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1
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Prochera A, Muppirala AN, Kuziel GA, Soualhi S, Shepherd A, Sun L, Issac B, Rosenberg HJ, Karim F, Perez K, Smith KH, Archibald TH, Rakoff-Nahoum S, Hagen SJ, Rao M. Enteric glia regulate Paneth cell secretion and intestinal microbial ecology. eLife 2025; 13:RP97144. [PMID: 40227232 PMCID: PMC11996175 DOI: 10.7554/elife.97144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025] Open
Abstract
Glial cells of the enteric nervous system (ENS) interact closely with the intestinal epithelium and secrete signals that influence epithelial cell proliferation and barrier formation in vitro. Whether these interactions are important in vivo, however, is unclear because previous studies reached conflicting conclusions (Prochera and Rao, 2023). To better define the roles of enteric glia in steady state regulation of the intestinal epithelium, we characterized the glia in closest proximity to epithelial cells and found that the majority express the gene Proteolipid protein 1 (PLP1) in both mice and humans. To test their functions using an unbiased approach, we genetically depleted PLP1+ cells in mice and transcriptionally profiled the small and large intestines. Surprisingly, glial loss had minimal effects on transcriptional programs and the few identified changes varied along the gastrointestinal tract. In the ileum, where enteric glia had been considered most essential for epithelial integrity, glial depletion did not drastically alter epithelial gene expression but caused a modest enrichment in signatures of Paneth cells, a secretory cell type important for innate immunity. In the absence of PLP1+ glia, Paneth cell number was intact, but a subset appeared abnormal with irregular and heterogenous cytoplasmic granules, suggesting a secretory deficit. Consistent with this possibility, ileal explants from glial-depleted mice secreted less functional lysozyme than controls with corresponding effects on fecal microbial composition. Collectively, these data suggest that enteric glia do not exert broad effects on the intestinal epithelium but have an essential role in regulating Paneth cell function and gut microbial ecology.
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Affiliation(s)
- Aleksandra Prochera
- Division of Gastroenterology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
| | - Anoohya N Muppirala
- Division of Gastroenterology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
| | - Gavin A Kuziel
- Division of Gastroenterology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
- Division of Infectious Diseases, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
- Department of Microbiology, Harvard Medical SchoolBostonUnited States
| | - Salima Soualhi
- Division of Gastroenterology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
| | - Amy Shepherd
- Division of Gastroenterology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
| | - Liang Sun
- Research Computing, Department of Information Technology, Boston Children’s HospitalBostonUnited States
| | - Biju Issac
- Research Computing, Department of Information Technology, Boston Children’s HospitalBostonUnited States
| | - Harry J Rosenberg
- Division of Gastroenterology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
- Department of Pathology, Beth Israel Deaconess Medical CenterBostonUnited States
| | - Farah Karim
- Institute of Human Nutrition, Columbia University Irving Medical CenterNew YorkUnited States
| | - Kristina Perez
- Division of Gastroenterology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
| | - Kyle H Smith
- Department of Surgery, Beth Israel Deaconess Medical CenterBostonUnited States
| | - Tonora H Archibald
- Research Computing, Department of Information Technology, Boston Children’s HospitalBostonUnited States
| | - Seth Rakoff-Nahoum
- Division of Gastroenterology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
- Division of Infectious Diseases, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
- Department of Microbiology, Harvard Medical SchoolBostonUnited States
| | - Susan J Hagen
- Department of Surgery, Beth Israel Deaconess Medical CenterBostonUnited States
| | - Meenakshi Rao
- Division of Gastroenterology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical SchoolBostonUnited States
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2
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Rao M, Gulbransen BD. Enteric Glia. Cold Spring Harb Perspect Biol 2025; 17:a041368. [PMID: 38951022 PMCID: PMC11960695 DOI: 10.1101/cshperspect.a041368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
Enteric glia are a unique type of peripheral neuroglia that accompany neurons in the enteric nervous system (ENS) of the digestive tract. The ENS displays integrative neural circuits that are capable of governing moment-to-moment gut functions independent of input from the central nervous system. Enteric glia are interspersed with neurons throughout these intrinsic gut neural circuits and are thought to fulfill complex roles directed at maintaining homeostasis in the neuronal microenvironment and at neuroeffector junctions in the gut. Changes to glial functions contribute to a wide range of gastrointestinal diseases, but the precise roles of enteric glia in gut physiology and pathophysiology are still under examination. This review summarizes current concepts regarding enteric glial development, diversity, and functions in health and disease.
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Affiliation(s)
- Meenakshi Rao
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Brian D Gulbransen
- Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA
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3
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Gonzales J, Gulbransen BD. The Physiology of Enteric Glia. Annu Rev Physiol 2025; 87:353-380. [PMID: 39546562 DOI: 10.1146/annurev-physiol-022724-105016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
Enteric glia are the partners of neurons in the enteric nervous system throughout the gastrointestinal tract. Roles fulfilled by enteric glia are diverse and contribute to maintaining intestinal homeostasis through interactions with neurons, immune cells, and the intestinal epithelium. Glial influences optimize physiological gut processes such as intestinal motility and epithelial barrier integrity through actions that regulate the microenvironment of the enteric nervous system, the activity of enteric neurons, intestinal epithelial functions, and immune response. Changes to glial phenotype in disease switch glial functions and contribute to intestinal inflammation, dysmotility, pain, neuroplasticity, and tumorigenesis. This review summarizes current concepts regarding the physiological roles of enteric glial cells and their potential contributions to gut disease. The discussion is focused on recent evidence that suggests important glial contributions to gastrointestinal health and pathophysiology.
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Affiliation(s)
- Jacques Gonzales
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA;
| | - Brian D Gulbransen
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA;
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4
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Prochera A, Muppirala AN, Kuziel GA, Soualhi S, Shepherd A, Sun L, Issac B, Rosenberg HJ, Karim F, Perez K, Smith KH, Archibald TH, Rakoff-Nahoum S, Hagen SJ, Rao M. Enteric glia regulate Paneth cell secretion and intestinal microbial ecology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.15.589545. [PMID: 38659931 PMCID: PMC11042301 DOI: 10.1101/2024.04.15.589545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Glial cells of the enteric nervous system (ENS) interact closely with the intestinal epithelium and secrete signals that influence epithelial cell proliferation and barrier formation in vitro. Whether these interactions are important in vivo, however, is unclear because previous studies reached conflicting conclusions [1]. To better define the roles of enteric glia in steady state regulation of the intestinal epithelium, we characterized the glia in closest proximity to epithelial cells and found that the majority express PLP1 in both mice and humans. To test their functions using an unbiased approach, we genetically depleted PLP1+ cells in mice and transcriptionally profiled the small and large intestines. Surprisingly, glial loss had minimal effects on transcriptional programs and the few identified changes varied along the gastrointestinal tract. In the ileum, where enteric glia had been considered most essential for epithelial integrity, glial depletion did not drastically alter epithelial gene expression but caused a modest enrichment in signatures of Paneth cells, a secretory cell type important for innate immunity. In the absence of PLP1+ glia, Paneth cell number was intact, but a subset appeared abnormal with irregular and heterogenous cytoplasmic granules, suggesting a secretory deficit. Consistent with this possibility, ileal explants from glial-depleted mice secreted less functional lysozyme than controls with corresponding effects on fecal microbial composition. Collectively, these data suggest that enteric glia do not exert broad effects on the intestinal epithelium but have an essential role in regulating Paneth cell function and gut microbial ecology.
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Affiliation(s)
- Aleksandra Prochera
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
| | - Anoohya N Muppirala
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
| | - Gavin A Kuziel
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
- Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Salima Soualhi
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
| | - Amy Shepherd
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
| | - Liang Sun
- Research Computing, Department of Information Technology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Biju Issac
- Research Computing, Department of Information Technology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Harry J Rosenberg
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Farah Karim
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY, USA
| | - Kristina Perez
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
| | - Kyle H Smith
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Tonora H Archibald
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Seth Rakoff-Nahoum
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
- Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Susan J Hagen
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Meenakshi Rao
- Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
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Septyaningtrias DE, Muliyantoro NSS, Sumiwi YAA, Susilowati R. Anti-inflammatory and glial response maintain normal colon function in trimethyltin-treated rats. Histochem Cell Biol 2024; 162:477-486. [PMID: 39172242 DOI: 10.1007/s00418-024-02320-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2024] [Indexed: 08/23/2024]
Abstract
Studies on the contribution of enteric neuropathy and intestinal homeostasis to central nervous system degeneration using animal models have reported varying results. Recently, colonic myenteric plexus degeneration was observed in trimethyltin-treated rats. Further characterization of this animal model is necessary to determine its potential for investigating the relationship between the enteric nervous system and central nervous system degeneration. In this study, trimethyltin-treated rats (8 mg/kg body weight, i.p.) were used to measure colonic function, structure, and possible colon abnormalities. The colonic function was assessed by measuring fecal pellet output and transit time. Hematoxylin and eosin staining and immunohistochemistry were performed to evaluate inflammatory profiles and intestinal epithelial cell homeostasis. The expression of mRNA encoding tight junction proteins was quantified with quantitative PCR to determine colon permeability. Histological examination of the colon revealed mucosal immune cell infiltration, crypt damage, and high iNOS and arginase-1 expression in the mucosal layer of trimethyltin-treated rats. At the same time, trimethyltin induced high expression of iNOS, arginase-1, and GFAP and increased cell death in the colonic myenteric plexus. The low cell proliferation and low goblet cell distribution suggested altered intestinal epithelial cell homeostasis in trimethyltin-treated rats. Trimethyltin also upregulated claudin 1 expression. However, normal colon function was preserved. In conclusion, the results show that trimethyltin induces colon inflammation and cell death in the colonic myenteric plexus, and disrupts intestinal epithelial cell homeostasis. However, the balance between anti-inflammatory and pro-inflammatory responses maintains normal colon function in trimethyltin-treated rats.
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Affiliation(s)
- Dian Eurike Septyaningtrias
- Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Jalan Farmako Sekip Utara, Yogyakarta, 55281, Indonesia
| | - Nur Salisa Siddik Muliyantoro
- Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Jalan Farmako Sekip Utara, Yogyakarta, 55281, Indonesia
| | - Yustina Andwi Ari Sumiwi
- Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Jalan Farmako Sekip Utara, Yogyakarta, 55281, Indonesia
| | - Rina Susilowati
- Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Jalan Farmako Sekip Utara, Yogyakarta, 55281, Indonesia.
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6
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Blank N, Weiner M, Patel S, Köhler S, Thaiss CA. Mind the GAPS: Glia associated with psychological stress. J Neuroendocrinol 2024:e13451. [PMID: 39384366 DOI: 10.1111/jne.13451] [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: 05/20/2024] [Revised: 09/01/2024] [Accepted: 09/05/2024] [Indexed: 10/11/2024]
Abstract
Glial cells are an integral component of the nervous system, performing crucial functions that extend beyond structural support, including modulation of the immune system, tissue repair, and maintaining tissue homeostasis. Recent studies have highlighted the importance of glial cells as key mediators of stress responses across different organs. This review focuses on the roles of glial cells in peripheral tissues in health and their involvement in diseases linked to psychological stress. Populations of glia associated with psychological stress ("GAPS") emerge as a promising target cell population in our basic understanding of stress-associated pathologies, highlighting their role as mediators of the deleterious effects of psychological stress on various health conditions. Ultimately, new insights into the impact of stress on glial cell populations in the periphery may support clinical efforts aimed at improving the psychological state of patients for improved health outcomes.
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Affiliation(s)
- Niklas Blank
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Molly Weiner
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Shaan Patel
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sarah Köhler
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Christoph A Thaiss
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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7
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Shatunova S, Aktar R, Peiris M, Lee JYP, Vetter I, Starobova H. The role of the gut microbiome in neuroinflammation and chemotherapy-induced peripheral neuropathy. Eur J Pharmacol 2024; 979:176818. [PMID: 39029779 DOI: 10.1016/j.ejphar.2024.176818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/05/2024] [Accepted: 07/17/2024] [Indexed: 07/21/2024]
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most debilitating adverse effects caused by chemotherapy drugs such as paclitaxel, oxaliplatin and vincristine. It is untreatable and often leads to the discontinuation of cancer therapy and a decrease in the quality of life of cancer patients. It is well-established that neuroinflammation and the activation of immune and glial cells are among the major drivers of CIPN. However, these processes are still poorly understood, and while many chemotherapy drugs alone can drive the activation of these cells and consequent neuroinflammation, it remains elusive to what extent the gut microbiome influences these processes. In this review, we focus on the peripheral mechanisms driving CIPN, and we address the bidirectional pathways by which the gut microbiome communicates with the immune and nervous systems. Additionally, we critically evaluate literature addressing how chemotherapy-induced dysbiosis and the consequent imbalance in bacterial products may contribute to the activation of immune and glial cells, both of which drive neuroinflammation and possibly CIPN development, and how we could use this knowledge for the development of effective treatment strategies.
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Affiliation(s)
- Svetlana Shatunova
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Rubina Aktar
- Centre for Neuroscience, Surgery and Trauma, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Madusha Peiris
- Centre for Neuroscience, Surgery and Trauma, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Jia Yu Peppermint Lee
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Irina Vetter
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia; The School of Pharmacy, The University of Queensland, Woollsiana, QLD, Australia
| | - Hana Starobova
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.
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8
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Santhosh S, Zanoletti L, Stamp LA, Hao MM, Matteoli G. From diversity to disease: unravelling the role of enteric glial cells. Front Immunol 2024; 15:1408744. [PMID: 38957473 PMCID: PMC11217337 DOI: 10.3389/fimmu.2024.1408744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/27/2024] [Indexed: 07/04/2024] Open
Abstract
Enteric glial cells (EGCs) are an essential component of the enteric nervous system (ENS) and play key roles in gastrointestinal development, homeostasis, and disease. Derived from neural crest cells, EGCs undergo complex differentiation processes regulated by various signalling pathways. Being among the most dynamic cells of the digestive system, EGCs react to cues in their surrounding microenvironment and communicate with various cell types and systems within the gut. Morphological studies and recent single cell RNA sequencing studies have unveiled heterogeneity among EGC populations with implications for regional functions and roles in diseases. In gastrointestinal disorders, including inflammatory bowel disease (IBD), infections and cancer, EGCs modulate neuroplasticity, immune responses and tumorigenesis. Recent evidence suggests that EGCs respond plastically to the microenvironmental cues, adapting their phenotype and functions in disease states and taking on a crucial role. They exhibit molecular abnormalities and alter communication with other intestinal cell types, underscoring their therapeutic potential as targets. This review delves into the multifaceted roles of EGCs, particularly emphasizing their interactions with various cell types in the gut and their significant contributions to gastrointestinal disorders. Understanding the complex roles of EGCs in gastrointestinal physiology and pathology will be crucial for the development of novel therapeutic strategies for gastrointestinal disorders.
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Affiliation(s)
- Sneha Santhosh
- Department of Chronic Diseases, Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Lisa Zanoletti
- Department of Chronic Diseases, Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Pavia, Italy
| | - Lincon A. Stamp
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Marlene M. Hao
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
| | - Gianluca Matteoli
- Department of Chronic Diseases, Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Leuven Institute for Single-cell Omics (LISCO), KU Leuven, Leuven, Belgium
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9
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Llorente C. The Imperative for Innovative Enteric Nervous System-Intestinal Organoid Co-Culture Models: Transforming GI Disease Modeling and Treatment. Cells 2024; 13:820. [PMID: 38786042 PMCID: PMC11119846 DOI: 10.3390/cells13100820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/29/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024] Open
Abstract
This review addresses the need for innovative co-culture systems integrating the enteric nervous system (ENS) with intestinal organoids. The breakthroughs achieved through these techniques will pave the way for a transformative era in gastrointestinal (GI) disease modeling and treatment strategies. This review serves as an introduction to the companion protocol paper featured in this journal. The protocol outlines the isolation and co-culture of myenteric and submucosal neurons with small intestinal organoids. This review provides an overview of the intestinal organoid culture field to establish a solid foundation for effective protocol application. Remarkably, the ENS surpasses the number of neurons in the spinal cord. Referred to as the "second brain", the ENS orchestrates pivotal roles in GI functions, including motility, blood flow, and secretion. The ENS is organized into myenteric and submucosal plexuses. These plexuses house diverse subtypes of neurons. Due to its proximity to the gut musculature and its cell type complexity, there are methodological intricacies in studying the ENS. Diverse approaches such as primary cell cultures, three-dimensional (3D) neurospheres, and induced ENS cells offer diverse insights into the multifaceted functionality of the ENS. The ENS exhibits dynamic interactions with the intestinal epithelium, the muscle layer, and the immune system, influencing epithelial physiology, motility, immune responses, and the microbiome. Neurotransmitters, including acetylcholine (ACh), serotonin (5-HT), and vasoactive intestinal peptide (VIP), play pivotal roles in these intricate interactions. Understanding these dynamics is imperative, as the ENS is implicated in various diseases, ranging from neuropathies to GI disorders and neurodegenerative diseases. The emergence of organoid technology presents an unprecedented opportunity to study ENS interactions within the complex milieu of the small and large intestines. This manuscript underscores the urgent need for standardized protocols and advanced techniques to unravel the complexities of the ENS and its dynamic relationship with the gut ecosystem. The insights gleaned from such endeavors hold the potential to revolutionize GI disease modeling and treatment paradigms.
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Affiliation(s)
- Cristina Llorente
- Department of Medicine, University of California San Diego, MC0063, 9500 Gilman Drive, La Jolla, CA 92093, USA
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10
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Thomasi B, Valdetaro L, Gulbransen B, Tavares-Gomes AL. Neuroimmune Connectomes in the Gut and Their Implications in Parkinson's Disease. Mol Neurobiol 2024; 61:2081-2098. [PMID: 37840070 PMCID: PMC11151216 DOI: 10.1007/s12035-023-03679-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 09/28/2023] [Indexed: 10/17/2023]
Abstract
The gastrointestinal tract is the largest immune organ and it receives dense innervation from intrinsic (enteric) and extrinsic (sympathetic, parasympathetic, and somatosensory) neurons. The immune and neural systems of the gut communicate with each other and their interactions shape gut defensive mechanisms and neural-controlled gut functions such as motility and secretion. Changes in neuroimmune interactions play central roles in the pathogenesis of diseases such as Parkinson's disease (PD), which is a multicentric disorder that is heterogeneous in its manifestation and pathogenesis. Non-motor and premotor symptoms of PD are common in the gastrointestinal tract and the gut is considered a potential initiation site for PD in some cases. How the enteric nervous system and neuroimmune signaling contribute to PD disease progression is an emerging area of interest. This review focuses on intestinal neuroimmune loops such as the neuroepithelial unit, enteric glial cells and their immunomodulatory effects, anti-inflammatory cholinergic signaling and the relationship between myenteric neurons and muscularis macrophages, and the role of α-synuclein in gut immunity. Special consideration is given to the discussion of intestinal neuroimmune connectomes during PD and their possible implications for various aspects of the disease.
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Affiliation(s)
- Beatriz Thomasi
- Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building - Gulbransen lab, 567, Wilson Rd, Room 3199, East Lansing, MI, USA.
| | - Luisa Valdetaro
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, USA
| | - Brian Gulbransen
- Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building - Gulbransen lab, 567, Wilson Rd, Room 3199, East Lansing, MI, USA
| | - Ana Lúcia Tavares-Gomes
- Programa de Pós-Graduação Em Neurociências, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
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11
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Ziegler AL, Caldwell ML, Craig SE, Hellstrom EA, Sheridan AE, Touvron MS, Pridgen TA, Magness ST, Odle J, Van Landeghem L, Blikslager AT. Enteric glial cell network function is required for epithelial barrier restitution following intestinal ischemic injury in the early postnatal period. Am J Physiol Gastrointest Liver Physiol 2024; 326:G228-G246. [PMID: 38147796 PMCID: PMC11211042 DOI: 10.1152/ajpgi.00216.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 08/23/2023] [Accepted: 09/12/2023] [Indexed: 12/28/2023]
Abstract
Ischemic damage to the intestinal epithelial barrier, such as in necrotizing enterocolitis or small intestinal volvulus, is associated with higher mortality rates in younger patients. We have recently reported a powerful pig model to investigate these age-dependent outcomes in which mucosal barrier restitution is strikingly absent in neonates but can be rescued by direct application of homogenized mucosa from older, juvenile pigs by a yet-undefined mechanism. Within the mucosa, a postnatally developing network of enteric glial cells (EGCs) is gaining recognition as a key regulator of the mucosal barrier. Therefore, we hypothesized that the developing EGC network may play an important role in coordinating intestinal barrier repair in neonates. Neonatal and juvenile jejunal mucosa recovering from surgically induced intestinal ischemia was visualized by scanning electron microscopy and the transcriptomic phenotypes were assessed by bulk RNA sequencing. EGC network density and glial activity were examined by Gene Set Enrichment Analysis, three-dimensional (3-D) volume imaging, and Western blot and its function in regulating epithelial restitution was assessed ex vivo in Ussing chamber using the glia-specific inhibitor fluoroacetate (FA), and in vitro by coculture assay. Here we refine and elaborate our translational model, confirming a neonatal phenotype characterized by a complete lack of coordinated reparative signaling in the mucosal microenvironment. Furthermore, we report important evidence that the subepithelial EGC network changes significantly over the early postnatal period and demonstrate that the proximity of a specific functional population of EGC to wounded intestinal epithelium contributes to intestinal barrier restitution following ischemic injury.NEW & NOTEWORTHY This study refines a powerful translational pig model, defining an age-dependent relationship between enteric glia and the intestinal epithelium during intestinal ischemic injury and confirming an important role for enteric glial cell (EGC) activity in driving mucosal barrier restitution. This study suggests that targeting the enteric glial network could lead to novel interventions to improve recovery from intestinal injury in neonatal patients.
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Affiliation(s)
- Amanda L Ziegler
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States
| | - Madison L Caldwell
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States
| | - Sara E Craig
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States
| | - Emily A Hellstrom
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States
| | - Anastasia E Sheridan
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States
| | - Melissa S Touvron
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States
| | - Tiffany A Pridgen
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States
| | - Scott T Magness
- Joint Department of Biomedical Engineering, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States
| | - Jack Odle
- Department of Animal Science, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, North Carolina, United States
| | - Laurianne Van Landeghem
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States
| | - Anthony T Blikslager
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States
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12
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Aidos L, Pallaoro M, Mirra G, Serra V, Castrica M, Agradi S, Curone G, Vigo D, Riva F, Balzaretti CM, De Bellis R, Pastorelli G, Brecchia G, Modina SC, Di Giancamillo A. Intestine Health and Barrier Function in Fattening Rabbits Fed Bovine Colostrum. Vet Sci 2023; 10:657. [PMID: 37999480 PMCID: PMC10675739 DOI: 10.3390/vetsci10110657] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/07/2023] [Accepted: 11/11/2023] [Indexed: 11/25/2023] Open
Abstract
The permeability of the immature intestine is higher in newborns than in adults; a damaged gut barrier in young animals increases the susceptibility to digestive and infectious diseases later in life. It is therefore of major importance to avoid impairment of the intestinal barrier, specifically in a delicate phase of development, such as weaning. This study aimed to evaluate the effects of bovine colostrum supplementation on the intestinal barrier, such as the intestinal morphology and proliferation level and tight junctions expression (zonulin) and enteric nervous system (ENS) inflammation status (through the expression of PGP9.5 and GFAP) in fattening rabbits. Rabbits of 35 days of age were randomly divided into three groups (n = 13) based on the dietary administration: commercial feed (control group, CTR) and commercial feed supplemented with 2.5% and 5% bovine colostrum (BC1 and BC2 groups, respectively). Rabbits receiving the BC1 diet showed a tendency to have better duodenum morphology and higher proliferation rates (p < 0.001) than the control group. An evaluation of the zonulin expression showed that it was higher in the BC2 group, suggesting increased permeability, which was partially confirmed by the expression of GFAP. Our results suggest that adding 2.5% BC into the diet could be a good compromise between intestinal morphology and permeability, since rabbits fed the highest inclusion level of BC showed signs of higher intestinal permeability.
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Affiliation(s)
- Lucia Aidos
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Margherita Pallaoro
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Giorgio Mirra
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Valentina Serra
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Marta Castrica
- Dipartimento di Biomedicina Comparata e Alimentazione—BCA, University of Padua, Viale dell’Università, 16, 35020 Legnaro, Italy;
| | - Stella Agradi
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Giulio Curone
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Daniele Vigo
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Federica Riva
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Claudia Maria Balzaretti
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Roberta De Bellis
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Via A. Saffi 2, 61029 Urbino, Italy;
| | - Grazia Pastorelli
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Gabriele Brecchia
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Silvia Clotilde Modina
- Department of Veterinary Medicine and Animal Sciences, University of Milan, Via dell’Università 6, 26900 Lodi, Italy; (L.A.); (M.P.); (G.M.); (V.S.); (S.A.); (G.C.); (D.V.); (F.R.); (C.M.B.); (G.P.); (G.B.); (S.C.M.)
| | - Alessia Di Giancamillo
- Department of Biomedical Sciences for Health, University of Milan, Via Mangiagalli 31, 20133 Milan, Italy
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13
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van Baarle L, Stakenborg M, Matteoli G. Enteric neuro-immune interactions in intestinal health and disease. Semin Immunol 2023; 70:101819. [PMID: 37632991 DOI: 10.1016/j.smim.2023.101819] [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: 09/30/2022] [Revised: 07/19/2023] [Accepted: 08/11/2023] [Indexed: 08/28/2023]
Abstract
The enteric nervous system is an autonomous neuronal circuit that regulates many processes far beyond the peristalsis in the gastro-intestinal tract. This circuit, consisting of enteric neurons and enteric glial cells, can engage in many intercellular interactions shaping the homeostatic microenvironment in the gut. Perhaps the most well documented interactions taking place, are the intestinal neuro-immune interactions which are essential for the fine-tuning of oral tolerance. In the context of intestinal disease, compelling evidence demonstrates both protective and detrimental roles for this bidirectional neuro-immune signaling. This review discusses the different immune cell types that are recognized to engage in neuronal crosstalk during intestinal health and disease. Highlighting the molecular pathways involved in the neuro-immune interactions might inspire novel strategies to target intestinal disease.
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Affiliation(s)
- Lies van Baarle
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium
| | - Michelle Stakenborg
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium
| | - Gianluca Matteoli
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium.
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14
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Mariant CL, Bacola G, Van Landeghem L. Mini-Review: Enteric glia of the tumor microenvironment: An affair of corruption. Neurosci Lett 2023; 814:137416. [PMID: 37572875 PMCID: PMC10967235 DOI: 10.1016/j.neulet.2023.137416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 07/07/2023] [Accepted: 08/02/2023] [Indexed: 08/14/2023]
Abstract
The tumor microenvironment corresponds to a complex mixture of bioactive products released by local and recruited cells whose normal functions have been "corrupted" by cues originating from the tumor, mostly to favor cancer growth, dissemination and resistance to therapies. While the immune and the mesenchymal cellular components of the tumor microenvironment in colon cancer have been under intense scrutiny over the last two decades, the influence of the resident neural cells of the gut on colon carcinogenesis has only very recently begun to draw attention. The vast majority of the resident neural cells of the gastrointestinal tract belong to the enteric nervous system and correspond to enteric neurons and enteric glial cells, both of which have been understudied in the context of colon cancer development and progression. In this review, we especially discuss available evidence on enteric glia impact on colon carcinogenesis. To highlight "corrupted" functioning in enteric glial cells of the tumor microenvironment and its repercussion on tumorigenesis, we first review the main regulatory effects of enteric glial cells on the intestinal epithelium in homeostatic conditions and we next present current knowledge on enteric glia influence on colon tumorigenesis. We particularly examine how enteric glial cell heterogeneity and plasticity require further appreciation to better understand the distinct regulatory interactions enteric glial cell subtypes engage with the various cell types of the tumor, and to identify novel biological targets to block enteric glia pro-carcinogenic signaling.
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Affiliation(s)
- Chloe L Mariant
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.
| | - Gregory Bacola
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.
| | - Laurianne Van Landeghem
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.
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15
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Bubeck M, Becker C, Patankar JV. Guardians of the gut: influence of the enteric nervous system on the intestinal epithelial barrier. Front Med (Lausanne) 2023; 10:1228938. [PMID: 37692784 PMCID: PMC10485265 DOI: 10.3389/fmed.2023.1228938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/24/2023] [Indexed: 09/12/2023] Open
Abstract
The intestinal mucosal surface forms one of the largest areas of the body, which is in direct contact with the environment. Co-ordinated sensory functions of immune, epithelial, and neuronal cells ensure the timely detection of noxious queues and potential pathogens and elicit proportional responses to mitigate the threats and maintain homeostasis. Such tuning and maintenance of the epithelial barrier is constantly ongoing during homeostasis and its derangement can become a gateway for systemic consequences. Although efforts in understanding the gatekeeping functions of immune cells have led the way, increasing number of studies point to a crucial role of the enteric nervous system in fine-tuning and maintaining this delicate homeostasis. The identification of immune regulatory functions of enteric neuropeptides and glial-derived factors is still in its infancy, but has already yielded several intriguing insights into their important contribution to the tight control of the mucosal barrier. In this review, we will first introduce the reader to the current understanding of the architecture of the enteric nervous system and the epithelial barrier. Next, we discuss the key discoveries and cellular pathways and mediators that have emerged as links between the enteric nervous, immune, and epithelial systems and how their coordinated actions defend against intestinal infectious and inflammatory diseases. Through this review, the readers will gain a sound understanding of the current neuro-immune-epithelial mechanisms ensuring intestinal barrier integrity and maintenance of intestinal homeostasis.
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Affiliation(s)
- Marvin Bubeck
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Jay V. Patankar
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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16
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Scantlen MD, Majd H, Fattahi F. Modeling enteric glia development, physiology and disease using human pluripotent stem cells. Neurosci Lett 2023; 811:137334. [PMID: 37315730 DOI: 10.1016/j.neulet.2023.137334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 06/01/2023] [Accepted: 06/07/2023] [Indexed: 06/16/2023]
Abstract
Enteric glia play an integral role in many functions of the gastrointestinal (GI) system, but they have not been characterized comprehensively compared to other cells of the gut. Enteric glia are a specialized type of neuroglia in the enteric nervous system (ENS) that support neurons and interact with other cells of the gut such as immune and epithelial cells. The ENS is diffusely spread throughout the GI tract, making it extremely difficult to access and manipulate. As a result, it has remained extremely understudied. Nevertheless, much more is known about enteric neurons than enteric glia despite the glia being 6 times more abundant in humans [1]. In the past two decades, our understanding of enteric glia has greatly expanded and their many roles in the gut have been described and reviewed elsewhere [2-5]. While the field has made substantial progress, there are still a multitude of open questions about enteric glia biology and their role in disease. Many of these questions have remained intractable due to technical limitations of currently available experimental models of the ENS. In this review, we describe the benefits and limitations of the models commonly used to study enteric glia and discuss the ways in which a human pluripotent stem cell (hPSC) derived enteric glia model could help advance the field.
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Affiliation(s)
- Megan D Scantlen
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA 94110, USA
| | - Homa Majd
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Faranak Fattahi
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA 94110, USA; Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94110, USA.
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17
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Teramoto H, Hirashima N, Tanaka M. Calcineurin B1 Deficiency Reduces Proliferation, Increases Apoptosis, and Alters Secretion in Enteric Glial Cells of Mouse Small Intestine in Culture. Cells 2023; 12:1867. [PMID: 37508531 PMCID: PMC10378349 DOI: 10.3390/cells12141867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 06/30/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023] Open
Abstract
To investigate the roles of calcineurin (CN) in glial cells, we previously generated conditional knockout (CKO) mice lacking CNB1 in glial cells. Because these CKO mice showed dysfunction and inflammation of the small intestine in addition to growth impairment and postweaning death, we have focused on enteric glial cells (EGCs) in the small intestine. In this study, we examined the effects of CNB1 deficiency on the proliferation and survival of EGCs and the expression and secretion of EGC-derived substances in culture to reveal the mechanisms of how CNB1 deficiency leads to dysfunction and inflammation of the small intestine. In primary myenteric cultures of the small intestine, EGCs from the CKO mice showed reduced proliferation and increased apoptosis compared with EGCs from control mice. In purified EGC cultures from the CKO mice, Western blot analysis showed increased expression of S100B, iNOS, GFAP, and GDNF, and increased phosphorylation of NF-κB p65. In the supernatants of purified EGC cultures from the CKO mice, ELISA showed reduced secretion of TGF-β1. In contrast, GDNF secretion was not altered in purified EGC cultures from the CKO mice. Furthermore, treatment with an S100B inhibitor partially rescued the CKO mice from growth impairment and postweaning death in vivo. In conclusion, CNB1 deficiency leads to reduced proliferation and increased apoptosis of EGCs and abnormal expression and secretion of EGC-derived substances, which may contribute to dysfunction and inflammation of the small intestine.
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Affiliation(s)
- Hikaru Teramoto
- Department of Cellular Biophysics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
| | - Naohide Hirashima
- Department of Cellular Biophysics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
| | - Masahiko Tanaka
- Department of Cellular Biophysics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
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18
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Prochera A, Rao M. Mini-Review: Enteric glial regulation of the gastrointestinal epithelium. Neurosci Lett 2023; 805:137215. [PMID: 37001854 PMCID: PMC10125724 DOI: 10.1016/j.neulet.2023.137215] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/11/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
Many enteric glia are located along nerve fibers in the gut mucosa where they form close associations with the epithelium lining the gastrointestinal tract. The gut epithelium is essential for absorbing nutrients, regulating fluid flux, forming a physical barrier to prevent the entry of pathogens and toxins into the host, and participating in immune responses. Disruptions to this epithelium are linked to numerous diseases, highlighting its central importance in maintaining health. Accumulating evidence indicates that glia regulate gut epithelial homeostasis. Observations from glial-epithelial co-cultures in vitro and mouse genetic models in vivo suggest that enteric glia influence several important features of the gut epithelium including barrier integrity, ion transport, and capacity for self-renewal. Here we review the evidence for enteric glial regulation of the intestinal epithelium, with a focus on these three features of its biology.
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Affiliation(s)
- Aleksandra Prochera
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA; Program in Immunology, Harvard Medical School, Boston, MA, USA
| | - Meenakshi Rao
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA.
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19
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Baghdadi MB, Kim TH. The multiple roles of enteric glial cells in intestinal homeostasis and regeneration. Semin Cell Dev Biol 2023:S1084-9521(23)00005-8. [PMID: 36658046 DOI: 10.1016/j.semcdb.2023.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 12/16/2022] [Accepted: 01/06/2023] [Indexed: 01/18/2023]
Abstract
The gastrointestinal tract is innervated by the enteric nervous system (ENS), a complex network of neurons and glial cells, also called the "second brain". Enteric glial cells, one of the major cell types in the ENS, are located throughout the entire gut wall. Accumulating evidence has demonstrated their critical requirement for gut physiology. Notably, recent studies have shown that enteric glial cells control new aspects of gut function such as regulation of intestinal stem cell behavior and immunity. In addition, the emergence of single-cell genomics technologies has revealed enteric glial cell heterogeneity and plasticity. In this review, we discuss established and emerging concepts regarding the roles of mammalian enteric glial cells and their heterogeneity in gut development, homeostasis, and regeneration.
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Affiliation(s)
- Meryem B Baghdadi
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
| | - Tae-Hee Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
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20
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Nerves in gastrointestinal cancer: from mechanism to modulations. Nat Rev Gastroenterol Hepatol 2022; 19:768-784. [PMID: 36056202 DOI: 10.1038/s41575-022-00669-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/20/2022] [Indexed: 12/08/2022]
Abstract
Maintenance of gastrointestinal health is challenging as it requires balancing multifaceted processes within the highly complex and dynamic ecosystem of the gastrointestinal tract. Disturbances within this vibrant environment can have detrimental consequences, including the onset of gastrointestinal cancers. Globally, gastrointestinal cancers account for ~19% of all cancer cases and ~22.5% of all cancer-related deaths. Developing new ways to more readily detect and more efficiently target these malignancies are urgently needed. Whereas members of the tumour microenvironment, such as immune cells and fibroblasts, have already been in the spotlight as key players of cancer initiation and progression, the importance of the nervous system in gastrointestinal cancers has only been highlighted in the past few years. Although extrinsic innervations modulate gastrointestinal cancers, cells and signals from the gut's intrinsic innervation also have the ability to do so. Here, we shed light on this thriving field and discuss neural influences during gastrointestinal carcinogenesis. We focus on the interactions between neurons and components of the gastrointestinal tract and tumour microenvironment, on the neural signalling pathways involved, and how these factors affect the cancer hallmarks, and discuss the neural signatures in gastrointestinal cancers. Finally, we highlight neural-related therapies that have potential for the management of gastrointestinal cancers.
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21
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The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals? MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27196773. [PMID: 36235308 PMCID: PMC9570628 DOI: 10.3390/molecules27196773] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/21/2022] [Accepted: 09/26/2022] [Indexed: 11/29/2022]
Abstract
The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.
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22
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Bonaz B. Anti-inflammatory effects of vagal nerve stimulation with a special attention to intestinal barrier dysfunction. Neurogastroenterol Motil 2022; 34:e14456. [PMID: 36097404 PMCID: PMC9787579 DOI: 10.1111/nmo.14456] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 12/30/2022]
Abstract
The vagus nerve (VN), the longest nerve of the organism innervating the gastrointestinal tract, is a mixed nerve with anti-inflammatory properties through its afferents, activating the hypothalamic-pituitary adrenal axis, and its efferents through the cholinergic anti-inflammatory pathway inhibiting the release of pro-inflammatory cytokines (e.g., TNFα) by splenic and gut macrophages. In addition, the VN is also able to modulate the permeability of the intestinal barrier although the VN does not innervate directly the intestinal epithelium. Targeting the VN through VN stimulation (VNS) has been developed in experimental model of intestinal inflammation and in inflammatory bowel disease (IBD) and might be of interest to decrease intestinal permeability in gastrointestinal disorders with intestinal barrier defect such as IBD, irritable bowel syndrome (IBS), and celiac disease. In this issue of neurogastroenterology and motility, Mogilevski et al. report that a brief non-invasive transcutaneous auricular VNS in healthy volunteers consistently reduces the permeability of the small intestine induced by intravenous administration of the stress peptide corticotropin releasing hormone, known to increase intestinal permeability and to inhibit the VN. In this review, we outline the mechanistic underpinning the effect of stress, of the VN and VNS on intestinal permeability. In particular, the VN can act on intestinal permeability through enteric nerves, and/or cells such as enteric glial cells. We also review the existing evidence of the effects VNS on intestinal permeability in models such as burn intestinal injury and traumatic brain injury, which pave the way for future clinical trials in IBD, IBS, and celiac disease.
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Affiliation(s)
- Bruno Bonaz
- Division of Hepato‐GastroenterologyCentre Hospitalier Universitaire Grenoble AlpesGrenobleFrance,Grenoble Institute of Neurosciences, Inserm U1216University Grenoble AlpesGrenobleFrance
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23
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The Brain–Gut Axis in Traumatic Brain Injury: Implications for Nutrition Support. CURRENT SURGERY REPORTS 2022. [DOI: 10.1007/s40137-022-00325-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Abstract
Purpose of Review
Early enteral nutrition improves outcomes following traumatic brain injury (TBI). This can prove difficult due to TBI-induced feeding intolerance secondary to disruption of the brain-gut axis, a network composed of central nervous system (CNS) input, autonomic signaling, and immunologic regulation that controls gut and CNS homeostasis. Here, we discuss the pathophysiology of brain–gut axis dysregulation and outline nutrition strategies in patients with TBI.
Recent Findings
Feeding intolerance following TBI is multifactorial; complex signaling between the CNS, sympathetic nervous system, parasympathetic nervous system, and enteric nervous system that controls gut homeostasis is disrupted within hours post-injury. This has profound effects on the immune system and gut microbiome, further complicating post-TBI recovery. Despite this disruption, calorie and protein requirements increase considerably following TBI, and early nutritional supplementation improves survival following TBI. Enteral nutrition has proven more efficacious than parenteral nutrition in TBI patients and should be initiated within 48 hours following admission. Immune-fortified nutrition reduces CNS and gut inflammation and may improve outcomes in TBI patients.
Summary
Although autonomic dysregulation of the brain–gut axis results in feeding intolerance following TBI, early enteral nutrition is of paramount importance. Enteral nutrition reduces post-TBI inflammation and enhances immunologic and gut function. When feasible, enteral nutrition should be initiated within 48 hours following injury.
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24
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Progatzky F, Pachnis V. The role of enteric glia in intestinal immunity. Curr Opin Immunol 2022; 77:102183. [DOI: 10.1016/j.coi.2022.102183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/31/2022] [Accepted: 04/05/2022] [Indexed: 11/17/2022]
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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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Drumm BT, Cobine CA, Baker SA. Insights on gastrointestinal motility through the use of optogenetic sensors and actuators. J Physiol 2022; 600:3031-3052. [PMID: 35596741 DOI: 10.1113/jp281930] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 05/13/2022] [Indexed: 11/08/2022] Open
Abstract
The muscularis of the gastrointestinal (GI) tract consists of smooth muscle cells (SMCs) and various populations of interstitial cells of Cajal (ICC), platelet-derived growth factor receptor α+ (PDGFRα+ ) cells, as well as excitatory and inhibitory enteric motor nerves. SMCs, ICC and PDGFRα+ cells form an electrically coupled syncytium, which together with inputs from the enteric nervous system (ENS) regulate GI motility. Early studies evaluating Ca2+ signalling behaviours in the GI tract relied upon indiscriminate loading of tissues with Ca2+ dyes. These methods lacked the means to study activity in specific cells of interest without encountering contamination from other cells within the preparation. Development of mice expressing optogenetic sensors (GCaMP, RCaMP) has allowed visualization of Ca2+ signalling behaviours in a cell specific manner. Additionally, availability of mice expressing optogenetic modulators (channelrhodopsins or halorhodospins) has allowed manipulation of specific signalling pathways using light. GCaMP expressing animals have been used to characterize Ca2+ signalling behaviours of distinct classes of ICC and SMCs throughout the GI musculature. These findings illustrate how Ca2+ signalling in ICC is fundamental in GI muscles, contributing to tone in sphincters, pacemaker activity in rhythmic muscles and relaying enteric signals to SMCs. Animals that express channelrhodopsin in specific neuronal populations have been used to map neural circuitry and to examine post junctional neural effects on GI motility. Thus, optogenetic approaches provide a novel means to examine the contribution of specific cell types to the regulation of motility patterns within complex multi-cellular systems. Abstract Figure Legends Optogenetic activators and sensors can be used to investigate the complex multi-cellular nature of the gastrointestinal (GI tract). Optogenetic activators that are activated by light such as channelrhodopsins (ChR2), OptoXR and halorhodopsinss (HR) proteins can be genetically encoded into specific cell types. This can be used to directly activate or silence specific GI cells such as various classes of enteric neurons, smooth muscle cells (SMC) or interstitial cells, such as interstitial cells of Cajal (ICC). Optogenetic sensors that are activated by different wavelengths of light such as green calmodulin fusion protein (GCaMP) and red CaMP (RCaMP) make high resolution of sub-cellular Ca2+ signalling possible within intact tissues of specific cell types. These tools can provide unparalleled insight into mechanisms underlying GI motility and innervation. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Bernard T Drumm
- Smooth Muscle Research Centre, Department of Life & Health Science, Dundalk Institute of Technology, Dundalk, Co. Louth, Ireland.,Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, USA
| | - Caroline A Cobine
- Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, USA
| | - Salah A Baker
- Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, USA
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Almeida PP, Valdetaro L, Thomasi BBDM, Stockler-Pinto MB, Tavares-Gomes AL. High-fat diets on the enteric nervous system: Possible interactions and mechanisms underlying dysmotility. Obes Rev 2022; 23:e13404. [PMID: 34873814 DOI: 10.1111/obr.13404] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/25/2021] [Accepted: 11/15/2021] [Indexed: 01/09/2023]
Abstract
Obesity is a chronic disease that affects various physiological systems. Among them, the gastrointestinal tract appears to be a main target of this disease. High-fat diet (HFD) animal models can help recapitulate the classic signs of obesity and present a series of gastrointestinal alterations, mainly dysmotility. Because intestinal motility is governed by the enteric nervous system (ENS), enteric neurons, and glial cells have been studied in HFD models. Given the importance of the ENS in general gut physiology, this review aims to discuss the relationship between HFD-induced neuroplasticity and gut dysmotility observed in experimental models. Furthermore, we highlight components of the gut environment that might influence enteric neuroplasticity, including gut microbiota, enteric glio-epithelial unit, serotonin release, immune cells, and disturbances such as inflammation and oxidative stress.
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Affiliation(s)
| | - Luisa Valdetaro
- Postgraduate Program in Neurosciences, Fluminense Federal University, Niterói, Brazil
| | | | - Milena Barcza Stockler-Pinto
- Postgraduate Program in Cardiovascular Sciences, Fluminense Federal University, Niterói, Brazil.,Postgraduate Program in Nutrition Sciences, Fluminense Federal University, Niterói, Brazil
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28
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Teramoto H, Hirashima N, Tanaka M. A Simple Method for Purified Primary Culture of Enteric Glial Cells from Mouse Small Intestine. Biol Pharm Bull 2022; 45:547-551. [DOI: 10.1248/bpb.b22-00038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Hikaru Teramoto
- Department of Cellular Biophysics, Graduate School of Pharmaceutical Sciences, Nagoya City University
| | - Naohide Hirashima
- Department of Cellular Biophysics, Graduate School of Pharmaceutical Sciences, Nagoya City University
| | - Masahiko Tanaka
- Department of Cellular Biophysics, Graduate School of Pharmaceutical Sciences, Nagoya City University
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Abstract
Chemotherapy-induced gastrointestinal dysfunction is a common occurrence associated with many different classes of chemotherapeutic agents. Gastrointestinal toxicity includes mucositis, diarrhea, and constipation, and can often be a dose-limiting complication, induce cessation of treatment and could be life threatening. The gastrointestinal epithelium is rich in rapidly dividing cells and hence is a prime target for chemotherapeutic drugs. The incidence of gastrointestinal toxicity, including diarrhea and mucositis, is extremely high for a wide array of chemotherapeutic and radiation regimens. In fact, 60%-100% of patients on high-dose chemotherapy suffer from gastrointestinal side effects. Unfortunately, treatment options are limited, and therapy is often restricted to palliative care. Therefore, there is a great unmet therapeutic need for preventing and treating chemotherapy-induced gastrointestinal toxicities in the clinic. In this review, we discuss our current understanding of the mechanisms underlying chemotherapy-induced diarrhea and mucositis, and emerging mechanisms involving the enteric nervous system, smooth muscle cells and enteric immune cells. Recent evidence has also implicated gut dysbiosis in the pathogenesis of not only chemotherapy-induced mucositis and diarrhea, but also chemotherapy-induced peripheral neuropathy. Oxidative stress induced by chemotherapeutic agents results in post-translational modification of ion channels altering neuronal excitability. Thus, investigating how chemotherapy-induced changes in the gut- microbiome axis may lead to gut-related toxicities will be critical in the discovery of new drug targets for mitigating adverse gastrointestinal effects associated with chemotherapy treatment.
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Affiliation(s)
- Hamid I Akbarali
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States.
| | - Karan H Muchhala
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Donald K Jessup
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Stanley Cheatham
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
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30
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Almeida PPD, Thomasi BBDM, Costa NDS, Valdetaro L, Pereira AD, Gomes ALT, Stockler-Pinto MB. Brazil Nut ( Bertholletia excelsa H.B.K) Retards Gastric Emptying and Modulates Enteric Glial Cells in a Dose-Dependent Manner. JOURNAL OF THE AMERICAN NUTRITION ASSOCIATION 2022; 41:157-165. [PMID: 33301378 DOI: 10.1080/07315724.2020.1852981] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/04/2020] [Accepted: 11/15/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND The role of food and nutrients in the regulation of enteric glial cell functions is unclear. Some foods influence enteric neurophysiology and can affect glial cell functions that include regulation of the intestinal barrier, gastric emptying, and colonic transit. Brazil nuts are the most abundant natural source of selenium, unsaturated fatty acids, fibers, and polyphenols. OBJECTIVE The study investigated the effects of a Brazil nut-enriched diet on enteric glial cells and gastrointestinal transit. METHODS Two-month-old male Wistar rats were randomized to a standard diet (control group, CG), standard diet containing 5% (wt/wt) Brazil nut (BN5), and standard diet containing 10% (wt/wt) Brazil nut (BN10) (n = 9 per group). After eight weeks, the animals underwent constipation and gastric emptying tests to assess motility. Evaluations of colonic immunofluorescence staining for glial fibrillary acidic protein (GFAP) and myenteric ganglia area were performed. RESULTS The BN5 group showed increased weight gain while the BN10 group did not (p < 0.0001). The BN10 group showed higher gastric residue amounts compared to the other groups (p = 0.0008). The colon exhibited an increase in GFAP immunoreactivity in the BN5 group compared to that in the other groups (p = 0.0016), and the BN10 group presented minor immunoreactivity compared to the CG (p = 0.04). The BN10 group presented a minor ganglia area compared to the CG (p = 0.0155). CONCLUSION The Brazil nut-enriched diet modified the gastric residual, colonic GFAP immunoreactivity, and myenteric ganglia area after eight weeks in healthy male Wistar rats.
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Affiliation(s)
| | | | - Nathalia da Silva Costa
- Postgraduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil
| | - Luisa Valdetaro
- Postgraduate Program in Neurosciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil
| | - Aline D'Avila Pereira
- Postgraduate Program in Medical Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil
| | - Ana Lúcia Tavares Gomes
- Postgraduate Program in Neurosciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil
| | - Milena Barcza Stockler-Pinto
- Postgraduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil
- Postgraduate Program in Nutrition Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil
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31
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Reale O, Bodi D, Huguet A, Fessard V. Role of enteric glial cells in the toxicity of phycotoxins: Investigation with a tri-culture intestinal cell model. Toxicol Lett 2021; 351:89-98. [PMID: 34461197 DOI: 10.1016/j.toxlet.2021.08.013] [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] [Received: 04/27/2021] [Revised: 08/21/2021] [Accepted: 08/25/2021] [Indexed: 02/07/2023]
Abstract
Lipophilic phycotoxins are secondary metabolites produced by phytoplankton. They can accumulate in edible filtering-shellfish and cause human intoxications, particularly gastrointestinal symptoms. Up to now, the in vitro intestinal effects of these toxins have been mainly investigated on simple monolayers of intestinal cells such as the enterocyte-like Caco-2 cell line. Recently, the combination of Caco-2 cells with mucus secreting HT29-MTX cell line has been also used to mimic the complexity of the human intestinal epithelium. Besides, enteric glial cells (EGC) from the enteric nervous system identified in the gut mucosa have been largely shown to be involved in gut functions. Therefore, using a novel model integrating Caco-2 and HT29-MTX cells co-cultured on inserts with EGC seeded in the basolateral compartment, we examined the toxicological effects of two phycotoxins, pectenotoxin-2 (PTX2) and okadaic acid (OA). Cell viability, morphology, barrier integrity, inflammation, barrier crossing, and the response of some specific glial markers were evaluated using a broad set of methodologies. The toxicity of PTX2 was depicted by a slight decrease of viability and integrity as well as a slight increase of inflammation of the Caco-2/HT29-MTX co-cultures. PTX2 induced some modifications of EGC morphology. OA induced IL-8 release and decreased viability and integrity of Caco-2/HT29-MTX cell monolayers. EGC viability was slightly affected by OA. The presence of EGC reinforced barrier integrity and reduced the inflammatory response of the epithelial barrier following OA exposure. The release of GDNF and BDNF gliomediators by EGC could be implicated in the protection observed.
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Affiliation(s)
- Océane Reale
- Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety (Anses), Fougères Laboratory, 10B Rue Claude Bourgelat, 35306, Fougères Cedex, France
| | - Dorina Bodi
- Unit Contaminants, German Federal Institute for Risk Assessment, Department Safety in the Food Chain, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany
| | - Antoine Huguet
- Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety (Anses), Fougères Laboratory, 10B Rue Claude Bourgelat, 35306, Fougères Cedex, France
| | - Valérie Fessard
- Toxicology of Contaminants Unit, French Agency for Food, Environmental and Occupational Health & Safety (Anses), Fougères Laboratory, 10B Rue Claude Bourgelat, 35306, Fougères Cedex, France.
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32
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Modeling Intestinal Stem Cell Function with Organoids. Int J Mol Sci 2021; 22:ijms222010912. [PMID: 34681571 PMCID: PMC8535974 DOI: 10.3390/ijms222010912] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 12/11/2022] Open
Abstract
Intestinal epithelial cells (IECs) are crucial for the digestive process and nutrient absorption. The intestinal epithelium is composed of the different cell types of the small intestine (mainly, enterocytes, goblet cells, Paneth cells, enteroendocrine cells, and tuft cells). The small intestine is characterized by the presence of crypt-villus units that are in a state of homeostatic cell turnover. Organoid technology enables an efficient expansion of intestinal epithelial tissue in vitro. Thus, organoids hold great promise for use in medical research and in the development of new treatments. At present, the cholinergic system involved in IECs and intestinal stem cells (ISCs) are attracting a great deal of attention. Thus, understanding the biological processes triggered by epithelial cholinergic activation by acetylcholine (ACh), which is produced and released from neuronal and/or non-neuronal tissue, is of key importance. Cholinergic signaling via ACh receptors plays a pivotal role in IEC growth and differentiation. Here, we discuss current views on neuronal innervation and non-neuronal control of the small intestinal crypts and their impact on ISC proliferation, differentiation, and maintenance. Since technology using intestinal organoid culture systems is advancing, we also outline an organoid-based organ replacement approach for intestinal diseases.
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33
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Organ-on-Chip Approaches for Intestinal 3D In Vitro Modeling. Cell Mol Gastroenterol Hepatol 2021; 13:351-367. [PMID: 34454168 PMCID: PMC8688162 DOI: 10.1016/j.jcmgh.2021.08.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022]
Abstract
The intestinal epithelium has one of the highest turnover rates in the human body, which is supported by intestinal stem cells. Culture models of intestinal physiology have been evolving to incorporate different tissue and microenvironmental elements. However, these models also display gaps that limit their similarity with native conditions. Microfluidics technology arose from the application of microfabrication techniques to fluid manipulation. Recently, microfluidic approaches have been coupled with cell culture, creating self-contained and modular in vitro models with easily controllable features named organs-on-chip. Intestine-on-chip models have enabled the recreation of the proliferative and differentiated compartments of the intestinal epithelium, the long-term maintenance of commensals, and the intraluminal perfusion of organoids. In addition, studies based on human primary intestinal cells have shown that these systems have a closer transcriptomic profile and functionality to the intestine in vivo, when compared with other in vitro models. The design flexibility inherent to microfluidic technology allows the simultaneous combination of components such as shear stress, peristalsis-like strain, 3-dimensional structure, oxygen gradient, and co-cultures with other important cell types involved in gut physiology. The versatility and complexity of the intestine-on-chip grants it the potential for applications in disease modeling, host-microbiota studies, stem cell biology, and, ultimately, the translation to the pharmaceutical industry and the clinic as a reliable high-throughput platform for drug testing and personalized medicine, respectively. This review focuses on the physiological importance of several components that have been incorporated into intestine-on-chip models and highlights interesting features developed in other types of in vitro models that might contribute to the refinement of these systems.
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34
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Abstract
Glia, the non-neuronal cells of the nervous system, were long considered secondary cells only necessary for supporting the functions of their more important neuronal neighbors. Work by many groups over the past two decades has completely overturned this notion, revealing the myriad and vital functions of glia in nervous system development, plasticity, and health. The largest population of glia outside the brain is in the enteric nervous system, a division of the autonomic nervous system that constitutes a key node of the gut-brain axis. Here, we review the latest in the understanding of these enteric glia in mammals with a focus on their putative roles in human health and disease.
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Affiliation(s)
- Harry J. Rosenberg
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Meenakshi Rao
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
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35
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Seguella L, Gulbransen BD. Enteric glial biology, intercellular signalling and roles in gastrointestinal disease. Nat Rev Gastroenterol Hepatol 2021; 18:571-587. [PMID: 33731961 PMCID: PMC8324524 DOI: 10.1038/s41575-021-00423-7] [Citation(s) in RCA: 179] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/28/2021] [Indexed: 02/07/2023]
Abstract
One of the most transformative developments in neurogastroenterology is the realization that many functions normally attributed to enteric neurons involve interactions with enteric glial cells: a large population of peripheral neuroglia associated with enteric neurons throughout the gastrointestinal tract. The notion that glial cells function solely as passive support cells has been refuted by compelling evidence that demonstrates that enteric glia are important homeostatic cells of the intestine. Active signalling mechanisms between enteric glia and neurons modulate gastrointestinal reflexes and, in certain circumstances, function to drive neuroinflammatory processes that lead to long-term dysfunction. Bidirectional communication between enteric glia and immune cells contributes to gastrointestinal immune homeostasis, and crosstalk between enteric glia and cancer stem cells regulates tumorigenesis. These neuromodulatory and immunomodulatory roles place enteric glia in a unique position to regulate diverse gastrointestinal disease processes. In this Review, we discuss current concepts regarding enteric glial development, heterogeneity and functional roles in gastrointestinal pathophysiology and pathophysiology, with a focus on interactions with neurons and immune cells. We also present a working model to differentiate glial states based on normal function and disease-induced dysfunctions.
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Affiliation(s)
- Luisa Seguella
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy
- Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, MI, USA
| | - Brian D Gulbransen
- Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, MI, USA.
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Hanscom M, Loane DJ, Shea-Donohue T. Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury. J Clin Invest 2021; 131:143777. [PMID: 34128471 PMCID: PMC8203445 DOI: 10.1172/jci143777] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Traumatic brain injury (TBI) is a chronic and progressive disease, and management requires an understanding of both the primary neurological injury and the secondary sequelae that affect peripheral organs, including the gastrointestinal (GI) tract. The brain-gut axis is composed of bidirectional pathways through which TBI-induced neuroinflammation and neurodegeneration impact gut function. The resulting TBI-induced dysautonomia and systemic inflammation contribute to the secondary GI events, including dysmotility and increased mucosal permeability. These effects shape, and are shaped by, changes in microbiota composition and activation of resident and recruited immune cells. Microbial products and immune cell mediators in turn modulate brain-gut activity. Importantly, secondary enteric inflammatory challenges prolong systemic inflammation and worsen TBI-induced neuropathology and neurobehavioral deficits. The importance of brain-gut communication in maintaining GI homeostasis highlights it as a viable therapeutic target for TBI. Currently, treatments directed toward dysautonomia, dysbiosis, and/or systemic inflammation offer the most promise.
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Affiliation(s)
- Marie Hanscom
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - David J. Loane
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Terez Shea-Donohue
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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37
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Feng XY, Xue H, Guo ZH, Yan JT, Liu S, Zhu JX. Dopamine and Gastrointestinal Mucosa Function. DOPAMINE IN THE GUT 2021:87-131. [DOI: 10.1007/978-981-33-6586-5_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Enteric Glia at the Crossroads between Intestinal Immune System and Epithelial Barrier: Implications for Parkinson Disease. Int J Mol Sci 2020; 21:ijms21239199. [PMID: 33276665 PMCID: PMC7730281 DOI: 10.3390/ijms21239199] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 11/30/2020] [Accepted: 11/30/2020] [Indexed: 12/15/2022] Open
Abstract
Over recent years, several investigations have suggested that Parkinson’s disease (PD) can be regarded as the consequence of a bowel disorder. Indeed, gastrointestinal symptoms can occur at all stages of this neurodegenerative disease and in up to a third of cases, their onset can precede the involvement of the central nervous system. Recent data suggest that enteric glial cells (EGCs) may play a major role in PD-related gastrointestinal disturbances, as well as in the development and progression of the central disease. In addition to their trophic and structural functions, EGCs are crucial for the homeostatic control of a wide range of gastrointestinal activities. The main purpose of this review was to provide a detailed overview of the role of EGCs in intestinal PD-associated alterations, with particular regard for their participation in digestive and central inflammation as well as the dynamic interactions between glial cells and intestinal epithelial barrier. Accumulating evidence suggests that several pathological intestinal conditions, associated with an impairment of barrier permeability, may trigger dysfunctions of EGCs and their shift towards a proinflammatory phenotype. The reactive gliosis is likely responsible for PD-related neuroinflammation and the associated pathological changes in the ENS. Thus, ameliorating the efficiency of mucosal barrier, as well as avoiding IEB disruption and the related reactive gliosis, might theoretically prevent the onset of PD or, at least, counteract its progression.
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Yuan R, Bhattacharya N, Kenkel JA, Shen J, DiMaio MA, Bagchi S, Prestwood TR, Habtezion A, Engleman EG. Enteric Glia Play a Critical Role in Promoting the Development of Colorectal Cancer. Front Oncol 2020; 10:595892. [PMID: 33282743 PMCID: PMC7691584 DOI: 10.3389/fonc.2020.595892] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/16/2020] [Indexed: 12/15/2022] Open
Abstract
Enteric glia are a distinct population of peripheral glial cells in the enteric nervous system that regulate intestinal homeostasis, epithelial barrier integrity, and gut defense. Given these unique attributes, we investigated the impact of enteric glia depletion on tumor development in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice, a classical model of colorectal cancer (CRC). Depleting GFAP+ enteric glia resulted in a profoundly reduced tumor burden in AOM/DSS mice and additionally reduced adenomas in the ApcMin /+ mouse model of familial adenomatous polyposis, suggesting a tumor-promoting role for these cells at an early premalignant stage. This was confirmed in further studies of AOM/DSS mice, as enteric glia depletion did not affect the properties of established malignant tumors but did result in a marked reduction in the development of precancerous dysplastic lesions. Surprisingly, the protective effect of enteric glia depletion was not dependent on modulation of anti-tumor immunity or intestinal inflammation. These findings reveal that GFAP+ enteric glia play a critical pro-tumorigenic role during early CRC development and identify these cells as a potential target for CRC prevention.
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Affiliation(s)
- Robert Yuan
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, CA, United States
| | - Nupur Bhattacharya
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, CA, United States
| | - Justin A Kenkel
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, CA, United States
| | - Jeanne Shen
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States
| | - Michael A DiMaio
- Department of Pathology, Marin Medical Laboratories, Novato, CA, United States
| | - Sreya Bagchi
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, CA, United States
| | - Tyler R Prestwood
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, School of Medicine, Stanford University, Stanford, CA, United States
| | - Edgar G Engleman
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, CA, United States
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García-Salvador A, Domínguez-Monedero A, Gómez-Fernández P, García-Bilbao A, Carregal-Romero S, Castilla J, Goñi-de-Cerio F. Evaluation of the Influence of Astrocytes on In Vitro Blood-Brain Barrier Models. Altern Lab Anim 2020; 48:184-200. [PMID: 33136430 DOI: 10.1177/0261192920966954] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In vitro blood-brain barrier (BBB) models are a useful tool to screen the permeability and toxicity of new drugs. Currently, many different in vitro BBB models coexist, but none stands out as being notably better than the rest. Therefore, there is still a need to evaluate the quality of BBB models under various conditions and assess their ability to mimic the in vivo situation. In this study, two brain endothelial cell lines (bEnd.3 and hCMEC/D3) and two epithelial-like cell lines (MDCKII and Caco-2) were selected for BBB modelling purposes. They were grown as monolayers of a single cell type, under the following conditions: in coculture with either primary or immortalised astrocytes; or in the presence of primary or immortalised astrocyte-derived conditioned media. A total of 20 different BBB models were established in this manner, in order to assess the effects of the astroglial components on the BBB phenotype in each case. To this end, six parameters were studied: the expression of selected tight junction proteins; the enzyme activities of alkaline phosphatase and of gamma glutamyl transpeptidase; the transendothelial/transepithelial electrical resistance (TEER); restriction in paracellular transport; and efflux transporter inhibition were each evaluated and correlated. The results showed that coculturing with either primary or immortalised astrocytes led to a general improvement in all parameters studied, evidencing the contribution of this cell type to effective BBB formation. Furthermore, the permeability coefficient (P e) of the tracer molecule, Lucifer Yellow, correlated with three of the six parameters studied. In addition, this study highlights the potential for the use of the Lucifer Yellow P e value as an indicator of barrier integrity in in vitro BBB models, which could be useful for screening the permeability of new drugs.
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Affiliation(s)
- Adrián García-Salvador
- 73049GAIKER Technology Centre, Basque Research and Technology Alliance (BRTA), Zamudio, Bizkaia, Spain
| | - Alazne Domínguez-Monedero
- 73049GAIKER Technology Centre, Basque Research and Technology Alliance (BRTA), Zamudio, Bizkaia, Spain
| | - Paloma Gómez-Fernández
- 73049GAIKER Technology Centre, Basque Research and Technology Alliance (BRTA), Zamudio, Bizkaia, Spain
| | - Amaia García-Bilbao
- 73049GAIKER Technology Centre, Basque Research and Technology Alliance (BRTA), Zamudio, Bizkaia, Spain
| | - Susana Carregal-Romero
- Molecular and Functional Biomarkers Group, 90216CIC biomaGUNE (BRTA), Donostia-San Sebastián, Spain
- CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Joaquín Castilla
- 73038CIC bioGUNE (BRTA), Derio, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Felipe Goñi-de-Cerio
- 73049GAIKER Technology Centre, Basque Research and Technology Alliance (BRTA), Zamudio, Bizkaia, Spain
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Wang YM, Jia YT, Li ZX. Role of enteric glial cells in intestinal function and intestinal diseases. Shijie Huaren Xiaohua Zazhi 2020; 28:979-985. [DOI: 10.11569/wcjd.v28.i19.979] [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
Enteric glial cells, as a key component of the intestinal nervous system, not only have the function of nutrition and supporting intestinal neurons, but also participate in the regulation of various intestinal functions. Abnormal activation of enteric glial cells may also be one of the important pathogenic factors for inflammatory bowel disease, intestinal infection, intestinal obstruction, colon cancer, and other intestinal diseases. At present, the role of enteric glial cells in the occurrence and development of digestive system diseases remains to be elucidated. This paper reviews the research progress in this area.
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Affiliation(s)
- Ya-Mei Wang
- Graduate School of Hebei Medical University, Shijiazhuang 050017, Hebei Province, China,Department of Oncology, Heibei General Hospital, Shijiazhuang 050051, Hebei Province, China
| | - Yi-Tao Jia
- Department of Oncology, Heibei General Hospital, Shijiazhuang 050051, Hebei Province, China
| | - Zhong-Xin Li
- the Second Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
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Morel L, Domingues O, Zimmer J, Michel T. Revisiting the Role of Neurotrophic Factors in Inflammation. Cells 2020; 9:cells9040865. [PMID: 32252363 PMCID: PMC7226825 DOI: 10.3390/cells9040865] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 03/31/2020] [Accepted: 03/31/2020] [Indexed: 12/13/2022] Open
Abstract
The neurotrophic factors are well known for their implication in the growth and the survival of the central, sensory, enteric and parasympathetic nervous systems. Due to these properties, neurturin (NRTN) and Glial cell-derived neurotrophic factor (GDNF), which belong to the GDNF family ligands (GFLs), have been assessed in clinical trials as a treatment for neurodegenerative diseases like Parkinson’s disease. In addition, studies in favor of a functional role for GFLs outside the nervous system are accumulating. Thus, GFLs are present in several peripheral tissues, including digestive, respiratory, hematopoietic and urogenital systems, heart, blood, muscles and skin. More precisely, recent data have highlighted that different types of immune and epithelial cells (macrophages, T cells, such as, for example, mucosal-associated invariant T (MAIT) cells, innate lymphoid cells (ILC) 3, dendritic cells, mast cells, monocytes, bronchial epithelial cells, keratinocytes) have the capacity to release GFLs and express their receptors, leading to the participation in the repair of epithelial barrier damage after inflammation. Some of these mechanisms pass on to ILCs to produce cytokines (such as IL-22) that can impact gut microbiota. In addition, there are indications that NRTN could be used in the treatment of inflammatory airway diseases and it prevents the development of hyperglycemia in the diabetic rat model. On the other hand, it is suspected that the dysregulation of GFLs produces oncogenic effects. This review proposes the discussion of the biological understanding and the potential new opportunities of the GFLs, in the perspective of developing new treatments within a broad range of human diseases.
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Pellegrini C, Ippolito C, Segnani C, Dolfi A, Errede M, Virgintino D, Fornai M, Antonioli L, Garelli F, Nericcio A, Colucci R, Cerri S, Blandini F, Blandizzi C, Bernardini N. Pathological remodelling of colonic wall following dopaminergic nigrostriatal neurodegeneration. Neurobiol Dis 2020; 139:104821. [PMID: 32088380 DOI: 10.1016/j.nbd.2020.104821] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 01/30/2020] [Accepted: 02/19/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND AIM Patients with Parkinson's disease (PD) are often characterized by functional gastrointestinal disorders. Such disturbances can occur at all stages of PD and precede the typical motor symptoms of the disease by many years. However, the morphological alterations associated with intestinal disturbances in PD are undetermined. This study examined the remodelling of colonic wall in 6-hydroxydopamine (6-OHDA)-induced PD rats. METHODS 8 weeks after 6-OHDA injection animals were sacrificed. Inflammatory infiltrates, collagen deposition and remodelling of intestinal epithelial barrier and tunica muscularis in the colonic wall were assessed by histochemistry, immunohistochemistry, immunofluorescence and western blot analysis. RESULTS 6-OHDA rats displayed significant alterations of colonic tissues as compared with controls. Signs of mild inflammation (eosinophil infiltration) and a transmural deposition of collagen fibres were observed. Superficial colonic layers were characterized by severe morphological alterations. In particular, lining epithelial cells displayed a reduced claudin-1 and transmembrane 16A/Anoctamin 1 (TMEM16A/ANO1) expression; goblet cells increased their mucin expression; colonic crypts were characterized by an increase in proliferating epithelial cells; the density of S100-positive glial cells and vimentin-positive fibroblast-like cells was increased as well. Several changes were found in the tunica muscularis: downregulation of α-smooth muscle actin/desmin expression and increased proliferation of smooth muscle cells; increased vimentin expression and proliferative phenotype in myenteric ganglia; reduction of interstitial cells of Cajal (ICCs) density. CONCLUSIONS A pathological remodelling occurs in the colon of 6-OHDA rats. The main changes include: enhanced fibrotic deposition; alterations of the epithelial barrier; activation of mucosal defense; reduction of ICCs. These results indicate that central nigrostriatal denervation is associated with histological changes in the large bowel at mucosal, submucosal and muscular level. These alterations might represent morphological correlates of digestive symptoms in PD.
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Affiliation(s)
| | - Chiara Ippolito
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Cristina Segnani
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Amelio Dolfi
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Mariella Errede
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, School of Medicine, University of Bari, Bari, Italy
| | - Daniela Virgintino
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, School of Medicine, University of Bari, Bari, Italy
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesca Garelli
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Anna Nericcio
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Silvia Cerri
- Laboratory of Functional Neurochemistry, Centre for Research in Neurodegenerative Diseases, "C. Mondino" National Neurological Institute, University of Pavia, Pavia, Italy
| | - Fabio Blandini
- Laboratory of Functional Neurochemistry, Centre for Research in Neurodegenerative Diseases, "C. Mondino" National Neurological Institute, University of Pavia, Pavia, Italy
| | - Corrado Blandizzi
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Nunzia Bernardini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Interdepartmental Research Centre "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy.
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Snyder J, Wang CM, Zhang AQ, Li Y, Luchan J, Hosic S, Koppes R, Carrier RL, Koppes A. Materials and Microenvironments for Engineering the Intestinal Epithelium. Ann Biomed Eng 2020; 48:1916-1940. [DOI: 10.1007/s10439-020-02470-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 01/27/2020] [Indexed: 12/12/2022]
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Valès S, Bacola G, Biraud M, Touvron M, Bessard A, Geraldo F, Dougherty KA, Lashani S, Bossard C, Flamant M, Duchalais E, Marionneau-Lambot S, Oullier T, Oliver L, Neunlist M, Vallette FM, Van Landeghem L. Tumor cells hijack enteric glia to activate colon cancer stem cells and stimulate tumorigenesis. EBioMedicine 2019; 49:172-188. [PMID: 31662289 PMCID: PMC6945247 DOI: 10.1016/j.ebiom.2019.09.045] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 09/25/2019] [Accepted: 09/25/2019] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Colon cancer stem cells (CSCs), considered responsible for tumor initiation and cancer relapse, are constantly exposed to regulatory cues emanating from neighboring cells present in the tumor microenvironment. Among these cells are enteric glial cells (EGCs) that are potent regulators of the epithelium functions in a healthy intestine. However, whether EGCs impact CSC-driven tumorigenesis remains unknown. METHODS Impact of human EGC primary cultures or a non-transformed EGC line on CSCs isolated from human primary colon adenocarcinomas or colon cancer cell lines with different p53, MMR system and stemness status was determined using murine xenograft models and 3D co-culture systems. Supernatants of patient-matched human primary colon adenocarcinomas and non-adjacent healthy mucosa were used to mimic tumor versus healthy mucosa secretomes and compare their effects on EGCs. FINDINGS Our data show that EGCs stimulate CSC expansion and ability to give rise to tumors via paracrine signaling. Importantly, only EGCs that were pre-activated by tumor epithelial cell-derived soluble factors increased CSC tumorigenicity. Pharmacological inhibition of PGE2 biosynthesis in EGCs or IL-1 knockdown in tumor epithelial cells prevented EGC acquisition of a pro-tumorigenic phenotype. Inhibition of PGE2 receptor EP4 and EGFR in CSCs inhibited the effects of tumor-activated EGCs. INTERPRETATION Altogether, our results show that EGCs, once activated by the tumor, acquire a pro-tumorigenic phenotype and stimulate CSC-driven tumorigenesis via a PGE2/EP4/EGFR-dependent pathway. FUNDING This work was supported by grants from the French National Cancer Institute, La Ligue contre le Cancer, the 'Région des Pays de la Loire' and the UNC Lineberger Comprehensive Cancer Center.
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Affiliation(s)
- Simon Valès
- Bretagne Loire University, Nantes University, INSERM 1235, IMAD, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France
| | - Gregory Bacola
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
| | - Mandy Biraud
- Bretagne Loire University, Nantes University, INSERM 1235, IMAD, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France
| | - Mélissa Touvron
- Bretagne Loire University, Nantes University, INSERM 1235, IMAD, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France,Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
| | - Anne Bessard
- Bretagne Loire University, Nantes University, INSERM 1235, IMAD, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France
| | - Fanny Geraldo
- Nantes University, INSERM 1232, CRCINA, Nantes, France
| | - Kelsie A. Dougherty
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
| | - Shaian Lashani
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
| | | | - Mathurin Flamant
- Nantes University Hospital, Nantes, France,Jules Verne Clinic, Nantes, France
| | - Emilie Duchalais
- Bretagne Loire University, Nantes University, INSERM 1235, IMAD, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France,Nantes University Hospital, Nantes, France
| | | | | | - Lisa Oliver
- Nantes University, INSERM 1232, CRCINA, Nantes, France,Nantes University Hospital, Nantes, France
| | - Michel Neunlist
- Bretagne Loire University, Nantes University, INSERM 1235, IMAD, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France,Nantes University Hospital, Nantes, France
| | | | - Laurianne Van Landeghem
- Bretagne Loire University, Nantes University, INSERM 1235, IMAD, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France,Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA,Corresponding author at: North Carolina State University, College of Veterinary Medicine, 1060 William Moore Drive, CB# 8401, Raleigh, NC 27607, USA.
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Veríssimo CP, Carvalho JDS, da Silva FJM, Campanati L, Moura-Neto V, Coelho-Aguiar JDM. Laminin and Environmental Cues Act in the Inhibition of the Neuronal Differentiation of Enteric Glia in vitro. Front Neurosci 2019; 13:914. [PMID: 31551680 PMCID: PMC6733987 DOI: 10.3389/fnins.2019.00914] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 08/16/2019] [Indexed: 12/31/2022] Open
Abstract
The enteric glia, a neural crest-derived cell type that composes the Enteric Nervous System, is involved in controlling gut functions, including motility, gut permeability, and neuronal communication. Moreover this glial cell could to give rise to new neurons. It is believed that enteric neurons are generated up to 21 days postnatally; however, adult gut cells with glial characteristics can give rise to new enteric neurons under certain conditions. The factors that activate this capability of enteric glia to differentiate into neurons remain unknown. Here, we followed the progress of this neuronal differentiation and investigated this ability by challenging enteric glial cells with different culture conditions. We found that, in vitro, enteric glial cells from the gut of adult and neonate mice have a high capability to acquire neuronal markers and undergoing morphological changes. In a co-culture system with 3T3 fibroblasts, the number of glial cells expressing βIIItubulin decreased after 7 days. The effect of 3T3-conditioned medium on adult cells was not significant, and fewer enteric glial cells from neonate mice began the neurogenic process in this medium. Laminin, an extracellular matrix protein that is highly expressed by the niche of the enteric ganglia, seemed to have a large role in inhibiting the differentiation of enteric glia, at least in cells from the adult gut. Our results suggest that, in an in vitro approach that provides conditions more similar to those of enteric glial cells in vivo, these cells could, to some extent, retain their morphology and marker expression, with their neurogenic potential inhibited. Importantly, laminin seemed to inhibit differentiation of adult enteric glial cells. It is possible that the differentiation of enteric glia into neurons is related to severe changes in the microenvironment, leading to disruption of the basement membrane. In summary, our data indicated that the interaction between the enteric glial cells and their microenvironment molecules significantly affects the control of their behavior and functions.
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Affiliation(s)
- Carla Pires Veríssimo
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde do Rio de Janeiro, Rio de Janeiro, Brazil.,Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Pós-graduação em Anatomia Patológica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Juliana da Silva Carvalho
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Loraine Campanati
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vivaldo Moura-Neto
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde do Rio de Janeiro, Rio de Janeiro, Brazil.,Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Juliana de Mattos Coelho-Aguiar
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde do Rio de Janeiro, Rio de Janeiro, Brazil.,Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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47
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Di ZS, Yang ZJ, Zhu MJ, Wang FF, Li LS, Xu JD. Regulation of intestinal epithelial barrier by and dysfunction of intestinal glial cells. Shijie Huaren Xiaohua Zazhi 2019; 27:1013-1021. [DOI: 10.11569/wcjd.v27.i16.1013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The enteric glia is an important component of the enteric nervous system and forms a broad network in the mucosa of the gastrointestinal tract. Enteric glial cells (EGC) are located in all layers of the intestinal wall and respond to neurotransmitters and neuromodulators through signal transduction pathways. The enteric nervous system interacts with resident glial cells in the gut, and there is increasing evidence that EGC are involved in the regulation of epithelial function. Epithelial cells have important absorption and secretion functions and are also involved in the formation of intestinal epithelial barrier. Studies have found that the enteric glia is not only involved in the regulation of gastrointestinal motility and epithelial barrier function, but also in the formation of cellular molecular bridges between intestinal neurons, enteroendocrine cells, immune cells, and epithelial cells. This article reviews the recent progress in the understanding of the role of EGC in the intestinal barrier and defense functions.
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Affiliation(s)
- Zhi-Shan Di
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Ze-Jun Yang
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Min-Jia Zhu
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Fei-Fei Wang
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Li-Sheng Li
- School of Basic Medicine, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
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Ganz J, Melancon E, Wilson C, Amores A, Batzel P, Strader M, Braasch I, Diba P, Kuhlman JA, Postlethwait JH, Eisen JS. Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development. Dev Biol 2019; 455:473-484. [PMID: 31394080 DOI: 10.1016/j.ydbio.2019.08.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 07/05/2019] [Accepted: 08/01/2019] [Indexed: 12/15/2022]
Abstract
Intestinal tract development is a coordinated process involving signaling among the progenitors and developing cells from all three germ layers. Development of endoderm-derived intestinal epithelium has been shown to depend on epigenetic modifications, but whether that is also the case for intestinal tract cell types from other germ layers remains unclear. We found that functional loss of a DNA methylation machinery component, ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1), leads to reduced numbers of ectoderm-derived enteric neurons and severe disruption of mesoderm-derived intestinal smooth muscle. Genetic chimeras revealed that Uhrf1 functions both cell-autonomously in enteric neuron precursors and cell-non-autonomously in surrounding intestinal cells, consistent with what is known about signaling interactions between these cell types that promote one another's development. Uhrf1 recruits the DNA methyltransferase Dnmt1 to unmethylated DNA during replication. Dnmt1 is also expressed in enteric neurons and smooth muscle progenitors. dnmt1 mutants have fewer enteric neurons and disrupted intestinal smooth muscle compared to wildtypes. Because dnmt1;uhrf1 double mutants have a similar phenotype to dnmt1 and uhrf1 single mutants, Dnmt1 and Uhrf1 must function together during enteric neuron and intestinal muscle development. This work shows that genes controlling epigenetic modifications are important to coordinate intestinal tract development, provides the first demonstration that these genes influence development of the ENS, and advances uhrf1 and dnmt1 as potential new Hirschsprung disease candidates.
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Affiliation(s)
- Julia Ganz
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, 97403, USA
| | - Ellie Melancon
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, 97403, USA
| | - Catherine Wilson
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, 97403, USA
| | - Angel Amores
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, 97403, USA
| | - Peter Batzel
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, 97403, USA
| | - Marie Strader
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, 97403, USA
| | - Ingo Braasch
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, 97403, USA
| | - Parham Diba
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, 97403, USA
| | - Julie A Kuhlman
- Department of Genetics, Development and Cell Biology, Iowa State University, Ames, IA, 50011, USA
| | - John H Postlethwait
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, 97403, USA
| | - Judith S Eisen
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, 97403, USA.
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Novel Insights on the Toxicity of Phycotoxins on the Gut through the Targeting of Enteric Glial Cells. Mar Drugs 2019; 17:md17070429. [PMID: 31340532 PMCID: PMC6669610 DOI: 10.3390/md17070429] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/15/2019] [Accepted: 07/19/2019] [Indexed: 02/08/2023] Open
Abstract
In vitro and in vivo studies have shown that phycotoxins can impact intestinal epithelial cells and can cross the intestinal barrier to some extent. Therefore, phycotoxins can reach cells underlying the epithelium, such as enteric glial cells (EGCs), which are involved in gut homeostasis, motility, and barrier integrity. This study compared the toxicological effects of pectenotoxin-2 (PTX2), yessotoxin (YTX), okadaic acid (OA), azaspiracid-1 (AZA1), 13-desmethyl-spirolide C (SPX), and palytoxin (PlTX) on the rat EGC cell line CRL2690. Cell viability, morphology, oxidative stress, inflammation, cell cycle, and specific glial markers were evaluated using RT-qPCR and high content analysis (HCA) approaches. PTX2, YTX, OA, AZA1, and PlTX induced neurite alterations, oxidative stress, cell cycle disturbance, and increase of specific EGC markers. An inflammatory response for YTX, OA, and AZA1 was suggested by the nuclear translocation of NF-κB. Caspase-3-dependent apoptosis and induction of DNA double strand breaks (γH2AX) were also observed with PTX2, YTX, OA, and AZA1. These findings suggest that PTX2, YTX, OA, AZA1, and PlTX may affect intestinal barrier integrity through alterations of the human enteric glial system. Our results provide novel insight into the toxicological effects of phycotoxins on the gut.
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50
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Brinkman DJ, Ten Hove AS, Vervoordeldonk MJ, Luyer MD, de Jonge WJ. Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity. Cells 2019; 8:670. [PMID: 31269754 PMCID: PMC6679154 DOI: 10.3390/cells8070670] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 06/24/2019] [Accepted: 06/28/2019] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) have a complex, multifactorial pathophysiology with an unmet need for effective treatment. This calls for novel strategies to improve disease outcome and quality of life for patients. Increasing evidence suggests that autonomic nerves and neurotransmitters, as well as neuropeptides, modulate the intestinal immune system, and thereby regulate the intestinal inflammatory processes. Although the autonomic nervous system is classically divided in a sympathetic and parasympathetic branch, both play a pivotal role in the crosstalk with the immune system, with the enteric nervous system acting as a potential interface. Pilot clinical trials that employ vagus nerve stimulation to reduce inflammation are met with promising results. In this paper, we review current knowledge on the innervation of the gut, the potential of cholinergic and adrenergic systems to modulate intestinal immunity, and comment on ongoing developments in clinical trials.
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Affiliation(s)
- David J Brinkman
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
- Department of Surgery, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
| | - Anne S Ten Hove
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
| | - Margriet J Vervoordeldonk
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
- Galvani Bioelectronics, Stevenage SG1 2NY, UK
| | - Misha D Luyer
- Department of Surgery, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
| | - Wouter J de Jonge
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands.
- Department of General, Visceral-, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany.
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