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Iqbal A, Bokhari SFH, Rehman MU, Faizan Sattar SM, Bakht D, Dost W, Basit A. Gut-brain connection in schizophrenia: A narrative review. World J Psychiatry 2025; 15:103751. [DOI: 10.5498/wjp.v15.i5.103751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 02/23/2025] [Accepted: 03/31/2025] [Indexed: 04/30/2025] Open
Abstract
Schizophrenia is a complex neuropsychiatric disorder characterized by cognitive, emotional, and behavioral impairments. The microbiota-gut-brain axis is crucial in its pathophysiology, mediating communication between the gut and brain through neural, immune, endocrine, and metabolic pathways. Dysbiosis, or an imbalance in gut microbiota, is linked to neuroinflammation, systemic inflammation, and neurotransmitter disruptions, all of which contribute to the symptoms of schizophrenia. Gut microbiota-derived metabolites, such as short-chain fatty acids, influence brain function, including immune responses and neurotransmitter synthesis. These findings suggest that microbial imbalances exacerbate schizophrenia, providing a novel perspective on the disorder’s underlying mechanisms. Emerging microbiota-targeted therapies—such as probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation—show promise as adjunctive treatments, aiming to restore microbial balance and improve clinical outcomes. While further research is needed, targeting the microbiota-gut-brain axis offers an innovative approach to schizophrenia management, with the potential to enhance patient outcomes and quality of life.
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Affiliation(s)
- Asma Iqbal
- Department of Medicine and Surgery, King Edward Medical University, Lahore 54000, Punjab, Pakistan
| | | | - Muneeb Ur Rehman
- Department of Medicine and Surgery, King Edward Medical University, Lahore 54000, Punjab, Pakistan
| | | | - Danyal Bakht
- Department of Medicine and Surgery, King Edward Medical University, Lahore 54000, Punjab, Pakistan
| | - Wahidullah Dost
- Department of Curative Medicine, Kabul University of Medical Sciences, Kabul 10001, Afghanistan
| | - Abdul Basit
- Department of Medicine and Surgery, King Edward Medical University, Lahore 54000, Punjab, Pakistan
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2
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Nardini P, Filippi L, Zizi V, Molino M, Fazi C, Chivetti M, Pini A. Beta-3 Adrenoceptor Agonism Protects the Enteric Nervous Tissue Against Hyperoxia-Induced Damage. Cells 2025; 14:475. [PMID: 40214429 PMCID: PMC11988099 DOI: 10.3390/cells14070475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 03/19/2025] [Accepted: 03/21/2025] [Indexed: 04/14/2025] Open
Abstract
The beta-3 adrenergic receptor (β3-AR), whose expression is modulated by oxygen levels, was found to play a key role in organ maturation, and its agonism was reported to mitigate hyperoxia-induced large bowel damage by preventing organ hypoplasia, preserving epithelial integrity, vascularization, and the neurochemical coding in the colonic myenteric plexus. This study explored the effects of β3-AR agonism in preventing hyperoxia-related alterations on the ileal enteric nervous system (ENS). Sprague-Dawley rat pups were reared under normoxia or hyperoxia (85%) during the first two weeks after birth and treated or not with the β3-AR agonist BRL37344 at 1, 3, or 6 mg/kg. Hyperoxia caused an imbalance of inhibitory nitrergic and excitatory cholinergic neurons in both the myenteric and submucosal plexuses and decreased the amounts of neurons in the submucosal plexus and that of S100β+ and GFAP+ glial cells in the myenteric plexus. Administration of 3 mg/kg BRL37344 preserved the neuronal chemical coding and partially prevented the loss of myenteric GFAP+ glial cells, while it did not counteract submucosal neuronal loss. Our findings indicate the potential of β3-AR agonism as a new therapeutic strategy for hyperoxia-induced ileal ENS alterations.
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Affiliation(s)
- Patrizia Nardini
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (P.N.); (V.Z.); (M.M.); (M.C.)
| | - Luca Filippi
- Neonatology and Neonatal Intensive Care Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56124 Pisa, Italy;
| | - Virginia Zizi
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (P.N.); (V.Z.); (M.M.); (M.C.)
| | - Marta Molino
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (P.N.); (V.Z.); (M.M.); (M.C.)
| | - Camilla Fazi
- Department of Pediatric, Meyer Children’s University Hospital, 50139 Florence, Italy;
| | - Matteo Chivetti
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (P.N.); (V.Z.); (M.M.); (M.C.)
| | - Alessandro Pini
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (P.N.); (V.Z.); (M.M.); (M.C.)
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Han MN, Di Natale MR, Lei E, Furness JB, Finkelstein DI, Hao MM, Diwakarla S, McQuade RM. Assessment of gastrointestinal function and enteric nervous system changes over time in the A53T mouse model of Parkinson's disease. Acta Neuropathol Commun 2025; 13:58. [PMID: 40075409 PMCID: PMC11899089 DOI: 10.1186/s40478-025-01956-7] [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: 11/06/2024] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
Gastrointestinal (GI) dysfunctions, including constipation and delayed stomach emptying, are prevalent and debilitating non-motor symptoms of Parkinson's disease (PD). These symptoms have been associated with damage in the enteric nervous system (ENS) and the accumulation of pathogenic alpha-synuclein (α-Syn) within the GI tract. While motor deficits and dopaminergic neuron loss in the central nervous system (CNS) of the A53T mouse model are well-characterised, the temporal relationship between GI dysfunction, ENS pathology, and motor symptoms remains unclear. This study aimed to investigate functional alterations in the GI tract at the early stages of the disease, before the appearance of motor deficits, both in vivo and ex vivo. Early colonic motility deficits observed in A53T mice, measured via bead expulsion, preceded motor impairments emerged at 36 weeks. Although whole-gut transit remained unchanged, reduced faecal output was concurrent with marked colonic dysmotility at 36 weeks. Despite a lack of significant neuronal loss, a greater number of enteric neurons in A53T mice showed signs of neuronal hypertrophy and increased nuclear translocation of HuC/D proteins indicative of neuronal stress at 12 and 36 weeks. Calcium imaging revealed differential enteric neuron activity, characterised by exaggerated calcium transients at 12 weeks that normalized by 36 weeks. Furthermore, a reduction in enteric glial populations was observed as early as 12 weeks in both the ileum and colon of A53T mice. These findings provide compelling evidence that ENS pathology, including neuronal stress, disrupted calcium signalling, and glial cell loss, precedes the onset of motor symptoms and may contribute to early GI dysfunction in PD.
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Affiliation(s)
- Myat Noe Han
- Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia
| | - Madeleine R Di Natale
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Enie Lei
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3010, Australia
| | - John B Furness
- Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3010, Australia
| | - David I Finkelstein
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Marlene M Hao
- Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia
| | - Shanti Diwakarla
- Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia
| | - Rachel M McQuade
- Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia.
- Gut Barrier and Disease Laboratory, Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia.
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Wattchow DA, Brookes SJH, Spencer NJ, De Giorgio R, Costa M, Dinning PG. Gut Neuropathies and Intestinal Motility Disorders. Neurogastroenterol Motil 2025:e14995. [PMID: 39777822 DOI: 10.1111/nmo.14995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 11/26/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND The enteric nervous system plays a key role in the coordination of gastrointestinal motility together with sympathetic, parasympathetic, and extrinsic sensory pathways. In some cases, abnormalities in neural activity in these pathways contribute to disorders of gut motility. Where this is associated with damage or death of enteric neurons, usually detected by microscopy, this is considered a gut neuropathy. PURPOSE This review summarizes recent advances in the identification of neuropathies in a range of gastrointestinal motility disorders.
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Affiliation(s)
- David A Wattchow
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
- Department of Surgery, Flinders Medical Centre, Adelaide, South Australia, Australia
- Department of Gastroenterology, Flinders Medical Centre, Adelaide, South Australia, Australia
| | - Simon J H Brookes
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Nick J Spencer
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Marcello Costa
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Phil G Dinning
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
- Department of Surgery, Flinders Medical Centre, Adelaide, South Australia, Australia
- Department of Gastroenterology, Flinders Medical Centre, Adelaide, South Australia, Australia
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Baidoo N, Sanger GJ. The human colon: Evidence for degenerative changes during aging and the physiological consequences. Neurogastroenterol Motil 2024:e14848. [PMID: 38887160 DOI: 10.1111/nmo.14848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/16/2024] [Accepted: 06/05/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND The incidence of constipation increases among the elderly (>65 years), while abdominal pain decreases. Causes include changes in lifestyle (e.g., diet and reduced exercise), disease and medications affecting gastrointestinal functions. Degenerative changes may also occur within the colo-rectum. However, most evidence is from rodents, animals with relatively high rates of metabolism and accelerated aging, with considerable variation in time course. In humans, cellular and non-cellular changes in the aging intestine are poorly investigated. PURPOSE To examine all available studies which reported the effects of aging on cellular and tissue functions of human isolated colon, noting the region studied, sex and age of tissue donors and study size. The focus on human colon reflects the ability to access full-thickness tissue over a wide age range, compared with other gastrointestinal regions. Details are important because of natural human variability. We found age-related changes within the muscle, in the enteric and nociceptor innervation, and in the submucosa. Some involve all regions of colon, but the ascending colon appears more vulnerable. Changes can be cell- and sublayer-dependent. Mechanisms are unclear but may include development of "senescent-like" and associated inflammaging, perhaps associated with increased mucosal permeability to harmful luminal contents. In summary, reduced nociceptor innervation can explain diminished abdominal pain among the elderly. Degenerative changes within the colon wall may have little impact on symptoms and colonic functions, because of high "functional reserve," but are likely to facilitate the development of constipation during age-related challenges (e.g., lifestyle, disease, and medications), now operating against a reduced functional reserve.
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Affiliation(s)
- Nicholas Baidoo
- School of Life Sciences, University of Westminster, London, UK
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Gareth J Sanger
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Graves CL, Norloff E, Thompson D, Kosyk O, Sang Y, Chen A, Zannas AS, Wallet SM. Chronic early life stress alters the neuroimmune profile and functioning of the developing zebrafish gut. Brain Behav Immun Health 2023; 31:100655. [PMID: 37449287 PMCID: PMC10336164 DOI: 10.1016/j.bbih.2023.100655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 05/30/2023] [Accepted: 06/15/2023] [Indexed: 07/18/2023] Open
Abstract
Chronic early life stress (ELS) potently impacts the developing central nervous and immune systems and is associated with the onset of gastrointestinal disease in humans. Though the gut-brain axis is appreciated to be a major target of the stress response, the underlying mechanisms linking ELS to gut dysfunction later in life is incompletely understood. Zebrafish are a powerful model validated for stress research and have emerged as an important tool in delineating neuroimmune mechanisms in the developing gut. Here, we developed a novel model of ELS and utilized a comparative transcriptomics approach to assess how chronic ELS modulated expression of neuroimmune genes in the developing gut and brain. Zebrafish exposed to ELS throughout larval development exhibited anxiety-like behavior and altered expression of neuroimmune genes in a time- and tissue-dependent manner. Further, the altered gut neuroimmune profile, which included increased expression of genes associated with neuronal modulation, correlated with a reduction in enteric neuronal density and delayed gut transit. Together, these findings provide insights into the mechanisms linking ELS with gastrointestinal dysfunction and highlight the zebrafish model organism as a valuable tool in uncovering how "the body keeps the score."
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Affiliation(s)
- Christina L. Graves
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Carolina Stress Initiative, University of North Carolina School of Medicine, Chapel Hill, NC, 27514, USA
| | - Erik Norloff
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Darius Thompson
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Oksana Kosyk
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yingning Sang
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Angela Chen
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Anthony S. Zannas
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA
- Carolina Stress Initiative, University of North Carolina School of Medicine, Chapel Hill, NC, 27514, USA
| | - Shannon M. Wallet
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Le Berre C, Naveilhan P, Rolli-Derkinderen M. Enteric glia at center stage of inflammatory bowel disease. Neurosci Lett 2023; 809:137315. [PMID: 37257681 DOI: 10.1016/j.neulet.2023.137315] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 06/02/2023]
Abstract
Although our understanding of the pathophysiology of inflammatory bowel disease (IBD) is increasing, the expanding body of knowledge does not simplify the equation but rather reveals diverse, interconnected, and complex mechanisms in IBD. In addition to immune overactivation, defects in intestinal epithelial barrier (IEB) functioning, dysbiosis, and structural and functional abnormalities of the enteric nervous system are emerging as new elements contributing to the development of IBD. In addition to molecular changes in IBD, enteric glia from patients with Crohn's disease (CD) exhibits the inability to strengthen the IEB; these defects are not observed in patients with ulcerative colitis. In addition, there is a growing body of work describing that enteric glia interacts with not only enterocytes and enteric neurons but also other local cellular neighbours. Thus, because of their functions as connectors and regulators of immune cells, IEB, and microbiota, enteric glia could be the keystone of digestive homeostasis that is lacking in patients with CD.
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Affiliation(s)
- Catherine Le Berre
- Hépato-Gastro-Entérologie et Assistance Nutritionnelle, Inserm CIC 1413, Institut des Maladies de l'Appareil Digestif (IMAD), CHU Nantes, 1 place Alexis Ricordeau, F-44000 Nantes, France; Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, 1 rue Gaston Veil, 44035 Nantes Cedex 1, F-44000 Nantes, France
| | - Philippe Naveilhan
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, 1 rue Gaston Veil, 44035 Nantes Cedex 1, F-44000 Nantes, France
| | - Malvyne Rolli-Derkinderen
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, 1 rue Gaston Veil, 44035 Nantes Cedex 1, F-44000 Nantes, France.
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Zanoletti L, Valdata A, Nehlsen K, Faris P, Casali C, Cacciatore R, Sbarsi I, Carriero F, Arfini D, van Baarle L, De Simone V, Barbieri G, Raimondi E, May T, Moccia F, Bozzola M, Matteoli G, Comincini S, Manai F. Cytological, molecular, cytogenetic, and physiological characterization of a novel immortalized human enteric glial cell line. Front Cell Neurosci 2023; 17:1170309. [PMID: 37153631 PMCID: PMC10158601 DOI: 10.3389/fncel.2023.1170309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 03/22/2023] [Indexed: 05/10/2023] Open
Abstract
Enteric glial cells (EGCs), the major components of the enteric nervous system (ENS), are implicated in the maintenance of gut homeostasis, thereby leading to severe pathological conditions when impaired. However, due to technical difficulties associated with EGCs isolation and cell culture maintenance that results in a lack of valuable in vitro models, their roles in physiological and pathological contexts have been poorly investigated so far. To this aim, we developed for the first time, a human immortalized EGC line (referred as ClK clone) through a validated lentiviral transgene protocol. As a result, ClK phenotypic glial features were confirmed by morphological and molecular evaluations, also providing the consensus karyotype and finely mapping the chromosomal rearrangements as well as HLA-related genotypes. Lastly, we investigated the ATP- and acetylcholine, serotonin and glutamate neurotransmitters mediated intracellular Ca2+ signaling activation and the response of EGCs markers (GFAP, SOX10, S100β, PLP1, and CCL2) upon inflammatory stimuli, further confirming the glial nature of the analyzed cells. Overall, this contribution provided a novel potential in vitro tool to finely characterize the EGCs behavior under physiological and pathological conditions in humans.
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Affiliation(s)
- Lisa Zanoletti
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Aurora Valdata
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | - Pawan Faris
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Iraq
| | - Claudio Casali
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Rosalia Cacciatore
- Immunohematology and Transfusion Service, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
| | - Ilaria Sbarsi
- Immunohematology and Transfusion Service, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
| | - Francesca Carriero
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Davide Arfini
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Lies van Baarle
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Veronica De Simone
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Giulia Barbieri
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Elena Raimondi
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | - Francesco Moccia
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | - Gianluca Matteoli
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Sergio Comincini
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Federico Manai
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
- *Correspondence: Federico Manai,
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Bin1 targeted immunotherapy alters the status of the enteric neurons and the microbiome during ulcerative colitis treatment. PLoS One 2022; 17:e0276910. [PMID: 36322599 PMCID: PMC9629549 DOI: 10.1371/journal.pone.0276910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 10/16/2022] [Indexed: 11/07/2022] Open
Abstract
Ulcerative colitis (UC) is a common chronic disease of the large intestine. Current anti-inflammatory drugs prescribed to treat this disease have limited utility due to significant side-effects. Thus, immunotherapies for UC treatment are still sought. In the DSS mouse model of UC, we recently demonstrated that systemic administration of the Bin1 monoclonal antibody 99D (Bin1 mAb) developed in our laboratory was sufficient to reinforce intestinal barrier function and preserve an intact colonic mucosa, compared to control subjects which displayed severe mucosal lesions, high-level neutrophil and lymphocyte infiltration of mucosal and submucosal areas, and loss of crypts. A dysbiotic microbiome may lead to UC. We determined the effects of Bin1 mAb on the gut microbiome and colonic neurons and correlated the benefits of immunotherapeutic treatment. In the DSS model, we found that induction of UC was associated with disintegration of enteric neurons and elevated levels of glial cells, which translocated to the muscularis at distinct sites. Further, we characterized an altered gut microbiome in DSS treated mice associated with pathogenic proinflammatory characters. Both of these features of UC induction were normalized by Bin1 mAb treatment. With regard to microbiome changes, we observed in particular, increase in Enterobacteriaceae; whereas Firmicutes were eliminated by UC induction and Bin1 mAb treatment restored this phylum including the genus Lactobacillus. Overall, our findings suggest that the intestinal barrier function restored by Bin1 immunotherapy in the DSS model of UC is associated with an improvement in the gut microbiome and preservation of enteric neurons, contributing overall to a healthy intestinal tract.
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Enteric glia: extent, cohesion, axonal contacts, membrane separations and mitochondria in Auerbach's ganglia of guinea pigs. Cell Tissue Res 2022; 389:409-426. [PMID: 35729372 PMCID: PMC9436829 DOI: 10.1007/s00441-022-03656-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/14/2022] [Indexed: 11/04/2022]
Abstract
Studied by electron microscopy and morphometry, Auerbach’s ganglia comprise nerve cell bodies that occupy ~ 40% of volume; of the neuropil, little over 30% is neural processes (axons, dendrites) and little less than 30% is glia (cell bodies, processes). The amount of surface membrane of neural elements only marginally exceeds that of glia. Glial cells extend laminar processes radially between axons, reaching the ganglion’s surface with specialized membrane domains. Nerve cells and glia are tightly associated, eliminating any free space in ganglia. Glia expands maximally its cell membrane with a minimum of cytoplasm, contacting a maximal number of axons, which, with their near-circular profile, have minimal surface for a given volume. Shape of glia is moulded by the neural elements (predominantly concave the first, predominantly convex the second); the glia extends its processes to maximize contact with neural elements. Yet, a majority of axons is not reached by glia and only few are wrapped by it. Despite the large number of cells, the glia is not sufficiently developed to wrap around or just contact many of the neural elements. Mitochondria are markedly fewer in glia than in neurons, indicating a lower metabolic rate. Compactness of ganglia, their near-circular profile, absence of spaces between elements and ability to withstand extensive deformation suggest strong adhesion between the cellular elements, holding them together and keeping them at a fixed distance. Many axonal varicosities, with vesicles and membrane densities, abut on non-specialized areas of glia, suggesting the possibility of neurotransmitters being released outside synaptic sites.
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11
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Opioid Use, Gut Dysbiosis, Inflammation, and the Nervous System. J Neuroimmune Pharmacol 2022; 17:76-93. [PMID: 34993905 DOI: 10.1007/s11481-021-10046-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/17/2021] [Indexed: 12/29/2022]
Abstract
Opioid use disorder (OUD) is defined as the chronic use or misuse of prescribed or illicitly obtained opioids and is characterized by clinically significant impairment. The etiology of OUD is multifactorial as it is influenced by genetics, environmental factors, stress response and behavior. Given the profound role of the gut microbiome in health and disease states, in recent years there has been a growing interest to explore interactions between the gut microbiome and the central nervous system as a causal link and potential therapeutic source for OUD. This review describes the role of the gut microbiome and opioid-induced immunopathological disturbances at the gut epithelial surface, which collectively contribute to OUD and perpetuate the vicious cycle of addiction and relapse.
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12
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Liu C, Yang J. Enteric Glial Cells in Immunological Disorders of the Gut. Front Cell Neurosci 2022; 16:895871. [PMID: 35573829 PMCID: PMC9095930 DOI: 10.3389/fncel.2022.895871] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/07/2022] [Indexed: 11/13/2022] Open
Abstract
Enteric glial cells (EGCs) are one of the major cell types of neural crest lineage distributed in the gastrointestinal tract. EGCs represent an integral part of the enteric nervous system (ENS) and significantly outnumber ENS neurons. Studies have suggested that EGCs would exert essential roles in supporting the survival and functions of the ENS neurons. Notably, recent evidence has begun to reveal that EGCs could possess multiple immune functions and thereby may participate in the immune homeostasis of the gut. In this review article, we will summarize the current evidence supporting the potential involvement of EGCs in several important immunological disorders, including inflammatory bowel disease, celiac disease, and autoimmune enteropathy. Further, we highlight critical questions on the immunological aspects of EGCs that warrant future research attention.
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Affiliation(s)
- Chang Liu
- Center for Life Sciences, Peking University, Beijing, China
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- College of Life Sciences, Wuhan University, Wuhan, China
| | - Jing Yang
- Center for Life Sciences, Peking University, Beijing, China
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, China
- *Correspondence: Jing Yang
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Meling S, Bertoli D, Sangnes DA, Brock C, Drewes A, Ejskjaer N, Dimcevski G, Søfteland E. Diabetic Gastroenteropathy: Soothe the Symptoms or Unravel a Cure? Curr Diabetes Rev 2022; 18:e220321192412. [PMID: 34225633 DOI: 10.2174/1573399817666210322154618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/19/2021] [Accepted: 02/13/2021] [Indexed: 11/22/2022]
Abstract
Autonomic neuropathy in patients with diabetes mellitus, and especially complications related to gastrointestinal neuropathy, are often overlooked in the clinic. Diabetic gastroenteropathy affects every segment of the gastrointestinal tract and generates symptoms that may include nausea, early satiety, vomiting, abdominal pain, constipation, and diarrhea. Severe cases can be complicated by weight loss, dehydration, and electrolyte disturbances. The pathophysiology is complex, the diagnostics and treatment options are multidisciplinary, and there is generally a lack of evidence for the treatment options. The aims for this review are first to summarize the pathophysiology and describe possible and expected symptoms and complications.Further, we will try to supply the clinician with a straightforward tool for diagnostics, and then, we shall summarize established treatment options, including diet recommendations, pharmacological and non-pharmacological options. Finally, we will explore the multiple possibilities of novel treatment, looking at medications related to the pathophysiology of neuropathy, other manifestations of autonomic neuropathies, and symptomatic treatment for other gastrointestinal disorders, also including new knowledge of endosurgical and neuromodulatory treatment. The overall goal is to increase awareness and knowledge on this frequent diabetic complication and to provide better tools for diagnosis and treatment. Ultimately, we hope to encourage further research in this field, as there are clear shortcomings in terms of biomarkers, pathophysiology, as well as treatment possibilities. In conclusion, diagnosis and management of diabetic gastroenteropathy are challenging and often require multidisciplinary teams and multimodal therapies. Treatment options are sparse, but new pharmacological, endoscopic, and neuromodulatory techniques have shown promising results in initial studies.
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Affiliation(s)
- Sondre Meling
- Department of Medicine, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Davide Bertoli
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Dag A Sangnes
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Christina Brock
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Steno Diabetes Center North Jutland, Aalborg, Denmark
| | - Asbjørn Drewes
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Steno Diabetes Center North Jutland, Aalborg, Denmark
| | - Niels Ejskjaer
- Steno Diabetes Center North Jutland, Aalborg, Denmark
- Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Georg Dimcevski
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Eirik Søfteland
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
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14
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Chen H, Han T, Gao L, Zhang D. The Involvement of Glial Cell-Derived Neurotrophic Factor in Inflammatory Bowel Disease. J Interferon Cytokine Res 2021; 42:1-7. [PMID: 34846920 DOI: 10.1089/jir.2021.0116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory gastrointestinal diseases characterized by dysregulation of the intestinal epithelial barrier (IEB) and intermittent relapses. Recent data show that the glial cell line-derived neurotrophic factor (GDNF) promotes IEB function and wound healing. Apart from protective effects of GDNF on enteric nervous system and IEB, an immunomodulatory role has been assumed. However, it is inconsistent whether GDNF levels are increased or decreased in the inflamed colon of patients with IBD. Furthermore, GDNF is 1 of 3 protein markers associated with relapse in a prospective cohort study in IBD patients with clinically and endoscopically quiescent disease. Additionally, not only enteric glial cells (EGCs), but also intestinal smooth muscle cells and enterocytes synthesize GDNF in significant amounts; in addition, its receptors are expressed in intestinal neurons, EGCs, immune cells and epithelial cells, which points to a potential auto- or paracrine signaling loop between some of these cells. Whether GDNF is involved in IBD-associated fibrosis and colitis-associated colorectal cancer remains to be confirmed. In this review we aim to summarize and discuss the current knowledge on the effects of GDNF and its potential role in the contribution to the pathogenesis of IBD.
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Affiliation(s)
- HuiLing Chen
- Department of Hematology and Lanzhou University Second Hospital, Gansu, P.R. China
| | - TiYun Han
- Department of Gastroenterology, Lanzhou University Second Hospital, Gansu, P.R. China
| | - LiPing Gao
- Department of Gastroenterology, Lanzhou University Second Hospital, Gansu, P.R. China
| | - DeKui Zhang
- Department of Gastroenterology, Lanzhou University Second Hospital, Gansu, P.R. China
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15
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Interactions between the microbiota and enteric nervous system during gut-brain disorders. Neuropharmacology 2021; 197:108721. [PMID: 34274348 DOI: 10.1016/j.neuropharm.2021.108721] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/13/2021] [Accepted: 07/13/2021] [Indexed: 02/08/2023]
Abstract
For the last 20 years, researchers have focused their intention on the impact of gut microbiota in healthy and pathological conditions. This year (2021), more than 25,000 articles can be retrieved from PubMed with the keywords "gut microbiota and physiology", showing the constant progress and impact of gut microbes in scientific life. As a result, numerous therapeutic perspectives have been proposed to modulate the gut microbiota composition and/or bioactive factors released from microbes to restore our body functions. Currently, the gut is considered a primary site for the development of pathologies that modify brain functions such as neurodegenerative (Parkinson's, Alzheimer's, etc.) and metabolic (type 2 diabetes, obesity, etc.) disorders. Deciphering the mode of interaction between microbiota and the brain is a real original option to prevent (and maybe treat in the future) the establishment of gut-brain pathologies. The objective of this review is to describe recent scientific elements that explore the communication between gut microbiota and the brain by focusing our interest on the enteric nervous system (ENS) as an intermediate partner. The ENS, which is known as the "second brain", could be under the direct or indirect influence of the gut microbiota and its released factors (short-chain fatty acids, neurotransmitters, gaseous factors, etc.). Thus, in addition to their actions on tissue (adipose tissue, liver, brain, etc.), microbes can have an impact on local ENS activity. This potential modification of ENS function has global repercussions in the whole body via the gut-brain axis and represents a new therapeutic strategy.
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16
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Felipe GZ, Zanoni JN, Sehaber-Sierakowski CC, Bossolani GDP, Souza SRG, Flores FC, Oliveira LES, Pereira RM, Costa YMG. Automatic chronic degenerative diseases identification using enteric nervous system images. Neural Comput Appl 2021; 33:15373-15395. [PMID: 34177126 PMCID: PMC8211315 DOI: 10.1007/s00521-021-06164-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 05/24/2021] [Indexed: 12/26/2022]
Abstract
Studies recently accomplished on the Enteric Nervous System have shown that chronic degenerative diseases affect the Enteric Glial Cells (EGC) and, thus, the development of recognition methods able to identify whether or not the EGC are affected by these type of diseases may be helpful in its diagnoses. In this work, we propose the use of pattern recognition and machine learning techniques to evaluate if a given animal EGC image was obtained from a healthy individual or one affect by a chronic degenerative disease. In the proposed approach, we have performed the classification task with handcrafted features and deep learning-based techniques, also known as non-handcrafted features. The handcrafted features were obtained from the textural content of the ECG images using texture descriptors, such as the Local Binary Pattern (LBP). Moreover, the representation learning techniques employed in the approach are based on different Convolutional Neural Network (CNN) architectures, such as AlexNet and VGG16, with and without transfer learning. The complementarity between the handcrafted and non-handcrafted features was also evaluated with late fusion techniques. The datasets of EGC images used in the experiments, which are also contributions of this paper, are composed of three different chronic degenerative diseases: Cancer, Diabetes Mellitus, and Rheumatoid Arthritis. The experimental results, supported by statistical analysis, show that the proposed approach can distinguish healthy cells from the sick ones with a recognition rate of 89.30% (Rheumatoid Arthritis), 98.45% (Cancer), and 95.13% (Diabetes Mellitus), being achieved by combining classifiers obtained on both feature scenarios.
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Affiliation(s)
- Gustavo Z Felipe
- Universidade Estadual de Maringá (UEM), Av. Colombo 5790, 87020-900 Maringá, PR Brazil
| | - Jacqueline N Zanoni
- Universidade Estadual de Maringá (UEM), Av. Colombo 5790, 87020-900 Maringá, PR Brazil
| | | | - Gleison D P Bossolani
- Universidade Estadual de Maringá (UEM), Av. Colombo 5790, 87020-900 Maringá, PR Brazil
| | - Sara R G Souza
- Universidade Estadual de Maringá (UEM), Av. Colombo 5790, 87020-900 Maringá, PR Brazil
| | - Franklin C Flores
- Universidade Estadual de Maringá (UEM), Av. Colombo 5790, 87020-900 Maringá, PR Brazil
| | - Luiz E S Oliveira
- Universidade Federal do Paraná (UFPR), Rua Cel. Francisco H. dos Santos 100, 81531-990 Curitiba, PR Brazil
| | - Rodolfo M Pereira
- Instituto Federal do Paraná (IFPR), R. Humberto de A. C. Branco 1575, 83330-200 Pinhais, PR Brazil
| | - Yandre M G Costa
- Universidade Estadual de Maringá (UEM), Av. Colombo 5790, 87020-900 Maringá, PR Brazil
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17
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Joly A, Leulier F, De Vadder F. Microbial Modulation of the Development and Physiology of the Enteric Nervous System. Trends Microbiol 2020; 29:686-699. [PMID: 33309188 DOI: 10.1016/j.tim.2020.11.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 12/15/2022]
Abstract
The gastrointestinal tract harbors an intrinsic neuronal network, the enteric nervous system (ENS). The ENS controls motility, fluid homeostasis, and blood flow, but also interacts with other components of the intestine such as epithelial and immune cells. Recent studies indicate that gut microbiota diversification, which occurs alongside postnatal ENS maturation, could be critical for the development and function of the ENS. Here we discuss the possibility that this functional relationship starts in utero, whereby the maternal microbiota would prime the developing ENS and shape its physiology. We review ENS/microbiota interactions and their modulation in physiological and pathophysiological contexts. While microbial modulation of the ENS physiology is now well established, further studies are required to understand the contribution of the gut microbiota to the development and pathology of the ENS and to reveal the precise mechanisms underlying microbiota-to-ENS communications.
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Affiliation(s)
- Amélie Joly
- Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, École Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard Lyon 1, UMR5242, Lyon, France
| | - François Leulier
- Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, École Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard Lyon 1, UMR5242, Lyon, France
| | - Filipe De Vadder
- Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, École Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Université Claude Bernard Lyon 1, UMR5242, Lyon, France.
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18
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Yang PC, Li XJ, Yang YH, Qian W, Li SY, Yan CH, Wang J, Wang Q, Hou XH, Dai CB. The Influence of Bifidobacterium bifidum and Bacteroides fragilis on Enteric Glial Cell-Derived Neurotrophic Factors and Inflammasome. Inflammation 2020; 43:2166-2177. [PMID: 32638263 DOI: 10.1007/s10753-020-01284-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Enteric glial cells (EGCs) and enteric glial-derived neurotrophic factor (GDNF) are directly involved in intestinal inflammation. In this study, we sought to examine the possible mechanisms for how Bifidobacterium bifidum (B.b.) and Bacteroides fragilis (B.f.) influence EGC regulation. In this study, lipopolysaccharide (LPS) and interferon-γ (IFN-γ) were used as exogenous stimuli of EGCs to establish an intestinal inflammation model. After stimulation with LPS and IFN-γ, B.b. and B.f. supernatants were used to activate EGCs and to examine EGC immune mechanisms. For this purpose, qRT-PCR, western blotting, and laser scanning confocal microscopy (LSCM) were used to detect the expression of NLRP3, NLRP6, NGF, NT-3, IL-18, IL-1β, and caspase-1. We found that EGCs, after stimulation with LPS and IFN-γ, could express NLRP3, NLRP6, NT-3, NGF, IL-18, IL-1β, and caspase-1 through LSCM. In intestinal inflammation, B.b. and B.f. could trigger an increase in NGF and NT-3 expression in EGCs in order to protect the intestine. Furthermore, B.b. and B.f. could upregulate NLRP3 expression in EGCs and promote an inflammatory response. B.b. had a dual regulatory role in EGC NLRP6 expression, while B.f. inhibited NLRP6 protein expression. Moreover, B.b. could decrease the expression of IL-18, IL-1β, and caspase-1 in EGCs in order to inhibit the inflammatory response. Contrary to this, B.f. could upregulate IL-18, IL-1β, and caspase-1 expression in EGCs in order to promote the inflammatory response. B.b. and B.f. can influence the expression of NGF, NT-3, NLRP3, NLRP6, IL-18, IL-1β, and caspase-1 in EGCs in order to inhibit or promote intestinal inflammation.
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Affiliation(s)
- Peng-Chun Yang
- Affiliated Renhe Hospital of Three Gorges University, Yichang, 443001, China
| | - Xi-Jun Li
- Affiliated Renhe Hospital of Three Gorges University, Yichang, 443001, China
- Yichang Yiling Hospital, Yichang, 443100, China
| | - Yan-Hua Yang
- Affiliated Renhe Hospital of Three Gorges University, Yichang, 443001, China
| | - Wei Qian
- Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shi-Yu Li
- Affiliated Renhe Hospital of Three Gorges University, Yichang, 443001, China
| | - Cai-Hua Yan
- Affiliated Renhe Hospital of Three Gorges University, Yichang, 443001, China
| | - Jing Wang
- Affiliated Renhe Hospital of Three Gorges University, Yichang, 443001, China
| | - Qin Wang
- Affiliated Renhe Hospital of Three Gorges University, Yichang, 443001, China
| | - Xiao-Hua Hou
- Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chi-Bing Dai
- Affiliated Renhe Hospital of Three Gorges University, Yichang, 443001, China.
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19
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Abstract
The gut-brain axis is a coordinated communication system that not only maintains homeostasis, but significantly influences higher cognitive functions and emotions, as well as neurological and behavioral disorders. Among the large populations of sensory and motor neurons that innervate the gut, insights into the function of primary afferent nociceptors, whose cell bodies reside in the dorsal root ganglia and nodose ganglia, have revealed their multiple crosstalk with several cell types within the gut wall, including epithelial, vascular, and immune cells. These bidirectional communications have immunoregulatory functions, control host response to pathogens, and modulate sensations associated with gastrointestinal disorders, through activation of immune cells and glia in the peripheral and central nervous system, respectively. Here, we will review the cellular and neurochemical basis of these interactions at the periphery, in dorsal root ganglia, and in the spinal cord. We will discuss the research gaps that should be addressed to get a better understanding of the multifunctional role of sensory neurons in maintaining gut homeostasis and regulating visceral sensitivity.
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Affiliation(s)
- Nasser Abdullah
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Manon Defaye
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Christophe Altier
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
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20
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Nardini P, Pini A, Bessard A, Duchalais E, Niccolai E, Neunlist M, Vannucchi MG. GLP-2 Prevents Neuronal and Glial Changes in the Distal Colon of Mice Chronically Treated with Cisplatin. Int J Mol Sci 2020; 21:ijms21228875. [PMID: 33238628 PMCID: PMC7700273 DOI: 10.3390/ijms21228875] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/19/2020] [Accepted: 11/21/2020] [Indexed: 12/20/2022] Open
Abstract
Cisplatin is a chemotherapeutic agent widely used for the treatment of solid cancers. Its administration is commonly associated with acute and chronic gastrointestinal dysfunctions, likely related to mucosal and enteric nervous system (ENS) injuries, respectively. Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone exerting trophic/reparative activities on the intestine, via antiapoptotic and pro-proliferating pathways, to guarantee mucosal integrity, energy absorption and motility. Further, it possesses anti-inflammatory properties. Presently, cisplatin acute and chronic damages and GLP-2 protective effects were investigated in the mouse distal colon using histological, immunohistochemical and biochemical techniques. The mice received cisplatin and the degradation-resistant GLP-2 analog ([Gly2]GLP-2) for 4 weeks. Cisplatin-treated mice showed mucosal damage, inflammation, IL-1β and IL-10 increase; decreased number of total neurons, ChAT- and nNOS-immunoreactive (IR) neurons; loss of SOX-10-IR cells and reduced expression of GFAP- and S100β-glial markers in the myenteric plexus. [Gly2]GLP-2 co-treatment partially prevented mucosal damage and counteracted the increase in cytokines and the loss of nNOS-IR and SOX-10-IR cells but not that of ChAT-IR neurons. Our data demonstrate that cisplatin causes mucosal injuries, neuropathy and gliopathy and that [Gly2]GLP-2 prevents these injuries, partially reducing mucosal inflammation and inducing ENS remodeling. Hence, this analog could represent an effective strategy to overcome colonic injures induced by cisplatin.
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Affiliation(s)
- Patrizia Nardini
- Histology and Embryology Research Unit, Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (P.N.); (A.P.); (E.N.)
| | - Alessandro Pini
- Histology and Embryology Research Unit, Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (P.N.); (A.P.); (E.N.)
| | - Anne Bessard
- Inserm, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, University of Nantes, 44035 Nantes, France; (A.B.); (E.D.); (M.N.)
| | - Emilie Duchalais
- Inserm, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, University of Nantes, 44035 Nantes, France; (A.B.); (E.D.); (M.N.)
| | - Elena Niccolai
- Histology and Embryology Research Unit, Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (P.N.); (A.P.); (E.N.)
| | - Michel Neunlist
- Inserm, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, University of Nantes, 44035 Nantes, France; (A.B.); (E.D.); (M.N.)
| | - Maria Giuliana Vannucchi
- Histology and Embryology Research Unit, Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (P.N.); (A.P.); (E.N.)
- Correspondence: ; Tel.: +39-055-275-8152
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21
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NDRG2 is expressed on enteric glia and altered in conditions of inflammation and oxygen glucose deprivation/reoxygenation. J Mol Histol 2020; 52:101-111. [PMID: 33205345 DOI: 10.1007/s10735-020-09927-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/11/2020] [Indexed: 01/07/2023]
Abstract
Enteric glial cells are more abundant than neurons in the enteric nervous system. Accumulating evidence has demonstrated that enteric glial cells share many properties with astrocytes and play pivotal roles in intestinal diseases. NDRG2 is specifically expressed in astrocytes and is involved in various diseases in the central nervous system. However, no studies have demonstrated the expression of NDRG2 in enteric glial cells. We performed immunostaining of adult mouse tissue, human colon sections, and primary enteric glial cells and the results showed that NDRG2 was widely expressed in enteric glial cells. Meanwhile, our results showed that NDRG2 was upregulated after treatment with pro-inflammatory cytokines and exposure to oxygen glucose deprivation/reoxygenation, indicating that NDRG2 might be involved in these conditions. Moreover, we determined that NDRG2 translocated to the nucleus after treatment with pro-inflammatory cytokines but not after exposure to oxygen glucose deprivation/reoxygenation. This study is the first to show the expression and distribution of NDRG2 in the enteric glia. Our results indicate that NDRG2 might be involved in the pathogenesis of enteric inflammation and ischemia/reperfusion injury. This study shows that NDRG2 might be a molecular target for enteric nervous system diseases.
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22
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Heymans C, de Lange IH, Lenaerts K, Kessels LCGA, Hadfoune M, Rademakers G, Melotte V, Boesmans W, Kramer BW, Jobe AH, Saito M, Kemp MW, van Gemert WG, Wolfs TGAM. Chorioamnionitis induces enteric nervous system injury: effects of timing and inflammation in the ovine fetus. Mol Med 2020; 26:82. [PMID: 32883198 PMCID: PMC7469100 DOI: 10.1186/s10020-020-00206-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 07/28/2020] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Chorioamnionitis, inflammation of the chorion and amnion, which often results from intrauterine infection, is associated with premature birth and contributes to significant neonatal morbidity and mortality, including necrotizing enterocolitis (NEC). Recently, we have shown that chronic chorioamnionitis is associated with significant structural enteric nervous system (ENS) abnormalities that may predispose to later NEC development. Understanding time point specific effects of an intra-amniotic (IA) infection on the ENS is important for further understanding the pathophysiological processes and for finding a window for optimal therapeutic strategies for an individual patient. The aim of this study was therefore to gain insight in the longitudinal effects of intrauterine LPS exposure (ranging from 5 h to 15 days before premature delivery) on the intestinal mucosa, submucosa, and ENS in fetal lambs by use of a well-established translational ovine chorioamnionitis model. METHODS We used an ovine chorioamnionitis model to assess outcomes of the fetal ileal mucosa, submucosa and ENS following IA exposure to one dose of 10 mg LPS for 5, 12 or 24 h or 2, 4, 8 or 15 days. RESULTS Four days of IA LPS exposure causes a decreased PGP9.5- and S100β-positive surface area in the myenteric plexus along with submucosal and mucosal intestinal inflammation that coincided with systemic inflammation. These changes were preceded by a glial cell reaction with early systemic and local gut inflammation. ENS changes and inflammation recovered 15 days after the IA LPS exposure. CONCLUSIONS The pattern of mucosal and submucosal inflammation, and ENS alterations in the fetus changed over time following IA LPS exposure. Although ENS damage seemed to recover after prolonged IA LPS exposure, additional postnatal inflammatory exposure, which a premature is likely to encounter, may further harm the ENS and influence functional outcome. In this context, 4 to 8 days of IA LPS exposure may form a period of increased ENS vulnerability and a potential window for optimal therapeutic strategies.
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Affiliation(s)
- C Heymans
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - I H de Lange
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.,Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, P.O. Box 616, Universiteitssingel 50, 6200, MD, Maastricht, The Netherlands
| | - K Lenaerts
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - L C G A Kessels
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, P.O. Box 616, Universiteitssingel 50, 6200, MD, Maastricht, The Netherlands
| | - M Hadfoune
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - G Rademakers
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands
| | - V Melotte
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands
| | - W Boesmans
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands.,Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - B W Kramer
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, P.O. Box 616, Universiteitssingel 50, 6200, MD, Maastricht, The Netherlands.,Neonatology, Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands
| | - A H Jobe
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia.,Division of Neonatology/Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - M Saito
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia.,Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - M W Kemp
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia.,School of Veterinary and Life Sciences, Murdoch University, Perth, Western Australia, Australia
| | - W G van Gemert
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.,Pediatric surgery, Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands.,Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - T G A M Wolfs
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, P.O. Box 616, Universiteitssingel 50, 6200, MD, Maastricht, The Netherlands. .,Department of Biomedical Engineering (BMT), Maastricht University, Maastricht, the Netherlands.
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23
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Rissato DF, de Santi Rampazzo AP, Borges SC, Sousa FC, Busso C, Buttow NC, Natali MRM. Chronic ingestion of deoxynivalenol-contaminated diet dose-dependently decreases the area of myenteric neurons and gliocytes of rats. Neurogastroenterol Motil 2020; 32:e13770. [PMID: 31793155 DOI: 10.1111/nmo.13770] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 10/18/2019] [Accepted: 11/10/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Deoxynivalenol (DON), a mycotoxin produced by Fusarium spp., is commonly found in cereals ingested by humans and animals. Its ingestion is correlated with hepatic, hematologic, renal, splenic, cardiac, gastrointestinal, and neural damages, according to dose, duration of exposure and species. In this work, the effects of the ingestion of DON-contaminated diet at concentrations considered tolerable for human and animal intake were assessed. METHODS Male Wistar rats aging 21 days were allotted to five groups that were given, for 42 days, diets contaminated with different concentrations of DON (0, 0.2, 0.75, 1.75, and 2 mg kg-1 of chow). Food ingestion, bodyweight, oxidative status and morphometric analyses of gliocytes, and neurons of jejunal myenteric ganglia were recorded. KEY RESULTS At these concentrations, there was no food rejection, decrease in bodyweight gain, changes in oxidative status, or loss of either neurons or gliocytes. However, DON decreased gliocyte area, general neuronal population, nitrergic, cholinergic and NADH-diaphorase positive subpopulations and, as a result, ganglion area. CONCLUSIONS & INFERENCES It was concluded that, even in the absence of visible effect, DON exposure reduces cell body area of gliocytes and neurons of the myenteric plexus of the rat jejunum.
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Affiliation(s)
- Débora Furlan Rissato
- Ingá University Center, Maringá, Paraná, Brazil.,Department of Morphological Sciences, State University of Maringá, Maringá, Paraná, Brazil
| | | | | | - Fernando Carlos Sousa
- Coordination of Biological Sciences, Federal University of Technology - Paraná, Dois Vizinhos Campus, Dois Vizinhos, Paraná, Brazil
| | - Cleverson Busso
- Coordination of Biological Sciences, Federal University of Technology - Paraná, Dois Vizinhos Campus, Dois Vizinhos, Paraná, Brazil
| | - Nilza Cristina Buttow
- Department of Morphological Sciences, State University of Maringá, Maringá, Paraná, Brazil
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24
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Heymans C, de Lange IH, Hütten MC, Lenaerts K, de Ruijter NJE, Kessels LCGA, Rademakers G, Melotte V, Boesmans W, Saito M, Usuda H, Stock SJ, Spiller OB, Beeton ML, Payne MS, Kramer BW, Newnham JP, Jobe AH, Kemp MW, van Gemert WG, Wolfs TGAM. Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses. Front Immunol 2020; 11:189. [PMID: 32256485 PMCID: PMC7089942 DOI: 10.3389/fimmu.2020.00189] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 01/24/2020] [Indexed: 01/18/2023] Open
Abstract
Background: Chorioamnionitis, inflammation of the fetal membranes during pregnancy, is often caused by intra-amniotic (IA) infection with single or multiple microbes. Chorioamnionitis can be either acute or chronic and is associated with adverse postnatal outcomes of the intestine, including necrotizing enterocolitis (NEC). Neonates with NEC have structural and functional damage to the intestinal mucosa and the enteric nervous system (ENS), with loss of enteric neurons and glial cells. Yet, the impact of acute, chronic, or repetitive antenatal inflammatory stimuli on the development of the intestinal mucosa and ENS has not been studied. The aim of this study was therefore to investigate the effect of acute, chronic, and repetitive microbial exposure on the intestinal mucosa, submucosa and ENS in premature lambs. Materials and Methods: A sheep model of pregnancy was used in which the ileal mucosa, submucosa, and ENS were assessed following IA exposure to lipopolysaccharide (LPS) for 2 or 7 days (acute), Ureaplasma parvum (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS). Results: IA LPS exposure for 7 days or IA UP exposure for 42 days caused intestinal injury and inflammation in the mucosal and submucosal layers of the gut. Repetitive microbial exposure did not further aggravate injury of the terminal ileum. Chronic IA UP exposure caused significant structural ENS alterations characterized by loss of PGP9.5 and S100β immunoreactivity, whereas these changes were not found after re-exposure of chronic UP-exposed fetuses to LPS for 2 or 7 days. Conclusion: The in utero loss of PGP9.5 and S100β immunoreactivity following chronic UP exposure corresponds with intestinal changes in neonates with NEC and may therefore form a novel mechanistic explanation for the association of chorioamnionitis and NEC.
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Affiliation(s)
- Cathelijne Heymans
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Ilse H de Lange
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands.,Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands
| | - Matthias C Hütten
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands.,Neonatology, Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands.,Neonatology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany.,Neonatology, Department of Pediatrics, University Children's Hospital Würzburg, Würzburg, Germany
| | - Kaatje Lenaerts
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Nadine J E de Ruijter
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands
| | - Lilian C G A Kessels
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands
| | - Glenn Rademakers
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, Netherlands
| | - Veerle Melotte
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, Netherlands
| | - Werend Boesmans
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, Netherlands.,Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
| | - Masatoshi Saito
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia.,Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - Haruo Usuda
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia.,Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - Sarah J Stock
- Usher Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Owen B Spiller
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Michael L. Beeton
- Division of Neonatology/Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, United States
| | - Matthew S Payne
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia
| | - Boris W Kramer
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands.,Neonatology, Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands
| | - John P Newnham
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia
| | - Alan H Jobe
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia.,Division of Neonatology/Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, United States
| | - Matthew W Kemp
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia.,Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan.,School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia
| | - Wim G van Gemert
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands.,Pediatric Surgery, Department of Surgery, Maastricht University Medical Center, Maastricht, Netherlands.,Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - Tim G A M Wolfs
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands.,Department of Biomedical Engineering (BMT), School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, Netherlands
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25
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Piovezana Bossolani GD, Silva BT, Colombo Martins Perles JV, Lima MM, Vieira Frez FC, Garcia de Souza SR, Sehaber-Sierakowski CC, Bersani-Amado CA, Zanoni JN. Rheumatoid arthritis induces enteric neurodegeneration and jejunal inflammation, and quercetin promotes neuroprotective and anti-inflammatory actions. Life Sci 2019; 238:116956. [DOI: 10.1016/j.lfs.2019.116956] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 10/08/2019] [Accepted: 10/10/2019] [Indexed: 02/07/2023]
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26
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Yeh KM, Johansson O, Le H, Rao K, Markus I, Perera DS, Lubowski DZ, King DW, Zhang L, Chen H, Liu L. Cystic fibrosis transmembrane conductance regulator modulates enteric cholinergic activities and is abnormally expressed in the enteric ganglia of patients with slow transit constipation. J Gastroenterol 2019; 54:994-1006. [PMID: 31392489 DOI: 10.1007/s00535-019-01610-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/31/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Cystic fibrosis transmembrane conductance regulator (CFTR) was recently found in the enteric nervous system, where its role is unclear. We aimed to identify which enteric neuronal structures express CFTR, whether CFTR modulates enteric neurotransmission and if altered CFTR expression is associated with slow transit constipation (STC). METHODS Immunofluorescence double labeling was performed to localize CFTR with various neuronal and glial cell markers in the human colon. The immunoreactivity (IR) of CFTR and choline acetyltransferase (ChAT) on myenteric plexus of control and STC colon was quantitatively analyzed. In control colonic muscle strips, electrical field stimulation (EFS) evoked contractile responses and the release of acetylcholine (ACh) was measured in the presence of the CFTR channel inhibitor, CFTR(inh)-172. RESULTS CFTR-IR was densely localized to myenteric ganglia, where it was co-localized with neuronal markers HuC/D and β-tubulin, and glial marker S-100 but little with glial fibrillary acidic protein. Vesicular ACh transport was almost exclusively co-localized with CFTR, but neurons expressing nitric oxide synthase were CFTR negative. Significant reductions of CFTR-IR (P < 0.01) and ChAT-IR (P < 0.05) were observed on myenteric ganglia of STC compared to control. Pre-treatment of colonic muscle strips with CFTR(inh)-172 (10 µM) significantly inhibited EFS-evoked contractile responses (P < 0.01) and ACh release (P < 0.05). CONCLUSIONS Co-localization of CFTR-IR with cholinergic markers, inhibition of EFS-induced colonic muscle contractility and ACh release by CFTR(inh)-172 suggest that CFTR modulates enteric cholinergic neurotransmission. The downregulation of CFTR and ChAT in myenteric ganglia of STC correlated with the impaired contractile responses to EFS.
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Affiliation(s)
- Ka Ming Yeh
- Department of Pharmacology, Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Olle Johansson
- Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Huy Le
- Department of Pharmacology, Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Karan Rao
- Department of Pharmacology, Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Irit Markus
- Department of Pharmacology, Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
| | | | | | | | - Li Zhang
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Hongzhuan Chen
- School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lu Liu
- Department of Pharmacology, Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
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27
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Jiang Y, Xu L, Yu L, Xu X, Feng C, Li J. NOX4 inhibition protects enteric glial cells against Clostridium difficile toxin B toxicity via attenuating oxidative and Endoplasmic reticulum stresses. Free Radic Res 2019; 53:932-940. [PMID: 31370714 DOI: 10.1080/10715762.2019.1649670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Enteric glial cells (EGCs), one main cell population of the enteric nervous system (ENS), play a major role in regulating intestinal barrier function. Clostridium difficile toxin B (TcdB) is the major virulence factor produced by C. difficile and estimated to be toxic to EGCs by inducing cell death, cell cycle arrest, and inflammatory cytokine production; however, the detailed mechanism for such effect is still unclear. In this study, we further evaluated the toxic effect of TcdB on EGCs and the involvement of NADPH oxidases in such process using the rat-transformed EGCs (CRL-2690). The results showed that NOX4 was activated by TcdB in EGCs and functioned as the major factor causing cytotoxicity and cell apoptosis. Mechanically, NOX4-generated H2O2 was the inducer of oxidative stress, Ca2+ homeostasis disorder, and ER stress in EGCs upon TcdB treatment, and NOX4 inhibition protected EGCs against TcdB toxicity via attenuating these dysfunctions. These findings contribute to our understanding of the mechanism by which TcdB affects EGCs and suggest the potential value of NOX4 inhibition for treatment against C. difficile infection.
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Affiliation(s)
- Yanmin Jiang
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University , Wuxi , China
| | - Lan Xu
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University , Wuxi , China
| | - Lin Yu
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University , Wuxi , China
| | - Xiang Xu
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University , Wuxi , China
| | - Chen Feng
- Department of Endocrinology, Wuxi People's Hospital Affiliated to Nanjing Medical University , Wuxi , China
| | - Jianbo Li
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University , Nanjing , China
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28
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Xu Y, Xie MZ, Liang GG. Advances in morphologic study of enteric glial cells. Shijie Huaren Xiaohua Zazhi 2019; 27:521-526. [DOI: 10.11569/wcjd.v27.i8.521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
As an important part of the intestinal nervous system, enteric glial cells are about four times as many as intestinal neurons. Furthermore, a large population of astrocyte-like glial cells populate gut muscle layers and the intestinal mucosa, and mounting new evidence points toward enteric glial cells as an active participant in gut pathology. They are similar in morphology and function to the astrocytes of the central nervous system and play an important role in nutrition, supporting gastrointestinal nerve, maintaining gastrointestinal homeostasis, and regulating gastrointestinal function. Because of their complex and diverse roles in the intestinal tract, they have become the focus of research. As the study of their functional mechanism has been extensively deepened, the research methods for intestinal glial cells are also on constant progress and improvement, especially in studying their morphology. This paper mainly introduces the morphological characteristics of enteric glial cells under the conditions of gastrointestinal physiology and pathology, so as to provide a reference for the future study of enteric glial cells and promote the development of this field.
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Affiliation(s)
- Ying Xu
- Department of Emergency Abdominal Surgery/Institute of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Ming-Zheng Xie
- Department of Emergency Abdominal Surgery/Institute of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Guo-Gang Liang
- Department of Emergency Abdominal Surgery/Institute of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
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29
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Vergnolle N, Cirillo C. Neurons and Glia in the Enteric Nervous System and Epithelial Barrier Function. Physiology (Bethesda) 2019; 33:269-280. [PMID: 29897300 DOI: 10.1152/physiol.00009.2018] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The intestinal epithelial barrier is the largest exchange surface between the body and the external environment. Its functions are regulated by luminal, and also internal, components including the enteric nervous system. This review summarizes current knowledge about the role of the digestive "neuronal-glial-epithelial unit" on epithelial barrier function.
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Affiliation(s)
- Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse , France.,Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary , Calgary, Alberta , Canada
| | - Carla Cirillo
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse , France.,Laboratory for Enteric Neuroscience, TARGID, University of Leuven , Leuven , Belgium
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30
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Abstract
Enteric glial cells (EGCs) are an important part of the enteric nervous system and play an important role in maintaining gastrointestinal function. They can nourish and support gastrointestinal neurons, participate in the integration and regulation of neural activities in the gastrointestinal tract, mediate intestinal inflammation, and directly or indirectly regulate gastrointestinal motor function. Investigating the effect of EGCs on neurons and their role in intestinal inflammation caused by gastrointestinal movement disorders may help to reveal the mechanism underlying the impact of EGCs on gastrointestinal dynamics. In clinical practice, EGCs have the potential to be used as a therapeutic target for various gastrointestinal motor function disorders. This review will summarize current knowledge regarding the effect of EGCs on gastrointestinal motor function.
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Affiliation(s)
- Ying Xu
- Department of Emergency Abdominal Surgery, the First Affiliated Hospital of Dalian Medical University / Institute of Integrative Medicine, Dalian 116000, Liaoning Province, China
| | - Ming-Zheng Xie
- Department of Emergency Abdominal Surgery, the First Affiliated Hospital of Dalian Medical University / Institute of Integrative Medicine, Dalian 116000, Liaoning Province, China
| | - Guo-Gang Liang
- Department of Emergency Abdominal Surgery, the First Affiliated Hospital of Dalian Medical University / Institute of Integrative Medicine, Dalian 116000, Liaoning Province, China
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31
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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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32
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Brown IAM, Gulbransen BD. The antioxidant glutathione protects against enteric neuron death in situ, but its depletion is protective during colitis. Am J Physiol Gastrointest Liver Physiol 2018; 314:G39-G52. [PMID: 28882823 PMCID: PMC5866372 DOI: 10.1152/ajpgi.00165.2017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Enteric glia play an important neuroprotective role in the enteric nervous system (ENS) by producing neuroprotective compounds such as the antioxidant reduced glutathione (GSH). The specific cellular pathways that regulate glial production of GSH and how these pathways are altered during, or contribute to, neuroinflammation in situ and in vivo are not fully understood. We investigated this issue using immunohistochemistry to localize GSH synthesis enzymes within the myenteric plexus and tested how the inhibition of GSH synthesis with the selective inhibitor l-buthionine sulfoximine impacts neuronal survival and inflammation. Both enteric glia and neurons express the cellular machinery necessary for GSH synthesis. Furthermore, glial GSH synthesis is necessary for neuronal survival in isolated preparations of myenteric plexus. In vivo depletion of GSH does not induce colitis but alters myenteric plexus neuronal phenotype and survival. Importantly, global depletion of glutathione is protective against some macroscopic and microscopic measures of colonic inflammation. Together, our data highlight the heterogeneous roles of GSH in the myenteric plexus of the ENS and during gastrointestinal inflammation. NEW & NOTEWORTHY Our results show that both enteric glia and neurons express the cellular machinery necessary for glutathione (GSH) synthesis and that glial GSH synthesis is necessary for neuronal survival in isolated enteric nervous system (ENS) preparations. In vivo depletion of GSH with the selective inhibitor l-buthionine sulfoximine is not sufficient to induce inflammation but does alter neuronal neurochemical composition and survival. Together, our data highlight novel heterogeneous roles for GSH in the ENS and during gastrointestinal inflammation.
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Affiliation(s)
- Isola A. M. Brown
- 1Department of Physiology, Michigan State University, East Lansing, Michigan,2Pharmacology and Toxicology Program, Michigan State University, East Lansing, Michigan
| | - Brian D. Gulbransen
- 1Department of Physiology, Michigan State University, East Lansing, Michigan,3Neuroscience Program, Michigan State University, East Lansing, Michigan
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33
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Lerner A, Neidhöfer S, Matthias T. The Gut Microbiome Feelings of the Brain: A Perspective for Non-Microbiologists. Microorganisms 2017; 5:66. [PMID: 29023380 PMCID: PMC5748575 DOI: 10.3390/microorganisms5040066] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 09/28/2017] [Accepted: 10/09/2017] [Indexed: 02/06/2023] Open
Abstract
Objectives: To comprehensively review the scientific knowledge on the gut-brain axis. Methods: Various publications on the gut-brain axis, until 31 July 2017, were screened using the Medline, Google, and Cochrane Library databases. The search was performed using the following keywords: "gut-brain axis", "gut-microbiota-brain axis", "nutrition microbiome/microbiota", "enteric nervous system", "enteric glial cells/network", "gut-brain pathways", "microbiome immune system", "microbiome neuroendocrine system" and "intestinal/gut/enteric neuropeptides". Relevant articles were selected and reviewed. Results: Tremendous progress has been made in exploring the interactions between nutrients, the microbiome, and the intestinal, epithelium-enteric nervous, endocrine and immune systems and the brain. The basis of the gut-brain axis comprises of an array of multichannel sensing and trafficking pathways that are suggested to convey the enteric signals to the brain. These are mediated by neuroanatomy (represented by the vagal and spinal afferent neurons), the neuroendocrine-hypothalamic-pituitary-adrenal (HPA) axis (represented by the gut hormones), immune routes (represented by multiple cytokines), microbially-derived neurotransmitters, and finally the gate keepers of the intestinal and brain barriers. Their mutual and harmonious but intricate interaction is essential for human life and brain performance. However, a failure in the interaction leads to a number of inflammatory-, autoimmune-, neurodegenerative-, metabolic-, mood-, behavioral-, cognitive-, autism-spectrum-, stress- and pain-related disorders. The limited availability of information on the mechanisms, pathways and cause-and-effect relationships hinders us from translating and implementing the knowledge from the bench to the clinic. Implications: Further understanding of this intricate field might potentially shed light on novel preventive and therapeutic strategies to combat these disorders. Nutritional approaches, microbiome manipulations, enteric and brain barrier reinforcement and sensing and trafficking modulation might improve physical and mental health outcomes.
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Affiliation(s)
- Aaron Lerner
- B. Rappaport School of Medicine, Technion-Israel Institute of Technology, Bat Galim, Haifa 3200003, Israel.
- AESKU.KIPP Institute, Mikroforum Ring 2, 55234 Wendelsheim, Germany.
| | - Sandra Neidhöfer
- AESKU.KIPP Institute, Mikroforum Ring 2, 55234 Wendelsheim, Germany.
| | - Torsten Matthias
- AESKU.KIPP Institute, Mikroforum Ring 2, 55234 Wendelsheim, Germany.
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34
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The Gut and Nonmotor Symptoms in Parkinson's Disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2017; 134:787-809. [PMID: 28805583 DOI: 10.1016/bs.irn.2017.05.027] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Gastrointestinal (GI) symptoms are one of the most common nonmotor symptoms (NMS) in patients with Parkinson's disease (PD) involving the whole GI tract (GIT) and being evident throughout the whole course of the disease. Furthermore, constipation serves as a risk factor for PD as well as an early prodromal NMS of PD. The gut as gateway to the environment with its enteric nervous system (ENS) plays a crucial role in the neurodegenerative process that leads to PD. Alpha-synucleinopathy as the pathological hallmark of PD could be found within the whole GIT in a rostrocaudal gradient interacting with the ENS, the gut microbiome, and enteric glial cells. Bidirectional interactions between the ENS and the central nervous system (CNS) via a brain-gut-enteric microbiota axis have been reported. As well as there is evidence out of animal, autopsy, and epidemiological studies that α-synuclein spreads via rostrocranial transmission by transsynaptic cell-to-cell transfer via the sympathetic and parasympathetic nervous system to the CNS causing the typical neuropathological changes of PD. Recognition of GI NMS as prodromal markers of PD as well as a better understanding of the brain-gut connection offers new insights in the pathophysiology of PD and might provide the opportunity of PD diagnosis before CNS involvement. Hereby the opportunity for development of neuroprotective and disease-modifying therapeutics, respectively, seem to be promising. This chapter covers the variety of GI NMS and its consequences in PD as well as the important role of the gut as part of the pathological process in PD.
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35
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Wang N, Song S, Chen J. Synchronized dual pulse gastric electrical stimulation improves gastric emptying and activates enteric glial cells via upregulation of GFAP and S100B with different courses of subdiaphragmatic vagotomy in rats. Mol Med Rep 2017; 15:3826-3832. [PMID: 28440477 DOI: 10.3892/mmr.2017.6471] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 02/16/2017] [Indexed: 11/06/2022] Open
Abstract
Previous research and clinical practice have indicated that damage to the vagal nerve may seriously affect gastrointestinal physiological movement behavior. The aim of the current study was to observe the change of gastric motility, as well as enteric glial cells (EGCs) in the stomach with different courses of vagal nerve transection in rats prior to and following synchronized dual pulse gastric electrical stimulation. The gastric emptying rates were measured to assess the gastric motility. The glial markers, containing calcium binding protein (S100B) and glial fibrillary acidic protein (GFAP), were detected by reverse transcription‑quantitative polymerase chain reaction and double‑labeling immunofluorescence analysis. Ultrastructural changes of EGCs were observed using transmission electron microscopy. Gastric emptying was delayed in the terminal vagotomy group, compared with the terminal control group. The effect of long‑term synchronized dual pulse gastric electrical stimulation (SGES) was superior to short‑term SGES in terminal groups. The expression levels of S100B/GFAP were markedly decreased in the terminal vagotomy group compared with the terminal control group. Following short‑term or long‑term SGES, S100B/GFAP gene and protein expression increased in terminal groups. However, long‑term SGES was more effective than short‑term SGES and the difference was statistically significant. Vagal nerve damage leads to gastric motility disorder and weakens the function of EGCs. Therefore, SGES may improve stomach movement behavior and restore the impaired EGCs. The underlying mechanism of the effect remains elusive, but maybe associated with activation of EGCs.
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Affiliation(s)
- Nian Wang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Shuangning Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jie Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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Fettucciari K, Ponsini P, Gioè D, Macchioni L, Palumbo C, Antonelli E, Coaccioli S, Villanacci V, Corazzi L, Marconi P, Bassotti G. Enteric glial cells are susceptible to Clostridium difficile toxin B. Cell Mol Life Sci 2017; 74:1527-1551. [PMID: 27891552 PMCID: PMC11107567 DOI: 10.1007/s00018-016-2426-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 10/27/2016] [Accepted: 11/21/2016] [Indexed: 02/06/2023]
Abstract
Clostridium difficile causes nosocomial/antibiotic-associated diarrhoea and pseudomembranous colitis. The major virulence factors are toxin A and toxin B (TcdB), which inactivate GTPases by monoglucosylation, leading to cytopathic (cytoskeleton alteration, cell rounding) and cytotoxic effects (cell-cycle arrest, apoptosis). C. difficile toxins breaching the intestinal epithelial barrier can act on underlying cells, enterocytes, colonocytes, and enteric neurons, as described in vitro and in vivo, but until now no data have been available on enteric glial cell (EGC) susceptibility. EGCs are crucial for regulating the enteric nervous system, gut homeostasis, the immune and inflammatory responses, and digestive and extradigestive diseases. Therefore, we evaluated the effects of C. difficile TcdB in EGCs. Rat-transformed EGCs were treated with TcdB at 0.1-10 ng/ml for 1.5-48 h, and several parameters were analysed. TcdB induces the following in EGCs: (1) early cell rounding with Rac1 glucosylation; (2) early G2/M cell-cycle arrest by cyclin B1/Cdc2 complex inactivation caused by p27 upregulation, the downregulation of cyclin B1 and Cdc2 phosphorylated at Thr161 and Tyr15; and (3) apoptosis by a caspase-dependent but mitochondria-independent pathway. Most importantly, the stimulation of EGCs with TNF-α plus IFN-γ before, concomitantly or after TcdB treatment strongly increased TcdB-induced apoptosis. Furthermore, EGCs that survived the cytotoxic effect of TcdB did not recover completely and showed not only persistent Rac1 glucosylation, cell-cycle arrest and low apoptosis but also increased production of glial cell-derived neurotrophic factor, suggesting self-rescuing mechanisms. In conclusion, the high susceptibility of EGCs to TcdB in vitro, the increased sensitivity to inflammatory cytokines related to apoptosis and the persistence of altered functions in surviving cells suggest an important in vivo role of EGCs in the pathogenesis of C. difficile infection.
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Affiliation(s)
- Katia Fettucciari
- Department of Experimental Medicine, Histology and Medical Embryology Section, Perugia University, Piazza Lucio Severi 1, Edificio B IV piano, Sant'Andrea delle Fratte, 06132, Perugia, Italy.
| | - Pamela Ponsini
- Department of Experimental Medicine, Histology and Medical Embryology Section, Perugia University, Piazza Lucio Severi 1, Edificio B IV piano, Sant'Andrea delle Fratte, 06132, Perugia, Italy
| | - Davide Gioè
- Department of Experimental Medicine, Histology and Medical Embryology Section, Perugia University, Piazza Lucio Severi 1, Edificio B IV piano, Sant'Andrea delle Fratte, 06132, Perugia, Italy
| | - Lara Macchioni
- Department of Experimental Medicine, Physiology and Biochemistry Section, Perugia University, Perugia, Italy
| | - Camilla Palumbo
- Department of Clinical Sciences and Translational Medicine, Tor Vergata University, Rome, Italy
| | | | - Stefano Coaccioli
- Department of Medicine, Internal Medicine, Rheumatology and Medical Therapy of Pain Section, Perugia University, District of Terni, Perugia, Italy
| | | | - Lanfranco Corazzi
- Department of Experimental Medicine, Physiology and Biochemistry Section, Perugia University, Perugia, Italy
| | - Pierfrancesco Marconi
- Department of Experimental Medicine, Histology and Medical Embryology Section, Perugia University, Piazza Lucio Severi 1, Edificio B IV piano, Sant'Andrea delle Fratte, 06132, Perugia, Italy
| | - Gabrio Bassotti
- Department of Medicine, Gastroenterology, Hepatology and Digestive Endoscopy Section, Perugia University, Perugia, Italy
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de Souza SRG, de Miranda Neto MH, Martins Perles JVC, Vieira Frez FC, Zignani I, Ramalho FV, Hermes-Uliana C, Bossolani GDP, Zanoni JN. Antioxidant Effects of the Quercetin in the Jejunal Myenteric Innervation of Diabetic Rats. Front Med (Lausanne) 2017; 4:8. [PMID: 28224126 PMCID: PMC5293826 DOI: 10.3389/fmed.2017.00008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 01/19/2017] [Indexed: 12/31/2022] Open
Abstract
Purpose Enteric glial cells (EGCs) exert a critical role in the structural integrity, defense, and metabolic function of enteric neurons. Diabetes mellitus is a chronic disease characterized by metabolic disorders and chronic autonomic neuropathy. Quercetin supplementation, which is a potent antioxidant, has been used in order to reduce the effects of diabetes-induced oxidative stress. The purpose of this research was to investigate the effects of quercetin supplementation in the drinking water at a daily dose of 40 mg on the glial cells and neurons in the jejunum of diabetic rats. Materials and methods Twenty 90-day-old male adult Wistar rats were split into four groups: normoglycemic control (C), normoglycemic control supplemented with quercetin (Q), diabetic (D), and diabetic supplemented with quercetin (DQ). After 120 days, the jejunums were collected, and immunohistochemical technique was performed to label S-100-immunoreactive glial cells and HuC/D-immunoreactive neurons. Results An intense neuronal and glial reduction was observed in the jejunum of diabetic rats. Quercetin displayed neuroprotective effects due to reduced cell body areas of neurons and glial cells in Q and DQ groups compared to their controls (C and D groups). Interestingly, quercetin prevented the glial and neuronal loss with a higher density for the HuC/D-immunoreactive neurons (23.06%) and for the S100-immunoreactive glial cells (14.55%) in DQ group compared to D group. Conclusion Quercetin supplementation promoted neuroprotective effects through the reduction of neuronal and glial body areas and a slight prevention of neuronal and glial density reduction.
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Affiliation(s)
- Sara R Garcia de Souza
- Department of Morphological Sciences, Universidade Estadual de Maringá , Maringá, Paraná , Brazil
| | | | | | | | - Isabela Zignani
- Department of Morphological Sciences, Universidade Estadual de Maringá , Maringá, Paraná , Brazil
| | - Francielle Veiga Ramalho
- Department of Morphological Sciences, Universidade Estadual de Maringá , Maringá, Paraná , Brazil
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Abstract
Neuroimmune communications are facilitated by the production of neurotransmitters by immune cells and the generation of immune mediators by immune cells, which form a functional entity called the "neuroimmune synapse." There are several mechanisms that further facilitate neuroimmune interactions including the anatomic proximity between immune cells and nerves, the expression of receptors for neurotransmitters on immune cells and for immune mediators on nerves, and the receptor-mediated activation of intracellular signaling pathways that modulate nerve and immune phenotype and function. The bidirectional communication between nerves and immune cells is implicated in allostasis, a process that describes the continuous adaptation to an ever-changing environment. Neuroimmune interactions are amplified during inflammation by the influx of activated immune cells that significantly alter the microenvironment. In this context, the types of neurotransmitters released by activated neurons or immune cells can exert pro- or anti-inflammatory effects. Dysregulation of the enteric nervous system control of gastrointestinal functions, such as epithelial permeability and secretion as well as smooth muscle contractility, also contribute to the chronicity of inflammation. Persistent active inflammation in the gut leads to neuroimmune plasticity, which is a structural and functional remodeling in both the neural and immune systems. The importance of neuroimmune interactions has made them an emerging target in the development of novel therapies for GI pathologies.
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Affiliation(s)
- Terez Shea-Donohue
- Department of Radiation Oncology, University of Maryland School of Medicine, DTRS, MSTF Rm 700C, 10 Pine Street, Baltimore, MD, 21201, USA.
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
| | - Joseph F Urban
- U.S. Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, MD, 20705, USA
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Yamamoto M, Nishiyama M, Iizuka S, Suzuki S, Suzuki N, Aiso S, Nakahara J. Transient receptor potential vanilloid 1-immunoreactive signals in murine enteric glial cells. World J Gastroenterol 2016; 22:9752-9764. [PMID: 27956799 PMCID: PMC5124980 DOI: 10.3748/wjg.v22.i44.9752] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/19/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the possible involvement of transient receptor potential vanilloid 1 (TRPV1) in maturation of enteric glial cells (EGCs).
METHODS Immunohistochemical and immunocytochemical techniques were used to analyze EGC markers in myenteric plexus (MP) as well as cultured MP cells and EGCs using TRPV1 knockout (KO) mice.
RESULTS We detected TRPV1-immunoreactive signals in EGC in the MP of wild-type (WT) but not KO mice. Expression of glial fibrillary acidic protein (GFAP) immunoreactive signals was lower at postnatal day (PD) 6 in KO mice, though the difference was not clear at PD 13 and PD 21. When MP cells were isolated and cultured from isolated longitudinal muscle-MP preparation from WT and KO mice, the yield of KO EGC was lower than that of WT EGC, while the yield of KO and WT smooth muscle cells showed no difference. Addition of BCTC, a TRPV1 antagonist, to enriched EGC culture resulted in a decrease in the protein ratio of GFAP to S100B, another EGC/astrocyte-specific marker.
CONCLUSION These results address the possibility that TRPV1 may be involved in the maturation of EGC, though further studies are necessary to validate this possibility.
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Xiao WD, Peng K, Yang H. Enteric glial cells: An emerging key player in intestinal homeostasis modulation under physiological and pathological conditions. Shijie Huaren Xiaohua Zazhi 2016; 24:3657-3665. [DOI: 10.11569/wcjd.v24.i25.3657] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The intestine contains multiple components including epithelial cells, microbiome as well as various neuroendocrine pathways, all of which are essential for maintaining dynamic mucosal homeostasis through complex interactions among different components in the gastrointestinal tract. Beyond the basic neurosupportive and neurotrophic effects, growing evidence reveals the key role of enteric glial cells (EGCs) in the modulation of bowel movement, nutrient absorption and secretion, intestinal immunity as well as barrier function. As well, abnormally activated EGCs are believed to be a vital player in the pathogenesis of a variety of diseases including inflammatory bowel disease, intestinal barrier dysfunction and infections. Here we provide a brief overview of recent research progress about the precise role and the molecule mechanisms of EGCs in modulating intestinal homeostasis, and highlight the critical role of EGC in various intestinal diseases.
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Cossais F, Durand T, Chevalier J, Boudaud M, Kermarrec L, Aubert P, Neveu I, Naveilhan P, Neunlist M. Postnatal development of the myenteric glial network and its modulation by butyrate. Am J Physiol Gastrointest Liver Physiol 2016; 310:G941-51. [PMID: 27056724 DOI: 10.1152/ajpgi.00232.2015] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 03/16/2016] [Indexed: 02/08/2023]
Abstract
The postnatal period is crucial for the development of gastrointestinal (GI) functions. The enteric nervous system is a key regulator of GI functions, and increasing evidences indicate that 1) postnatal maturation of enteric neurons affect the development of GI functions, and 2) microbiota-derived short-chain fatty acids can be involved in this maturation. Although enteric glial cells (EGC) are central regulators of GI functions, the postnatal evolution of their phenotype remains poorly defined. We thus characterized the postnatal evolution of EGC phenotype in the colon of rat pups and studied the effect of short-chain fatty acids on their maturation. We showed an increased expression of the glial markers GFAP and S100β during the first postnatal week. As demonstrated by immunohistochemistry, a structured myenteric glial network was observed at 36 days in the rat colons. Butyrate inhibited EGC proliferation in vivo and in vitro but had no effect on glial marker expression. These results indicate that the EGC myenteric network continues to develop after birth, and luminal factors such as butyrate endogenously produced in the colon may affect this development.
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Affiliation(s)
- François Cossais
- INSERM, U913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, France; and Centre de Recherche en Nutrition Humaine, Nantes, France
| | - Tony Durand
- INSERM, U913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, France; and Centre de Recherche en Nutrition Humaine, Nantes, France
| | - Julien Chevalier
- INSERM, U913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, France; and Centre de Recherche en Nutrition Humaine, Nantes, France
| | - Marie Boudaud
- INSERM, U913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, France; and Centre de Recherche en Nutrition Humaine, Nantes, France
| | - Laetitia Kermarrec
- INSERM, U913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, France; and Centre de Recherche en Nutrition Humaine, Nantes, France
| | - Philippe Aubert
- INSERM, U913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, France; and Centre de Recherche en Nutrition Humaine, Nantes, France
| | - Isabelle Neveu
- INSERM, U913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, France; and Centre de Recherche en Nutrition Humaine, Nantes, France
| | - Philippe Naveilhan
- INSERM, U913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, France; and Centre de Recherche en Nutrition Humaine, Nantes, France
| | - Michel Neunlist
- INSERM, U913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, France; and Centre de Recherche en Nutrition Humaine, Nantes, France
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Enteric nervous system assembly: Functional integration within the developing gut. Dev Biol 2016; 417:168-81. [PMID: 27235816 DOI: 10.1016/j.ydbio.2016.05.030] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 04/26/2016] [Accepted: 05/24/2016] [Indexed: 02/08/2023]
Abstract
Co-ordinated gastrointestinal function is the result of integrated communication between the enteric nervous system (ENS) and "effector" cells in the gastrointestinal tract. Unlike smooth muscle cells, interstitial cells, and the vast majority of cell types residing in the mucosa, enteric neurons and glia are not generated within the gut. Instead, they arise from neural crest cells that migrate into and colonise the developing gastrointestinal tract. Although they are "later" arrivals into the developing gut, enteric neural crest-derived cells (ENCCs) respond to many of the same secreted signalling molecules as the "resident" epithelial and mesenchymal cells, and several factors that control the development of smooth muscle cells, interstitial cells and epithelial cells also regulate ENCCs. Much progress has been made towards understanding the migration of ENCCs along the gastrointestinal tract and their differentiation into neurons and glia. However, our understanding of how enteric neurons begin to communicate with each other and extend their neurites out of the developing plexus layers to innervate the various cell types lining the concentric layers of the gastrointestinal tract is only beginning. It is critical for postpartum survival that the gastrointestinal tract and its enteric circuitry are sufficiently mature to cope with the influx of nutrients and their absorption that occurs shortly after birth. Subsequently, colonisation of the gut by immune cells and microbiota during postnatal development has an important impact that determines the ultimate outline of the intrinsic neural networks of the gut. In this review, we describe the integrated development of the ENS and its target cells.
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De Giorgio R, Bianco F, Latorre R, Caio G, Clavenzani P, Bonora E. Enteric neuropathies: Yesterday, Today and Tomorrow. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 891:123-33. [PMID: 27379640 DOI: 10.1007/978-3-319-27592-5_12] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Enteric neuropathy is a term indicating an impairment of the innervation supplying the gastrointestinal tract. The clinical phenotypes of the enteric neuropathies are the 'tip of the iceberg' of severe functional digestive diseases, such as intestinal pseudo-obstruction syndromes (e.g., chronic intestinal pseudo-obstruction). Despite progress acquired over the years, the pathogenetic mechanisms leading to enteric neuropathies are still far from being elucidated and the therapeutic approaches to these patients are mainly supportive, rather than curative.The purpose of this chapter is to review the advancements that have been done in the knowledge of enteric neuropathies identified in adult patients ('tomorrow'), going through where we currently are ('today') following a brief history of the major milestones on the pioneering discoveries in the field ('yesterday').
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Affiliation(s)
- Roberto De Giorgio
- Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Via Massarenti 9, Bologna, Italy.
- Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, Bologna, Italy.
| | - Francesca Bianco
- Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Via Massarenti 9, Bologna, Italy
- Department of Medical and Veterinary Sciences, University of Bologna, Bologna, Italy
| | - Rocco Latorre
- Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Via Massarenti 9, Bologna, Italy
- Centro di Ricerca Biomedica Applicata (C.R.B.A.), University of Bologna, Bologna, Italy
| | - Giacomo Caio
- Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Via Massarenti 9, Bologna, Italy
| | - Paolo Clavenzani
- Department of Medical and Veterinary Sciences, University of Bologna, Bologna, Italy
| | - Elena Bonora
- Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Via Massarenti 9, Bologna, Italy
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Stavely R, Robinson AM, Miller S, Boyd R, Sakkal S, Nurgali K. Allogeneic guinea pig mesenchymal stem cells ameliorate neurological changes in experimental colitis. Stem Cell Res Ther 2015; 6:263. [PMID: 26718461 PMCID: PMC4697327 DOI: 10.1186/s13287-015-0254-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 11/12/2015] [Accepted: 12/02/2015] [Indexed: 12/13/2022] Open
Abstract
Background The use of mesenchymal stem cells (MSCs) to treat inflammatory bowel disease (IBD) is of great interest because of their immunomodulatory properties. Damage to the enteric nervous system (ENS) is implicated in IBD pathophysiology and disease progression. The most commonly used model to study inflammation-induced changes to the ENS is 2,4,6-trinitrobenzene-sulfonate acid (TNBS)-induced colitis in guinea pigs; however, no studies using guinea pig MSCs in colitis have been performed. This study aims to isolate and characterise guinea pig MSCs and then test their therapeutic potential for the treatment of enteric neuropathy associated with intestinal inflammation. Methods MSCs from guinea pig bone marrow and adipose tissue were isolated and characterised in vitro. In in vivo experiments, guinea pigs received either TNBS for the induction of colitis or sham treatment by enema. MSCs were administered at a dose of 1 × 106 cells via enema 3 h after the induction of colitis. Colon tissues were collected 24 and 72 h after TNBS administration to assess the level of inflammation and damage to the ENS. The secretion of transforming growth factor-β1 (TGF-β1) was analysed in MSC conditioned medium by flow cytometry. Results Cells isolated from both sources were adherent to plastic, multipotent and expressed some human MSC surface markers. In vitro characterisation revealed distinct differences in growth kinetics, clonogenicity and cell morphology between MSC types. In an in vivo model of TNBS-induced colitis, guinea pig bone marrow MSCs were comparatively more efficacious than adipose tissue MSCs in attenuating weight loss, colonic tissue damage and leukocyte infiltration into the mucosa and myenteric plexus. MSCs from both sources were equally neuroprotective in the amelioration of enteric neuronal loss and changes to the neurochemical coding of neuronal subpopulations. MSCs from both sources secreted TGF-β1 which exerted neuroprotective effects in vitro. Conclusions This study is the first evaluating the functional capacity of guinea pig bone marrow and adipose tissue-derived MSCs and providing evidence of their neuroprotective value in an animal model of colitis. In vitro characteristics of MSCs cannot be extrapolated to their therapeutic efficacy. TGF-β1 released by both types of MSCs might have contributed to the attenuation of enteric neuropathy associated with colitis.
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Affiliation(s)
- Rhian Stavely
- Centre for Chronic Disease, College of Health and Biomedicine, Western Centre for Health, Research and Education, Sunshine Hospital, 176 Furlong road, Melbourne, 3021, Victoria, Australia.
| | - Ainsley M Robinson
- Centre for Chronic Disease, College of Health and Biomedicine, Western Centre for Health, Research and Education, Sunshine Hospital, 176 Furlong road, Melbourne, 3021, Victoria, Australia.
| | - Sarah Miller
- Centre for Chronic Disease, College of Health and Biomedicine, Western Centre for Health, Research and Education, Sunshine Hospital, 176 Furlong road, Melbourne, 3021, Victoria, Australia.
| | - Richard Boyd
- Department of Anatomy and Developmental Biology, Monash University, 19 Innovation Walk, Clayton, 3800, Victoria, Australia.
| | - Samy Sakkal
- Centre for Chronic Disease, College of Health and Biomedicine, Western Centre for Health, Research and Education, Sunshine Hospital, 176 Furlong road, Melbourne, 3021, Victoria, Australia.
| | - Kulmira Nurgali
- Centre for Chronic Disease, College of Health and Biomedicine, Western Centre for Health, Research and Education, Sunshine Hospital, 176 Furlong road, Melbourne, 3021, Victoria, Australia.
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Coelho-Aguiar JDM, Bon-Frauches AC, Gomes ALT, Veríssimo CP, Aguiar DP, Matias D, Thomasi BBDM, Gomes AS, Brito GADC, Moura-Neto V. The enteric glia: identity and functions. Glia 2015; 63:921-35. [PMID: 25703790 DOI: 10.1002/glia.22795] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 01/07/2015] [Indexed: 01/04/2023]
Abstract
Enteric glial cells were first described at the end of the 19th century, but they attracted more interest from researchers only in the last decades of the 20th. Although, they have a different embryological origin, the enteric GLIA share many characteristics with astrocytes, the main glial cell type of the central nervous system (CNS), such as in their expression of the same markers and in their functions. Here we review the construction of the enteric nervous system (ENS), with a focus on enteric glia, and also the main studies that have revealed the action of enteric glia in different aspects of gastrointestinal tract homeostasis, such as in the intestinal barrier, in communications with neurons, and in their action as progenitor cells. We also discuss recent discoveries about the roles of enteric glia in different disorders that affect the ENS, such as degenerative pathologies including Parkinson's and prion diseases, and in cases of intestinal diseases and injury.
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Affiliation(s)
- Juliana de Mattos Coelho-Aguiar
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde do Rio de Janeiro - SES/RJ, Rio de Janeiro, Brazil; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Ranson RN, Saffrey MJ. Neurogenic mechanisms in bladder and bowel ageing. Biogerontology 2015; 16:265-84. [PMID: 25666896 PMCID: PMC4361768 DOI: 10.1007/s10522-015-9554-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 01/28/2015] [Indexed: 01/18/2023]
Abstract
The prevalence of both urinary and faecal incontinence, and also chronic constipation, increases with ageing and these conditions have a major impact on the quality of life of the elderly. Management of bladder and bowel dysfunction in the elderly is currently far from ideal and also carries a significant financial burden. Understanding how these changes occur is thus a major priority in biogerontology. The functions of the bladder and terminal bowel are regulated by complex neuronal networks. In particular neurons of the spinal cord and peripheral ganglia play a key role in regulating micturition and defaecation reflexes as well as promoting continence. In this review we discuss the evidence for ageing-induced neuronal dysfunction that might predispose to neurogenic forms of incontinence in the elderly.
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Affiliation(s)
- Richard N Ranson
- Department of Applied Sciences (Biomedical Sciences), Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, UK,
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Yu YB, Li YQ. Enteric glial cells and their role in the intestinal epithelial barrier. World J Gastroenterol 2014; 20:11273-11280. [PMID: 25170211 PMCID: PMC4145765 DOI: 10.3748/wjg.v20.i32.11273] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Revised: 03/11/2014] [Accepted: 05/12/2014] [Indexed: 02/06/2023] Open
Abstract
The intestinal epithelium constitutes a physical and functional barrier between the external environment and the host organism. It is formed by a continuous monolayer of intestinal epithelial cells maintained together by intercellular junctional complex, limiting access of pathogens, toxins and xenobiotics to host tissues. Once this barrier integrity is disrupted, inflammatory disorders and tissue injury are initiated and perpetuated. Beneath the intestinal epithelial cells lies a population of astrocyte-like cells that are known as enteric glia. The morphological characteristics and expression markers of these enteric glia cells were identical to the astrocytes of the central nervous system. In the past few years, enteric glia have been demonstrated to have a trophic and supporting relationship with intestinal epithelial cells. Enteric glia lesions and/or functional defects can be involved in the barrier dysfunction. Besides, factors secreted by enteric glia are important for the regulation of gut barrier function. Moreover, enteric glia have an important impact on epithelial cell transcriptome and induce a shift in epithelial cell phenotype towards increased cell adhesion and cell differentiation. Enteric glia can also preserve epithelial barrier against intestinal bacteria insult. In this review, we will describe the current body of evidence supporting functional roles of enteric glia on intestinal barrier.
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Boesmans W, Lasrado R, Vanden Berghe P, Pachnis V. Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system. Glia 2014; 63:229-41. [PMID: 25161129 DOI: 10.1002/glia.22746] [Citation(s) in RCA: 205] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 08/05/2014] [Indexed: 12/24/2022]
Abstract
Enteric glial cells are vital for the autonomic control of gastrointestinal homeostasis by the enteric nervous system. Several different functions have been assigned to enteric glial cells but whether these are performed by specialized subtypes with a distinctive phenotype and function remains elusive. We used Mosaic Analysis with Double Markers and inducible lineage tracing to characterize the morphology and dynamic molecular marker expression of enteric GLIA in the myenteric plexus. Functional analysis in individually identified enteric glia was performed by Ca(2+) imaging. Our experiments have identified four morphologically distinct subpopulations of enteric glia in the gastrointestinal tract of adult mice. Marker expression analysis showed that the majority of glia in the myenteric plexus co-express glial fibrillary acidic protein (GFAP), S100β, and Sox10. However, a considerable fraction (up to 80%) of glia outside the myenteric ganglia, did not label for these markers. Lineage tracing experiments suggest that these alternative combinations of markers reflect dynamic gene regulation rather than lineage restrictions. At the functional level, the three myenteric glia subtypes can be distinguished by their differential response to adenosine triphosphate. Together, our studies reveal extensive heterogeneity and phenotypic plasticity of enteric glial cells and set a framework for further investigations aimed at deciphering their role in digestive function and disease.
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Affiliation(s)
- Werend Boesmans
- Laboratory for Enteric NeuroScience (LENS), TARGID, Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium
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Desmet AS, Cirillo C, Vanden Berghe P. Distinct subcellular localization of the neuronal marker HuC/D reveals hypoxia-induced damage in enteric neurons. Neurogastroenterol Motil 2014; 26:1131-43. [PMID: 24861242 DOI: 10.1111/nmo.12371] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 04/29/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Correct neuronal identification is essential to study neurons in health and disease. Although commonly used as pan-neuronal marker, HuC/D's expression pattern varies substantially between healthy and (patho)physiological conditions. This heterogenic labeling has received very little attention. We sought to investigate the subcellular HuC/D localization in enteric neurons in different conditions. METHODS The localization of neuronal RNA-binding proteins HuC/D was investigated by immunohistochemistry in the mouse myenteric plexus using different toxins and caustic agents. Preparations were also stained with Sox10 and glial fibrillary acidic protein (GFAP) antibodies to assess enteric glial cell appearance. KEY RESULTS Mechanically induced tissue damage, interference with the respiratory chain and oxygen (O2 ) deprivation increased nuclear HuC/D immunoreactivity. This effect was paralleled by a distortion of the GFAP-labeled glial network along with a loss of Sox10 expression and coincided with the activation of a non-apoptotic genetic program. Chemically induced damage and specific noxious stimuli did not induce a change in HuC/D immunoreactivity, supporting the specific nature of the nuclear HuC/D localization. CONCLUSIONS & INFERENCES HuC/D is not merely a pan-neuronal marker but its subcellular localization also reflects the condition of a neuron at the time of fixation. The functional meaning of this change in HuC/D localization is not entirely clear, but disturbance in O2 supply in combination with the support of enteric glial cells seems to play a crucial role. The molecular consequence of changes in HuC/D expression needs to be further investigated.
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Affiliation(s)
- A-S Desmet
- Laboratory for Enteric NeuroScience (LENS), Translational Research Center for GastroIntestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
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