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• W4283274944 abstract "The maintenance of intestinal homeostasis is fundamentally important to health. Intestinal barrier function and immune regulation are key determinants of intestinal homeostasis and are therefore tightly regulated by a variety of signaling mechanisms. The endocannabinoid system is a lipid mediator signaling system widely expressed in the gastrointestinal tract. Accumulating evidence suggests the endocannabinoid system is a critical nexus involved in the physiological processes that underlie the control of intestinal homeostasis. In this review we will illustrate how the endocannabinoid system is involved in regulation of intestinal permeability, fluid secretion, and immune regulation. We will also demonstrate a reciprocal regulation between the endocannabinoid system and the gut microbiome. The role of the endocannabinoid system is complex and multifaceted, responding to both internal and external factors while also serving as an effector system for the maintenance of intestinal homeostasis. The maintenance of intestinal homeostasis is fundamentally important to health. Intestinal barrier function and immune regulation are key determinants of intestinal homeostasis and are therefore tightly regulated by a variety of signaling mechanisms. The endocannabinoid system is a lipid mediator signaling system widely expressed in the gastrointestinal tract. Accumulating evidence suggests the endocannabinoid system is a critical nexus involved in the physiological processes that underlie the control of intestinal homeostasis. In this review we will illustrate how the endocannabinoid system is involved in regulation of intestinal permeability, fluid secretion, and immune regulation. We will also demonstrate a reciprocal regulation between the endocannabinoid system and the gut microbiome. The role of the endocannabinoid system is complex and multifaceted, responding to both internal and external factors while also serving as an effector system for the maintenance of intestinal homeostasis. SummaryThe endocannabinoid system is a lipid mediator signaling system widely distributed throughout the gastrointestinal tract. The endocannabinoid system plays a pivotal role in the maintenance of intestinal homeostasis and gut barrier integrity, responding to internal and external environmental factors while also serving as a homeostatic effector system. The endocannabinoid system is a lipid mediator signaling system widely distributed throughout the gastrointestinal tract. The endocannabinoid system plays a pivotal role in the maintenance of intestinal homeostasis and gut barrier integrity, responding to internal and external environmental factors while also serving as a homeostatic effector system. The maintenance of intestinal homeostasis is of fundamental importance to health. Intestinal homeostasis requires the integration of digestive and defensive functions of the gut to protect against the insults that arise from digestion, harmful pathogens and toxins, and the commensal microbiota that live in the gut, while simultaneously promoting the efficient utilization of food. A central determinant of intestinal homeostasis is intestinal barrier function.1Zuo L. Kuo W.T. Turner J.R. Tight junctions as targets and effectors of mucosal immune homeostasis.Cell Mol Gastroenterol Hepatol. 2020; 10: 327-340Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 2Odenwald M.A. Turner J.R. The intestinal epithelial barrier: a therapeutic target?.Nat Rev Gastroenterol Hepatol. 2017; 14: 9Crossref PubMed Scopus (434) Google Scholar, 3Allaire J.M. Crowley S.M. Law H.T. Chang S.Y. Ko H.J. Vallance B.A. The intestinal epithelium: central coordinator of mucosal immunity.Trends Immunol. 2018; 39: 677-696Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar The intestinal barrier is a dynamic arrangement composed of a physical barrier (tight junctions) between the epithelial cells and a variety of secretory processes that together preserve the integrity of the epithelium, while being sufficiently permeable to allow for antigen sampling and the passage of nutrients, electrolytes, and water. The gut is poised to trigger effective mechanisms to rapidly rid itself of unwanted luminal contents through enteric neuroimmune mechanisms and has enormous capacity to mount immune responses to microbial pathogens and potentially harmful food antigens.4Sharkey K.A. Beck P.L. McKay D.M. Neuroimmunophysiology of the gut: advances and emerging concepts focusing on the epithelium.Nat Rev Gastroenterol Hepatol. 2018; 15: 765-784Crossref PubMed Scopus (23) Google Scholar, 5Chu C. Artis D. Chiu I.M. Neuro-immune interactions in the tissues.Immunity. 2020; 52: 464-474Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 6Veiga-Fernandes H. Mucida D. Neuro-immune interactions at barrier surfaces.Cell. 2016; 165: 801-811Abstract Full Text Full Text PDF PubMed Google Scholar Dysregulation of intestinal homeostasis has serious consequences, driving a variety of pathologic conditions, including inflammatory bowel disease (IBD), celiac disease, and diseases of gut-brain interaction such as irritable bowel syndrome.2Odenwald M.A. Turner J.R. The intestinal epithelial barrier: a therapeutic target?.Nat Rev Gastroenterol Hepatol. 2017; 14: 9Crossref PubMed Scopus (434) Google Scholar,7Farré R. Vicario M. Abnormal barrier function in gastrointestinal disorders.Handb Exp Pharmacol. 2017; 239: 193-217Crossref PubMed Scopus (27) Google Scholar, 8Barbara G. Barbaro M.R. Fuschi D. Palombo M. Falangone F. Cremon C. Marasco G. Stanghellini V. Inflammatory and microbiota-related regulation of the intestinal epithelial barrier.Front Nutr. 2021; 8718356Google Scholar, 9Camilleri M. Madsen K. Spiller R. Van Meerveld B.G. Verne G.N. Intestinal barrier function in health and gastrointestinal disease.Neurogastroenterol Motil. 2012; 24: 503-512Crossref PubMed Scopus (402) Google Scholar Because of the importance of preserving the integrity of the gastrointestinal (GI) tract, it is not surprising that there are numerous, highly sophisticated systems controlling various aspects of intestinal homeostasis. These include intrinsic cellular mechanisms, autocrine and paracrine factors, immune and microbial mediators, and intercellular signaling molecules, as well as intrinsic and extrinsic nervous mechanisms.2Odenwald M.A. Turner J.R. The intestinal epithelial barrier: a therapeutic target?.Nat Rev Gastroenterol Hepatol. 2017; 14: 9Crossref PubMed Scopus (434) Google Scholar, 3Allaire J.M. Crowley S.M. Law H.T. Chang S.Y. Ko H.J. Vallance B.A. The intestinal epithelium: central coordinator of mucosal immunity.Trends Immunol. 2018; 39: 677-696Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 4Sharkey K.A. Beck P.L. McKay D.M. Neuroimmunophysiology of the gut: advances and emerging concepts focusing on the epithelium.Nat Rev Gastroenterol Hepatol. 2018; 15: 765-784Crossref PubMed Scopus (23) Google Scholar,10Peterson L.W. Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis.Nat Rev Immunol. 2014; 14: 141-153Crossref PubMed Scopus (1445) Google Scholar, 11Honda K. Littman D.R. The microbiota in adaptive immune homeostasis and disease.Nature. 2016; 535: 75-84Crossref PubMed Scopus (847) Google Scholar, 12Wells J.M. Brummer R.J. Derrien M. MacDonald T.T. Troost F. Cani P.D. Theodorou V. Dekker J. Méheust A. De Vos W.M. Mercenier A. Nauta A. Garcia-Rodenas C.L. Homeostasis of the gut barrier and potential biomarkers.Am J Physiol Gastrointest Liver Physiol. 2017; 312: G171-G193Crossref PubMed Scopus (242) Google Scholar Accumulating evidence indicates that the endocannabinoid system (ECS) is a vital nexus in the brain-gut-microbiota axis, serving as a critical regulator of intestinal homeostasis.13Cani P.D. Plovier H. Van Hul M. Geurts L. Delzenne N.M. Druart C. Everard A. Endocannabinoids: at the crossroads between the gut microbiota and host metabolism.Nat Rev Endocrinol. 2016; 12: 133-143Crossref PubMed Google Scholar,14Sharkey K.A. Wiley J.W. The role of the endocannabinoid system in the brain–gut axis.Gastroenterology. 2016; 151: 252-266Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The ECS is a widely distributed lipid mediator signaling system affecting a multitude of physiological and pathophysiological processes throughout the body.15Lu H.C. Mackie K. Review of the endocannabinoid system.Biol Psychiatry Cogn Neurosci Neuroimaging. 2021; 6: 607-615Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar,16Pertwee R.G. Endocannabinoids and their pharmacological actions.Handb Exp Pharmacol. 2015; 231: 1-37Crossref PubMed Scopus (129) Google Scholar In this review we will highlight the complex role the ECS plays in the maintenance of intestinal homeostasis and gut barrier integrity. We will develop the idea that it is pivotal because it responds to internal and external environmental factors, while also serving as a homeostatic effector system. We have not addressed the effects of the ECS on gut motility, because this topic has been comprehensively reviewed.14Sharkey K.A. Wiley J.W. The role of the endocannabinoid system in the brain–gut axis.Gastroenterology. 2016; 151: 252-266Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,17Taschler U. Hasenoehrl C. Storr M. Schicho R. Cannabinoid receptors in regulating the GI tract: experimental evidence and therapeutic relevance.Handb Exp Pharmacol. 2017; 239: 343-362Crossref PubMed Scopus (6) Google Scholar,18Izzo A.A. Sharkey K.A. Cannabinoids and the gut: new developments and emerging concepts.Pharmacol Ther. 2010; 126: 21-38Crossref PubMed Scopus (301) Google Scholar The ECS or endocannabinoidome has a multitude of functions in physiological and pathophysiological processes in the brain and body.19Cristino L. Bisogno T. Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders.Nature Reviews Neurology. 2020; 16: 9-29Crossref PubMed Scopus (0) Google Scholar It is perhaps best known for playing important roles in food intake and energy metabolism, regulation of the hypothalamic-pituitary-adrenal axis, pain transmission, and a variety of emotional and behavioral conditions.14Sharkey K.A. Wiley J.W. The role of the endocannabinoid system in the brain–gut axis.Gastroenterology. 2016; 151: 252-266Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,19Cristino L. Bisogno T. Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders.Nature Reviews Neurology. 2020; 16: 9-29Crossref PubMed Scopus (0) Google Scholar, 20Di Marzo V. Silvestri C. Lifestyle and metabolic syndrome: contribution of the endocannabinoidome.Nutrients. 2019; 11: 1956Crossref Scopus (58) Google Scholar, 21Iannotti F.A. Di Marzo V. The gut microbiome, endocannabinoids and metabolic disorders.J Endocrinol. 2021; 248: R83-R97Crossref PubMed Scopus (25) Google Scholar, 22Maldonado R. Cabañero D. Martín-García E. The endocannabinoid system in modulating fear, anxiety, and stress.Dialogues Clin Neurosci. 2020; 22: 229-239Crossref PubMed Google Scholar, 23Micale V. Drago F. Endocannabinoid system, stress and HPA axis.Eur J Pharmacol. 2018; 834: 230-239Crossref PubMed Scopus (66) Google Scholar, 24Gallego-Landin I. García-Baos A. Castro-Zavala A. Valverde O. Reviewing the role of the endocannabinoid system in the pathophysiology of depression.Front Pharmacol. 2021; 12762738Crossref PubMed Scopus (5) Google Scholar, 25van den Hoogen N.J. Harding E.K. Davidson C.E.D. Trang T. Cannabinoids in chronic pain: therapeutic potential through microglia modulation.Front Neural Circuits. 2022; 15816747Crossref PubMed Scopus (0) Google Scholar The ECS was discovered after the isolation of Δ9-tetrahydrocannabinol (THC) as the major psychoactive constituent of cannabis.26Mechoulam R. Hanuš L.O. Pertwee R. Howlett A.C. Early phytocannabinoid chemistry to endocannabinoids and beyond.Nat Rev Neurosci. 2014; 15: 757-764Crossref PubMed Scopus (200) Google Scholar This finding led to the development of ligands that were used to identify the receptors for cannabis. There are now 3 major classes of cannabinoids that are recognized: phytocannabinoids that are derived from the cannabis plant, such as THC and cannabidiol (CBD); synthetic cannabinoids, such as the chemical agonists HU210, CP55,940, and WIN55,212-2 and antagonists rimonabant, AM250, and AM630; and endocannabinoids, the lipid mediators, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), that we will discuss further in this review.27Pertwee R.G. Howlett A.C. Abood M.E. Alexander S.P.H. Di Marzo V. Elphick M.R. Greasley P.J. Hansen H.S. Kunos G. Mackie K. Mechoulam R. Ross R.A. International union of basic and clinical pharmacology: LXXIX—cannabinoid receptors and their ligands: beyond CB1 and CB2.Pharmacol Rev. 2010; 62: 588-631Crossref PubMed Scopus (0) Google Scholar Interested readers are directed to excellent reviews of cannabinoids.15Lu H.C. Mackie K. Review of the endocannabinoid system.Biol Psychiatry Cogn Neurosci Neuroimaging. 2021; 6: 607-615Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar,27Pertwee R.G. Howlett A.C. Abood M.E. Alexander S.P.H. Di Marzo V. Elphick M.R. Greasley P.J. Hansen H.S. Kunos G. Mackie K. Mechoulam R. Ross R.A. International union of basic and clinical pharmacology: LXXIX—cannabinoid receptors and their ligands: beyond CB1 and CB2.Pharmacol Rev. 2010; 62: 588-631Crossref PubMed Scopus (0) Google Scholar, 28Pacher P. Kogan N.M. Mechoulam R. Beyond THC and endocannabinoids.Annu Rev Pharmacol Toxicol. 2020; 60: 637-659Crossref PubMed Scopus (0) Google Scholar, 29Di Marzo V. Piscitelli F. The endocannabinoid system and its modulation by phytocannabinoids.Neurotherapeutics. 2015; 12: 692-698Crossref PubMed Scopus (159) Google Scholar, 30Ligresti A. De Petrocellis L. Di Marzo V. From phytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex pharmacology.Physiol Rev. 2016; 96: 1593-1659Crossref PubMed Scopus (213) Google Scholar In its original description, the ECS consists of two G protein-coupled receptors (GPCRs), cannabinoid (CB) receptor 1 (CB1) and 2 (CB2), their endogenous ligands endocannabinoids, and the biosynthetic and degradative enzymes that control the availability of these ligands.15Lu H.C. Mackie K. Review of the endocannabinoid system.Biol Psychiatry Cogn Neurosci Neuroimaging. 2021; 6: 607-615Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar,31Piomelli D. The molecular logic of endocannabinoid signalling.Nat Rev Neurosci. 2003; 4: 873-884Crossref PubMed Scopus (1567) Google Scholar Since this original description, many other receptors and ligands are now considered part of the ECS,19Cristino L. Bisogno T. Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders.Nature Reviews Neurology. 2020; 16: 9-29Crossref PubMed Scopus (0) Google Scholar as we will outline below. Endocannabinoids are membrane-derived lipid signaling molecules. The 2 primary endocannabinoids are N-arachidonoyl ethanolamine (AEA) and 2-AG. Unlike classical neurotransmitters that are stored in vesicles, endocannabinoids are synthesized “on demand” in response to a stimulus.32Lutz B. Neurobiology of cannabinoid receptor signaling.Dialogues Clin Neurosci. 2020; 22: 207-222Crossref PubMed Google Scholar Primary stimuli for their synthesis are an elevation of intracellular calcium and activation of a number of GPCRs.32Lutz B. Neurobiology of cannabinoid receptor signaling.Dialogues Clin Neurosci. 2020; 22: 207-222Crossref PubMed Google Scholar The synthesis and degradation pathways of the 2 main endocannabinoids are shown in Figure 1. Anandamide synthesis begins with the conversion of phosphatidylethanolamine into N-arachidonoyl phosphatidylethanolamine (NAPE) by the calcium-dependent enzyme N-acyltransferase. Anandamide is then produced from the hydrolysis of NAPE by N-acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD). Three additional pathways for AEA synthesis have also been described.33Liu J. Wang L. Harvey-White J. Osei-Hyiaman D. Razdan R. Gong Q. Chan A.C. Zhou Z. Huang B.X. Kim H.-Y. Kunos G. A biosynthetic pathway for anandamide.Proc Natl Acad Sci U S A. 2006; 103: 13345-13350Crossref PubMed Scopus (350) Google Scholar, 34Hussain Z. Uyama T. Tsuboi K. Ueda N. Mammalian enzymes responsible for the biosynthesis of N-acylethanolamines.Biochim Biophys Acta - Mol Cell Biol Lipids. 2017; 1862: 1546-1561Crossref PubMed Scopus (0) Google Scholar, 35Simon G.M. Cravatt B.F. Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for α/β-hydrolase 4 in this pathway.J Biol Chem. 2006; 281: 26465-26472Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar (1) Phospholipase C (PLC) converts NAPE into phosphoanandamide, which is then dephosphorylated to form AEA. (2) α/β-hydrolase 4 produces glycerophosphoanandamide from NAPE, which is then converted into AEA by glycerophosphodiesterase-1, and (3) soluble phospholipase A2 acts on NAPE to form 2-lyso-NAPE, which is then converted to AEA by lyso-PLD. The primary enzyme responsible for the degradation of AEA is fatty acid amide hydrolase (FAAH). FAAH hydrolyzes AEA into arachidonic acid and ethanolamine.36Fowler C.J. Jonsson K.O. Tiger G. Fatty acid amide hydrolase: biochemistry, pharmacology, and therapeutic possibilities for an enzyme hydrolyzing anandamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleamide.Biochem Pharmacol. 2001; 62: 517-526Crossref PubMed Scopus (114) Google Scholar,37Van Egmond N. Straub V.M. Van Der Stelt M. Targeting endocannabinoid signaling: FAAH and MAG lipase inhibitors.Annu Rev Pharmacol Toxicol. 2021; 61: 441-463Crossref PubMed Scopus (11) Google Scholar The synthesis of 2-AG is dependent on the calcium-dependent enzyme PLC and the activity of diacylglycerol lipase (DAGL). PLC hydrolyzes arachidonic acid-containing membrane lipids to produce diacylglycerol, which is then converted into 2-AG by DAGL.38Fowler C.J. Doherty P. Alexander S.P.H. Endocannabinoid turnover.Adv Pharmacol. 2017; 80: 31-66Crossref PubMed Scopus (23) Google Scholar In addition, 2-AG may be made from the conversion of 2-arachidonoyl-phosphoinositol to 2-arachidonoyl-lyso-phosphoinositol by phospholipase A1, which is subsequently converted to 2-AG by lyso-phosphoinositol-PLC.38Fowler C.J. Doherty P. Alexander S.P.H. Endocannabinoid turnover.Adv Pharmacol. 2017; 80: 31-66Crossref PubMed Scopus (23) Google Scholar,39Labar G. Wouters J. Lambert D.M. A review on the monoacylglycerol lipase: at the interface between fat and endocannabinoid signalling.Curr Med Chem. 2010; 17: 2588-2607Crossref PubMed Scopus (0) Google Scholar 2-AG is primarily metabolized by monoacylglycerol lipase (MAGL) into glycerol and arachidonic acid.39Labar G. Wouters J. Lambert D.M. A review on the monoacylglycerol lipase: at the interface between fat and endocannabinoid signalling.Curr Med Chem. 2010; 17: 2588-2607Crossref PubMed Scopus (0) Google Scholar,40Fowler C.J. Monoacylglycerol lipase: a target for drug development?.Br J Pharmacol. 2012; 166: 1568-1585Crossref PubMed Scopus (0) Google Scholar However, studies in mice have revealed 2 additional degradation pathways via the enzymes α/β-hydrolase domain-containing protein (ABHD)-6 and ABHD-12.41Cao J.K. Kaplan J. Stella N. ABHD6: its place in endocannabinoid signaling and beyond.Trends Pharmacol Sci. 2019; 40: 267-277Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 42Navia-Paldanius D. Savinainen J.R. Laitinen J.T. Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12).J Lipid Res. 2012; 53: 2413-2424Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 43Ogasawara D. Ichu T.A. Jing H. Hulce J.J. Reed A. Ulanovskaya O.A. Cravatt B.F. 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A single-cell survey of the small intestinal epithelium.Nature. 2017; 551: 333-339Crossref PubMed Scopus (611) Google Scholar However, although we are gaining an understanding of expression of the relevant ECS-related genes, the functional cellular sources of endocannabinoids in the gut are not entirely clear, and we do not have a complete understanding of how sources of endocannabinoids change during pathophysiological conditions. The CB receptors are GPCRs coupled to Gi/o proteins leading to an inhibition of adenylyl cyclase and decreased production of cyclic adenosine monophosphate (cAMP).48Howlett A.C. Abood M.E. CB1 and CB2 receptor pharmacology.Adv Pharmacol. 2017; 80: 169-206Crossref PubMed Scopus (124) Google Scholar The release of βγ dimers after CB receptor activation also causes inhibition of N- and P/Q-type Ca2+ channels and activation of inwardly rectifying and A-type potassium channels.32Lutz B. Neurobiology of cannabinoid receptor signaling.Dialogues Clin Neurosci. 2020; 22: 207-222Crossref PubMed Google Scholar,48Howlett A.C. Abood M.E. CB1 and CB2 receptor pharmacology.Adv Pharmacol. 2017; 80: 169-206Crossref PubMed Scopus (124) Google Scholar The βγ dimers initiate Src-mediated signaling cascades leading to activation of mitogen-activated protein kinases and focal adhesion kinases. Activation of CB receptors is generally inhibitory, serving as a “molecular brake”, to limit excitation across the synapse, reduce secretory processes by epithelial cells, and reduce mediator release from immune cells. Interaction of ligand-bound CB receptor with β-arrestin is required for internalization and termination of extracellular signaling, but β-arrestins are themselves signal transducers for intracellular signaling pathways, including extracellular signal-regulated kinase and c-Jun terminal kinase, which mediate some of the actions of cannabinoids.32Lutz B. 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Cannabinoid CB 1 and CB 2 receptor signaling and bias.Cannabis Cannabinoid Res. 2017; 2: 48-60Crossref PubMed Google Scholar Cannabinoid receptor signaling is illustrated in Figure 2. Cannabinoid receptors may exist in multiple forms as heterodimers or homodimers, are very widely distributed in essentially every organ and tissue in the body, and are subject to dysregulation in pathophysiological conditions.15Lu H.C. Mackie K. Review of the endocannabinoid system.Biol Psychiatry Cogn Neurosci Neuroimaging. 2021; 6: 607-615Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar,48Howlett A.C. Abood M.E. CB1 and CB2 receptor pharmacology.Adv Pharmacol. 2017; 80: 169-206Crossref PubMed Scopus (124) Google Scholar,52Trautmann S.M. Sharkey K.A. The endocannabinoid system and its role in regulating the intrinsic neural circuitry of the gastrointestinal tract.Int Rev Neurobiol. 2015; 125: 85-126Crossref PubMed Google Scholar Of particular relevance, CB1 is expressed in the enteric nervous system (ENS) and the autonomic and central nervous systems (CNS) and is one of the most abundant GPCRs in the brain.53Duncan M. Davison J.S. Sharkey K.A. Review article: endocannabinoids and their receptors in the enteric nervous system.Aliment Pharmacol Ther. 2005; 22: 667-683Crossref PubMed Scopus (0) Google Scholar In the GI tract, CB1 is expressed presynaptically on all classes of enteric neurons, except nitric oxide synthase-expressing inhibitory motor neurons.52Trautmann S.M. Sharkey K.A. The endocannabinoid system and its role in regulating the intrinsic neural circuitry of the gastrointestinal tract.Int Rev Neurobiol. 2015; 125: 85-126Crossref PubMed Google Scholar,53Duncan M. Davison J.S. Sharkey K.A. Review article: endocannabinoids and their receptors in the enteric nervous system.Aliment Pharmacol Ther. 2005; 22: 667-683Crossref PubMed Scopus (0) Google Scholar It is also found on the terminals of primary afferent nerves innervating the gut and on glucose-dependent insulinotropic polypeptide producing (K cells) and cholecystokinin producing (I cells) enteroendocrine cells in the upper small intestine.54Glass L.L. Calero-Nieto F.J. Jawaid W. Larraufie P. Kay R.G. Göttgens B. Reimann F. Gribble F.M. Single-cell RNA-sequencing reveals a distinct population of proglucagon-expressing cells specific to the mouse upper small intestine.Mol Metab. 2017; 6: 1296-1303Crossref PubMed Scopus (49) Google Scholar,55Argueta D.A. Perez P.A. Makriyannis A. Di Patrizio N.V. 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• W4283274944 date "2022-01-01" @default.
• W4283274944 modified "2023-10-15" @default.
• W4283274944 title "Role of the Endocannabinoid System in the Regulation of Intestinal Homeostasis" @default.
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