The recent study published in the World Journal of Gastroenterology examines the interplay among the neuroendocrine axis, gut microbiota, inflammatory markers, and gastrointestinal symptoms in irritable bowel syndrome (IBS). By integrating all these factors into a single study, this approach reflects the modern concept of functional gastrointestinal disorders as disorders of the gut-brain interaction to be approached in a multiparametric manner, also incorporating non-gastroenterological elements and extending evaluations to parameters related to the neuroendocrine axis. This invited letter to the editor summarizes the main results of the aforementioned study and highlights its multiparametric approach, including variables not strictly gastroenterological, in the study of IBS, and discusses its strengths and limitations.

• Neuroendocrine axis
• Gut microbiota
• Inflammatory response
• Irritable bowel syndrome
• Functional gastrointestinal disorders
• Biopsychosocial model
• Mucosal inflammation
• Cytokines
• Serotonergic system
• Melanocortin system

• Inflammation
• Irritable bowel syndrome (IBS)
• Rats
• STW 5-II
• Stress
• Visceral hypersensitivity

• Animals
• Male
• Disease Models, Animal
• Rats, Sprague-Dawley
• Irritable Bowel Syndrome/drug therapy
• Colitis/drug therapy
• Colitis/chemically induced
• Colon/drug effects
• Rats
• Trinitrobenzenesulfonic Acid
• Ganglia, Spinal/drug effects
• Ganglia, Spinal/metabolism
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Analgesics/pharmacology
• Stress, Psychological/drug therapy
• Plant Extracts/pharmacology
• Visceral Pain/drug therapy
• Spinal Cord/drug effects
• Phosphorylation

• dysbiosis
• gut–brain axis
• irritable bowel syndrome
• low-grade inflammation
• pathophysiology

• Treatment
• cytochrome P450
• epigenetics
• irritable bowel syndrome
• serotonergic

• Humans
• Genome-Wide Association Study
• Pharmacogenetics
• Irritable Bowel Syndrome/drug therapy
• Irritable Bowel Syndrome/genetics
• Precision Medicine/methods
• Cytochrome P-450 CYP2C19/genetics
• Cytochrome P-450 CYP2D6/genetics
• Cytochrome P-450 CYP2D6/metabolism
• Gastrointestinal Agents/pharmacology
• Gastrointestinal Agents/pharmacokinetics
• Gastrointestinal Agents/administration & dosage
• Pharmaceutical Preparations/metabolism
• Pharmaceutical Preparations/administration & dosage
• Epigenesis, Genetic
• Animals

• T32 DK007198 NIDDK NIH HHS

• CRF receptors
• CRH
• colitis
• colitis-associated colon cancer
• stress

• Humans
• Colitis-Associated Neoplasms
• Corticotropin-Releasing Hormone
• Colitis/complications
• Colonic Neoplasms/etiology
• Inflammation

• NHANES
• chronic constipation
• live microbe

• Adult
• Humans
• Nutrition Surveys
• Prospective Studies
• Constipation/epidemiology
• Diet
• Eating

• irritable bowel syndrome
• nutraceuticals
• vagus nerve
• visceral hypersensitivity

• 675 Medical University of Lublin

• cortico-tropine releasing hormone
• intestinal permeability
• irritable bowel syndrome
• traumatic brain injury
• visceral hypersensitivity

• Humans
• Rats
• Animals
• Irritable Bowel Syndrome
• Corticotropin-Releasing Hormone/metabolism
• Brain Concussion
• Disease Models, Animal
• RNA, Messenger

Irritable bowel syndrome (IBS) is a chronic functional disorder which alters gastrointestinal (GI) functions, thus leading to compromised health status. Pathophysiology of IBS is not fully understood, whereas abnormal gut brain axis (GBA) has been identified as a major etiological factor. Recent studies are suggestive for visceral hyper-sensitivity, altered gut motility and dysfunctional autonomous nervous system as the main clinical abnormalities in IBS patients. Bidirectional signalling interactions among these abnormalities are derived through various exogenous and endogenous factors, such as microbiota population and diversity, microbial metabolites, dietary uptake, and psychological abnormalities. Strategic efforts focused to study these interactions including probiotics, antibiotics and fecal transplantations in normal and germ-free animals are clearly suggestive for the pivotal role of gut microbiota in IBS etiology. Additionally, neurotransmitters act as communication tools between enteric microbiota and brain functions, where serotonin (5-hydroxytryptamine) plays a key role in pathophysiology of IBS. It regulates GI motility, pain sense and inflammatory responses particular to mucosal and brain activity. In the absence of a better understanding of various interconnected crosstalks in GBA, more scientific efforts are required in the search of novel and targeted therapies for the management of IBS. In this review, we have summarized the gut microbial composition, interconnected signalling pathways and their regulators, available therapeutics, and the gaps needed to fill for a better management of IBS.

• Irritable bowel syndrome
• Microbiota
• Gut brain axis
• Stress
• Serotonin

• FUNCTIONAL BOWEL DISORDER
• FUNCTIONAL DYSPEPSIA
• INTESTINAL MAST CELLS
• IRRITABLE BOWEL SYNDROME
• Intestinal eosinophils

• Attention-deficit/hyperactivity disorder
• Corticotropin-releasing hormone
• Early-life stress
• Irritable bowel syndrome
• Maternal separation
• Visceral hypersensitivity

• acetylcholine
• enteric nervous system
• glucocorticoid receptor
• motility
• stress

Visceral hypersensitivity in irritable bowel syndrome (IBS) is widespread, but effective therapies for it remain elusive. As a canonical anti‐inflammatory protein, suppressor of cytokine signaling 3 (SOCS3) reportedly relays exchange protein 1 directly activated by cAMP (Epac1) signaling and inhibits the intracellular response to inflammatory cytokines. Despite the inhibitory effect of SOCS3 on the pro‐inflammatory response and neuroinflammation in PVN, the systematic investigation of Epac1‐SOCS3 signaling involved in visceral hypersensitivity remains unknown. This study aimed to explore Epac1‐SOCS3 signaling in the activity of hypothalamic paraventricular nucleus (PVN) corticotropin‐releasing factor (CRF) neurons and visceral hypersensitivity in adult rats experiencing neonatal colorectal distension (CRD).

Rats were subjected to neonatal CRD to simulate visceral hypersensitivity to investigate the effect of Epac1‐SOCS3 signaling on PVN CRF neurons. The expression and activity of Epac1 and SOCS3 in nociceptive hypersensitivity were determined by western blot, RT‐PCR, immunofluorescence, radioimmunoassay, electrophysiology, and pharmacology.

In neonatal‐CRD‐induced visceral hypersensitivity model, Epac1 and SOCS3 expressions were downregulated and IL‐6 levels elevated in PVN. However, infusion of Epac agonist 8‐pCPT in PVN reduced CRF neuronal firing rates, and overexpression of SOCS3 in PVN by AAV‐SOCS3 inhibited the activation of PVN neurons, reduced visceral hypersensitivity, and precluded pain precipitation. Intervention with IL‐6 neutralizing antibody also alleviated the visceral hypersensitivity. In naïve rats, Epac antagonist ESI‐09 in PVN increased CRF neuronal firing. Consistently, genetic knockdown of Epac1 or SOCS3 in PVN potentiated the firing rate of CRF neurons, functionality of HPA axis, and sensitivity of visceral nociception. Moreover, pharmacological intervention with exogenous IL‐6 into PVN simulated the visceral hypersensitivity.

Inactivation of Epac1‐SOCS3 pathway contributed to the neuroinflammation accompanied by the sensitization of CRF neurons in PVN, precipitating visceral hypersensitivity and pain in rats experiencing neonatal CRD.

• Epac1
• SOCS3
• corticotrophin-releasing factor
• neonatal colorectal distension
• visceral hypersensitivity

• Chitosan
• Irritable bowel syndrome with diarrhea
• Puerarin
• ROS-responsive
• Sodium alginate

Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, also known as disorders of the gut–brain interaction; however, the pathophysiology of IBS remains unclear. Early life stress (ELS) is one of the most common risk factors for IBS development. However, the molecular mechanisms by which ELS induces IBS remain unclear. Enterochromaffin cells (ECs), as a prime source of peripheral serotonin (5-HT), play a pivotal role in intestinal motility, secretion, proinflammatory and anti-inflammatory effects, and visceral sensation. ECs can sense various stimuli and microbiota metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids. ECs can sense the luminal environment and transmit signals to the brain via exogenous vagal and spinal nerve afferents. Increasing evidence suggests that an ECs-5-HT signaling imbalance plays a crucial role in the pathogenesis of ELS-induced IBS. A recent study using a maternal separation (MS) animal model mimicking ELS showed that MS induced expansion of intestinal stem cells and their differentiation toward secretory lineages, including ECs, leading to ECs hyperplasia, increased 5-HT production, and visceral hyperalgesia. This suggests that ELS-induced IBS may be associated with increased ECs-5-HT signaling. Furthermore, ECs are closely related to corticotropin-releasing hormone, mast cells, neuron growth factor, bile acids, and SCFAs, all of which contribute to the pathogenesis of IBS. Collectively, ECs may play a role in the pathogenesis of ELS-induced IBS. Therefore, this review summarizes the physiological function of ECs and focuses on their potential role in the pathogenesis of IBS based on clinical and pre-clinical evidence.

• Anorexia nervosa
• Cerebral evoked potential
• Depression
• Doxepin
• H1 receptor
• Histamine
• Irritable bowel syndrome
• Positron emission tomography

• Animals
• Brain/diagnostic imaging
• Brain/metabolism
• Depressive Disorder, Major/metabolism
• Doxepin/metabolism
• Female
• Histamine/metabolism
• Humans
• Hypnotics and Sedatives/metabolism
• Irritable Bowel Syndrome/metabolism
• Ligands
• Male
• Neuroimaging
• Receptors, Histamine H1/metabolism
• Tomography, X-Ray Computed

Psychological stress exacerbates mast cell (MC)-dependent inflammation, including nasal allergy, but the underlying mechanisms are not thoroughly understood. Because the key stress-mediating neurohormone, corticotropin-releasing hormone (CRH), induces human skin MC degranulation, we hypothesized that CRH may be a key player in stress-aggravated nasal allergy. In the current study, we probed this hypothesis in human nasal mucosa MCs (hM-MCs) in situ using nasal polyp organ culture and tested whether CRH is required for murine M-MC activation by perceived stress in vivo. CRH stimulation significantly increased the number of hM-MCs, stimulated both their degranulation and proliferation ex vivo, and increased stem cell factor (SCF) expression in human nasal mucosa epithelium. CRH also sensitized hM-MCs to further CRH stimulation and promoted a pro-inflammatory hM-MC phenotype. The CRH-induced increase in hM-MCs was mitigated by co-administration of CRH receptor type 1 (CRH-R1)-specific antagonist antalarmin, CRH-R1 small interfering RNA (siRNA), or SCF-neutralizing antibody. In vivo, restraint stress significantly increased the number and degranulation of murine M-MCs compared with sham-stressed mice. This effect was mitigated by intranasal antalarmin. Our data suggest that CRH is a major activator of hM-MC in nasal mucosa, in part via promoting SCF production, and that CRH-R1 antagonists such as antalarmin are promising candidate therapeutics for nasal mucosa neuroinflammation induced by perceived stress.

• CRH
• mast cell
• nasal mucosa
• psychological stress
• stem cell factor (SCF)

The aim of this study was to detect the expression of interleukin (IL)-1β and transforming growth factor (TGF)-β1 in the colonic tissue and serum of irritable bowel syndrome (IBS) rats, as well as the distribution and expression of corticotropin-releasing factor (CRF) in the spinal cord and brain of the visceral hypersensitivity rats, thus to ascertain the mechanism of visceral hypersensitivity signal conduction pathway.

The expression of IL-1β and TGF-β1 in the colonic tissue and serum of IBS rats was screened by the liquid chip technology and verified by RT-PCR technology. Then the quantitative analysis of CRF in the spinal cord and brain was achieved by the immunohistochemical method and computerized image system.

The rat model with visceral hypersensitivity was successfully established. Among the screened indicators of IL-1β and TGF-β1 in colon tissue and serum, only the expression of IL-1β in the model group was up-regulated (P < 0.05). The immunohistochemical method showed that CRF was expressed in the spinal cord, hypothalamus, and the third ventricle. The positive index number of the model groups was higher than that of the control group (P < 0.01).

From the research, it can be inferred that IL-1β may participate in the pathogenesis mechanism of IBS via regulating the colon function. The increasing expression of CRF linked to stress in the spinal cord, hypothalamus and the third ventricle indicated that it might play an important role in the mechanisms of visceral hypersensitivity signal conduction pathway.

• CRF
• Colonic mucosa
• IL-1β
• Irritable bowel syndrome
• TGF-β1

• irritable bowel syndrome
• mucosal immunology

• Cell Line, Tumor
• Corticotropin-Releasing Hormone/metabolism
• Diarrhea/metabolism
• Eosinophils/metabolism
• Female
• Humans
• Intestinal Mucosa/metabolism
• Irritable Bowel Syndrome/metabolism
• Jejunum/metabolism
• Male
• Permeability
• Stress, Psychological/metabolism

• Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad
• Programa de becas predoctorales Amics de Vall d’Hebron
• Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
• Ministerio de Educación, Dirección General de Investigación

• Clinical symptoms
• Corticotropin-releasing hormone
• Interleukin-6
• Irritable bowel syndrome
• Vitamin D3

• colorectal cancer (CRC)
• corticotropin releasing hormone (CRH)
• inflammation
• stress

• R01 DK101671 NIDDK NIH HHS

• Asia
• Constipation
• Diarrhea
• Intestines
• Irritable bowel syndrome

• Clostridium butyricum
• Nod-like receptor pyrin domain-containing protein 6
• corticotropin-releasing factor
• cytokine
• irritable bowel syndrome

Psychological disorders are prevalent in patients with inflammatory bowel disease, but the underlying mechanisms remain unknown. The aim of this study was to study whether electroacupuncture (EA) and moxibustion (MB) can improve anxiety behavior in DSS-induced colitis mice and to investigate whether this effect is related to hypothalamic-pituitary-adrenocortical (HPA) axis.

The colitis model was established by drinking 2.5% dextran sodium sulfate (DSS). DSS-induced colitis mice were treated by EA or MB. Disease activity index (DAI) was scored; intestinal morphological and pathological structure was observed; anxiety behavior was tested by the elevated plus maze and open field. The concentration of corticotropin-releasing hormone (CRH) and cortisol (CORT) in serum was measured by enzyme-linked immunosorbent assay (ELISA). The protein expression of CRH in the colon and hypothalamus was detected by Western blot (WB).

Both EA and MB treatments can improvethe morphology of their distal colonic mucosal epithelia, as well as the disease activity index. Meanwhile, anxiety behavior in colitis mice was improved slightly after EA and MB treatment. In addition, the levels of CRH and CORT in the serum were slightly improved after EA and MB treatment. These effects are further supported by WB results. The expression of CRH in the colon and hypothalamus was increased significantly after treatment, compared with the model group.

EA and MB were able to regulate the concentration of CRH in serum and protein expression in the peripheral and central at different levels and promote the recovery of the HPA axis that may be the basis for EA and MB to improve colonic pathology and alleviate anxiety behavior in DSS-induced colitis.

• CRF peptides
• CRF receptor antagonists
• gut secreto-motor function
• irritable bowel syndrome
• stress
• visceral pain

The bidirectional communication between the central nervous system (CNS) and the gut microbiota plays a pivotal role in human health. Increasing numbers of studies suggest that the gut microbiota can influence the brain and behavior of patients. Various metabolites secreted by the gut microbiota can affect the cognitive ability of patients diagnosed with neurodegenerative diseases. Nearly one in every ten Korean senior citizens suffers from Alzheimer’s disease (AD), the most common form of dementia. This review highlights the impact of metabolites from the gut microbiota on communication pathways between the brain and gut, as well as the neuroinflammatory roles they may have in AD patients. The objectives of this review are as follows: (1) to examine the role of the intestinal microbiota in homeostatic communication between the gut microbiota and the brain, termed the microbiota–gut–brain (MGB) axis; (2) to determine the underlying mechanisms of signal dysfunction; and (3) to assess the impact of signal dysfunction induced by the microbiota on AD. This review will aid in understanding the microbiota of elderly people and the neuroinflammatory roles they may have in AD.

• Alzheimer’s disease
• MGB axis
• germ-free animal
• gut microbiota
• neurodegenerative diseases
• probiotic

• Alzheimer Disease
• Central Nervous System
• Gastrointestinal Microbiome/physiology
• Homeostasis
• Humans
• Inflammation/metabolism
• Inflammation/microbiology

• Dyspepsia
• Homeostasis
• Irritable bowel syndrome
• Neuroimaging
• Visceral pain

• G0300195 Medical Research Council
• G0600965 Medical Research Council

• Colorectal neoplasms
• Heterogeneous methylation
• Interaction effect
• Peripheral blood

• high-affinity choline transporter
• irritable bowel syndrome
• myenteric plexus
• visceral hyperalgesia

The aim of present study is to estimate the effects of Melissa officinalis L. (MO) on visceral hypersensitivity (VH), defecation pattern and biochemical factors in 2 experimental models of irritable bowel syndrome (IBS) and the possible role of nitric oxide.

Two individual models of IBS were induced in male Wistar-albino rats. In the acetic acid model, the animals were exposed to rectal distension and abdominal withdrawal reflex, and the defecation patterns were determined. In the restraint stress model, the levels of TNF-α, myeloperoxidase, lipid peroxidation, and antioxidant powers were determined in the (removed) colon. Rats had been treated with MO, L-NG-nitroarginine methyl ester (L-NAME), aminoguanidine (AG), MO + AG, or MO + L-NAME in the mentioned experimental models.

Hypersensitive response to rectal distension and more stool defecation in control rats have been observed in comparison to shams. MO-300 significantly reduced VH and defecation frequency in comparison to controls. VH and defecation pattern did not show significant change in AG + MO and L-NAME + MO groups compared to controls. Also, significant reduction in TNF-α, myeloperoxidase, thiobarbituric acid reactive substances (TBARS), and an increase in antioxidant power in MO-300 group was recorded compared to controls. AG + MO and L-NAME + MO groups showed a reverse pattern compared to MO-300 group.

MO can ameliorate IBS by modulating VH and defecation patterns. Antioxidant and anti-inflammatory properties along with its effect on the nitrergic pathway seem to play important roles in its pharmacological activity.

• Irritable bowel syndrome
• Lemon balm
• Melissa officinalis
• Nitric oxide
• Visceral hypersensitivity

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal diseases in humans. It is characterized by visceral pain and/or discomfort, hypersensitivity and abnormal motor responses along with change in gut habits. Although the etio-pathogenesis of IBS is only partially understood, a main role has been attributed to psychosocial stress of different origin. Animal models such as neonatal maternal separation, water avoidance stress and wrap restraint stress have been developed as psychosocial stressors in the attempt to reproduce the IBS symptomatology and identify the cellular mechanisms responsible for the disease. The study of these models has led to the production of drugs potentially useful for IBS treatment. This review intends to give an overview on the results obtained with the animal models; to emphasize the role of the enteric nervous system in IBS appearance and evolution and as a possible target of drug therapies.

• corticotropin releasing factor (CRF)
• irritable bowel syndrome (IBS)
• maternal separation (MS)
• neurotransmitters
• pain
• psychosocial stress
• visceral hyperalgesia
• water avoidance stress (WAS)
• wrap restrain stress (WRS)

• culture
• gastroenterologists
• irritable bowel syndrome
• psychological factors

Stress is a known trigger of irritable bowel syndrome (IBS) and exacerbates its gastrointestinal symptoms. However, underlying the physiological mechanism remains unknown. Here, we investigated hypothalamic–pituitary–adrenal (HPA) axis, colonic motility, and autonomic responses to corticotropin-releasing hormone (CRH) administration as well as brain activity alterations in IBS. The study included 28 IBS patients and 34 age and sex-matched healthy control subjects. IBS patients demonstrated greater adrenocorticotropic hormone (ACTH) responses to CRH than control subjects. Male IBS patients had greater increases in colonic motility than male HCs after CRH. Female IBS patients showed altered sympathovagal balance and lower basal parasympathetic tone relative to female control subjects. Brain responses to rectal distention were measured in the same subjects using functional magnetic resonance imaging, and their associations with individual ACTH responses to CRH were tested. A negative association between ACTH response to CRH and activity in the pregenual anterior cingulate cortex (pACC) during rectal distention was identified in controls but not in IBS patients. Impaired top-down inhibitory input from the pregenual ACC to the HPA axis may lead to altered neuroendocrine and gastrointestinal responses to CRH. Centrally acting treatments may dampen the stress induced physical symptoms in IBS.

• corticotropin-releasing hormone
• cytokine
• glucocorticoid resistance
• hypothalamic-pituitary-adrenal
• neuroendocrine immunology
• stress

• Z99 AI999999 Intramural NIH HHS

• Acoustic startle response
• Corticotropin releasing hormone receptor 1
• Genetic polymorphism
• Irritable bowel syndrome

• T lymphocyte
• cytokine
• enterochromaffin cell
• interleukin
• irritable bowel syndrome
• mast cell

• Animals
• Chronic Disease
• Colitis/etiology
• Colitis/psychology
• Disease Models, Animal
• Female
• Genes, T-Cell Receptor alpha/genetics
• Intestinal Mucosa/immunology
• Intestinal Mucosa/microbiology
• Intestinal Mucosa/pathology
• Lactobacillus/growth & development
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Probiotics/administration & dosage
• RNA, Ribosomal, 16S/genetics
• Stress, Psychological/complications

• Carrier Proteins/genetics
• Case-Control Studies
• Corticotropin-Releasing Hormone/genetics
• Depression/genetics
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Irritable Bowel Syndrome/genetics
• Male
• Polymorphism, Single Nucleotide/genetics
• Psychometrics
• Sex Characteristics
• Young Adult

Corticotropin-releasing hormone (CRH) plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and regulates the stress response through two CRH receptors (R1 and R2). Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436) and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients.

A total of 142 IBS patients and 142 healthy controls participated in this study. Seven single nucleotide polymorphisms (SNPs) of the CRHR2 gene (rs4722999, rs3779250, rs2240403, rs2267710, rs2190242, rs2284217, and rs2284220) were genotyped. Subjects' psychological states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-Rating Depression Scale.

We found that rs4722999 and rs3779250, located in intronic region, were associated with IBS in terms of genotype frequency (rs4722999: P = 0.037; rs3779250: P = 0.017) and that the distribution of the major allele was significantly different between patients and controls. There was a significant group effect (controls vs. IBS), and a CRHR2 genotype effect was observed for three psychological scores, but the interaction was not significant. We found a haplotype of four SNPs (rs4722999, rs3779250, rs2240403, and rs2267710) and two SNPs (rs2284217 and rs2284220) in strong linkage disequilibrium (D′ > 0.90). We also found that haplotypes of the CRHR2 gene were significantly different between IBS patients and controls and that they were associated with negative emotion.

Our findings support the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are related to IBS. In addition, we found associations between CRHR2 genotypes and haplotypes and negative emotion in IBS patients and controls. Further studies on IBS and the CRH system are warranted.

• Afferent
• Drugs
• Irritable bowel syndrome
• Sensitization
• Stress
• Visceral pain

• Adult
• Age Factors
• Aged
• Alcohol-Related Disorders/epidemiology
• Comorbidity
• Female
• Humans
• Incidence
• Insurance Claim Review
• Irritable Bowel Syndrome/epidemiology
• Male
• Middle Aged
• Proportional Hazards Models
• Retrospective Studies
• Risk Factors
• Severity of Illness Index
• Sex Factors
• Taiwan/epidemiology

Supplemental digital content is available in the text.

Corticotropin-releasing hormone (CRH), a major regulator of the stress response, regulates various biological functions through its interaction with CRH receptors 1 (CRHR1) and 2 (CRHR2). CRH, CRHR1, and CRHR2 have recently been reported in several types of carcinoma, but the significance of these proteins has remained largely unknown in human endometrial carcinoma.

A total of 87 endometrial carcinoma specimens were obtained from Japanese female patients who underwent surgical treatment, fixed in 10% formalin, and embedded in paraffin wax. Immunohistochemistry for CRH, CRHR1, and CRHR2 was performed, and clinical data were obtained from the medical records.

Immunopositivity of CRH, CRHR1, and CRHR2 in the specimens was 26%, 15%, and 10%, respectively. Univariate analysis revealed that immunohistochemical CRH status was positively associated with CRHR1 and CRHR2 status and that CRHR1 status was significantly associated with the risk of recurrence and poorer clinical outcome, whereas CRHR2 status was marginally associated with better prognosis for overall survival. Multivariate analysis demonstrated CRHR1 status as an independent prognostic factor for both disease-free and overall survival.

These results suggest that intratumoral CRH-CRHR1 signaling plays an important role in the progression of endometrial carcinoma and that CRHR1 is a potent prognostic factor in patients with this disease.

AIM: To investigate the effect of electroacupuncture on corticotropin-releasing hormone (CRH) in the colon, spinal cord, and hypothalamus of rats with chronic visceral hypersensitivity.

METHODS: A rat model of chronic visceral hypersensitivity was generated according to the internationally accepted method of colorectal balloon dilatation. In the 7^th week after the procedure, rats were randomly divided into a model group (MG), electroacupuncture group (EA), and sham electroacupuncture group (S-EA). After treatment, the abdominal withdrawal reflex (AWR) score was used to assess the behavioral response of visceral hyperalgesia. Immunohistochemistry (EnVision method), ELISA, and fluorescence quantitative PCR methods were applied to detect the expression of CRH protein and mRNA in the colon, spinal cord, and hypothalamus.

RESULTS: The sensitivity of the rats to the colorectal distension stimulus applied at different strengths (20-80 mmHg) increased with increasing stimulus strength, resulting in increasing AWR scores in each group. Compared with NG, the AWR score of MG was significantly increased (P < 0.01). After conducting EA, the AWR scores of the rats were decreased compared with MG rats. The relative expression of CRH mRNA in the colon, spinal cord, and hypothalamus of MG rats was significantly increased compared with NG rats (P < 0.01). CRH mRNA in the colon and spinal cord of EA and S-EA rats was decreased to varying degrees (P > 0.05) compared with normal rats (NG). However, the decrease in EA compared with MG rats was statistically significant (P < 0.01). The average optical density of CRH expression in the colon of the MG rats was significantly enhanced compared with NG (P < 0.05), while the average optical density of CRH expression in the EA and S-EA rats was significantly decreased compared with MG rats (P < 0.01, P < 0.05, respectively). Compared with MG rats, the CRH concentration in the spinal cord of EA rats was significantly reduced (P < 0.01), but there was no significant change in S-EA rats (P > 0.05).

CONCLUSION: Electroacupuncture at the Shangjuxu acupoint was able to significantly reduce the visceral hypersensitivity in rats, and regulated the expression of CRH protein and mRNA in the colon, spinal cord and hypothalamus at different levels, playing a therapeutic role in this model of irritable bowel syndrome.

• Corticotropin-releasing hormone
• Electroacupuncture
• Irritable bowel syndrome
• Visceral pain
• Shangjuxu

• Animals
• Animals, Newborn
• Behavior, Animal
• Chronic Pain/genetics
• Chronic Pain/metabolism
• Chronic Pain/physiopathology
• Chronic Pain/therapy
• Colon/innervation
• Colon/metabolism
• Corticotropin-Releasing Hormone/genetics
• Corticotropin-Releasing Hormone/metabolism
• Dilatation
• Disease Models, Animal
• Electroacupuncture
• Gene Expression Regulation
• Hyperalgesia/genetics
• Hyperalgesia/metabolism
• Hyperalgesia/physiopathology
• Hyperalgesia/therapy
• Hypothalamus/metabolism
• Immunohistochemistry
• Irritable Bowel Syndrome/genetics
• Irritable Bowel Syndrome/metabolism
• Irritable Bowel Syndrome/physiopathology
• Irritable Bowel Syndrome/therapy
• Male
• Pain Perception
• Pain Threshold
• Polymerase Chain Reaction/methods
• Pressure
• RNA, Messenger/metabolism
• Rats, Sprague-Dawley
• Spinal Cord/metabolism
• Visceral Pain/genetics
• Visceral Pain/metabolism
• Visceral Pain/physiopathology
• Visceral Pain/therapy

The corticotropin-releasing factor (CRF) signaling systems encompass CRF and the structurally related peptide urocortin (Ucn) 1, 2, and 3 along with 2 G-protein coupled receptors, CRF₁ and CRF₂. CRF binds with high and moderate affinity to CRF₁ and CRF₂ receptors, respectively while Ucn1 is a high-affinity agonist at both receptors, and Ucn2 and Ucn3 are selective CRF₂ agonists. The CRF systems are expressed in both the brain and the colon at the gene and protein levels. Experimental studies established that the activation of CRF₁ pathway in the brain or the colon recaptures cardinal features of diarrhea predominant irritable bowel syndrome (IBS) (stimulation of colonic motility, activation of mast cells and serotonin, defecation/watery diarrhea, and visceral hyperalgesia). Conversely, selective CRF₁ antagonists or CRF₁/CRF₂ antagonists, abolished or reduced exogenous CRF and stress-induced stimulation of colonic motility, defecation, diarrhea and colonic mast cell activation and visceral hyperalgesia to colorectal distention. By contrast, the CRF₂ signaling in the colon dampened the CRF₁ mediated stimulation of colonic motor function and visceral hyperalgesia. These data provide a conceptual framework that sustained activation of the CRF₁ system at central and/or peripheral sites may be one of the underlying basis of IBS-diarrhea symptoms. While targeting these mechanisms by CRF₁ antagonists provided a relevant novel therapeutic venue, so far these promising preclinical data have not translated into therapeutic use of CRF₁ antagonists. Whether the existing or newly developed CRF₁ antagonists will progress to therapeutic benefits for stress-sensitive diseases including IBS for a subset of patients is still a work in progress.

• Colonic motility, Corticotropin-releasing factor, Irritable bowel syndrome, Stress, Visceral pain

The interface between the intestinal lumen and the mucosa is the location where the majority of ingested immunogenic particles face the scrutiny of the vast gastrointestinal immune system. Upon regular physiological conditions, the intestinal micro-flora and the epithelial barrier are well prepared to process daily a huge amount of food-derived antigens and non-immunogenic particles. Similarly, they are ready to prevent environmental toxins and microbial antigens to penetrate further and interact with the mucosal-associated immune system. These functions promote the development of proper immune responses and oral tolerance and prevent disease and inflammation. Brain-gut axis structures participate in the processing and execution of response signals to external and internal stimuli. The brain-gut axis integrates local and distant regulatory networks and super-systems that serve key housekeeping physiological functions including the balanced functioning of the intestinal barrier. Disturbance of the brain-gut axis may induce intestinal barrier dysfunction, increasing the risk of uncontrolled immunological reactions, which may indeed trigger transient mucosal inflammation and gut disease. There is a large body of evidence indicating that stress, through the brain-gut axis, may cause intestinal barrier dysfunction, mainly via the systemic and peripheral release of corticotropin-releasing factor. In this review, we describe the role of stress and corticotropin-releasing factor in the regulation of gastrointestinal permeability, and discuss the link to both health and pathological conditions.

• Corticotropin-releasing factor
• Inflammation
• Permeability
• Stress