-
Journal of Virology Jul 2021Rotavirus infection is highly prevalent in children, and the most severe effects are diarrhea and vomiting. It is well accepted that the enteric nervous system (ENS) is...
Rotavirus infection is highly prevalent in children, and the most severe effects are diarrhea and vomiting. It is well accepted that the enteric nervous system (ENS) is activated and plays an important role, but knowledge of how rotavirus activates nerves within ENS and to the vomiting center is lacking. Serotonin is released during rotavirus infection, and antagonists to the serotonin receptor subtype 3 (5-HT receptor) can attenuate rotavirus-induced diarrhea. In this study, we used a 5-HT receptor knockout (KO) mouse model to investigate the role of this receptor in rotavirus-induced diarrhea, motility, electrolyte secretion, inflammatory response, and vomiting reflex. The number of diarrhea days ( = 0.03) and the number of mice with diarrhea were lower in infected 5-HT receptor KO than wild-type pups. investigation of fluorescein isothiocyanate (FITC)-dextran transit time showed that intestinal motility was lower in the infected 5-HT receptor KO compared to wild-type mice ( = 0.0023). Ussing chamber measurements of potential difference across the intestinal epithelia showed no significant difference in electrolyte secretion between the two groups. Immediate early gene cFos expression level showed no difference in activation of the vomiting center in the brain. Cytokine analysis of the intestine indicated a low effect of inflammatory response in rotavirus-infected mice lacking the 5-HT receptor. Our findings indicate that the 5-HT receptor is involved in rotavirus-induced diarrhea via its effect on intestinal motility and that the vagus nerve signaling to the vomiting center occurs also in the absence of the 5-HT receptor. The mechanisms underlying rotavirus-induced diarrhea and vomiting are not yet fully understood. To better understand rotavirus pathophysiology, characterization of nerve signaling within the ENS and through vagal efferent nerves to the brain, which have been shown to be of great importance to the disease, is necessary. Serotonin (5-HT), a mediator of both diarrhea and vomiting, has been shown to be released from enterochromaffin cells in response to rotavirus infection and the rotavirus enterotoxin NSP4. Here, we investigated the role of the serotonin receptor 5-HT, which is known to be involved in the nerve signals that regulate gut motility, intestinal secretion, and signal transduction through the vagus nerve to the brain. We show that the 5-HT receptor is involved in rotavirus-induced diarrhea by promoting intestinal motility. The findings shed light on new treatment possibilities for rotavirus diarrhea.
Topics: Animals; Diarrhea; Enteric Nervous System; Enterochromaffin Cells; Gastrointestinal Motility; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Serotonin, 5-HT3; Rotavirus; Rotavirus Infections; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 33980599
DOI: 10.1128/JVI.00751-21 -
World Journal of Gastroenterology Jan 2014Chronic abdominal pain accompanying intestinal inflammation emerges from the hyperresponsiveness of neuronal, immune and endocrine signaling pathways within the... (Review)
Review
Chronic abdominal pain accompanying intestinal inflammation emerges from the hyperresponsiveness of neuronal, immune and endocrine signaling pathways within the intestines, the peripheral and the central nervous system. In this article we review how the sensory nerve information from the healthy and the hypersensitive bowel is encoded and conveyed to the brain. The gut milieu is continuously monitored by intrinsic enteric afferents, and an extrinsic nervous network comprising vagal, pelvic and splanchnic afferents. The extrinsic afferents convey gut stimuli to second order neurons within the superficial spinal cord layers. These neurons cross the white commissure and ascend in the anterolateral quadrant and in the ipsilateral dorsal column of the dorsal horn to higher brain centers, mostly subserving regulatory functions. Within the supraspinal regions and the brainstem, pathways descend to modulate the sensory input. Because of this multiple level control, only a small proportion of gut signals actually reaches the level of consciousness to induce sensation or pain. In inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) patients, however, long-term neuroplastic changes have occurred in the brain-gut axis which results in chronic abdominal pain. This sensitization may be driven on the one hand by peripheral mechanisms within the intestinal wall which encompasses an interplay between immunocytes, enterochromaffin cells, resident macrophages, neurons and smooth muscles. On the other hand, neuronal synaptic changes along with increased neurotransmitter release in the spinal cord and brain leads to a state of central wind-up. Also life factors such as but not limited to inflammation and stress contribute to hypersensitivity. All together, the degree to which each of these mechanisms contribute to hypersensitivity in IBD and IBS might be disease- and even patient-dependent. Mapping of sensitization throughout animal and human studies may significantly improve our understanding of sensitization in IBD and IBS. On the long run, this knowledge can be put forward in potential therapeutic targets for abdominal pain in these conditions.
Topics: Abdominal Pain; Afferent Pathways; Animals; Enteric Nervous System; Gastrointestinal Tract; Humans; Hyperalgesia; Inflammatory Bowel Diseases; Irritable Bowel Syndrome; Pain Perception; Pain Threshold
PubMed: 24574773
DOI: 10.3748/wjg.v20.i4.1005 -
Journal of Neurogastroenterology and... Jul 2022Disorders of gut-brain interaction (DGBIs) are common conditions in community and clinical practice. As specialized enteroendocrine cells, enterochromaffin (EC) cells... (Review)
Review
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.
PubMed: 35719046
DOI: 10.5056/jnm22008 -
International Journal of Molecular... Aug 2021The monoamine serotonin, 5-hydroxytryptamine (5-HT), is a remarkable molecule with conserved production in prokaryotes and eukaryotes and a wide range of functions. In... (Review)
Review
The monoamine serotonin, 5-hydroxytryptamine (5-HT), is a remarkable molecule with conserved production in prokaryotes and eukaryotes and a wide range of functions. In the gastrointestinal tract, enterochromaffin cells are the most important source for 5-HT production. Some intestinal bacterial species are also able to produce 5-HT. Besides its role as a neurotransmitter, 5-HT acts on immune cells to regulate their activation. Several lines of evidence indicate that intestinal 5-HT signaling is altered in patients with inflammatory bowel disease. In this review, we discuss the current knowledge on the production, secretion, and signaling of 5-HT in the intestine. We present an inventory of intestinal immune and epithelial cells that respond to 5-HT and describe the effects of these signaling processes on intestinal homeostasis. Further, we detail the mechanisms by which 5-HT could affect inflammatory bowel disease course and describe the effects of interventions that target intestinal 5-HT signaling.
Topics: Animals; Colitis; Enterochromaffin Cells; Epithelial Cells; Gastrointestinal Tract; Homeostasis; Humans; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Serotonin; Signal Transduction
PubMed: 34502396
DOI: 10.3390/ijms22179487 -
Cell Proliferation Oct 2020Enterochromaffin (EC) cells have been associated with functional gastrointestinal disorders such as IBS. Recently, we found that glial cell-derived neurotrophic factor...
OBJECTIVES
Enterochromaffin (EC) cells have been associated with functional gastrointestinal disorders such as IBS. Recently, we found that glial cell-derived neurotrophic factor (GDNF)-rearranged during transfection (RET) localized in EC cells in human colonic epithelia. Here, we examine the role of GDNF-RET in the pathophysiology of diarrhoea-predominant irritable bowel syndrome (IBS-D).
MATERIALS AND METHODS
GDNF was assessed by ELISA and immunohistochemistry in biopsies from IBS-D patients and healthy controls. Stress was induced by using a wrap-restraint stress (WRS) procedure to serve as an acute stress-induced IBS model. The function of GDNF-RET axis to intestinal stem cell (ISC) homeostasis, and EC cell numbers were assessed in vivo and in vitro.
RESULTS
GDNF-RET was expressed in EC cells in human colon. GDNF was significantly increased in IBS-D patients. WRS mice showed increased GDNF-RET levels in colon. WRS induced visceral hypersensitivity by expanding of ISC and differentiation of EC cell via GDNF-RET. Furthermore, GDNF-treated mice recapitulated the phenotype of WRS mice. In vitro, GDNF treatment amplified Wnt signal and increased serotonin levels in colonic organoids in a dose-dependent manner.
CONCLUSIONS
We identified GDNF-RET was presented in colonic epithelium of patients with IBS-D. GDNF-RET played important roles in regulating ISC and EC cell differentiation. Our findings, thus, provide RET inhibitor as new therapeutic targets for treatment of patients with IBS-D.
Topics: Adult; Animals; Enterochromaffin Cells; Female; Glial Cell Line-Derived Neurotrophic Factor; Homeostasis; Humans; Intestinal Mucosa; Intestines; Irritable Bowel Syndrome; Male; Mice, Inbred C57BL; Middle Aged; Proto-Oncogene Proteins c-ret; Stress, Physiological
PubMed: 32808420
DOI: 10.1111/cpr.12889 -
Acta Gastro-enterologica Belgica Mar 2016Irritable bowel syndrome (IBS) is a common functional gastro-intestinal disorder, characterized by abdominal pain and altered intestinal motility. Visceral... (Review)
Review
Irritable bowel syndrome (IBS) is a common functional gastro-intestinal disorder, characterized by abdominal pain and altered intestinal motility. Visceral hypersensitivity is an important hallmark feature of IBS and is believed to underlie abdominal pain in patients with IBS. The two main risk factors associated with the development of IBS are gastrointestinal inflammation and psychological distress. On a peripheral level, visceral sensitivity seems to be modulated by several mechanisms. Immune cells in the mucosal wall, such as mast cells, and enterochromaffin cells may sensitize afferent nerves by release of their mediators. Furthermore, increased mucosal permeability, altered intestinal microflora and dietary habits may contribute to this feature. On a central level, an increased prevalence of psychiatric comorbidities is demonstrated in IBS patients, alongside alterations in the hormonal brain-gut axis, increased vigilance towards intestinal stimuli and functional and structural changes in the brain. The pathogenesis of IBS is complicated and multifactorial and the treatment remains clinically challenging. Dietary measures and symptomatic control are the cornerstones for IBS treatment and may be sufficient for patients experiencing mild symptoms, alongside education, reassurance and an effective therapeutic physician-patient relationship. New pharmacological therapies are aimed at interfering with mediator release and/or blockade of the relevant receptors within the gut wall, while modulation of the intestinal flora and diet may also be of therapeutic benefit. Tricyclic anti-depressants and serotonin reuptake inhibitors act both on a central and peripheral level by modulating pain signalling pathways.
Topics: Abdominal Pain; Brain; Humans; Hyperalgesia; Hyperesthesia; Intestines; Irritable Bowel Syndrome; Stress, Psychological
PubMed: 26852761
DOI: No ID Found -
Journal of Physiology and Pharmacology... Sep 2001Guanylin and uroguanylin are short peptides homologous to heat-stable enterotoxins of Escherichia coli and other enteric bacteria. Guanylin and uroguanylin are... (Review)
Review
Guanylin and uroguanylin are short peptides homologous to heat-stable enterotoxins of Escherichia coli and other enteric bacteria. Guanylin and uroguanylin are synthetized from the respective prepropeptides mainly in gastrointestinal mucosa and are secreted both into intestinal lumen and into the blood. Luminally secreted peptides stimulate chloride and bicarbonate secretion in the intestine through the mechanism involving guanylate cyclase C receptor, cyclic GMP, protein kinase G and cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Bacterial enterotoxins, which have greater potency than endogenous peptides, induce excessive fluid secretion into intestinal lumen leading to secretory diarhea. Uroguanylin is expressed mainly in enterochromaffin cells of duodenum and proximal small intestine whereas guanylin is abundant in goblet cells of colonic epithelium. Uroguanylin and guanylin increase urinary sodium and potassium excretion both as circulating hormones and as paracrine mediators produced within the kidney. Uroguanylin functions as "intestinal natriuretic hormone" which is secreted in response to oral sodium loading and maintains sodium balance during postprandial period. Plasma and urinary concentrations of guanylin and uroguanylin increase in renal failure and heart failure. Guanylin peptides possess antiproliferative activity in intestinal cells culture and their expression decreases in colonic carcinoma indicating that their deficiency may contribute to the pathogenesis of this disease.
Topics: Amino Acid Sequence; Animals; Cystic Fibrosis Transmembrane Conductance Regulator; Digestive System Physiological Phenomena; Gastrointestinal Hormones; Guanylate Cyclase; Humans; Kidney; Molecular Sequence Data; Natriuretic Peptides; Peptides; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Signal Transduction; Water-Electrolyte Balance
PubMed: 11596856
DOI: No ID Found -
Scientific Reports Feb 2019Peripheral serotonin (5-hydroxytryptamine: 5-HT) synthesized in the intestine by enterochromaffin cells (ECs), plays an important role in the regulation of peristaltic...
Peripheral serotonin (5-hydroxytryptamine: 5-HT) synthesized in the intestine by enterochromaffin cells (ECs), plays an important role in the regulation of peristaltic of the gut, epithelial secretion and promotes the development and maintenance of the enteric neurons. Recent studies showed that the indigenous gut microbiota modulates 5-HT signalling and that ECs use sensory receptors to detect dietary and microbiota-derived signals from the lumen to subsequently transduce the information to the nervous system. We hypothesized that Clostridium ramosum by increasing gut 5-HT availability consequently contributes to high-fat diet-induced obesity. Using germ-free mice and mice monoassociated with C. ramosum, intestinal cell lines and mouse organoids, we demonstrated that bacterial cell components stimulate host 5-HT secretion and program the differentiation of colonic intestinal stem progenitors toward the secretory 5-HT-producing lineage. An elevated 5-HT level regulates the expression of major proteins involved in intestinal fatty acid absorption in vitro, suggesting that the presence of C. ramosum in the gut promotes 5-HT secretion and thereby could facilitates intestinal lipid absorption and the development of obesity.
Topics: Animals; Cell Line; Enterochromaffin Cells; Firmicutes; Mice; Organoids; Serotonin; Serotonin Receptor Agonists
PubMed: 30718836
DOI: 10.1038/s41598-018-38018-z -
American Journal of Physiology.... Oct 2020Small intestinal neuroendocrine tumors (SI-NET) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. Recent... (Review)
Review
Small intestinal neuroendocrine tumors (SI-NET) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. Recent studies recognize a subset of EC cells that is label-retaining at the +4 position in the crypt and functions as a reserve intestinal stem cell. Importantly, this +4 reserve EC cell subset not only contributes to regeneration of the intestinal epithelium during injury and inflammation but also to basal crypt homeostasis at a constant rate. The latter function suggests that the +4 EC cell subset serves as an active reserve stem cell via a constant rate of dedifferentiation. Characterization of early tumor formation of SI-NET, observed as crypt-based EC cell clusters in many cases of familial SI-NETs, suggests that the +4 active reserve EC cell subset is the cell of origin. This newly discovered active reserve stem cell property of EC cells can account for unique biological mechanisms and processes associated with the genesis and development of SI-NETs. The recognition of this property of the +4 active reserve EC cell subset may provide novel opportunities to explore NETs in the gastrointestinal tract and other organs.
Topics: Animals; Carcinogenesis; Cell Dedifferentiation; Enterochromaffin Cells; Humans; Intestinal Neoplasms; Intestine, Small; Mice; Neuroendocrine Tumors; Serotonin; Stem Cells
PubMed: 32845170
DOI: 10.1152/ajpgi.00278.2020 -
American Journal of Physiology.... Mar 2023Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin....
Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Here, we examined whether the gain of Myc and the loss of RB1 and Trp53 function in EC cells result in SI-NET using tryptophan hydroxylase 1 (TPH1) Cre-ERT2-driven RB1 Trp53 Myc (RPM) mice. TPH1Cre-induced gain of Myc and loss of RB1 and Trp53 function resulted in endocrine or neuronal tumors in pancreas, lung, enteric neurons, and brain. Lineage tracing indicated that the cellular origin for these tumors was TPH1-expressing neuroendocrine, neuronal, or their precursor cells in these organs. However, despite that TPH1 is most highly expressed in EC cells of the small intestine, we observed no incidence of EC cell tumors. Instead, the tumor of epithelial cell origin in the intestine was exclusively nonendocrine adenocarcinoma, suggesting dedifferentiation of EC cells into intestinal stem cells (ISCs) as a cellular mechanism. Furthermore, ex vivo organoid studies indicated that loss of functions of Rb1 and Trp53 accelerated dedifferentiation of EC cells that were susceptible to apoptosis with expression of activated MycT58A, suggesting that the rare dedifferentiating cells escaping cell death went on to develop adenocarcinomas. Lineage tracing demonstrated that EC cells in the small intestine were short-lived compared with neuroendocrine or neuronal cells in other organs. In contrast, EC cell-derived ISCs were long-lasting and actively cycling and thus susceptible to transformation. These results suggest that tissue- and cell-specific properties of EC cells such as rapid cell turnover and homeostatic dedifferentiation, affect the fate and rate of tumorigenesis induced by genetic alterations and provide important insights into EC cell-derived tumorigenesis. Small intestinal neuroendocrine tumors are of putative enterochromaffin (EC) cell origin and are the most common malignancy in the small intestine, followed by adenocarcinoma. However, the tumorigenesis of these tumor types remains poorly understood. The present lineage tracing studies showed that tissue- and cell-specific properties of EC cells such as rapid cell turnover and homeostatic dedifferentiation affect the fate and rate of tumorigenesis induced by genetic alterations toward a rare occurrence of adenocarcinoma.
Topics: Mice; Animals; Enterochromaffin Cells; Intestine, Small; Carcinogenesis; Cell Transformation, Neoplastic; Intestinal Neoplasms; Neuroendocrine Tumors; Adenocarcinoma
PubMed: 36537709
DOI: 10.1152/ajpgi.00205.2022