Enterochromaffin Cells–Gut Microbiota Crosstalk: Underpinning the Symptoms, Pathogenesis, and Pharmacotherapy in Disorders of Gut-Brain Interaction

Lai Wei,Rajan Singh,Uday C Ghoshal 대한소화기 기능성질환·운동학회 2022 Journal of Neurogastroenterology and Motility (JNM Vol.28 No.3

Disorders of gut-brain interaction (DGBIs) are common conditions in community and clinical practice. As specialized enteroendocrine cells, enterochromaffin (EC) cells produce up to 95% of total body serotonin and coordinate luminal and basolateral communication in the gastrointestinal (GI) tract. EC cells affect a broad range of gut physiological processes, such as motility, absorption, secretion, chemo/mechanosensation, and pathologies, including visceral hypersensitivity, immune dysfunction, and impaired gastrointestinal barrier function. We aim to review EC cell and serotonin-mediated physiology and pathophysiology with particular emphasis on DGBIs. We explored the knowledge gap and attempted to suggest new perspectives of physiological and pathophysiological insights of DGBIs, such as (1) functional heterogeneity of regionally distributed EC cells throughout the entire GI tract; (2) potential pathophysiological mechanisms mediated by EC cell defect in DGBIs; (3) cellular and molecular mechanisms characterizing EC cells and gut microbiota bidirectional communication; (4) differential modulation of EC cells through GI segment-specific gut microbiota; (5) uncover whether crosstalk between EC cells and (i) luminal contents; (ii) enteric nervous system; and (iii) central nervous system are core mechanisms modulating gut-brain homeostasis; and (6) explore the therapeutic modalities for physiological and pathophysiological mechanisms mediated through EC cells. Insights discussed in this review will fuel the conception and realization of pathophysiological mechanisms and therapeutic clues to improve the management and clinical care of DGBIs.

Quercetin Attenuates Visceral Hypersensitivity and 5-Hydroxytryptamine Availability in Postinflammatory Irritable Bowel Syndrome Rats: Role of Enterochromaffin Cells in the Colon

Hong-Yan Qin,Kai-hong Zang,Xiao Zuo,Xin-An Wu,Zhaoxiang Bian 한국식품영양과학회 2019 Journal of medicinal food Vol.22 No.7

Intestinal enterochromaffin (EC) cell hyperplasia and increased 5-hydroxytryptamine (5-HT) availability play key roles in the pathogenesis of abdominal hypersensitivity of irritable bowel syndrome (IBS). This study aims to study the effect of quercetin on visceral pain and 5-HT availability in postinflammatory IBS (PI-IBS) rats. PI-IBS model rats were administered quercetin by gavage at doses of 5, 10, and 20 mg/kg for 14 days. Compared with normal rats, the visceral pain threshold of PI-IBS rats was markedly decreased and the abdominal motor response to colon distension was markedly increased. The EC cell count and 5-HT level, as well as tryptophan hydroxylase (TPH) protein, were all significantly elevated in PI-IBS rats, while the 5-HT reuptake transporter (serotonin transporter) was reduced. Genes that are responsible for enteroendocrine cell differentiation, that is, Ngn3 and pdx1, were significantly increased in the PI-IBS group. Quercetin treatment markedly elevated the pain threshold pressure and decreased the visceral motor response of PI-IBS animals; and EC cell density and 5-HT level, as well as TPH expression, in the PI-IBS group were all reduced by quercetin. Quercetin treatment also significantly reduced colonic expression of Ngn3 and pdx1 of PI-IBS. Findings from the present study indicated that the analgesic effect of quercetin on PI-IBS may result from reduction of 5-HT availability in the colon, and the regulatory role of quercetin in endocrine progenitors may contribute to reduced EC cells.

Clinical importance of histamine in coronavirus disease 2019

Sang-Hoon Lee,Sang Man Kim 대한기능의학회 2021 Journal of Korean Institute for Functional Medicin Vol.4 No.1

중증급성호흡증후군 코로나바이러스 2 (SARS-CoV-2)에 의한 코로나바이러스감염증-19 (COVID-19)는 현재 전 세계에서 가장 중대한 건강 문제이다. 많은 사이토카인들이 COVID-19의 병태생리를 밝히기 위해 연구되고 있으나, 상대적으로 히스타민에 대한 관심과 연구는 적은 편이다. 몇몇 연구 결과에 따르면 SARS-CoV-2는 인체의 다양한 면역 세포들을 활성화시키며, 그중 비만 세포(mast cell)와 장크롬친화성 유사 세포(enterochromaffin-like cell)도 포함된다. 이 세포들은 체 내 히스타민의 주요 저장소로, 이 세포들이 자극되어 체 내 히스타민이 과다해지게 되면 혈관 확장, 피부 반응, 부종, 복통 등의 증상이 나타나게 되며 중증일 경우 혈압 저하, 쇼크까지 발생할 수 있다. 이러한 히스타민 과다의 증상 및 병태생리는 COVID-19의 증상 및 병태생리와 일부 유사한 면이 있다. 특히 사이토카인 방출 증후군(cytokine release syndrome), COVID-19의 소화기 증상, 소아 다기관 염증 증후군 (multisystem inflammatory syndrome in children) 등에서 히스타민의 역할을 생각해 볼 수 있으며, 히스타민 2 수용체 길항제인 famotidine 성분이 COVID-19 환자 치료에 도움이 되었다는 몇몇 연구 결과도 있다. 이에 저자들은 COVID-19에서 히스타민의 임상적 중요성에 대해 살펴보고자 한다. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (coronavirus disease 2019, COVID-19) is still spreading globally, and it is the most important issue in the world. Many cytokines are evaluated to elucidate the pathophysiology of COVID-19, but relatively little is known about histamine. Some research data shows SARS-CoV-2 can activate many immune cells, including mast cells and enterochromaffin-like cells. These cells are the main source of body histamine. Excessive histamine release can cause many problems, such as excessive vasodilation, skin reactions, edema, abdominal cramping, hypotension, and shock. These are somewhat in line with the pathophysiology and clinical presentation of SARS-CoV-2 infection, notably cytokine release syndrome, gastrointestinal symptoms, and multisystem inflammatory syndrome in children. The clinical efficacy of famotidine on COVID-19 also suggests a relationship. In this study, the authors will review the clinical importance of histamine in COVID-19.

The alteration of enterochromaffin cell, mast cell, and lamina propria T lymphocyte numbers in irritable bowel syndrome and its relationship with psychological factors

Lee, Kwang Jae,Kim, Yeong Bae,Kim, Jang Hee,Kwon, Hoek Chun,Kim, Dong Kyu,Cho, Sung Won Blackwell Publishing Asia 2008 Journal of gastroenterology and hepatology Vol.23 No.11

<P>Abstract</P><P>Background/Aims: </P><P>Psychological factors and subtle histopathological changes have been implicated in irritable bowel syndrome (IBS). The aims of the present study were to investigate whether the numbers of enterochromaffin (EC) cells, mast cells, and lamina propria T lymphocytes are altered in IBS, and evaluate the relationship of such alterations with psychological factors.</P><P>Methods: </P><P>Forty-two consecutive IBS patients (M : F = 17:25, mean age 48 years) fulfilling the Rome III criteria and twelve asymptomatic healthy controls underwent rectal biopsy. Immunostaining was performed for EC cells, mast cells, and lamina propria T lymphocytes.</P><P>Results: </P><P>The IBS group included five post-infectious (PI) IBS and 37 non-PI IBS patients. Significantly more EC cells, mast cells and lamina propria T lymphocytes were observed in PI IBS patients. Mast cells significantly increased in non-PI IBS-D (diarrhea) patients, but not in non-PI IBS-C (constipation) and non-PI IBS-M (mixed) patients. Enterochromaffin cell numbers were not significantly altered in non-PI IBS patients. Anxiety and depression scores did not differ between IBS patients with and without abnormal increase in EC cell or mast cell counts, defined as more than the mean of controls + 2 standard deviations. Enterochromaffin cell, mast cell, or lamina propria T lymphocyte numbers were poorly correlated with anxiety and depression scores in the IBS group.</P><P>Conclusions: </P><P>Enterochromaffin cells, mast cells, and lamina propria T lymphocytes significantly increase in PI IBS, whereas only mast cells significantly increase in non-PI IBS-D. Such histopathological changes do not seem to be directly associated with psychological factors.</P>

Stress-induced Alterations in Mast Cell Numbers and Proteinaseactivated Receptor-2 Expression of the Colon: Role of Corticotrophin-releasing Factor

김동훈,조영주,김장희,김영배,이광재 대한의학회 2010 Journal of Korean medical science Vol.25 No.9

This study was performed in order to assess whether acute stress can increase mast cell and enterochromaffin (EC) cell numbers, and proteinase-activated receptor-2 (PAR2) expression in the rat colon. In addition, we aimed to investigate the involvement of corticotrophinreleasing factor in these stress-related alterations. Eighteen adult rats were divided into 3experimental groups: 1) a saline-pretreated non-stressed group, 2) a saline-pretreated stressed group, and 3) an astressin-pretreated stressed group. The numbers of mast cells, EC cells, and PAR2-positive cells were counted in 6 high power fields. In proximal colonic segments, mast cell numbers of stressed rats tended to be higher than those of nonstressed rats, and their PAR2-positive cell numbers were significantly higher than those of non-stressed rats. In distal colonic segments, mast cell numbers and PAR2-positive cell numbers of stressed rats were significantly higher than those of non-stressed rats. Mast cell and PAR2-positive cell numbers of astressin-pretreated stressed rats were significantly lower than those of saline-pretreated stressed rats. EC cell numbers did not differ among the three experimental groups. Acute stress in rats increases mast cell numbers and mucosal PAR2 expression in the colon. These stress-related alterations seem to be mediated by release of corticotrophin-releasing factor.

Stress-induced Alterations in Mast Cell Numbers and Proteinase-activated Receptor-2 Expression of the Colon: Role of Corticotrophin-releasing Factor

Kim, Dong Hoon,Cho, Young Ju,Kim, Jang Hee,Kim, Young Bae,Lee, Kwang Jae The Korean Academy of Medical Sciences 2010 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.25 No.9

<P>This study was performed in order to assess whether acute stress can increase mast cell and enterochromaffin (EC) cell numbers, and proteinase-activated receptor-2 (PAR2) expression in the rat colon. In addition, we aimed to investigate the involvement of corticotrophin-releasing factor in these stress-related alterations. Eighteen adult rats were divided into 3 experimental groups: 1) a saline-pretreated non-stressed group, 2) a saline-pretreated stressed group, and 3) an astressin-pretreated stressed group. The numbers of mast cells, EC cells, and PAR2-positive cells were counted in 6 high power fields. In proximal colonic segments, mast cell numbers of stressed rats tended to be higher than those of non-stressed rats, and their PAR2-positive cell numbers were significantly higher than those of non-stressed rats. In distal colonic segments, mast cell numbers and PAR2-positive cell numbers of stressed rats were significantly higher than those of non-stressed rats. Mast cell and PAR2-positive cell numbers of astressin-pretreated stressed rats were significantly lower than those of saline-pretreated stressed rats. EC cell numbers did not differ among the three experimental groups. Acute stress in rats increases mast cell numbers and mucosal PAR2 expression in the colon. These stress-related alterations seem to be mediated by release of corticotrophin-releasing factor.</P>

Increased Immunoendocrine Cells in Intestinal Mucosa of Postinfectious Irritable Bowel Syndrome Patients 3 Years after Acute Shigella Infection - An Observation in a Small Case Control Study

김희선,임정현,이상인,박효진 연세대학교의과대학 2010 Yonsei medical journal Vol.51 No.1

Purpose: Postinfectiously irritable bowel syndrome (PI-IBS) develops in 3-30% of individuals with bacterial gastroenteritis. Recent studies demonstrated increases in inflammatory components in gut mucosa of PI-IBS patients even after complete resolution of infection. We aimed to investigate histological changes in colon and rectum of PI-IBS subjects after long term period of infection. Materials and Methods: We recruited PI-IBS subjects who had been diagnosed IBS after complete resolution of enteritis caused by shigellosis outbreak 3 years earlier. We compared unmatched four groups, PI-IBS (n = 4), non PI-IBS (n = 7), D-IBS (n = 7, diarrhea predominant type) and healthy controls (n = 10). All of them underwent colonoscopic biopsy at three areas, including descending colon (DC), sigmoid colon (SC) and rectum, which were assessed for 5-hydroxytryptamine (5-HT)/peptide YY (PYY)-containing enterochromaffin (EC) cell, intraepithelial (IEL) and lamina propria T lymphocyte (CD3), CD8 lymphocytes, mast cells and CD68/calprotectin+ macrophages. Results: All subjects had no structural or gross abnormalities at colonoscopy. In PI-IBS, 5-HT containing EC cells, PYY containing EC cells, IELs, CD3lymphocytes, CD8 lymphocytes, mast cells, and CD68 + macrophages were increased compared to control (p <0.05). In D-IBS, PYY containing EC cells, IELs, and CD3 lymphocytes were increased compared to control (p <0.05). In PI-IBS, 5-HT containing EC cells tended to increase and PYY containing EC cells, CD8 lymphocytes,mast cells, and CD68+ macrophages were increased compared to non PI-IBS (p < 0.05). Calprotectin + marcrophages were decreased in PI-IBS, non PI-IBS and IBS compared to control. Conclusion: The immunoendocrine cells were sporadically increased in PI-IBS, non PI-IBS and D-IBS compared with control. Our findings in a very small number of patients suggest that mucosal inflammation may play a role in long-term PI-IBS, and that other sub-groups of IBS and larger scale studies are needed to confirm this observation.

Oridonin Alleviates Visceral Hyperalgesia in a Rat Model of Postinflammatory Irritable Bowel Syndrome: Role of Colonic Enterochromaffin Cell and Serotonin Availability

Kai-hong Zang,Yun-yun Shao,Xiao Zuo,Zhi Rao,Hongyan Qin 한국식품영양과학회 2016 Journal of medicinal food Vol.19 No.6

The aim of this present study was to investigate the effect of oridonin on visceral hyperalgesia and colonic serotonin availability in a rat model of trinitrobenzenesulfonic acid-induced postinflammatory irritable bowel syndrome (PI-IBS). Rats were randomly divided into five groups: normal control, PI-IBS model, PI-IBS+low-dose oridonin (5 mg/kg), PI-IBS+median-dose oridonin (10 mg/kg), and PI-IBS+high-dose oridonin (20 mg/kg). Rats in control and model groups were orally administered with water by gavage, whereas rats in oridonin-treated groups were orally administered with different dosages of oridonin, and drugs were given for 14 consecutive days. Compared with the control group, the pain threshold pressure was significantly reduced in PI-IBS rats. The colonic enterochromaffin (EC) cell number, serotonin content, and the protein expression of tryptophan hydroxylase (TPH) were markedly increased and the protein expression of serotonin reuptake transporter was significantly decreased in PI-IBS rats. The spleen index in PI-IBS rats was decreased, and the levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-4, and IL-13 in the colon of PI-IBS rats were also markedly decreased. Oridonin treatment dose dependently increased pain threshold pressure, and markedly decreased colon EC cell numbers, TPH expression, and serotonin content in PI-IBS rats. Oridonin treatment also significantly increased the spleen index as well as the levels of TNF-α, IFN-γ, IL-4, and IL-13 in the colon of PI-IBS rats. Results of this study demonstrate that the analgesic effect of oridonin in PI-IBS rats is associated with reduced colonic EC cell hyperplasia and 5-HT availability, the regulatory effect of oridonin on colonic cytokine production may be correlated with its effect on colonic EC cell number.

Review : Mechanism of Interdigestive Migrating Motor Complex

( Toku Takahashi ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2012 Journal of Neurogastroenterology and Motility (JNM Vol.18 No.3

Migrating motor complex (MMC) is well characterized by the appearance of gastrointestinal contractions in the interdigestive state. This review article discussed the mechanism of gastrointestinal MMC. Luminal administration of 5-hydroxytryptamine (5-HT) initiates duodenal phase II followed by gastrointestinal phase III with a concomitant increase of plasma motilin release in conscious dogs. Duodenal 5-HT concentration is increased during gastric phase II and phase III. Intravenous infusion of motilin increases luminal 5-HT content and induces gastrointestinal phase III. 5-HT4 antagonists significantly inhibits both of gastric and intestinal phase III, while 5-HT3 antagonists inhibited only gastric phase III. These suggest that gastrointestinal MMC cycle is mediated via the interaction between motilin and 5-HT by the positive feedback mechanism. Gastric MMC is regulated via vagus, 5-HT3/4 receptors and motilin, while intestinal MMC is regulated via intrinsic primary afferent neurons and 5-HT4 receptors. Stress is highly associated with the pathogenesis of functional dyspepsia. Acoustic stress attenuates gastric phase III without affecting intestinal phase III in conscious dogs, via reduced vagal activity and increased sympathetic activity. It has been shown that subset of functional dyspepsia patients show reduced vagal activity and impaired gastric phase III. The physiological importance of gastric MMC is a mechanical and chemical cleansing of the empty stomach in preparation for the next meal. The impaired gastric MMC may aggravate dyspeptic symptoms following a food ingestion. Thus, maintaining gastric MMC in the interdigestive state is an important factor to prevent the postprandial dyspeptic symptoms. (J Neurogastroenterol Motil 2012;18:246-257)