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Chang H, Zhang H, Jiang S, Hu J, Ma H, Cheng B, Wang Q, Li Y. Targeting enteric glial CRF-R1/Cx43 attenuates stress-induced accelerated colonic motility. J Pharmacol Sci 2025; 157:167-178. [PMID: 39929591 DOI: 10.1016/j.jphs.2025.01.009] [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: 12/04/2024] [Revised: 01/07/2025] [Accepted: 01/22/2025] [Indexed: 03/17/2025] Open
Abstract
Stress triggers disorders in accelerated peristalsis, with corticotropin releasing factor receptor 1 (CRF-R1) playing a pivotal role. Enteric glia cells (EGCs) and glial Cx43 are known to influence gastrointestinal motility, yet their involvement in colonic motor responses to stress remains unclear. Using immunofluorescence and single-cell RNA sequencing data, we identified CRF-R1 expression in EGCs. Male C57BL/6 mice subjected to wrap restraint stress (WRS) revealed stress-induced colonic motility changes. By employing Fluoroacetate, NBI 27914, and Gap26, we elucidated the impact of glial CRF-R1/Cx43 on stress-induced colonic motor responses. Our study demonstrated CRF-R1 expression in EGCs of the small intestine and colon, along with elevated CRF levels and upregulated CRF-R1 in the distal colon under stress. Antagonizing CRF-R1 and disrupting EGC function made mice resistant to colonic stress responses. Mechanistically, increased glial Cx43 expression and activity influenced colonic motor responses in a CRF-R1-dependent manner. Our findings highlight the role of EGC-derived CRF-R1 in stress-induced colonic motor responses via Cx43 activation. Targeting CRF-R1/Cx43 signaling in EGCs may offer a promising approach to mitigate stress-induced colonic transit changes.
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Affiliation(s)
- Haiqing Chang
- Department of Anesthesiology, West China Hospital, Sichuan University, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Haifeng Zhang
- Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710061, Shaanxi, China
| | - Shiqiu Jiang
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Juan Hu
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China; Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Hongli Ma
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Bo Cheng
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Qiang Wang
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
| | - Yansong Li
- Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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Zhang X, Qi F, Yang J, Xu C. Distribution and ultrastructural characteristics of enteric glial cell in the chicken cecum. Poult Sci 2024; 103:104070. [PMID: 39094494 PMCID: PMC11345566 DOI: 10.1016/j.psj.2024.104070] [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: 04/10/2024] [Revised: 06/29/2024] [Accepted: 07/02/2024] [Indexed: 08/04/2024] Open
Abstract
Enteric glial cell (EGC) is involved in neuroimmune regulation within the enteric nervous system (ENS); however, limited information exists on the distribution and ultrastructure of EGC in the poultry gut. We aim to investigate the morphological features and distribution of EGC in the chicken cecum. Here, we investigated the distribution and ultrastructural features of chicken cecum EGC using immunohistochemistry (IHC) and transmission electron microscopy (TEM). IHC showed that EGC was widely distributed throughout the chicken cecum. In the mucosal layer, EGC was morphologically irregular, with occasionally interconnecting protrusions that outlined signal-negative neurons. The morphology of EGC in the submucosal layer was also irregular. In the inner circular muscle layer and between the inner circular and outer longitudinal muscle layers, EGC aligned parallel to the circular muscle cells. A small number of EGC with an irregular morphology were found in the outer longitudinal muscle layer. In addition, in the submucosal and myenteric plexus, EGC were aggregated, and the protrusions of the immunoreactive cells interconnected to outline the bodies of nonreactive neurons. TEM-guided ultrastructural characterization confirmed the IHC findings that EGC were morphologically irregular and revealed they developed either a star, bipolar, or fibrous shape. The nucleus was also irregular, with electron-dense heterochromatin distributed in the center of the nucleus or on the nuclear membrane. The cytoplasm contained many glial filaments and vesicle-containing protrusions from neuronal cells; organelles were rare. EGC was in close contact with other cells in their vicinity. These findings suggest that EGC is well-situated to exert influence on intestinal motility and immune functions through mechanical contraction and chemical secretion.
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Affiliation(s)
- Xiaoting Zhang
- College of Animal Science and Technology, Shihezi University, Shihezi 832003, China
| | - Fenghua Qi
- College of Animal Science and Technology, Shihezi University, Shihezi 832003, China
| | - Jie Yang
- College of Animal Science and Technology, Shihezi University, Shihezi 832003, China
| | - Chunsheng Xu
- College of Animal Science and Technology, Shihezi University, Shihezi 832003, China.
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3
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Bassotti G. Targeting diarrhea-predominant irritable bowel syndrome: hopes or hypes? Expert Opin Investig Drugs 2024:1-4. [PMID: 38653572 DOI: 10.1080/13543784.2024.2347296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 04/22/2024] [Indexed: 04/25/2024]
Affiliation(s)
- Gabrio Bassotti
- Gastroenterology & Hepatology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- Gastroenterology Unit, Perugia General Hospital, Perugia, Italy
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Fettucciari K, Spaterna A, Marconi P, Bassotti G. Pro-Inflammatory Cytokines Enhanced In Vitro Cytotoxic Activity of Clostridioides difficile Toxin B in Enteric Glial Cells: The Achilles Heel of Clostridioides difficile Infection? Int J Mol Sci 2024; 25:958. [PMID: 38256032 PMCID: PMC10815653 DOI: 10.3390/ijms25020958] [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: 11/16/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Bacterial infections are characterized by an inflammatory response, which is essential for infection containment but is also responsible for negative effects on the host. The pathogen itself may have evolved molecular mechanisms to antagonize the antimicrobial effects of an inflammatory response and to enhance its pathogenicity using inflammatory response mediators, such as cytokines. Clostridioides difficile (C. difficile) infection (CDI) causes gastrointestinal diseases with markedly increasing global incidence and mortality rates. The main C. difficile virulence factors, toxin A and B (TcdA/TcdB), cause cytopathic/cytotoxic effects and inflammation. We previously demonstrated that TcdB induces enteric glial cell (EGC) apoptosis, which is enhanced by the pro-inflammatory cytokine tumor necrosis factor alpha plus interferon gamma (CKs). However, it is unknown whether CKs-enhanced TcdB cytotoxicity (apoptosis/necrosis) is affected by the timing of the appearance of the CKs. Thus, we simulated in vitro, in our experimental model with TcdB and EGCs, three main situations of possible interactions between TcdB and the timing of CK stimulation: before TcdB infection, concomitantly with infection, or at different times after infection and persisting over time. In these experimental conditions, which all represent situations of possible interactions between C. difficile and the timing of CK stimulation, we evaluated apoptosis, necrosis, and cell cycle phases. The CKs, in all of these conditions, enhanced TcdB cytotoxicity, which from apoptosis became necrosis when CK stimulation persisted over time, and was most relevant after 48 h of TcdB:EGCs interaction. Particularly, the enhancement of apoptosis by CKs was dependent on the TcdB dose and in a less relevant manner on the CK stimulation time, while the enhancement of necrosis occurred always independently of the TcdB dose and CK stimulation time. However, since in all conditions stimulation with CKs strongly enhanced the TcdB cytotoxicity, it always had a negative impact on C. difficile pathogenicity. This study might have important implications for the treatment of CDI.
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Affiliation(s)
- Katia Fettucciari
- Biosciences & Medical Embryology Section, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy;
| | - Andrea Spaterna
- School of Biosciences and Veterinary Medicine, University of Camerino, 62024 Macerata, Italy
| | - Pierfrancesco Marconi
- Biosciences & Medical Embryology Section, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy;
| | - Gabrio Bassotti
- Gastroenterology, Hepatology & Digestive Endoscopy Section, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy;
- Gastroenterology & Hepatology Unit, Santa Maria Della Misericordia Hospital, 06129 Perugia, Italy
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Mao X, Shen J. Potential roles of enteric glial cells in Crohn's disease: A critical review. Cell Prolif 2024; 57:e13536. [PMID: 37551711 PMCID: PMC10771111 DOI: 10.1111/cpr.13536] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 07/23/2023] [Accepted: 07/26/2023] [Indexed: 08/09/2023] Open
Abstract
Enteric glial cells in the enteric nervous system are critical for the regulation of gastrointestinal homeostasis. Increasing evidence suggests two-way communication between enteric glial cells and both enteric neurons and immune cells. These interactions may be important in the pathogenesis of Crohn's disease (CD), a chronic relapsing disease characterized by a dysregulated immune response. Structural abnormalities in glial cells have been identified in CD. Furthermore, classical inflammatory pathways associated with CD (e.g., the nuclear factor kappa-B pathway) function in enteric glial cells. However, the specific mechanisms by which enteric glial cells contribute to CD have not been summarized in detail. In this review, we describe the possible roles of enteric glial cells in the pathogenesis of CD, including the roles of glia-immune interactions, neuronal modulation, neural plasticity, and barrier integrity. Additionally, the implications for the development of therapeutic strategies for CD based on enteric glial cell-mediated pathogenic processes are discussed.
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Affiliation(s)
- Xinyi Mao
- Division of Gastroenterology and HepatologyBaoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghaiChina
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and HepatologyMinistry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive DiseaseShanghaiChina
| | - Jun Shen
- Division of Gastroenterology and HepatologyBaoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghaiChina
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and HepatologyMinistry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive DiseaseShanghaiChina
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Li X, Wang J, Li L, Yang C, Zhao X, Yang B, Zhang P, Liu B, Li Y, Zhang Z, Duan R. Epstein-Barr virus: To be a trigger of autoimmune glial fibrillary acidic protein astrocytopathy? CNS Neurosci Ther 2023; 29:4139-4146. [PMID: 37458208 PMCID: PMC10651959 DOI: 10.1111/cns.14336] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 05/30/2023] [Accepted: 06/18/2023] [Indexed: 11/17/2023] Open
Abstract
BACKGROUND Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel autoimmune disease of central nervous system (CNS). It is unclear whether Epstein-Barr virus (EBV) is related to autoimmune GFAP astrocytopathy. OBJECTIVE To describe the clinical, laboratory, and imaging characteristics of patients with autoimmune GFAP astrocytopathy. METHODS The clinical, laboratory, and imaging findings of patients are presented. The levels of GFAP in CSF were detected by ELISA. T and B cell subsets in CSF were detected by flow cytometry. GFAP-IgG in serum and cerebrospinal fluid (CSF) were tested by cell-based assay (CBA) and tissue-based assay (TBA). RESULTS All three patients had fever, cognitive dysfunction, limb weakness, and positive GFAP-IgG with EBV infection in CSF. Enteric glia cells may involve in this disease. Typical imaging findings include the gadolinium enhancement of linear perivascular radial perpendicular to the ventricle, meningeal enhancement (especially in midbrain interpeduncal fossa), longitudinally extensive lesions involving spindle cords, and more T2/Flair-hyperintense lesions in the periventricular white matter at late stage. The patients had poor response to antiviral treatment and strong response to steroid pulse therapy. CONCLUSION EBV could induce CNS autoimmune response in autoimmune GFAP astrocytopathy. The detection of GFAP-IgG and EBV may facilitate the early diagnosis in these patients.
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Affiliation(s)
- Xiao‐Li Li
- Department of NeurologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
- Department of Neurology, Shandong Provincial Qianfoshan HospitalCheeloo College of Medicine, Shandong UniversityJinanChina
- Shandong Institute of NeuroimmunologyJinanChina
| | - Jun‐Yan Wang
- Department of NeurologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
| | - Liang‐Kang Li
- Department of Neurology, Shandong Provincial Qianfoshan HospitalCheeloo College of Medicine, Shandong UniversityJinanChina
| | - Chun‐Lin Yang
- Department of NeurologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
- Department of Neurology, Shandong Provincial Qianfoshan HospitalCheeloo College of Medicine, Shandong UniversityJinanChina
- Shandong Institute of NeuroimmunologyJinanChina
| | - Xue‐Lu Zhao
- Department of NeurologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
| | - Bing Yang
- Department of NeurologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
- Department of Neurology, Shandong Provincial Qianfoshan HospitalCheeloo College of Medicine, Shandong UniversityJinanChina
- Shandong Institute of NeuroimmunologyJinanChina
| | - Peng Zhang
- Department of NeurologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
- Department of Neurology, Shandong Provincial Qianfoshan HospitalCheeloo College of Medicine, Shandong UniversityJinanChina
- Shandong Institute of NeuroimmunologyJinanChina
| | - Bin Liu
- Department of NeurologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
- Department of Neurology, Shandong Provincial Qianfoshan HospitalCheeloo College of Medicine, Shandong UniversityJinanChina
- Shandong Institute of NeuroimmunologyJinanChina
| | - Yan‐Bin Li
- Department of NeurologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
- Department of Neurology, Shandong Provincial Qianfoshan HospitalCheeloo College of Medicine, Shandong UniversityJinanChina
- Shandong Institute of NeuroimmunologyJinanChina
| | - Zhao‐Xu Zhang
- Department of NeurologyPeking University People's HospitalBeijingChina
| | - Rui‐Sheng Duan
- Department of NeurologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
- Department of Neurology, Shandong Provincial Qianfoshan HospitalCheeloo College of Medicine, Shandong UniversityJinanChina
- Shandong Institute of NeuroimmunologyJinanChina
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7
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Deng Z, Li D, Yan X, Lan J, Han D, Fan K, Chang J, Ma Y. Activation of GABA receptor attenuates intestinal inflammation by modulating enteric glial cells function through inhibiting NF-κB pathway. Life Sci 2023; 329:121984. [PMID: 37527767 DOI: 10.1016/j.lfs.2023.121984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/18/2023] [Accepted: 07/26/2023] [Indexed: 08/03/2023]
Abstract
AIMS Emerging research indicates that γ-aminobutyric acid (GABA) provides substantial benefits during enteritis. Nevertheless, GABA signaling roles on enteric glial cells (EGCs) remain unknown. The study's objective was to evaluate the underlying mechanisms of GABA signaling on EGCs in vitro and in vivo. MAIN METHODS We established LPS-induced mouse models and stimulated EGCs with LPS to mimic intestinal inflammation, and combined GABA, GABAA receptor (GABAAR) or GABAB receptor (GABABR) agonists to explore the exact mechanisms of GABA signaling. KEY FINDINGS EGCs were immunopositive for GAD65, GAD67, GAT1, GABAARα1, GABAARα3, and GABABR1, indicating GABAergic and GABAceptive properties. GABA receptor activation significantly inhibited the high secretions of proinflammatory factors in EGCs upon LPS stimulation. Interestingly, we found that EGCs express immune-related molecules such as CD16, CD32, CD80, CD86, MHC II, iNOS, Arg1, and CD206, thus establishing their characterization of E1 and E2 phenotype. EGCs exposed to LPS mainly acted as E1 phenotype, whereas GABABR activation strongly promoted EGCs polarization into E2 phenotype. Transcriptome analysis of EGCs indicated that GABA, GABAAR or GABABR agonists treatment participated in various biological processes, however all of these treatments exhibit inhibitory effects on NF-κB pathway. Notably, in LPS-induced mice, activation of GABABR mitigated intestinal damage through modulating inflammatory factors expressions, strengthening sIgA and IgG levels, inhibiting NF-κB pathway and facilitating EGCs to transform into E2 phenotype. SIGNIFICANCE These data demonstrate that the anti-inflammatory actions of GABA signaling system offer in enteritis via regulating EGCs-polarized function through impeding NF-κB pathway, thus providing potential targets for intestinal inflammatory diseases.
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Affiliation(s)
- Ziteng Deng
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Dan Li
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Xue Yan
- New Hope Liuhe Co., Ltd., Key Laboratory of Feed and Livestock and Poultry Products Quality & Safety Control, Ministry of Agriculture, Chengdu, Sichuan, China
| | - Jing Lan
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Deping Han
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China; Peking University Institute of Advanced Agricultural Sciences, Weifang, Shandong, China
| | - Kai Fan
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jianyu Chang
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yunfei Ma
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
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Miyazaki I, Asanuma M. Multifunctional Metallothioneins as a Target for Neuroprotection in Parkinson's Disease. Antioxidants (Basel) 2023; 12:antiox12040894. [PMID: 37107269 PMCID: PMC10135286 DOI: 10.3390/antiox12040894] [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: 03/14/2023] [Revised: 03/27/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
Parkinson's disease (PD) is characterized by motor symptoms based on a loss of nigrostriatal dopaminergic neurons and by non-motor symptoms which precede motor symptoms. Neurodegeneration accompanied by an accumulation of α-synuclein is thought to propagate from the enteric nervous system to the central nervous system. The pathogenesis in sporadic PD remains unknown. However, many reports indicate various etiological factors, such as oxidative stress, inflammation, α-synuclein toxicity and mitochondrial impairment, drive neurodegeneration. Exposure to heavy metals contributes to these etiopathogenesis and increases the risk of developing PD. Metallothioneins (MTs) are cysteine-rich metal-binding proteins; MTs chelate metals and inhibit metal-induced oxidative stress, inflammation and mitochondrial dysfunction. In addition, MTs possess antioxidative properties by scavenging free radicals and exert anti-inflammatory effects by suppression of microglial activation. Furthermore, MTs recently received attention as a potential target for attenuating metal-induced α-synuclein aggregation. In this article, we summarize MTs expression in the central and enteric nervous system, and review protective functions of MTs against etiopathogenesis in PD. We also discuss neuroprotective strategies for the prevention of central dopaminergic and enteric neurodegeneration by targeting MTs. This review highlights multifunctional MTs as a target for the development of disease-modifying drugs for PD.
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Affiliation(s)
- Ikuko Miyazaki
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Masato Asanuma
- Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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9
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Claudino Dos Santos JC, Lima MPP, Brito GADC, Viana GSDB. Role of enteric glia and microbiota-gut-brain axis in parkinson disease pathogenesis. Ageing Res Rev 2023; 84:101812. [PMID: 36455790 DOI: 10.1016/j.arr.2022.101812] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 11/24/2022] [Accepted: 11/25/2022] [Indexed: 11/30/2022]
Abstract
The microbiota-gut-brain axis or simple gut-brain axis (GBA) is a complex and interactive bidirectional communication network linking the gut to the brain. Alterations in the composition of the gut microbiome have been linked to GBA dysfunction, central nervous system (CNS) inflammation, and dopaminergic degeneration, as those occurring in Parkinson's disease (PD). Besides inflammation, the activation of brain microglia is known to play a central role in the damage of dopaminergic neurons. Inflammation is attributed to the toxic effect of aggregated α-synuclein, in the brain of PD patients. It has been suggested that the α-synuclein misfolding might begin in the gut and spread "prion-like", via the vagus nerve into the lower brainstem and ultimately to the midbrain, known as the Braak hypothesis. In this review, we discuss how the microbiota-gut-brain axis and environmental influences interact with the immune system to promote a pro-inflammatory state that is involved in the initiation and progression of misfolded α-synuclein proteins and the beginning of the early non-motor symptoms of PD. Furthermore, we describe a speculative bidirectional model that explains how the enteric glia is involved in the initiation and spreading of inflammation, epithelial barrier disruption, and α-synuclein misfolding, finally reaching the central nervous system and contributing to neuroinflammatory processes involved with the initial non-motor symptoms of PD.
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Affiliation(s)
- Júlio César Claudino Dos Santos
- Medical School of the Christus University Center - UNICHRISTUS, Fortaleza, CE, Brazil; Graduate Program in Morphofunctional Sciences, Federal University of Ceará - UFC, Fortaleza, CE, Brazil.
| | | | - Gerly Anne de Castro Brito
- Physiology and Pharmacology Department of the Federal University of Ceará - UFC, Fortaleza, CE, Brazil; Morphology Department of the Federal University of Ceará - UFC, Fortaleza, CE, Brazil
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10
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Baidoo N, Sanger GJ, Belai A. Effect of old age on the subpopulations of enteric glial cells in human descending colon. Glia 2023; 71:305-316. [PMID: 36128665 PMCID: PMC10087700 DOI: 10.1002/glia.24272] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 08/22/2022] [Accepted: 08/29/2022] [Indexed: 11/06/2022]
Abstract
Old age is associated with a higher incidence of lower bowel conditions such as constipation. Recent evidence suggest that colonic motility may be influenced by enteric glial cells (EGCs). Little is known about the effect of aging on the subpopulation of EGCs in the human colon. We assessed and compared the pattern of distribution of EGCs in adult and elderly human colon. Human descending colon were obtained from 23 cancer patients comprising of adults (23-63 years; 6 male, 7 female) and elderly (66-81 year; 6 male, 4 female). Specimens were serially-sectioned and immunolabeled with anti-Sox-10, anti-S100 and anti-GFAP for morphometric analysis. Standardized procedures were utilized to ensure unbiased counting and densitometric evaluation of EGCs. The number of Sox-10 immunoreactive (IR) EGCs were unaltered with age in both the myenteric plexus (MP) (respectively, in adult and elderly patients, 1939 ± 82 and 1760 ± 44/mm length; p > .05) and submucosal plexus; there were no apparent differences between adult males and females. The density of S100-IR EGCs declined among the elderly in the circular muscle and within the MP per ganglionic area. In the adult colon, there were more S100-IR EGCs distributed in the circular muscle per unit area than the Taenia coli. There was little or no GFAP-IR EGCs in both adult and elderly colon. We concluded that aging of the human descending colon does not result in a loss of Sox-10-IR EGCs in the MP and SMP but reduces S100-IR EGCs density within the musculature. This alteration in myenteric EGCs density with age may contribute to colonic dysfunction.
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Affiliation(s)
- Nicholas Baidoo
- School of Life and Health Sciences, University of Roehampton, London, UK
| | - Gareth J Sanger
- Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Abi Belai
- School of Life and Health Sciences, University of Roehampton, London, UK
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11
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Zanoletti L, Valdata A, Nehlsen K, Faris P, Casali C, Cacciatore R, Sbarsi I, Carriero F, Arfini D, van Baarle L, De Simone V, Barbieri G, Raimondi E, May T, Moccia F, Bozzola M, Matteoli G, Comincini S, Manai F. Cytological, molecular, cytogenetic, and physiological characterization of a novel immortalized human enteric glial cell line. Front Cell Neurosci 2023; 17:1170309. [PMID: 37153631 PMCID: PMC10158601 DOI: 10.3389/fncel.2023.1170309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 03/22/2023] [Indexed: 05/10/2023] Open
Abstract
Enteric glial cells (EGCs), the major components of the enteric nervous system (ENS), are implicated in the maintenance of gut homeostasis, thereby leading to severe pathological conditions when impaired. However, due to technical difficulties associated with EGCs isolation and cell culture maintenance that results in a lack of valuable in vitro models, their roles in physiological and pathological contexts have been poorly investigated so far. To this aim, we developed for the first time, a human immortalized EGC line (referred as ClK clone) through a validated lentiviral transgene protocol. As a result, ClK phenotypic glial features were confirmed by morphological and molecular evaluations, also providing the consensus karyotype and finely mapping the chromosomal rearrangements as well as HLA-related genotypes. Lastly, we investigated the ATP- and acetylcholine, serotonin and glutamate neurotransmitters mediated intracellular Ca2+ signaling activation and the response of EGCs markers (GFAP, SOX10, S100β, PLP1, and CCL2) upon inflammatory stimuli, further confirming the glial nature of the analyzed cells. Overall, this contribution provided a novel potential in vitro tool to finely characterize the EGCs behavior under physiological and pathological conditions in humans.
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Affiliation(s)
- Lisa Zanoletti
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Aurora Valdata
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | - Pawan Faris
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Iraq
| | - Claudio Casali
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Rosalia Cacciatore
- Immunohematology and Transfusion Service, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
| | - Ilaria Sbarsi
- Immunohematology and Transfusion Service, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
| | - Francesca Carriero
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Davide Arfini
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Lies van Baarle
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Veronica De Simone
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Giulia Barbieri
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Elena Raimondi
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | - Francesco Moccia
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | | | - Gianluca Matteoli
- Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Sergio Comincini
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Federico Manai
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
- *Correspondence: Federico Manai,
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12
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Chevalier NR. Physical organogenesis of the gut. Development 2022; 149:276365. [DOI: 10.1242/dev.200765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
ABSTRACT
The gut has been a central subject of organogenesis since Caspar Friedrich Wolff’s seminal 1769 work ‘De Formatione Intestinorum’. Today, we are moving from a purely genetic understanding of cell specification to a model in which genetics codes for layers of physical–mechanical and electrical properties that drive organogenesis such that organ function and morphogenesis are deeply intertwined. This Review provides an up-to-date survey of the extrinsic and intrinsic mechanical forces acting on the embryonic vertebrate gut during development and of their role in all aspects of intestinal morphogenesis: enteric nervous system formation, epithelium structuring, muscle orientation and differentiation, anisotropic growth and the development of myogenic and neurogenic motility. I outline numerous implications of this biomechanical perspective in the etiology and treatment of pathologies, such as short bowel syndrome, dysmotility, interstitial cells of Cajal-related disorders and Hirschsprung disease.
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Affiliation(s)
- Nicolas R. Chevalier
- Laboratoire Matière et Systèmes Complexes, Université Paris Cité, CNRS UMR 7057 , 10 rue Alice Domon et Léonie Duquet, 75013 Paris , France
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13
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Krugliak Cleveland N, Torres J, Rubin DT. What Does Disease Progression Look Like in Ulcerative Colitis, and How Might It Be Prevented? Gastroenterology 2022; 162:1396-1408. [PMID: 35101421 DOI: 10.1053/j.gastro.2022.01.023] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023]
Abstract
Ulcerative colitis (UC) has been characterized by inflammation limited to the mucosa. Although sustained and durable remission has been associated with mucosal healing, the recurrent phenomenon of persistent clinical disease activity despite mucosal healing has been observed in clinical practice and across pivotal trials. Over time, UC appears to confer an increased risk of progression, defined as changes of disease phenotype; adverse transmural effects on the bowel wall; increased risk of neoplasia development; worsening colorectal function; and increased risk of colectomy, hospitalizations, and other extraintestinal comorbidities. Although the treatment paradigm for Crohn's disease has shifted toward early aggressive intervention to prevent disease progression and irreversible bowel damage, such urgency in efforts to halt disease progression in UC have been largely overlooked. This review summarizes the multiple facets of UC contributing to a modified perception of the disease as a progressive one. We propose further study of the natural history and priorities for further treatment goals that include these considerations.
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Affiliation(s)
| | - Joana Torres
- Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Lisbon, Portugal; Division of Gastroenterology, Hospital da Luz, Lisbon, Portugal
| | - David T Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois.
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14
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Mischopoulou M, D'Ambrosio M, Bigagli E, Luceri C, Farrugia G, Cipriani G. Role of Macrophages and Mast Cells as Key Players in the Maintenance of Gastrointestinal Smooth Muscle Homeostasis and Disease. Cell Mol Gastroenterol Hepatol 2022; 13:1849-1862. [PMID: 35245688 PMCID: PMC9123576 DOI: 10.1016/j.jcmgh.2022.02.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 02/18/2022] [Accepted: 02/22/2022] [Indexed: 12/18/2022]
Abstract
The gut contains the largest macrophage pool in the body, with populations of macrophages residing in the mucosa and muscularis propria of the gastrointestinal (GI) tract. Muscularis macrophages (MMs), which are located within the muscularis propria, interact with cells essential for GI function, such as interstitial cells of Cajal, enteric neurons, smooth muscle cells, enteric glia, and fibroblast-like cells, suggesting that these immune cells contribute to several aspects of GI function. This review focuses on the latest insights on the factors contributing to MM heterogeneity and the functional interaction of MMs with other cell types essential for GI function. This review integrates the latest findings on macrophages in other organs with increasing knowledge of MMs to better understand their role in a healthy and diseased gut. We describe the factors that contribute to (muscularis macrophage) MM heterogeneity, and the nature of MM interactions with cells regulating GI function. Finally, we also describe the increasing evidence suggesting a critical role of another immune cell type, the mast cell, in normal and diseased GI physiology.
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Affiliation(s)
| | - Mario D'Ambrosio
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Elisabetta Bigagli
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Cristina Luceri
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
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15
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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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16
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Stakenborg M, Abdurahiman S, De Simone V, Goverse G, Stakenborg N, van Baarle L, Wu Q, Pirottin D, Kim JS, Chappell-Maor L, Pintelon I, Thys S, Pollenus E, Boon L, Van den Steen P, Hao M, Van Ginderachter JA, Boeckxstaens GE, Timmermans JP, Jung S, Marichal T, Ibiza S, Matteoli G. Enteric glial cells favor accumulation of anti-inflammatory macrophages during the resolution of muscularis inflammation. Mucosal Immunol 2022; 15:1296-1308. [PMID: 36071145 PMCID: PMC9705256 DOI: 10.1038/s41385-022-00563-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 08/16/2022] [Accepted: 08/16/2022] [Indexed: 02/04/2023]
Abstract
Monocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for monocyte recruitment and anti-inflammatory Mφ differentiation in this paradigm. Here, we investigate Mφ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue-protective Mφs. Results showed that muscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c+ monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mφ subpopulations during the resolution of muscularis inflammation, i.e. Cd206+ MhcIIhi and Timp2+ MhcIIlo Mφs. Interestingly, we found that damage to the micro-environment upon muscularis inflammation resulted in EGC activation, which in turn stimulated monocyte infiltration and the consequent differentiation in anti-inflammatory CD206+ Mφs via CCL2 and CSF1, respectively. In addition, CSF1-CSF1R signaling was shown to be essential for the differentiation of monocytes into CD206+ Mφs and EGC proliferation during muscularis inflammation. Our study provides a comprehensive insight into pro-resolving Mφ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mφs, thereby highlighting pro-resolving Mφ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.
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Affiliation(s)
- Michelle Stakenborg
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Saeed Abdurahiman
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Veronica De Simone
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Gera Goverse
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Nathalie Stakenborg
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Lies van Baarle
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Qin Wu
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Dimitri Pirottin
- grid.4861.b0000 0001 0805 7253Laboratory of Cellular and Molecular Immunology, GIGA Institute, Liege University, Liege, Belgium
| | - Jung-Seok Kim
- grid.13992.300000 0004 0604 7563Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Louise Chappell-Maor
- grid.13992.300000 0004 0604 7563Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Isabel Pintelon
- grid.5284.b0000 0001 0790 3681Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Sofie Thys
- grid.5284.b0000 0001 0790 3681Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Emilie Pollenus
- grid.415751.3Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical research, KU Leuven, Leuven, Belgium
| | - Louis Boon
- grid.450202.10000 0004 0646 560XPolpharma Biologics, Utrecht, the Netherlands
| | - Philippe Van den Steen
- grid.415751.3Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical research, KU Leuven, Leuven, Belgium
| | - Marlene Hao
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Jo A. Van Ginderachter
- grid.8767.e0000 0001 2290 8069Cellular and Molecular Immunology Lab, Department of Bio-engineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium ,grid.510970.aMyeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
| | - Guy E. Boeckxstaens
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Jean-Pierre Timmermans
- grid.5284.b0000 0001 0790 3681Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Steffen Jung
- grid.13992.300000 0004 0604 7563Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Thomas Marichal
- grid.4861.b0000 0001 0805 7253Laboratory of Immunophysiology, GIGA Institute, Liege University, Liege, Belgium ,grid.4861.b0000 0001 0805 7253Department of Functional Sciences, Faculty of Veterinary Medicine, Liege University, Liege, Belgium
| | - Sales Ibiza
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium ,grid.5284.b0000 0001 0790 3681Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Gianluca Matteoli
- grid.5596.f0000 0001 0668 7884Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
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17
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Bassotti G, Pellegrini C, Bernardini N. Neuromuscular Function Abnormalities. COLONIC DIVERTICULAR DISEASE 2022:31-39. [DOI: 10.1007/978-3-030-93761-4_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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18
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Bassotti G, Fruganti A, Maconi G, Marconi P, Fettucciari K. Clostridioides difficile Infection in Patients with Inflammatory Bowel Disease May be Favoured by the Effects of Proinflammatory Cytokines on the Enteroglial Network. J Inflamm Res 2021; 14:7443-7453. [PMID: 35002278 PMCID: PMC8722535 DOI: 10.2147/jir.s328628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 10/02/2021] [Indexed: 11/23/2022] Open
Abstract
Clostridioides difficile infection is widespread throughout countries and represents an important cause of nosocomial diarrhoea, with relatively high morbidity. This infection often occurs in patients with inflammatory bowel diseases and may complicate their clinical picture. Here, we propose, on the basis of evidence from basic science studies, that in patients affected by inflammatory bowel diseases, this infection might be facilitated by a derangement of the enteric glial cell (EGC) network caused by the effects of proinflammatory cytokines, such as tumour necrosis factor alpha and interferon gamma, which enhance the cytotoxic effects of C. difficile toxin B on EGCs. This hypothesis, if confirmed, could open the door to alternative treatment approaches to fight C. difficile infection.
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Affiliation(s)
- Gabrio Bassotti
- Department of Medicine and Surgery, Gastroenterology, Hepatology & Digestive Endoscopy Section, University of Perugia, Perugia, Italy
- Gastroenterology & Hepatology Unit, Santa Maria della Misericordia Hospital, Perugia, Italy
| | - Alessandro Fruganti
- School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy
| | - Giovanni Maconi
- Department of Biomedical and Clinical Sciences, Gastroenterology Unit, “L. Sacco” Hospital, University of Milano, Milano, Italy
| | - Pierfrancesco Marconi
- Department of Medicine and Surgery, Biosciences & Medical Embryology Section, University of Perugia, Perugia, Italy
| | - Katia Fettucciari
- Department of Medicine and Surgery, Biosciences & Medical Embryology Section, University of Perugia, Perugia, Italy
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19
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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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20
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Engineered liposomes targeting the gut-CNS Axis for comprehensive therapy of spinal cord injury. J Control Release 2021; 331:390-403. [PMID: 33485884 DOI: 10.1016/j.jconrel.2021.01.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/17/2020] [Accepted: 01/19/2021] [Indexed: 02/08/2023]
Abstract
Effective curative therapies for spinal cord injury (SCI), which is often accompanied by intestinal complications, are lacking. Potential therapeutic targets include astrocytes and their enteric nervous system counterpart, enteric glial cells (EGCs). Based on shared biomarkers and similar functions of both cell types, we designed an orally administered targeted delivery system in which the neuropeptide apamin, stabilized by sulfur replacement with selenium, was adopted as a targeting moiety, and the liposome surface was protected with a non-covalent cross-linked chitosan oligosaccharide lactate layer. The system effectively permeated through oral absorption barriers, targeted local EGCs and astrocytes after systemic circulation, allowing for comprehensive SCI therapy. Given the involvement of the gut-organ axis in a growing number of diseases, our research may shed light on new aspects of the oral administration route as a bypass for multiple interventions and targeted therapy.
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21
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Abstract
The gut-brain axis is a coordinated communication system that not only maintains homeostasis, but significantly influences higher cognitive functions and emotions, as well as neurological and behavioral disorders. Among the large populations of sensory and motor neurons that innervate the gut, insights into the function of primary afferent nociceptors, whose cell bodies reside in the dorsal root ganglia and nodose ganglia, have revealed their multiple crosstalk with several cell types within the gut wall, including epithelial, vascular, and immune cells. These bidirectional communications have immunoregulatory functions, control host response to pathogens, and modulate sensations associated with gastrointestinal disorders, through activation of immune cells and glia in the peripheral and central nervous system, respectively. Here, we will review the cellular and neurochemical basis of these interactions at the periphery, in dorsal root ganglia, and in the spinal cord. We will discuss the research gaps that should be addressed to get a better understanding of the multifunctional role of sensory neurons in maintaining gut homeostasis and regulating visceral sensitivity.
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Affiliation(s)
- Nasser Abdullah
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Manon Defaye
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Christophe Altier
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
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22
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Deffner F, Scharr M, Klingenstein S, Klingenstein M, Milazzo A, Scherer S, Wagner A, Hirt B, Mack AF, Neckel PH. Histological Evidence for the Enteric Nervous System and the Choroid Plexus as Alternative Routes of Neuroinvasion by SARS-CoV2. Front Neuroanat 2020; 14:596439. [PMID: 33122999 PMCID: PMC7573115 DOI: 10.3389/fnana.2020.596439] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 09/16/2020] [Indexed: 12/21/2022] Open
Abstract
Evidence is mounting that the novel corona virus SARS-CoV2 inflicts neurological symptoms in a subgroup of COVID-19 patients. While plenty of theories on the route of neuroinvasion have been proposed, little histological evidence has been presented supporting any of these hypotheses. Therefore, we carried out immunostainings for ACE2 and TMPRSS2, two proteinases crucial for the entry of SARS-CoV2 into host cells, in the human enteric nervous system (ENS), as well as in the choroid plexus of the lateral ventricles. Both of these sites are important, yet often neglected entry gates to the nervous system. We found that ACE2 and TMPRSS2 are expressed by enteric neurons and glial cells of the small and large intestine, as well as choroid plexus epithelial cells, indicating that these cells meet the molecular requirements for viral entry. Together, our results are fundamental histological evidence substantiating current theories of neuroinvasion by SARS-CoV2.
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Affiliation(s)
- Felix Deffner
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany
| | - Melanie Scharr
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany
| | - Stefanie Klingenstein
- Institute of Neuroanatomy and Developmental Biology, University of Tübingen, Tübingen, Germany
| | - Moritz Klingenstein
- Institute of Neuroanatomy and Developmental Biology, University of Tübingen, Tübingen, Germany
| | - Alfio Milazzo
- Institute of Neuroanatomy and Developmental Biology, University of Tübingen, Tübingen, Germany
| | - Simon Scherer
- Department of Pediatric Surgery, University Children’s Hospital, Tübingen, Germany
| | - Andreas Wagner
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany
| | - Bernhard Hirt
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany
| | - Andreas F. Mack
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany
| | - Peter H. Neckel
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Tübingen, Germany
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23
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Bassotti G, Marchegiani A, Marconi P, Fettucciari K. The cytotoxic synergy between Clostridioides difficile toxin B and proinflammatory cytokines: an unholy alliance favoring the onset of Clostridioides difficile infection and relapses. Microbiologyopen 2020; 9:e1061. [PMID: 32657021 PMCID: PMC7424247 DOI: 10.1002/mbo3.1061] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/31/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023] Open
Abstract
Clostridioides difficile infection (CDI) represents an important health problem worldwide, with significant morbidity and mortality. This infection has also high recurrence rates, whose pathophysiological grounds are still poorly understood. Based on our experiments in vitro with Clostridioides difficile toxin B and existing experimental and clinical evidence, we propose that primary CDI and relapses might be favored by a mechanism that involves the enhancement of the toxicity of toxin B by proinflammatory cytokines, tumor necrosis factor alpha, and interferon gamma on the enteric glial cells and their network in an environment characterized by a strong dysmicrobism.
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Affiliation(s)
- Gabrio Bassotti
- Gastroenterology & Hepatology SectionDepartment of MedicineUniversity of Perugia Medical SchoolPerugiaItaly
- Gastroenterology & Hepatology UnitSanta Maria della Misericordia HospitalPerugiaItaly
| | - Andrea Marchegiani
- School of Biosciences and Veterinary MedicineUniversity of CamerinoMacerataItaly
| | | | - Katia Fettucciari
- Department of Experimental MedicineUniversity of Perugia Medical SchoolPerugiaItaly
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24
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Bassotti G, Antonelli E, Villanacci V, Nascimbeni R, Dore MP, Pes GM, Maconi G. Abnormal gut motility in inflammatory bowel disease: an update. Tech Coloproctol 2020; 24:275-282. [PMID: 32062797 DOI: 10.1007/s10151-020-02168-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 02/07/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND There is substantial evidence linking disturbed gastrointestinal motility to inflammation. Thus, it is not surprising that abnormalities of gastrointestinal motility play a role in inflammatory bowel disease (IBD), affecting patient outcomes. We performed a review of the literature to investigate the relationship between abnormal gut motility and IBD. METHODS With an extensive literature search, we retrieved the pertinent articles linking disturbed gut motility to IBD in various anatomical districts. RESULTS The evidence in the literature suggests that abnormal gastrointestinal motility plays a role in the clinical setting of IBD and may confuse the clinical picture. CONCLUSIONS Abnormal gut motility may be important in the clinical setting of IBD. However, additional data obtained with modern techniques (e.g., magnetic resonance imaging) are needed to individuate in a more precise manner gastrointestinal motor dysfunctions, to understand the nature of clinical manifestations and properly tailor the treatment of patients.
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Affiliation(s)
- G Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy.
- Clinica Di Gastroenterologia Ed Epatologia, Ospedale Santa Maria della Misericordia, Piazzale Menghini, 1, San Sisto, 06156, Perugia, Italy.
| | - E Antonelli
- Gastroenterology Unit, Perugia General Hospital, Perugia, Italy
| | - V Villanacci
- Pathology Institute, Spedali Civili, Brescia, Italy
| | - R Nascimbeni
- Surgical Section Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - M P Dore
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy
| | - G M Pes
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy
| | - G Maconi
- Gastroenterology Unit, Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Milan, Italy
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Xu Y, Xie MZ, Liang GG. Advances in morphologic study of enteric glial cells. Shijie Huaren Xiaohua Zazhi 2019; 27:521-526. [DOI: 10.11569/wcjd.v27.i8.521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
As an important part of the intestinal nervous system, enteric glial cells are about four times as many as intestinal neurons. Furthermore, a large population of astrocyte-like glial cells populate gut muscle layers and the intestinal mucosa, and mounting new evidence points toward enteric glial cells as an active participant in gut pathology. They are similar in morphology and function to the astrocytes of the central nervous system and play an important role in nutrition, supporting gastrointestinal nerve, maintaining gastrointestinal homeostasis, and regulating gastrointestinal function. Because of their complex and diverse roles in the intestinal tract, they have become the focus of research. As the study of their functional mechanism has been extensively deepened, the research methods for intestinal glial cells are also on constant progress and improvement, especially in studying their morphology. This paper mainly introduces the morphological characteristics of enteric glial cells under the conditions of gastrointestinal physiology and pathology, so as to provide a reference for the future study of enteric glial cells and promote the development of this field.
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Affiliation(s)
- Ying Xu
- Department of Emergency Abdominal Surgery/Institute of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Ming-Zheng Xie
- Department of Emergency Abdominal Surgery/Institute of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Guo-Gang Liang
- Department of Emergency Abdominal Surgery/Institute of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
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Schneider S, Wright CM, Heuckeroth RO. Unexpected Roles for the Second Brain: Enteric Nervous System as Master Regulator of Bowel Function. Annu Rev Physiol 2019; 81:235-259. [DOI: 10.1146/annurev-physiol-021317-121515] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
At the most fundamental level, the bowel facilitates absorption of small molecules, regulates fluid and electrolyte flux, and eliminates waste. To successfully coordinate this complex array of functions, the bowel relies on the enteric nervous system (ENS), an intricate network of more than 500 million neurons and supporting glia that are organized into distinct layers or plexi within the bowel wall. Neuron and glial diversity, as well as neurotransmitter and receptor expression in the ENS, resembles that of the central nervous system. The most carefully studied ENS functions include control of bowel motility, epithelial secretion, and blood flow, but the ENS also interacts with enteroendocrine cells, influences epithelial proliferation and repair, modulates the intestinal immune system, and mediates extrinsic nerve input. Here, we review the many different cell types that communicate with the ENS, integrating data about ENS function into a broader view of human health and disease. In particular, we focus on exciting new literature highlighting relationships between the ENS and its lesser-known interacting partners.
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Affiliation(s)
- Sabine Schneider
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Christina M. Wright
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Robert O. Heuckeroth
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Abramson Research Center, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA
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Chen Y, Liu G, He F, Zhang L, Yang K, Yu H, Zhou J, Gan H. MicroRNA 375 modulates hyperglycemia-induced enteric glial cell apoptosis and Diabetes-induced gastrointestinal dysfunction by targeting Pdk1 and repressing PI3K/Akt pathway. Sci Rep 2018; 8:12681. [PMID: 30140011 PMCID: PMC6107553 DOI: 10.1038/s41598-018-30714-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 08/02/2018] [Indexed: 02/06/2023] Open
Abstract
Diabetic neuropathy can damage systemic nervous system, including alteration of enteric nervous system and subsequent gastrointestinal dysfunction. The effect of diabetes on enteric glia cell (EGC) is not clear. We investigated the effect of diabetes and hyperglycemia on EGC, and the role of microRNA375 in modulating EGC survival in vivo and in vitro. Streptozotocin-induced diabetic mice were intraperitoneally injected with microRNA375 inhibitor or its negative control. EGC was transfected with microRNA375 inhibitor or its mimic. Diabetes mice with gastrointestinal dysfunction showed increased apoptosis of EGC (no difference in cell numbers) and gene expression of micorRNA375 in the myenteric plexus. Hyperglycemia triggered apoptosis of EGC in vitro with decreased expression of Pdk1 and p-Akt, but increased expression of micorRNA375. MicorRNA375 mimic induced apoptosis of EGC in vitro with repressed Pdk1and p-Akt. MicorRNA375 inhibitor could both prevent hyperglycemia-induced apoptosis of EGC in vitro and diabetes-induced gastrointestinal dysfunction in vivo. Our results suggest that diabetes-induced gastrointestinal dysfunction is related to increased apoptosis of EGC in the myenteric plexus. Hyperglycemia can increase the expression of microRNA375 and damage EGC survival through PI3K/Akt pathway. MicroRNA375 specific inhibition can prevent hyperglycemia induced EGC damage and diabetes-induced gastrointestinal dysfunction.
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Affiliation(s)
- Yan Chen
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Gongxiang Liu
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fuqian He
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Zhang
- Department of elderly digestive, Sichuan Provincial People's Hospital, Chengdu, 610072, China
| | - Kun Yang
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Huan Yu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jinqiu Zhou
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Huatian Gan
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Macchioni L, Petricciuolo M, Davidescu M, Fettucciari K, Scarpelli P, Vitale R, Gatticchi L, Orvietani PL, Marchegiani A, Marconi P, Bassotti G, Corcelli A, Corazzi L. Palmitate lipotoxicity in enteric glial cells: Lipid remodeling and mitochondrial ROS are responsible for cyt c release outside mitochondria. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:895-908. [PMID: 29729479 DOI: 10.1016/j.bbalip.2018.04.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 04/05/2018] [Accepted: 04/29/2018] [Indexed: 02/08/2023]
Abstract
Enteric glial cells (EGCs) are components of the enteric nervous system, an organized structure that controls gut functions. EGCs may be vulnerable to different agents, such as bacterial infections that could alter the intestinal epithelial barrier, allowing bacterial toxins and/or other agents possessing intrinsic toxic effect to access cells. Palmitate, known to exhibit lipotoxicity, is released in the gut during the digestion process. In this study, we investigated the lipotoxic effect of palmitate in cultured EGCs, with particular emphasis on palmitate-dependent intracellular lipid remodeling. Palmitate but not linoleate altered mitochondrial and endoplasmic reticulum lipid composition. In particular, the levels of phosphatidic acid, key precursor of phospholipid synthesis, increased, whereas those of mitochondrial cardiolipin (CL) decreased; in parallel, phospholipid remodeling was induced. CL remodeling (chains shortening and saturation) together with palmitate-triggered mitochondrial burst, caused cytochrome c (cyt c) detachment from its CL anchor and accumulation in the intermembrane space as soluble pool. Palmitate decreased mitochondrial membrane potential and ATP levels, without mPTP opening. Mitochondrial ROS permeation into the cytosol and palmitate-induced ER stress activated JNK and p38, culminating in Bim and Bax overexpression, factors known to increase the outer mitochondrial membrane permeability. Overall, in EGCs palmitate produced weakening of cyt c-CL interactions and favoured the egress of the soluble cyt c pool outside mitochondria to trigger caspase-3-dependent viability loss. Elucidating the mechanisms of palmitate lipotoxicity in EGCs may be relevant in gut pathological conditions occurring in vivo such as those following an insult that may damage the intestinal epithelial barrier.
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Affiliation(s)
- Lara Macchioni
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
| | - Maya Petricciuolo
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy
| | - Magdalena Davidescu
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy
| | - Katia Fettucciari
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy
| | - Paolo Scarpelli
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy
| | - Rita Vitale
- Department of Basic Medical Sciences, Neuroscience and Sense. Organs, University of Bari "A. Moro", 70124 Bari, Italy
| | - Leonardo Gatticchi
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy
| | - Pier Luigi Orvietani
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy
| | - Andrea Marchegiani
- School of Biosciences and Veterinary Medicine, University of Camerino, 62024 Matelica (MC), Italy
| | | | - Gabrio Bassotti
- Department of Medicine, University of Perugia, 06132 Perugia, Italy
| | - Angela Corcelli
- Department of Basic Medical Sciences, Neuroscience and Sense. Organs, University of Bari "A. Moro", 70124 Bari, Italy
| | - Lanfranco Corazzi
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
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Fujita M, Yagi T, Okura U, Tanaka J, Hirashima N, Tanaka M. Calcineurin B1 Deficiency in Glial Cells Induces Mucosal Degeneration and Inflammation in Mouse Small Intestine. Biol Pharm Bull 2018; 41:786-796. [DOI: 10.1248/bpb.b18-00041] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Maya Fujita
- Department of Cellular Biophysics, Graduate School of Pharmaceutical Sciences, Nagoya City University
| | - Takaki Yagi
- Department of Cellular Biophysics, Graduate School of Pharmaceutical Sciences, Nagoya City University
| | - Umi Okura
- Department of Cellular Biophysics, Graduate School of Pharmaceutical Sciences, Nagoya City University
| | - Jun’ichi Tanaka
- 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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Bassotti G, Macchioni L, Corazzi L, Marconi P, Fettucciari K. Clostridium difficile-related postinfectious IBS: a case of enteroglial microbiological stalking and/or the solution of a conundrum? Cell Mol Life Sci 2018; 75:1145-1149. [PMID: 29285574 PMCID: PMC11105427 DOI: 10.1007/s00018-017-2736-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/11/2017] [Accepted: 12/20/2017] [Indexed: 02/06/2023]
Abstract
Post-infectious irritable bowel syndrome is a well-defined pathological entity that develops in about one-third of subjects after an acute infection (bacterial, viral) or parasitic infestation. Only recently it has been documented that an high incidence of post-infectious irritable bowel syndrome occurs after Clostridium difficile infection. However, until now it is not known why in some patients recovered from this infection the gastrointestinal disturbances persist for months or years. Based on our in vitro studies on enteric glial cells exposed to the effects of C. difficile toxin B, we hypothesize that persistence of symptoms up to the development of irritable bowel syndrome might be due to a disturbance/impairment of the correct functions of the enteroglial intestinal network.
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Affiliation(s)
- Gabrio Bassotti
- Department of Medicine, University of Perugia Medical School, Perugia, Italy.
- Gastroenterology and Hepatology Section, Santa Maria della Misericordia Hospital, Piazzale Menghini, 1, 06156, San Sisto (Perugia), Italy.
| | - Lara Macchioni
- Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy
| | - Lanfranco Corazzi
- Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy
| | - Pierfrancesco Marconi
- Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy
| | - Katia Fettucciari
- Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy
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HIV-1 Tat-induced diarrhea evokes an enteric glia-dependent neuroinflammatory response in the central nervous system. Sci Rep 2017; 7:7735. [PMID: 28798420 PMCID: PMC5552820 DOI: 10.1038/s41598-017-05245-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 05/25/2017] [Indexed: 02/07/2023] Open
Abstract
Despite the effectiveness of combined anti-retroviral therapy, human immunodeficiency virus (HIV) infected-patients frequently report diarrhea and neuropsychological deficits. It is claimed that the viral HIV-1 Trans activating factor (HIV-1 Tat) protein is responsible for both diarrhea and neurotoxic effects, but the underlying mechanisms are not known. We hypothesize that colonic application of HIV-1 Tat activates glial cells of the enteric nervous system (EGCs), leading to a neuroinflammatory response able to propagate to the central nervous system. We demonstrated that HIV-1 Tat-induced diarrhea was associated with a significant activation of glial cells within the colonic wall, the spinal cord and the frontal cortex, and caused a consistent impairment of the cognitive performances. The inhibition of glial cells activity by lidocaine, completely abolished the above-described effects. These observations point out the role of glial cells as putative effectors in HIV-1 Tat-associated gastrointestinal and neurological manifestations and key regulators of gut-brain signaling.
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Martinez-Pereira MA, Franceschi RDC, Coelho BP, Zancan DM. The Stomatogastric and Enteric Nervous System of the Pulmonate SnailMegalobulimus abbreviatus: A Neurochemical Analysis. Zoolog Sci 2017; 34:300-311. [DOI: 10.2108/zs160136] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Malcon Andrei Martinez-Pereira
- Center of Rural Sciences, Federal University of Santa Catarina, 89.520-000, Curitibanos, SC, Brazil
- Neuroscience Graduate Program, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), 90050-170, Porto Alegre, RS, Brazil
- Laboratory of Comparative Neurobiology, Department of Physiology, ICBS, UFRGS, 90050-170, Porto Alegre, RS, Brazil
| | - Raphaela da Cunha Franceschi
- Neuroscience Graduate Program, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), 90050-170, Porto Alegre, RS, Brazil
- Laboratory of Comparative Neurobiology, Department of Physiology, ICBS, UFRGS, 90050-170, Porto Alegre, RS, Brazil
| | - Bárbara Paranhos Coelho
- Laboratory of Comparative Neurobiology, Department of Physiology, ICBS, UFRGS, 90050-170, Porto Alegre, RS, Brazil
| | - Denise M. Zancan
- Neuroscience Graduate Program, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), 90050-170, Porto Alegre, RS, Brazil
- Laboratory of Comparative Neurobiology, Department of Physiology, ICBS, UFRGS, 90050-170, Porto Alegre, RS, Brazil
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Macchioni L, Davidescu M, Fettucciari K, Petricciuolo M, Gatticchi L, Gioè D, Villanacci V, Bellini M, Marconi P, Roberti R, Bassotti G, Corazzi L. Enteric glial cells counteract Clostridium difficile Toxin B through a NADPH oxidase/ROS/JNK/caspase-3 axis, without involving mitochondrial pathways. Sci Rep 2017; 7:45569. [PMID: 28349972 PMCID: PMC5368562 DOI: 10.1038/srep45569] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 02/27/2017] [Indexed: 02/06/2023] Open
Abstract
Enteric glial cells (EGCs) are components of the intestinal epithelial barrier essential for regulating the enteric nervous system. Clostridium difficile is the most common cause of antibiotic-associated colitis, toxin B (TcdB) being the major virulence factor, due to its ability to breach the intestinal epithelial barrier and to act on other cell types. Here we investigated TcdB effects on EGCs and the activated molecular mechanisms. Already at 2 hours, TcdB triggered ROS formation originating from NADPH-oxidase, as demonstrated by their reduction in the presence of the NADPH-oxidase inhibitor ML171. Although EGCs mitochondria support almost completely the cellular ATP need, TcdB exerted weak effects on EGCs in terms of ATP and mitochondrial functionality, mitochondrial ROS production occurring as a late event. ROS activated the JNK signalling and overexpression of the proapoptotic Bim not followed by cytochrome c or AIF release to activate the downstream apoptotic cascade. EGCs underwent DNA fragmentation through activation of the ROS/JNK/caspase-3 axis, evidenced by the ability of ML171, N-acetylcysteine, and the JNK inhibitor SP600125 to inhibit caspase-3 or to contrast apoptosis. Therefore, TcdB aggressiveness towards EGCs is mainly restricted to the cytosolic compartment, which represents a peculiar feature, since TcdB primarily influences mitochondria in other cellular types.
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Affiliation(s)
- Lara Macchioni
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Magdalena Davidescu
- Scientific and educational center of Terni, University of Perugia, Perugia, Italy
| | - Katia Fettucciari
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Maya Petricciuolo
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Leonardo Gatticchi
- Scientific and educational center of Terni, University of Perugia, Perugia, Italy
| | - Davide Gioè
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | | | - Massimo Bellini
- Department of Gastroenterology, University of Pisa, Pisa, Italy
| | | | - Rita Roberti
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Gabrio Bassotti
- Department of Medicine, University of Perugia, Perugia, Italy
| | - Lanfranco Corazzi
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
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Bhattarai Y, Muniz Pedrogo DA, Kashyap PC. Irritable bowel syndrome: a gut microbiota-related disorder? Am J Physiol Gastrointest Liver Physiol 2017; 312:G52-G62. [PMID: 27881403 PMCID: PMC5283907 DOI: 10.1152/ajpgi.00338.2016] [Citation(s) in RCA: 204] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 11/07/2016] [Accepted: 11/16/2016] [Indexed: 01/31/2023]
Abstract
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders. Despite its prevalence, the pathophysiology of IBS is not well understood although multiple peripheral and central factors are implicated. Recent studies suggest a role for alterations in gut microbiota in IBS. Significant advances in next-generation sequencing technology and bioinformatics and the declining cost have now allowed us to better investigate the role of gut microbiota in IBS. In the following review, we propose gut microbiota as a unifying factor in the pathophysiology of IBS. We first describe how gut microbiota can be influenced by factors predisposing individuals to IBS such as host genetics, stress, diet, antibiotics, and early life experiences. We then highlight the known effects of gut microbiota on mechanisms implicated in the pathophysiology of IBS including disrupted gut brain axis (GBA), visceral hypersensitivity (VH), altered GI motility, epithelial barrier dysfunction, and immune activation. While there are several gaps in the field that preclude us from connecting the dots to establish causation, we hope this overview will allow us to identify and fill in the voids.
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Affiliation(s)
- Yogesh Bhattarai
- 1Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota; and ,2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - David A. Muniz Pedrogo
- 1Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota; and ,2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Purna C. Kashyap
- 1Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota; and ,2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Yamamoto M, Nishiyama M, Iizuka S, Suzuki S, Suzuki N, Aiso S, Nakahara J. Transient receptor potential vanilloid 1-immunoreactive signals in murine enteric glial cells. World J Gastroenterol 2016; 22:9752-9764. [PMID: 27956799 PMCID: PMC5124980 DOI: 10.3748/wjg.v22.i44.9752] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/19/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the possible involvement of transient receptor potential vanilloid 1 (TRPV1) in maturation of enteric glial cells (EGCs).
METHODS Immunohistochemical and immunocytochemical techniques were used to analyze EGC markers in myenteric plexus (MP) as well as cultured MP cells and EGCs using TRPV1 knockout (KO) mice.
RESULTS We detected TRPV1-immunoreactive signals in EGC in the MP of wild-type (WT) but not KO mice. Expression of glial fibrillary acidic protein (GFAP) immunoreactive signals was lower at postnatal day (PD) 6 in KO mice, though the difference was not clear at PD 13 and PD 21. When MP cells were isolated and cultured from isolated longitudinal muscle-MP preparation from WT and KO mice, the yield of KO EGC was lower than that of WT EGC, while the yield of KO and WT smooth muscle cells showed no difference. Addition of BCTC, a TRPV1 antagonist, to enriched EGC culture resulted in a decrease in the protein ratio of GFAP to S100B, another EGC/astrocyte-specific marker.
CONCLUSION These results address the possibility that TRPV1 may be involved in the maturation of EGC, though further studies are necessary to validate this possibility.
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Nikiforou M, Willburger C, de Jong AE, Kloosterboer N, Jellema RK, Ophelders DRMG, Steinbusch HWM, Kramer BW, Wolfs TGAM. Global hypoxia-ischemia induced inflammation and structural changes in the preterm ovine gut which were not ameliorated by mesenchymal stem cell treatment. Mol Med 2016; 22:244-257. [PMID: 27257938 PMCID: PMC5023518 DOI: 10.2119/molmed.2015.00252] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 04/11/2016] [Indexed: 12/13/2022] Open
Abstract
Perinatal asphyxia, a condition of impaired gas exchange during birth, leads to fetal hypoxia-ischemia (HI) and is associated with postnatal adverse outcomes including intestinal dysmotility and necrotizing enterocolitis (NEC). Evidence from adult animal models of transient, locally-induced intestinal HI has shown that inflammation is essential in HI-induced injury of the gut. Importantly, mesenchymal stem cell (MSC) treatment prevented this HI-induced intestinal damage. We therefore assessed whether fetal global HI induced inflammation, injury and developmental changes in the gut and whether intravenous MSC administration ameliorated these HI-induced adverse intestinal effects. In a preclinical ovine model, fetuses were subjected to umbilical cord occlusion (UCO), with or without MSC treatment, and sacrificed 7 days after UCO. Global HI increased the number of myeloperoxidase positive cells in the mucosa, upregulated mRNA levels of interleukin (IL)-1β and IL-17 in gut tissue and caused T-cell invasion in the intestinal muscle layer. Intestinal inflammation following global HI was associated with increased Ki67+ cells in the muscularis and subsequent muscle hyperplasia. Global HI caused distortion of glial fibrillary acidic protein immunoreactivity in the enteric glial cells and increased synaptophysin and serotonin expression in the myenteric ganglia. Intravenous MSC treatment did not ameliorate these HI-induced adverse intestinal events. Global HI resulted in intestinal inflammation and enteric nervous system abnormalities which are clinically associated with postnatal complications including feeding intolerance, altered gastrointestinal transit and NEC. The intestinal histopathological changes were not prevented by intravenous MSC treatment directly after HI, indicating that alternative treatment regimens for cell-based therapies should be explored.
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Affiliation(s)
- Maria Nikiforou
- Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Carolin Willburger
- Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Anja E de Jong
- Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Nico Kloosterboer
- Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Reint K Jellema
- Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Daan RMG Ophelders
- Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Harry WM Steinbusch
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Boris W Kramer
- Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
- School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Tim GAM Wolfs
- Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands
- School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
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Abstract
Functions of the gastrointestinal tract include motility, digestion and absorption of nutrients. These functions are mediated by several specialized cell types including smooth muscle cells, neurons, interstitial cells and epithelial cells. In gastrointestinal diseases, some of the cells become degenerated or fail to accomplish their normal functions. Surgical resection of the diseased segments of the gastrointestinal tract is considered the gold-standard treatment in many cases, but patients might have surgical complications and quality of life can remain low. Tissue engineering and regenerative medicine aim to restore, repair, or regenerate the function of the tissues. Gastrointestinal tissue engineering is a challenging process given the specific phenotype and alignment of each cell type that colonizes the tract - these properties are critical for proper functionality. In this Review, we summarize advances in the field of gastrointestinal tissue engineering and regenerative medicine. Although the findings are promising, additional studies and optimizations are needed for translational purposes.
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Affiliation(s)
- Khalil N Bitar
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way NE, Winston Salem, North Carolina 27101, USA.,Department of Molecular Medicine and Translational Sciences, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston Salem, North Carolina 27157, USA.,Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, 391 Technology Way NE, Winston Salem, North Carolina 27101, USA
| | - Elie Zakhem
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way NE, Winston Salem, North Carolina 27101, USA.,Department of Molecular Medicine and Translational Sciences, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston Salem, North Carolina 27157, USA
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Wu ZP, Zhang DK. Role of glial cell line-derived neurotrophic factor in intestinal inflammatory diseases. Shijie Huaren Xiaohua Zazhi 2016; 24:827-832. [DOI: 10.11569/wcjd.v24.i6.827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Glial cell line-derived neurotrophic factor (GDNF), a member of the neurotrophic factor family, promotes the survival, proliferation, migration, differentiation, and axonal growth of intestinal neurons. With studies on the role that enteric glia cells (EGCs) play in intestinal inflammation, GDNF has come into vision as an anti-inflammatory factor in the gut. Recent studies have gradually witnessed that, besides the role in protecting the intestinal epithelial barrier, GDNF plays an important part in a variety of protective mechanisms against intestinal inflammation, and has become the focus of numerous defense mechanisms in intestinal inflammation. GDNF also plays a very important role in the occurrence and development of intestinal inflammatory diseases. This review summarizes the results of recent studies in this field to fully discuss the roles of GDNF in the occurrence and development of intestinal inflammatory diseases.
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Capoccia E, Cirillo C, Gigli S, Pesce M, D’Alessandro A, Cuomo R, Sarnelli G, Steardo L, Esposito G. Enteric glia: A new player in inflammatory bowel diseases. Int J Immunopathol Pharmacol 2015; 28:443-51. [DOI: 10.1177/0394632015599707] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
In addition to the well-known involvement of macrophages and neutrophils, other cell types have been recently reported to substantially contribute to the onset and progression of inflammatory bowel diseases (IBD). Enteric glial cells (EGC) are the equivalent cell type of astrocyte in the central nervous system (CNS) and share with them many neurotrophic and neuro-immunomodulatory properties. This short review highlights the role of EGC in IBD, describing the role played by these cells in the maintenance of gut homeostasis, and their modulation of enteric neuronal activities. In pathological conditions, EGC have been reported to trigger and support bowel inflammation through the specific over-secretion of S100B protein, a pivotal neurotrophic factor able to induce chronic inflammatory changes in gut mucosa. New pharmacological tools that may improve the current therapeutic strategies for inflammatory bowel diseases (IBD), lowering side effects (i.e. corticosteroids) and costs (i.e. anti-TNFα monoclonal antibodies) represent a very important challenge for gastroenterologists and pharmacologists. Novel drugs capable to modulate enteric glia reactivity, limiting the pro-inflammatory release of S100B, may thus represent a significant innovation in the field of pharmacological interventions for inflammatory bowel diseases.
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Affiliation(s)
- E Capoccia
- Department of Physiology and Pharmacology ‘Vittorio Erspamer’, University Sapienza of Rome, P.le Aldo Moro 5, 00185, Rome, Italy
| | - C Cirillo
- Laboratory for Enteric NeuroScience (LENS), TARGID, KU Leuven, Herestraat 49, 3000, Leuven, Belgium
| | - S Gigli
- Department of Physiology and Pharmacology ‘Vittorio Erspamer’, University Sapienza of Rome, P.le Aldo Moro 5, 00185, Rome, Italy
| | - M Pesce
- Department of Clinical and Experimental Medicine, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy
| | - A D’Alessandro
- Department of Clinical and Experimental Medicine, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy
| | - R Cuomo
- Department of Clinical and Experimental Medicine, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy
| | - G Sarnelli
- Department of Clinical and Experimental Medicine, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy
| | - L Steardo
- Department of Physiology and Pharmacology ‘Vittorio Erspamer’, University Sapienza of Rome, P.le Aldo Moro 5, 00185, Rome, Italy
| | - G Esposito
- Department of Physiology and Pharmacology ‘Vittorio Erspamer’, University Sapienza of Rome, P.le Aldo Moro 5, 00185, Rome, Italy
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Finkbeiner SR, Freeman JJ, Wieck MM, El-Nachef W, Altheim CH, Tsai YH, Huang S, Dyal R, White ES, Grikscheit TC, Teitelbaum DH, Spence JR. Generation of tissue-engineered small intestine using embryonic stem cell-derived human intestinal organoids. Biol Open 2015; 4:1462-72. [PMID: 26459240 PMCID: PMC4728347 DOI: 10.1242/bio.013235] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Short bowel syndrome (SBS) is characterized by poor nutrient absorption due to a deficit of healthy intestine. Current treatment practices rely on providing supportive medical therapy with parenteral nutrition; while life saving, such interventions are not curative and are still associated with significant co-morbidities. As approaches to lengthen remaining intestinal tissue have been met with only limited success and intestinal transplants have poor survival outcomes, new approaches to treating SBS are necessary. Human intestine derived from embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs), called human intestinal organoids (HIOs), have the potential to offer a personalized and scalable source of intestine for regenerative therapies. However, given that HIOs are small three-dimensional structures grown in vitro, methods to generate usable HIO-derived constructs are needed. We investigated the ability of hESCs or HIOs to populate acellular porcine intestinal matrices and artificial polyglycolic/poly L lactic acid (PGA/PLLA) scaffolds, and examined the ability of matrix/scaffolds to thrive when transplanted in vivo. Our results demonstrate that the acellular matrix alone is not sufficient to instruct hESC differentiation towards an endodermal or intestinal fate. We observed that while HIOs reseed acellular porcine matrices in vitro, the HIO-reseeded matrices do not thrive when transplanted in vivo. In contrast, HIO-seeded PGA/PLLA scaffolds thrive in vivo and develop into tissue that looks nearly identical to adult human intestinal tissue. Our results suggest that HIO-seeded PGA/PLLA scaffolds are a promising avenue for developing the mucosal component of tissue engineered human small intestine, which need to be explored further to develop them into fully functional tissue. Summary: HIO-seeded PGA/PLLA scaffolds thrive in vivo and develop into tissue that looks nearly identical to adult human intestinal tissue. These scaffolds appear to be suitable for further tissue engineering approaches to develop functional intestine.
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Affiliation(s)
- Stacy R Finkbeiner
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Jennifer J Freeman
- Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA Department of Surgery, Section of Pediatric Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Minna M Wieck
- Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital, Los Angeles, CA, USA
| | - Wael El-Nachef
- Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital, Los Angeles, CA, USA
| | - Christopher H Altheim
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Yu-Hwai Tsai
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Sha Huang
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Rachel Dyal
- Department of Internal Medicine, Section of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Eric S White
- Department of Internal Medicine, Section of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Tracy C Grikscheit
- Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital, Los Angeles, CA, USA
| | - Daniel H Teitelbaum
- Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA Department of Surgery, Section of Pediatric Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Jason R Spence
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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Bassotti G, Antonelli E, Villanacci V, Baldoni M, Dore MP. Colonic motility in ulcerative colitis. United European Gastroenterol J 2014; 2:457-462. [PMID: 25452840 PMCID: PMC4245297 DOI: 10.1177/2050640614548096] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 07/23/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Inflammatory conditions affecting the gut may cause motility disturbances, and ulcerative colitis - one of the main disorders among the inflammatory bowel diseases - may display abnormal colonic motility. AIM To review the abnormalities of the large bowel in ulcerative colitis, by considering the motility, laboratory (in vitro) and pathological studies dealing with this topic. METHODS A comprehensive online search of Medline and the Science Citation Index was carried out. RESULTS Patients with ulcerative colitis frequently display colonic motor abnormalities, including lack of contractility, an increase of propulsive contractile waves, an excessive production of nitric oxide, vasoactive intestinal polypeptide nerves, interleukin 1 beta, neurotensin, tachykinins levels and the weaker action of substance P, likely related to a neuromuscular dysfunction due to the inflammatory process. CONCLUSIONS A better understanding of the pathophysiological grounds of altered colonic motility in ulcerative colitis may lead to a more in-depth knowledge of the accompanying symptoms and to better and more targeted therapeutic approaches.
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Affiliation(s)
- Gabrio Bassotti
- Gastroenterology Section, Department of Medicine, University of Perugia, Perugia, Italy
| | | | - Vincenzo Villanacci
- Pathology Section, Department of Molecular and Translational Medicine, Spedali Civili and University of Brescia, Italy
| | - Monia Baldoni
- Gastroenterology Section, Department of Medicine, University of Perugia, Perugia, Italy
| | - Maria Pina Dore
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
- Baylor College of Medicine, Houston, Texas, USA
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Neunlist M, Rolli-Derkinderen M, Latorre R, Van Landeghem L, Coron E, Derkinderen P, De Giorgio R. Enteric glial cells: recent developments and future directions. Gastroenterology 2014; 147:1230-7. [PMID: 25305504 DOI: 10.1053/j.gastro.2014.09.040] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 09/11/2014] [Accepted: 09/12/2014] [Indexed: 12/12/2022]
Abstract
Since their discovery at the end of the 19th century, enteric glial cells (EGCs), the major cellular component of the enteric nervous system, have long been considered mere supportive cells for neurons. However, recent evidence has challenged this view and highlighted their central role in the regulation of gut homeostasis as well as their implication in digestive and extradigestive diseases. In this review, we summarize emerging concepts as to how EGCs regulate neuromediator expression, exert neuroprotective roles, and even act as neuronal as well as glial progenitors in the enteric nervous system. A particularly crucial property of EGCs is their ability to maintain the integrity of the intestinal epithelial barrier, a role that may have important clinical implications not only for digestive diseases, such as postoperative ileus and inflammatory bowel diseases, but also for extradigestive diseases, such as Parkinson disease or obesity. EGCs could also contribute directly to disease processes (eg, inflammation) by their ability to secrete chemokines/cytokines in response to bacterial or inflammatory challenges. Defining the pleiotropic roles exerted by EGCs may reveal better knowledge and help develop new targeted therapeutic options for a variety of gastrointestinal diseases.
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Affiliation(s)
- Michel Neunlist
- INSERM Unité 913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, Nantes, France.
| | - Malvyne Rolli-Derkinderen
- INSERM Unité 913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Rocco Latorre
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Laurianne Van Landeghem
- INSERM Unité 913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Emmanuel Coron
- INSERM Unité 913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Pascal Derkinderen
- INSERM Unité 913, Nantes, France; Université Nantes, Nantes, France; CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, Nantes, France; Department of Neurology, CHU Nantes, Nantes, France
| | - Roberto De Giorgio
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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Yang W, Wang N, Shi X, Chen J. Synchronized dual pulse gastric electrical stimulation induces activation of enteric glial cells in rats with diabetic gastroparesis. Gastroenterol Res Pract 2014; 2014:964071. [PMID: 24860604 PMCID: PMC4003764 DOI: 10.1155/2014/964071] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 03/09/2014] [Accepted: 03/10/2014] [Indexed: 12/23/2022] Open
Abstract
Objective. The aims of this study were to investigate the effects of synchronized dual pulse gastric electrical stimulation (SGES) on gastric motility in different periods for diabetic rats and try to explore the possible mechanisms of the effects. Methods. Forty-six rats were used in the study. Gastric slow waves were recorded at baseline, 7-14-day diabetes and 56-63-day diabetes before and after stimulation and the age-matched control groups. SGES-60 mins and SGES-7 days (60 mins/day) were performed to test the effects on gastric motility and to evaluate glial marker S100B expression in stomach. Results. (1) Gastric emptying was accelerated in 7-14-day diabetes and delayed in 56-63-day diabetes. (2) The S100B expression in 56-63-day diabetes decreased and the ultrastructure changed. (3) The age-associated loss of EGC was observed in 56-63-day control group. (4) SGES was able to not only accelerate gastric emptying but also normalize gastric slow waves. (5) The S100B expression increased after SGES and the ultrastructure of EGC was partially restored. The effect of SGES-7 days was superior to SGES-60 mins. Conclusions. Delayed gastric emptying due to the growth of age may be related to the EGC inactivation. The effects of the SGES on gastric motility may be associated with EGC activation.
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Affiliation(s)
- Wei Yang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Nian Wang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xue Shi
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jie Chen
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Bassotti G, Villanacci V, Creƫoiu D, Creƫoiu SM, Becheanu G. Cellular and molecular basis of chronic constipation: taking the functional/idiopathic label out. World J Gastroenterol 2013; 19:4099-4105. [PMID: 23864772 PMCID: PMC3710411 DOI: 10.3748/wjg.v19.i26.4099] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 05/16/2013] [Accepted: 05/18/2013] [Indexed: 02/06/2023] Open
Abstract
In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called "functional" or "idiopathic" disease, where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have, in fact, be reconducted to an organic basis (or, at the very least, have shown one or more demonstrable abnormalities). This is particularly true, for instance, for irritable bowel syndrome, the prototype entity of "functional" gastrointestinal disorders, where low-grade inflammation of both mucosa and myenteric plexus has been repeatedly demonstrated. Thus, researchers have also investigated other functional/idiopathic gastrointestinal disorders, and found that some organic ground is present, such as abnormal neurotransmission and myenteric plexitis in esophageal achalasia and mucosal immune activation and mild eosinophilia in functional dyspepsia. Here we show evidence, based on our own and other authors' work, that chronic constipation has several abnormalities reconductable to alterations in the enteric nervous system, abnormalities mainly characterized by a constant decrease of enteric glial cells and interstitial cells of Cajal (and, sometimes, of enteric neurons). Thus, we feel that (at least some forms of) chronic constipation should no more be considered as a functional/idiopathic gastrointestinal disorder, but instead as a true enteric neuropathic abnormality.
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Antonioli L, Colucci R, Pellegrini C, Giustarini G, Tuccori M, Blandizzi C, Fornai M. The role of purinergic pathways in the pathophysiology of gut diseases: pharmacological modulation and potential therapeutic applications. Pharmacol Ther 2013; 139:157-88. [PMID: 23588157 DOI: 10.1016/j.pharmthera.2013.04.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 03/15/2013] [Indexed: 02/08/2023]
Abstract
Gut homeostasis results from complex neuro-immune interactions aimed at triggering stereotypical and specific programs of coordinated mucosal secretion and powerful motor propulsion. A prominent role in the regulation of this highly integrated network, comprising a variety of immune/inflammatory cells and the enteric nervous system, is played by purinergic mediators. The cells of the digestive tract are literally plunged into a "biological sea" of functionally active nucleotides and nucleosides, which carry out the critical task of driving regulatory interventions on cellular functions through the activation of P1 and P2 receptors. Intensive research efforts are being made to achieve an integrated view of the purinergic system, since it is emerging that the various components of purinergic pathways (i.e., enzymes, transporters, mediators and receptors) are mutually linked entities, deputed to finely modulating the magnitude and the duration of purinergic signaling, and that alterations occurring in this balanced network could be intimately involved in the pathophysiology of several gut disorders. This review article intends to provide a critical appraisal of current knowledge on the purinergic system role in the regulation of gastrointestinal functions, considering these pathways as a whole integrated network, which is capable of finely controlling the levels of bioactive nucleotides and nucleosides in the biophase of their respective receptors. Special attention is paid to the mechanisms through which alterations in the various compartments of the purinergic system could contribute to the pathophysiology of gut disorders, and to the possibility of counteracting such dysfunctions by means of pharmacological interventions on purinergic molecular targets.
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Affiliation(s)
- Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Italy.
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Dietary restriction interferes with oxidative status and intrinsic intestinal innervation in aging rats. Nutrition 2013; 29:673-80. [PMID: 23317927 DOI: 10.1016/j.nut.2012.09.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 08/20/2012] [Accepted: 09/24/2012] [Indexed: 02/06/2023]
Abstract
OBJECTIVES To evaluate the effects of dietary restriction on oxidative status, the HuC/D-neuronal nitric oxide synthase (nNOS) myenteric neuron population, HuC/D-S100 glial cells, and the morphometry of the small intestine in rats at various ages. METHODS Fifteen Wistar rats were divided into 7-and 12-mo-old control groups and a 12-mo-old experimental group subjected to dietary restrictions (50% of normal ration) for 5 mo. At 7 and 12 mo of age, the animals were anesthetized, and blood was collected to assess the biochemical components and oxidative status. Ileum samples were subjected to double-marker (HuC/D-nNOS and HuC/D-S100) immunostaining and histologic processing to morphometrically analyze intestinal wall elements and determine the metaphase index and rate of caliciform cells. The data were subjected to analysis of variance and the Tukey post hoc test with a 5% significance level. RESULTS Age affected the oxidative status by increasing lipid peroxidation, with no effect on blood components, intrinsic innervation, and intestinal wall elements. The animals subjected to dietary restriction showed improved levels of total cholesterol, triacylglycerols, and oxidative status, with no changes in the nNOS neuron population. However, the dietary restriction dramatically decreased the glial and HuC/D myenteric populations, led to atrophy of the neuronal cell body, induced glial hypertrophy, and decreased the thickness of the intestinal wall. CONCLUSION The high oxidative status of the aging animals was reversed by dietary restriction, which also lowered cholesterol and triacylglycerol levels. The present dietary restriction elicited morpho-quantitative changes in the myenteric plexus and histology of the ileum, with likely effects on intestinal functions.
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De Giorgio R, Giancola F, Boschetti E, Abdo H, Lardeux B, Neunlist M. Enteric glia and neuroprotection: basic and clinical aspects. Am J Physiol Gastrointest Liver Physiol 2012; 303:G887-93. [PMID: 22878122 DOI: 10.1152/ajpgi.00096.2012] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The enteric nervous system (ENS), a major regulatory system for gastrointestinal function, is composed of neurons and enteric glial cells (EGCs). Enteric glia have long been thought to provide only structural support to neurons. However, recent evidence indicates enteric glia-neuron cross talk significantly contributes to neuronal maintenance, survival, and function. Thus damage to EGCs may trigger neurodegenerative processes thought to play a role in gastrointestinal dysfunctions and symptoms. The purpose of this review is to provide an update on EGCs, particularly focusing on their possible neuroprotective features and the resultant enteric neuron abnormalities subsequent to EGC damage. These neuroprotective mechanisms may have pathogenetic relevance in a variety of functional and inflammatory gut diseases. Basic and clinical (translational) studies support a neuroprotective role mediated by EGCs. Different models have been developed to test whether selective EGC damage/ablation has an impact on gut functions and the ENS. Preclinical data indicated that selective EGC alterations were associated with changes in gut physiology related to enteric neuron abnormalities. In humans, a substantial loss of EGCs was described in patients with various functional and/or inflammatory gastrointestinal diseases. However, whether EGC changes precede or follow neuronal degeneration and loss and how this damage occurs is not defined. Additional studies on EGC neuroprotective capacity are expected to improve knowledge of gut diseases and pave the way for targeted therapeutic strategies of underlying neuropathies.
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Affiliation(s)
- Roberto De Giorgio
- Department of Clinical Medicine and Digestive Diseases and Internal Medicine, 40138 Bologna, Italy.
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Colonic inflammation in Parkinson's disease. Neurobiol Dis 2012; 50:42-8. [PMID: 23017648 DOI: 10.1016/j.nbd.2012.09.007] [Citation(s) in RCA: 451] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 08/28/2012] [Accepted: 09/15/2012] [Indexed: 02/06/2023] Open
Abstract
Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and data from recent genetic studies suggest a link between PD and gut inflammation. We therefore undertook the present survey to investigate whether gastrointestinal inflammation occurs in PD patients. Nineteen PD patients and 14 age-matched healthy controls were included. For each PD patients, neurological and gastrointestinal symptoms were assessed using the Unified Parkinson's Disease Rating Scale part III and the Rome III questionnaire, respectively and cumulative lifetime dose of L-dopa was calculated. Four biopsies were taken from the ascending colon during the course of a total colonoscopy in controls and PD patients. The mRNA expression levels of pro-inflammatory cytokines (tumor necrosis factor alpha, interferon gamma, interleukin-6 and interleukin-1 beta) and glial marker (Glial fibrillary acidic protein, Sox-10 and S100-beta) were analyzed using real-time PCR in two-pooled biopsies. Immunohistochemical analysis was performed on the two remaining biopsies using antibodies against phosphorylated alpha-synuclein to detect Lewy pathology. The mRNA expression levels of pro-inflammatory cytokines as well as of two glial markers (Glial fibrillary acidic protein and Sox-10) were significantly elevated in the ascending colon of PD patients with respect to controls. The levels of tumor necrosis factor alpha, interferon gamma, interleukin-6, interleukin-1 beta and Sox-10 were negatively correlated with disease duration. By contrast, no correlations were found between the levels of pro-inflammatory cytokines or glial markers and disease severity, gastrointestinal symptoms or cumulative lifetime dose of L-dopa. There was no significant difference in the expression of pro-inflammatory cytokines or glial marker between patients with and without enteric Lewy pathology. Our findings provide evidence that enteric inflammation occurs in PD and further reinforce the role of peripheral inflammation in the initiation and/or the progression of the disease.
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Bagyánszki M, Bódi N. Diabetes-related alterations in the enteric nervous system and its microenvironment. World J Diabetes 2012; 3:80-93. [PMID: 22645637 PMCID: PMC3360223 DOI: 10.4239/wjd.v3.i5.80] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 04/06/2012] [Accepted: 05/11/2012] [Indexed: 02/05/2023] Open
Abstract
Gastric intestinal symptoms common among diabetic patients are often caused by intestinal motility abnormalities related to enteric neuropathy. It has recently been demonstrated that the nitrergic subpopulation of myenteric neurons are especially susceptible to the development of diabetic neuropathy. Additionally, different susceptibility of nitrergic neurons located in different intestinal segments to diabetic damage and their different levels of responsiveness to insulin treatment have been revealed. These findings indicate the importance of the neuronal microenvironment in the pathogenesis of diabetic nitrergic neuropathy. The main focus of this review therefore was to summarize recent advances related to the diabetes-related selective nitrergic neuropathy and associated motility disturbances. Special attention was given to the findings on capillary endothelium and enteric glial cells. Growing evidence indicates that capillary endothelium adjacent to the myenteric ganglia and enteric glial cells surrounding them are determinative in establishing the ganglionic microenvironment. Additionally, recent advances in the development of new strategies to improve glycemic control in type 1 and type 2 diabetes mellitus are also considered in this review. Finally, looking to the future, the recent and promising results of metagenomics for the characterization of the gut microbiome in health and disease such as diabetes are highlighted.
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Affiliation(s)
- Mária Bagyánszki
- Mária Bagyánszki, Nikolett Bódi, Department of Physiology, Anatomy and Neuroscience, Faculty of Science, University of Szeged, H-6726 Szeged, Hungary
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Chuenkova MV, Pereiraperrin M. Neurodegeneration and neuroregeneration in Chagas disease. ADVANCES IN PARASITOLOGY 2011; 76:195-233. [PMID: 21884893 DOI: 10.1016/b978-0-12-385895-5.00009-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Autonomic dysfunction plays a significant role in the development of chronic Chagas disease (CD). Destruction of cardiac parasympathetic ganglia can underlie arrhythmia and heart failure, while lesions of enteric neurons in the intestinal plexuses are a direct cause of aperistalsis and megasyndromes. Neuropathology is generated by acute infection when the parasite, though not directly damaging to neuronal cells, elicits immune reactions that can become cytotoxic, inducing oxidative stress and neurodegeneration. Anti-neuronal autoimmunity may further contribute to neuropathology. Much less clear is the mechanism of subsequent neuronal regeneration in patients that survive acute infection. Morphological and functional recovery of the peripheral neurons in these patients correlates with the absence of CD clinical symptoms, while persistent neuronal deficiency is observed for the symptomatic group. The discovery that Trypanosoma cruzi trans-sialidase can moonlight as a parasite-derived neurotrophic factor (PDNF) suggests that the parasite might influence the balance between neuronal degeneration and regeneration. PDNF functionally mimics mammalian neurotrophic factors in that it binds and activates neurotrophin Trk tyrosine kinase receptors, a mechanism which prevents neurodegeneration. PDNF binding to Trk receptors triggers PI3K/Akt/GSK-3β and MAPK/Erk/CREB signalling cascades which in neurons translates into resistance to oxidative and nutritional stress, and inhibition of apoptosis, whereas in the cytoplasm of infected cells, PDNF represents a substrate-activator of the host Akt kinase, enhancing host-cell survival until completion of the intracellular cycle of the parasite. Such dual activity of PDNF provides sustained activation of survival mechanisms which, while prolonging parasite persistence in host tissues, can underlie distinct outcomes of CD.
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Affiliation(s)
- Marina V Chuenkova
- Department of Pathology and Sackler School of Graduate Students, Tufts University School of Medicine, Boston, Massachusetts, USA
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