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1
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The Potential Role of Microorganisms on Enteric Nervous System Development and Disease. Biomolecules 2023; 13:biom13030447. [PMID: 36979382 PMCID: PMC10046024 DOI: 10.3390/biom13030447] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/14/2023] [Accepted: 02/25/2023] [Indexed: 03/06/2023] Open
Abstract
The enteric nervous system (ENS), the inherent nervous system of the gastrointestinal (GI) tract is a vast nervous system that controls key GI functions, including motility. It functions at a critical interface between the gut luminal contents, including the diverse population of microorganisms deemed the microbiota, as well as the autonomic and central nervous systems. Critical development of this axis of interaction, a key determinant of human health and disease, appears to occur most significantly during early life and childhood, from the pre-natal through to the post-natal period. These factors that enable the ENS to function as a master regulator also make it vulnerable to damage and, in turn, a number of GI motility disorders. Increasing attention is now being paid to the potential of disruption of the microbiota and pathogenic microorganisms in the potential aetiopathogeneis of GI motility disorders in children. This article explores the evidence regarding the relationship between the development and integrity of the ENS and the potential for such factors, notably dysbiosis and pathogenic bacteria, viruses and parasites, to impact upon them in early life.
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2
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Reed CB, Feltri ML, Wilson ER. Peripheral glia diversity. J Anat 2022; 241:1219-1234. [PMID: 34131911 PMCID: PMC8671569 DOI: 10.1111/joa.13484] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/20/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022] Open
Abstract
Recent years have seen an evolving appreciation for the role of glial cells in the nervous system. As we move away from the typical neurocentric view of neuroscience, the complexity and variability of central nervous system glia is emerging, far beyond the three main subtypes: astrocytes, oligodendrocytes, and microglia. Yet the diversity of the glia found in the peripheral nervous system remains rarely discussed. In this review, we discuss the developmental origin, morphology, and function of the different populations of glia found in the peripheral nervous system, including: myelinating Schwann cells, Remak Schwann cells, repair Schwann cells, satellite glia, boundary cap-derived glia, perineurial glia, terminal Schwann cells, glia found in the skin, olfactory ensheathing cells, and enteric glia. The morphological and functional heterogeneity of glia found in the periphery reflects the diverse roles the nervous system performs throughout the body. Further, it highlights a complexity that should be appreciated and considered when it comes to a complete understanding of the peripheral nervous system in health and disease.
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Affiliation(s)
- Chelsey B. Reed
- Hunter James Kelly Research InstituteJacobs School of Medicine and Biomedical Sciences StateUniversity of New York at BuffaloBuffaloNew YorkUSA
- Department of NeurologyJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
| | - M. Laura Feltri
- Hunter James Kelly Research InstituteJacobs School of Medicine and Biomedical Sciences StateUniversity of New York at BuffaloBuffaloNew YorkUSA
- Department of NeurologyJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
- Department of BiochemistryJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
| | - Emma R. Wilson
- Hunter James Kelly Research InstituteJacobs School of Medicine and Biomedical Sciences StateUniversity of New York at BuffaloBuffaloNew YorkUSA
- Department of BiochemistryJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
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3
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Chandramowlishwaran P, Raja S, Maheshwari A, Srinivasan S. Enteric Nervous System in Neonatal Necrotizing Enterocolitis. Curr Pediatr Rev 2022; 18:9-24. [PMID: 34503418 DOI: 10.2174/1573396317666210908162745] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/26/2021] [Accepted: 06/08/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The pathophysiology of necrotizing enterocolitis (NEC) is not clear, but increasing information suggests that the risk and severity of NEC may be influenced by abnormalities in the enteric nervous system (ENS). OBJECTIVE The purpose of this review was to scope and examine the research related to ENS-associated abnormalities that have either been identified in NEC or have been noted in other inflammatory bowel disorders (IBDs) with histopathological abnormalities similar to NEC. The aim was to summarize the research findings, identify research gaps in existing literature, and disseminate them to key knowledge end-users to collaborate and address the same in future studies. METHODS Articles that met the objectives of the study were identified through an extensive literature search in the databases PubMed, EMBASE, and Scopus. RESULTS The sources identified through the literature search revealed that: (1) ENS may be involved in NEC development and post-NEC complications, (2) NEC development is associated with changes in the ENS, and (3) NEC-associated changes could be modulated by the ENS. CONCLUSION The findings from this review identify the enteric nervous as a target in the development and progression of NEC. Thus, factors that can protect the ENS can potentially prevent and treat NEC and post-NEC complications. This review serves to summarize the existing literature and highlights a need for further research on the involvement of ENS in NEC.
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Affiliation(s)
- Pavithra Chandramowlishwaran
- Department of Medicine, Emory University School of Medicine, Decatur, GA, USA.,Gastroenterology Research, Atlanta VA Medical Center, Decatur, GA, USA
| | - Shreya Raja
- Department of Medicine, Emory University School of Medicine, Decatur, GA, USA.,Gastroenterology Research, Atlanta VA Medical Center, Decatur, GA, USA
| | - Akhil Maheshwari
- Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA
| | - Shanthi Srinivasan
- Department of Medicine, Emory University School of Medicine, Decatur, GA, USA.,Gastroenterology Research, Atlanta VA Medical Center, Decatur, GA, USA
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4
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de Lange IH, van Gorp C, Eeftinck Schattenkerk LD, van Gemert WG, Derikx JPM, Wolfs TGAM. Enteral Feeding Interventions in the Prevention of Necrotizing Enterocolitis: A Systematic Review of Experimental and Clinical Studies. Nutrients 2021; 13:1726. [PMID: 34069699 PMCID: PMC8161173 DOI: 10.3390/nu13051726] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/14/2021] [Accepted: 05/15/2021] [Indexed: 12/11/2022] Open
Abstract
Necrotizing enterocolitis (NEC), which is characterized by severe intestinal inflammation and in advanced stages necrosis, is a gastrointestinal emergency in the neonate with high mortality and morbidity. Despite advancing medical care, effective prevention strategies remain sparse. Factors contributing to the complex pathogenesis of NEC include immaturity of the intestinal immune defense, barrier function, motility and local circulatory regulation and abnormal microbial colonization. Interestingly, enteral feeding is regarded as an important modifiable factor influencing NEC pathogenesis. Moreover, breast milk, which forms the currently most effective prevention strategy, contains many bioactive components that are known to support neonatal immune development and promote healthy gut colonization. This systematic review describes the effect of different enteral feeding interventions on the prevention of NEC incidence and severity and the effect on pathophysiological mechanisms of NEC, in both experimental NEC models and clinical NEC. Besides, pathophysiological mechanisms involved in human NEC development are briefly described to give context for the findings of altered pathophysiological mechanisms of NEC by enteral feeding interventions.
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Affiliation(s)
- Ilse H. de Lange
- European Surgical Center Aachen/Maastricht, Department of Pediatric Surgery, School for Nutrition, Toxicology and Metabolism (NUTRIM), 6202 AZ Maastricht, The Netherlands; (I.H.d.L.); (W.G.v.G.)
- Department of Surgery, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University, 6202 AZ Maastricht, The Netherlands
- Department of Pediatrics, School of Oncology and Developmental Biology (GROW), Maastricht University, 6202 AZ Maastricht, The Netherlands;
| | - Charlotte van Gorp
- Department of Pediatrics, School of Oncology and Developmental Biology (GROW), Maastricht University, 6202 AZ Maastricht, The Netherlands;
| | - Laurens D. Eeftinck Schattenkerk
- Department of Pediatric Surgery, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam and Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands; (L.D.E.S.); (J.P.M.D.)
| | - Wim G. van Gemert
- European Surgical Center Aachen/Maastricht, Department of Pediatric Surgery, School for Nutrition, Toxicology and Metabolism (NUTRIM), 6202 AZ Maastricht, The Netherlands; (I.H.d.L.); (W.G.v.G.)
- Department of Surgery, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University, 6202 AZ Maastricht, The Netherlands
| | - Joep P. M. Derikx
- Department of Pediatric Surgery, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam and Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands; (L.D.E.S.); (J.P.M.D.)
| | - Tim G. A. M. Wolfs
- Department of Pediatrics, School of Oncology and Developmental Biology (GROW), Maastricht University, 6202 AZ Maastricht, The Netherlands;
- Department of Biomedical Engineering (BMT), School for Cardiovascular Diseases (CARIM), Maastricht University, 6202 AZ Maastricht, The Netherlands
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5
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Chen X, Meng X, Zhang H, Feng C, Wang B, Li N, Abdullahi KM, Wu X, Yang J, Li Z, Jiao C, Wei J, Xiong X, Fu K, Yu L, Besner GE, Feng J. Intestinal proinflammatory macrophages induce a phenotypic switch in interstitial cells of Cajal. J Clin Invest 2020; 130:6443-6456. [PMID: 32809970 PMCID: PMC7685750 DOI: 10.1172/jci126584] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 08/13/2020] [Indexed: 01/06/2023] Open
Abstract
Interstitial cells of Cajal (ICCs) are pacemaker cells in the intestine, and their function can be compromised by loss of C-KIT expression. Macrophage activation has been identified in intestine affected by Hirschsprung disease-associated enterocolitis (HAEC). In this study, we examined proinflammatory macrophage activation and explored the mechanisms by which it downregulates C-KIT expression in ICCs in colon affected by HAEC. We found that macrophage activation and TNF-α production were dramatically increased in the proximal dilated colon of HAEC patients and 3-week-old Ednrb-/- mice. Moreover, ICCs lost their C-KIT+ phenotype in the dilated colon, resulting in damaged pacemaker function and intestinal dysmotility. However, macrophage depletion or TNF-α neutralization led to recovery of ICC phenotype and restored their pacemaker function. In isolated ICCs, TNF-α-mediated phosphorylation of p65 induced overexpression of microRNA-221 (miR-221), resulting in suppression of C-KIT expression and pacemaker currents. We also identified a TNF-α/NF-κB/miR-221 pathway that downregulated C-KIT expression in ICCs in the colon affected by HAEC. These findings suggest the important roles of proinflammatory macrophage activation in a phenotypic switch of ICCs, representing a promising therapeutic target for HAEC.
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Affiliation(s)
- Xuyong Chen
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College; and
| | - Xinyao Meng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College; and
| | - Hongyi Zhang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College; and
| | - Chenzhao Feng
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Wang
- Department of Pediatric Surgery, Shenzhen Children’s Hospital, Shenzhen, China
| | - Ning Li
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College; and
| | | | - Xiaojuan Wu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College; and
| | - Jixin Yang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College; and
| | - Zhi Li
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College; and
| | - Chunlei Jiao
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College; and
| | - Jia Wei
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College; and
| | - Xiaofeng Xiong
- Department of Neonatal Surgery, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kang Fu
- Department of Neonatal Surgery, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Yu
- Department of Neonatal Surgery, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gail E. Besner
- Department of Pediatric Surgery, Center for Perinatal Research, Nationwide Children’s Hospital, The Ohio State University, Columbus, Ohio, USA
| | - Jiexiong Feng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College; and
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6
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Heymans C, de Lange IH, Lenaerts K, Kessels LCGA, Hadfoune M, Rademakers G, Melotte V, Boesmans W, Kramer BW, Jobe AH, Saito M, Kemp MW, van Gemert WG, Wolfs TGAM. Chorioamnionitis induces enteric nervous system injury: effects of timing and inflammation in the ovine fetus. Mol Med 2020; 26:82. [PMID: 32883198 PMCID: PMC7469100 DOI: 10.1186/s10020-020-00206-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 07/28/2020] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Chorioamnionitis, inflammation of the chorion and amnion, which often results from intrauterine infection, is associated with premature birth and contributes to significant neonatal morbidity and mortality, including necrotizing enterocolitis (NEC). Recently, we have shown that chronic chorioamnionitis is associated with significant structural enteric nervous system (ENS) abnormalities that may predispose to later NEC development. Understanding time point specific effects of an intra-amniotic (IA) infection on the ENS is important for further understanding the pathophysiological processes and for finding a window for optimal therapeutic strategies for an individual patient. The aim of this study was therefore to gain insight in the longitudinal effects of intrauterine LPS exposure (ranging from 5 h to 15 days before premature delivery) on the intestinal mucosa, submucosa, and ENS in fetal lambs by use of a well-established translational ovine chorioamnionitis model. METHODS We used an ovine chorioamnionitis model to assess outcomes of the fetal ileal mucosa, submucosa and ENS following IA exposure to one dose of 10 mg LPS for 5, 12 or 24 h or 2, 4, 8 or 15 days. RESULTS Four days of IA LPS exposure causes a decreased PGP9.5- and S100β-positive surface area in the myenteric plexus along with submucosal and mucosal intestinal inflammation that coincided with systemic inflammation. These changes were preceded by a glial cell reaction with early systemic and local gut inflammation. ENS changes and inflammation recovered 15 days after the IA LPS exposure. CONCLUSIONS The pattern of mucosal and submucosal inflammation, and ENS alterations in the fetus changed over time following IA LPS exposure. Although ENS damage seemed to recover after prolonged IA LPS exposure, additional postnatal inflammatory exposure, which a premature is likely to encounter, may further harm the ENS and influence functional outcome. In this context, 4 to 8 days of IA LPS exposure may form a period of increased ENS vulnerability and a potential window for optimal therapeutic strategies.
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Affiliation(s)
- C Heymans
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - I H de Lange
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.,Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, P.O. Box 616, Universiteitssingel 50, 6200, MD, Maastricht, The Netherlands
| | - K Lenaerts
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - L C G A Kessels
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, P.O. Box 616, Universiteitssingel 50, 6200, MD, Maastricht, The Netherlands
| | - M Hadfoune
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - G Rademakers
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands
| | - V Melotte
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands
| | - W Boesmans
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, the Netherlands.,Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - B W Kramer
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, P.O. Box 616, Universiteitssingel 50, 6200, MD, Maastricht, The Netherlands.,Neonatology, Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands
| | - A H Jobe
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia.,Division of Neonatology/Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - M Saito
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia.,Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - M W Kemp
- Division of Obstetrics and Gynecology, The University of Western Australia, Crawley, Australia.,School of Veterinary and Life Sciences, Murdoch University, Perth, Western Australia, Australia
| | - W G van Gemert
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.,Pediatric surgery, Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands.,Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - T G A M Wolfs
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, P.O. Box 616, Universiteitssingel 50, 6200, MD, Maastricht, The Netherlands. .,Department of Biomedical Engineering (BMT), Maastricht University, Maastricht, the Netherlands.
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7
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Heymans C, de Lange IH, Hütten MC, Lenaerts K, de Ruijter NJE, Kessels LCGA, Rademakers G, Melotte V, Boesmans W, Saito M, Usuda H, Stock SJ, Spiller OB, Beeton ML, Payne MS, Kramer BW, Newnham JP, Jobe AH, Kemp MW, van Gemert WG, Wolfs TGAM. Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses. Front Immunol 2020; 11:189. [PMID: 32256485 PMCID: PMC7089942 DOI: 10.3389/fimmu.2020.00189] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 01/24/2020] [Indexed: 01/18/2023] Open
Abstract
Background: Chorioamnionitis, inflammation of the fetal membranes during pregnancy, is often caused by intra-amniotic (IA) infection with single or multiple microbes. Chorioamnionitis can be either acute or chronic and is associated with adverse postnatal outcomes of the intestine, including necrotizing enterocolitis (NEC). Neonates with NEC have structural and functional damage to the intestinal mucosa and the enteric nervous system (ENS), with loss of enteric neurons and glial cells. Yet, the impact of acute, chronic, or repetitive antenatal inflammatory stimuli on the development of the intestinal mucosa and ENS has not been studied. The aim of this study was therefore to investigate the effect of acute, chronic, and repetitive microbial exposure on the intestinal mucosa, submucosa and ENS in premature lambs. Materials and Methods: A sheep model of pregnancy was used in which the ileal mucosa, submucosa, and ENS were assessed following IA exposure to lipopolysaccharide (LPS) for 2 or 7 days (acute), Ureaplasma parvum (UP) for 42 days (chronic), or repetitive microbial exposure (42 days UP with 2 or 7 days LPS). Results: IA LPS exposure for 7 days or IA UP exposure for 42 days caused intestinal injury and inflammation in the mucosal and submucosal layers of the gut. Repetitive microbial exposure did not further aggravate injury of the terminal ileum. Chronic IA UP exposure caused significant structural ENS alterations characterized by loss of PGP9.5 and S100β immunoreactivity, whereas these changes were not found after re-exposure of chronic UP-exposed fetuses to LPS for 2 or 7 days. Conclusion: The in utero loss of PGP9.5 and S100β immunoreactivity following chronic UP exposure corresponds with intestinal changes in neonates with NEC and may therefore form a novel mechanistic explanation for the association of chorioamnionitis and NEC.
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Affiliation(s)
- Cathelijne Heymans
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Ilse H de Lange
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands.,Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands
| | - Matthias C Hütten
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands.,Neonatology, Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands.,Neonatology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany.,Neonatology, Department of Pediatrics, University Children's Hospital Würzburg, Würzburg, Germany
| | - Kaatje Lenaerts
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Nadine J E de Ruijter
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands
| | - Lilian C G A Kessels
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands
| | - Glenn Rademakers
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, Netherlands
| | - Veerle Melotte
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, Netherlands
| | - Werend Boesmans
- Department of Pathology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, Netherlands.,Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
| | - Masatoshi Saito
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia.,Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - Haruo Usuda
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia.,Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan
| | - Sarah J Stock
- Usher Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Owen B Spiller
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Michael L. Beeton
- Division of Neonatology/Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, United States
| | - Matthew S Payne
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia
| | - Boris W Kramer
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands.,Neonatology, Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands
| | - John P Newnham
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia
| | - Alan H Jobe
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia.,Division of Neonatology/Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, United States
| | - Matthew W Kemp
- Division of Obstetrics and Gynecology, University of Western Australia, Perth, WA, Australia.,Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Japan.,School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia
| | - Wim G van Gemert
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands.,Pediatric Surgery, Department of Surgery, Maastricht University Medical Center, Maastricht, Netherlands.,Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - Tim G A M Wolfs
- Department of Pediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, Netherlands.,Department of Biomedical Engineering (BMT), School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, Netherlands
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8
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Xiao WD, Peng K, Yang H. Enteric glial cells: An emerging key player in intestinal homeostasis modulation under physiological and pathological conditions. Shijie Huaren Xiaohua Zazhi 2016; 24:3657-3665. [DOI: 10.11569/wcjd.v24.i25.3657] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The intestine contains multiple components including epithelial cells, microbiome as well as various neuroendocrine pathways, all of which are essential for maintaining dynamic mucosal homeostasis through complex interactions among different components in the gastrointestinal tract. Beyond the basic neurosupportive and neurotrophic effects, growing evidence reveals the key role of enteric glial cells (EGCs) in the modulation of bowel movement, nutrient absorption and secretion, intestinal immunity as well as barrier function. As well, abnormally activated EGCs are believed to be a vital player in the pathogenesis of a variety of diseases including inflammatory bowel disease, intestinal barrier dysfunction and infections. Here we provide a brief overview of recent research progress about the precise role and the molecule mechanisms of EGCs in modulating intestinal homeostasis, and highlight the critical role of EGC in various intestinal diseases.
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9
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Bernardazzi C, Pêgo B, de Souza HSP. Neuroimmunomodulation in the Gut: Focus on Inflammatory Bowel Disease. Mediators Inflamm 2016; 2016:1363818. [PMID: 27471349 PMCID: PMC4947661 DOI: 10.1155/2016/1363818] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 06/07/2016] [Indexed: 12/17/2022] Open
Abstract
Intestinal immunity is finely regulated by several concomitant and overlapping mechanisms, in order to efficiently sense external stimuli and mount an adequate response of either tolerance or defense. In this context, a complex interplay between immune and nonimmune cells is responsible for the maintenance of normal homeostasis. However, in certain conditions, the disruption of such an intricate network may result in intestinal inflammation, including inflammatory bowel disease (IBD). IBD is believed to result from a combination of genetic and environmental factors acting in concert with an inappropriate immune response, which in turn interacts with nonimmune cells, including nervous system components. Currently, evidence shows that the interaction between the immune and the nervous system is bidirectional and plays a critical role in the regulation of intestinal inflammation. Recently, the maintenance of intestinal homeostasis has been shown to be under the reciprocal control of the microbiota by immune mechanisms, whereas intestinal microorganisms can modulate mucosal immunity. Therefore, in addition to presenting the mechanisms underlying the interaction between immune and nervous systems in the gut, here we discuss the role of the microbiota also in the regulation of neuroimmune crosstalk involved in intestinal homeostasis and inflammation, with potential implications to IBD pathogenesis.
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Affiliation(s)
- Claudio Bernardazzi
- Serviço de Gastroenterologia & Laboratório Multidisciplinar de Pesquisa, Hospital Universitário, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
| | - Beatriz Pêgo
- Serviço de Gastroenterologia & Laboratório Multidisciplinar de Pesquisa, Hospital Universitário, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
| | - Heitor Siffert P. de Souza
- Serviço de Gastroenterologia & Laboratório Multidisciplinar de Pesquisa, Hospital Universitário, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
- D'Or Institute for Research and Education (IDOR), 22281-100 Rio de Janeiro, RJ, Brazil
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Coyle D, Murphy JM, Doyle B, O’Donnell AM, Gillick J, Puri P. Altered tryptophan hydroxylase 2 expression in enteric serotonergic nerves in Hirschsprung’s-associated enterocolitis. World J Gastroenterol 2016; 22:4662-4672. [PMID: 27217698 PMCID: PMC4870073 DOI: 10.3748/wjg.v22.i19.4662] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 01/11/2016] [Accepted: 01/18/2016] [Indexed: 02/07/2023] Open
Abstract
AIM: To determine if expression of colonic tryptophan hydroxylase-2 (TPH2), a surrogate marker of neuronal 5-hydroxytryptamine, is altered in Hirschsprung’s-associated enterocolitis.
METHODS: Entire resected colonic specimens were collected at the time of pull-through operation in children with Hirschsprung’s disease (HSCR, n = 12). Five of these patients had a history of pre-operative Hirschsprung’s-associated enterocolitis (HAEC). Controls were collected at colostomy closure in children with anorectal malformation (n = 10). The distribution of expression of TPH2 was evaluated using immunofluorescence and confocal microscopy. Protein expression of TPH2 was quantified using western blot analysis in the deep smooth muscle layers.
RESULTS: TPH2 was co-expressed in nitrergic and cholinergic ganglia in the myenteric and submucosal plexuses in ganglionic colon in HSCR and healthy controls. Co-expression was also seen in submucosal interstitial cells of Cajal and PDGFRα+ cells. The density of TPH2 immuno-positive fibers decreased incrementally from ganglionic bowel to transition zone bowel to aganglionic bowel in the myenteric plexus. Expression of TPH2 was reduced in ganglionic bowel in those affected by pre-operative HAEC compared to those without HAEC and healthy controls. However, expression of TPH2 was similar or high compared to controls in the colons of children who had undergone diverting colostomy for medically refractory HAEC.
CONCLUSION: Altered TPH2 expression in colonic serotonergic nerves of patients with HSCR complicated by HAEC may contribute to intestinal secretory and motor disturbances, including recurrent HAEC.
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Ochoa-Cortes F, Turco F, Linan-Rico A, Soghomonyan S, Whitaker E, Wehner S, Cuomo R, Christofi FL. Enteric Glial Cells: A New Frontier in Neurogastroenterology and Clinical Target for Inflammatory Bowel Diseases. Inflamm Bowel Dis 2016; 22:433-49. [PMID: 26689598 PMCID: PMC4718179 DOI: 10.1097/mib.0000000000000667] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 08/29/2015] [Indexed: 12/12/2022]
Abstract
The word "glia" is derived from the Greek word "γλoια," glue of the enteric nervous system, and for many years, enteric glial cells (EGCs) were believed to provide mainly structural support. However, EGCs as astrocytes in the central nervous system may serve a much more vital and active role in the enteric nervous system, and in homeostatic regulation of gastrointestinal functions. The emphasis of this review will be on emerging concepts supported by basic, translational, and/or clinical studies, implicating EGCs in neuron-to-glial (neuroglial) communication, motility, interactions with other cells in the gut microenvironment, infection, and inflammatory bowel diseases. The concept of the "reactive glial phenotype" is explored as it relates to inflammatory bowel diseases, bacterial and viral infections, postoperative ileus, functional gastrointestinal disorders, and motility disorders. The main theme of this review is that EGCs are emerging as a new frontier in neurogastroenterology and a potential therapeutic target. New technological innovations in neuroimaging techniques are facilitating progress in the field, and an update is provided on exciting new translational studies. Gaps in our knowledge are discussed for further research. Restoring normal EGC function may prove to be an efficient strategy to dampen inflammation. Probiotics, palmitoylethanolamide (peroxisome proliferator-activated receptor-α), interleukin-1 antagonists (anakinra), and interventions acting on nitric oxide, receptor for advanced glycation end products, S100B, or purinergic signaling pathways are relevant clinical targets on EGCs with therapeutic potential.
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Affiliation(s)
| | - Fabio Turco
- Department of Anesthesiology, The Ohio State University, Columbus, Ohio
- Department of Clinical and Experimental Medicine, Gastroenterological Unit, “Federico II” University of Naples, Naples, Italy; and
| | | | - Suren Soghomonyan
- Department of Anesthesiology, The Ohio State University, Columbus, Ohio
| | - Emmett Whitaker
- Department of Anesthesiology, The Ohio State University, Columbus, Ohio
| | - Sven Wehner
- Department of Surgery, University of Bonn, Bonn, Germany
| | - Rosario Cuomo
- Department of Clinical and Experimental Medicine, Gastroenterological Unit, “Federico II” University of Naples, Naples, Italy; and
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Coelho-Aguiar JDM, Bon-Frauches AC, Gomes ALT, Veríssimo CP, Aguiar DP, Matias D, Thomasi BBDM, Gomes AS, Brito GADC, Moura-Neto V. The enteric glia: identity and functions. Glia 2015; 63:921-35. [PMID: 25703790 DOI: 10.1002/glia.22795] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 01/07/2015] [Indexed: 01/04/2023]
Abstract
Enteric glial cells were first described at the end of the 19th century, but they attracted more interest from researchers only in the last decades of the 20th. Although, they have a different embryological origin, the enteric GLIA share many characteristics with astrocytes, the main glial cell type of the central nervous system (CNS), such as in their expression of the same markers and in their functions. Here we review the construction of the enteric nervous system (ENS), with a focus on enteric glia, and also the main studies that have revealed the action of enteric glia in different aspects of gastrointestinal tract homeostasis, such as in the intestinal barrier, in communications with neurons, and in their action as progenitor cells. We also discuss recent discoveries about the roles of enteric glia in different disorders that affect the ENS, such as degenerative pathologies including Parkinson's and prion diseases, and in cases of intestinal diseases and injury.
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Affiliation(s)
- Juliana de Mattos Coelho-Aguiar
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde do Rio de Janeiro - SES/RJ, Rio de Janeiro, Brazil; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Enteric nervous system abnormalities are present in human necrotizing enterocolitis: potential neurotransplantation therapy. Stem Cell Res Ther 2014; 4:157. [PMID: 24423414 PMCID: PMC4054965 DOI: 10.1186/scrt387] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2013] [Revised: 10/15/2013] [Accepted: 11/11/2013] [Indexed: 02/07/2023] Open
Abstract
Introduction Intestinal dysmotility following human necrotizing enterocolitis suggests that the enteric nervous system is injured during the disease. We examined human intestinal specimens to characterize the enteric nervous system injury that occurs in necrotizing enterocolitis, and then used an animal model of experimental necrotizing enterocolitis to determine whether transplantation of neural stem cells can protect the enteric nervous system from injury. Methods Human intestinal specimens resected from patients with necrotizing enterocolitis (n = 18), from control patients with bowel atresia (n = 8), and from necrotizing enterocolitis and control patients undergoing stoma closure several months later (n = 14 and n = 6 respectively) were subjected to histologic examination, immunohistochemistry, and real-time reverse-transcription polymerase chain reaction to examine the myenteric plexus structure and neurotransmitter expression. In addition, experimental necrotizing enterocolitis was induced in newborn rat pups and neurotransplantation was performed by administration of fluorescently labeled neural stem cells, with subsequent visualization of transplanted cells and determination of intestinal integrity and intestinal motility. Results There was significant enteric nervous system damage with increased enteric nervous system apoptosis, and decreased neuronal nitric oxide synthase expression in myenteric ganglia from human intestine resected for necrotizing enterocolitis compared with control intestine. Structural and functional abnormalities persisted months later at the time of stoma closure. Similar abnormalities were identified in rat pups exposed to experimental necrotizing enterocolitis. Pups receiving neural stem cell transplantation had improved enteric nervous system and intestinal integrity, differentiation of transplanted neural stem cells into functional neurons, significantly improved intestinal transit, and significantly decreased mortality compared with control pups. Conclusions Significant injury to the enteric nervous system occurs in both human and experimental necrotizing enterocolitis. Neural stem cell transplantation may represent a novel future therapy for patients with necrotizing enterocolitis.
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Enteric neural disruption in necrotizing enterocolitis occurs in association with myenteric glial cell CCL20 expression. J Pediatr Gastroenterol Nutr 2013; 57:788-93. [PMID: 24280992 DOI: 10.1097/mpg.0b013e3182a86fd4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVE The aetiology of necrotising enterocolitis (NEC) is unknown, but luminal factors and epithelial leakiness appear critical triggers of an inflammatory cascade. A separate finding has been suggested in mouse models, in which disruption of glial cells in the myenteric plexus induced a severe NEC-like lesion. We have thus looked for evidence of neuroglial abnormality in NEC. METHODS We studied full-thickness resected specimens from 20 preterm infants with acute NEC and from 13 control infants undergoing resection for other indications. Immunohistochemical analysis was performed for immunological (CD3, syndecan-1, human leucocyte antigen-DR), neural (glial fibrillary acidic protein [GFAP], nerve growth factor receptor, neurofilament protein, neuron-specific enolase), and functional markers (Ki67), and for potential inflammatory regulators (interleukin-12, transforming growth factor-β, CCL20, CCR6). RESULTS Expression of the chemokine CCL20 and its receptor CCR6 was significantly upregulated in myenteric plexus in NEC, with CCL20 strongly expressed by glial cells. In 9 of 20 cases with NEC, myenteric plexus architecture and GFAP+ glial cells were normal, with preserved submucosal and mucosal innervation; however, 11 cases showed disrupted myenteric plexus architecture, reduced GFAP expression, and loss of submucosal and mucosal innervation. Persistent abnormalities were identified in the 2 infants who had ongoing inflammation at ileostomy closure. CONCLUSIONS Our findings identified heterogeneity among patients with NEC. Approximately half showed evidence of marked neural abnormality extending from the deeper layers of the intestine, associated with glial activation and myenteric plexus disruption. The factors that may activate enteric glia in this manner, potentially including bacterial products or viruses, remain to be determined.
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Wojtkiewicz J, Równiak M, Crayton R, Barczewska M, Bladowski M, Robak A, Pidsudko Z, Majewski M. Inflammation-induced changes in the chemical coding pattern of colon-projecting neurons in the inferior mesenteric ganglia of the pig. J Mol Neurosci 2011; 46:450-8. [PMID: 21826392 DOI: 10.1007/s12031-011-9613-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Accepted: 07/25/2011] [Indexed: 12/31/2022]
Abstract
The present study examines the chemical coding of the inferior mesenteric ganglia after chemically induced colitis in the pig animal model. In all animals (n = 6), a median laparotomy was performed under anesthesia, and the Fast Blue retrograde tracer was injected into the descending colon wall. In experimental animals (n = 3), the thick descending colon were injected with formalin solution to induce inflammation. The animals were euthanized and the inferior mesenteric ganglion was harvested and processed for double-labeling immunofluorescence for calbindin-D28k (CB) in combination with either tyrosine hydroxylase (TH), neuropeptide Y (NPY), somatostatin (SOM), vasoactive intestinal polypeptide (VIP), nitric oxide synthase (NOS), Leu-enkephalin (LENK), substance P (SP), vesicular acetylcholine transporter (VAChT), or galanin (GAL). Immunohistochemistry revealed significant changes in the chemical coding pattern of inferior mesenteric ganglion neurons. In control animals, Fast Blue-positive neurons were immunoreactive to TH, NPY, SOM, VIP, LENK, CB, and NOS. In the experimental group, TH, NPY, SOM, VIP, and LENK expressing neurons were reduced, whereas the number of neurons immunoreactive to CB, NOS, and GAL were increased. The increase of so-called neuroprotective neuropeptides suggests that the changes in the chemical coding of inferior mesenteric ganglion neurons reflect adaption under pathological conditions to promote their own survival.
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Affiliation(s)
- Joanna Wojtkiewicz
- Department of Neurology and Neurosurgery, Division of Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury, Warszawska 30, 10-082, Olsztyn, Poland.
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Boudry G, Morise A, Seve B, LE Huërou-Luron I. Effect of milk formula protein content on intestinal barrier function in a porcine model of LBW neonates. Pediatr Res 2011; 69:4-9. [PMID: 20856168 DOI: 10.1203/pdr.0b013e3181fc9d13] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Our study aimed at investigating the impact of the level of protein in milk formula on intestinal structure, barrier function, and its nervous regulation in normal and LBW neonates using a porcine model. Normal birth weight (NBW) or LBW piglets were fed from d7 to d28 of age either with a high protein (HP) or with an adequate protein (AP) formula or stayed with their mother [mother fed (MF)]. The proximal jejunum and distal ileum were sampled at d28 for morphometry analysis and ex vivo permeability measurement in Ussing chambers. Formula feeding induced a trophic effect on the jejunum and ileum of both NBW and LBW piglets, which exhibited longer villi than MF animals, irrespective of the type of formula. In NBW piglets, intestinal permeability was not altered by formula feeding. On the contrary, LBW piglets fed with HP formula, but not AP, exhibited a greater ileal permeability than MF piglets. Feeding the HP formula also disturbed jejunal and ileal regulation of permeability by acetylcholine and vasoactive intestinal peptide (VIP) in LBW compared with MF LBW piglets. In conclusion, the level of protein in formulas did not modify intestinal structure and function in NBW individuals but dramatically modified intestinal barrier function physiology in LBW individuals.
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Affiliation(s)
- Gaëlle Boudry
- Unité Mixte de Recherche 1079, Institut National de la Recherche Agronomique, Saint-Gilles F-35590, France.
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Gangliosides protect bowel in an infant model of necrotizing enterocolitis by suppressing proinflammatory signals. J Pediatr Gastroenterol Nutr 2009; 49:382-92. [PMID: 19745762 DOI: 10.1097/mpg.0b013e3181b6456d] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVES Necrotizing enterocolitis (NEC) has high morbidity in premature infants. Hypoxia-ischemia, infection, and enteral feeding are risk factors associated with NEC, whereas feeding human milk is protective. Vasoactive and inflammatory mediators in NEC remain elusive. Gangliosides are found in human milk and enterocyte membranes. An infant bowel model of NEC was developed to test the hypothesis that gangliosides modulate the inflammatory response to infection and hypoxia. PATIENTS AND METHODS Viable, noninflamed bowel was obtained from 9 infants between 26 and 40 weeks' gestational age. Infant bowel was treated in culture with Escherichia coli lipopolysaccharide (LPS) and hypoxia in the presence or absence of preexposure to gangliosides. Bowel necrosis and production of nitric oxide, endothelin-1, serotonin, eicosanoids, hydrogen peroxide, and proinflammatory cytokines were measured. RESULTS Ganglioside preexposure reduced bowel necrosis and endothelin-1 production in response to LPS. Gangliosides suppressed infant bowel production of nitric oxide, leukotriene B4, prostaglandin E2, hydrogen peroxide, interleukin-1beta, interleukin-6, and interleukin-8 in response to LPS exposure and hypoxia. CONCLUSIONS A bowel protective effect of gangliosides is indicated by modulation of vasoactive mediators and proinflammatory signal suppression.
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van Haver ER, de Vooght L, Oste M, Sangild PT, Thymann T, Weyns ALM, van Ginneken CJ. Postnatal and diet-dependent increases in enteric glial cells and VIP-containing neurones in preterm pigs. Neurogastroenterol Motil 2008; 20:1070-9. [PMID: 18643892 DOI: 10.1111/j.1365-2982.2008.01160.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A mature enteric nervous system (ENS) is required to ensure a normal pattern of intestinal motility in order to regulate digestion after birth. We hypothesized that neuronal and glial components of the ENS would mature during the first postnatal days in preterm pigs that are a sensitive animal model of food intolerance and necrotizing enterocolitis (NEC). Stereological volume densities of the general neuronal population [assessed by betaIII-tubulin immunoreactivity (IR)] and subsets of neuronal (VIP-IR and nitrergic IR) and glial cells (GFAP-IR and S100-IR) were determined in the small intestine of newborn preterm piglets (93% gestation), after 3 days of receiving total parenteral nutrition (TPN) and after 3 days of TPN plus 2 days of enteral feeding with sow's colostrum or milk formula. Following TPN, VIP in the myenteric and inner submucous plexus and GFAP in the inner submucous plexus increased, while the relative volume of the total neuronal population remained constant. Introduction of enteral food induced variable degrees of food intolerance and NEC, especially after formula feeding, a diet that gave rise to a higher myenteric VIP and GFAP content in the inner submucous plexus than colostrum feeding. However, the ENS seemed unaffected by the presence of NEC-like intestinal lesions. Nevertheless, this study shows that the ENS is highly plastic during the first days after premature birth and adapts in an age- and diet-dependent manner. The observed postnatal adaptation in enteric VIP and GFAP may help to maintain intestinal homeostasis during suboptimal feeding regimens in preterm neonates.
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Affiliation(s)
- E R van Haver
- Department of Veterinary Medicine, University of Antwerp, Wilrijk, Belgium
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Wedel T, Böttner M, Krammer HJ. [The enteric nervous system and interstitial cells of Cajal. Changes in chronic constipation in adults]. DER PATHOLOGE 2008; 28:143-8. [PMID: 17294155 DOI: 10.1007/s00292-007-0900-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Intestinal innervation disorders are part of the broad etiological spectrum of chronic constipation and need to be specifically addressed in differential diagnosis. The enteric nervous system constitutes the largest peripheral nervous system of its own ("brain in the gut"), and is involved in the mediation of intestinal motility. Morphologically different nerve cell types aggregate into intramural plexus layers and release a multitude of neurotransmitters. Malformations or lesions of the enteric nervous system may lead to a severely prolonged intestinal transit time resulting in chronic constipation resistant to conservative treatment. In contrast to the early manifestation of aganglionosis, non-aganglionic or acquired alterations to the intramural nerve plexus often remain unrecognised up to adulthood. Histopathological diagnosis is carried out by enzyme or immunohistochemical staining, either on sections or whole mount preparations, allowing an optimal visualization of the nerve plexus architecture. To diagnose hypoganglionosis, enteric ganglionitis or alterations in interstitial cells of Cajal, full-thickness biopsies are required. Interstitial cells of Cajal contribute significantly to the mediation of intestinal motility by generating "slow wave" activity. In adult patients with slow-transit constipation and megacolon, the intramuscular networks of the interstitial cells of Cajal show a significantly reduced density.
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Affiliation(s)
- T Wedel
- Anatomisches Institut, Christian-Albrechts-Universität zu Kiel, Otto-Hahn-Platz 8, 24118 Kiel, Germany.
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Nasser Y, Keenan CM, Ma AC, McCafferty DM, Sharkey KA. Expression of a functional metabotropic glutamate receptor 5 on enteric glia is altered in states of inflammation. Glia 2007; 55:859-72. [PMID: 17405149 DOI: 10.1002/glia.20507] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The metabotropic glutamate receptor 5 (mGluR5) is expressed by astrocytes and its expression is modulated by inflammation. Enteric glia have many similarities to astrocytes and are the most numerous cell in the enteric nervous system (ENS). We investigated whether enteric glia express a functional mGluR5 and whether expression of this receptor was altered in colitis. In both enteric plexuses of the ileum and colon of guinea pigs and mice, we observed widespread glial mGluR5 expression. Incubation of isolated segments of the guinea pig ileum with the mGluR5 specific agonist RS-2-chloro-5-hydroxyphenylglycine (CHPG) caused a dose-dependent increase in the glial expression of c-Fos and the phosphorylated form of the extracellular signal-regulated kinase 1/2. Preincubation of tissues with the group I metabotropic glutamate receptor antagonist, S-4-carboxyphenylglycine, abolished the effects of CHPG. We examined mGluR5 expression in the guinea pig trinitrobenzene sulfonic acid and the IL-10 gene-deficient (IL-10(-/-)) mouse models of colitis. In guinea pigs, mGluR5 immunoreactivity became diffusely localized over the colonic myenteric ganglia, suggesting a change in receptor distribution. In contrast, glial mGluR5 expression was significantly reduced in the colonic myenteric plexus of IL-10(-/-) mice, as assessed with both real-time quantitative RT-PCR as well as immunohistochemistry and image analysis. These changes occurred without concomitant changes to enteric ganglia or glial fibrillary acidic protein expression in the IL-10(-/-) mouse. Our data suggest that enteric glia are a functional target of the glutamatergic neurotransmitter system in the ENS and that changes in mGluR5 expression may be of physiological significance during colitis.
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Affiliation(s)
- Yasmin Nasser
- Institute for Infection, Immunity and Inflammation, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
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Oste M, Van Ginneken CJ, Van Haver ER, Bjornvad CR, Thymann T, Sangild PT. The intestinal trophic response to enteral food is reduced in parenterally fed preterm pigs and is associated with more nitrergic neurons. J Nutr 2005; 135:2657-63. [PMID: 16251626 DOI: 10.1093/jn/135.11.2657] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
In term neonates, total parenteral nutrition (TPN) induces mucosal atrophy, whereas the first intake of milk is followed by intestinal growth. This may be explained in part by an NO-mediated increased blood flow. We hypothesized that the immature gut has an altered response to TPN and enteral nutrition. In Expt. 1, preterm caesarean-delivered pigs were administered elemental nutrients for 3 d, infused parenterally (TPN, n = 7) or enterally (TENT, n = 7). In Expt. 2, preterm pigs were fed sow's colostrum, cow's colostrum, or infant formula for 2 d after a 3-d TPN period (TPN-SOW, TPN-COW, TPN-FORM, n = 8-11). Intestinal morphology and the number of enteric neurons containing nitric oxide synthase-1 (NOS-1) were quantified. Both the TPN and TENT groups had increases in intestinal mass, circumference, and mucosal mass, volume, and surface density, relative to values at birth (+30-50%, P < 0.05). In Expt. 2, the magnitudes of the intestinal trophic responses to feeding were similar to those in Expt. 1, but were also associated with an increased number of nitrergic myenteric neurons and some mucosal damage, most frequently observed for the formula group. We conclude that 1) a short period of TPN does not induce mucosal atrophy in preterm pigs, whereas elemental nutrients infused luminally do not mimic the trophic response seen with milk diets, 2) enteral feeding of preterm pigs after a short period of TPN is associated with a modest, diet-dependent trophic response that may be related in part to the actions of an increased population of enteric NOS-1 neurons.
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Affiliation(s)
- M Oste
- Laboratory of Veterinary Anatomy and Embryology, Department of Veterinary Medicine, University of Antwerp, 2610 Wilrijk, Belgium
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Balemba OB, Mortensen K, Semuguruka WD, Hay-Schmidt A, Johansen MV, Dantzer V. Neuronal nitric oxide synthase activity is increased during granulomatous inflammation in the colon and caecum of pigs infected with Schistosoma japonicum. Auton Neurosci 2002; 99:1-12. [PMID: 12171250 DOI: 10.1016/s1566-0702(02)00042-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Neuronal nitric oxide is a non-adrenergic non-cholinergic neurotransmitter in the enteric nervous system and plays a role in a variety of enteropathies including Crohn's and Chagas' diseases, ulcerative colitis, diabetes, atrophy and hypertrophy. The content of neuronal nitric oxide synthase (nNOS) in the colon and the caecum from pigs infected with Schistosoma japonicum was studied using immunohistochemical and histochemical staining for nNOS and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-diaphorase), respectively. In the infected pigs, lightly, moderately and less severely inflamed tissues showed increased nNOS and NADPH-diaphorase activities in nerve cell bodies and nerve fibres in the enteric plexuses compared to control pigs. There was a significant increase in the nerve cell body density of nNOS immunoreactive nerve cell bodies in the inner submucous plexus, outer submucous plexus and in the myenteric plexus. More intensely stained nerve cell bodies and varicosities were observed in tissue from prenatally infected and prenatally infected, postnatally re-infected pigs compared to postnatally infected pigs. However, the latter showed the highest numerical density of nNOS immunoreactive nerve cell bodies. Marked increases were seen in the inner submucous plexus followed by myenteric plexus, inner circular muscle, outer submucous plexus and mucous plexus. However, in very severe inflamed tissues, the number and staining intensity of nerve cell bodies and nerve fibre varicosities were reduced in plexuses located in the lesions with the inner submucous and mucous plexuses being the most affected. There was no staining in the nervous tissue within the eosinophilic cell abscesses and productive granulomas. The apparent alterations in the activities of enzymes responsible for the generation of nitric oxide (NO) show possible alterations in the NO mediated non-adrenergic non-cholinergic reflexes in the enteric nervous tissue. These alterations might contribute to impaired intestinal motility and absorption, and other pathophysiological conditions seen during S. japonicum infections.
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Affiliation(s)
- O B Balemba
- Department of Veterinary Anatomy, Sokoine University of Agriculture, Morogoro, Tanzania
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Cornet A, Savidge TC, Cabarrocas J, Deng WL, Colombel JF, Lassmann H, Desreumaux P, Liblau RS. Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn's disease? Proc Natl Acad Sci U S A 2001; 98:13306-11. [PMID: 11687633 PMCID: PMC60866 DOI: 10.1073/pnas.231474098] [Citation(s) in RCA: 248] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Early pathological manifestations of Crohn's disease (CD) include vascular disruption, T cell infiltration of nerve plexi, neuronal degeneration, and induction of T helper 1 cytokine responses. This study demonstrates that disruption of the enteric glial cell network in CD patients represents another early pathological feature that may be modeled after CD8(+) T cell-mediated autoimmune targeting of enteric glia in double transgenic mice. Mice expressing a viral neoself antigen in astrocytes and enteric glia were crossed with specific T cell receptor transgenic mice, resulting in apoptotic depletion of enteric glia to levels comparable in CD patients. Intestinal and mesenteric T cell infiltration, vasculitis, T helper 1 cytokine production, and fulminant bowel inflammation were characteristic hallmarks of disease progression. Immune-mediated damage to enteric glia therefore may participate in the initiation and/or the progression of human inflammatory bowel disease.
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Affiliation(s)
- A Cornet
- Institut National de la Santé et de la Recherche Médicale U546 and Immunology Laboratory, Pitié-Salpêtrière Hospital, Paris 75013, France
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Balemba OB, Semuguruka WD, Hay-Schmidt A, Johansen MV, Dantzer V. Vasoactive intestinal peptide and substance P-like immunoreactivities in the enteric nervous system of the pig correlate with the severity of pathological changes induced by Schistosoma japonicum. Int J Parasitol 2001; 31:1503-14. [PMID: 11595238 DOI: 10.1016/s0020-7519(01)00273-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Limited studies have shown that in intestinal schistosomosis, the enteric nervous tissue becomes inflamed, disrupted and destroyed by granulomas and peptides, amines and neurofilaments contents are altered. Therefore, immunoreactivities of vasoactive intestinal peptide and substance P were correlated to pathological lesions in the large intestine from pigs infected with Schistosoma japonicum. Ganglia situated within or near granulomas showed ganglionitis, and necrosis of neurons as well as infiltration by eosinophils, mast cells, lymphocytes, plasma cells, neutrophils and macrophages. The inner submucous and mucous plexuses were the most damaged. In all categories of inflamed areas, the vasoactive intestinal peptide-like immunoreactive was reduced in all plexuses whereas, that of substance P was increased both in the enteric nerve plexuses and enterochromaffin cells in lightly, moderately and severely inflamed tissues. However, both peptides were highly diminished or absent in very severe lesions and areas surrounding schistosome eggs and mature worms laying eggs in the submucosal veins. The alterations of the levels of vasoactive intestinal peptide and substance P were correlated with severity of inflammation. Our observations show alterations of vasoactive intestinal peptide and substance P contents in the local microenvironment in the vasoactive intestinal peptide- and substance P-mediated reflex pathways which regulate intestinal motility, epithelial transport and modulate immunity. These changes could cause alterations in bowel motility, electrolyte and fluid secretion, vascular and immune functions during S. japonicum infections in the pig. This may, therefore, partly play a role in the pathobiology of migration and egress of schistosome eggs as well as influence trapping of eggs in granulomas, and account for diarrhoea, loss of body weight and failure to thrive, which are recorded in schistosomosis.
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Affiliation(s)
- O B Balemba
- Department of Veterinary Anatomy, Sokoine University of Agriculture, Morogoro, Tanzania
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Zamora R, Vodovotz Y, Billiar TR. Inducible Nitric Oxide Synthase and Inflammatory Diseases. Mol Med 2000. [DOI: 10.1007/bf03401781] [Citation(s) in RCA: 158] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
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