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Current Opinion in Pharmacology Dec 2016Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like cells, via gastrin/cholecystokinin-2 receptor (CCKR) binding and... (Review)
Review
Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like cells, via gastrin/cholecystokinin-2 receptor (CCKR) binding and downstream signalling. Studies in animal models, healthy subjects and patients with gastric neuroendocrine tumours provide compelling evidence to justify developing a CCKR antagonist (CCKRA) for preventing or treating the trophic effects of hypergastrinaemia or conditions expressing CCKR, and with or without a proton pump inhibitor, for treating gastric acid-related conditions. Many compounds have been studied, but most have had problems with potency, selectivity for CCK versus CCK receptor, solubility or oral bioavailability. None has yet been marketed. Netazepide and Z-360 are currently undergoing clinical development, for treatment of gastric neuroendocrine tumours and pancreatic cancer, respectively. There are several other potential indications for a CCKRA and an unmet need.
Topics: Animals; Antineoplastic Agents; Benzodiazepinones; Disease Models, Animal; Drug Design; Gastric Acid; Gastrins; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Phenylurea Compounds; Receptor, Cholecystokinin B; Stomach Neoplasms
PubMed: 27710813
DOI: 10.1016/j.coph.2016.09.002 -
Current Topics in Membranes 2017Sensation of mechanical forces is critical for normal function of the gastrointestinal (GI) tract and abnormalities in mechanosensation are linked to GI pathologies. In... (Review)
Review
Sensation of mechanical forces is critical for normal function of the gastrointestinal (GI) tract and abnormalities in mechanosensation are linked to GI pathologies. In the GI tract there are several mechanosensitive cell types-epithelial enterochromaffin cells, intrinsic and extrinsic enteric neurons, smooth muscle cells and interstitial cells of Cajal. These cells use mechanosensitive ion channels that respond to mechanical forces by altering transmembrane ionic currents in a process called mechanoelectrical coupling. Several mechanosensitive ionic conductances have been identified in the mechanosensory GI cells, ranging from mechanosensitive voltage-gated sodium and calcium channels to the mechanogated ion channels, such as the two-pore domain potassium channels K2P (TREK-1) and nonselective cation channels from the transient receptor potential family. The recently discovered Piezo channels are increasingly recognized as significant contributors to cellular mechanosensitivity. Piezo1 and Piezo2 are nonselective cationic ion channels that are directly activated by mechanical forces and have well-defined biophysical and pharmacologic properties. The role of Piezo channels in the GI epithelium is currently under investigation and their role in the smooth muscle syncytium and enteric neurons is still not known. In this review, we outline the current state of knowledge on mechanosensitive ion channels in the GI tract, with a focus on the known and potential functions of the Piezo channels.
Topics: Animals; Gastrointestinal Tract; Humans; Ion Channels; Mechanotransduction, Cellular
PubMed: 28728818
DOI: 10.1016/bs.ctm.2016.11.003 -
Cancer Dec 2017Neuroendocrine tumors are a heterogeneous group of slow-growing neoplasms arising mainly from the enterochromaffin cells of the digestive and respiratory tract. Although... (Review)
Review
Neuroendocrine tumors are a heterogeneous group of slow-growing neoplasms arising mainly from the enterochromaffin cells of the digestive and respiratory tract. Although they are relatively rare, their incidence is rising. It has long been observed that they often are associated with the development of fibrosis, both local and distant. Fibrotic complications, such as carcinoid heart disease and mesenteric desmoplasia, may lead to considerable morbidity or even affect prognosis. The elucidation of the pathophysiology of fibrosis would be of critical importance for the development of targeted therapeutic strategies. In this article, the authors review the available evidence regarding the biological basis of fibrosis in neuroendocrine tumors. They explore the role of the tumor microenvironment and the interplay between tumor cells and fibroblasts as a key factor in fibrogenesis and tumor development/progression. They also review the role of serotonin, growth factors, and other peptides in the development of carcinoid-related fibrotic reactions. Cancer 2017;123:4770-90. © 2017 American Cancer Society.
Topics: Animals; Biomarkers, Tumor; Biopsy, Needle; Cell Transformation, Neoplastic; Disease Progression; Female; Fibrosis; Humans; Immunohistochemistry; Male; Neuroendocrine Tumors; Prognosis; Rare Diseases; Risk Factors
PubMed: 29112233
DOI: 10.1002/cncr.31079 -
The Journal of Clinical Investigation Dec 2022As a highly regenerative organ, the intestine is a promising source for cellular reprogramming for replacing lost pancreatic β cells in diabetes. Gut enterochromaffin...
As a highly regenerative organ, the intestine is a promising source for cellular reprogramming for replacing lost pancreatic β cells in diabetes. Gut enterochromaffin cells can be converted to insulin-producing cells by forkhead box O1 (FoxO1) ablation, but their numbers are limited. In this study, we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine. Accordingly, lineage-tracing experiments show that, upon genetic or pharmacologic FoxO1 ablation, the Paneth/goblet lineage can also undergo conversion to the insulin lineage. We designed a screening platform in gut organoids to accurately quantitate β-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process in mice and human adult intestinal organoids. We identified a triple blockade of FOXO1, Notch, and TGF-β that, when tested in insulin-deficient streptozotocin (STZ) or NOD diabetic animals, resulted in near normalization of glucose levels, associated with the generation of intestinal insulin-producing cells. The findings illustrate a therapeutic approach for replacing insulin treatment in diabetes.
Topics: Humans; Mice; Animals; Forkhead Box Protein O1; Forkhead Transcription Factors; Mice, Inbred NOD; Insulin-Secreting Cells; Insulin; Diabetes Mellitus
PubMed: 36282594
DOI: 10.1172/JCI162720 -
Journal of Animal Science and... Aug 2023Serotonin is an important signaling molecule that regulates secretory and sensory functions in the gut. Gut microbiota has been demonstrated to affect serotonin...
BACKGROUND
Serotonin is an important signaling molecule that regulates secretory and sensory functions in the gut. Gut microbiota has been demonstrated to affect serotonin synthesis in rodent models. However, how gut microbes regulate intestinal serotonin production in piglets remains vague. To investigate the relationship between microbiota and serotonin specifically in the colon, microbial composition and serotonin concentration were analyzed in ileum-cannulated piglets subjected to antibiotic infusion from the ileum when comparing with saline infusion. Microbes that correlated positively with serotonin production were isolated from piglet colon and were further used to investigate the regulation mechanisms on serotonin production in IPEC-J2 and a putative enterochromaffin cell line RIN-14B cells.
RESULTS
Antibiotic infusion increased quantities of Lactobacillus amylovorus (LA) that positively correlated with increased serotonin concentrations in the colon, while no effects observed for Limosilactobacillus reuteri (LR). To understand how microbes regulate serotonin, representative strains of LA, LR, and Streptococcus alactolyticus (SA, enriched in feces from prior observation) were selected for cell culture studies. Compared to the control group, LA, LR and SA supernatants significantly up-regulated tryptophan hydroxylase 1 (TPH1) expression and promoted serotonin production in IPEC-J2 cells, while in RIN-14B cells only LA exerted similar action. To investigate potential mechanisms mediated by microbe-derived molecules, microbial metabolites including lactate, acetate, glutamine, and γ-aminobutyric acid were selected for cell treatment based on computational and metabolite profiling in bacterial supernatant. Among these metabolites, acetate upregulated the expression of free fatty acid receptor 3 and TPH1 while downregulated indoleamine 2,3-dioxygenase 1. Similar effects were also recapitulated when treating the cells with AR420626, an agonist targeting free fatty acid receptor 3.
CONCLUSIONS
Overall, these results suggest that Lactobacillus amylovorus showed a positive correlation with serotonin production in the pig gut and exhibited a remarkable ability to regulate serotonin production in cell cultures. These findings provide evidence that microbial metabolites mediate the dialogue between microbes and host, which reveals a potential approach using microbial manipulation to regulate intestinal serotonin biosynthesis.
PubMed: 37542282
DOI: 10.1186/s40104-023-00903-7 -
Frontiers in Cellular and Infection... 2021In recent years, increasing studies have been conducted on the mechanism of gut microbiota in neuropsychiatric diseases and non-neuropsychiatric diseases. The academic... (Review)
Review
In recent years, increasing studies have been conducted on the mechanism of gut microbiota in neuropsychiatric diseases and non-neuropsychiatric diseases. The academic community has also recognized the existence of the microbiota-gut-brain axis. Chronic pain has always been an urgent difficulty for human beings, which often causes anxiety, depression, and other mental symptoms, seriously affecting people's quality of life. Hyperalgesia is one of the main adverse reactions of chronic pain. The mechanism of gut microbiota in hyperalgesia has been extensively studied, providing a new target for pain treatment. Enterochromaffin cells, as the chief sentinel for sensing gut microbiota and its metabolites, can play an important role in the interaction between the gut microbiota and hyperalgesia through paracrine or neural pathways. Therefore, this systematic review describes the role of gut microbiota in the pathological mechanism of hyperalgesia, learns about the role of enterochromaffin cell receptors and secretions in hyperalgesia, and provides a new strategy for pain treatment by targeting enterochromaffin cells through restoring disturbed gut microbiota or supplementing probiotics.
Topics: Brain; Enterochromaffin Cells; Gastrointestinal Microbiome; Humans; Hyperalgesia; Probiotics; Quality of Life
PubMed: 34722345
DOI: 10.3389/fcimb.2021.760076 -
Endocrinology May 2017Serotonin (5-hydroxytryptamine or 5-HT) is a multifunctional bioamine with important signaling roles in a range of physiological pathways. Almost all of the 5-HT in our... (Review)
Review
Serotonin (5-hydroxytryptamine or 5-HT) is a multifunctional bioamine with important signaling roles in a range of physiological pathways. Almost all of the 5-HT in our bodies is synthesized in specialized enteroendocrine cells within the gastrointestinal (GI) mucosa called enterochromaffin (EC) cells. These cells provide all of our circulating 5-HT. We have long appreciated the important contributions of 5-HT within the gut, including its role in modulating GI motility. However, evidence of the physiological and clinical significance of gut-derived 5-HT outside of the gut has recently emerged, implicating 5-HT in regulation of glucose homeostasis, lipid metabolism, bone density, and diseases associated with metabolic syndrome, such as obesity and type 2 diabetes. Although a new picture has developed in the last decade regarding the various metabolic roles of peripheral serotonin, so too has our understanding of the physiology of EC cells. Given that they are scattered throughout the lining of the GI tract within the epithelial cell layer, these cells are typically difficult to study. Advances in isolation procedures now allow the study of pure EC-cell cultures and single cells, enabling studies of EC-cell physiology to occur. EC cells are sensory cells that are capable of integrating cues from ingested nutrients, the enteric nervous system, and the gut microbiome. Thus, levels of peripheral 5-HT can be modulated by a multitude of factors, resulting in both local and systemic effects for the regulation of a raft of physiological pathways related to metabolism and obesity.
Topics: Animals; Energy Metabolism; Enteric Nervous System; Enteroendocrine Cells; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Serotonin; Signal Transduction
PubMed: 28323941
DOI: 10.1210/en.2016-1839 -
Scandinavian Journal of Gastroenterology Jun 2015Nordic research on physiology and pathophysiology of the upper gastrointestinal tract has flourished during the last 50 years. Swedish surgeons and physiologists were in... (Review)
Review
Nordic research on physiology and pathophysiology of the upper gastrointestinal tract has flourished during the last 50 years. Swedish surgeons and physiologists were in the frontline of research on the regulation of gastric acid secretion. This research finally led to the development of omeprazole, the first proton pump inhibitor. When Swedish physiologists developed methods allowing the assessment of acid secretion in isolated oxyntic glands and isolated parietal cells, the understanding of mechanisms by which gastric acid secretion is regulated took a great step forward. Similarly, in Trondheim, Norway, the acid producing isolated rat stomach model combined with a sensitive and specific method for determination of histamine made it possible to evaluate this regulation qualitatively as well as quantitatively. In Lund, Sweden, the identification of the enterochromaffin-like cell as the cell taking part in the regulation of acid secretion by producing and releasing histamine was of fundamental importance both physiologically and clinically. Jorpes and Mutt established a center at Karolinska Institutet in Stockholm for the purification of gastrointestinal hormones in the 1960s, and Danes followed up this work by excelling in the field of determination and assessment of biological role of gastrointestinal hormones. A Finnish group was for a long period in the forefront of research on gastritis, and the authors' own studies on the classification of gastric cancer and the role of gastrin in the development of gastric neoplasia are of importance. It can, accordingly, be concluded that Nordic researchers have been central in the research on area of the upper gastrointestinal physiology and diseases.
Topics: Animals; Biomedical Research; Gastrointestinal Diseases; Gastrointestinal Tract; Humans; Scandinavian and Nordic Countries
PubMed: 25857514
DOI: 10.3109/00365521.2015.1009157 -
Frontiers in Oncology 2023The prevalence of gastric cancer has markedly declined, but due to the high mortality rates associated with gastric cancer, it is still a serious disease. The preferred... (Review)
Review
The prevalence of gastric cancer has markedly declined, but due to the high mortality rates associated with gastric cancer, it is still a serious disease. The preferred classification of gastric cancer is according to Lauren into either the intestinal type, which has a glandular growth pattern, or the diffuse type, which does not have glandular structures. Both types have been classified as adenocarcinomas, with the latter type based on periodic acid-Schiff (PAS) positivity presumed to reflect mucin. However, the presence of mucin in the diffuse type, in contrast to neuroendocrine/enterochromaffin-like (ECL) cell markers, has not been confirmed by immunohistochemistry and hybridization. The ECL cells are probably prone to becoming cancerous because they do not express E-cadherin. Gastric cancer is unique in that a bacterium, , is thought to be its main cause. predisposes infected individuals to cancer only after having caused oxyntic atrophy leading to gastric hypoacidity and hypergastrinemia. No single factor has been convincingly proved to be carcinogenic. It is probable that gastrin is the pathogenetic factor for gastric cancer due to , autoimmune gastritis, and long-term prolonged inhibition of gastric acid secretion. Hypergastrinemia induces ECL cell hyperplasia, which develops into neuroendocrine tumors (NETs) and then into neuroendocrine carcinomas in rodents, a sequence that has also been described in humans. During carcinogenesis, the tumor cells lose specific traits, requiring that sensitive methods be used to recognize their origin. Gastric cancer occurrence may hopefully be prevented by eradication at a young age, and by the reduced use of inhibitors of acid secretion and use of a gastrin antagonist in those with previous long-term infection and those with autoimmune gastritis.
PubMed: 37941554
DOI: 10.3389/fonc.2023.1176673 -
The Journal of Nutrition Apr 2023Long-term exposure to adverse life events that provoke acute or chronic psychological stress (hereinafter "stress") can negatively affect physical health and even... (Review)
Review
Long-term exposure to adverse life events that provoke acute or chronic psychological stress (hereinafter "stress") can negatively affect physical health and even increase susceptibility to psychological illnesses, such as anxiety and depression. As a part of the hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor (CRF) released from the hypothalamus is primarily responsible for the stress response. Typically, CRF disrupts the gastrointestinal system and leads to gut microbiota dysbiosis, thereby increasing risk of functional gastrointestinal diseases, such as irritable bowel syndrome. Furthermore, CRF increases oxidative damage to the colon and triggers immune responses involving mast cells, neutrophils, and monocytes. CRF even affects the differentiation of intestinal stem cells (ISCs), causing enterochromaffin cells to secrete excessive amounts of 5-hydroxytryptamine (5-HT). Therefore, stress is often accompanied by damage to the intestinal epithelial barrier function, followed by increased intestinal permeability and bacterial translocation. There are multi-network interactions between the gut microbiota and stress, and gut microbiota may relieve the effects of stress on the body. Dietary intake of probiotics can provide energy for ISCs through glycolysis, thereby alleviating the disruption to homeostasis caused by stress, and it significantly bolsters the intestinal barrier, alleviates intestinal inflammation, and maintains endocrine homeostasis. Gut microbiota also directly affect the synthesis of hormones and neurotransmitters, such as CRF, 5-HT, dopamine, and norepinephrine. Moreover, the Mediterranean diet enhances the stress resistance to some extent by regulating the intestinal flora. This article reviews recent research on how stress damages the gut and microbiota, how the gut microbiota can improve gut health by modulating injury due to stress, and how the diet relieves stress injury by interfering with intestinal microflora. This review gives insight into the potential role of the gut and its microbiota in relieving the effects of stress via the gut-brain axis.
Topics: Corticotropin-Releasing Hormone; Hypothalamo-Hypophyseal System; Serotonin; Pituitary-Adrenal System; Stress, Psychological; Homeostasis
PubMed: 36806451
DOI: 10.1016/j.tjnut.2023.01.026