Beyond the Brain: Perinatal Exposure of Rats to Serotonin Enhancers Induces Long-Term Changes in the Jejunum and Liver.

Serotonin (5-hydroxytryptamine, 5HT) homeostasis is essential for many physiological processes in the central nervous system and peripheral tissues. Hyperserotonemia, a measurable sign of 5HT homeostasis disruption, can be caused by 5HT-directed treatment of psychiatric and gastrointestinal diseases. Its impact on the long-term balance and function of 5HT in the peripheral compartment remains unresolved and requires further research due to possible effects on human health. We explored the effects of perinatal 5HT imbalance on the peripheral organs responsible for serotonin metabolism-the jejunum, a synthesis site, and the liver, a catabolism site-in adult rats. Hyperserotonemia was induced by subchronic treatment with serotonin precursor 5-hydroxytryptophan (5HTP) or serotonin degradation inhibitor tranylcypromine (TCP). The jejunum and liver were collected on postnatal day 70 and analyzed histomorphometrically. Relative mRNA levels of 5HT-regulating proteins were determined using qRT-PCR. Compared to controls, 5HTP- and TCP-treated rats had a reduced number of 5HT-producing cells and expression of the 5HT-synthesising enzyme in the jejunum, and an increased expression of 5HT-transporter accompanied by karyomegaly in hepatocytes, with these differences being more pronounced in the TCP-treated animals. Here, we report that perinatal 5HT disbalance induced long-term cellular and molecular changes in organs regulating 5HT-metabolism, which may have a negative impact on 5HT availability and function in the periphery. Our rat model demonstrates a link between the developmental abnormalities of serotonin homeostasis and 5HT-related changes in adult life and may be suitable for exploring the neurobiological substrates of vulnerability to behavioral and metabolic disorders, as well as for modeling the adverse effects of the prenatal exposure to 5HT enhancers in the human population.

Astragaloside IV improves slow transit constipation by regulating gut microbiota and enterochromaffin cells.

Purpose: Slow transit constipation (STC) is a common gastrointestinal disorder characterized by altered gut microbiota and reduced number of enterochromaffin cells (ECs). Astragaloside IV (AS-IV), a low drug permeability saponin, has showed beneficial effects on patients with STC. However, the specific mechanism by which AS-IV regulates STC remains unclear. In this study, we aimed to investigate the effect of AS-IV on STC and its associated mechanisms involving gut microbiota. Methods: The effect of AS-IV on STC was evaluated on STC mice induced with loperamide. We measured defecation frequency, intestinal mobility, ECs loss, and colonic lesions in STC mice treated with AS-IV. We also analyzed the changes in gut microbiota and metabolites after AS-IV treatment. Moreover, we investigated the relationship between specific gut microbes and altered fecal metabolites, such as 3-bromotyrosine (3-BrY). We also conducted in vitro experiments to investigate the effect of 3-BrY on caspase-dependent apoptosis of ECs and the activation of the p38 MAPK and ERK signaling pathways induced by loperamide. Results: AS-IV treatment promoted defecation, improved intestinal mobility, suppressed ECs loss, and alleviated colonic lesions in STC mice. AS-IV treatment also affected gut microbiota and metabolites, with a significant correlation between specific gut microbes and altered fecal metabolites such as 3-BrY. Furthermore, 3-BrY may potentially reduce caspase-dependent apoptosis of ECs and protect cell survival by inhibiting the activation of the p38 MAPK and ERK signaling pathways induced by loperamide. Conclusion: Our findings suggest that changes in gut microbiota and ECs mediated the therapeutic effect of STC by AS-IV. These results provide a basis for the use of AS-IV as a prebiotic agent for treating STC. The specific mechanism by which AS-IV regulates gut microbiota and ECs warrants further investigation.

The dimerized pentraxin-like domain of the adhesion G protein-coupled receptor 112 (ADGRG4) suggests function in sensing mechanical forces.

Adhesion G protein-coupled receptors (aGPCRs) feature large extracellular regions with modular domains that often resemble protein classes of various function. The pentraxin (PTX) domain, which is predicted by sequence homology within the extracellular region of four different aGPCR members, is well known to form pentamers and other oligomers. Oligomerization of GPCRs is frequently reported and mainly driven by interactions of the seven-transmembrane region and N or C termini. While the functional importance of dimers is well-established for some class C GPCRs, relatively little is known about aGPCR multimerization. Here, we showcase the example of ADGRG4, an orphan aGPCR that possesses a PTX-like domain at its very N-terminal tip, followed by an extremely long stalk containing serine-threonine repeats. Using X-ray crystallography and biophysical methods, we determined the structure of this unusual PTX-like domain and provide experimental evidence for a homodimer equilibrium of this domain which is Ca2+-independent and driven by intermolecular contacts that differ vastly from the known soluble PTXs. The formation of this dimer seems to be conserved in mammalian ADGRG4 indicating functional relevance. Our data alongside of theoretical considerations lead to the hypothesis that ADGRG4 acts as an in vivo sensor for shear forces in enterochromaffin and Paneth cells of the small intestine.

Stratification of enterochromaffin cells by single-cell expression analysis.

Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine (5-HT) to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify fourteen EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.

[Consideration of the Characteristics of Oral Iron Preparations from the Viewpoint of the Mechanism of Nausea and Vomiting].

The nausea and vomiting that occur as a result of oral iron administration for the treatment of iron-deficiency anemia (IDA) can cause significant physical and emotional stress in patients. Because iron is absorbed from the intestine as ferrous iron, the most widely used treatment for IDA is oral ferrous agents. However, ferrous forms are more toxic than ferric forms because ferrous forms readily generate free radicals. A randomized, double-blind, active-controlled, multicenter non-inferiority study conducted in Japan showed that ferric citrate hydrate (FC) was just as effective as sodium ferrous citrate (SF) in the treatment of IDA, with a lower incidence of adverse reactions such as nausea and vomiting compared with SF. Animal studies have shown that chemotherapy-induced nausea and vomiting (CINV) involves the release of 5-hydroxytryptamine from enterochromaffin cells by free radicals, and that some chemotherapeutic agents cause hyperplasia of these cells. Enterochromaffin cells also contain substance P, which is known to be also closely related to CINV. We found that administration of SF to rats causes hyperplasia of enterochromaffin cells in the small intestine, whereas FC has no effect on enterochromaffin cells. Oral iron agents may induce nausea and vomiting via the effect of ferrous iron on reactive oxygen species production in the intestine and subsequent enterochromaffin cell hyperplasia. Further research to elucidate the detailed mechanism of enterochromaffin cell hyperplasia induced by ferrous iron preparations is needed to develop a treatment for iron deficiency anemia that causes less gastrointestinal damage.

Lipids regulate peripheral serotonin release via gut CD1d.

The crosstalk between the immune and neuroendocrine systems is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune cells participate in gut sensation of hormones and neurotransmitters release in response to environmental cues, such as self-lipids and microbial lipids. We show here that lipid-mediated engagement of invariant natural killer T (iNKT) cells with enterochromaffin (EC) cells, a subset of intestinal epithelial cells, promoted peripheral serotonin (5-HT) release via a CD1d-dependent manner, regulating gut motility and hemostasis. We also demonstrated that inhibitory sphingolipids from symbiotic microbe Bacteroides fragilis represses 5-HT release. Mechanistically, CD1d ligation on EC cells transduced a signal and restrained potassium conductance through activation of protein tyrosine kinase Pyk2, leading to calcium influx and 5-HT secretion. Together, our data reveal that by engaging with iNKT cells, gut chemosensory cells selectively perceive lipid antigens via CD1d to control 5-HT release, modulating intestinal and systemic homeostasis.

Low-dose nafamostat mesilate ameliorates tissue injury and inhibits 5-hydroxytryptamine synthesis in the rat intestine after methotrexate administration.

We aimed to clarify the effect of nafamostat mesilate (nafamostat) on intestinal mucositis as well as the potentiation of intestinal 5-hydroxytryptamine (5-HT) dynamics induced by methotrexate, an anti-cancer drug, in rats. Rats received intraperitoneal methotrexate at 12.5 mg/kg/day for 4 days. In addition, 1, 3, or 10 mg/kg/day of nafamostat was given subcutaneously for 4 days. Ninety-six hours after the first administration of methotrexate, jejunal tissues were collected for analysis. The results showed that 1 mg/kg, but not 3 or 10 mg/kg, of nafamostat significantly ameliorated the methotrexate-induced body weight loss. Moreover, 1 mg/kg of nafamostat significantly improved methotrexate-induced mucositis, including villus atrophy. Nafamostat (1 mg/kg) significantly inhibited the methotrexate-induced mRNA expression of pro-inflammatory cytokines and cyclooxygenase-2, as well as methotrexate-induced 5-HT content and tryptophan hydroxylase (TPH) activity. In addition, it tended to inhibit the number of anti-TPH antibody-positive cells and significantly inhibited the number of anti-substance P antibody-positive cells. These findings suggest that low-dose nafamostat ameliorates tissue injury and 5-HT and substance P synthesis in methotrexate-induced mucositis. Nafamostat may be a novel therapeutic strategy for the prevention and treatment of mucositis as well as 5-HT- and/or substance P-related adverse effects in cancer chemotherapy.

Paracrine relationship between incretin hormones and endogenous 5-hydroxytryptamine in the small and large intestine.

BACKGROUND: Enterochromaffin (EC) cell-derived 5-hydroxytryptamine (5-HT) is a mediator of toxin-induced reflexes, initiating emesis via vagal and central 5-HT3 receptors. The amine is also involved in gastrointestinal (GI) reflexes that are prosecretory and promotile, and recently 5-HT's roles in chemosensation in the distal bowel have been described. We set out to establish the efficacy of 5-HT signaling, local 5-HT levels and pharmacology in discrete regions of the mouse small and large intestine. We also investigated the inter-relationships between incretin hormones, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) and endogenous 5-HT in mucosal and motility assays. METHODS: Adult mouse GI mucosae were mounted in Ussing chambers and area-specific studies were performed to establish the 5-HT3 and 5-HT4 pharmacology, the sidedness of responses, and the inter-relationships between incretins and endogenous 5-HT. Natural fecal pellet transit in vitro and full-length GI transit in vivo were also measured. KEY RESULTS: We observed the greatest level of tonic and exogenous 5-HT-induced ion transport and highest levels of 5-HT in ascending colon mucosa. Here both 5-HT3 and 5-HT4 receptors were involved but elsewhere in the GI tract epithelial basolateral 5-HT4 receptors mediate 5-HT's prosecretory effect. Exendin-4 and GIP induced 5-HT release in the ascending colon, while L cell-derived PYY also contributed to GIP mucosal effects in the descending colon. Both peptides slowed colonic transit. CONCLUSIONS & INFERENCES: We provide functional evidence for paracrine interplay between 5-HT, GLP-1 and GIP, particularly in the colonic mucosal region. Basolateral epithelial 5-HT4 receptors mediated both 5-HT and incretin mucosal responses in healthy colon.

Linking serotonin homeostasis to gut function: Nutrition, gut microbiota and beyond.

Serotonin (5-HT) produced by enterochromaffin (EC) cells in the digestive tract is crucial for maintaining gut function and homeostasis. Nutritional and non-nutritional stimuli in the gut lumen can modulate the ability of EC cells to produce 5-HT in a temporal- and spatial-specific manner that toning gut physiology and immune response. Of particular interest, the interactions between dietary factors and the gut microbiota exert distinct impacts on gut 5-HT homeostasis and signaling in metabolism and the gut immune response. However, the underlying mechanisms need to be unraveled. This review aims to summarize and discuss the importance of gut 5-HT homeostasis and its regulation in maintaining gut metabolism and immune function in health and disease with special emphasis on different types of nutrients, dietary supplements, processing, and gut microbiota. Cutting-edge discoveries in this area will provide the basis for the development of new nutritional and pharmaceutical strategies for the prevention and treatment of serotonin homeostasis-related gut and systematic disorders and diseases.

Serotonin and Melatonin in Human Lower Gastrointestinal Tract.

BACKGROUND AND AIMS: Melatonin is a ubiquitous hormone produced not only by the pineal gland but also by other organs and tissues. It is involved in the regulation of several gastrointestinal functions. The main cells responsible for the production and release of extrapineal melatonin are the enterochromaffin (EC) cells that produce serotonin. They are involved in the pathogenesis of neuromotor disorders that characterize functional gastrointestinal disorders and in the pathophysiology of inflammatory intestinal diseases. Our aim was the immunohistochemical highlighting on biopsy samples of normal gastrointestinal mucosa and in ulcerative colitis (UC) of immunoreactive cells for melatonin and serotonin in order to identify any differences in their distribution. MATERIALS AND METHODS: Our prospective case-control study involves the highlighting on human mucosal biopsies of immunoreactive cells for melatonin and serotonin. All patients undergoing colonoscopy + ileoscopy were considered eligible for the study, divided into two groups: 1. patients with active ulcerative colitis (UC); 2. control group consisting of patients undergoing endoscopic examination for colorectal cancer screening. RESULTS: Twenty-one patients were enrolled. The controls had a higher concentration of EC cells containing 5HT particularly in the rectum (p value ≤ 0.05). In patients with active colitis the expression of 5-HT-iR was greater in all tracts of the colon. The correlation analysis in UC patients shows that a higher expression of 5-HT-iR+ cells corresponds to a lower extension of the disease and a greater severity of the same. CONCLUSIONS: 5HT+ cells decreased in the case of UC compared to healthy controls. In the severe disease, there was an increase in the expression of melatonin-secreting cells, probably as a compensatory response to the inflammation and oxidative stress. This increase is negatively correlated with the extent of the disease and positively with the severity of the same.

Naringenin modulates Cobalt activities on gut motility through mechanosensors and serotonin signalling.

IntroductionCobalt chloride-(CoCl2) exerts beneficial and toxic activities depending on dose however Naringenin-(Nar) a flavonoid, chelates heavy metals. Absorption of ingested heavy metals, or chelates are dependent on gut motility (gastric emptying and intestinal transit time) and mechanosensor regulation. Literature is vague on CoCl2 activities on gut motility and mechanosensor nor probable chelating actions with naringenin which was investigated in this study.MethodOne hundred male Wistar rats were grouped viz; A to D (25, 62, 150 and 300 mg/kg CoCl2), E to H doses of CoCl2+Nar (50 mg/kg), I-Narigenin and J-Control. Gastric emptying and intestinal transit time were evaluated by day eight, intestinal tissue assayed for biochemical, histological and immunohistochemistry reactivity.ResultCoCl2 significantly increased Gastric emptying (150 and 300 mg/kg) and Intestinal transit time unlike Naringenin. CoCl2 (150 mg/kg) significantly increased Catalase and Nitric oxide but ameliorated by Naringenin. ATPase activities significantly increased in 150 mg/kg-CoCl2 but ameliorated by Naringenin. Carbonyl levels increased in all CoCl2+Nar groups. High Enterochromaffin-cell count in 25 and 62 mg/kg-CoCl2 were ameliorated by Naringenin. Serotonin immunoreactivity increased in CoCl2 (25, 62, 300 mg/kg) but reduced in CoCl2+Nar groups.ConclusionCobalt chloride enhanced gastric motility via increased mechanosensor activities and serotonin expression at low doses. Naringenin ameliorated toxicity of high cobalt chloride via metal-flavonoid chelates.

Serotonergic Paracrine Targets in the Intestinal Mucosa.

Serotonin functions as a neurotransmitter in the enteric nervous system. Aside from its neurotransmitter role, serotonin also is a paracrine mediatorial signal in the digestive tract. It is a major paracrine signaling molecule in the integrated physiology of several classes of cells in the intestinal mucosa. Paracrine action can be initiation or suppression of activity in populations of cells that make up divergent phenotypic classes. This underlies phenotypic plasticity in single classes and links single classes to other neighboring phenotypic classes, thereby forming a single and higher-order organization in which different categories of function are integrated to work in harmony as a single homeostatic entity at higher levels of physiological organization. Phenotypic classes of cells that are linked by serotonergic paracrine signaling at upper levels of functional organization in the small intestine are (1) enterochromaffin cells; (2) enteric mast cells; (3) spinal sensory afferents; (4) sympathetic postganglionic neurons; (5) enteric neurons.

Ferric Citrate Hydrate Has Little Impact on Hyperplasia of Enterochromaffin Cells in the Rat Small Intestine Compared to Sodium Ferrous Citrate.

INTRODUCTION: The most detrimental factor preventing the use of oral iron in the treatment of iron deficiency anemia is gastrointestinal side effects accompanied by nausea and vomiting. Anorexia is a known secondary effect of nausea and vomiting. The important gastrointestinal signaling molecule 5-hydroxytryptamine (5-HT) is critically involved in not only physiological function but also nausea and vomiting. The present study was designed to compare the effects of the administration of sodium ferrous citrate (SF) and ferric citrate hydrate (FC) to rats on anorexia and hyperplasia of enterochromaffin cells, which mainly synthesize and store 5-HT. METHODS: Rats received either SF (3 or 30 mg/kg/day) or FC (30 mg/kg/day) orally for 4 days. Food and water intakes were measured every 24 h during the study. At 96 h after the first administration of the oral iron preparation, the duodenal and jejunal tissues were collected for analysis. Enterochromaffin cells were detected by immunohistochemical analysis. RESULTS: Administration of 3 mg/kg SF had no effect on anorexia but led to increased hyperplasia of enterochromaffin cells in the duodenum (p < 0.1). Administration of 30 mg/kg SF significantly decreased food and water intakes and significantly increased hyperplasia of enterochromaffin cells in the duodenum and jejunum. Alternatively, administration of 30 mg/kg FC had no significant effect on food and water intakes or hyperplasia of enterochromaffin cells. CONCLUSION: The lower impact on the hyperplasia of enterochromaffin cells of FC compared to SF may contribute to the maintenance of rats' physical condition.

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

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.

Peripheral serotonin: cultivating companionship with gut microbiota in intestinal homeostasis.

Serotonin, also known as 5-hydroxytryptamine (5-HT), is an evolutionarily ancient and phylogenetically conserved monoamine that regulates multifaceted physiological functions in mammals. 5-HT was, at one time, most extensively studied as a neurotransmitter within the central nervous system but is now known to regulate nonneuronal functions including immune responses in an autocrine-paracrine-endocrine manner. Compelling evidence from intervention studies using germ-free mice or antibiotic-associated microbiota perturbation suggests that novel interactions between 5-HT and the gut microbiota are essential in maintaining intestinal homeostasis. Importantly, recent studies reveal that bidirectional host-microbial interactions mediated by the host serotonergic system can promote distinct changes within the gut microbiota. These changes may potentially lead to a state known as "dysbiosis" that has been strongly associated with various gut pathologies including inflammatory bowel disease (IBD). In this review, we update the current understanding of host-microbiota interaction by focusing on the impact of peripheral 5-HT signaling within this dynamic. We also briefly highlight key environmental risk factors for IBD, such as the Western diet, and draw attention to the interaction of synthetic food colorants with 5-HT signaling that may facilitate future research.

Refractory iron deficiency anemia as an early manifestation of autoimmune gastritis in a teenager / Anemia ferropénica refractaria como presentación temprana de gastritis autoinmune en un adolescente

Abstract Autoimmune gastritis is an underdiagnosed disease in the pediatric population due to the absence of specific signs and symptoms and late clinical manifestations. Iron deficiency anemia has recently been identified as an early hematological manifestation, allowing an early diagnostic approach. We present the case of a Colombian teenager, with no history of autoimmunity, with refractory iron deficiency. He underwent extension studies; biopsies and serology compatible with autoimmune gastritis were documented, requiring parenteral iron in its evolution. This pathology is underdiagnosed in our context since early diagnosis requires a high index of suspicion to prevent associated complications.

Resumen La gastritis autoinmune es una enfermedad subdiagnosticada en la población pediátrica. Lo anterior se debe a la ausencia de signos y síntomas específicos y manifestaciones clínicas tardías. Recientemente se ha identificado la anemia ferropénica como una manifestación hematológica precoz, lo que permite un enfoque diagnóstico temprano. Se presenta el caso de un adolescente colombiano, sin antecedentes de autoinmunidad, con ferropenia refractaria, en el que se realizaron estudios de extensión y se documentaron biopsias y serología compatible con gastritis autoinmune, con requerimiento de hierro parenteral en su evolución. Esta patología es subdiagnosticada en nuestro medio, ya que el diagnóstico temprano requiere un alto índice de sospecha, lo que permite la prevención de las complicaciones asociadas.

Not Only COVID-19: Involvement of Multiple Chemosensory Systems in Human Diseases.

Chemosensory systems are deemed marginal in human pathology. In appraising their role, we aim at suggesting a paradigm shift based on the available clinical and experimental data that will be discussed. Taste and olfaction are polymodal sensory systems, providing inputs to many brain structures that regulate crucial visceral functions, including metabolism but also endocrine, cardiovascular, respiratory, and immune systems. Moreover, other visceral chemosensory systems monitor different essential chemical parameters of "milieu intérieur," transmitting their data to the brain areas receiving taste and olfactory inputs; hence, they participate in regulating the same vital functions. These chemosensory cells share many molecular features with olfactory or taste receptor cells, thus they may be affected by the same pathological events. In most COVID-19 patients, taste and olfaction are disturbed. This may represent only a small portion of a broadly diffuse chemosensory incapacitation. Indeed, many COVID-19 peculiar symptoms may be explained by the impairment of visceral chemosensory systems, for example, silent hypoxia, diarrhea, and the "cytokine storm". Dysregulation of chemosensory systems may underlie the much higher mortality rate of COVID-19 Acute Respiratory Distress Syndrome (ARDS) compared to ARDSs of different origins. In chronic non-infectious diseases like hypertension, diabetes, or cancer, the impairment of taste and/or olfaction has been consistently reported. This may signal diffuse chemosensory failure, possibly worsening the prognosis of these patients. Incapacitation of one or few chemosensory systems has negligible effects on survival under ordinary life conditions but, under stress, like metabolic imbalance or COVID-19 pneumonia, the impairment of multiple chemosensory systems may lead to dire consequences during the course of the disease.

A Focus on Enterochromaffin Cells among the Enteroendocrine Cells: Localization, Morphology, and Role.

The intestinal epithelium plays a key role in managing the relationship with the environment, the internal and external inputs, and their changes. One percent of the gut epithelium is represented by the enteroendocrine cells. Among the enteroendocrine cells, a group of specific cells characterized by the presence of yellow granules, the enterochromaffin cells, has been identified. These granules contain many secretion products. Studies showed that these cells are involved in gastrointestinal inflammatory conditions and hyperalgesia; their number increases in these conditions both in affected and not-affected zones of the gut. Moreover, they are involved in the preservation and modulation of the intestinal function and motility, and they sense metabolic-nutritional alterations. Sometimes, they are confused or mixed with other enteroendocrine cells, and it is difficult to define their activity. However, it is known that they change their functions during diseases; they increased in number, but their involvement is related mainly to some secretion products (serotonin, melatonin, substance P). The mechanisms linked to these alterations are not well investigated. Herein, we provide an up-to-date highlight of the main findings about these cells, from their discovery to today. We emphasized their origin, morphology, and their link with diet to better evaluate their role for preventing or treating metabolic disorders considering that these diseases are currently a public health burden.

Potential Roles of Enterochromaffin Cells in Early Life Stress-Induced Irritable Bowel Syndrome.

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.

Distinguishing the contributions of neuronal and mucosal serotonin in the regulation of colonic motility.

BACKGROUND: Specialized enterochromaffin (EC) cells within the mucosal lining of the gut synthesize and secrete almost all serotonin (5-hydroxytryptamine, 5-HT) in the body. Significantly lower amounts of 5-HT are made by other peripheral tissues and serotonergic neurons within the enteric nervous system (ENS). EC cells are in close proximity to 5-HT receptors in the ENS, and the role of 5-HT as a modulator of gut motility, particularly colonic motor complexes, has been well defined. However, the relative contribution of neuronal 5-HT to this process under resting and stimulus-evoked conditions is unclear. METHODS: In this study, we combined the use of the selective serotonin transporter (SERT) inhibitor, fluoxetine, with two models of mucosal 5-HT depletion-surgical removal of the mucosa and our Tph1Cre/ERT2 ; Rosa26DTA mouse line-to determine the relative contribution of neuronal and mucosal 5-HT to resting and distension-evoked colonic motility. KEY RESULTS: Fluoxetine significantly reduced the frequency of colonic migrating complexes (CMCs) in flat-sheet preparations with the mucosa present and in intact control Tph1-DTA colons in which EC cells were present. No such effect was observed in mucosa-free preparations or in intact Tph1-DTA preparations lacking EC cell 5-HT. CONCLUSIONS AND INFERENCES: We demonstrate that mucosal 5-HT release plays an important role in distension-evoked colonic motility, and that SERT inhibition no longer alters gut motility when EC cells are absent, thus demonstrating that ENS 5-HT does not play a role in regulating gut motility.