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Yuan PQ, Li T, Mahurkar-Joshi S, Sohn J, Chang L, Taché Y. Three-dimensional imaging and computational quantitation as a novel approach to assess nerve fibers, enteric glial cells, mast cells, and the proximity of mast cells to the nerve fibers in human sigmoid mucosal biopsies from healthy subjects. J Neurosci Methods 2025; 418:110436. [PMID: 40180160 DOI: 10.1016/j.jneumeth.2025.110436] [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: 12/20/2024] [Revised: 03/14/2025] [Accepted: 03/24/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND The visualization and quantitation of nerve fibers (NFs), enteric glial cells (EGCs), mast cells (MCs), and their spatial configurations in the human colonic mucosa represent considerable challenges due to the meshed network of these components and the arborizing of NFs in a three-dimensional (3D) structure. NEW METHOD We developed a novel approach combining tissue clearing, 3D imaging and computerized quantitation of NFs, EGCs and MCs in sigmoid mucosal biopsies of healthy subjects using a modified CLARITY tissue clearing protocol and adapting Imaris Surfaces Rendering Technology. RESULTS The cleared colonic biopsies are compatible with immunostaining using 10 marker antibodies and capable of generating 3D images rendering clear spatial views and computational quantitation of NFs, MCs, EGCs, in particular the proximity of MCs to NFs with Imaris 9.7-9.9. COMPARISON WITH EXISTING METHODS Our modified tissue clearing protocol shortened the membrane lipid removal time to 1 day from the original 1-2 weeks and total tissue clearing time to 3-4 days from the original 2-4 weeks. The 3D images displayed a clear spatial landscape of NFs, MCs and EGCs in the biopsies which cannot be portrayed with 2D images acquired from sections. Computerized quantitation is faster than measuring manually, allowing us to quantify a larger number of samples with less bias. CONCLUSION The novel approach enables faster tissue clearing/immunolabeling, high-quality 3D imaging and precise computational quantitation of NFs, cells and proximity of MCs to NFs in human sigmoid biopsies which may allow new insight to detect alterations in colonic-related diseases.
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Affiliation(s)
- Pu-Qing Yuan
- Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, UCLA, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
| | - Tao Li
- Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, UCLA, USA
| | - Swapna Mahurkar-Joshi
- Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, UCLA, USA; G Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, UCLA, USA
| | - Jessica Sohn
- Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, UCLA, USA; G Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, UCLA, USA
| | - Lin Chang
- Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, UCLA, USA; G Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, UCLA, USA
| | - Yvette Taché
- Digestive Diseases Research Center, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, UCLA, USA; G Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine, UCLA, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
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Meng MY, Paine LW, Sagnat D, Bello I, Oldroyd S, Javid F, Harper MT, Hockley JRF, St John Smith E, Owens RM, Alric L, Buscail E, Welsh F, Vergnolle N, Bulmer DC. TRPV4 stimulates colonic afferents through mucosal release of ATP and glutamate. Br J Pharmacol 2025; 182:1324-1340. [PMID: 39626870 DOI: 10.1111/bph.17408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 02/11/2025] Open
Abstract
BACKGROUND AND PURPOSE Abdominal pain is a leading cause of morbidity for people living with gastrointestinal disease. Whereas the transient receptor potential vanilloid 4 (TRPV4) ion channel has been implicated in the pathogenesis of abdominal pain, the relative paucity of TRPV4 expression in colon-projecting sensory neurons suggests that non-neuronal cells may contribute to TRPV4-mediated nociceptor stimulation. EXPERIMENTAL APPROACH Changes in murine colonic afferent activity were examined using ex vivo electrophysiology in tissues with the gut mucosa present or removed. ATP and glutamate release were measured by bioluminescence assays from human colon organoid cultures and mouse colon. Dorsal root ganglion sensory neuron activity was evaluated by Ca2+ imaging when cultured alone or co-cultured with colonic mucosa. KEY RESULTS Bath application of TRPV4 agonist GSK1016790A elicited a robust increase in murine colonic afferent activity, which was abolished by removing the gut mucosa. GSK1016790A promoted ATP and glutamate release from human colon organoid cultures and mouse colon. Inhibition of ATP degradation in mouse colon enhanced the afferent response to GSK1016790A. Pretreatment with purinoceptor or glutamate receptor antagonists attenuated and abolished the response to GSK1016790A when given alone or in combination, respectively. Sensory neurons co-cultured with colonic mucosal cells produced a marked increase in intracellular Ca2+ to GSK1016790A compared with neurons cultured alone. CONCLUSION AND IMPLICATIONS Our data indicate that mucosal release of ATP and glutamate is responsible for the stimulation of colonic afferents following TRPV4 activation. These findings highlight an opportunity to target the gut mucosa for the development of new visceral analgesics.
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Affiliation(s)
- Michelle Y Meng
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Luke W Paine
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - David Sagnat
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
| | - Ivana Bello
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Sophie Oldroyd
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
| | - Farideh Javid
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, UK
| | - Matthew T Harper
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | | | | | - Róisín M Owens
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
| | - Laurent Alric
- Internal Medicine Department of Digestive Disease, CHU Toulouse-Rangueil and Université de Toulouse, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
| | - Etienne Buscail
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
- Department of Surgery, CHU Toulouse-Rangueil and Université de Toulouse, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
| | - Fraser Welsh
- BioPharmaceuticals R&D, AstraZeneca, Neuroscience, Cambridge, UK
| | - Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France
- Department of Physiology and Pharmacology, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - David C Bulmer
- Department of Pharmacology, University of Cambridge, Cambridge, UK
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Ten Barge JA, van den Bosch GE, Slater R, van den Hoogen NJ, Reiss IKM, Simons SHP. Visceral Pain in Preterm Infants with Necrotizing Enterocolitis: Underlying Mechanisms and Implications for Treatment. Paediatr Drugs 2025; 27:201-220. [PMID: 39752054 PMCID: PMC11829917 DOI: 10.1007/s40272-024-00676-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2024] [Indexed: 01/04/2025]
Abstract
Necrotizing enterocolitis (NEC) is a relatively rare but very severe gastrointestinal disease primarily affecting very preterm infants. NEC is characterized by excessive inflammation and ischemia in the intestines, and is associated with prolonged, severe visceral pain. Despite its recognition as a highly painful disease, current pain management for NEC is often inadequate, and research on optimal analgesic therapy for these patients is lacking. Insight into the mechanisms underlying intestinal pain in infants with NEC-visceral pain-could help identify the most effective analgesics for these vulnerable patients. Therefore, this comprehensive review aims to provide an overview of visceral nociception, including transduction, transmission, modulation, and experience, and discuss the implications for analgesic therapy in preterm infants with NEC. The transmission of visceral pain differs from that of somatic pain, contributing to the diffuse nature of visceral pain. Studies evaluating the effectiveness of analgesics for treating visceral pain in infants are scarce. However, research in visceral pain models highlights agents that may be particularly effective for treating visceral pain based on their mechanisms of action. Further research is necessary to determine whether agents that have shown promise for treating visceral pain in preclinical studies and adults are effective in infants with NEC as well.
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Affiliation(s)
- Judith A Ten Barge
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
| | - Gerbrich E van den Bosch
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
| | | | | | - Irwin K M Reiss
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Sinno H P Simons
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
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Decraecker L, Cuende Estévez M, Van Remoortel S, Quan R, Stakenborg N, Wang Z, De Marco E, Denadai-Souza A, Viola MF, Garcia Caraballo S, Brierley S, Tsukimi Y, Hicks G, Winchester W, Wykosky J, Fanjul A, Gibson T, Wouters M, Vanden Berghe P, Hussein H, Boeckxstaens G. Characterisation of MRGPRX2 + mast cells in irritable bowel syndrome. Gut 2025:gutjnl-2024-334037. [PMID: 39988359 DOI: 10.1136/gutjnl-2024-334037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 02/11/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND Mast cell activation is an important driver of abdominal pain in irritable bowel syndrome (IBS). While evidence supports the role of IgE-mediated mast cell activation in visceral pain development in IBS, the role of pseudoallergic MRGPRX2-mediated mast cell activation in this process remains unknown. OBJECTIVE We investigated whether MRGPRX2-mediated mast cell activation plays a role in abdominal pain development in patients with IBS. DESIGN MRGPRX2 expression in mast cells and other immune cells was characterised across colon layers using flow cytometry. We evaluated whether MRGPRX2 agonists trigger mast cell degranulation and transient receptor potential vanilloid 1 (TRPV1) sensitisation in healthy human colonic submucosal plexus samples using live imaging. Rectal biopsies were then collected from patients with IBS and healthy volunteers (HV) and MRGPRX2+ mast cell frequency, MRGPRX2 expression per cell, mast cell degranulation kinetics in response to MRGPRX2 agonists, MRGPRX2 agonistic activity and presence of MRGPRX2 agonists in biopsy supernatants were assessed. RESULTS MRGPRX2+ mast cells are enriched in the submucosa and muscularis of the healthy human colon. MRGPRX2 agonists induce mast cell degranulation and TRPV1 sensitisation in the healthy colon submucosa. While the frequency of rectal MRGPRX2+ mast cells was unaltered in IBS, submucosal mast cells showed increased degranulation in response to MRGPRX2 agonists in IBS compared with HV. MRGPRX2 agonistic activity was increased in IBS rectal biopsy supernatant compared with HV, which was associated with increased levels of substance P. CONCLUSION The MRGPRX2 pathway is functionally upregulated in the colon of patients with IBS, supporting its role in abdominal pain in IBS.
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Affiliation(s)
- Lisse Decraecker
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - María Cuende Estévez
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - Samuel Van Remoortel
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - Runze Quan
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - Nathalie Stakenborg
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - Zheng Wang
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - Elisabetta De Marco
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - Alexandre Denadai-Souza
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - Maria Francesca Viola
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - Sonia Garcia Caraballo
- Visceral Pain Research Group, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute Limited, Adelaide, South Australia, Australia
- Faculty of Health and Medical Sciences, The University of Adelaide - North Terrace Campus, Adelaide, South Australia, Australia
| | - Stuart Brierley
- Visceral Pain Research Group, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute Limited, Adelaide, South Australia, Australia
- Faculty of Health and Medical Sciences, The University of Adelaide - North Terrace Campus, Adelaide, South Australia, Australia
| | | | - Gareth Hicks
- Takeda Pharmaceutical Company Limited, Osaka, Japan
| | | | - Jill Wykosky
- Takeda Pharmaceutical Company Limited, Osaka, Japan
| | | | - Tony Gibson
- Takeda Pharmaceutical Company Limited, Osaka, Japan
| | - Mira Wouters
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - Pieter Vanden Berghe
- Laboratory for Enteric Neuroscience (LENS), Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium, KU Leuven, Leuven, Flanders, Belgium
| | - Hind Hussein
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
| | - Guy Boeckxstaens
- Center for Intestinal Neuroimmune Interactions, Translational Research in GastroIntestinal Disorders (TARGID), Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven Biomedical Sciences Group, Leuven, Flanders, Belgium
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Yu LCH. Gastrointestinal pathophysiology in long COVID: Exploring roles of microbiota dysbiosis and serotonin dysregulation in post-infectious bowel symptoms. Life Sci 2024; 358:123153. [PMID: 39454992 DOI: 10.1016/j.lfs.2024.123153] [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: 08/27/2024] [Revised: 10/01/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024]
Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered an unprecedented public health crisis known as the coronavirus disease 2019 (COVID-19) pandemic. Gastrointestinal (GI) symptoms develop in patients during acute infection and persist after recovery from airway distress in a chronic form of the disease (long COVID). A high incidence of irritable bowel syndrome (IBS) manifested by severe abdominal pain and defecation pattern changes is reported in COVID patients. Although COVID is primarily considered a respiratory disease, fecal shedding of SARS-CoV-2 antigens positively correlates with bowel symptoms. Active viral infection in the GI tract was identified by human intestinal organoid studies showing SARS-CoV-2 replication in gut epithelial cells. In this review, we highlight the key findings in post-COVID bowel symptoms and explore possible mechanisms underlying the pathophysiology of the illness. These mechanisms include mucosal inflammation, gut barrier dysfunction, and microbiota dysbiosis during viral infection. Viral shedding through the GI route may be the primary factor causing the alteration of the microbiome ecosystem, particularly the virome. Recent evidence in experimental models suggested that microbiome dysbiosis could be further aggravated by epithelial barrier damage and immune activation. Moreover, altered microbiota composition has been associated with dysregulated serotonin pathways, resulting in intestinal nerve hypersensitivity. These mechanisms may explain the development of post-infectious IBS-like symptoms in long COVID. Understanding how coronavirus infection affects gut pathophysiology, including microbiome changes, would benefit the therapeutic advancement for managing post-infectious bowel symptoms.
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Affiliation(s)
- Linda Chia-Hui Yu
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
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Liu D, Mao M, Liu W, Xie L, Zhong X, Cao W, Chen L. The Role of the TRPV4 Channel in Intestinal Physiology and Pathology. J Inflamm Res 2024; 17:9307-9317. [PMID: 39588136 PMCID: PMC11587805 DOI: 10.2147/jir.s483350] [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: 06/19/2024] [Accepted: 11/06/2024] [Indexed: 11/27/2024] Open
Abstract
The transient receptor potential vanilloid 4 channel (TRPV4) is an important member of the TRP superfamily of cation channels. The channel can be activated by different physical and chemical stimuli, such as heat, osmotic, and mechanical stress. It regulates the release of nociceptive peptides (substance P and calcitonin gene-related peptide), and mediates neurogenic inflammation, which indicates the involvement of TRPV4 as a nociceptor. Previous studies show that TRPV4 regulates the contraction of intestinal smooth muscle, mucosal barrier permeability, intestinal ion transport, activation of submucosal enteric neurons, and generation of immune cells. TRPV4 is involved in various pathophysiological activities, and altered TRPV4 expression has been detected in some intestinal diseases (IBD, IBS, intestinal tumors, etc). Evidence indicates that TRPV4 plays a noxious role in intestinal barrier function when the intestine is damaged. This review focuses on the role of the TRPV4 channel in the physiological and pathological functions of the intestine, and evaluates the potential clinical significance to target TRPV4 channel in the treatment of intestinal diseases.
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Affiliation(s)
- Dandan Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Mingli Mao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Wenjia Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Lihua Xie
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Xiaolin Zhong
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Wenyu Cao
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
| | - Ling Chen
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China
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Yang D, Bai R, Li C, Sun Y, Jing H, Wang Z, Chen Y, Dong Y. Early-Life Stress Induced by Neonatal Maternal Separation Leads to Intestinal 5-HT Accumulation and Causes Intestinal Dysfunction. J Inflamm Res 2024; 17:8945-8964. [PMID: 39588137 PMCID: PMC11586501 DOI: 10.2147/jir.s488290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 11/14/2024] [Indexed: 11/27/2024] Open
Abstract
Background The early childhood period is a critical development stage, and experiencing stress during this time may increase the risk of gastrointestinal disorders, including irritable bowel syndrome (IBS). Neonatal maternal separation (NMS) in rodent models has been shown to cause bowel dysfunctions similar to IBS, and 5-HT is considered to be a key regulator regulating intestinal function, but the precise underlying mechanisms remain unclear. Results We established a maternal separation stress mouse model to simulate early-life stress, exploring the expression patterns of 5-HT under chronic stress and its mechanisms affecting gut function. We observed a significant increase in 5-HT expression due to NMS, leading to disruptions in intestinal structure and function. However, inhibiting 5-HT reversed these effects, suggesting its potential as a therapeutic target. Furthermore, our research revealed that excess 5-HT in mice with early life stress increased intestinal neural network density and promoted excitatory motor neuron expression. Mechanistically, 5-HT activated the Wnt signaling pathway through the 5-HT4 receptor, promoting neurogenesis within the intestinal nervous system. Conclusion These findings shed light on the intricate changes induced by early life stress in the intestines, confirming the regulatory role of 5-HT in the enteric nervous system and providing potential insights for the development of novel therapies for gastrointestinal disorders.
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Affiliation(s)
- Ding Yang
- College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Rulan Bai
- College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Chengzhong Li
- Department of Horticulture and Landscape Architecture, Jiangsu Agri-Animal Husbandry Vocational College, Taizhou, People’s Republic of China
| | - Yan Sun
- Department of Horticulture and Landscape Architecture, Jiangsu Agri-Animal Husbandry Vocational College, Taizhou, People’s Republic of China
| | - Hongyu Jing
- College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Zixu Wang
- College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Yaoxing Chen
- College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Yulan Dong
- College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
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8
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Van Remoortel S, Hussein H, Boeckxstaens G. Mast cell modulation: A novel therapeutic strategy for abdominal pain in irritable bowel syndrome. Cell Rep Med 2024; 5:101780. [PMID: 39378882 PMCID: PMC11513802 DOI: 10.1016/j.xcrm.2024.101780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/10/2024] [Accepted: 09/17/2024] [Indexed: 10/10/2024]
Abstract
Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders characterized by recurrent abdominal pain and an altered defecation pattern. Chronic abdominal pain represents the hallmark IBS symptom and is reported to have the most bothersome impact on the patient's quality of life. Unfortunately, effective therapeutic strategies reducing abdominal pain are lacking, mainly attributed to a limited understanding of the contributing mechanisms. In the past few years, exciting new insights have pointed out that altered communication between gut immune cells and pain-sensing nerves acts as a hallmark driver of IBS-related abdominal pain. In this review, we aim to summarize our current knowledge on altered neuro-immune crosstalk as the main driver of altered pain signaling, with a specific focus on altered mast cell functioning herein, and highlight the relevance of targeting mast cell-mediated mechanisms as a novel therapeutic strategy for chronic abdominal pain in IBS patients.
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Affiliation(s)
- Samuel Van Remoortel
- Translational Research Centre for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Hind Hussein
- Translational Research Centre for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Guy Boeckxstaens
- Translational Research Centre for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
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9
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Hussein H, Van Remoortel S, Boeckxstaens GE. Irritable bowel syndrome: When food is a pain in the gut. Immunol Rev 2024; 326:102-116. [PMID: 39037230 DOI: 10.1111/imr.13374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
Irritable bowel syndrome (IBS) is a chronic gastrointestinal condition associated with altered bowel habits and recurrent abdominal pain, often triggered by food intake. Current treatments focus on improving stool pattern, but effective treatments for pain in IBS are still lacking due to our limited understanding of pathophysiological mechanisms. Visceral hypersensitivity (VHS), or abnormal visceral pain perception, underlies abdominal pain development in IBS, and mast cell activation has been shown to play an important role in the development of VHS. Our work recently revealed that abdominal pain in response to food intake is induced by the sensitization of colonic pain-sensing neurons by histamine produced by activated mast cells following a local IgE response to food. In this review, we summarize the current knowledge on abdominal pain and VHS pathophysiology in IBS, we outline the work leading to the discovery of the role of histamine in abdominal pain, and we introduce antihistamines as a novel treatment option to manage chronic abdominal pain in patients with IBS.
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Affiliation(s)
- Hind Hussein
- Center for Intestinal Neuro-Immune Interactions, Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Samuel Van Remoortel
- Center for Intestinal Neuro-Immune Interactions, Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Center for Intestinal Neuro-Immune Interactions, Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
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10
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Guo R, Gao S, Feng X, Liu H, Ming X, Sun J, Luan X, Liu Z, Liu W, Guo F. The GABAergic pathway from anterior cingulate cortex to lateral hypothalamus area regulates irritable bowel syndrome in mice and its underlying mechanism. J Neurochem 2024; 168:2814-2831. [PMID: 38877776 DOI: 10.1111/jnc.16150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 06/16/2024]
Abstract
Irritable bowel syndrome (IBS), which is characterized by chronic abdominal pain, has a high global prevalence. The anterior cingulate cortex (ACC), which is a pivotal region involved in pain processing, should be further investigated regarding its role in the regulation of visceral sensitivity and mental disorders. A C57BL/6J mouse model for IBS was established using chronic acute combining stress (CACS). IBS-like symptoms were assessed using behavioral tests, intestinal motility measurements, and abdominal withdrawal reflex scores. Fluoro-Gold retrograde tracing and immunohistochemistry techniques were employed to investigate the projection of ACC gamma-aminobutyric acid-producing (GABAergic) neurons to the lateral hypothalamus area (LHA). Chemogenetic approaches enabled the selective activation or inhibition of the ACC-LHA GABAergic pathway. Enzyme-linked immunosorbent assay (ELISA) and western blot analyses were conducted to determine the expression of histamine, 5-hydroxytryptamine (5-HT), and transient receptor potential vanilloid 4 (TRPV4). Our findings suggest that CACS induced IBS-like symptoms in mice. The GABA type A receptors (GABAAR) within LHA played a regulatory role in modulating IBS-like symptoms. The chemogenetic activation of ACC-LHA GABAergic neurons elicited anxiety-like behaviors, intestinal dysfunction, and visceral hypersensitivity in normal mice; however, these effects were effectively reversed by the administration of the GABAAR antagonist Bicuculline. Conversely, the chemogenetic inhibition of ACC-LHA GABAergic neurons alleviated anxiety-like behaviors, intestinal dysfunction, and visceral hypersensitivity in the mouse model for IBS. These results highlight the crucial involvement of the ACC-LHA GABAergic pathway in modulating anxiety-like behaviors, intestinal motility alterations, and visceral hypersensitivity, suggesting a potential therapeutic strategy for alleviating IBS-like symptoms.
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Affiliation(s)
- Ruixiao Guo
- Department of Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Shengli Gao
- Biomedical Center, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xufei Feng
- Department of Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Hua Liu
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xing Ming
- Department of Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Jinqiu Sun
- Department of Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xinchi Luan
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Zhenyu Liu
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Weiyi Liu
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Feifei Guo
- Department of Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
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11
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Reddy AP, Rawat P, Rohr N, Alvir R, Bisht J, Bushra MA, Luong J, Reddy AP. Role of Serotonylation and SERT Posttranslational Modifications in Alzheimer's Disease Pathogenesis. Aging Dis 2024; 16:841-858. [PMID: 39254383 PMCID: PMC11964421 DOI: 10.14336/ad.2024.0328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 03/28/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is implicated mainly in Alzheimer's disease (AD) and reported to be responsible for several processes and roles in the human body, such as regulating sleep, food intake, sexual behavior, anxiety, and drug abuse. It is synthesized from the amino acid tryptophan. Serotonin also functions as a signal between neurons to mature, survive, and differentiate. It plays a crucial role in neuronal plasticity, including cell migration and cell contact formation. Various psychiatric disorders, such as depression, schizophrenia, autism, and Alzheimer's disease, have been linked to an increase in serotonin-dependent signaling during the development of the nervous system. Recent studies have found 5-HT and other monoamines embedded in the nuclei of various cells, including immune cells, the peritoneal mast, and the adrenal medulla. Evidence suggests these monoamines to be involved in widespread intracellular regulation by posttranslational modifications (PTMs) of proteins. Serotonylation is the calcium-dependent process in which 5-HT forms a long-lasting covalent bond to small cytoplasmic G-proteins by endogenous transglutaminase 2 (TGM2). Serotonylation plays a role in various biological processes. The purpose of our article is to summarize historical developments and recent advances in serotonin research and serotonylation in depression, aging, AD, and other age-related neurological diseases. We also discussed several of the latest developments with Serotonin, including biological functions, pathophysiological implications and therapeutic strategies to treat patients with depression, dementia, and other age-related conditions.
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Affiliation(s)
| | | | | | | | | | | | | | - Aananya P. Reddy
- Nutritional Sciences Department, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USA
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12
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Chen C, Zhang DY, Chen S, Huang S, Zeng F, Li D, Lv YT, Xiang X, Chen RX, Zhang X, Mao F, Huang X, Wang J, Bai F. Prevalence, types, and risk factors of functional gastrointestinal diseases in Hainan Province, China. Sci Rep 2024; 14:4553. [PMID: 38402323 PMCID: PMC10894239 DOI: 10.1038/s41598-024-55363-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 02/22/2024] [Indexed: 02/26/2024] Open
Abstract
To investigate the prevalence, types, and risk factors of functional gastrointestinal diseases (FGIDs) in Hainan Province, China, in order to provide insights for future prevention and treatment strategies. A questionnaire survey was conducted from July 2022 to May 2023, using stratified sampling to sample local residents in five cities (20 townships) in Hainan Province. Out of 2057 local residents surveyed, 659 individuals (32.0%) reported experiencing at least one FGID. The most prevalent FGIDs were functional dyspepsia (FD) (10.7%), functional constipation (FC) (9.3%), irritable bowel syndrome (IBS) (6.8%), functional bloating (2.2%), belching disorder (2.2%), functional diarrhea (FDr) (1.5%), functional heartburn (1.5%), and fecal incontinence (0.98%). The study revealed significant associations between FGIDs and factors such as age, sleep quality, anxiety, smoking, alcohol consumption, and the consumption of pickled food (P < 0.05). Older age, poor sleep quality, anxiety, and the consumption of pickled food were identified as independent risk factors for the prevalence of FGIDs (P < 0.05). In Hainan Province, the overall prevalence of FGIDs was found to be 32.0%, with higher prevalences of FC and FD. Older age, poor sleep quality, anxiety, and the consumption of pickled food were identified as risk factors for FGIDs.
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Affiliation(s)
- Chen Chen
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Da-Ya Zhang
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Shiju Chen
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Shimei Huang
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Fan Zeng
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Da Li
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Yan-Ting Lv
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Xiaohong Xiang
- Department of Pediatrics Affiliated Chifeng Clinical College, Inner Mongolia Medical University, Chifeng, 010110, China
| | - Run-Xiang Chen
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Xiaodong Zhang
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Fengjiao Mao
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Xianfeng Huang
- Graduate School, Hainan Medical University, Haikou, 571199, China
| | - Jun Wang
- Department of Gastroenterology, The 986 Hospital of Xijing Hospital, Air Force Military Medical University, Xi'an, 710054, China.
| | - Feihu Bai
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Yehai Avenue, #368, Longhua District, Haikou, 570216, Hainan, China.
- The Gastroenterology Clinical Medical Center of Hainan Province, Haikou, 570216, China.
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13
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Wiese JJ, Manna S, Kühl AA, Fascì A, Elezkurtaj S, Sonnenberg E, Bubeck M, Atreya R, Becker C, Weixler B, Siegmund B, Patankar JV, Prüß MS, Schumann M. Myenteric Plexus Immune Cell Infiltrations and Neurotransmitter Expression in Crohn's Disease and Ulcerative Colitis. J Crohns Colitis 2024; 18:121-133. [PMID: 37565754 PMCID: PMC10821712 DOI: 10.1093/ecco-jcc/jjad122] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Indexed: 08/12/2023]
Abstract
BACKGROUND AND AIMS Pain is a cardinal symptom in inflammatory bowel disease [IBD]. An important structure in the transduction of pain signalling is the myenteric plexus [MP]. Nevertheless, IBD-associated infiltration of the MP by immune cells lacks in-depth characterisation. Herein, we decipher intra- and periganglionic immune cell infiltrations in Crohn´s disease [CD] and ulcerative colitis [UC] and provide a comparison with murine models of colitis. METHODS Full wall specimens of surgical colon resections served to examine immune cell populations by either conventional immuno-histochemistry or immunofluorescence followed by either bright field or confocal microscopy. Results were compared with equivalent examinations in various murine models of intestinal inflammation. RESULTS Whereas the MP morphology was not significantly altered in IBD, we identified intraganglionic IBD-specific B cell- and monocyte-dominant cell infiltrations in CD. In contrast, UC-MPs were infiltrated by CD8+ T cells and revealed a higher extent of ganglionic cell apoptosis. With regard to the murine models of intestinal inflammation, the chronic dextran sulphate sodium [DSS]-induced colitis model reflected CD [and to a lesser extent UC] best, as it also showed increased monocytic infiltration as well as a modest B cell and CD8+ T cell infiltration. CONCLUSIONS In CD, MPs were infiltrated by B cells and monocytes. In UC, mostly CD8+ cytotoxic T cells were found. The chronic DSS-induced colitis in the mouse model reflected best the MP-immune cell infiltrations representative for IBD.
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Affiliation(s)
- Jakob J Wiese
- Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Subhakankha Manna
- Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anja A Kühl
- Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, iPATH.Berlin, Berlin, Germany
| | - Alberto Fascì
- Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sefer Elezkurtaj
- Institute of Pathology, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Elena Sonnenberg
- Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Marvin Bubeck
- Department of Internal Medicine 1, University Hospital Erlangen, Faculty of Medicine, Erlangen, Germany
| | - Raja Atreya
- Department of Internal Medicine 1, University Hospital Erlangen, Faculty of Medicine, Erlangen, Germany
| | - Christoph Becker
- Department of Internal Medicine 1, University Hospital Erlangen, Faculty of Medicine, Erlangen, Germany
| | - Benjamin Weixler
- Klinik für Allgemein- und Viszeralchirurgie, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Britta Siegmund
- Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Jay V Patankar
- Department of Internal Medicine 1, University Hospital Erlangen, Faculty of Medicine, Erlangen, Germany
| | - Magdalena S Prüß
- Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin, – Berlin, BIH Biomedical Innovation Academy, BIH, Charité Clinician Scientist Program, 10178 Berlin, Germany
| | - Michael Schumann
- Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin, – Berlin, BIH Biomedical Innovation Academy, BIH, Charité Clinician Scientist Program, 10178 Berlin, Germany
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14
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Mota-Rojas D, Ogi A, Villanueva-García D, Hernández-Ávalos I, Casas-Alvarado A, Domínguez-Oliva A, Lendez P, Ghezzi M. Thermal Imaging as a Method to Indirectly Assess Peripheral Vascular Integrity and Tissue Viability in Veterinary Medicine: Animal Models and Clinical Applications. Animals (Basel) 2023; 14:142. [PMID: 38200873 PMCID: PMC10777915 DOI: 10.3390/ani14010142] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 12/24/2023] [Accepted: 12/30/2023] [Indexed: 01/12/2024] Open
Abstract
Infrared thermography (IRT) is a technique that indirectly assesses peripheral blood circulation and its resulting amount of radiated heat. Due to these properties, thermal imaging is currently applied in human medicine to noninvasively evaluate peripheral vascular disorders such as thrombosis, thromboembolisms, and other ischemic processes. Moreover, tissular damage (e.g., burn injuries) also causes microvasculature compromise. Therefore, thermography can be applied to determine the degree of damage according to the viability of tissues and blood vessels, and it can also be used as a technique to monitor skin transplant procedures such as grafting and free flaps. The present review aims to summarize and analyze the application of IRT in veterinary medicine as a method to indirectly assess peripheral vascular integrity and its relation to the amount of radiated heat and as a diagnostic technique for tissue viability, degree of damage, and wound care.
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Affiliation(s)
- Daniel Mota-Rojas
- Neurophysiology of Pain, Behavior and Assessment of Welfare in Domestic Animals, DPAA, Universidad Autónoma Metropolitana (UAM), Mexico City 14389, Mexico
| | - Asahi Ogi
- Department of Neurobiology and Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy
| | - Dina Villanueva-García
- Division of Neonatology, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
| | - Ismael Hernández-Ávalos
- Clinical Pharmacology and Veterinary Anesthesia, Biological Sciences Department, FESC, Universidad Nacional Autónoma de México, Cuautitlán 54714, Mexico
| | - Alejandro Casas-Alvarado
- Neurophysiology of Pain, Behavior and Assessment of Welfare in Domestic Animals, DPAA, Universidad Autónoma Metropolitana (UAM), Mexico City 14389, Mexico
| | - Adriana Domínguez-Oliva
- Neurophysiology of Pain, Behavior and Assessment of Welfare in Domestic Animals, DPAA, Universidad Autónoma Metropolitana (UAM), Mexico City 14389, Mexico
| | - Pamela Lendez
- Anatomy Area, Faculty of Veterinary Sciences (FCV), Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), University Campus, Tandil 7000, Argentina
| | - Marcelo Ghezzi
- Anatomy Area, Faculty of Veterinary Sciences (FCV), Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), University Campus, Tandil 7000, Argentina
- Animal Welfare Area, Faculty of Veterinary Sciences (FCV), Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), University Campus, Tandil 7000, Argentina
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15
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Londregan A, Alexander TD, Covarrubias M, Waldman SA. Fundamental Neurochemistry Review: The role of enteroendocrine cells in visceral pain. J Neurochem 2023; 167:719-732. [PMID: 38037432 PMCID: PMC10917140 DOI: 10.1111/jnc.16022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/03/2023] [Accepted: 11/15/2023] [Indexed: 12/02/2023]
Abstract
While visceral pain is commonly associated with disorders of the gut-brain axis, underlying mechanisms are not fully understood. Dorsal root ganglion (DRG) neurons innervate visceral structures and undergo hypersensitization in inflammatory models. The characterization of peripheral DRG neuron terminals is an active area of research, but recent work suggests that they communicate with enteroendocrine cells (EECs) in the gut. EECs sense stimuli in the intestinal lumen and communicate information to the brain through hormonal and electrical signaling. In that context, EECs are a target for developing therapeutics to treat visceral pain. Linaclotide is an FDA-approved treatment for chronic constipation that activates the intestinal membrane receptor guanylyl cyclase C (GUCY2C). Clinical trials revealed that linaclotide relieves both constipation and visceral pain. We recently demonstrated that the analgesic effect of linaclotide reflects the overexpression of GUCY2C on neuropod cells, a specialized subtype of EECs. While this brings some clarity to the relationship between linaclotide and visceral analgesia, questions remain about the intracellular signaling mechanisms and neurotransmitters mediating this communication. In this Fundamental Neurochemistry Review, we discuss what is currently known about visceral nociceptors, enteroendocrine cells, and the gut-brain axis, and ongoing areas of research regarding that axis and visceral pain.
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Affiliation(s)
- Annie Londregan
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Tyler D. Alexander
- Department of Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
- Vicki & Jack Farber Institute of Neuroscience at Jefferson Health, Philadelphia, Pennsylvania 19107
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Manuel Covarrubias
- Department of Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
- Vicki & Jack Farber Institute of Neuroscience at Jefferson Health, Philadelphia, Pennsylvania 19107
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Scott A. Waldman
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
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16
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McClain JL, Morales-Soto W, Gonzales J, Parmar V, Demireva EY, Gulbransen BD. Sexually Dimorphic Effects of Histamine Degradation by Enteric Glial Histamine N-Methyltransferase (HNMT) on Visceral Hypersensitivity. Biomolecules 2023; 13:1651. [PMID: 38002333 PMCID: PMC10669271 DOI: 10.3390/biom13111651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/26/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Histamine is a neuromodulator that affects gut motility and visceral sensitivity through intrinsic and extrinsic neural pathways, yet the mechanisms regulating histamine availability in these pathways remain poorly understood. Here, we show that enteric glia contribute to histamine clearance in the enteric nervous system (ENS) through their expression of the enzyme histamine N-methyltransferase (HNMT). Glial HNMT expression was initially assessed using immunolabeling and gene expression, and functionally tested using CRISPR-Cas9 to create a Cre-dependent conditional Hnmt ablation model targeting glia. Immunolabeling, calcium imaging, and visceromotor reflex recordings were used to assess the effects on ENS structure and visceral hypersensitivity. Immunolabeling and gene expression data show that enteric neurons and glia express HNMT. Deleting Hnmt in Sox10+ enteric glia increased glial histamine levels and altered visceromotor responses to colorectal distension in male mice, with no effect in females. Interestingly, deleting glial Hnmt protected males from histamine-driven visceral hypersensitivity. These data uncover a significant role for glial HNMT in histamine degradation in the gut, which impacts histamine-driven visceral hypersensitivity in a sex-dependent manner. Changes in the capacity of glia to clear histamines could play a role in the susceptibility to developing visceral pain in disorders of the gut-brain interaction.
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Affiliation(s)
- Jonathon L. McClain
- Department of Physiology, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA; (J.L.M.); (W.M.-S.); (J.G.)
| | - Wilmarie Morales-Soto
- Department of Physiology, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA; (J.L.M.); (W.M.-S.); (J.G.)
| | - Jacques Gonzales
- Department of Physiology, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA; (J.L.M.); (W.M.-S.); (J.G.)
| | - Visha Parmar
- Department of Physiology, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA; (J.L.M.); (W.M.-S.); (J.G.)
| | - Elena Y. Demireva
- Transgenic and Genome Editing Facility, Institute for Quantitative Health and Engineering, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA;
| | - Brian D. Gulbransen
- Department of Physiology, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA; (J.L.M.); (W.M.-S.); (J.G.)
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17
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Maqoud F, Tricarico D, Mallamaci R, Orlando A, Russo F. The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets. Int J Mol Sci 2023; 24:11074. [PMID: 37446251 DOI: 10.3390/ijms241311074] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Several gastrointestinal (GI) tract abnormalities, including visceral hypersensitivity, motility, and intestinal permeability alterations, have been implicated in functional GI disorders (FGIDs). Ion channels play a crucial role in all the functions mentioned above. Hormones and natural molecules modulate these channels and represent targets of drugs and bacterial toxins. Mutations and abnormal functional expression of ion channel subunits can lead to diseases called channelopathies. These channelopathies in gastroenterology are gaining a strong interest, and the evidence of co-relationships is increasing. In this review, we describe the correlation status between channelopathies and FGIDs. Different findings are available. Among others, mutations in the ABCC7/CFTR gene have been described as a cause of constipation and diarrhea. Mutations of the SCN5A gene are instead associated with irritable bowel syndrome. In contrast, mutations of the TRPV1 and TRPA genes of the transient receptor potential (TRP) superfamily manifest hypersensitivity and visceral pain in sensory nerves. Recently, mice and humans affected by Cantu syndrome (CS), which is associated with the mutations of the KCNJ8 and ABCC9 genes encoding for the Kir6.1 and SUR2 subunits, showed dysfunction of contractility throughout the intestine and death in the mice after the weaning on solid food. The discovery of a correlation between channelopathies and FIGD opens new avenues for discovering new direct drug targets for specific channelopathies, leading to significant implications for diagnosing and treating functional GI diseases.
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Affiliation(s)
- Fatima Maqoud
- Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS "Saverio de Bellis", Castellana Grotte, 70013 Bari, Italy
| | - Domenico Tricarico
- Section of Pharmacology, Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, 70125 Bari, Italy
| | - Rosanna Mallamaci
- Department of Biosciences, Biotechnologies and Environment University of Bari Aldo Moro, 70125 Bari, Italy
| | - Antonella Orlando
- Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS "Saverio de Bellis", Castellana Grotte, 70013 Bari, Italy
| | - Francesco Russo
- Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS "Saverio de Bellis", Castellana Grotte, 70013 Bari, Italy
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18
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Afolabi JM, Michael OS, Falayi OO, Kanthakumar P, Mankuzhy PD, Soni H, Adebiyi A. Activation of renal vascular smooth muscle TRPV4 channels by 5-hydroxytryptamine impairs kidney function in neonatal pigs. Microvasc Res 2023; 148:104516. [PMID: 36889668 PMCID: PMC10258165 DOI: 10.1016/j.mvr.2023.104516] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/10/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Abstract
Control of microvascular reactivity by 5-hydroxytryptamine (5-HT; serotonin) is complex and may depend on vascular bed type and 5-HT receptors. 5-HT receptors consist of seven families (5-HT1-5-HT7), with 5-HT2 predominantly mediating renal vasoconstriction. Cyclooxygenase (COX) and smooth muscle intracellular Ca2+ levels ([Ca2+]i) have been implicated in 5-HT-induced vascular reactivity. Although 5-HT receptor expression and circulating 5-HT levels are known to be dependent on postnatal age, control of neonatal renal microvascular function by 5-HT is unclear. In the present study, we demonstrate that 5-HT stimulated human TRPV4 transiently expressed in Chinese hamster ovary cells. 5-HT2A is the predominant 5-HT2 receptor subtype in freshly isolated neonatal pig renal microvascular smooth muscle cells (SMCs). HC-067047 (HC), a selective TRPV4 blocker, attenuated cation currents induced by 5-HT in the SMCs. HC also inhibited the 5-HT-induced increase in renal microvascular [Ca2+]i and constriction. Intrarenal artery infusion of 5-HT had minimal effects on systemic hemodynamics but reduced renal blood flow (RBF) and increased renal vascular resistance (RVR) in the pigs. Transdermal measurement of glomerular filtration rate (GFR) indicated that kidney infusion of 5-HT reduced GFR. HC and 5-HT2 receptor antagonist ritanserin attenuated 5-HT effects on RBF, RVR, and GFR. Moreover, the serum and urinary COX-1 and COX-2 levels in 5-HT-treated piglets were unchanged compared with the control. These data suggest that activation of renal microvascular SMC TRPV4 channels by 5-HT impairs kidney function in neonatal pigs independently of COX production.
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Affiliation(s)
- Jeremiah M Afolabi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Olugbenga S Michael
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Olufunke O Falayi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Praghalathan Kanthakumar
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Pratheesh D Mankuzhy
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Hitesh Soni
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Adebowale Adebiyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
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Yang Q, Zhao Y, Zhao X, Sun S, Chen Y, Chen J, Zou D, Zhang L. Exploring the potential targets of Biling Weitong Granules on visceral hypersensitivity through integration of network pharmacology and in vivo analysis. JOURNAL OF ETHNOPHARMACOLOGY 2023:116701. [PMID: 37257703 DOI: 10.1016/j.jep.2023.116701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/13/2023] [Accepted: 05/28/2023] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Biling Weitong Granules(BLWTG) are a newly developed traditional Chinese medicine prescription based on the ancient prescription Jinlingzi San and Zuojin Wan. It is used for the treatment of functional gastrointestinal disorders (FGIDs) featured as visceral hypersensitivity(VH). However, its active ingredients and protein targets involved still remain unknown. AIM OF THE STUDY To explore the potential targets of BLWTG for the treatment of visceral hypersensitivity. MATERIALS AND METHODS Active components and their protein targets of BLWTG were screened from TCMSP database and the component-target network were constructed with Cytoscape software. Irritable bowel syndrome (IBS) was the representative disease in this study and information on its linked pathways was obtained from NCBI, Drugbank and Genecard. Target pathways of BLWTG were analyzed through KEGG to verify the correlation with IBS related pathways.Then, the VH mouse models was induced by maternal separation(MS), randomly divided into normal saline(NS),BLWTG1(low-dosage) and BLWTG2(high-dosage) group. After intervention, threshold intensity of colorectal distension (CRD) and body weight were measured to evaluate relief of IBS symptoms. Elisa was performed to evaluate 5-HT concentration changes of colon tissues. Flow cytometry was performed to assess changes of colon eosinophils and mast cells proportion. Transcriptome sequencing was employed to analyze changes of pathways and differential genes. RESULTS 199 protein targets and 132 active components of BLWTG were identified. KEGG analysis revealed the overlap between BLWTG target pathways and IBS related pathways such as neuroactive ligand-receptor interaction, tryptophan metabolism and inflammatory reaction. 34 genes were not only BLWTG target proteins but also recognized targets for treating IBS. After maternal separation(MS), the mice showed a significant decrease in threshold intensity of CRD, a progressive decrease in body weight and an increase of 5-HT concentration of colon tissue. The proportion of mast cells and eosinophils in the colon increased. Differential genes including Hp,Ido1 and Aqp7 were significantly increased in MS mice group and IBS-related pathways were upregulated. After treatment of BLWTG, threshold intensity of CRD and body weight were significantly improved and IBS related pathways were downregulated. In addition, among BLWTG protein targets, Il1b,Tnf,Adrb1 and Nos2 were found upregulated in MS + NS mice and downregulated after BLWTG intervention through combination of transcriptome sequencing. CONCLUSIONS In maternal separation-induced mouse models, BLWTG could alleviate visceral hypersensitivity, possibly through downregulation of 5-HT concentration and eosinophils and mast cells proportion in colon and critical pathways such as neuroactive ligand-receptor pathway. Potential targets of BLWTG including Il1b,Tnf,Adrb1 and Nos2 were found through integration of network pharmacology database and transcriptome sequencing, providing evidence for further study on mechanisms underlying visceral hypersensitivity.
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Affiliation(s)
- Qidi Yang
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Yizhou Zhao
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Xiangyu Zhao
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Sishen Sun
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Yifei Chen
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Jiayin Chen
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Duowu Zou
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
| | - Ling Zhang
- Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.197, Rui Jin Er Road, Shanghai, 200025, China.
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20
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Vanuytsel T, Bercik P, Boeckxstaens G. Understanding neuroimmune interactions in disorders of gut-brain interaction: from functional to immune-mediated disorders. Gut 2023; 72:787-798. [PMID: 36657961 PMCID: PMC10086308 DOI: 10.1136/gutjnl-2020-320633] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 12/08/2022] [Indexed: 01/21/2023]
Abstract
Functional gastrointestinal disorders-recently renamed into disorders of gut-brain interaction-such as irritable bowel syndrome and functional dyspepsia are highly prevalent conditions with bothersome abdominal symptoms in the absence of structural abnormalities. While traditionally considered as motility disorders or even psychosomatic conditions, our understanding of the pathophysiology has evolved significantly over the last two decades. Initial observations of subtle mucosal infiltration with immune cells, especially mast cells and eosinophils, are since recently being backed up by mechanistic evidence demonstrating increased release of nociceptive mediators by immune cells and the intestinal epithelium. These mediators can activate sensitised neurons leading to visceral hypersensitivity with bothersome symptoms. The interaction between immune activation and an impaired barrier function of the gut is most likely a bidirectional one with alterations in the microbiota, psychological stress and food components as upstream players in the pathophysiology. Only few immune-targeting treatments are currently available, but an improved understanding through a multidisciplinary scientific approach will hopefully identify novel, more precise treatment targets with ultimately better outcomes.
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Affiliation(s)
- Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium.,Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Premysl Bercik
- Faculty of Health Sciences, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Guy Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium .,Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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21
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De Logu F, Maglie R, Titiz M, Poli G, Landini L, Marini M, Souza Monteiro de Araujo D, De Siena G, Montini M, Cabrini DA, Otuki MF, Pawloski PL, Antiga E, Tuccinardi T, Calixto JB, Geppetti P, Nassini R, André E. miRNA-203b-3p Induces Acute and Chronic Pruritus through 5-HTR2B and TRPV4. J Invest Dermatol 2023; 143:142-153.e10. [PMID: 36049541 DOI: 10.1016/j.jid.2022.08.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 06/17/2022] [Accepted: 08/05/2022] [Indexed: 12/29/2022]
Abstract
Growing evidence indicates that transient receptor potential (TRP) channels contribute to different forms of pruritus. However, the endogenous mediators that cause itch through transient receptor potential channels signaling are poorly understood. In this study, we show that genetic deletion or pharmacological antagonism of TRPV4 attenuated itch in a mouse model of psoriasis induced by topical application of imiquimod. Human psoriatic lesions showed increased expression of several microRNAs, including the miR-203b-3p, which induced a calcium ion response in rodent dorsal root ganglion neurons and scratching behavior in mice through 5-HTR2B activation and the protein kinase C‒dependent phosphorylation of TRPV4. Computer simulation revealed that the miR-203b-3p core sequence (GUUAAGAA) that causes 5-HTR2B/TRPV4-dependent itch targets the extracellular side of 5-HTR2B by interacting with a portion of the receptor pocket consistent with its activation. Overall, we reveal the unconventional pathophysiological role of an extracellular microRNA that can behave as an itch promoter through 5-HTR2B and TRPV4.
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Affiliation(s)
- Francesco De Logu
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Roberto Maglie
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Mustafa Titiz
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Giulio Poli
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | - Lorenzo Landini
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Matilde Marini
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | | | - Gaetano De Siena
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Marco Montini
- Medical Genetics Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | | | | | | | - Emiliano Antiga
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | | | | | | | - Romina Nassini
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
| | - Eunice André
- Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil
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22
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Spekker E, Körtési T, Vécsei L. TRP Channels: Recent Development in Translational Research and Potential Therapeutic Targets in Migraine. Int J Mol Sci 2022; 24:ijms24010700. [PMID: 36614146 PMCID: PMC9820749 DOI: 10.3390/ijms24010700] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/22/2022] [Accepted: 12/29/2022] [Indexed: 01/03/2023] Open
Abstract
Migraine is a chronic neurological disorder that affects approximately 12% of the population. The cause of migraine headaches is not yet known, however, when the trigeminal system is activated, neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) are released, which cause neurogenic inflammation and sensitization. Advances in the understanding of migraine pathophysiology have identified new potential pharmacological targets. In recent years, transient receptor potential (TRP) channels have been the focus of attention in the pathophysiology of various pain disorders, including primary headaches. Genetic and pharmacological data suggest the role of TRP channels in pain sensation and the activation and sensitization of dural afferents. In addition, TRP channels are widely expressed in the trigeminal system and brain regions which are associated with the pathophysiology of migraine and furthermore, co-localize several neuropeptides that are implicated in the development of migraine attacks. Moreover, there are several migraine trigger agents known to activate TRP channels. Based on these, TRP channels have an essential role in migraine pain and associated symptoms, such as hyperalgesia and allodynia. In this review, we discuss the role of the certain TRP channels in migraine pathophysiology and their therapeutic applicability.
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Affiliation(s)
- Eleonóra Spekker
- ELKH-SZTE Neuroscience Research Group, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
| | - Tamás Körtési
- ELKH-SZTE Neuroscience Research Group, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
- Faculty of Health Sciences and Social Studies, University of Szeged, Temesvári krt. 31, H-6726 Szeged, Hungary
| | - László Vécsei
- ELKH-SZTE Neuroscience Research Group, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
- Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
- Correspondence: ; Tel.: +36-62-545351; Fax: +36-62-545597
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23
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Chang WY, Yang YT, She MP, Tu CH, Lee TC, Wu MS, Sun CH, Hsin LW, Yu LCH. 5-HT 7 receptor-dependent intestinal neurite outgrowth contributes to visceral hypersensitivity in irritable bowel syndrome. J Transl Med 2022; 102:1023-1037. [PMID: 36775417 PMCID: PMC9420680 DOI: 10.1038/s41374-022-00800-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 12/19/2022] Open
Abstract
Irritable bowel syndrome (IBS) is characterized by visceral hypersensitivity (VH) associated with abnormal serotonin/5-hydroxytryptamine (5-HT) metabolism and neurotrophin-dependent mucosal neurite outgrowth. The underlying mechanisms of VH remain poorly understood. We investigated the role of 5-HT7 receptor in mucosal innervation and intestinal hyperalgesia. A high density of mucosal nerve fibres stained for 5-HT7 was observed in colonoscopic biopsy specimens from IBS patients compared with those from healthy controls. Staining of 5-HT3 and 5-HT4 receptors was observed mainly in colonic epithelia with comparable levels between IBS and controls. Visceromotor responses to colorectal distension were evaluated in two mouse models, one postinfectious with Giardia and subjected to water avoidance stress (GW) and the other postinflammatory with trinitrobenzene sulfonic acid-induced colitis (PT). Increased VH was associated with higher mucosal density of 5-HT7-expressing nerve fibres and elevated neurotrophin and neurotrophin receptor levels in the GW and PT mice. The increased VH was inhibited by intraperitoneal injection of SB-269970 (a selective 5-HT7 antagonist). Peroral multiple doses of CYY1005 (a novel 5-HT7 ligand) decreased VH and reduced mucosal density of 5-HT7-expressing nerve fibres in mouse colon. Human neuroblastoma SH-SY5Y cells incubated with bacteria-free mouse colonic supernatant, 5-HT, nerve growth factor, or brain-derived neurotrophic factor exhibited nerve fibre elongation, which was inhibited by 5-HT7 antagonists. Gene silencing of HTR7 also reduced the nerve fibre length. Activation of 5-HT7 upregulated NGF and BDNF gene expression, while stimulation with neurotrophins increased the levels of tryptophan hydroxylase 2 and 5-HT7 in neurons. A positive-feedback loop was observed between serotonin and neurotrophin pathways via 5-HT7 activation to aggravate fibre elongation, whereby 5-HT3 and 5-HT4 had no roles. In conclusion, 5-HT7-dependent mucosal neurite outgrowth contributed to VH. A novel 5-HT7 antagonist could be used as peroral analgesics for IBS-related pain.
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Affiliation(s)
- Wen-Ying Chang
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan ROC
| | - Yi-Ting Yang
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan ROC
| | - Meng-Ping She
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan ROC
| | - Chia-Hung Tu
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan ROC
| | - Tsung-Chun Lee
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan ROC
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan ROC
| | - Chin-Hung Sun
- Department of Tropical Medicine and Parasitology, National Taiwan University College of Medicine, Taipei, Taiwan ROC
| | - Ling-Wei Hsin
- Graduate Institute of Pharmacy, National Taiwan University School of Pharmacy, Taipei, Taiwan ROC.
- Center for Innovative Therapeutics Discovery, National Taiwan University, Taipei, Taiwan ROC.
| | - Linda Chia-Hui Yu
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan ROC.
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24
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Expression of TRP Channels in Colonic Mucosa of IBS-D Patients and Its Correlation with the Severity of the Disease. Gastroenterol Res Pract 2022; 2022:7294775. [PMID: 35677724 PMCID: PMC9168202 DOI: 10.1155/2022/7294775] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 05/10/2022] [Accepted: 05/17/2022] [Indexed: 11/18/2022] Open
Abstract
Aim Lots of researches have endeavored to elucidate the pathogenetic mechanism of visceral hypersensitivity in order to guide the therapy of diarrhea predominant-irritable bowel syndrome (IBS-D). Transient receptor potential (TRP) channels and their role in visceral nociception have been vastly investigated. We investigated the expression of TRP channels in IBS-D colonic biopsies and its correlation with the severity of the disease. Methods Sigmoid biopsies were obtained from 34 IBS-D patients and 28 healthy controls (HCs). IBS-D was diagnosed according to Rome IV criteria. Their clinical parameters were assessed through questionnaires. Expression of TRPV1, TRPV4, TRPA1, TRPM2, and TRPM8 was evaluated with immunohistology staining. Results Expression levels of TRPV1, TRPV4, and TRPA1 in the colonic mucosa of IBS-D patients were significantly higher than those in HCs (p < 0.05), while there was no obvious difference of TRPM2 and TRPM8 expression between IBS-D patients and HCs. In addition, the expression levels of TRPV1 and TRPA1, but TRPV4, in the colonic mucosa correlated positively with the severity of diseases (r = 0.6303 and 0.4506, respectively, p < 0.05). Conclusions Expression of TRPV1, TRPA1, and TRPV4 in the colonic mucosa was enhanced in IBS-D patients compared with HCs with the former two correlated with the severity of the disease. TRP channels might be promising biomarkers in the diagnosis and estimate of the severity in IBS-D.
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25
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Xie Y, Nishijima Y, Zinkevich NS, Korishettar A, Fang J, Mathison AJ, Zimmermann MT, Wilcox DA, Gutterman DD, Shen Y, Zhang DX. NADPH oxidase 4 contributes to TRPV4-mediated endothelium-dependent vasodilation in human arterioles by regulating protein phosphorylation of TRPV4 channels. Basic Res Cardiol 2022; 117:24. [PMID: 35469044 PMCID: PMC9119129 DOI: 10.1007/s00395-022-00932-9] [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: 10/01/2021] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 02/07/2023]
Abstract
Impaired endothelium-dependent vasodilation has been suggested to be a key component of coronary microvascular dysfunction (CMD). A better understanding of endothelial pathways involved in vasodilation in human arterioles may provide new insight into the mechanisms of CMD. The goal of this study is to investigate the role of TRPV4, NOX4, and their interaction in human arterioles and examine the underlying mechanisms. Arterioles were freshly isolated from adipose and heart tissues obtained from 71 patients without coronary artery disease, and vascular reactivity was studied by videomicroscopy. In human adipose arterioles (HAA), ACh-induced dilation was significantly reduced by TRPV4 inhibitor HC067047 and by NOX 1/4 inhibitor GKT137831, but GKT137831 did not further affect the dilation in the presence of TRPV4 inhibitors. GKT137831 also inhibited TRPV4 agonist GSK1016790A-induced dilation in HAA and human coronary arterioles (HCA). NOX4 transcripts and proteins were detected in endothelial cells of HAA and HCA. Using fura-2 imaging, GKT137831 significantly reduced GSK1016790A-induced Ca2+ influx in the primary culture of endothelial cells and TRPV4-WT-overexpressing human coronary artery endothelial cells (HCAEC). However, GKT137831 did not affect TRPV4-mediated Ca2+ influx in non-phosphorylatable TRPV4-S823A/S824A-overexpressing HCAEC. In addition, treatment of HCAEC with GKT137831 decreased the phosphorylation level of Ser824 in TRPV4. Finally, proximity ligation assay (PLA) revealed co-localization of NOX4 and TRPV4 proteins. In conclusion, both TRPV4 and NOX4 contribute to ACh-induced dilation in human arterioles from patients without coronary artery disease. NOX4 increases TRPV4 phosphorylation in endothelial cells, which in turn enhances TRPV4-mediated Ca2+ entry and subsequent endothelium-dependent dilation in human arterioles.
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Affiliation(s)
- Yangjing Xie
- School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei 230032, China.,Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Cardiovascular Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.,Biopharmaceutical Institute, Anhui Medical University, 81 Meishan Road, Hefei 230032, China
| | - Yoshinori Nishijima
- Cardiovascular Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Natalya S. Zinkevich
- Cardiovascular Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.,Department of Biology, College of Liberal Arts and Sciences, University of Illinois at Springfield, Springfield, IL, USA
| | - Ankush Korishettar
- Cardiovascular Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.,Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Juan Fang
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.,Children’s Research Institute, Children’s Wisconsin, Milwaukee, WI, USA
| | - Angela J. Mathison
- Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center (GSPMC), Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Michael T. Zimmermann
- Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center (GSPMC), Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - David A. Wilcox
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.,Children’s Research Institute, Children’s Wisconsin, Milwaukee, WI, USA
| | - David D. Gutterman
- Cardiovascular Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.,Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yuxian Shen
- School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei 230032, China.,Biopharmaceutical Institute, Anhui Medical University, 81 Meishan Road, Hefei 230032, China.,Article correspondence to: David X. Zhang, Ph.D., Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI, 53226, USA, Tel: (414) 955-5633, Fax: (414) 955-6572, And Yuxian Shen, Ph.D., School of Basic Medical Sciences and Biopharmaceutical Institute, Anhui Medical University, 81 Meishan Road, Hefei 230032, China, Tel: +86-551-6511-3776,
| | - David X. Zhang
- Cardiovascular Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.,Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.,Article correspondence to: David X. Zhang, Ph.D., Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI, 53226, USA, Tel: (414) 955-5633, Fax: (414) 955-6572, And Yuxian Shen, Ph.D., School of Basic Medical Sciences and Biopharmaceutical Institute, Anhui Medical University, 81 Meishan Road, Hefei 230032, China, Tel: +86-551-6511-3776,
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26
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Aguilera-Lizarraga J, Hussein H, Boeckxstaens GE. Immune activation in irritable bowel syndrome: what is the evidence? Nat Rev Immunol 2022; 22:674-686. [PMID: 35296814 DOI: 10.1038/s41577-022-00700-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2022] [Indexed: 12/15/2022]
Abstract
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that is characterized by abdominal pain and an altered defecation pattern. It affects between 5 and 20% of the general population and can seriously impact quality of life. The pathophysiology of IBS is rather complex and multifactorial including, for example, altered signalling by the gut-brain axis, dysbiosis, abnormal visceral pain signalling and intestinal immune activation. The latter has gained particular interest in recent years, with growing insight into the bidirectional communication between the nervous system and the immune system. In this Review, we detail the current evidence suggesting that immune activation contributes to the pathology seen in patients with IBS and discuss the potential mechanisms involved. Moreover, we describe how immune mediators, particularly those released by mast cells, can directly activate or sensitize pain-transmitting nerves, leading to increased pain signalling and abdominal pain. Finally, we discuss the potential of interventions targeting immune activation as a new therapeutic strategy for patients suffering from IBS.
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Affiliation(s)
- Javier Aguilera-Lizarraga
- Laboratory for Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Hind Hussein
- Laboratory for Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Laboratory for Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
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27
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Lyubashina OA, Sivachenko IB, Panteleev SS. Supraspinal Mechanisms of Intestinal Hypersensitivity. Cell Mol Neurobiol 2022; 42:389-417. [PMID: 33030712 PMCID: PMC11441296 DOI: 10.1007/s10571-020-00967-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 09/22/2020] [Indexed: 12/13/2022]
Abstract
Gut inflammation or injury causes intestinal hypersensitivity (IHS) and hyperalgesia, which can persist after the initiating pathology resolves, are often referred to somatic regions and exacerbated by psychological stress, anxiety or depression, suggesting the involvement of both the spinal cord and the brain. The supraspinal mechanisms of IHS remain to be fully elucidated, however, over the last decades the series of intestinal pathology-associated neuroplastic changes in the brain has been revealed, being potentially responsible for the phenomenon. This paper reviews current clinical and experimental data, including the authors' own findings, on these functional, structural, and neurochemical/molecular changes within cortical, subcortical and brainstem regions processing and modulating sensory signals from the gut. As concluded in the review, IHS can develop and maintain due to the bowel inflammation/injury-induced persistent hyperexcitability of viscerosensory brainstem and thalamic nuclei and sensitization of hypothalamic, amygdala, hippocampal, anterior insular, and anterior cingulate cortical areas implicated in the neuroendocrine, emotional and cognitive modulation of visceral sensation and pain. An additional contribution may come from the pathology-triggered dysfunction of the brainstem structures inhibiting nociception. The mechanism underlying IHS-associated regional hyperexcitability is enhanced NMDA-, AMPA- and group I metabotropic receptor-mediated glutamatergic neurotransmission in association with altered neuropeptide Y, corticotropin-releasing factor, and cannabinoid 1 receptor signaling. These alterations are at least partially mediated by brain microglia and local production of cytokines, especially tumor necrosis factor α. Studying the IHS-related brain neuroplasticity in greater depth may enable the development of new therapeutic approaches against chronic abdominal pain in inflammatory bowel disease.
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Affiliation(s)
- Olga A Lyubashina
- Laboratory of Cortico-Visceral Physiology, Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Nab. Makarova, Saint Petersburg, 199034, Russia.
| | - Ivan B Sivachenko
- Laboratory of Cortico-Visceral Physiology, Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Nab. Makarova, Saint Petersburg, 199034, Russia
| | - Sergey S Panteleev
- Laboratory of Cortico-Visceral Physiology, Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Nab. Makarova, Saint Petersburg, 199034, Russia
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28
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Buscail E, Deraison C. Postoperative Ileus: a Pharmacological Perspective. Br J Pharmacol 2022; 179:3283-3305. [PMID: 35048360 DOI: 10.1111/bph.15800] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 11/29/2022] Open
Abstract
Post-operative ileus (POI) is a frequent complication after abdominal surgery. The consequences of POI can be potentially serious such as bronchial inhalation or acute functional renal failure. Numerous advances in peri-operative management, particularly early rehabilitation, have made it possible to decrease POI. Despite this, the rate of prolonged POI ileus remains high and can be as high as 25% of patients in colorectal surgery. From a pathophysiological point of view, POI has two phases, an early neurological phase and a later inflammatory phase, to which we could add a "pharmacological" phase during which analgesic drugs, particularly opiates, play a central role. The aim of this review article is to describe the phases of the pathophysiology of POI, to analyse the pharmacological treatments currently available through published clinical trials and finally to discuss the different research areas for potential pharmacological targets.
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Affiliation(s)
- Etienne Buscail
- IRSD, INSERM, INRAE, ENVT, University of Toulouse, CHU Purpan (University Hospital Centre), Toulouse, France.,Department of digestive surgery, colorectal surgery unit, Toulouse University Hospital, Toulouse, France
| | - Céline Deraison
- IRSD, INSERM, INRAE, ENVT, University of Toulouse, CHU Purpan (University Hospital Centre), Toulouse, France
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29
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Acharya TK, Sahu RP, Kumar S, Kumar S, Rokade TP, Chakraborty R, Dubey NK, Shikha D, Chawla S, Goswami C. Function and regulation of thermosensitive ion channel TRPV4 in the immune system. CURRENT TOPICS IN MEMBRANES 2022; 89:155-188. [DOI: 10.1016/bs.ctm.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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30
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Peng S, Poole DP, Veldhuis NA. Mini-review: Dissecting receptor-mediated stimulation of TRPV4 in nociceptive and inflammatory pathways. Neurosci Lett 2021; 770:136377. [PMID: 34856355 DOI: 10.1016/j.neulet.2021.136377] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/15/2021] [Accepted: 10/17/2021] [Indexed: 12/15/2022]
Abstract
Transient Receptor Potential Vanilloid 4 (TRPV4) is a polymodal, non-selective cation channel that detects thermal, mechanical, and environmental cues and contributes to a range of diverse physiological processes. The effects of chronic TRPV4 stimulation and gain-of-function genetic mutations suggest that TRPV4 may also be a valuable therapeutic target for pathophysiological events including neurogenic inflammation, peripheral neuropathies, and impaired wound healing. There has been significant interest in defining how and where TRPV4 may promote inflammation and pain. Endogenous stimuli such as osmotic stress and lipid binding are established TRPV4 activators. The TRP channel family is also well-known to be controlled by 'receptor-operated' pathways. For example, G protein-coupled receptors (GPCRs) expressed by primary afferent neurons or other cells in inflammatory pathways utilize TRPV4 as an effector protein to amplify nociceptive and inflammatory signaling. Contributing to disorders including arthritis, neuropathies, and pulmonary edema, GPCRs such as the protease-activated receptor PAR2 mediate activation of kinase signaling cascades to increase TRPV4 phosphorylation, resulting in sensitization and enhanced neuronal excitability. Phospholipase activity also leads to production of polyunsaturated fatty acid lipid mediators that directly activate TRPV4. Consistent with the contribution of TRPV4 to disease, pharmacological inhibition or genetic ablation of TRPV4 can diminish receptor-mediated inflammatory events. This review outlines how receptor-mediated signaling is a major endogenous driver of TRPV4 gating and discusses key signaling pathways and emerging TRPV4 modulators such as the mechanosensitive Piezo1 ion channel. A collective understanding of how endogenous stimuli can influence TRPV4 function is critical for future therapeutic endeavors to modulate this channel.
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Affiliation(s)
- Scott Peng
- Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
| | - Daniel P Poole
- Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
| | - Nicholas A Veldhuis
- Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
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31
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Xu X, Chen R, Zhan G, Wang D, Tan X, Xu H. Enterochromaffin Cells: Sentinels to Gut Microbiota in Hyperalgesia? Front Cell Infect Microbiol 2021; 11:760076. [PMID: 34722345 PMCID: PMC8552036 DOI: 10.3389/fcimb.2021.760076] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
In recent years, increasing studies have been conducted on the mechanism of gut microbiota in neuropsychiatric diseases and non-neuropsychiatric diseases. The academic community has also recognized the existence of the microbiota-gut-brain axis. Chronic pain has always been an urgent difficulty for human beings, which often causes anxiety, depression, and other mental symptoms, seriously affecting people's quality of life. Hyperalgesia is one of the main adverse reactions of chronic pain. The mechanism of gut microbiota in hyperalgesia has been extensively studied, providing a new target for pain treatment. Enterochromaffin cells, as the chief sentinel for sensing gut microbiota and its metabolites, can play an important role in the interaction between the gut microbiota and hyperalgesia through paracrine or neural pathways. Therefore, this systematic review describes the role of gut microbiota in the pathological mechanism of hyperalgesia, learns about the role of enterochromaffin cell receptors and secretions in hyperalgesia, and provides a new strategy for pain treatment by targeting enterochromaffin cells through restoring disturbed gut microbiota or supplementing probiotics.
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Affiliation(s)
- Xiaolin Xu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rongmin Chen
- Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Gaofeng Zhan
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Danning Wang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Tan
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Xu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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32
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Videlock EJ, Chang L. Latest Insights on the Pathogenesis of Irritable Bowel Syndrome. Gastroenterol Clin North Am 2021; 50:505-522. [PMID: 34304785 DOI: 10.1016/j.gtc.2021.04.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The pathogenesis of irritable bowel syndrome is multifactorial and complex. Our understanding of its pathophysiology has evolved, but remains incompletely understood. Symptoms result from a dysregulation of brain-gut interactions. Evidence has identified alterations in central and peripheral (gut) mechanisms in irritable bowel syndrome and the bidirectional communication between the brain and the gut. Pertinent mechanisms include disturbed gut motility, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered central nervous system processing. This review addresses factors that increase the risk of irritable bowel syndrome and the central and peripheral mechanisms thought to underlie its symptoms.
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Affiliation(s)
- Elizabeth J Videlock
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Lin Chang
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
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33
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Gaus OV, Livzan MA. “Gastrointestinal” comorbidity in irritable bowel syndrome. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021; 1:104-111. [DOI: 10.31146/1682-8658-ecg-190-6-104-111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/17/2024]
Abstract
Among the large and heterogeneous group of patients with irritable bowel syndrome (IBS) comorbidity is characteristic feature. Comorbidity is an urgent problem in real clinical practice. Gastrointestinal comorbidity of a patient with IBS is associated with the presence of common pathogenetic links and is represented by combined pathology with functional disorders and the formation of “overlap syndrome” with organic diseases. Often, with a comorbid course, the phenomenon of “mutual burdening” is observed, when the severity of the course of each of them increases. All this requires optimization of approaches to the diagnosis and treatment of this cohort of patients. Obviously, with a comorbid course of IBS, it is advisable to prescribe drugs that affect the general links of pathogenesis, rather than focusing on individual symptoms. This article presents modern information on the gastrointestinal comorbidity of a patient with IBS.
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Affiliation(s)
- O. V. Gaus
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
| | - M. A. Livzan
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
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34
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Brenner D, Shorten GD, O'Mahony SM. Postoperative pain and the gut microbiome. NEUROBIOLOGY OF PAIN 2021; 10:100070. [PMID: 34409198 PMCID: PMC8361255 DOI: 10.1016/j.ynpai.2021.100070] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 06/24/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Poorly controlled postoperative pain remains a major unresolved challenge globally. The gut microbiome impacts on inflammatory pain and neuropathic pain. Microbiota metabolites can regulate peripheral and central sensitisation. Stress is linked to both postoperative pain and an altered gut microbiome. In excess of 300 million surgical procedures are undertaken worldwide each year. Despite recognition of the prevalence of postoperative pain, and improvements in pain management techniques, poorly controlled postoperative pain remains a major unresolved challenge globally. An estimated 71% and 51% of patients experience moderate to severe pain after surgery in in-patient and outpatient settings, respectively. Inadequately controlled pain after surgery is associated with significant perioperative morbidity including myocardial infarction and pulmonary complications. As many as 20–56% of patients develop chronic pain after commonly performed procedures such as hernia repair, hysterectomy, and thoracotomy. Traditional analgesics and interventions are often ineffective or partially effective in the treatment of postoperative pain, resulting in a chronic pain condition with related socio-economic impacts and reduced quality of life for the patient. Such chronic pain which occurs after surgery is referred to as Persistent Post-Surgical Pain (PPSP). The complex ecosystem that is the gastrointestinal microbiota (including bacteria, fungi, viruses, phage) plays essential roles in the maintenance of the healthy state of the host. A disruption to the balance of this microbiome has been implicated not only in gastrointestinal disease but also neurological disorders including chronic pain. The influence of the gut microbiome is well documented in the context of visceral pain from the gastrointestinal tract while a greater understanding is emerging of the impact on inflammatory pain and neuropathic pain (both of which can occur during the perioperative period). The gut microbiome is an essential source for driving immune maturation and maintaining appropriate immune response. Given that inflammatory processes have been implicated in postoperative pain, aberrant microbiome profiles may play a role in the development of this type of pain. Furthermore, the microorganisms in our gut produce metabolites, neurotransmitters, and neuromodulators which interact with their receptors to regulate peripheral and central sensitisation associated with chronic pain. Microbiota-derived mediators can also regulate neuroinflammation, which is associated with activation of microglia as well as infiltration by immune cells, known to modulate the development and maintenance of central sensitisation. Moreover, risk factors for developing postoperative pain include anxiety, depression, and increased stress response. These central nervous system-related disorders have been associated with an altered gut microbiome and microbiome targeted intervention studies indicate improvements. Females are more likely to suffer from postoperative pain. As gonadal hormones are associated with a differential microbiome and pre-clinical studies show that male microbiome confers protection from inflammatory pain, it is possible that the composition of the microbiome and its by-products contribute to the increased risk for the development of postoperative pain. Very little evidence exists relating the microbiome to somatic pain. Here we discuss the potential role of the gut microbiome in the aetiology and pathophysiology of postoperative pain in the context of other somatic pain syndromes and what is known about microbe-neuron interactions. Investigations are needed to determine the specific role of the gut microbiome in this type of pain which may help inform the development of preventative interventions as well as management strategies to improve patient outcome.
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Affiliation(s)
- David Brenner
- Department of Anesthesia and Intensive Care Medicine, Cork University Hospital and University College Cork, Ireland
| | - George D Shorten
- Department of Anesthesia and Intensive Care Medicine, Cork University Hospital and University College Cork, Ireland
| | - Siobhain M O'Mahony
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
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35
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Retamal JS, Grace MS, Dill LK, Ramirez-Garcia P, Peng S, Gondin AB, Bennetts F, Alvi S, Rajasekhar P, Almazi JG, Carbone SE, Bunnett NW, Davis TP, Veldhuis NA, Poole DP, McIntyre P. Serotonin-induced vascular permeability is mediated by transient receptor potential vanilloid 4 in the airways and upper gastrointestinal tract of mice. J Transl Med 2021; 101:851-864. [PMID: 33859334 PMCID: PMC8047529 DOI: 10.1038/s41374-021-00593-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 03/12/2021] [Accepted: 03/14/2021] [Indexed: 01/07/2023] Open
Abstract
Endothelial and epithelial cells form physical barriers that modulate the exchange of fluid and molecules. The integrity of these barriers can be influenced by signaling through G protein-coupled receptors (GPCRs) and ion channels. Serotonin (5-HT) is an important vasoactive mediator of tissue edema and inflammation. However, the mechanisms that drive 5-HT-induced plasma extravasation are poorly defined. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an established enhancer of signaling by GPCRs that promote inflammation and endothelial barrier disruption. Here, we investigated the role of TRPV4 in 5-HT-induced plasma extravasation using pharmacological and genetic approaches. Activation of either TRPV4 or 5-HT receptors promoted significant plasma extravasation in the airway and upper gastrointestinal tract of mice. 5-HT-mediated extravasation was significantly reduced by pharmacological inhibition of the 5-HT2A receptor subtype, or with antagonism or deletion of TRPV4, consistent with functional interaction between 5-HT receptors and TRPV4. Inhibition of receptors for the neuropeptides substance P (SP) or calcitonin gene-related peptide (CGRP) diminished 5-HT-induced plasma extravasation. Supporting studies assessing treatment of HUVEC with 5-HT, CGRP, or SP was associated with ERK phosphorylation. Exposure to the TRPV4 activator GSK1016790A, but not 5-HT, increased intracellular Ca2+ in these cells. However, 5-HT pre-treatment enhanced GSK1016790A-mediated Ca2+ signaling, consistent with sensitization of TRPV4. The functional interaction was further characterized in HEK293 cells expressing 5-HT2A to reveal that TRPV4 enhances the duration of 5-HT-evoked Ca2+ signaling through a PLA2 and PKC-dependent mechanism. In summary, this study demonstrates that TRPV4 contributes to 5-HT2A-induced plasma extravasation in the airways and upper GI tract, with evidence supporting a mechanism of action involving SP and CGRP release.
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Affiliation(s)
- Jeffri S Retamal
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia
| | - Megan S Grace
- School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia
- Department of Physiology, School of Medicine Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
- Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia
- School of Clinical Medicine, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Larissa K Dill
- School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Paulina Ramirez-Garcia
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia
| | - Scott Peng
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia
| | - Arisbel B Gondin
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia
| | - Felix Bennetts
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Sadia Alvi
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Pradeep Rajasekhar
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia
| | - Juhura G Almazi
- School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia
| | - Simona E Carbone
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia
| | - Nigel W Bunnett
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, USA
| | - Thomas P Davis
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia
| | - Nicholas A Veldhuis
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia.
| | - Daniel P Poole
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash University, Parkville, VIC, Australia.
| | - Peter McIntyre
- School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
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36
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Dvornikova KA, Bystrova EY, Churilov LP, Lerner A. Pathogenesis of the inflammatory bowel disease in context of SARS-COV-2 infection. Mol Biol Rep 2021; 48:5745-5758. [PMID: 34296352 PMCID: PMC8297608 DOI: 10.1007/s11033-021-06565-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023]
Abstract
To date, the latest research results suggest that the novel severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) can enter host cells directly via the gastrointestinal tract by binding to the enterocyte-expressed ACE2 receptor, or indirectly as a result of infection of type II alveolar epithelial cells. At the same time, entry of SARS-CoV-2 through the gastrointestinal tract initiates the activation of innate and adaptive immune responses, the formation of an excessive inflammatory reaction and critical increase in the expression of proinflammatory cytokines, which, subsequently, can presumably increase inflammation and induce intestinal damage in patients suffering from inflammatory bowel disease (IBD). The aims of the present review were to reveal and analyze possible molecular pathways and consequences of the induction of an innate and adaptive immune response during infection with SARS-CoV-2 in patients with IBD. A thorough literature search was carried out by using the keywords: IBD, SARS-CoV-2, COVID-19. Based on the screening, a number of intracellular and extracellular pathways were considered and discussed, which can impact the immune response during SARS-CoV-2 infection in IBD patients. Additionally, the possible consequences of the infection for such patients were estimated. We further hypothesize that any virus, including the new SARS-CoV-2, infecting intestinal tissues and/or entering the host's body through receptors located on intestinal enterocytes may be a trigger for the onset of IBD in individuals with a genetic predisposition and/or the risk of developing IBD associated with other factors.
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Affiliation(s)
- K. A. Dvornikova
- Pavlov Institute of Physiology, Russian Academy of Sciences, Saint Petersburg, Russian Federation
| | - E. Yu. Bystrova
- Pavlov Institute of Physiology, Russian Academy of Sciences, Saint Petersburg, Russian Federation
| | - L. P. Churilov
- Saint Petersburg State University, Saint Petersburg, Russian Federation
| | - A. Lerner
- Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, Israel
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37
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Brizuela M, Castro J, Harrington AM, Brierley SM. Pruritogenic mechanisms and gut sensation: putting the "irritant" into irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2021; 320:G1131-G1141. [PMID: 33949199 DOI: 10.1152/ajpgi.00331.2020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic abdominal pain is a common clinical condition experienced by patients with irritable bowel syndrome (IBS). A general lack of suitable treatment options for the management of visceral pain is the major contributing factor to the debilitating nature of the disease. Understanding the underlying causes of chronic visceral pain is pivotal to identifying new effective therapies for IBS. This review provides the current evidence, demonstrating that mediators and receptors that induce itch in the skin also act as "gut irritants" in the gastrointestinal tract. Activation of these receptors triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system leading to visceral hypersensitivity and visceral pain. Accumulating evidence points to significant roles of irritant mediators and their receptors in visceral hypersensitivity and thus constitutes potential targets for the development of more effective therapeutic options for IBS.
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Affiliation(s)
- Mariana Brizuela
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Joel Castro
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Andrea M Harrington
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Stuart M Brierley
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia.,Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.,Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
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38
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Gottesman-Katz L, Latorre R, Vanner S, Schmidt BL, Bunnett NW. Targeting G protein-coupled receptors for the treatment of chronic pain in the digestive system. Gut 2021; 70:970-981. [PMID: 33272979 PMCID: PMC9716638 DOI: 10.1136/gutjnl-2020-321193] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 10/21/2020] [Accepted: 11/07/2020] [Indexed: 12/14/2022]
Abstract
Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.
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Affiliation(s)
- Lena Gottesman-Katz
- Molecular Pathobiology, New York University, New York, New York, USA,Division of Pediatric Gastroenterology, Columbia University Medical Center/New York Presbyterian, New York, New York, USA
| | - Rocco Latorre
- Molecular Pathobiology, New York University, New York, New York, USA
| | - Stephen Vanner
- Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queens University, Kingston, Ontario, Canada
| | - Brian L Schmidt
- Bluestone Center, New York University, New York, New York, USA
| | - Nigel W Bunnett
- Molecular Pathobiology, New York University, New York, New York, USA
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39
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Lagomarsino VN, Kostic AD, Chiu IM. Mechanisms of microbial-neuronal interactions in pain and nociception. NEUROBIOLOGY OF PAIN 2020; 9:100056. [PMID: 33392418 PMCID: PMC7772816 DOI: 10.1016/j.ynpai.2020.100056] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 11/18/2020] [Accepted: 11/27/2020] [Indexed: 02/06/2023]
Abstract
Molecular mechanisms of how microorganisms communicate with sensory afferent neurons. How pathogenic microorganisms directly communicate with nociceptor neurons to inflict pain on the host. Symbiotic bacterial communication with gut-extrinsic sensory afferent neurons. Plausible roles on how gut symbionts directly mediate pain and nociception. Nociceptor sensory neurons innervate barrier tissues that are constantly exposed to microbial stimuli. During infection, pathogenic microorganisms can breach barrier surfaces and produce pain by directly activating nociceptors. Microorganisms that live in symbiotic relationships with their hosts, commensals and mutualists, have also been associated with pain, but the molecular mechanisms of how symbionts act on nociceptor neurons to modulate pain remain largely unknown. In this review, we will discuss the known molecular mechanisms of how microbes directly interact with sensory afferent neurons affecting nociception in the gut, skin and lungs. We will touch on how bacterial, viral and fungal pathogens signal to the host to inflict or suppress pain. We will also discuss recent studies examining how gut symbionts affect pain. Specifically, we will discuss how gut symbionts may interact with sensory afferent neurons either directly, through secretion of metabolites or neurotransmitters, or indirectly,through first signaling to epithelial cells or immune cells, to regulate visceral, neuropathic and inflammatory pain. While this area of research is still in its infancy, more mechanistic studies to examine microbial-sensory neuron crosstalk in nociception may allow us to develop new therapies for the treatment of acute and chronic pain.
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Affiliation(s)
- Valentina N Lagomarsino
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.,Joslin Diabetes Center, Boston, MA 02115, USA.,Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Aleksandar D Kostic
- Joslin Diabetes Center, Boston, MA 02115, USA.,Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Isaac M Chiu
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
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40
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McClain JL, Mazzotta EA, Maradiaga N, Duque-Wilckens N, Grants I, Robison AJ, Christofi FL, Moeser AJ, Gulbransen BD. Histamine-dependent interactions between mast cells, glia, and neurons are altered following early-life adversity in mice and humans. Am J Physiol Gastrointest Liver Physiol 2020; 319:G655-G668. [PMID: 32996781 PMCID: PMC7792668 DOI: 10.1152/ajpgi.00041.2020] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Early-life adversity contributes to the development of functional bowel disorders later in life through unresolved mechanisms. Here, we tested the hypothesis that early-life adversity alters anatomical and functional interactions between mast cells and enteric glia. The effects of early-life stress were studied using the neonatal maternal separation (NMS) stress mouse model. Anatomical relationships between mast cells and enteric glia were assessed using immunohistochemistry and mast cell reporter mice (Mcpt5Cre;GCaMP5g-tdT). Immunohistochemistry was used to assess the expression of histamine, histamine 1 (H1) receptors, and glial fibrillary acidic protein. Functional responses of glia to mast cell mediators were assessed in calcium imaging experiments using Sox10CreERT2;GCaMP5g-tdT mice and cultured human enteric glial cells. NMS increases mast cell numbers at the level of the myenteric plexus and their proximity to myenteric ganglia. Myenteric glia respond to mediators released by activated mast cells that are blocked by H1 receptor antagonists in mice and humans and by blocking neuronal activity with tetrodotoxin in mouse tissue. Histamine replicates the effects of mast cell supernatants on enteric glia, and NMS increases histamine production by mast cells. NMS reduces glial responses to mast cell mediators in mouse tissue, while potentiating responses in cultured human enteric glia. NMS increases myenteric glial fibrillary acidic protein expression and reduces glial process length but does not cause neurodegeneration. Histamine receptor expression is not altered by NMS and is localized to neurons in mice, but glia in humans. Early-life stress increases the potential for interactions between enteric glia and mast cells, and histamine is a potential mediator of mast cell-glial interactions through H1 receptors. We propose that glial-mast cell signaling is a mechanism that contributes to enteric neuroplasticity driven by early-life adversity.NEW & NOTEWORTHY Early-life adversity places an individual at risk for developing functional gastrointestinal disorders later in life through unknown mechanisms. Here, we show that interactions between mast cells and glia are disrupted by early-life stress in mice and that histamine is a potential mediator of mast cell-glial interactions.
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Affiliation(s)
- Jonathon L. McClain
- 1Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Elvio A. Mazzotta
- 2Department of Anesthesiology, The Wexner Medical Center, The Ohio State University, Columbus, Ohio
| | - Nidia Maradiaga
- 3Gastrointestinal Stress Biology Laboratory, Department Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan
| | - Natalia Duque-Wilckens
- 1Department of Physiology, Michigan State University, East Lansing, Michigan,3Gastrointestinal Stress Biology Laboratory, Department Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan
| | - Iveta Grants
- 2Department of Anesthesiology, The Wexner Medical Center, The Ohio State University, Columbus, Ohio
| | - Alfred J. Robison
- 1Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Fievos L. Christofi
- 2Department of Anesthesiology, The Wexner Medical Center, The Ohio State University, Columbus, Ohio
| | - Adam J. Moeser
- 1Department of Physiology, Michigan State University, East Lansing, Michigan,3Gastrointestinal Stress Biology Laboratory, Department Large Animal Clinical Sciences, Michigan State University, East Lansing, Michigan
| | - Brian D. Gulbransen
- 1Department of Physiology, Michigan State University, East Lansing, Michigan
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41
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Silverman HA, Chen A, Kravatz NL, Chavan SS, Chang EH. Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation. Front Immunol 2020; 11:590261. [PMID: 33193423 PMCID: PMC7645044 DOI: 10.3389/fimmu.2020.590261] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 09/30/2020] [Indexed: 12/11/2022] Open
Abstract
Transient receptor potential (TRP) channels are a superfamily of non-selective cation channels that act as polymodal sensors in many tissues throughout mammalian organisms. In the context of ion channels, they are unique for their broad diversity of activation mechanisms and their cation selectivity. TRP channels are involved in a diverse range of physiological processes including chemical sensing, nociception, and mediating cytokine release. They also play an important role in the regulation of inflammation through sensory function and the release of neuropeptides. In this review, we discuss the functional contribution of a subset of TRP channels (TRPV1, TRPV4, TRPM3, TRPM8, and TRPA1) that are involved in the body’s immune responses, particularly in relation to inflammation. We focus on these five TRP channels because, in addition to being expressed in many somatic cell types, these channels are also expressed on peripheral ganglia and nerves that innervate visceral organs and tissues throughout the body. Activation of these neural TRP channels enables crosstalk between neurons, immune cells, and epithelial cells to regulate a wide range of inflammatory actions. TRP channels act either through direct effects on cation levels or through indirect modulation of intracellular pathways to trigger pro- or anti-inflammatory mechanisms, depending on the inflammatory disease context. The expression of TRP channels on both neural and immune cells has made them an attractive drug target in diseases involving inflammation. Future work in this domain will likely yield important new pathways and therapies for the treatment of a broad range of disorders including colitis, dermatitis, sepsis, asthma, and pain.
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Affiliation(s)
- Harold A Silverman
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Adrian Chen
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Nigel L Kravatz
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Sangeeta S Chavan
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, NY, United States
| | - Eric H Chang
- Laboratory of Biomedical Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States.,Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, NY, United States
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42
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Sarnelli G, Pesce M, Seguella L, Lu J, Efficie E, Tack J, Elisa De Palma FD, D’Alessandro A, Esposito G. Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia. Cell Mol Gastroenterol Hepatol 2020; 11:841-855. [PMID: 33065341 PMCID: PMC7858681 DOI: 10.1016/j.jcmgh.2020.10.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 10/01/2020] [Accepted: 10/07/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Acid hypersensitivity is claimed to be a symptomatic trigger in functional dyspepsia (FD); however, the neuroimmune pathway(s) and the mediators involved in this process have not been investigated systematically. Palmitoylethanolamide (PEA) is an endogenous compound, able to modulate nociception and inflammation, but its role in FD has not been assessed. METHODS Duodenal biopsy specimens from FD and control subjects, and peroxisome proliferator-activated receptor-α (PPARα) null mice were cultured at a pH of 3.0 and 7.4. Mast cell (MC) number, the release of their mediators, and the expression of transient receptor potential vanilloid receptor (TRPV)1 and TRPV4, were evaluated. All measurements also were performed in the presence of a selective blocker of neuronal action potential (tetradotoxin). FD and control biopsy specimens in acidified medium also were incubated in the presence of different PEA concentrations, alone or combined with a selective PPARα or PPAR-γ antagonist. RESULTS An acid-induced increase in MC density and the release of their mediators were observed in both dyspeptic patients and controls; however, this response was amplified significantly in FD. This effect was mediated by submucosal nerve fibers and up-regulation of TRPV1 and TRPV4 receptors because pretreatment with tetradotoxin significantly reduced MC infiltration. The acid-induced endogenous release of PEA was impaired in FD and its exogenous administration counteracts MC activation and TRPV up-regulation. CONCLUSIONS Duodenal acid exposure initiates a cascade of neuronal-mediated events culminating in MC activation and TRPV overexpression. These phenomena are consequences of an impaired release of endogenous PEA. PEA might be regarded as an attractive therapeutic strategy for the treatment of FD.
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Affiliation(s)
- Giovanni Sarnelli
- Department of Clinical Medicine and Surgery, Naples, Italy,United Nations Educational, Scientific and Cultural Organization Chair, University of Naples "Federico II," Naples, Italy,Correspondence Address correspondence to: Giovanni Sarnelli, MD, PhD, Department of Clinical Medicine and Surgery, University of Naples "Federico II," Via Pansini 5 80131, Naples, Italy. fax: (39) 0817463892.
| | - Marcella Pesce
- Department of Clinical Medicine and Surgery, Naples, Italy
| | - Luisa Seguella
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Jie Lu
- Department of Human Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang City, Liaoning, China
| | | | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Fatima Domenica Elisa De Palma
- Centro Ingegneria Genetica-Biotecnologie Avanzate s.c.a rl, Department of Molecular Medicine and Medical Biotechnologies, Naples, Italy
| | | | - Giuseppe Esposito
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
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43
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Carco C, Young W, Gearry RB, Talley NJ, McNabb WC, Roy NC. Increasing Evidence That Irritable Bowel Syndrome and Functional Gastrointestinal Disorders Have a Microbial Pathogenesis. Front Cell Infect Microbiol 2020; 10:468. [PMID: 33014892 PMCID: PMC7509092 DOI: 10.3389/fcimb.2020.00468] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
The human gastrointestinal tract harbors most of the microbial cells inhabiting the body, collectively known as the microbiota. These microbes have several implications for the maintenance of structural integrity of the gastrointestinal mucosal barrier, immunomodulation, metabolism of nutrients, and protection against pathogens. Dysfunctions in these mechanisms are linked to a range of conditions in the gastrointestinal tract, including functional gastrointestinal disorders, ranging from irritable bowel syndrome, to functional constipation and functional diarrhea. Irritable bowel syndrome is characterized by chronic abdominal pain with changes in bowel habit in the absence of morphological changes. Despite the high prevalence of irritable bowel syndrome in the global population, the mechanisms responsible for this condition are poorly understood. Although alterations in the gastrointestinal microbiota, low-grade inflammation and immune activation have been implicated in the pathophysiology of functional gastrointestinal disorders, there is inconsistency between studies and a lack of consensus on what the exact role of the microbiota is, and how changes to it relate to these conditions. The complex interplay between host factors, such as microbial dysbiosis, immune activation, impaired epithelial barrier function and motility, and environmental factors, including diet, will be considered in this narrative review of the pathophysiology of functional gastrointestinal disorders.
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Affiliation(s)
- Caterina Carco
- School of Food and Advanced Technology, Massey University, Palmerston North, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand.,Food Nutrition and Health Team, AgResearch Grasslands, Palmerston North, New Zealand.,The High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Wayne Young
- Riddet Institute, Massey University, Palmerston North, New Zealand.,Food Nutrition and Health Team, AgResearch Grasslands, Palmerston North, New Zealand.,The High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Richard B Gearry
- The High-Value Nutrition National Science Challenge, Auckland, New Zealand.,Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Nicholas J Talley
- Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
| | - Warren C McNabb
- Riddet Institute, Massey University, Palmerston North, New Zealand.,The High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Nicole C Roy
- Riddet Institute, Massey University, Palmerston North, New Zealand.,The High-Value Nutrition National Science Challenge, Auckland, New Zealand.,Liggins Institute, University of Auckland, Auckland, New Zealand.,Department of Human Nutrition, University of Otago, Dunedin, New Zealand
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44
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Grubišić V, McClain JL, Fried DE, Grants I, Rajasekhar P, Csizmadia E, Ajijola OA, Watson RE, Poole DP, Robson SC, Christofi FL, Gulbransen BD. Enteric Glia Modulate Macrophage Phenotype and Visceral Sensitivity following Inflammation. Cell Rep 2020; 32:108100. [PMID: 32905782 PMCID: PMC7518300 DOI: 10.1016/j.celrep.2020.108100] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 07/02/2020] [Accepted: 08/11/2020] [Indexed: 12/20/2022] Open
Abstract
Mechanisms resulting in abdominal pain include altered neuro-immune interactions in the gastrointestinal tract, but the signaling processes that link immune activation with visceral hypersensitivity are unresolved. We hypothesized that enteric glia link the neural and immune systems of the gut and that communication between enteric glia and immune cells modulates the development of visceral hypersensitivity. To this end, we manipulated a major mechanism of glial intercellular communication that requires connexin-43 and assessed the effects on acute and chronic inflammation, visceral hypersensitivity, and immune responses. Deleting connexin-43 in glia protected against the development of visceral hypersensitivity following chronic colitis. Mechanistically, the protective effects of glial manipulation were mediated by disrupting the glial-mediated activation of macrophages through the macrophage colony-stimulating factor. Collectively, our data identified enteric glia as a critical link between gastrointestinal neural and immune systems that could be harnessed by therapies to ameliorate abdominal pain.
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Affiliation(s)
- Vladimir Grubišić
- Department of Physiology and Neuroscience Program, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA
| | - Jonathon L McClain
- Department of Physiology and Neuroscience Program, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA
| | - David E Fried
- Department of Physiology and Neuroscience Program, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA
| | - Iveta Grants
- Department of Anesthesiology, The Wexner Medical Center, The Ohio State University, 420 West 12th Avenue, Room 216, Columbus, OH 43210, USA
| | - Pradeep Rajasekhar
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Melbourne, VIC, Australia
| | - Eva Csizmadia
- Division of Gastroenterology, Department of Medicine and of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Olujimi A Ajijola
- Cardiac Arrhythmia Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA
| | - Ralph E Watson
- Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Daniel P Poole
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Melbourne, VIC, Australia
| | - Simon C Robson
- Division of Gastroenterology, Department of Medicine and of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Fievos L Christofi
- Department of Anesthesiology, The Wexner Medical Center, The Ohio State University, 420 West 12th Avenue, Room 216, Columbus, OH 43210, USA
| | - Brian D Gulbransen
- Department of Physiology and Neuroscience Program, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, USA.
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45
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Lin B, Wang Y, Zhang P, Yuan Y, Zhang Y, Chen G. Gut microbiota regulates neuropathic pain: potential mechanisms and therapeutic strategy. J Headache Pain 2020; 21:103. [PMID: 32807072 PMCID: PMC7433133 DOI: 10.1186/s10194-020-01170-x] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 08/10/2020] [Indexed: 02/08/2023] Open
Abstract
Neuropathic pain (NP) is a sustained and nonreversible condition characterized by long-term devastating physical and psychological damage. Therefore, it is urgent to identify an effective treatment for NP. Unfortunately, the precise pathogenesis of NP has not been elucidated. Currently, the microbiota-gut-brain axis has drawn increasing attention, and the emerging role of gut microbiota is investigated in numerous diseases including NP. Gut microbiota is considered as a pivotal regulator in immune, neural, endocrine, and metabolic signaling pathways, which participates in forming a complex network to affect the development of NP directly or indirectly. In this review, we conclude the current understanding of preclinical and clinical findings regarding the role of gut microbiota in NP and provide a novel therapeutic method for pain relief by medication and dietary interventions.
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Affiliation(s)
- Binbin Lin
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Zhejiang, 310016, Hangzhou, China
| | - Yuting Wang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Zhejiang, 310016, Hangzhou, China
| | - Piao Zhang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Zhejiang, 310016, Hangzhou, China
| | - Yanyan Yuan
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Zhejiang, 310016, Hangzhou, China
| | - Ying Zhang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Zhejiang, 310016, Hangzhou, China
| | - Gang Chen
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun East Road, Zhejiang, 310016, Hangzhou, China.
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46
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Chen Y, Mu J, Zhu M, Mukherjee A, Zhang H. Transient Receptor Potential Channels and Inflammatory Bowel Disease. Front Immunol 2020; 11:180. [PMID: 32153564 PMCID: PMC7044176 DOI: 10.3389/fimmu.2020.00180] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/23/2020] [Indexed: 02/05/2023] Open
Abstract
The transient receptor potential (TRP) cation channels are present in abundance across the gastrointestinal (GI) tract, serving as detectors for a variety of stimuli and secondary transducers for G-protein coupled receptors. The activation of TRP channels triggers neurogenic inflammation with related neuropeptides and initiates immune reactions by extra-neuronally regulating immune cells, contributing to the GI homeostasis. However, under pathological conditions, such as inflammatory bowel disease (IBD), TRP channels are involved in intestinal inflammation. An increasing number of human and animal studies have indicated that TRP channels are correlated to the visceral hypersensitivity (VHS) and immune pathogenesis in IBD, leading to an exacerbation or amelioration of the VHS or intestinal inflammation. Thus, TRP channels are a promising target for novel therapeutic methods for IBD. In this review, we comprehensively summarize the functions of TRP channels, especially their potential roles in immunity and IBD. Additionally, we discuss the contradictory findings of prior studies and offer new insights with regard to future research.
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Affiliation(s)
- Yiding Chen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Jingxi Mu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Min Zhu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
| | | | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
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47
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Grundy L, Caldwell A, Garcia Caraballo S, Erickson A, Schober G, Castro J, Harrington AM, Brierley SM. Histamine induces peripheral and central hypersensitivity to bladder distension via the histamine H1 receptor and TRPV1. Am J Physiol Renal Physiol 2020; 318:F298-F314. [DOI: 10.1152/ajprenal.00435.2019] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common chronic pelvic disorder with sensory symptoms of urinary urgency, frequency, and pain, indicating a key role for hypersensitivity of bladder-innervating sensory neurons. The inflammatory mast cell mediator histamine has long been implicated in IC/BPS, yet the direct interactions between histamine and bladder afferents remain unclear. In the present study, we show, using a mouse ex vivo bladder afferent preparation, that intravesical histamine enhanced the mechanosensitivity of subpopulations of afferents to bladder distension. Histamine also recruited “silent afferents” that were previously unresponsive to bladder distension. Furthermore, in vivo intravesical histamine enhanced activation of dorsal horn neurons within the lumbosacral spinal cord, indicating increased afferent signaling in the central nervous system. Quantitative RT-PCR revealed significant expression of histamine receptor subtypes ( Hrh1– Hrh3) in mouse lumbosacral dorsal root ganglia (DRG), bladder detrusor smooth muscle, mucosa, and isolated urothelial cells. In DRG, Hrh1 was the most abundantly expressed. Acute histamine exposure evoked Ca2+ influx in select populations of DRG neurons but did not elicit calcium transients in isolated primary urothelial cells. Histamine-induced mechanical hypersensitivity ex vivo was abolished in the presence of the histamine H1 receptor antagonist pyrilamine and was not present in preparations from mice lacking transient receptor potential vanilloid 1 (TRPV1). Together, these results indicate that histamine enhances the sensitivity of bladder afferents to distension via interactions with histamine H1 receptor and TRPV1. This hypersensitivity translates to increased sensory input and activation in the spinal cord, which may underlie the symptoms of bladder hypersensitivity and pain experienced in IC/BPS.
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Affiliation(s)
- Luke Grundy
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, Faculty of Health and Medical Science, University of Adelaide, Adelaide, South Australia, Australia
- Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, South Australia, Australia
| | - Ashlee Caldwell
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, Faculty of Health and Medical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Sonia Garcia Caraballo
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, Faculty of Health and Medical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Andelain Erickson
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, Faculty of Health and Medical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Gudrun Schober
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, Faculty of Health and Medical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Joel Castro
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, Faculty of Health and Medical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Andrea M. Harrington
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, Faculty of Health and Medical Science, University of Adelaide, Adelaide, South Australia, Australia
| | - Stuart M. Brierley
- Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, Faculty of Health and Medical Science, University of Adelaide, Adelaide, South Australia, Australia
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48
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Manion J, Waller MA, Clark T, Massingham JN, Neely GG. Developing Modern Pain Therapies. Front Neurosci 2019; 13:1370. [PMID: 31920521 PMCID: PMC6933609 DOI: 10.3389/fnins.2019.01370] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 12/04/2019] [Indexed: 12/24/2022] Open
Abstract
Chronic pain afflicts as much as 50% of the population at any given time but our methods to address pain remain limited, ineffective and addictive. In order to develop new therapies an understanding of the mechanisms of painful sensitization is essential. We discuss here recent progress in the understanding of mechanisms underlying pain, and how these mechanisms are being targeted to produce modern, specific therapies for pain. Finally, we make recommendations for the next generation of targeted, effective, and safe pain therapies.
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Affiliation(s)
- John Manion
- The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia
| | - Matthew A. Waller
- The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia
| | - Teleri Clark
- The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia
| | - Joshua N. Massingham
- The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia
| | - G. Gregory Neely
- The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia
- Genome Editing Initiative, The University of Sydney, Sydney, NSW, Australia
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49
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Stakenborg N, Viola MF, Boeckxstaens GE. Intestinal neuro-immune interactions: focus on macrophages, mast cells and innate lymphoid cells. Curr Opin Neurobiol 2019; 62:68-75. [PMID: 31862627 PMCID: PMC7294228 DOI: 10.1016/j.conb.2019.11.020] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/19/2019] [Accepted: 11/25/2019] [Indexed: 12/27/2022]
Abstract
Neuro-immune crosstalk occurs in distinct anatomical niches in the intestine. Neuro-immune cell niches maintain gut homeostasis and modulate inflammation. Neuron-macrophage crosstalk in the muscularis is crucial for neuronal survival and peristalsis. Mast cell mediators activate and sensitize nerve terminals, leading to aberrant pain perception. Neurons modulate ILC function during infection and inflammation. Intestinal homeostasis relies on the reciprocal crosstalk between enteric neurons and immune cells, which together form neuro-immune units that occupy distinct anatomical niches within the gut. Here we will review the recent advances in our understanding of neuro-immune crosstalk within the gut, with focus on macrophages, mast cells and innate lymphoid cells. In particular, we will discuss the role of neuron-immune cell crosstalk in homeostasis, and how aberrant communication may underlie disease in the gastro-intestinal tract.
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Affiliation(s)
- Nathalie Stakenborg
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Maria F Viola
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium.
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Castro J, Harrington AM, Lieu T, Garcia-Caraballo S, Maddern J, Schober G, O’Donnell T, Grundy L, Lumsden AL, Miller P, Ghetti A, Steinhoff MS, Poole DP, Dong X, Chang L, Bunnett NW, Brierley SM. Activation of pruritogenic TGR5, MrgprA3, and MrgprC11 on colon-innervating afferents induces visceral hypersensitivity. JCI Insight 2019; 4:131712. [PMID: 31536477 PMCID: PMC6824308 DOI: 10.1172/jci.insight.131712] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 09/11/2019] [Indexed: 12/17/2022] Open
Abstract
Itch induces scratching that removes irritants from the skin, whereas pain initiates withdrawal or avoidance of tissue damage. While pain arises from both the skin and viscera, we investigated whether pruritogenic irritant mechanisms also function within visceral pathways. We show that subsets of colon-innervating sensory neurons in mice express, either individually or in combination, the pruritogenic receptors Tgr5 and the Mas-gene-related GPCRs Mrgpra3 and Mrgprc11. Agonists of these receptors activated subsets of colonic sensory neurons and evoked colonic afferent mechanical hypersensitivity via a TRPA1-dependent mechanism. In vivo intracolonic administration of individual TGR5, MrgprA3, or MrgprC11 agonists induced pronounced visceral hypersensitivity to colorectal distension. Coadministration of these agonists as an "itch cocktail" augmented hypersensitivity to colorectal distension and changed mouse behavior. These irritant mechanisms were maintained and enhanced in a model of chronic visceral hypersensitivity relevant to irritable bowel syndrome. Neurons from human dorsal root ganglia also expressed TGR5, as well as the human ortholog MrgprX1, and showed increased responsiveness to pruritogenic agonists in pathological states. These data support the existence of an irritant-sensing system in the colon that is a visceral representation of the itch pathways found in skin, thereby contributing to sensory disturbances accompanying common intestinal disorders.
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Affiliation(s)
- Joel Castro
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Andrea M. Harrington
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - TinaMarie Lieu
- Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Sonia Garcia-Caraballo
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Jessica Maddern
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Gudrun Schober
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Tracey O’Donnell
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Luke Grundy
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Amanda L. Lumsden
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Paul Miller
- AnaBios Corporation, San Diego, California, USA
| | | | - Martin S. Steinhoff
- Department of Dermatology and Dermatology Immunology Institute, Hamad Medical Corporation, Doha, Qatar
- Department of Dermatology, Weill Cornell Medicine-Qatar and Weill Cornell University, New York, New York, USA
- School of Medicine Qatar University, Doha, Qatar
| | - Daniel P. Poole
- Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, School of Medicine, Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland, USA
| | - Lin Chang
- G. Oppenheimer Centre for Neurobiology of Stress and Resilience, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA
| | - Nigel W. Bunnett
- Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia
- Department of Surgery and
- Department of Pharmacology, Columbia University, New York, New York, USA
| | - Stuart M. Brierley
- Visceral Pain Research Group, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
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