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Belelli D, Lambert JJ, Wan MLY, Monteiro AR, Nutt DJ, Swinny JD. From bugs to brain: unravelling the GABA signalling networks in the brain-gut-microbiome axis. Brain 2025; 148:1479-1506. [PMID: 39716883 PMCID: PMC12074267 DOI: 10.1093/brain/awae413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/21/2024] [Accepted: 12/01/2024] [Indexed: 12/25/2024] Open
Abstract
Convergent data across species paint a compelling picture of the critical role of the gut and its resident microbiota in several brain functions and disorders. The chemicals mediating communication along these sophisticated highways of the brain-gut-microbiome (BGM) axis include both microbiota metabolites and classical neurotransmitters. Amongst the latter, GABA is fundamental to brain function, mediating most neuronal inhibition. Until recently, GABA's role and specific molecular targets in the periphery within the BGM axis had received limited attention. Yet, GABA is produced by neuronal and non-neuronal elements of the BGM, and recently, GABA-modulating bacteria have been identified as key players in GABAergic gut systems, indicating that GABA-mediated signalling is likely to transcend physiological boundaries and species. We review the available evidence to better understand how GABA facilitates the integration of molecularly and functionally disparate systems to bring about overall homeostasis and how GABA perturbations within the BGM axis can give rise to multi-system medical disorders, thereby magnifying the disease burden and the challenges for patient care. Analysis of transcriptomic databases revealed significant overlaps between GABAAR subunits expressed in the human brain and gut. However, in the gut, there are notable expression profiles for a select number of subunits that have received limited attention to date but could be functionally relevant for BGM axis homeostasis. GABAergic signalling, via different receptor subtypes, directly regulates BGM homeostasis by modulating the excitability of neurons within brain centres responsible for gastrointestinal (GI) function in a sex-dependent manner, potentially revealing mechanisms underlying the greater prevalence of GI disturbances in females. Apart from such top-down regulation of the BGM axis, a diverse group of cell types, including enteric neurons, glia, enteroendocrine cells, immune cells and bacteria, integrate peripheral GABA signals to influence brain functions and potentially contribute to brain disorders. We propose several priorities for this field, including the exploitation of available technologies to functionally dissect components of these GABA pathways within the BGM, with a focus on GI and brain-behaviour-disease. Furthermore, in silico ligand-receptor docking analyses using relevant bacterial metabolomic datasets, coupled with advances in knowledge of GABAAR 3D structures, could uncover new ligands with novel therapeutic potential. Finally, targeted design of dietary interventions is imperative to advancing their therapeutic potential to support GABA homeostasis across the BGM axis.
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Affiliation(s)
- Delia Belelli
- GABA Labs (Research) Ltd., Hemel Hempstead HP2 5HD, UK
- Division of Neuroscience, School of Medicine, Medical Sciences Institute, Dundee University, Dundee DD1 5HL, UK
- School of Medicine, Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK
| | - Jeremy J Lambert
- Division of Neuroscience, School of Medicine, Medical Sciences Institute, Dundee University, Dundee DD1 5HL, UK
| | - Murphy Lam Yim Wan
- School of Medicine, Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK
| | - Ana Rita Monteiro
- School of Medicine, Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK
| | - David J Nutt
- GABA Labs (Research) Ltd., Hemel Hempstead HP2 5HD, UK
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London W12 0NN, UK
| | - Jerome D Swinny
- School of Medicine, Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK
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Rao M, Gulbransen BD. Enteric Glia. Cold Spring Harb Perspect Biol 2025; 17:a041368. [PMID: 38951022 PMCID: PMC11960695 DOI: 10.1101/cshperspect.a041368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
Enteric glia are a unique type of peripheral neuroglia that accompany neurons in the enteric nervous system (ENS) of the digestive tract. The ENS displays integrative neural circuits that are capable of governing moment-to-moment gut functions independent of input from the central nervous system. Enteric glia are interspersed with neurons throughout these intrinsic gut neural circuits and are thought to fulfill complex roles directed at maintaining homeostasis in the neuronal microenvironment and at neuroeffector junctions in the gut. Changes to glial functions contribute to a wide range of gastrointestinal diseases, but the precise roles of enteric glia in gut physiology and pathophysiology are still under examination. This review summarizes current concepts regarding enteric glial development, diversity, and functions in health and disease.
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Affiliation(s)
- Meenakshi Rao
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Brian D Gulbransen
- Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA
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Gonzales J, Gulbransen BD. The Physiology of Enteric Glia. Annu Rev Physiol 2025; 87:353-380. [PMID: 39546562 DOI: 10.1146/annurev-physiol-022724-105016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
Enteric glia are the partners of neurons in the enteric nervous system throughout the gastrointestinal tract. Roles fulfilled by enteric glia are diverse and contribute to maintaining intestinal homeostasis through interactions with neurons, immune cells, and the intestinal epithelium. Glial influences optimize physiological gut processes such as intestinal motility and epithelial barrier integrity through actions that regulate the microenvironment of the enteric nervous system, the activity of enteric neurons, intestinal epithelial functions, and immune response. Changes to glial phenotype in disease switch glial functions and contribute to intestinal inflammation, dysmotility, pain, neuroplasticity, and tumorigenesis. This review summarizes current concepts regarding the physiological roles of enteric glial cells and their potential contributions to gut disease. The discussion is focused on recent evidence that suggests important glial contributions to gastrointestinal health and pathophysiology.
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Affiliation(s)
- Jacques Gonzales
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA;
| | - Brian D Gulbransen
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA;
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Gold MS, Loeza-Alcocer E. Experimental colitis-induced visceral hypersensitivity is attenuated by GABA treatment in mice. Am J Physiol Gastrointest Liver Physiol 2024; 326:G252-G263. [PMID: 38193198 PMCID: PMC11211035 DOI: 10.1152/ajpgi.00012.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 12/21/2023] [Accepted: 12/26/2023] [Indexed: 01/10/2024]
Abstract
Ulcerative colitis (UC) is linked with inflammation of the large intestine due to an overactive response of the colon-immune system. UC is associated with weight loss, rectal bleeding, diarrhea, and abdominal pain. Given that γ-amino butyric acid (GABA) suppresses immune cell activity and the excitability of colonic afferents, and that there is a decrease in colonic GABA during UC, we hypothesized that UC pain is due to a decrease in the inhibition of colonic afferents. Thus, restoring GABA in the colon will attenuate inflammatory hypersensitivity. We tested this hypothesis in a mouse model of colitis. Colon inflammation was induced with seven days of dextran sodium sulfate (DSS, 3%) in the drinking water. GABA (40 mg/kg) was administered orally for the same period as DSS, and body weight, colon length, colon permeability, clinical progression of colitis (disease activity index or DAI), and colon histological score (HS) were assessed to determine the effects of GABA on colitis. A day after the end of GABA treatment, visceral sensitivity was assessed with balloon distention (of the colon)-evoked visceromotor response and colon samples were collected for the measurement of GABA and cytokines. Treatment with GABA reduced the DSS-induced increase in the colon permeability, DAI, HS, and decrease in body weight and colon length. Furthermore, GABA inhibited the DSS-induced increase in the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-12 (IL-12), and increased the expression of the anti-inflammatory cytokine IL-10 in the colon tissue. Importantly, GABA reduced DSS-induced visceral hypersensitivity. These data suggest that increasing gastrointestinal levels of GABA may be useful for the treatment of colitis.NEW & NOTEWORTHY GABA treatment reduces the severity of colitis and inflammation and produces inhibition of visceral hypersensitivity in colon-inflamed mice. These results raise the promising possibility that GABA treatment may be an effective therapeutic strategy for the management of symptoms associated with colitis. However, clinical studies are required to corroborate whether this mouse-model data translates to human colon.
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Affiliation(s)
- Michael S Gold
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Emanuel Loeza-Alcocer
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
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Deng Z, Li D, Yan X, Lan J, Han D, Fan K, Chang J, Ma Y. Activation of GABA receptor attenuates intestinal inflammation by modulating enteric glial cells function through inhibiting NF-κB pathway. Life Sci 2023; 329:121984. [PMID: 37527767 DOI: 10.1016/j.lfs.2023.121984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/18/2023] [Accepted: 07/26/2023] [Indexed: 08/03/2023]
Abstract
AIMS Emerging research indicates that γ-aminobutyric acid (GABA) provides substantial benefits during enteritis. Nevertheless, GABA signaling roles on enteric glial cells (EGCs) remain unknown. The study's objective was to evaluate the underlying mechanisms of GABA signaling on EGCs in vitro and in vivo. MAIN METHODS We established LPS-induced mouse models and stimulated EGCs with LPS to mimic intestinal inflammation, and combined GABA, GABAA receptor (GABAAR) or GABAB receptor (GABABR) agonists to explore the exact mechanisms of GABA signaling. KEY FINDINGS EGCs were immunopositive for GAD65, GAD67, GAT1, GABAARα1, GABAARα3, and GABABR1, indicating GABAergic and GABAceptive properties. GABA receptor activation significantly inhibited the high secretions of proinflammatory factors in EGCs upon LPS stimulation. Interestingly, we found that EGCs express immune-related molecules such as CD16, CD32, CD80, CD86, MHC II, iNOS, Arg1, and CD206, thus establishing their characterization of E1 and E2 phenotype. EGCs exposed to LPS mainly acted as E1 phenotype, whereas GABABR activation strongly promoted EGCs polarization into E2 phenotype. Transcriptome analysis of EGCs indicated that GABA, GABAAR or GABABR agonists treatment participated in various biological processes, however all of these treatments exhibit inhibitory effects on NF-κB pathway. Notably, in LPS-induced mice, activation of GABABR mitigated intestinal damage through modulating inflammatory factors expressions, strengthening sIgA and IgG levels, inhibiting NF-κB pathway and facilitating EGCs to transform into E2 phenotype. SIGNIFICANCE These data demonstrate that the anti-inflammatory actions of GABA signaling system offer in enteritis via regulating EGCs-polarized function through impeding NF-κB pathway, thus providing potential targets for intestinal inflammatory diseases.
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Affiliation(s)
- Ziteng Deng
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Dan Li
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Xue Yan
- New Hope Liuhe Co., Ltd., Key Laboratory of Feed and Livestock and Poultry Products Quality & Safety Control, Ministry of Agriculture, Chengdu, Sichuan, China
| | - Jing Lan
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Deping Han
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China; Peking University Institute of Advanced Agricultural Sciences, Weifang, Shandong, China
| | - Kai Fan
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jianyu Chang
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yunfei Ma
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
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Baghdadi MB, Kim TH. The multiple roles of enteric glial cells in intestinal homeostasis and regeneration. Semin Cell Dev Biol 2023:S1084-9521(23)00005-8. [PMID: 36658046 DOI: 10.1016/j.semcdb.2023.01.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 12/16/2022] [Accepted: 01/06/2023] [Indexed: 01/18/2023]
Abstract
The gastrointestinal tract is innervated by the enteric nervous system (ENS), a complex network of neurons and glial cells, also called the "second brain". Enteric glial cells, one of the major cell types in the ENS, are located throughout the entire gut wall. Accumulating evidence has demonstrated their critical requirement for gut physiology. Notably, recent studies have shown that enteric glial cells control new aspects of gut function such as regulation of intestinal stem cell behavior and immunity. In addition, the emergence of single-cell genomics technologies has revealed enteric glial cell heterogeneity and plasticity. In this review, we discuss established and emerging concepts regarding the roles of mammalian enteric glial cells and their heterogeneity in gut development, homeostasis, and regeneration.
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Affiliation(s)
- Meryem B Baghdadi
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
| | - Tae-Hee Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
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The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals? MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27196773. [PMID: 36235308 PMCID: PMC9570628 DOI: 10.3390/molecules27196773] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/21/2022] [Accepted: 09/26/2022] [Indexed: 11/29/2022]
Abstract
The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.
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Hernandez S, Serrano AG, Solis Soto LM. The Role of Nerve Fibers in the Tumor Immune Microenvironment of Solid Tumors. Adv Biol (Weinh) 2022; 6:e2200046. [PMID: 35751462 DOI: 10.1002/adbi.202200046] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/12/2022] [Indexed: 01/28/2023]
Abstract
The importance of neurons and nerve fibers in the tumor microenvironment (TME) of solid tumors is now acknowledged after being unexplored for a long time; this is possible due to the development of new technologies that allow in situ characterization of the TME. Recent studies have shown that the density and types of nerves that innervate tumors can predict a patient's clinical outcome and drive several processes of tumor biology. Nowadays, several efforts in cancer research and neuroscience are taking place to elucidate the mechanisms that drive tumor-associated innervation and nerve-tumor and nerve-immune interaction. Assessment of neurons and nerves within the context of the TME can be performed in situ, in tumor tissue, using several pathology-based strategies that utilize histochemical and immunohistochemistry principles, hi-plex technologies, and computational pathology approaches to identify measurable histopathological characteristics of nerves. These features include the number and type of tumor associated nerves, topographical location and microenvironment of neural invasion of malignant cells, and investigation of neuro-related biomarker expression in nerves, tumor cells, and cells of the TME. A deeper understanding of these complex interactions and the impact of nerves in tumor biology will guide the design of better strategies for targeted therapy in clinical trials.
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Affiliation(s)
- Sharia Hernandez
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Houston, TX, 77030, USA
| | - Alejandra G Serrano
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Houston, TX, 77030, USA
| | - Luisa M Solis Soto
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Houston, TX, 77030, USA
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9
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Loeza-Alcocer E, Gold MS. Peripheral GABAA receptor signaling contributes to visceral hypersensitivity in a mouse model of colitis. Pain 2022; 163:1402-1413. [PMID: 34726659 PMCID: PMC9056586 DOI: 10.1097/j.pain.0000000000002526] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 09/16/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Pain is a common and debilitating symptom of inflammatory bowel disease (IBD). Based on evidence that peripheral GABAA receptor (GAR) inhibition plays an important role in establishing colonic afferent excitability and nociceptive threshold, we hypothesized that the increase in pain associated with IBD is due to, at least in part, a decrease in peripheral GAR-mediated inhibition. Acute colitis was induced with 5 days of dextran sodium sulfate (DSS, 3%) in the drinking water. Visceral sensitivity was assessed with the visceromotor response (VMR) evoked with balloon distention of the colon in control and DSS-treated mice before and after intracolonic administration of GAR agonist muscimol, the high-affinity GAR preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP), the GAR positive allosteric modulator diazepam, or the GAR antagonists gabazine and bicuculline. Low concentrations of muscimol or THIP increased the VMR in DSS-treated mice but not in control mice. However, high concentrations of muscimol decreased the VMR in both control and DSS-treated mice. Diazepam decreased the VMR in both DSS-treated and control mice. By contrast, at a concentration of gabazine that blocks only low-affinity GAR, there was no effect on the VMR in either DSS-treated or control mice, but at concentrations of the antagonist that block low-affinity and high-affinity GAR, the VMR was increased in control mice and decreased in DSS-treated mice. Furthermore, bicuculline increased the VMR in control mice but decreased it in DSS-treated mice. These data suggest that activating of low-affinity GAR or blocking high-affinity GAR may be effective therapeutic strategies for the management of pain in IBD.
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Affiliation(s)
- Emanuel Loeza-Alcocer
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Michael S Gold
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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10
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Hacene S, Le Friec A, Desmoulin F, Robert L, Colitti N, Fitremann J, Loubinoux I, Cirillo C. Present and future avenues of cell-based therapy for brain injury: The enteric nervous system as a potential cell source. Brain Pathol 2022; 32:e13105. [PMID: 35773942 PMCID: PMC9425017 DOI: 10.1111/bpa.13105] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/09/2022] [Indexed: 01/01/2023] Open
Abstract
Cell therapy is a promising strategy in the field of regenerative medicine; however, several concerns limit the effective clinical use, namely a valid cell source. The gastrointestinal tract, which contains a highly organized network of nerves called the enteric nervous system (ENS), is a valuable reservoir of nerve cells. Together with neurons and neuronal precursor cells, it contains glial cells with a well described neurotrophic potential and a newly identified neurogenic one. Recently, enteric glia is looked at as a candidate for cell therapy in intestinal neuropathies. Here, we present the therapeutic potential of the ENS as cell source for brain repair, too. The example of stroke is introduced as a brain injury where cell therapy appears promising. This disease is the first cause of handicap in adults. The therapies developed in recent years allow a partial response to the consequences of the disease. The only prospect of recovery in the chronic phase is currently based on rehabilitation. The urgency to offer other treatments is therefore tangible. In the first part of the review, some elements of stroke pathophysiology are presented. An update on the available therapeutic strategies is provided, focusing on cell‐ and biomaterial‐based approaches. Following, the ENS is presented with its anatomical and functional characteristics, focusing on glial cells. The properties of these cells are depicted, with particular attention to their neurotrophic and, recently identified, neurogenic properties. Finally, preliminary data on a possible therapeutic approach combining ENS‐derived cells and a biomaterial are presented.
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Affiliation(s)
- Sirine Hacene
- National Veterinary School of Toulouse, University of Toulouse, Toulouse, France.,Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Alice Le Friec
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France.,Department of Biological and Chemical Engineering-Medical Biotechnology, Aarhus University, Aarhus, Denmark
| | - Franck Desmoulin
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Lorenne Robert
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Nina Colitti
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Juliette Fitremann
- Laboratoire des IMRCP, CNRS UMR 5623, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Isabelle Loubinoux
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
| | - Carla Cirillo
- Toulouse NeuroImaging Center (ToNIC), Inserm, University of Toulouse-Paul Sabatier, Toulouse, France
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Thomasi BBDM, Valdetaro L, Ricciardi MCG, Hayashide L, Fernandes ACMN, Mussauer A, da Silva ML, da Cunha Faria-Melibeu A, Ribeiro MGL, de Mattos Coelho-Aguiar J, Campello-Costa P, Moura-Neto V, Tavares-Gomes AL. Enteric glial cell reactivity in colonic layers and mucosal modulation in a mouse model of Parkinson’s disease induced by 6-hydroxydopamine. Brain Res Bull 2022; 187:111-121. [DOI: 10.1016/j.brainresbull.2022.06.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 05/20/2022] [Accepted: 06/25/2022] [Indexed: 11/02/2022]
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Zizzo MG, Cicio A, Raimondo S, Alessandro R, Serio R. Age-related differences of γ-aminobutyric acid (GABA)ergic transmission in human colonic smooth muscle. Neurogastroenterol Motil 2022; 34:e14248. [PMID: 34432349 PMCID: PMC9285353 DOI: 10.1111/nmo.14248] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/10/2021] [Accepted: 08/10/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Enteric neurons undergo to functional changes during aging. We investigated the possible age-associated differences in enteric γ-aminobutyric acid (GABA)ergic transmission evaluating function and distribution of GABAergic receptors in human colon. METHODS Mechanical responses to GABA and GABA receptor agonists on slow phasic contractions were examined in vitro as changes in isometric tension in colonic muscle strips from young (<65 years old) and aged patients (>65 years old). GABAergic receptor expression was assessed by quantitative RT-PCR. KEY RESULTS In both preparations GABA induced an excitatory effect, consisting in an increase in the basal tone, antagonized by the GABAA receptor antagonist, bicuculline, and potentiated by phaclofen, GABAB receptor antagonist.Tetrodotoxin (TTX) and atropine-sensitive contractile responses to GABA and GABAA receptor agonist, muscimol, were more pronounced in old compared to young subjects. Baclofen, GABAB receptor agonist, induced a TTX-sensitive reduction of the amplitude of the spontaneous. Nω-nitro-l-arginine methyl ester (L-NAME), nitric oxide (NO) synthase inhibitor abolished the inhibitory responses in old preparations, but a residual responses persisted in young preparations, which in turn was abolished by suramin, purinergic receptor antagonist. α3-GABAA receptor subunit expression tends to change in an age-dependent manner. CONCLUSIONS AND INFERENCES Our results reveal age-related differences in GABAergic transmission in human colon. At all the age tested GABA regulates muscular contractility modulating the activity of the intrinsic neurons. Activation of GABAA receptor, through acetylcholine release, induces contraction, which increases in amplitude with age. GABAB receptor activation leads to neural release of NO and purines, being a loss of purinergic-component in aged group.
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Affiliation(s)
- Maria Grazia Zizzo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF)University of PalermoViale delle Scienze,ed 16Palermo90128Italy,ATeN (Advanced Technologies Network) CenterUniversity of PalermoViale delle Scienze, ed 18Palermo90128Italy
| | - Adele Cicio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF)University of PalermoViale delle Scienze,ed 16Palermo90128Italy
| | - Stefania Raimondo
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Bi.N.D)University of PalermoSection of Biology and GeneticsPalermo90133Italy
| | - Riccardo Alessandro
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Bi.N.D)University of PalermoSection of Biology and GeneticsPalermo90133Italy
| | - Rosa Serio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF)University of PalermoViale delle Scienze,ed 16Palermo90128Italy
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13
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Kikel-Coury NL, Brandt JP, Correia IA, O’Dea MR, DeSantis DF, Sterling F, Vaughan K, Ozcebe G, Zorlutuna P, Smith CJ. Identification of astroglia-like cardiac nexus glia that are critical regulators of cardiac development and function. PLoS Biol 2021; 19:e3001444. [PMID: 34793438 PMCID: PMC8601506 DOI: 10.1371/journal.pbio.3001444] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 10/18/2021] [Indexed: 01/09/2023] Open
Abstract
Glial cells are essential for functionality of the nervous system. Growing evidence underscores the importance of astrocytes; however, analogous astroglia in peripheral organs are poorly understood. Using confocal time-lapse imaging, fate mapping, and mutant genesis in a zebrafish model, we identify a neural crest-derived glial cell, termed nexus glia, which utilizes Meteorin signaling via Jak/Stat3 to drive differentiation and regulate heart rate and rhythm. Nexus glia are labeled with gfap, glast, and glutamine synthetase, markers that typically denote astroglia cells. Further, analysis of single-cell sequencing datasets of human and murine hearts across ages reveals astrocyte-like cells, which we confirm through a multispecies approach. We show that cardiac nexus glia at the outflow tract are critical regulators of both the sympathetic and parasympathetic system. These data establish the crucial role of glia on cardiac homeostasis and provide a description of nexus glia in the PNS.
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Affiliation(s)
- Nina L. Kikel-Coury
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America
- Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Notre Dame, Indiana, United States of America
| | - Jacob P. Brandt
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America
- Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Notre Dame, Indiana, United States of America
| | - Isabel A. Correia
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America
| | - Michael R. O’Dea
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America
| | - Dana F. DeSantis
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America
- Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Notre Dame, Indiana, United States of America
| | - Felicity Sterling
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America
| | - Kevin Vaughan
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America
| | - Gulberk Ozcebe
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana, United States of America
| | - Pinar Zorlutuna
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana, United States of America
| | - Cody J. Smith
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America
- Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Notre Dame, Indiana, United States of America
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14
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Seguella L, Gulbransen BD. Enteric glial biology, intercellular signalling and roles in gastrointestinal disease. Nat Rev Gastroenterol Hepatol 2021; 18:571-587. [PMID: 33731961 PMCID: PMC8324524 DOI: 10.1038/s41575-021-00423-7] [Citation(s) in RCA: 179] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/28/2021] [Indexed: 02/07/2023]
Abstract
One of the most transformative developments in neurogastroenterology is the realization that many functions normally attributed to enteric neurons involve interactions with enteric glial cells: a large population of peripheral neuroglia associated with enteric neurons throughout the gastrointestinal tract. The notion that glial cells function solely as passive support cells has been refuted by compelling evidence that demonstrates that enteric glia are important homeostatic cells of the intestine. Active signalling mechanisms between enteric glia and neurons modulate gastrointestinal reflexes and, in certain circumstances, function to drive neuroinflammatory processes that lead to long-term dysfunction. Bidirectional communication between enteric glia and immune cells contributes to gastrointestinal immune homeostasis, and crosstalk between enteric glia and cancer stem cells regulates tumorigenesis. These neuromodulatory and immunomodulatory roles place enteric glia in a unique position to regulate diverse gastrointestinal disease processes. In this Review, we discuss current concepts regarding enteric glial development, heterogeneity and functional roles in gastrointestinal pathophysiology and pathophysiology, with a focus on interactions with neurons and immune cells. We also present a working model to differentiate glial states based on normal function and disease-induced dysfunctions.
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Affiliation(s)
- Luisa Seguella
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy
- Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, MI, USA
| | - Brian D Gulbransen
- Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, MI, USA.
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15
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Nutraceuticals and Enteric Glial Cells. Molecules 2021; 26:molecules26123762. [PMID: 34205534 PMCID: PMC8234579 DOI: 10.3390/molecules26123762] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/21/2022] Open
Abstract
Until recently, glia were considered to be a structural support for neurons, however further investigations showed that glial cells are equally as important as neurons. Among many different types of glia, enteric glial cells (EGCs) found in the gastrointestinal tract, have been significantly underestimated, but proved to play an essential role in neuroprotection, immune system modulation and many other functions. They are also said to be remarkably altered in different physiopathological conditions. A nutraceutical is defined as any food substance or part of a food that provides medical or health benefits, including prevention and treatment of the disease. Following the description of these interesting peripheral glial cells and highlighting their role in physiological and pathological changes, this article reviews all the studies on the effects of nutraceuticals as modulators of their functions. Currently there are only a few studies available concerning the effects of nutraceuticals on EGCs. Most of them evaluated molecules with antioxidant properties in systemic conditions, whereas only a few studies have been performed using models of gastrointestinal disorders. Despite the scarcity of studies on the topic, all agree that nutraceuticals have the potential to be an interesting alternative in the prevention and/or treatment of enteric gliopathies (of systemic or local etiology) and their associated gastrointestinal conditions.
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16
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A chronic low dosage of taurine induces muscle weakness in castrated-aged mice. TRANSLATIONAL MEDICINE OF AGING 2021. [DOI: 10.1016/j.tma.2021.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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17
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Loeza-Alcocer E, McPherson TP, Gold MS. Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception. J Physiol 2019; 597:3425-3439. [PMID: 31077379 DOI: 10.1113/jp278025] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 05/10/2019] [Indexed: 12/11/2022] Open
Abstract
KEY POINTS While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from central terminals and/or signalling in the sensory neuron cell body. Evidence that GABA receptors are transported to peripheral terminals and that there are several sources of GABA in the colon raise the possibility that GABA signalling in the periphery may influence colonic afferent excitability. GABAA and GABAB are present and functional in the colon, where exogenous agonists decrease the excitability of colonic afferents and suppress visceral nociception. Endogenous GABA release within the colon is sufficient to establish the resting excitability of colonic afferents as well as the behavioural response to noxious stimulation of the colon, primarily via GABAA receptors. Peripheral GABA receptors may serve as a viable target for the treatment of visceral pain. ABSTRACT It is well established that GABA receptors at the central terminals of primary afferent fibres regulate afferent input to the superficial dorsal horn. However, the extent to which peripheral GABA signalling may also regulate afferent input remains to be determined. The colon was used to explore this issue because of the numerous endogenous sources of GABA that have been described in this tissue. The influence of GABA signalling on colonic afferent excitability was assessed in an ex vivo mouse colorectum pelvic nerve preparation where test compounds were applied to the receptive field. The visceromotor response (VMR) evoked by noxious colorectal distension was used to assess the impact of GABA signalling on visceral nociception, where test compounds were applied directly to the colon. Application of either GABAA or GABAB receptor agonists attenuated the colonic afferent response to colon stretch. Conversely, GABAA and GABAB receptor antagonists increased the stretch response. However, while the noxious distension-induced VMR was attenuated in the presence of GABAA and GABAB receptor agonists, the VMR was only consistently increased by GABAA receptor antagonists. These results suggest that GABA receptors are present and functional in the peripheral terminals of colonic afferents and activation of these receptors via endogenous GABA release contributes to the establishment of colonic afferent excitability and visceral nociception. These results suggest that increasing peripheral GABA receptor signalling could be used to treat visceral pain.
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Affiliation(s)
- Emanuel Loeza-Alcocer
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Thomas P McPherson
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Michael S Gold
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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18
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Chen S, Tan B, Xia Y, Liao S, Wang M, Yin J, Wang J, Xiao H, Qi M, Bin P, Liu G, Ren W, Yin Y. Effects of dietary gamma-aminobutyric acid supplementation on the intestinal functions in weaning piglets. Food Funct 2019; 10:366-378. [PMID: 30601517 DOI: 10.1039/c8fo02161a] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2023]
Abstract
This study aims to investigate the effects of dietary gamma-aminobutyric acid (GABA) supplementation on the growth performance, intestinal immunity, intestinal GABAergic system, amino acid profiles and gut microflora of the weaned piglets. Totally sixteen healthy piglets were randomly assigned into two groups to be fed with the basal diet (Con group) or the basal diet with GABA (20 mg kg-1) supplementation. Body weights and feed intakes were monitored weekly. Piglets were sacrificed after 3 weeks of GABA supplementation to collect the blood, ileum, ileal mucosa and luminal content. Immune-associated factors, GABAergic system, amino acid profiles, and microbiota in the ileum and serum amino acid profiles were explored. The results showed that GABA supplementation improved the growth performance and modulated the intestinal immunity with inhibiting the gene expressions of IL-22, proinflammatory cytokines (IL-1 and IL-18), and Muc1, but promoted the expressions of anti-inflammatory cytokines (IFN-γ, IL-4, and IL-10), TLR6 and MyD88. GABA regulated a few components of the intestinal GABAergic system, increased the levels of most amino acids in the ileal mucosa but reduced the serum amino acid profiles. GABA regulated the population and diversity of intestinal microbiota, such as the abundances of the dominant microbial populations, the community richness, and diversity of the ileal microbiota. In conclusion, GABA supplementation modulated the intestinal functions, including intestinal immunity, intestinal amino acid profiles and gut microbiota, and the results can be helpful for understanding the functions of GABA in the intestine.
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Affiliation(s)
- Shuai Chen
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, Hunan, China.
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19
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Valès S, Touvron M, Van Landeghem L. Enteric glia: Diversity or plasticity? Brain Res 2018; 1693:140-145. [PMID: 29425908 DOI: 10.1016/j.brainres.2018.02.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 01/27/2018] [Accepted: 02/01/2018] [Indexed: 01/16/2023]
Abstract
Glial cells of the enteric nervous system correspond to a unique glial lineage distinct from other central and peripheral glia, and form a vast and abundant network spreading throughout all the layers of the gastrointestinal wall. Research over the last two decades has demonstrated that enteric glia regulates all major gastrointestinal functions via multiple bi-directional crosstalk with enteric neurons and other neighboring cell types. Recent studies propose that enteric glia represents a heterogeneous population associated with distinct localization within the gut wall, phenotype and activity. Compelling evidence also indicates that enteric glial cells are capable of plasticity leading to phenotypic changes whose pinnacle so far has been shown to be the generation of enteric neurons. While alterations of the glial network have been heavily incriminated in the development of gastrointestinal pathologies, enteric glial cells have also recently emerged as an active player in gut-brain signaling. Therefore, the development of tools and techniques to better appraise enteric glia heterogeneity and plasticity will undoubtedly unveil critical regulatory mechanisms implicated in gut health and disease, as well as disorders of the gut-brain axis.
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Affiliation(s)
- Simon Valès
- Bretagne Loire University, Nantes University, INSERM 1235, IMAD, The Enteric Nervous System in Gut and Brain Disorders, 1 rue Gaston Veil, 44035 Nantes Cedex, France.
| | - Melissa Touvron
- Department of Molecular Biomedical Sciences, North Carolina State University, College of Veterinary Medicine, CVM Main Building, Campus Box #8401, 1060 William Moore Drive, Raleigh, NC 27607, USA.
| | - Laurianne Van Landeghem
- Department of Molecular Biomedical Sciences, North Carolina State University, College of Veterinary Medicine, CVM Main Building, Campus Box #8401, 1060 William Moore Drive, Raleigh, NC 27607, USA.
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20
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Lilli NL, Quénéhervé L, Haddara S, Brochard C, Aubert P, Rolli-Derkinderen M, Durand T, Naveilhan P, Hardouin JB, De Giorgio R, Barbara G, Bruley des Varannes S, Coron E, Neunlist M. Glioplasticity in irritable bowel syndrome. Neurogastroenterol Motil 2018; 30:e13232. [PMID: 29027719 DOI: 10.1111/nmo.13232] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 09/17/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Growing evidence indicates a wide array of cellular remodeling in the mucosal microenvironment during irritable bowel syndrome (IBS), which possibly contributes to pathophysiology and symptom generation. Here, we investigated whether enteric glial cells (EGC) may be altered, and which factors/mechanisms lead to these changes. METHODS Colonic mucosal biopsies of IBS patients (13 IBS-Constipation [IBS-C]; 10 IBS-Diarrhea [IBS-D]; 11 IBS-Mixed [IBS-M]) and 24 healthy controls (HC) were analyzed. Expression of S100β and GFAP was measured. Cultured rat EGC were incubated with supernatants from mucosal biopsies, then proliferation and Ca2+ response to ATP were analyzed using flow cytometry and Ca2+ imaging. Histamine and histamine 1-receptor (H1R) involvement in the effects of supernatant upon EGC was analyzed. KEY RESULTS Compared to HC, the mucosal area immunoreactive for S100β was significantly reduced in biopsies of IBS patients, independently of the IBS subtype. IBS-C supernatants reduced EGC proliferation and IBS-D and IBS-M supernatants reduced Ca2+ response to ATP in EGC. EGC expressed H1R and the effects of supernatant upon Ca2+ response to ATP in EGC were blocked by pyrilamine and reproduced by histamine via H1R. IBS supernatants reduced mRNA expression of connexin-43. The S100β-stained area was negatively correlated with the frequency and intensity of pain and bloating. CONCLUSION AND INFERENCES Changes in EGC occur in IBS, involving mucosal soluble factors. Histamine, via activation of H1R-dependent pathways, partly mediates altered Ca2+ response to ATP in EGC. These changes may contribute to the pathophysiology and the perception of pain and bloating in patients with IBS.
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Affiliation(s)
- N L Lilli
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France.,Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital Hôtel-Dieu, Nantes, France
| | - L Quénéhervé
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France.,Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital Hôtel-Dieu, Nantes, France
| | - S Haddara
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France.,Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital Hôtel-Dieu, Nantes, France
| | - C Brochard
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France
| | - P Aubert
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France.,Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital Hôtel-Dieu, Nantes, France
| | - M Rolli-Derkinderen
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France.,Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital Hôtel-Dieu, Nantes, France
| | - T Durand
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France.,Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital Hôtel-Dieu, Nantes, France
| | - P Naveilhan
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France.,Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital Hôtel-Dieu, Nantes, France
| | - J-B Hardouin
- Université de Nantes, INSERM, SPHERE, Université Bretagne Loire, Nantes, France
| | - R De Giorgio
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - G Barbara
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - S Bruley des Varannes
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France.,Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital Hôtel-Dieu, Nantes, France
| | - E Coron
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France.,Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital Hôtel-Dieu, Nantes, France
| | - M Neunlist
- Université de Nantes, INSERM, IMAD, The enteric nervous system in gut and brain disorders, Université Bretagne Loire, Nantes, France
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21
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Bassotti G, Macchioni L, Corazzi L, Marconi P, Fettucciari K. Clostridium difficile-related postinfectious IBS: a case of enteroglial microbiological stalking and/or the solution of a conundrum? Cell Mol Life Sci 2018; 75:1145-1149. [PMID: 29285574 PMCID: PMC11105427 DOI: 10.1007/s00018-017-2736-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/11/2017] [Accepted: 12/20/2017] [Indexed: 02/06/2023]
Abstract
Post-infectious irritable bowel syndrome is a well-defined pathological entity that develops in about one-third of subjects after an acute infection (bacterial, viral) or parasitic infestation. Only recently it has been documented that an high incidence of post-infectious irritable bowel syndrome occurs after Clostridium difficile infection. However, until now it is not known why in some patients recovered from this infection the gastrointestinal disturbances persist for months or years. Based on our in vitro studies on enteric glial cells exposed to the effects of C. difficile toxin B, we hypothesize that persistence of symptoms up to the development of irritable bowel syndrome might be due to a disturbance/impairment of the correct functions of the enteroglial intestinal network.
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Affiliation(s)
- Gabrio Bassotti
- Department of Medicine, University of Perugia Medical School, Perugia, Italy.
- Gastroenterology and Hepatology Section, Santa Maria della Misericordia Hospital, Piazzale Menghini, 1, 06156, San Sisto (Perugia), Italy.
| | - Lara Macchioni
- Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy
| | - Lanfranco Corazzi
- Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy
| | - Pierfrancesco Marconi
- Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy
| | - Katia Fettucciari
- Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy
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22
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Fried DE, Watson RE, Robson SC, Gulbransen BD. Ammonia modifies enteric neuromuscular transmission through glial γ-aminobutyric acid signaling. Am J Physiol Gastrointest Liver Physiol 2017; 313:G570-G580. [PMID: 28838986 PMCID: PMC5814673 DOI: 10.1152/ajpgi.00154.2017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/17/2017] [Accepted: 08/17/2017] [Indexed: 01/31/2023]
Abstract
Impaired gut motility may contribute, at least in part, to the development of systemic hyperammonemia and systemic neurological disorders in inherited metabolic disorders, or in severe liver and renal disease. It is not known whether enteric neurotransmission regulates intestinal luminal and hence systemic ammonia levels by induced changes in motility. Here, we propose and test the hypothesis that ammonia acts through specific enteric circuits to influence gut motility. We tested our hypothesis by recording the effects of ammonia on neuromuscular transmission in tissue samples from mice, pigs, and humans and investigated specific mechanisms using novel mutant mice, selective drugs, cellular imaging, and enzyme-linked immunosorbent assays. Exogenous ammonia increased neurogenic contractions and decreased neurogenic relaxations in segments of mouse, pig, and human intestine. Enteric glial cells responded to ammonia with intracellular Ca2+ responses. Inhibition of glutamine synthetase and the deletion of glial connexin-43 channels in hGFAP::CreERT2+/-/connexin43f/f mice potentiated the effects of ammonia on neuromuscular transmission. The effects of ammonia on neuromuscular transmission were blocked by GABAA receptor antagonists, and ammonia drove substantive GABA release as did the selective pharmacological activation of enteric glia in GFAP::hM3Dq transgenic mice. We propose a novel mechanism whereby local ammonia is operational through GABAergic glial signaling to influence enteric neuromuscular circuits that regulate intestinal motility. Therapeutic manipulation of these mechanisms may benefit a number of neurological, hepatic, and renal disorders manifesting hyperammonemia.NEW & NOTEWORTHY We propose that local circuits in the enteric nervous system sense and regulate intestinal ammonia. We show that ammonia modifies enteric neuromuscular transmission to increase motility in human, pig, and mouse intestine model systems. The mechanisms underlying the effects of ammonia on enteric neurotransmission include GABAergic pathways that are regulated by enteric glial cells. Our new data suggest that myenteric glial cells sense local ammonia and directly modify neurotransmission by releasing GABA.
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Affiliation(s)
- David E. Fried
- 1Neuroscience Program and Department of Physiology,
Michigan State University, East Lansing,
Michigan;
| | - Ralph E. Watson
- 2Department of Medicine, Michigan State
University, East Lansing, Michigan; and
| | - Simon C. Robson
- 3Divisions of Gastroenterology and Transplantation, Department
of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, Massachusetts
| | - Brian D. Gulbransen
- 1Neuroscience Program and Department of Physiology,
Michigan State University, East Lansing,
Michigan;
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23
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Kaewsaro K, Nualplub S, Bumrungsri S, Khuituan P. Furosemide suppresses ileal and colonic contractility via interactions with GABA-A receptor in mice. Clin Exp Pharmacol Physiol 2017; 44:1155-1165. [DOI: 10.1111/1440-1681.12824] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 06/28/2017] [Accepted: 07/19/2017] [Indexed: 11/28/2022]
Affiliation(s)
- Kannaree Kaewsaro
- Department of Physiology; Faculty of Science; Prince of Songkla University; Hat Yai Songkhla Thailand
- Department of Biology, Faculty of Science; Prince of Songkla University; Hat Yai Songkhla Thailand
| | - Suparp Nualplub
- Department of Physiology; Faculty of Science; Prince of Songkla University; Hat Yai Songkhla Thailand
| | - Sara Bumrungsri
- Department of Biology, Faculty of Science; Prince of Songkla University; Hat Yai Songkhla Thailand
| | - Pissared Khuituan
- Department of Physiology; Faculty of Science; Prince of Songkla University; Hat Yai Songkhla Thailand
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Abstract
AbstractBornaviruses cause neurologic diseases in several species of birds, especially parrots, waterfowl and finches. The characteristic lesions observed in these birds include encephalitis and gross dilatation of the anterior stomach — the proventriculus. The disease is thus known as proventricular dilatation disease (PDD). PDD is characterized by extreme proventricular dilatation, blockage of the passage of digesta and consequent death by starvation. There are few clinical resemblances between this and the bornaviral encephalitides observed in mammals. Nevertheless, there are common virus-induced pathogenic pathways shared across this disease spectrum that are explored in this review. Additionally, a review of the literature relating to gastroparesis in humans and the control of gastric mobility in mammals and birds points to several plausible mechanisms by which bornaviral infection may result in extreme proventricular dilatation.
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Le Berre‐Scoul C, Chevalier J, Oleynikova E, Cossais F, Talon S, Neunlist M, Boudin H. A novel enteric neuron-glia coculture system reveals the role of glia in neuronal development. J Physiol 2017; 595:583-598. [PMID: 27436013 PMCID: PMC5233665 DOI: 10.1113/jp271989] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 07/07/2016] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS Unlike astrocytes in the brain, the potential role of enteric glial cells (EGCs) in the formation of the enteric neuronal circuit is currently unknown. To examine the role of EGCs in the formation of the neuronal network, we developed a novel neuron-enriched culture model from embryonic rat intestine grown in indirect coculture with EGCs. We found that EGCs shape axonal complexity and synapse density in enteric neurons, through purinergic- and glial cell line-derived neurotrophic factor-dependent pathways. Using a novel and valuable culture model to study enteric neuron-glia interactions, our study identified EGCs as a key cellular actor regulating neuronal network maturation. ABSTRACT In the nervous system, the formation of neuronal circuitry results from a complex and coordinated action of intrinsic and extrinsic factors. In the CNS, extrinsic mediators derived from astrocytes have been shown to play a key role in neuronal maturation, including dendritic shaping, axon guidance and synaptogenesis. In the enteric nervous system (ENS), the potential role of enteric glial cells (EGCs) in the maturation of developing enteric neuronal circuit is currently unknown. A major obstacle in addressing this question is the difficulty in obtaining a valuable experimental model in which enteric neurons could be isolated and maintained without EGCs. We adapted a cell culture method previously developed for CNS neurons to establish a neuron-enriched primary culture from embryonic rat intestine which was cultured in indirect coculture with EGCs. We demonstrated that enteric neurons grown in such conditions showed several structural, phenotypic and functional hallmarks of proper development and maturation. However, when neurons were grown without EGCs, the complexity of the axonal arbour and the density of synapses were markedly reduced, suggesting that glial-derived factors contribute strongly to the formation of the neuronal circuitry. We found that these effects played by EGCs were mediated in part through purinergic P2Y1 receptor- and glial cell line-derived neurotrophic factor-dependent pathways. Using a novel and valuable culture model to study enteric neuron-glia interactions, our study identified EGCs as a key cellular actor required for neuronal network maturation.
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Auteri M, Zizzo MG, Mastropaolo M, Serio R. Opposite role played by GABAA and GABAB receptors in the modulation of peristaltic activity in mouse distal colon. Eur J Pharmacol 2014; 731:93-9. [PMID: 24642362 DOI: 10.1016/j.ejphar.2014.03.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 03/06/2014] [Indexed: 12/26/2022]
Abstract
We investigated the role of GABA on intestinal motility using as model the murine distal colon. Effects induced by GABA receptors recruitment were examined in whole colonic segments and isolated circular muscle preparations to analyze their influence on peristaltic reflex and on spontaneous and neurally-evoked contractions. Using a modified Trendelenburg set-up, rhythmic peristaltic contractions were evoked by gradual distension of the colonic segments. Spontaneous and neurally-evoked mechanical activity of circular muscle strips were recorded in vitro as changes in isometric tension. GABA, at low concentrations (10-50 µM), potentiated peristaltic activity and the neural cholinergic contractions, whilst it, at higher concentrations (500 µM-1mM), had inhibitory effects. GABA excitatory effects were mimicked by muscimol, GABAA-receptor agonist, and prevented by bicuculline, GABAA-receptor antagonist, which per se reduced peristaltic activity and the cholinergic contractile responses. Inhibitory effects were mimicked by baclofen, GABAB-receptor agonist, and antagonized by phaclofen, GABAB-receptor antagonist and by hexamethonium, neural nicotinic receptor antagonist. Guanethidine was ineffective on GABA effects. Non-cholinergic responses were not affected by GABA agents. All drugs failed to affect the response to carbachol. Lastly, GABAC receptor agonist/antagonist had any effect on colonic motility. In conclusion, GABA in mouse distal colon is a modulator of peristaltic activity via the regulation of acetylcholine release from cholinergic neurons through interaction with GABAA or GABAB receptors. GABAA receptors are recruited at low GABA concentrations, increasing acetylcholine release and propulsive activity. At high GABA concentrations the activation of GABAB receptors overrides GABAA receptor effects, decreasing acetylcholine release and peristaltic activity.
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Affiliation(s)
- Michelangelo Auteri
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Laboratorio di Fisiologia generale, Viale delle Scienze, I-90128 Palermo, Università di Palermo, Italy
| | - Maria Grazia Zizzo
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Laboratorio di Fisiologia generale, Viale delle Scienze, I-90128 Palermo, Università di Palermo, Italy
| | - Mariangela Mastropaolo
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Laboratorio di Fisiologia generale, Viale delle Scienze, I-90128 Palermo, Università di Palermo, Italy
| | - Rosa Serio
- Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Laboratorio di Fisiologia generale, Viale delle Scienze, I-90128 Palermo, Università di Palermo, Italy.
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Boesmans W, Cirillo C, Van den Abbeel V, Van den Haute C, Depoortere I, Tack J, Vanden Berghe P. Neurotransmitters involved in fast excitatory neurotransmission directly activate enteric glial cells. Neurogastroenterol Motil 2013; 25:e151-60. [PMID: 23279281 DOI: 10.1111/nmo.12065] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND The intimate association between glial cells and neurons within the enteric nervous system has confounded careful examination of the direct responsiveness of enteric glia to different neuroligands. Therefore, we aimed to investigate whether neurotransmitters known to elicit fast excitatory potentials in enteric nerves also activate enteric glia directly. METHODS We studied the effect of acetylcholine (ACh), serotonin (5-HT), and adenosine triphosphate (ATP) on intracellular Ca(2+) signaling using aequorin-expressing and Fluo-4 AM-loaded CRL-2690 rat and human enteric glial cell cultures devoid of neurons. The influence of these neurotransmitters on the proliferation of glia was measured and their effect on the expression of c-Fos as well as glial fibrillary acidic protein (GFAP), Sox10, and S100 was examined by immunohistochemistry and quantitative RT-PCR. KEY RESULTS Apart from ATP, also ACh and 5-HT induced a dose-dependent increase in intracellular Ca(2+) concentration in CRL-2690 cells. Similarly, these neurotransmitters also evoked Ca(2+) transients in human primary enteric glial cells obtained from mucosal biopsies. In contrast with ATP, stimulation with ACh and 5-HT induced early gene expression in CRL-2690 cells. The proliferation of enteric glia and their expression of GFAP, Sox10, and S100 were not affected following stimulation with these neurotransmitters. CONCLUSIONS & INFERENCES We provide evidence that enteric glial cells respond to fast excitatory neurotransmitters by changes in intracellular Ca(2+). On the basis of our experimental in vitro setting, we show that enteric glia are not only directly responsive to purinergic but also to serotonergic and cholinergic signaling mechanisms.
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Affiliation(s)
- W Boesmans
- Laboratory of Enteric NeuroScience, KU Leuven, Leuven, Belgium
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28
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Gulbransen BD, Sharkey KA. Novel functional roles for enteric glia in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 2012; 9:625-32. [PMID: 22890111 DOI: 10.1038/nrgastro.2012.138] [Citation(s) in RCA: 286] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Enteric glia are a unique class of peripheral glial cells within the gastrointestinal tract. Major populations of enteric glia are found in enteric ganglia in the myenteric and submucosal plexuses of the enteric nervous system (ENS); these cells are also found outside of the ENS, within the circular muscle and in the lamina propria of the mucosa. These different populations of cells probably represent unique classes of glial cells with differing functions. In the past few years, enteric glia have been found to be involved in almost every gut function including motility, mucosal secretion and host defence. Subepithelial glia seem to have a trophic and supporting relationship with intestinal epithelial cells, but the necessity of these roles in the maintenance of normal epithelial functions remains to be shown. Likewise, glia within enteric ganglia are activated by synaptic stimulation, suggesting an active role in synaptic transmission, but the precise role of glial activation in normal enteric network activity is unclear. Excitingly, enteric glia can also give rise to new neurons, but seemingly only under limited circumstances. In this Review, we discuss the current body of evidence supporting functional roles of enteric glia and identify key gaps in our understanding of the physiology of these unique cells.
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Affiliation(s)
- Brian D Gulbransen
- Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive North West Calgary, AB T2N 4N1, Canada
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29
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De Giorgio R, Giancola F, Boschetti E, Abdo H, Lardeux B, Neunlist M. Enteric glia and neuroprotection: basic and clinical aspects. Am J Physiol Gastrointest Liver Physiol 2012; 303:G887-93. [PMID: 22878122 DOI: 10.1152/ajpgi.00096.2012] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The enteric nervous system (ENS), a major regulatory system for gastrointestinal function, is composed of neurons and enteric glial cells (EGCs). Enteric glia have long been thought to provide only structural support to neurons. However, recent evidence indicates enteric glia-neuron cross talk significantly contributes to neuronal maintenance, survival, and function. Thus damage to EGCs may trigger neurodegenerative processes thought to play a role in gastrointestinal dysfunctions and symptoms. The purpose of this review is to provide an update on EGCs, particularly focusing on their possible neuroprotective features and the resultant enteric neuron abnormalities subsequent to EGC damage. These neuroprotective mechanisms may have pathogenetic relevance in a variety of functional and inflammatory gut diseases. Basic and clinical (translational) studies support a neuroprotective role mediated by EGCs. Different models have been developed to test whether selective EGC damage/ablation has an impact on gut functions and the ENS. Preclinical data indicated that selective EGC alterations were associated with changes in gut physiology related to enteric neuron abnormalities. In humans, a substantial loss of EGCs was described in patients with various functional and/or inflammatory gastrointestinal diseases. However, whether EGC changes precede or follow neuronal degeneration and loss and how this damage occurs is not defined. Additional studies on EGC neuroprotective capacity are expected to improve knowledge of gut diseases and pave the way for targeted therapeutic strategies of underlying neuropathies.
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Affiliation(s)
- Roberto De Giorgio
- Department of Clinical Medicine and Digestive Diseases and Internal Medicine, 40138 Bologna, Italy.
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30
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Kurjak M, Fichna J, Harbarth J, Sennefelder A, Allescher HD, Schusdziarra V, Storr M, Otto B. Effect of GABA-ergic mechanisms on synaptosomal NO synthesis and the nitrergic component of NANC relaxation in rat ileum. Neurogastroenterol Motil 2011; 23:e181-90. [PMID: 21414101 DOI: 10.1111/j.1365-2982.2011.01688.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND γ-Aminobutyric acid (GABA) acts on specific neural receptors [A, B and C(Aρ)] to modulate gastrointestinal function. The precise role of GABA receptor activation in the regulation of presynaptic nitric oxide (NO) synthesis in nerve terminals is unknown. METHODS Rat ileal nerve terminals were isolated by differential centrifugation. Nitric oxide synthesis was analysed using a L-[(3) H]arginine assay. In vitro studies were performed under non-adrenergic non-cholinergic (NANC) conditions on isolated ileal segments. KEY RESULTS γ-Aminobutyric acid inhibited NO synthesis significantly (n = 6, P < 0.05) [(fmol mg(-1) min(-1)) control: 27.7 ± 1.5, 10(-6) mol L(-1): 19.7 ± 1.3; 10(-5) mol L(-1): 17.5 ± 3.0]. This effect was antagonized by the GABA A receptor antagonist bicuculline and the GABA C receptor antagonist (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), but not by the GABA B receptor antagonist SCH 50911. The GABA A receptor agonist muscimol [(fmol mg(-1) min(-1)) control: 27.6 ± 1.0, 10(-6) mol L(-1): 19.1 ± 1.7, n = 5, P < 0.05] and the GABA C receptor agonist cis-4-aminocrotonic acid (CACA) [(fmol mg(-1) min(-1)) control: 29.5 ± 3.2, 10(-3) mol L(-1): 20.3 ± 2.5, n = 6, P < 0.05], mimicked the GABA-effect, whereas the GABA B agonist baclofen was ineffective. Bicuculline reversed the inhibitory effect of muscimol, TPMPA antagonized the effect of CACA. In functional experiments the GABA A and C receptor agonists reduced the NANC relaxation induced by electrical field stimulation in rat ileum by about 40%. After NOS-inhibition by Nε-nitro-L-arginine methyl ester (L-NAME) the GABA A receptor agonist had no effect, whereas the GABA C receptor agonist still showed a residual response. CONCLUSIONS & INFERENCES γ-Aminobutyric acid inhibits neural NO synthesis in rat ileum by GABA A and GABA C(Aρ) receptor-mediated mechanisms.
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Affiliation(s)
- M Kurjak
- Endooffice Abdomen, Munich, Germany.
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31
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Hyland NP, Cryan JF. A Gut Feeling about GABA: Focus on GABA(B) Receptors. Front Pharmacol 2010; 1:124. [PMID: 21833169 PMCID: PMC3153004 DOI: 10.3389/fphar.2010.00124] [Citation(s) in RCA: 128] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2010] [Accepted: 09/07/2010] [Indexed: 12/15/2022] Open
Abstract
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence GABA-mediated neurotransmission regulates many physiological functions, including those in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which are either ionotropic GABA(A) or metabotropic GABA(B). The latter which respond to the agonist baclofen have been least characterized, however accumulating data suggest that they play a key role in GI function in health and disease. Like GABA, GABA(B) receptors have been detected throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be determined, suggest GABA(B) receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABA(B) receptors makes it a potentially useful target in the treatment of several GI disorders. In light of the development of novel compounds such as peripherally acting GABA(B) receptor agonists, positive allosteric modulators of the GABA(B) receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABA(B) receptors within the GI tract.
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Affiliation(s)
- Niall P Hyland
- Alimentary Pharmabiotic Centre and Department of Pharmacology and Therapeutics, University College Cork Cork, Ireland
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32
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Shoji Y, Yamaguchi-Yamada M, Yamamoto Y. Glutamate- and GABA-mediated neuron–satellite cell interaction in nodose ganglia as revealed by intracellular calcium imaging. Histochem Cell Biol 2010; 134:13-22. [DOI: 10.1007/s00418-010-0711-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/14/2010] [Indexed: 12/19/2022]
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Satellite glial cells in sympathetic and parasympathetic ganglia: in search of function. ACTA ACUST UNITED AC 2010; 64:304-27. [PMID: 20441777 DOI: 10.1016/j.brainresrev.2010.04.009] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2009] [Revised: 04/14/2010] [Accepted: 04/27/2010] [Indexed: 01/08/2023]
Abstract
Glial cells are established as essential for many functions of the central nervous system, and this seems to hold also for glial cells in the peripheral nervous system. The main type of glial cells in most types of peripheral ganglia - sensory, sympathetic, and parasympathetic - is satellite glial cells (SGCs). These cells usually form envelopes around single neurons, which create a distinct functional unit consisting of a neuron and its attending SGCs. This review presents the knowledge on the morphology of SGCs in sympathetic and parasympathetic ganglia, and the (limited) available information on their physiology and pharmacology. It appears that SGCs carry receptors for ATP and can thus respond to the release of this neurotransmitter by the neurons. There is evidence that SGCs have an uptake mechanism for GABA, and possibly other neurotransmitters, which enables them to control the neuronal microenvironment. Damage to post- or preganglionic nerve fibers influences both the ganglionic neurons and the SGCs. One major consequence of postganglionic nerve section is the detachment of preganglionic nerve terminals, resulting in decline of synaptic transmission. It appears that, at least in sympathetic ganglia, SGCs participate in the detachment process, and possibly in the subsequent recovery of the synaptic connections. Unlike sensory neurons, neurons in autonomic ganglia receive synaptic inputs, and SGCs are in very close contact with synaptic boutons. This places the SGCs in a position to influence synaptic transmission and information processing in autonomic ganglia, but this topic requires much further work.
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34
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Xue H, Liu S, Ji T, Ren W, Zhang XH, Zheng LF, Wood JD, Zhu JX. Expression of NKCC2 in the rat gastrointestinal tract. Neurogastroenterol Motil 2009; 21:1068-e89. [PMID: 19460103 DOI: 10.1111/j.1365-2982.2009.01334.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
NKCC2, an isoform of Na+-K+-2Cl(-) cotransporter, is principally present in the kidney and plays a critical role in salt reabsorption. Expression of NKCC2 has been found in the apical membrane of intestinal epithelial cells in a number of marine fish, however, details for expression in the mammalian gastrointestinal tract are lacking. RT-PCR, Western blotting and immunohistochemistry were used to study the expression and localization of NKCC2 in the rat gastrointestinal tract. We found that mRNA transcripts, protein and immunoreactivity (IR) for NKCC2 were expressed in the stomach, small and large intestine of adult rats. NKCC2 IR was localized to the base of the gastric glands, intestinal epithelia, myenteric and submucosal plexuses. NKCC2 IR was expressed strongly in the apical membranes and weakly in the basolateral membranes of intestinal epithelial cells. In the enteric nervous system, NKCC2 IR was widely distributed and localized to enteric neurons with cholinergic, calretinin and nitrergic neuronal immunochemical codes in the myenteric plexus. It was localized to non-cholinergic secretomotor neurons in the submucosal plexus. In conclusion, this study for the first time clearly detected the expression of NKCC2 in the gastrointestinal tract of a mammalian species. Expression of NKCC2 in gastrointestinal epithelial cells suggested that this cation chloride cotransporter might be involved in gastrointestinal ion transport. Expression of NKCC2 in enteric neurons might contribute to the accumulation of Cl(-) and a more depolarized E(Cl)(-) in enteric neurons.
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Affiliation(s)
- H Xue
- Department of Physiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
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35
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Gomes P, Chevalier J, Boesmans W, Roosen L, van den Abbeel V, Neunlist M, Tack J, Vanden Berghe P. ATP-dependent paracrine communication between enteric neurons and glia in a primary cell culture derived from embryonic mice. Neurogastroenterol Motil 2009; 21:870-e62. [PMID: 19368656 DOI: 10.1111/j.1365-2982.2009.01302.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The importance of dynamic interactions between glia and neurons is increasingly recognized, both in the central and enteric nervous system. However, apart from their protective role, little is known about enteric neuro-glia interaction. The aim was to investigate neuro-glia intercellular communication in a mouse culture model using optical techniques. Complete embryonic (E13) guts were enzymatically dissociated, seeded on coverslips and studied with immunohistochemistry and Ca(2+)-imaging. Putative progenitor-like cells (expressing both PGP9.5 and S-100) differentiated over approximately 5 days into glia or neurons expressing typical cell-specific markers. The glia-neuron ratio could be manipulated by specific supplements (N2, G5). Neurons and glia were functionally identified both by their Ca(2+)-response to either depolarization (high K(+)) or lysophosphatidic acid and by the expression of typical markers. Neurons responded to ACh, DMPP, 5-HT, ATP and electrical stimulation, while glia responded to ATP and ADPbetas. Inhibition of glial responses by MRS2179 suggests involvement of P2Y1 receptors. Neuronal stimulation also caused delayed glial responses, which were reduced by suramin and by exogenous apyrases that catalyse nucleotide breakdown. Conversely, glial responses were enhanced by ARL-67156, an ecto-ATPase inhibitor. In this mouse enteric co-culture, functional glia and neurons can be easily monitored using optical techniques. Glial cells can be activated directly by ATP or ADPbetas. Activation of neuronal cells (DMPP, K(+)) causes secondary responses in glial cells, which can be modulated by tuning ATP and ADP breakdown. This strongly supports the involvement of paracrine purinergic communication between enteric neurons and glia.
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Affiliation(s)
- P Gomes
- Center for Gastroenterological Research, Katholieke Universiteit Leuven, Leuven, Belgium
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36
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Bassotti G, Villanacci V, Fisogni S, Rossi E, Baronio P, Clerici C, Maurer CA, Cathomas G, Antonelli E. Enteric glial cells and their role in gastrointestinal motor abnormalities: introducing the neuro-gliopathies. World J Gastroenterol 2007; 13:4035-4041. [PMID: 17696219 PMCID: PMC4205302 DOI: 10.3748/wjg.v13.i30.4035] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2007] [Revised: 05/03/2007] [Accepted: 05/12/2007] [Indexed: 02/06/2023] Open
Abstract
The role of enteric glial cells has somewhat changed from that of mere mechanical support elements, gluing together the various components of the enteric nervous system, to that of active participants in the complex interrelationships of the gut motor and inflammatory events. Due to their multiple functions, spanning from supporting elements in the myenteric plexuses to neurotransmitters, to neuronal homeostasis, to antigen presenting cells, this cell population has probably more intriguing abilities than previously thought. Recently, some evidence has been accumulating that shows how these cells may be involved in the pathophysiological aspects of some diseases. This review will deal with the properties of the enteric glial cells more strictly related to gastrointestinal motor function and the human pathological conditions in which these cells may play a role, suggesting the possibility of enteric neuro-gliopathies.
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37
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Nasser Y, Keenan CM, Ma AC, McCafferty DM, Sharkey KA. Expression of a functional metabotropic glutamate receptor 5 on enteric glia is altered in states of inflammation. Glia 2007; 55:859-72. [PMID: 17405149 DOI: 10.1002/glia.20507] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The metabotropic glutamate receptor 5 (mGluR5) is expressed by astrocytes and its expression is modulated by inflammation. Enteric glia have many similarities to astrocytes and are the most numerous cell in the enteric nervous system (ENS). We investigated whether enteric glia express a functional mGluR5 and whether expression of this receptor was altered in colitis. In both enteric plexuses of the ileum and colon of guinea pigs and mice, we observed widespread glial mGluR5 expression. Incubation of isolated segments of the guinea pig ileum with the mGluR5 specific agonist RS-2-chloro-5-hydroxyphenylglycine (CHPG) caused a dose-dependent increase in the glial expression of c-Fos and the phosphorylated form of the extracellular signal-regulated kinase 1/2. Preincubation of tissues with the group I metabotropic glutamate receptor antagonist, S-4-carboxyphenylglycine, abolished the effects of CHPG. We examined mGluR5 expression in the guinea pig trinitrobenzene sulfonic acid and the IL-10 gene-deficient (IL-10(-/-)) mouse models of colitis. In guinea pigs, mGluR5 immunoreactivity became diffusely localized over the colonic myenteric ganglia, suggesting a change in receptor distribution. In contrast, glial mGluR5 expression was significantly reduced in the colonic myenteric plexus of IL-10(-/-) mice, as assessed with both real-time quantitative RT-PCR as well as immunohistochemistry and image analysis. These changes occurred without concomitant changes to enteric ganglia or glial fibrillary acidic protein expression in the IL-10(-/-) mouse. Our data suggest that enteric glia are a functional target of the glutamatergic neurotransmitter system in the ENS and that changes in mGluR5 expression may be of physiological significance during colitis.
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Affiliation(s)
- Yasmin Nasser
- Institute for Infection, Immunity and Inflammation, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
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Zizzo MG, Mulè F, Serio R. Functional evidence for GABA as modulator of the contractility of the longitudinal muscle in mouse duodenum: Role of GABAA and GABAC receptors. Neuropharmacology 2007; 52:1685-90. [PMID: 17517423 DOI: 10.1016/j.neuropharm.2007.03.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2006] [Revised: 03/19/2007] [Accepted: 03/28/2007] [Indexed: 11/23/2022]
Abstract
We investigated, in vitro, the effects of gamma-aminobutyric acid (GABA) on the spontaneous mechanical activity of the longitudinal smooth muscle in mouse duodenum. GABA induced an excitatory effect, consisting in an increase in the basal tone, which was antagonized by the GABA(A)-receptor antagonist, bicuculline, potentiated by (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid hydrate (TPMPA), a GABA(C)-receptor antagonist and it was not affected by phaclofen, a GABA(B)-receptor antagonist. Muscimol, GABA(A) receptor agonist, induced a contractile effect markedly reduced by bicuculline, tetrodotoxin (TTX), hexamethonium and atropine. Cis-4-aminocrotonic acid (CACA), a specific GABA(C) receptor agonist, induced an inhibitory effect, consisting in the reduction of the amplitude of the spontaneous contractions and muscular relaxation, which was antagonised by TPMPA, GABA(C)-receptor antagonist, TTX or N(omega)-nitro-l-arginine methyl ester (L-NAME), nitric oxide (NO) synthase inhibitor, but not affected by hexamethonium. In conclusion, our study indicates that GABA is a modulator of mechanical activity of longitudinal muscle in mouse duodenum. GABA may act through neuronal presynaptic receptors, namely GABA(A) receptors, leading to the release of ACh from excitatory cholinergic neurons, and GABA(C) receptors increasing the release of NO from non-adrenergic, non-cholinergic inhibitory neurons.
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Affiliation(s)
- Maria Grazia Zizzo
- Dipartimento di Biologia Cellulare e dello Sviluppo, Laboratorio di Fisiologia generale, Università di Palermo, Viale delle Scienze, 90128 Palermo, Italy
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Nasser Y, Fernandez E, Keenan CM, Ho W, Oland LD, Tibbles LA, Schemann M, MacNaughton WK, Rühl A, Sharkey KA. Role of enteric glia in intestinal physiology: effects of the gliotoxin fluorocitrate on motor and secretory function. Am J Physiol Gastrointest Liver Physiol 2006; 291:G912-27. [PMID: 16798727 DOI: 10.1152/ajpgi.00067.2006] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The role of enteric glia in gastrointestinal physiology remains largely unexplored. We examined the actions of the gliotoxin fluorocitrate (FC) on intestinal motility, secretion, and inflammation after assessing its efficacy and specificity in vitro. FC (100 microM) caused a significant decrease in the phosphorylation of the glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diaz-4-yl)amino]-2-deoxyglucose in enteric glial cultures and a reduction in glial uptake of the fluorescent dipeptide Ala-Lys-7-amino-4-methylcoumarin-3-acetic acid in both the ileum and colon. Dipeptide uptake by resident murine macrophages or guinea pig myenteric neurons was unaffected by FC. Incubation of isolated guinea pig ileal segments with FC caused a specific and significant increase in glial expression of the phosphorylated form of ERK-1/2. Disruption of enteric glial function with FC in mice reduced small intestinal motility in vitro, including a significant decrease in basal tone and the amplitude of contractility in response to electrical field stimulation. Mice treated with 10 or 20 micromol/kg FC twice daily for 7 days demonstrated a concentration-dependent decrease in small intestinal transit. In contrast, no changes in colonic transit or ion transport in vitro were observed. There were no changes in glial or neuronal morphology, any signs of inflammation in the FC-treated mice, or any change in the number of myenteric nitric oxide synthase-expressing neurons. We conclude that FC treatment causes enteric glial dysfunction, without causing intestinal inflammation. Our data suggest that enteric glia are involved in the modulation of enteric neural circuits underlying the regulation of intestinal motility.
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Affiliation(s)
- Yasmin Nasser
- Institute for Infection, Immunity and Inflammation, University of Calgary, Alberta, Canada
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Reis HJ, Vanden Berghe P, Romano-Silva MA, Smith TK. GABA-induced calcium signaling in cultured enteric neurons is reinforced by activation of cholinergic pathways. Neuroscience 2006; 139:485-94. [PMID: 16446040 DOI: 10.1016/j.neuroscience.2005.12.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2005] [Revised: 12/15/2005] [Accepted: 12/20/2005] [Indexed: 11/24/2022]
Abstract
UNLABELLED GABA is an important inhibitory transmitter in the CNS. In the enteric nervous system, however, both excitatory and inhibitory actions have been reported. Here, we investigated the effects of GABA on the intracellular Ca2+ concentration of guinea-pig myenteric neurons (at 35 degrees C) using Fura-2-AM. Neurons were identified by 75 mM K+ depolarization (5 s), which evoked a transient intracellular Ca2+ concentration increase. GABA (10 s) induced a dose dependent (5 nM-1 microM) transient intracellular Ca2+ concentration rise in the majority of neurons (500 nM GABA: 251+/-17 nM, n=232/289). Interestingly, the response to 5 microM GABA (n=18) lasted several minutes and did not fully recover. GABA response amplitudes were significantly (P<0.001) reduced by GABAA and GABAB receptor antagonists (10 microM) bicuculline and phaclofen. The GABAA agonist isoguvacine (10 microM) and GABAB agonist baclofen (10 microM) induced similar responses as 50 nM GABA, while the GABAC agonist cis-4-aminocrotonic acid (CACA) (10 microM) only elicited small responses in a minority of neurons. Removal of extracellular Ca2+ abolished all responses while depletion of intracellular Ca2+ stores by thapsigargin (5 microM) did not alter the responses to 500 nM GABA (n=13), but reduction of Ca2+ influx through voltage-dependent Ca2+ channels did. The nicotinic antagonist hexamethonium (100 microM) also reduced GABA responses by almost 70% suggesting that GABA stimulates cholinergic pathways, while the purinergic receptor blocker pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) and the 5-HT3 receptor blocker ondansetron only had minor effects. CONCLUSION GABA elicits transient intracellular Ca2+ concentration responses in the majority of myenteric neurons through activation of GABAA and GABAB receptors and much of the response can be attributed to facilitation of ACh release. Thus GABA may act mainly as a modulator that sets the state of excitability of the enteric nerve network. A concentration of 5 microM GABA, although frequently used in pharmacological experiments, seems to cause a detrimental response reminiscent of the neurotoxic effects glutamate has in the CNS.
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Affiliation(s)
- H J Reis
- Department of Physiology and Cell Biology/352, University of Nevada, School of Medicine, 1660 North Virginia Street, Reno, NV 89557-0046, USA
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Abstract
The enteric nervous system is composed of both neurons and glia. Recent evidence indicates that enteric glia-which vastly outnumber enteric neurons-are actively involved in the control of gastrointestinal functions: they contain neurotransmitter precursors, have the machinery for uptake and degradation of neuroligands, and express neurotransmitter-receptors which makes them well suited as intermediaries in enteric neurotransmission and information processing in the ENS. Novel data further suggest that enteric glia have an important role in maintaining the integrity of the mucosal barrier of the gut. Finally, enteric glia may also serve as a link between the nervous and immune systems of the gut as indicated by their potential to synthesize cytokines, present antigen and respond to inflammatory insults. The role of enteric glia in human disease has not yet been systematically studied, but based on the available evidence it is predictable that enteric glia are involved in the etiopathogenesis of various pathological processes in the gut, particularly such with neuroinflammatory or neurodegenerative components.
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Affiliation(s)
- A Rühl
- Department of Human Biology, Technical University of Munich, Germany.
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Abstract
Inflammation of the bowel causes structural and functional changes to the enteric nervous system (ENS). While morphological alterations to the ENS are evident in some inflammatory conditions, it appears that relatively subtle modifications to the neurophysiology of enteric microcircuits may play a role in gastrointestinal (GI) dysfunction. These include changes to the excitability and synaptic properties of enteric neurones. The response of the ENS to inflammation varies according to the site and type of inflammation, with the functional consequences depending on the nature of the inflammatory stimulus. It has become clear that inflammation at one site can produce changes that occur at remotes sites in the GI tract. Immunohistochemical data from patients with inflammatory bowel disease (IBD) and animal models indicate that inflammation alters the neurochemical content of some functional classes of enteric neurones. A growing body of evidence supports an active role for enteric glia in neuronal and neuroimmune communication in the GI tract, particularly during inflammation. In conclusion, plasticity of the ENS is a feature of intestinal inflammation. Elucidation of the mechanisms whereby inflammation alters enteric neural control of GI functions may lead to novel treatments for IBD.
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Affiliation(s)
- A E Lomax
- Department of Physiology and Biophysics, Gastrointestinal, Neuroscience and Mucosal Inflammation Research Groups, University of Calgary, Calgary, Alberta, Canada
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Abstract
The enteric nervous system is composed of both enteric neurones and enteric glia. Enteric glial cells were first described by Dogiel and are now known to outnumber neurones approximately 4 : 1. In the past, these cells were assumed to subserve a largely supportive role; however, recent evidence indicates that enteric glial cells may play a more active role in the control of gut function. In transgenic mouse models, where enteric glial cells are selectively ablated, the loss of glia results in intestinal inflammation and disruption of the epithelial barrier. Enteric glia are activated specifically by inflammatory insults and may contribute actively to inflammatory pathology via antigen presentation and cytokine synthesis. Enteric glia also express receptors for neurotransmitters and so may serve as intermediaries in enteric neurotransmission. Thus, enteric glia may serve as a link between the nervous and immune systems of the gut and may also have an important role in maintaining the integrity of the mucosal barrier and in other aspects of intestinal homeostasis.
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Affiliation(s)
- A Rühl
- Department of Human Biology, Technical University Munich, Freising-Weihenstephan, Germany.
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Reis HJ, Bíscaro FV, Gomez MV, Romano-Silva MA. Depolarization-evoked GABA release from myenteric plexus is partially coupled to L-, N-, and P/Q-type calcium channels. Cell Mol Neurobiol 2002; 22:805-11. [PMID: 12585697 PMCID: PMC11533751 DOI: 10.1023/a:1021821427540] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
1. There are many evidences suggesting that gamma-aminobutyrate (GABA) is an important neurotransmitter and/or neuromodulator in the gut. 2. Using the myenteric plexus-longitudinal muscle preparation from the guinea pig ileum, we investigated the evoked release of [3H] GABA from enteric neurons by electrical pulses or high KCl, which occurs in a calcium-dependent and -independent way. In addition, using selective calcium channel blockers, we report the participation of distinct subtypes of calcium channels in the evoked release, showing a minor participation of L- and Q-type calcium channels, while N- and P-type have a participation of approximately 15%, each. However, regardless of the combination of Ca2+ channel blockers, we did not observe an inhibition greater than 50% of the calcium-dependent component of [3H] GABA release. 3. Thus, while the observed Ca2+-independent release mostly probable occur via reversal of the membrane GABA transporter, in our conditions, a considerable portion of the Ca2+-dependent evoked release of [3H] GABA is not coupled to L-, N-, or P/Q-type calcium channels, suggesting the involvement of intracellular calcium stores or other ways of getting calcium across the membrane.
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Affiliation(s)
- Helton J Reis
- Laboratório de Neurofarmacologia, Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
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