pressure source (including open field, elevated plus maze, hole-board, and light-dark box), the original anxiety-like behavior of mice is significantly reduced, while plasma administration of exogenous corticosterone cannot reverse this anti-anxiety effect.35 To sum up, PVN-CRH neurons are closely associated with both visceral hypersensitivity and mood disorders.

2. Amygdala

As one part of the limbic system, the amygdala is related to generating, recognizing and adjusting emotion, and plays a crucial role in the integration of the body's neurophysiological response to stress and the regulation of anxiety.11,36 It has been discovered that amygdala always shows an activation state for visceral stimulation in patients with IBS.37 CeA, one of the main nuclei of amygdala, plays an important role in regulating the generation of chronic pain and negative emotional state, and widely projects to BNST, ventral tegmental area, periaqueductal gray, LC, parabrachial nucleus and dorsal nucleus of vagus.38 Stresses like CRD could increase the expression of CRH and immune response within CeA, thus activating LC to up-regulate the norepinephrine (NE) system and eventually resulting in anxiety and visceral hypersensitivity.39-42 Similarly, water avoidance stress and maternal separation could lead to visceral hypersensitivity, which is associated with decreased methylation of CRH promoter, increased acetylation of histone and expression of CRH mRNA within CeA.43 As is well known that CRH released by hypothalamus combines with receptors in the anterior pituitary, which secretes adrenocorticotropic hormone into the peripheral blood circulation, resulting in increased cortisol in human or corticosterone in rodent, while the latter binds to glucocorticoid receptor, initiating negative feedback regulation of HPA axis at hypothalamus and hippocampus level, and reducing CRH secretion. On the contrary, the binding of corticosterone to glucocorticoid receptor in amygdala would promote the HPA axis and increase the expression of CRH, thus stimulating the stress-induced colonic hypersensitivity response, which can be inhibited by gene knock-out of CeA-CRH.11 Via chemical genetic and fluorescent labeling technology, anxiety-like behavior has been proved to be caused by dorsolateral BNST-projecting CRH from CeA that combines with CRHR1.44 Also, basolateral amygdala (BLA) is an important nucleus of amygdala, playing a key role in processing stressful events and emotional disorders. CRH could mediate depression and anxiety through BLA. Activation of CRH-CRHR1 signaling enhances synaptic efficiency of the outer vesicle-BLA pathway, sensitizes BLA neurons, and promotes depression-like behavior in rats induced by chronic forced swimming (a valid stress model used to test the clinical efficacy of antidepressants).45 Additionally, increased level of CRH in BLA of male rats treated with oral perfluorooctanoic acid-a hazardous environmental pollutant-induces anxiety-like behavior, which can be alleviated by injection of CRHR1 antagonists into BLA.46

3. Locus coeruleus

LC is located in the pons, and its neurons extensively innervate the brain and release neuromodulator NE in its terminal regions. LC-NE system is thought to be involved in the global regulation of behavior, wakefulness, physical and emotional responses to stress.33,47 Clinical studies have found that LC-NE system of IBS patients is usually in active state, and the NE efferent projection from LC cortex and corneal edge may cause anxiety as well as visceral hypersensitivity.7,48,49 CRH neurons from hypothalamus, CeA can project to LC, promoting LC to discharge and release NE, while NE can in turn activate HPA axis and prompt the secretion of CRH.47,50-52

4. Dorsal raphe nucleus

DRN, a vital nucleus of 5-hydroxytryptamine (5-HT) neurons CNS-including about 35% of the 26,000 neurons producing 5-HT in brain, is involved in pressure response, sleep, and temperature regulation.53 The 5-HT system plays an important role in stress-related mental diseases and is considered as a major neurotransmitter for depression, anxiety, bipolar disorder, obsessive-compulsive disorder and other psychiatric disorders.54,55 For example, low expression of 5-HT within CNS accounts for depression. Stressors could inhibit 5-HT neuron activity by stimulating the release of CRH in DRN, which is mediated by CRHR1 located on GABA afferent neurons, whereas CRHR2 mediates an opposite effect, promoting the release of 5-HT.56-59 Another study has shown that low-dose CRH binds to CRHR1 while high-dose CRH combines with CRHR2.60 In addition, inhibition of DRN 5-HT by CRH may lead to visceral hyperalgesia, for the reason that 5-HT is also a main factor of central descending pain-inhibiting system, however, this response can be inhibited by lateral ventricular injection of CRHR1 antagonists or CRHR2 agonists.61

5. Spinal cord

The spinal cord is the first position in CNS to perceive and regulate the signal of visceral hypersensitivity, and also the transfer station of information between intestine and the higher center. As is known that the mechanisms of visceral hypersensitivity include peripheral sensitization and central sensitization: Enhanced excitability of primary sensory neurons within intestinal tract could cause central sensitization state and heighten the response of spinal neurons to visceral harmful information, thus leading to more sustained visceral hypersensitivity.62-64 Researches have shown that 5-HT-ergic neurons in DRN can project to spinal cord, and the binding of 5-HT to 5-HT type 2 or 3 receptors released after stress would promote colorectal motility, while the binding of 5-HT to type 2C or 3 receptors could inhibit or promote visceral hypersensitivity respectively.65-67 The mouse model of visceral hypersensitivity induced by CRD has shown that the expression of CRH mRNA in spinal cord is significantly increased, especially in the lumbar swelling.28,68 CRHR2 is mainly distributed within the parasympathetic nucleus, central canal, layers I and II of the spinal dorsal horn, and is mainly expressed in inhibitory enkephalinergic intermediate neurons, which mediate abirritation and could raise the pain threshold of spinal secondary neurons and so inhibit visceral pain.69,70 By contrast, CRHR1 is low-expressed in spinal cord, and its combination with CRH would aggravate pain sensitivity.71

CRH IN PERIPHERY

CRH is diffusely expressed in peripheral tissues, such as heart, blood vessel, gastrointestinal tract, lung, kidney, pancreas, fat, testis, ovary, placenta, and so on.72 Peripheral CRH-CRHR1 binding mediates gastric mucosal protection and reduces sperm quantity and quality.73,74 However, CRH-CRHR2 signaling can dilate blood vessel, significantly increase the contractility of cardiac myocytes, induce arrhythmias, decrease food intake and delay gastric emptying via enhancing the mechanical sensitivity of vagal afferent nerves.75,76 CRH is commonly expressed in human intestine, and by means of immunohistochemistry, CRH mRNA expression is detected in lamina propria cells, submucosa, and intramuscular nerve plexus.77 Different from central CRH, the one secreted by neuroendocrine cells and immune cells in intestine could affect the contractility of smooth muscles, visceral sensitivity, mucosal permeability and transport capacity, which are strongly related to the colonic manifestations of IBS patients.78 CRHR1 and CRHR2 are located throughout the intestinal tract in a variety of cells, including the enteric nerve cell, endocrine cell (entero-chromaffin cell, EC) and immune cell (mast cell [MC], eosinophilic granulocyte [EG], and T-helper lymphocyte).7 CRHR2 antagonizes CRHR1 in the regulation of visceral sensation and intestinal motility: CRHR1 mediates intestinal injury by promoting intestinal inflammation, enhancing colonic motility, increasing intestinal permeability, changing intestinal morphology and regulating intestinal microbes. On the contrary, CRHR2 activates intestinal stem cell and repairs the injured intestine.13,78,79 Next, we will discuss how peripheral CRH is involved in IBS with comorbid dysthymic disorders through the mediating of MC, EC, macrophage, EG, and enteric nervous system (ENS).

1. Mast cell

MC is recognized as an important early immune effector cell in stress response and stress-related pathophysiology, which is widely distributed around the micro vessel beneath gut submucosa and meanwhile plays an important role in regulating intestinal barrier function, secretory function of epithelial cell, intestinal blood supply, neuro-immune system interaction, visceral sensitivity and intestinal motor function. The immunoglobulin E exists on MC surface, which tends to degranulate when sensitized by external factors (parasite, virus, bacterium, and food) or internal factors (neurotransmitter, hormone from CNS) and release intracellular histamine, protease, serotonin, prostaglandin, cytokine, which represent a defense mechanism that mobilizes pivotal resources for the host's “fight-or-flight” response and enhances immune function. Nevertheless, uncontrolled activation of MC can be harmful and associated with the onset and severity of diseases like allergy, asthma as well as IBS.80 The number of MC within colon usually increases in IBS patients or animal models, which is positively correlated not only with the severity of IBS, especially the level of abdominal pain, but also with depression scores.81,82 Hence, MC and its mediators are considered to be key components of the pathological factors of IBS.83 CRH could activate MC degranulation to release various mediators, which would promote colonic secretion and enhance the excitability of enteric neurons, leading to visceral allergy and increased intestinal permeability in IBS patients.84 For example, histamine and protease create prostaglandin-mediated pain-promoting effects, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and protease destroy intercellular tight junction protein and its component zonula occludens-1, inhibit the weakly inward rectifying K+ channel-related potassium channel-1 expression within colon epithelial cells, increase intestinal mucosal permeability and promote inflammation.85-89 Via immunohistochemical staining, a large proportion of CRHR1 and MC have been found labeled together in colonic mucosa, and the concentration of CRHR1 and MC increases in IBS model rats.90 Confocal microscopy has shown that CRHR1 is mainly distributed on MC cell membrane while CRHR2 is located on MC surface or inside it.80 Moreover, MC degranulation is mediated by CRHR1, and CRHR1 antagonists could prevent visceral hypersensitivity but could not reverse it after MC degranulation.91,92 By contrast, CRHR2 has been proved to be a negative regulator for MC degranulation, and its activation would reduce the severity of immunoglobulin E-mediated anaphylaxis and stress-induced intestinal hyperpermeability.93 Besides, it has been demonstrated that public speech, as a psychosocial stressor, mediates an increase of intestinal permeability of healthy volunteers via the activation of HPA axis, while this response can be blocked by preconditioning with MC stabilizer disodium cromoglycate.93,94

2. Entero-chromaffin cell

EC is the main cell type for the synthesis, storage and release of 5-HT within intestine: 95% of 5-HT comes from the intestine, in which 90% of 5-HT is derived from EC.95 Enteric 5-HT plays a key role in regulating visceral sensation, intestinal motility and permeability: It mainly binds to 5-HT3 receptors at the terminal of primary afferent neurons, leading to abdominal pain and diarrhea.96,97 Clinical data has indicated that EC density in rectum and plasma 5-HT level increase in IBS-diarrhea patients, while the latter decreases in IBS-constipation patients.96,98 Stress can activate the CRHR1 signaling pathway, which leads to EC hyperplasia and increased 5-HT secretion, thus stimulating enteric neurons to produce acetylcholine, which further excites sensory afferent nerves of spinal cord to amplify and project harmful signals from intestinal tract to CNS, resulting in visceral hypersensitivity and strengthened intestinal motility.99,100

3. Macrophage

Macrophage is also one kind of immune cells, and can be divided into M1 and M2 types. M1 type releases pro-inflammatory cytokines, such as tumor necrosis factor-α, IL-1β, and IL-6, which could be promoted by CRH-CRHR1.79 On the contrary, M2 type inhibits the function of M1 by producing anti-inflammatory factors such as IL-10.101 Additionally, macrophage plays an important role in intestinal motility by acting on the muscular plexus: M2 type infiltration is enhanced in the colon tissues of IBS patients, thus accelerating intestinal motility.101 There are also a large number of CRHRs on the surface of enteric macrophage: The combination of CRH and CRHR1 could induce macrophage to degranulate and release a series of active substances such as prostaglandin, cytokines, then activating afferent nerves or dorsal root ganglions, and forming visceral hypersensitivity,13 while the activation of CRHR2 may inhibit this effect.102 In addition to mediating intestinal symptoms, macrophage is implicated in mood disorders: Toll-like receptor 4 expressed on macrophage is an independent risk factor associated with the severity of major depression.103 CRH could activate Toll-like receptor 4, aggravating the psychiatric symptoms of IBS patients.104

4. Eosinophilic granulocyte

EG is widely distributed in the gastrointestinal tract, responsible for maintaining gastrointestinal homeostasis, and is also one of the main sources of CRH within intestine.81 Studies have found that increased EG in sigmoid colon is associated with higher anxiety scores, while psychological stress could stimulate EG, leading to the release of CRH and activation of MC, thus increasing intestinal permeability.82,105,106 Clinical tests have shown that the number of intestinal mucosa EG in IBS patients rises, and intracellular CRH expression increases, which is positively correlated with intestinal symptoms and depression.107-109

5. Enteric nervous system

ENS, a network of neurons and glial cells located within the intestinal wall, includes two major nerve plexus: the submucosal plexus (SMP), which regulates the absorption and secretion functions of mucosal epithelial cells, intramural blood flow, and neuroimmune interactions, and the myenteric plexus (MP), while the MP modulates intestinal movement. ENS provides intrinsic neurological control of almost all gastrointestinal functions, such as gastrointestinal motility and homeostasis, and is thought to underlie a range of gastrointestinal diseases, including IBS. Secretory motor neurons in SMP promote gastrointestinal secretory function by releasing acetylcholine or vasoactive intestinal peptide, while the increase of choline acetyltransferase and vasoactive intestinal peptide neurons in the ileum SMP of IBS-D rats may be related to the increase of intestinal secretion and the appearance of diarrhea symptoms. In addition, the decreased release of nitric oxide by inhibitory muscle motor neurons in MP may be the cause of the enhanced intestinal motility of IBS.110 According to research, the excitatory effect of CRH on the ENS is mediated by CRHR1, but not CRHR2: wrap restraint stress induces increased expression of CRHR1 in the MP and SMP of rats, especially in the SMP, which is associated with visceral hypersensitivity and high intestinal motility.111 Excitatory muscle motor neurons in the MP express CRHR1 receptors, explaining the activation effect of CRH on intestinal motility. Besides, CRH binds to CRHR1 expressed by secretomotor neurons in the SMP, inducing the secretion of water, electrolytes, and mucus.112 CRHR1 antagonists could block the neuronal activation of colon induced by IBS plasma, while CRHR2 antagonists exert no such effect.113

CRH-RELATED TREATMENT

In general, the guideline recommends the use of spasmolytic as the first-line therapy to relieve the overall symptoms of IBS. It alleviates abdominal pain and diarrhea via inhibiting the effect of acetylcholine on muscarinic or tachykinin neurokinin 2 receptors or blocking calcium channels in the enteric smooth muscle. However, it is also associated with a series of side effects, including dry mouth, dizziness, blurred vision, and constipation.1 At the same time, for patients with comorbid mood disorders, spasmolytic can not relieve their mental symptoms well. Therefore, we need a class of drugs that could both ease patients' intestinal symptoms and improve their dysthymic disorders, and CRH-related therapies may be able to resolve these problems.

Given that CRH-CRHR1 produces an effect that promoting intestinal and psychiatric symptoms, while CRH-CRHR2 generates an opposite effect, treatment with CRHR1 antagonists or CRHR2 agonists should be taken into account. Selective CRHR1 antagonists currently developed include antalarmin, pexacerfont, NBI-30775 (R121919), CP-376, JTC-017, NGD9002, and so on, and the combination of CRHR1 antagonists with CRHR1 in different parts of the body could create diverse effects.114 For example, R121919 has been successfully used in clinical treatment of depression and anxiety, which is associated with decreased blood oxygen level-dependent signal in brain regions related to emotional arousal circuit (amygdala, hippocampus, and ACC).115-117 JTC-017 could reduce the release of hippocampus NE after acute CRD stress in rats, and relieve visceral hypersensitivity as well as anxiety-like behavior.118 However, the clinical results of many CRHR1 antagonists are not satisfactory. They have yet brought plenty of problems, such as high affinity, long elimination half-life, active metabolites, high protein binding, pre-clinical screening, mismatch between dynamic characteristics of CRHR function and subject patients, acute versus advanced manifestations of the disease; NBI-77860 has the side effect of headache; R121919 significantly reduces the score of depressive patients, but the relevant study lacks blind, randomized, or placebo-controlled controls and causes elevated liver enzymes; there was no significant difference between CP-316,311 and placebo treatment.119-121 In addition, the balance between receptor affinity and the pharmacokinetic property of CRHR1 antagonists remains the focus of the pharmaceutical industry.114 Besides, CRHR2 agonists have an anti-anxiety effect in CNS, but can delay gastric empty, therefore, organ-selective CRHR2 agonists should be chosen in clinic.13

In addition to directly acting on the CRH-CRHR signaling pathway with CRHR1 antagonists or CRHR2 agonists, we can modulate CRH indirectly via brain neuromediators. Calcium imaging has shown that 12 kinds of substances (such as glutamic acid, serotonin, NE, dopamine, and neuromedin C) can activate PVN-CRH, while three kinds of substances (GABA, glycine, and nociceptin) can inhibit PVN-CRH, which can be used as the direction of CRH targeted therapy in the future.122 For example, GABA-ergic neurons from BNST, dorsomedial hypothalamus, arcuate nucleus, medial preoptic nucleus, and glutamic acid positive neurons from periaqueductal gray matter, zona incerta, PBN, raphe nucleus, nucleus tractus solitarius all project to PVN and regulate the function of HPA axis: GABA-ergic neurons inhibit the release of CRH, while glutamic acid positive neurons promote the secretion of CRH.31,123 Therefore, the excitatory/inhibitory balance mediated by rapid ion transfer is a key regulator of PVN-CRH neuron excitability, and the release of CRH can be effectively inhibited by the activation of GABA receptors or antagonism of glutamic acid receptors on PVN, thus improving splanchnic hypersensitivity.124 Besides, injection of the histone deacetylase inhibitor trichostatin A into CeA could hold back the activation of the CRH promoter, thereby preventing stress-induced visceral hypersensitivity.39

Furthermore, commonly used IBS treatments are increasingly shown to be involved in regulating CRH. Benzodiazepines, traditional anti-anxiety drugs, including clonazepam and alprazolam, have been proven to reduce the activity of CRH neurons within hypothalamus; selective serotonin reuptake inhibitors such as escitalopram can inhibit CeA-CRH release and increase glucocorticoid receptor density in hippocampus and hypothalamus, promoting negative feedback regulation of HPA axis; prophylactic use of tricyclic antidepressants, such as amitriptyline, can improve intestinal symptoms in IBS model rats and reduce the expression of CRH in hypothalamus and colon.41,125 Environmental enrichment, one novel kind of behavioral therapies, can prevent IBS through three approaches: preventing stress-induced increase of colon permeability, activating phosphorylation of extracellular signal-regulated kinases in spinal cord, restraining the activity of CRH promoter within CeA, and these effects would last long after environmental enrichment.126 In addition, Chinese traditional therapeutic methods such as acupuncture and moxibustion can not only improve intestine symptoms, but also has unique psychological and psychiatric therapeutic effects, such as reducing the expression of CRH and CRHR1 in hypothalamus to relieve anxiety and depression, decreasing the level of CRH, CRHR1, MC and 5-HT in colon to alleviate visceral hypersensitivity, increasing the expression of zonula occludens-1 to repair the intestine mucosal barrier, or reduce the expression of central and peripheral CRHR2 to improve jejunal dyskinesia, ultimately achieve the effect of simultaneous treatment to both body and mind.90,127-133

DISCUSSION

The latest standard of Rome IV highlights the importance of the brain-gut axis dysfunction in the pathogenesis of IBS, and names functional gastrointestinal disorders as disorders of brain-gut interaction. The brain-gut axis consists of CNS, autonomic nervous system, ENS, and HPA axis. The ACC of brain receives exogenous stimulation, while the ENS receives endogenous stimulation, which are transmitted to enteric nerve plexus or directly act on intestinal cells after integration by autonomic nerve or HPA axis. When emotional stress changes, sympathetic nerve excitation would cause intestinal vasoconstriction, and vagal nerve hyperfunction would lead to increased enteric secretion or movement. Epidemiological surveys have shown that many IBS patients have got depression or anxiety, and patients with pre-existing dysthymic disorders are more likely to suffer from IBS, which is also evidence for brain-gut interaction. So far, IBS still remains a challenge. Patients suffer from recurrent abdominal pain and diarrhea, and over a long period of time, they would develop varying degrees of anxiety or depression, which may more aggravate intestinal symptoms, the reason why IBS is hard to cure.

Recently, researchers have discovered that a variety of neuropeptides co-express in both the brain and intestine, such as serotonin, vasoactive intestinal peptide, substance P, neuropeptide Y, CRH, motilin, playing different roles in the pathogenesis of IBS, among which CRH is the key driver in IBS with comorbid dysthymic disorders. CRH is a vital neurotransmitter of HPA axis. When the body is under physiological or psychological stress, the HPA axis is activated and CRH is released to regulate the body and restore stability. However, the disordered CRH system would cause stress-related diseases, such as IBS and mood disorders. The hyperactivity of HPA axis is one of the common pathological mechanisms of mental diseases including depression: Clinically, it has been found that the concentration of CRH within plasma and cerebrospinal fluid of depressive patients rises; the prevalence of depression in females is several times higher than that in males, and animal experiments have shown that the binding rate of CRH-CRHR1 in females is generally higher than that in males.10,21 Similarly, increased CRH expression in colon of IBS patients is positively correlated with intestinal symptoms. CRH produced in CNS and intestine under stress would be combined with different CRHRs (mainly CRHR1) in different parts of the body, causing a variety of effects: CRH binding to receptors within DRN could inhibit the release of 5-HT, and then lead to visceral hypersensitivity or depression-like behavior; CRH-CRHR1 signaling would activate the LC-NE system, causing anxiety and visceral allergy; CRHR1 mediates MC degranulation, then leads to increased intestinal permeability, while CRHR2 acts as a negative regulator of this effect and improves symptoms of IBS patients.

Based on the understanding of the role of CRH in regulating IBS with comorbid dysthymic disorders, we may be able to use more precise treatment to help IBS patients relieve symptoms, improve living quality, and even get cured one day. The most targeted treatment for CRH is the use of CRHR1 antagonists or CRHR2 agonists. At present, a variety of drugs have been available, but due to the problems of long half-life and high affinity, related researches are still in the stage of animal experiments and clinical trials, and they have not been widely used in clinic. Besides, as researches progress, we have also found that some commonly used treatment, such as tricyclic antidepressants, benzodiazepines anti-anxiety agents, behavioral therapies, acupuncture, and moxibustion, could adjust CRH expression or change the combination of CRH with its receptors, to improve both physical and mental symptoms, which can better guide the clinical application. In the future, we need to focus on studying more about the working mechanisms of central and peripheral CRH in IBS with comorbid dysthymic disorders, developing relevant targeted drugs and gradually applying them to the clinic.

ACKNOWLEDGEMENTS

This study was supported by the National Natural Science Foundation of China (No.81904095 and No.81973936), Anhui University of Chinese Medicine 2018-2019 High-level Talents Introduction Support Plan (No.2019rcyb002).

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Fig 1.

Figure 1.Effect of CRH on irritable bowel syndrome with comorbid dysthymic disorders.
CNS, central nervous system; PVN, paraventricular nucleus; CRH, corticotropin-releasing hormone; CeA, central amygdala; CRHR1, corticotropin-releasing hormone receptor 1; LC, locus coeruleus; NE, norepinephrine; DRN, dorsal raphe nucleus; 5-HT, 5-hydroxytryptamine; MC, mast cell; IL-6, interleukin-6; EC, entero-chromaffin cell; PG, prostaglandin; EG, eosinophilic granulocyte.
Gut and Liver 2023; :

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Gut and Liver

Vol.18 No.1
January, 2024

pISSN 1976-2283
eISSN 2005-1212

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