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PURPOSE OF REVIEW: Gastrointestinal (GI) dysfunction limits enteral nutrition (EN) delivery in critical illness and contributes to systemic inflammation. The enteroendocrine (EE) axis plays an integral role in this interface between nutrition, inflammation, and GI function in critical illness. In this review, we present an overview of the EE system with a focus on its role in GI inflammation and function. RECENT FINDINGS: Enteroendocrine cells have been primarily described in their role in macronutrient digestion and absorption. Recent research has expanded on the diverse functions of EE cells including their ability to sense microbial peptides and metabolites and regulate immune function and inflammation. Therefore, EE cells may be both affected by and contribute to many pathophysiologic states and interventions of critical illness such as dysbiosis , inflammation, and alternative EN strategies. In this review, we present an overview of EE cells including their growing role in nonnutrient functions and integrate this understanding into relevant aspects of critical illness with a focus on EN. SUMMARY: The EE system is key in maintaining GI homeostasis in critical illness, and how it is impacted and contributes to outcomes in the setting of dysbiosis , inflammation and different feeding strategies in critical illness should be considered.
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Estado Terminal , Nutrição Enteral , Células Enteroendócrinas , Inflamação , Humanos , Inflamação/fisiopatologia , Células Enteroendócrinas/fisiologia , Disbiose/fisiopatologia , Trato Gastrointestinal/fisiopatologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/fisiologia , Microbioma Gastrointestinal/fisiologia , Gastroenteropatias/fisiopatologia , Estado Nutricional/fisiologiaRESUMO
Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient - but not GUCY2C-deficient - neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling in VP that was comparable with chemically induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes.
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Células Enteroendócrinas , Receptores de Enterotoxina , Dor Visceral , Animais , Humanos , Camundongos , GMP Cíclico/metabolismo , Células Enteroendócrinas/metabolismo , Células Enteroendócrinas/fisiologia , Intestinos/metabolismo , Intestinos/fisiologia , Receptores de Enterotoxina/metabolismo , Receptores Acoplados a Guanilato Ciclase/metabolismo , Transdução de Sinais/fisiologia , Dor Visceral/genética , Dor Visceral/metabolismoRESUMO
Gut hormones produced and released from enteroendocrine cells have key roles not only in nutrient digestion and absorption, but also in control of appetite, nutrient deposition and storage in the body. Several types of enteroendocrine cells sense nutrients after meal ingestion and release specific gut hormones. Understanding how gut hormone responses are controlled and in turn regulate physiological outcomes is an area of active research. In addition, the role of the endocrine system in human-physiology and in pathophysiology (obesity, diabetes, and gastrointestinal diseases) has begun being investigated. The symposium was organized to present and discuss recent advances in this research field from the aspects of bench to bedside.
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Hormônios Gastrointestinais , Trato Gastrointestinal , Humanos , Células Enteroendócrinas/fisiologia , Hormônios Gastrointestinais/fisiologia , Nutrientes , ApetiteRESUMO
Initial nutritional stimulation is a key driving force for small intestinal maturation. In chick embryos, administration of l-glutamine (Gln) into the amniotic fluid stimulates early development of the small intestinal epithelium by promoting enterocyte differentiation. In this study, we evaluated the effects of intra-amniotic administration of Gln on enterocyte morphology and function, and elucidated a potential enteroendocrine pathway through which Gln stimulates small intestinal maturation. Our results show that Gln stimulation at embryonic day 17 significantly increased enterocyte and microvilli dimensions by 10 and 20%, respectively, within 48 h. Post-hatch, enterocytes and microvilli were 20% longer in Gln-treated chicks. Correspondingly, Gln stimulation significantly upregulated mRNA expression of brush border nutrient transporters PepT-1 and SGLT-1 and tight junction proteins TJP-1 and TJP-2, before and after hatch (P < 0.05). Since GLP-2 signaling from intestinal L-cells is associated with enterocyte growth, functionality and integrity, we examined the effects of Gln stimulation on mRNA expression of key hormones and receptors within this enteroendocrine pathway and found significant increases in GLP-2R, IGF-1 and IGF-1R expression before and after hatch (P < 0.05). In conclusion, our findings link primary nutrient stimulation in the developing small intestine with enterocyte morphological and functional maturation and enteroendocrine signaling.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Embrião de Galinha/embriologia , Células Enteroendócrinas/efeitos dos fármacos , Glutamina/administração & dosagem , Glutamina/farmacologia , Mucosa Intestinal/embriologia , Mucosa Intestinal/crescimento & desenvolvimento , Intestino Delgado/embriologia , Intestino Delgado/crescimento & desenvolvimento , Líquido Amniótico , Animais , Embrião de Galinha/citologia , Embrião de Galinha/metabolismo , Células Enteroendócrinas/metabolismo , Células Enteroendócrinas/fisiologia , Receptor do Peptídeo Semelhante ao Glucagon 2/metabolismo , Injeções , Fator de Crescimento Insulin-Like I/metabolismo , Receptor IGF Tipo 1/metabolismo , Estimulação QuímicaRESUMO
PURPOSE OF REVIEW: The intestinal enteroendocrine cells (EECs) are specialized hormone-secreting cells that respond to both circulating and luminal cues. Collectively, EECs constitute the largest endocrine organ of the body and signal to a multitude of targets including locally to neighboring intestinal cells, enteric neurons, as well as systemically to other organs, such as the pancreas and brain. To accomplish their wide range of downstream signaling effects, EECs secrete multiple hormones; however, the mechanisms that influence EEC development in the embryo and differentiation in adults are not well defined. RECENT FINDINGS: This review highlights the recent discoveries in EEC differentiation and function while also discussing newly revealed roles of transcription factors and signaling networks involved in the allocation of EEC subtypes that were discovered using a combination of novel intestinal model systems and genetic sequencing. We also discuss the potential of these new experimental models that study the mechanisms regulating EEC function and development both to uncover novel therapeutic targets. SUMMARY: Several EEC hormones are being used to treat various metabolic disorders, such as type 2 diabetes and obesity. Therefore, understanding the signaling pathways and gene regulatory networks that facilitate EEC formation is paramount to the development of novel therapies.
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Diabetes Mellitus Tipo 2 , Diferenciação Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Enteroendócrinas/fisiologia , Hormônios , Humanos , IntestinosRESUMO
BACKGROUND AND AIMS: The gastrointestinal (GI) tract extracts nutrients from ingested meals while protecting the organism from infectious agents frequently present in meals. Consequently, most animals conduct the entire digestive process within the GI tract while keeping the luminal contents entirely outside the body, separated by the tightly sealed GI epithelium. Therefore, like the skin and oral cavity, the GI tract must sense the chemical and physical properties of the its external interface to optimize its function. Specialized sensory enteroendocrine cells (EECs) in GI epithelium interact intimately with luminal contents. A subpopulation of EECs express the mechanically gated ion channel Piezo2 and are developmentally and functionally like the skin's touch sensor- the Merkel cell. We hypothesized that Piezo2+ EECs endow the gut with intrinsic tactile sensitivity. METHODS: We generated transgenic mouse models with optogenetic activators in EECs and Piezo2 conditional knockouts. We used a range of reference standard and novel techniques from single cells to living animals, including single-cell RNA sequencing and opto-electrophysiology, opto-organ baths with luminal shear forces, and in vivo studies that assayed GI transit while manipulating the physical properties of luminal contents. RESULTS: Piezo2+ EECs have transcriptomic features of synaptically connected, mechanosensory epithelial cells. EEC activation by optogenetics and forces led to Piezo2-dependent alterations in colonic propagating contractions driven by intrinsic circuitry, with Piezo2+ EECs detecting the small luminal forces and physical properties of the luminal contents to regulate transit times in the small and large bowel. CONCLUSIONS: The GI tract has intrinsic tactile sensitivity that depends on Piezo2+ EECs and allows it to detect luminal forces and physical properties of luminal contents to modulate physiology.
Assuntos
Células Enteroendócrinas/metabolismo , Mucosa Intestinal/metabolismo , Canais Iônicos/genética , Tato/fisiologia , Animais , Células Enteroendócrinas/fisiologia , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Técnicas de Inativação de Genes , Mucosa Intestinal/citologia , Mucosa Intestinal/fisiologia , Canais Iônicos/metabolismo , Mecanorreceptores , Camundongos , Camundongos Transgênicos , Optogenética , Peristaltismo/fisiologiaRESUMO
Intestinal organoids are used to analyze the differentiation of enteroendocrine cells (EECs) and to manipulate their density for treating type 2 diabetes. EEC differentiation is a continuous process tightly regulated in the gut by a complex regulatory network. However, the effect of chronic hyperglycemia, in the modulation of regulatory networks controlling identity and differentiation of EECs, has not been analyzed. This study aimed to investigate the effect of glucotoxicity on EEC differentiation in small intestinal organoid platforms. Mouse intestinal organoids were cultured in the presence/absence of high glucose concentrations (35 mM) for 48 h to mimic glucotoxicity. Chronic hyperglycemia impaired the expression of markers related to the differentiation of EEC progenitors (Ngn3) and L-cells (NeuroD1), and it also reduced the expression of Gcg and GLP-1 positive cell number. In addition, the expression of intestinal stem cell markers was reduced in organoids exposed to high glucose concentrations. Our data indicate that glucotoxicity impairs L-cell differentiation, which could be associated with decreased intestinal stem cell proliferative capacity. This study provides the identification of new targets involved in new molecular signaling mechanisms impaired by glucotoxicity that could be a useful tool for the treatment of type 2 diabetes.
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Diferenciação Celular , Células Enteroendócrinas/metabolismo , Hiperglicemia/complicações , Intestino Delgado/metabolismo , Organoides , Animais , Diabetes Mellitus Tipo 2/complicações , Células Enteroendócrinas/efeitos dos fármacos , Células Enteroendócrinas/fisiologia , Glucose/metabolismo , Glucose/toxicidade , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/fisiopatologia , Células L , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de SinaisRESUMO
The primary functions of the gastrointestinal (GI) tract are to absorb nutrients, water, and electrolytes that are essential for life. This is accompanied by the capability of the GI tract to mix ingested content to maximize absorption and effectively excrete waste material. There have been major advances in understanding intrinsic neural mechanisms involved in GI motility. This review highlights major advances over the past few decades in our understanding of colonic motor complexes (CMCs), the major intrinsic neural patterns that control GI motility. CMCs are generated by rhythmic coordinated firing of large populations of myenteric neurons. Initially, it was thought that serotonin release from the mucosa was required for CMC generation. However, careful experiments have now shown that neither the mucosa nor endogenous serotonin are required, although, evidence suggests enteroendocrine (EC) cells modulate CMCs. The frequency and extent of propagation of CMCs are highly dependent on mechanical stimuli (circumferential stretch). In summary, the isolated mouse colon emerges as a good model to investigate intrinsic mechanisms underlying colonic motility and provides an excellent preparation to explore potential therapeutic agents on colonic motility, in a highly controlled in vitro environment. In addition, during CMCs, the mouse colon facilitates investigations into the emergence of dynamic assemblies of extensive neural networks, applicable to the nervous system of different organisms.
Assuntos
Colo/fisiologia , Sistema Nervoso Entérico/fisiologia , Motilidade Gastrointestinal/fisiologia , Músculo Liso/fisiologia , Animais , Células Enteroendócrinas/fisiologia , Trato Gastrointestinal/fisiologia , Camundongos , Complexo Mioelétrico Migratório/fisiologia , Neurônios/fisiologiaRESUMO
BACKGROUND & AIMS: Transient expression of Neurog3 commits intestinal secretory progenitors to become enteroendocrine-biased progenitors and hence drive enteroendocrine differentiation. Loss of Neurog3 in mouse resulted in the depletion of intestinal enteroendocrine cells (EECs) and an increase in goblet cells. Earlier studies in developing mouse pancreas identified a role of Neurog3 gene dosage in endocrine and exocrine cell fate allocation. We aimed to determine whether Neurog3 gene dosage controls fate choice of enteroendocrine progenitors. METHODS: We acquired mutant Neurog3 reporter mice carrying 2, 1, or null Neurog3 alleles to study Neurog3 gene dosage effect by lineage tracing. Cell types arising from Neurog3+ progenitors were determined by immunohistochemistry using antibodies against intestinal lineage-specific markers. RNA sequencing of sorted Neurog3+/+, Neurog3+/-, or bulk intestinal cells were performed and differentially expressed genes were analyzed. RESULTS: We identified 2731 genes enriched in sorted Neurog3+/+-derived cells in the Neurog3+/+EYFP mouse intestine when compared with bulk duodenum epithelial cells. In the intestine of Neurog3+/-EGFP heterozygous mouse, we observed a 63% decrease in EEC numbers. Many Neurog3-derived cells stained for goblet marker Mucin 2. RNA sequencing of sorted Neurog3+/- cells uncovered enriched expression of genes characteristic for both goblet and enteroendocrine cells, indicating the mixed lineages arose from Neurog3+ progenitors. Consistent with this hypothesis, deletion of both Neurog3 alleles resulted in the total absence of EECs. All Neurog3+-derived cells stained for Mucin 2. CONCLUSIONS: We identified that the fate of Neurog3+ enteroendocrine progenitors is dependent on Neurog3 gene dosage. High Neurog3 gene dosage enforces the commitment of secretory progenitors to an EE lineage, while constraining their goblet cell lineage potential. Transcriptome profiling data was deposited to Gene Ontology omnibus, accession number: GSE149203.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/genética , Células Enteroendócrinas/fisiologia , Células Caliciformes/fisiologia , Proteínas do Tecido Nervoso/genética , Animais , Linhagem da Célula , Dosagem de Genes , Mucosa Intestinal/citologia , Camundongos , Camundongos Transgênicos , RNA-SeqRESUMO
The intestinal epithelium senses nutritional and microbial stimuli using epithelial sensory enteroendocrine cells (EEC). EECs communicate nutritional information to the nervous system, but whether they also relay signals from intestinal microbes remains unknown. Using in vivo real-time measurements of EEC and nervous system activity in zebrafish, we discovered that the bacteria Edwardsiella tarda activate EECs through the receptor transient receptor potential ankyrin A1 (Trpa1) and increase intestinal motility. Microbial, pharmacological, or optogenetic activation of Trpa1+EECs directly stimulates vagal sensory ganglia and activates cholinergic enteric neurons by secreting the neurotransmitter 5-hydroxytryptamine (5-HT). A subset of indole derivatives of tryptophan catabolism produced by E. tarda and other gut microbes activates zebrafish EEC Trpa1 signaling. These catabolites also directly stimulate human and mouse Trpa1 and intestinal 5-HT secretion. These results establish a molecular pathway by which EECs regulate enteric and vagal neuronal pathways in response to microbial signals.
Assuntos
Edwardsiella tarda/metabolismo , Sistema Nervoso Entérico/metabolismo , Células Enteroendócrinas/fisiologia , Mucosa Intestinal/metabolismo , Canal de Cátion TRPA1/metabolismo , Animais , Animais Geneticamente Modificados , Neurônios Colinérgicos/metabolismo , Sistema Nervoso Entérico/citologia , Motilidade Gastrointestinal/fisiologia , Mucosa Intestinal/citologia , Mucosa Intestinal/inervação , Proteínas Proto-Oncogênicas c-ret/genética , Serotonina/metabolismo , Transdução de Sinais , Triptofano/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genéticaRESUMO
The recent intersection of enteroendocrine cell biology with single-cell technologies and novel in vitro model systems has generated a tremendous amount of new data. Here we highlight these recent developments and explore how these findings contribute to the understanding of endocrine lineages in the gut. In particular, the concept of hormonal plasticity, the ability of endocrine cells to produce different hormones over the course of their lifetime, challenges the classic notion of cell types. Enteroendocrine cells travel in the course of their life through different signaling environments that directly influence their hormonal repertoire. In this context, we examine how enteroendocrine cell fate is determined and modulated by signaling molecules such as bone morphogenetic proteins (BMPs) or location along the gastrointestinal tract. We analyze advantages and disadvantages of novel in vitro tools, adult stem cell or iPS-derived intestinal organoids, that have been crucial for recent findings on enteroendocrine development and plasticity. Finally, we illuminate the future perspectives of the field and discuss how understanding enteroendocrine plasticity can lead to new therapeutic approaches.
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Células-Tronco Adultas , Células Enteroendócrinas/fisiologia , Trato Gastrointestinal/fisiologia , Hormônios/metabolismo , Células-Tronco Pluripotentes Induzidas , Modelos Biológicos , Organoides , Animais , Células Cultivadas , Células Enteroendócrinas/citologia , Células Enteroendócrinas/metabolismo , Trato Gastrointestinal/citologia , Trato Gastrointestinal/metabolismo , HumanosRESUMO
The pathophysiology of irritable bowel syndrome (IBS) is not completely understood. However, several factors are known to play a role in pathophysiology of IBS such as genetics, diet, gut microbiota, gut endocrine cells, stress and low-grade inflammation. Understanding the pathophysiology of IBS may open the way for new treatment approaches. Low density of intestinal stem cells and low differentiation toward enteroendocrine cells has been reported recently in patients with IBS. These abnormalities are believed to be the cause of the low density of enteroendocrine cells seen in patients with IBS. Enteroendocrine cells regulate gastrointestinal motility, secretion, absorption and visceral sensitivity. Gastrointestinal dysmotility, abnormal absorption/secretion and visceral hypersensitivity are all seen in patients with IBS and haven been attributed to the low density the intestinal enteroendocrine cells in these patients. The present review conducted a literature search in Medline (PubMed) covering the last ten years until November 2019, where articles in English were included. Articles about the intestinal stem cells and their possible role in the pathophysiology of IBS are discussed in the present review. The present review discusses the assumption that intestinal stem cells play a central role in the pathophysiology of IBS and that the other factors known to contribute to the pathophysiology of IBS such as genetics, diet gut microbiota, stress, and low-grade inflammation exert their effects through affecting the intestinal stem cells. It reports further the data that support this assumption on genetics, diet, gut microbiota, stress with depletion of glutamine, and inflammation.
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Células Enteroendócrinas/fisiologia , Intestinos/citologia , Síndrome do Intestino Irritável/fisiopatologia , Células-Tronco/fisiologia , Diferenciação Celular , Motilidade Gastrointestinal/fisiologia , HumanosRESUMO
The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut-brain axis.
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Sistema Nervoso Entérico/fisiologia , Motilidade Gastrointestinal/fisiologia , Sensação/fisiologia , Células Receptoras Sensoriais/fisiologia , Vias Aferentes/fisiologia , Fibras Autônomas Pré-Ganglionares/fisiologia , Vias Eferentes/fisiologia , Sistema Nervoso Entérico/metabolismo , Células Enteroendócrinas/metabolismo , Células Enteroendócrinas/fisiologia , Humanos , Mecanotransdução Celular/fisiologia , Complexo Mioelétrico Migratório/fisiologia , Vias Neurais/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Neurotransmissores/metabolismo , Células Receptoras Sensoriais/metabolismo , Serotonina/metabolismoRESUMO
Advances in single-cell RNA-seq (scRNA-seq) and computational analysis have enabled the systematic interrogation of the cellular composition of tissues. Combined with tools from developmental biology, cell biology, and genetics, these approaches are revealing fundamental aspects of tissue geometry and physiology, including the distribution, origins, and inferred functions of specialized cell types, and the dynamics of cellular turnover and differentiation. By comparing different tissues, such studies can delineate shared and specialized features of cell types and their lineage. Here, we compare two developmentally related murine epithelia, the airway and the small intestinal epithelia, which are both derived from the embryonic endodermal gut tube. We examine how airway and intestine generate and functionalize common archetypal cell types to fulfill similar shared physiologic functionalities. We point to cases in which similar cell types are repurposed to accommodate each tissue's unique physiologic role, and highlight tissue-specific cells whose specializations contribute to the distinct functional roles of each organ. We discuss how archetypal and unique cell types are incorporated within a cellular lineage, and how the regulation of the proportions of these cell types enables tissue-level organization to meet functional demands and maintain homeostasis.
Assuntos
Diferenciação Celular/fisiologia , Células Enteroendócrinas/fisiologia , Mucosa Intestinal/citologia , Células Neuroendócrinas/fisiologia , Mucosa Respiratória/citologia , Animais , Mucosa Intestinal/crescimento & desenvolvimento , Camundongos , Mucosa Respiratória/crescimento & desenvolvimentoRESUMO
OBJECTIVES: Gastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the postoperative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release. METHODS: A specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after, and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA sequencing, mass-spectrometry and in situ hybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying glucose-induced secretin secretion and to study direct effects of secretin on glucagon, insulin, and somatostatin secretion. Secretin was administered alone or in combination with GLP-1 to non-sedated rats to evaluate effects on glucose regulation. RESULTS: Plasma postprandial secretin was more than doubled in humans after RYGB (P < 0.001). The distal small intestine harbored secretin expressing cells in both rats and humans. Glucose increased the secretion of secretin in a sodium-glucose cotransporter dependent manner when administered to the distal part but not into the proximal part of the rat small intestine. Secretin stimulated somatostatin secretion (fold change: 1.59, P < 0.05) from the perfused rat pancreas but affected neither insulin (P = 0.2) nor glucagon (P = 0.97) secretion. When administered to rats in vivo, insulin secretion was attenuated and glucagon secretion increased (P = 0.04), while blood glucose peak time was delayed (from 15 to 45 min) and gastric emptying time prolonged (P = 0.004). CONCLUSIONS: Glucose-sensing secretin cells located in the distal part of the small intestine may contribute to increased plasma concentrations observed after RYGB. The metabolic role of the distal S cells warrants further studies.
Assuntos
Células Enteroendócrinas , Derivação Gástrica , Glucose/metabolismo , Intestino Delgado/citologia , Animais , Células Enteroendócrinas/metabolismo , Células Enteroendócrinas/fisiologia , Masculino , Período Pós-Prandial/fisiologia , Ratos , Ratos WistarRESUMO
Guided by sight, scent, texture, and taste, animals ingest food. Once ingested, it is up to the gut to make sense of the food's nutritional value. Classic sensory systems rely on neuroepithelial circuits to convert stimuli into signals that guide behavior. However, sensation of the gut milieu was thought to be mediated only by the passive release of hormones until the discovery of synapses in enteroendocrine cells. These are gut sensory epithelial cells, and those that form synapses are referred to as neuropod cells. Neuropod cells provide the foundation for the gut to transduce sensory signals from the intestinal milieu to the brain through fast neurotransmission onto neurons, including those of the vagus nerve. These findings have sparked a new field of exploration in sensory neurobiology-that of gut-brain sensory transduction.
Assuntos
Encéfalo/fisiologia , Células Enteroendócrinas/fisiologia , Sinapses/fisiologia , Nervo Vago/fisiologia , Animais , Humanos , Neurônios/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein-coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of Gcg and transcription factors Ngn3 and NeuroD1 L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo. Further mechanistic examination revealed that the effect of L3740 on L cells required intact GLP-1 receptor and serotonin 5-hydroxytryptamine receptor 4 (5-HT4) signaling. Importantly, serotonin signaling through 5-HT4 mimicked the effects of L3740, acting downstream of GLP-1. Thus, GPBAR1 agonists and other powerful GLP-1 secretagogues facilitate L-cell differentiation through a paracrine GLP-1-dependent and serotonin-mediated mechanism.
Assuntos
Ácidos e Sais Biliares/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Enteroendócrinas/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Comunicação Parácrina/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Serotonina/metabolismo , Animais , Células Enteroendócrinas/fisiologia , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Camundongos , Comunicação Parácrina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Detection of nutritional and noxious food components in the gut is a crucial component of gastrointestinal function. Contents in the gut lumen interact with enteroendocrine cells dispersed throughout the gut epithelium. Enteroendocrine cells release many different hormones, neuropeptides, and neurotransmitters that communicate either directly or indirectly with the central nervous system and the enteric nervous system, a network of neurons and glia located within the gut wall. Several populations of enteric neurons extend processes that innervate the gastrointestinal lamina propria; however, how these processes develop and begin to transmit information from the mucosa is not fully understood. In this study, we found that Tuj1-immunoreactive neurites begin to project out of the myenteric plexus at embryonic day (E)13.5 in the mouse small intestine, even before the formation of villi. Using live calcium imaging, we discovered that neurites were capable of transmitting electrical information from stimulated villi to the plexus by E15.5. In unpeeled gut preparations where all layers were left intact, we also mimicked the basolateral release of 5-HT from enteroendocrine cells, which triggered responses in myenteric cell bodies at postnatal day (P)0. Altogether, our results show that enteric neurons extend neurites out of the myenteric plexus early during mouse enteric nervous system development, innervating the gastrointestinal mucosa, even before villus formation in mice of either sex. Neurites are already able to conduct electrical information at E15.5, and responses to 5-HT develop postnatally.NEW & NOTEWORTHY How enteric neurons project into the gut mucosa and begin to communicate with the epithelium during development is not known. Our study shows that enteric neurites project into the lamina propria as early as E13.5 in the mouse, before development of the submucous plexus and before formation of intestinal villi. These neurites are capable of transmitting electrical signals back to their cell bodies by E15.5 and respond to serotonin applied to neurite terminals by birth.
Assuntos
Mucosa Intestinal/inervação , Intestino Delgado/inervação , Microvilosidades/fisiologia , Plexo Mientérico/crescimento & desenvolvimento , Neuritos/fisiologia , Neurogênese , Animais , Células Enteroendócrinas/metabolismo , Células Enteroendócrinas/fisiologia , Potenciais Evocados , Feminino , Idade Gestacional , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plexo Mientérico/efeitos dos fármacos , Plexo Mientérico/metabolismo , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Serotonina/farmacologia , Tubulina (Proteína)/metabolismoRESUMO
BACKGROUND & AIMS: The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis. It was recently shown that EEC progenitors contribute to intestinal epithelial growth and renewal, but the underlying mechanisms remain poorly understood. MicroRNAs are under-explored along the entire EEC lineage trajectory, and comparatively little is known about their contributions to intestinal homeostasis. METHODS: We leverage unbiased sequencing and eight different mouse models and sorting methods to identify microRNAs enriched along the EEC lineage trajectory. We further characterize the functional role of EEC progenitor-enriched miRNA, miR-7, by in vivo dietary study as well as ex vivo enteroid in mice. RESULTS: First, we demonstrate that miR-7 is highly enriched across the entire EEC lineage trajectory and is the most enriched miRNA in EEC progenitors relative to Lgr5+ intestinal stem cells. Next, we show in vivo that in EEC progenitors miR-7 is dramatically suppressed under dietary conditions that favor crypt division and suppress EEC abundance. We then demonstrate by functional assays in mouse enteroids that miR-7 exerts robust control of growth, as determined by budding (proxy for crypt division), EdU and PH3 staining, and likely regulates EEC abundance also. Finally, we show by single-cell RNA sequencing analysis that miR-7 regulates Xiap in progenitor/stem cells and we demonstrate in enteroids that the effects of miR-7 on mouse enteroid growth depend in part on Xiap and Egfr signaling. CONCLUSIONS: This study demonstrates for the first time that EEC progenitor cell-enriched miR-7 is altered by dietary perturbations and that it regulates growth in enteroids via intact Xiap and Egfr signaling.
Assuntos
Células Enteroendócrinas/fisiologia , Proteínas Inibidoras de Apoptose/genética , Mucosa Intestinal/fisiologia , MicroRNAs/metabolismo , Células-Tronco/fisiologia , Animais , Linhagem da Célula/genética , Proliferação de Células/genética , Células Cultivadas , Biologia Computacional , Receptores ErbB/metabolismo , Comportamento Alimentar/fisiologia , Feminino , Proteínas Inibidoras de Apoptose/metabolismo , Mucosa Intestinal/citologia , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Organoides , Cultura Primária de Células , RNA-Seq , Transdução de Sinais/genética , Análise de Célula ÚnicaRESUMO
Enteroendocrine cells (EECs) in the intestine regulate many aspects of whole-body physiology and metabolism. EECs sense luminal and circulating nutrients and respond by secreting hormones that act on multiple organs and organ systems, such as the brain, gallbladder, and pancreas, to control satiety, digestion, and glucose homeostasis. In addition, EECs act locally, on enteric neurons, endothelial cells, and the gastrointestinal epithelium, to facilitate digestion and absorption of nutrients. Many recent reports raise the possibility that EECs and the enteric nervous system may coordinate to regulate gastrointestinal functions. Loss of all EECs results in chronic malabsorptive diarrhea, placing EECs in a central role regulating nutrient absorption in the gut. Because there is increasing evidence that EECs can directly modulate the efficiency of nutrient absorption, it is possible that EECs are master regulators of a feed-forward loop connecting appetite, digestion, metabolism, and abnormally augmented nutrient absorption that perpetuates metabolic disease. This review focuses on the roles that specific EEC hormones play on glucose, peptide, and lipid absorption within the intestine.