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Delprete C, Uhlig F, Caprini M, Hyland NP. Characterization of Fabry disease-associated lyso-Gb 3 on mouse colonic ion transport and motility. Am J Physiol Gastrointest Liver Physiol 2024; 327:G810-G817. [PMID: 39404773 DOI: 10.1152/ajpgi.00220.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 10/08/2024] [Accepted: 10/09/2024] [Indexed: 11/12/2024]
Abstract
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency in α-galactosidase A leading to the accumulation of globotriaosylceramide (Gb3) and subsequent increase in globotriaosylsphingosine (lyso-Gb3) in different cells and organs, including the gastrointestinal (GI) tract. GI symptoms represent some of the earliest manifestations of FD and significantly impact quality of life. The origin of these symptoms is complex, and the exact mechanisms remain poorly understood. Here, we sought to determine whether lyso-Gb3 contributes to the pathophysiology of GI symptoms associated with FD by examining its effects on mouse colonic ion transport and motility ex vivo using Ussing chambers and organ baths, respectively. Lyso-Gb3 significantly increased colonic baseline short-circuit current (Isc). This increase in Isc was insensitive to inhibition of the cystic fibrosis transmembrane conductance regulator and Na-K-Cl cotransporter 1, suggesting that the increase in Isc is Cl- ion independent. This response was also insensitive to inhibition by the neurotoxin, tetrodotoxin. In addition, pretreatment with lyso-Gb3 did not significantly influence subsequent responses to either veratridine or capsaicin implying that the response to lyso-Gb3 does not involve the enteric nervous system. In terms of colonic motility, lyso-Gb3 did not significantly influence colonic tone, spontaneous contractility, or cholinergic-induced contractions. These data suggest that lyso-Gb3 significantly influences ion transport in mouse colon, but that accumulation of Gb3 may be a prerequisite for the more pronounced disturbances in GI physiology characteristic of FD.NEW & NOTEWORTHY Fabry disease-associated lyso-Gb3 significantly influences mouse colonic ion transport in a Cl- ion-independent manner.
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Affiliation(s)
- Cecilia Delprete
- Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Friederike Uhlig
- Department of Physiology and APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Marco Caprini
- Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Niall P Hyland
- Department of Physiology and APC Microbiome Ireland, University College Cork, Cork, Ireland
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2
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Tough IR, Lund ML, Patel BA, Schwartz TW, Cox HM. Paracrine relationship between incretin hormones and endogenous 5-hydroxytryptamine in the small and large intestine. Neurogastroenterol Motil 2023; 35:e14589. [PMID: 37010838 PMCID: PMC10909488 DOI: 10.1111/nmo.14589] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 02/13/2023] [Accepted: 03/21/2023] [Indexed: 04/04/2023]
Abstract
BACKGROUND Enterochromaffin (EC) cell-derived 5-hydroxytryptamine (5-HT) is a mediator of toxin-induced reflexes, initiating emesis via vagal and central 5-HT3 receptors. The amine is also involved in gastrointestinal (GI) reflexes that are prosecretory and promotile, and recently 5-HT's roles in chemosensation in the distal bowel have been described. We set out to establish the efficacy of 5-HT signaling, local 5-HT levels and pharmacology in discrete regions of the mouse small and large intestine. We also investigated the inter-relationships between incretin hormones, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) and endogenous 5-HT in mucosal and motility assays. METHODS Adult mouse GI mucosae were mounted in Ussing chambers and area-specific studies were performed to establish the 5-HT3 and 5-HT4 pharmacology, the sidedness of responses, and the inter-relationships between incretins and endogenous 5-HT. Natural fecal pellet transit in vitro and full-length GI transit in vivo were also measured. KEY RESULTS We observed the greatest level of tonic and exogenous 5-HT-induced ion transport and highest levels of 5-HT in ascending colon mucosa. Here both 5-HT3 and 5-HT4 receptors were involved but elsewhere in the GI tract epithelial basolateral 5-HT4 receptors mediate 5-HT's prosecretory effect. Exendin-4 and GIP induced 5-HT release in the ascending colon, while L cell-derived PYY also contributed to GIP mucosal effects in the descending colon. Both peptides slowed colonic transit. CONCLUSIONS & INFERENCES We provide functional evidence for paracrine interplay between 5-HT, GLP-1 and GIP, particularly in the colonic mucosal region. Basolateral epithelial 5-HT4 receptors mediated both 5-HT and incretin mucosal responses in healthy colon.
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Affiliation(s)
- Iain R. Tough
- Wolfson Centre for Age‐Related Diseases, Institute of Psychology, Psychiatry and NeuroscienceKing's College LondonHodgkin Building, Guy's CampusLondonSE1 1ULUK
| | - Mari L. Lund
- The Novo Nordisk Foundation Centre for Basic Metabolic Research, Section for Metabolic Receptology and EnteroendocrinologyUniversity of CopenhagenCopenhagenDK‐2200Denmark
- Present address:
Chr. Hansen A/S, Human Health ResearchHoersholmDK‐2970Denmark
| | - Bhavik A. Patel
- Centre for Stress and Age‐Related Diseases, School of Applied SciencesUniversity of BrightonBrightonUK
| | - Thue W. Schwartz
- The Novo Nordisk Foundation Centre for Basic Metabolic Research, Section for Metabolic Receptology and EnteroendocrinologyUniversity of CopenhagenCopenhagenDK‐2200Denmark
| | - Helen M. Cox
- Wolfson Centre for Age‐Related Diseases, Institute of Psychology, Psychiatry and NeuroscienceKing's College LondonHodgkin Building, Guy's CampusLondonSE1 1ULUK
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Chakroborty D, Goswami S, Fan H, Frankel WL, Basu S, Sarkar C. Neuropeptide Y, a paracrine factor secreted by cancer cells, is an independent regulator of angiogenesis in colon cancer. Br J Cancer 2022; 127:1440-1449. [PMID: 35902640 PMCID: PMC9553928 DOI: 10.1038/s41416-022-01916-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Resistance to anti-angiogenic therapies targeting vascular endothelial growth factor-A (VEGF-A) stems from VEGF-A independent angiogenesis mediated by other proangiogenic factors. Therefore identifying these factors in colon adenocarcinoma (CA) will reveal new therapeutic targets. METHODS Neuropeptide Y (NPY) and Y2 receptor (Y2R) expressions in CA were studied by immunohistochemical analysis. Orthotopic HT29 with intact VEGF-A gene and VEGF-A knockdown (by CRISPR/Cas9 gene-editing technique) HT29 colon cancer-bearing mice were treated with specific Y2R antagonists, and the effects on angiogenesis and tumour growth were studied. The direct effect of NPY on angiogenesis and the underlying molecular mechanism was elucidated by the modulation of Y2R receptors expressed on colonic endothelial cells (CEC). RESULTS The results demonstrated that NPY and Y2R are overexpressed in human CA, orthotopic HT29, and most interestingly in VEGF-A-depleted orthotopic HT29 tumours. Treatment with Y2R antagonists inhibited angiogenesis and thereby HT29 tumour growth. Blocking /silencing Y2R abrogated NPY-induced angiogenic potential of CEC. Mechanistically, NPY regulated the activation of the ERK/MAPK signalling pathway in CEC. CONCLUSIONS NPY derived from cancer cells independently regulates angiogenesis in CA by acting through Y2R present on CEC. Targeting NPY/Y2R thus emerges as a novel potential therapeutic strategy in CA.
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Affiliation(s)
- Debanjan Chakroborty
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.,Department of Pathology, University of South Alabama, Mobile, AL, 36617, USA.,Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA
| | - Sandeep Goswami
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.,Department of Pathology, University of South Alabama, Mobile, AL, 36617, USA.,Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA
| | - Hao Fan
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA
| | - Wendy L Frankel
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
| | - Sujit Basu
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.,Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Chandrani Sarkar
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA. .,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. .,Department of Pathology, University of South Alabama, Mobile, AL, 36617, USA. .,Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA. .,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA.
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El-Salhy M, Patcharatrakul T, Gonlachanvit S. Fecal microbiota transplantation for irritable bowel syndrome: An intervention for the 21 st century. World J Gastroenterol 2021; 27:2921-2943. [PMID: 34168399 PMCID: PMC8192290 DOI: 10.3748/wjg.v27.i22.2921] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/03/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) affects about 12% of the global population. Although IBS does not develop into a serious disease or increase mortality, it results in a considerable reduction in the quality of life. The etiology of IBS is not known, but the intestinal microbiota appears to play a pivotal role in its pathophysiology. There is no effective treatment for IBS, and so the applied treatments clinically focus on symptom relief. Fecal microbiota transplantation (FMT), an old Chinese treatment, has been applied to IBS patients in seven randomized controlled trials (RCTs). Positive effects on IBS symptoms in various degrees were obtained in four of these RCTs, while there was no effect in the remaining three. Across the seven RCTs there were marked differences in the selection processes for the donor and treated patients, the transplant dose, the route of administration, and the methods used to measure how the patients responded to FMT. The present frontier discusses these differences and proposes: (1) criteria for selecting an effective donor (superdonor); (2) selection criteria for patients that are suitable for FMT; (3) the optimal FMT dose; and (4) the route of transplant administration. FMT appears to be safe, with only mild, self-limiting side effects of abdominal pain, cramping, tenderness, diarrhea, and constipation. Although it is early to speculate about the mechanisms underlying the effects of FMT, the available data suggest that changes in the intestinal bacteria accompanied by changes in fermentation patterns and fermentation products (specifically short-chain fatty acids) play an important role in improving the IBS symptoms seen after FMT. FMT appears to be a promising treatment for IBS, but further studies are needed before it can be applied in everyday clinical practice.
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Affiliation(s)
- Magdy El-Salhy
- Department of Medicine, Stord Helse Fonna Hospital and University of Bergen, Stord 5416, Norway
| | - Tanisa Patcharatrakul
- Department of Medicine, King Chulalongkorn Memorial Hospital and Center of Excellence in Neurogastroenterology and Motility, Chulalongkorn University, Bangkok 10330, Thailand
| | - Sutep Gonlachanvit
- Department of Medicine, King Chulalongkorn Memorial Hospital and Center of Excellence in Neurogastroenterology and Motility, Chulalongkorn University, Bangkok 10330, Thailand
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Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate. NPJ PARKINSONS DISEASE 2021; 7:9. [PMID: 33479243 PMCID: PMC7820491 DOI: 10.1038/s41531-020-00150-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 10/21/2020] [Indexed: 12/20/2022]
Abstract
The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson’s disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naïve controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naïve and MPTP-treated marmosets. The basal short circuit current (Isc) was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. There was no difference in basal cholinergic tone, however, there was an increased excitatory cholinergic response in MPTP-treated tissues when NOS was blocked with L-Nω-nitroarginine. The amplitude and frequency of spontaneous contractions in longitudinal smooth muscle as well as carbachol-evoked post-junctional contractile responses were unaltered, despite a decrease in choline acetyltransferase and an increase in the vasoactive intestinal polypeptide neuron numbers per ganglion in the proximal colon. There was a low-level inflammation in the proximal but not the distal colon accompanied by a change in α-synuclein immunoreactivity. This study suggests that MPTP treatment produces long-term alterations in colonic mucosal function associated with amplified muscarinic mucosal activity but decreased cholinergic innervation in myenteric plexi and increased nitrergic enteric neurotransmission. This suggests that long-term changes in either central or peripheral dopaminergic neurotransmission may lead to adaptive changes in colonic function resulting in alterations in ion transport across mucosal epithelia that may result in GI dysfunction in PD.
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6
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El-Salhy M, Hatlebakk JG, Hausken T. Possible role of peptide YY (PYY) in the pathophysiology of irritable bowel syndrome (IBS). Neuropeptides 2020; 79:101973. [PMID: 31727345 DOI: 10.1016/j.npep.2019.101973] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 08/15/2019] [Accepted: 09/18/2019] [Indexed: 12/19/2022]
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder of unknown aetiology for which there is no effective treatment. Although IBS does not increase mortality, it reduces the quality of life and is an economic burden to both the patients themselves and society as a whole. Peptide YY (PYY) is localized in endocrine cells located in the ileum, colon and rectum. The concentration of PYY and the density of PYY cells are decreased in both the colon and rectum but unchanged in the ileum of patients with IBS. The low density of PYY cells in the large intestine may be caused by a decreased number of stem cells and their progeny toward endocrine cells. PYY regulates the intestinal motility, secretion and absorption as well as visceral sensitivity via modulating serotonin release. An abnormality in PYY may therefore contribute to the intestinal dysmotility and visceral hypersensitivity seen in IBS patients. Diet management involving consuming a low-FODMAP diet restores the density of PYY cells in the large intestine and improves abdominal symptoms in patients with IBS. This review shows that diet management appears to be a valuable tool for correcting the PYY abnormalities in the large intestine of IBS patients in the clinic.
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Affiliation(s)
- Magdy El-Salhy
- Section for Gastroenterology, Department of Medicine, Stord Hospital, Stord, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Functional Gastrointestinal Disorders, Bergen, Norway..
| | - Jan Gunnar Hatlebakk
- Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Functional Gastrointestinal Disorders, Bergen, Norway..
| | - Trygve Hausken
- Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Functional Gastrointestinal Disorders, Bergen, Norway..
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Szymaszkiewicz A, Włodarczyk J, Wasilewski A, Di Marzo V, Storr M, Fichna J, Zielińska M. Desensitization of transient receptor potential vanilloid type-1 (TRPV1) channel as promising therapy of irritable bowel syndrome: characterization of the action of palvanil in the mouse gastrointestinal tract. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1357-1364. [PMID: 32002574 PMCID: PMC7351811 DOI: 10.1007/s00210-020-01829-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 01/23/2020] [Indexed: 02/06/2023]
Abstract
TRPV1 are involved in the control of the gastrointestinal (GI) functions and pain sensation. Their activation induces pain but it is followed by desensitization, which in turn causes analgesia. The studies from the last two decades indicate that TRPV1 are involved in visceral hypersensitivity in the GI tract and pathogenesis of irritable bowel syndrome (IBS). Therefore, the aim of this study is to assess the action of fast desensitizing agonist of TRPV1, palvanil (N-palmitoyl-vanillamine), in the murine GI tract and on nociception to evaluate its potential application in the therapy of IBS. The effect of palvanil on smooth muscle contractility was evaluated using organ baths. The impact of palvanil on intestinal secretion was assessed in Ussing chambers. In vivo, the action of palvanil (0.1–1 mg/kg) was assessed in whole GI transit, fecal pellet output, and colonic bead expulsion tests. The antinociceptive potency of palvanil was tested in the mustard oil-induced pain test. Palvanil inhibited colonic contractions (evoked by electrical field stimulation, EFS) and decreased the ion transport in the colon stimulated with forskolin. It did not affect secretion in experiments with veratridine. In vivo, palvanil prolonged whole GI transit at all doses tested. At the lower dose tested, it accelerated colonic motility during first 60 min following injection. By contrast, at the dose of 1 mg/kg, colonic motility was inhibited. Palvanil induced antinociceptive action at all tested doses in mustard oil-induced pain test. TRPV1 fast-desensitizing compounds, i.e., palvanil, may be promising agents in the therapy of IBS since it modulates intestinal motility and reduces visceral pain.
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Affiliation(s)
- Agata Szymaszkiewicz
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Jakub Włodarczyk
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Andrzej Wasilewski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Vincenzo Di Marzo
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.,Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Université Laval, Quebec City, Canada
| | - Martin Storr
- Walter Brendel Center of Experimental Medicine, Ludwig Maximilians University, Munich, Germany.,Center of Endoscopy, Starnberg, Germany
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Marta Zielińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
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8
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Holmes GM, Hubscher CH, Krassioukov A, Jakeman LB, Kleitman N. Recommendations for evaluation of bladder and bowel function in pre-clinical spinal cord injury research. J Spinal Cord Med 2019; 43:165-176. [PMID: 31556844 PMCID: PMC7054945 DOI: 10.1080/10790268.2019.1661697] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Objective: In order to encourage the inclusion of bladder and bowel outcome measures in preclinical spinal cord injury (SCI) research, this paper identifies and categorizes 1) fundamental, 2) recommended, 3) supplemental and 4) exploratory sets of outcome measures for pre-clinical assessment of bladder and bowel function with broad applicability to animal models of SCI.Methods: Drawing upon the collective research experience of autonomic physiologists and informed in consultation with clinical experts, a critical assessment of currently available bladder and bowel outcome measures (histological, biochemical, in vivo functional, ex vivo physiological and electrophysiological tests) was made to identify the strengths, deficiencies and ease of inclusion for future studies of experimental SCI.Results: Based upon pre-established criteria generated by the Neurogenic Bladder and Bowel Working Group that included history of use in experimental settings, citations in the literature by multiple independent groups, ease of general use, reproducibility and sensitivity to change, three fundamental measures each for bladder and bowel assessments were identified. Briefly defined, these assessments centered upon tissue morphology, voiding efficiency/volume and smooth muscle-mediated pressure studies. Additional assessment measures were categorized as recommended, supplemental or exploratory based upon the balance between technical requirements and potential mechanistic insights to be gained by the study.Conclusion: Several fundamental assessments share reasonable levels of technical and material investment, including some that could assess bladder and bowel function non-invasively and simultaneously. Such measures used more inclusively across SCI studies would advance progress in this high priority area. When complemented with a few additional investigator-selected study-relevant supplemental measures, they are highly recommended for research programs investigating the efficacy of therapeutic interventions in preclinical animal models of SCI that have a bladder and/or bowel focus.
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Affiliation(s)
- Gregory M. Holmes
- Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA,Correspondence to: Gregory M. Holmes, Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17036, USA. ;
| | - Charles H. Hubscher
- Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky, USA,Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky, USA
| | - Andrei Krassioukov
- ICORD, University of British Columbia, GF Strong Rehabilitation Centre, Vancouver, Canada
| | - Lyn B. Jakeman
- National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA
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9
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Aktar R, Peiris M, Fikree A, Cibert-Goton V, Walmsley M, Tough IR, Watanabe P, Araujo EJA, Mohammed SD, Delalande JM, Bulmer DC, Scott SM, Cox HM, Voermans NC, Aziz Q, Blackshaw LA. The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones. J Physiol 2018; 596:4237-4251. [PMID: 29917237 PMCID: PMC6117562 DOI: 10.1113/jp276300] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/11/2018] [Indexed: 12/15/2022] Open
Abstract
KEY POINTS Tenascin-X (TNX) is an extracellular matrix glycoprotein with anti-adhesive properties in skin and joints. Here we report the novel finding that TNX is expressed in human and mouse gut tissue where it is exclusive to specific subpopulations of neurones. Our studies with TNX-deficient mice show impaired defecation and neural control of distal colonic motility that can be rescued with a 5-HT4 receptor agonist. However, colonic secretion is unchanged. They are also susceptible to internal rectal intussusception. Colonic afferent sensitivity is increased in TNX-deficient mice. Correspondingly, there is increased density of and sensitivity of putative nociceptive fibres in TNX-deficient mucosa. A group of TNX-deficient patients report symptoms highly consistent with those in the mouse model. These findings suggest TNX plays entirely different roles in gut to non-visceral tissues - firstly a role in enteric motor neurones and secondly a role influencing nociceptive sensory neurones Studying further the mechanisms by which TNX influences neuronal function will lead to new targets for future treatment. ABSTRACT The extracellular matrix (ECM) is not only an integral structural molecule, but is also critical for a wide range of cellular functions. The glycoprotein tenascin-X (TNX) predominates in the ECM of tissues like skin and regulates tissue structure through anti-adhesive interactions with collagen. Monogenic TNX deficiency causes painful joint hypermobility and skin hyperelasticity, symptoms characteristic of hypermobility Ehlers Danlos syndrome (hEDS). hEDS patients also report consistently increased visceral pain and gastrointestinal (GI) dysfunction. We investigated whether there is a direct link between TNX deficiency and GI pain or motor dysfunction. We set out first to learn where TNX is expressed in human and mouse, then determine how GI function, specifically in the colon, is disordered in TNX-deficient mice and humans of either sex. In human and mouse tissue, TNX was predominantly associated with cholinergic colonic enteric neurones, which are involved in motor control. TNX was absent from extrinsic nociceptive peptidergic neurones. TNX-deficient mice had internal rectal prolapse and a loss of distal colonic contractility which could be rescued by prokinetic drug treatment. TNX-deficient patients reported increased sensory and motor GI symptoms including abdominal pain and constipation compared to controls. Despite absence of TNX from nociceptive colonic neurones, neuronal sprouting and hyper-responsiveness to colonic distension was observed in the TNX-deficient mice. We conclude that ECM molecules are not merely support structures but an integral part of the microenvironment particularly for specific populations of colonic motor neurones where TNX exerts functional influences.
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Affiliation(s)
- Rubina Aktar
- Blizard Institute, Queen Mary University of London, London, UK
| | - Madusha Peiris
- Blizard Institute, Queen Mary University of London, London, UK
| | - Asma Fikree
- Blizard Institute, Queen Mary University of London, London, UK
| | | | - Maxim Walmsley
- Blizard Institute, Queen Mary University of London, London, UK
| | - Iain R Tough
- Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK
| | - Paulo Watanabe
- Blizard Institute, Queen Mary University of London, London, UK.,Department of Histology, Centre for Biological Sciences, State University of Londrina, Brazil
| | - Eduardo J A Araujo
- Blizard Institute, Queen Mary University of London, London, UK.,Department of Histology, Centre for Biological Sciences, State University of Londrina, Brazil
| | | | | | - David C Bulmer
- Blizard Institute, Queen Mary University of London, London, UK
| | - S Mark Scott
- Blizard Institute, Queen Mary University of London, London, UK
| | - Helen M Cox
- Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK
| | - Nicol C Voermans
- Department of Neurology, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Qasim Aziz
- Blizard Institute, Queen Mary University of London, London, UK
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10
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Wasilewski A, Misicka A, Sacharczuk M, Fichna J. Prosecretory effect of loperamide in ileal and colonic mucosae of mice displaying high or low swim stress-induced analgesia associated with high and low endogenous opioid system activity. Neurogastroenterol Motil 2018; 30. [PMID: 28745837 DOI: 10.1111/nmo.13166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 06/23/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is characterized by abdominal pain, bloating, and changes in bowel habit. The aim of this study was to characterize the effect of loperamide hydrochloride (LOP) and naloxone hydrochloride (NLX), an opioid agonist and antagonist, respectively, on electrolyte equilibrium in ileal and colonic mucosae and to estimate the possible influence of divergent activity of the endogenous opioid system (EOS) on IBS therapy. METHODS Two mouse lines bidirectionally selected for high (HA) and low (LA) swim stress-induced analgesia associated with high and low EOS activity were used in this study. To assess the effect of LOP and NLX on HA/LA lines in vivo, we used the castor oil-induced diarrhea model. Changes in electrolyte equilibrium were determined on the basis of short-circuit current (ΔIsc ) in isolated mouse ileum and colon exposed to LOP and NLX and stimulated by forskolin (FSK), veratridine (VER), and bethanechol (BET). KEY RESULTS In vivo, we found that LOP significantly prolonged time to appearance of diarrhea in HA and LA lines. In vitro, LOP and NLX increased ΔIsc in FSK- and VER-stimulated colonic tissue, respectively, in HA line. In the ileum, LOP increased ΔIsc in FSK- and VER-stimulated tissue and decreased ΔIsc in BET-stimulated tissues in HA line. CONCLUSIONS & INFERENCES Individual differences in EOS activity may play a crucial role in the response to the IBS-D therapy, thus some patients may be at an increased risk of side effects such as constipation or diarrhea.
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Affiliation(s)
- A Wasilewski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - A Misicka
- Department of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - M Sacharczuk
- Laboratory of Neurogenomics, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland.,Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland.,Department of Internal Medicine, Hypertension and Vascular Diseases, Medical University of Warsaw, Warsaw, Poland
| | - J Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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Peptide Tyrosine Tyrosine 3-36 Reduces Meal Size and Activates the Enteric Neurons in Male Sprague-Dawley Rats. Dig Dis Sci 2017; 62:3350-3358. [PMID: 29030744 DOI: 10.1007/s10620-017-4788-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 10/04/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND Peptide tyrosine tyrosine 3-36 (peptide YY 3-36 or PYY 3-36) reduces food intake by unknown site(s). AIM To test the hypothesis that the gastrointestinal tract contains sites of action regulating meal size (MS) and intermeal interval (IMI) length by PYY 3-36. METHODS Peptide YY 3-36 (0, 1, 5, 10 and 20 nmol/kg) was injected in the aorta, the artery that supplies the gastrointestinal tract, prior to the onset of the dark cycle in free feeding male Sprague-Dawley rats and food intake was measured. Then, PYY 3-36 (25 nmol/kg) was injected intraperitoneally in these rats and Fos-like immunoreactivity (Fos-LI, a marker for neuronal activation) was quantified in the small intestinal enteric neurons, both myenteric and submucosal, and the dorsal vagal complex (DVC) of the hindbrain. RESULTS PYY 3-36 reduced first MS, decreased IMI length, shortened duration of first meal and increased Fos-LI in enteric and DVC neurons. However, PYY 3-36 failed to change the size of the second meal, satiety ratio, latency to first meal, number of meals and 24 h intake relative to saline control. CONCLUSION The gastrointestinal tract may contain sites of action regulating MS reduction by PYY 3-36.
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El-Salhy M, Solomon T, Hausken T, Gilja OH, Hatlebakk JG. Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease. World J Gastroenterol 2017; 23:5068-5085. [PMID: 28811704 PMCID: PMC5537176 DOI: 10.3748/wjg.v23.i28.5068] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/15/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic recurrent condition whose etiology is unknown, and it includes ulcerative colitis, Crohn’s disease, and microscopic colitis. These three diseases differ in clinical manifestations, courses, and prognoses. IBD reduces the patients’ quality of life and is an economic burden to both the patients and society. Interactions between the gastrointestinal (GI) neuroendocrine peptides/amines (NEPA) and the immune system are believed to play an important role in the pathophysiology of IBD. Moreover, the interaction between GI NEPA and intestinal microbiota appears to play also a pivotal role in the pathophysiology of IBD. This review summarizes the available data on GI NEPA in IBD, and speculates on their possible role in the pathophysiology and the potential use of this information when developing treatments. GI NEPA serotonin, the neuropeptide Y family, and substance P are proinflammatory, while the chromogranin/secretogranin family, vasoactive intestinal peptide, somatostatin, and ghrelin are anti-inflammatory. Several innate and adaptive immune cells express these NEPA and/or have receptors to them. The GI NEPA are affected in patients with IBD and in animal models of human IBD. The GI NEPA are potentially useful for the diagnosis and follow-up of the activity of IBD, and are candidate targets for treatments of this disease.
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Grubišić V, Gulbransen BD. Enteric glial activity regulates secretomotor function in the mouse colon but does not acutely affect gut permeability. J Physiol 2017; 595:3409-3424. [PMID: 28066889 DOI: 10.1113/jp273492] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Accepted: 11/30/2016] [Indexed: 12/11/2022] Open
Abstract
KEY POINTS The role of enteric glial cell activity in the acute regulation of epithelial barrier and secretomotor functions of the intestines under physiological conditions is not clear. We used transgenic mice to modify glial activity and found that enteric glia significantly contribute to the neurogenic ion transport while glial activity does not appear to play a major role in the acute regulation of barrier function. The selective activation of glial activity evoked electrogenic ion transport primarily through neural pathways and was sufficient to drive electrogenic ion transport to an extent equal to the direct activation of neurogenic ion transport. These findings provide novel insight into the cellular mechanisms that control fluid transport homeostasis in the intestine and might provide novel therapeutic avenues for functional diarrheal diseases. ABSTRACT Enteric glial cells are often implicated in the regulation of epithelial barrier and secretomotor functions of the intestines. But whether glial cell activity regulates these functions acutely under physiological conditions is not clear. We addressed this issue by using transgenic animal models to modify the activity of enteric glia, either reducing glial expression of connexin 43 in Sox10::CreERT2+/- /Cx43f/f mice or activating glial calcium responses in GFAP::hM3Dq mice, and tested the effects on colonic barrier function and electrogenic ion transport in Ussing chambers. We assessed neuronal-dependent and -independent contributions by activating or inhibiting neurogenic activity with veratridine and tetrodotoxin, respectively. Our results show that the reduction of glial Cx43 expression in Sox10::CreERT2+/- /Cx43f/f mice significantly reduced neurogenic ion transport. The selective glial activation in tissues from GFAP::hM3Dq mice evoked electrogenic ion transport to an extent equal to the direct activation of neurogenic ion transport with veratridine and glial driven responses consisted of both tetrodotoxin-sensitive and -insensitive components. The selective glial stimulation did not affect transmural ion conductance or cell-impermeant dye flux but the baseline ion conductance was more variable in Sox10::CreERT2+/- /Cx43f/f tissues. Together, our findings show that glial activity contributes to the regulation of electrogenic ion transport in the intestine through effects on neurons and possibly direct effects on epithelial cells. However, glial activity does not appear to play a major role in the acute regulation of barrier function. These findings provide novel insight into the cellular mechanisms that control fluid transport homeostasis in the intestine.
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Affiliation(s)
- Vladimir Grubišić
- Neuroscience Program, Department of Physiology, Michigan State University, 567 Wilson Road, East Lansing, MI, 48824, USA
| | - Brian D Gulbransen
- Neuroscience Program, Department of Physiology, Michigan State University, 567 Wilson Road, East Lansing, MI, 48824, USA
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Zielińska M, Jarmuż A, Wasilewski A, Cami-Kobeci G, Husbands S, Fichna J. Methyl-orvinol-Dual activity opioid receptor ligand inhibits gastrointestinal transit and alleviates abdominal pain in the mouse models mimicking diarrhea-predominant irritable bowel syndrome. Pharmacol Rep 2016; 69:350-357. [PMID: 28187396 DOI: 10.1016/j.pharep.2016.12.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/27/2016] [Accepted: 12/01/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND Diarrhea-predominant irritable bowel syndrome (IBS-D) is a functional disorder of the gastrointestinal (GI) tract. The major IBS-D symptoms include diarrhea, abdominal pain and discomfort. High density of opioid receptors (ORs) in the GI tract and their participation in the maintenance of GI homeostasis make ORs ligands an attractive option for developing new anti-IBS-D treatments. The aim of this study was to characterize the effect of methyl-orvinol on the GI motility and secretion and in mouse models mimicking symptoms of IBS-D. METHODS In vitro, the effects of methyl-orvinol on electrical field stimulated smooth muscle contractility and epithelial ion transport were characterized in the mouse colon. In vivo, the following tests were used to determine methyl-orvinol effect on mouse GI motility: colonic bead expulsion, whole GI transit and fecal pellet output. An antinociceptive action of methyl-orvinol was assessed in the mouse model of visceral pain induced by mustard oil. RESULTS Methyl-orvinol (10-10 to 10-6M) inhibited colonic smooth muscle contractions in a concentration-dependent manner. This effect was reversed by naloxone (non-selective opioid antagonist) and β-funaltrexamine (selective MOP antagonist). Experiments with a selective KOP receptor agonist, U50488 revealed that methyl-orvinol is a KOP receptor antagonist in the GI tract. Methyl-orvinol enhanced epithelial ion transport. In vivo, methyl-orvinol inhibited colonic bead expulsion and prolonged GI transit. Methyl-orvinol improved hypermotility and reduced abdominal pain in the mouse models mimicking IBS-D symptoms. CONCLUSION Methyl-orvinol could become a promising drug candidate in chronic therapy of functional GI diseases such as IBS-D.
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Affiliation(s)
- Marta Zielińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Agata Jarmuż
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Andrzej Wasilewski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Gerta Cami-Kobeci
- Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom
| | - Stephen Husbands
- Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
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El-Salhy M, Hausken T. The role of the neuropeptide Y (NPY) family in the pathophysiology of inflammatory bowel disease (IBD). Neuropeptides 2016; 55:137-44. [PMID: 26431932 DOI: 10.1016/j.npep.2015.09.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/11/2015] [Accepted: 09/15/2015] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD) includes three main disorders: ulcerative colitis, Crohn's disease, and microscopic colitis. The etiology of IBD is unknown and the current treatments are not completely satisfactory. Interactions between the gut neurohormones and the immune system are thought to play a pivot role in inflammation, especially in IBD. These neurohormones are believed to include members of the neuropeptide YY (NPY) family, which comprises NPY, peptide YY (PYY), and pancreatic polypeptide (PP). Understanding the role of these peptides may shed light on the pathophysiology of IBD and potentially yield an effective treatment tool. Intestinal NPY, PYY, and PP are abnormal in both patients with IBD and animal models of human IBD. The abnormality in NPY appears to be primarily caused by an interaction between immune cells and the NPY neurons in the enteric nervous system; the abnormalities in PYY and PP appear to be secondary to the changes caused by the abnormalities in other gut neurohormonal peptides/amines that occur during inflammation. NPY is the member of the NPY family that can be targeted in order to decrease the inflammation present in IBD.
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Affiliation(s)
- Magdy El-Salhy
- Section for Gastroenterology, Department of Medicine, Stord Hospital, Stord, Norway; Section for Neuroendocrine Gastroenterology, Division of Gastroenterology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen, Norway.
| | - Trygve Hausken
- Section for Neuroendocrine Gastroenterology, Division of Gastroenterology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Functional Gastrointestinal Disorders, Department of Medicine, Haukeland University Hospital, Bergen, Norway.
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Cuthbert AW, Murthy M, Darlington APS. Neural control of submucosal gland and apical membrane secretions in airways. Physiol Rep 2015; 3:e12398. [PMID: 26059031 PMCID: PMC4510617 DOI: 10.14814/phy2.12398] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 04/14/2015] [Accepted: 04/16/2015] [Indexed: 01/24/2023] Open
Abstract
The mechanisms that lay behind the low-level secretions from airway submucosal glands and the surface epithelium in the absence of external innervation have been investigated in small areas (1.0-1.5 cm(2)) of mucosa from sheep tracheas, freshly collected from a local abattoir. Glandular secretion was measured by an optical method while short circuit current was used as a measure of surface secretion. Activation of neurones in the intrinsic nerve net by veratrine alkaloids caused an immediate increase in both glandular secretion and short circuit current, both effects being blocked by the addition of tetrodotoxin. However, agents known to be acting directly on the glands, such as muscarinic agonists (e.g., carbachol) or adenylate cyclase activators (e.g., forskolin) were not influenced by tetrodotoxin. The toxin alone had no discernable effect on the low-level basal secretion shown by unstimulated glands. Calu-3 cell monolayers, generally agreed to be a surrogate for the secretory cells of submucosal glands, showed no sensitivity to veratrine alkaloids, strengthening the view that the veratrine-like drugs acted exclusively on the intrinsic nerve net. The data are discussed in relation way in which transplanted lungs can maintain mucociliary clearance and hence a sterile environment in the absence of external innervation, as in transplanted lungs.
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Affiliation(s)
- Alan W Cuthbert
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Meena Murthy
- Department of Medicine, University of Cambridge, Cambridge, UK
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Foong JPP, Tough IR, Cox HM, Bornstein JC. Properties of cholinergic and non-cholinergic submucosal neurons along the mouse colon. J Physiol 2013; 592:777-93. [PMID: 24344165 DOI: 10.1113/jphysiol.2013.265686] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Submucosal neurons are vital regulators of water and electrolyte secretion and local blood flow in the gut. Due to the availability of transgenic models for enteric neuropathies, the mouse has emerged as the research model of choice, but much is still unknown about the murine submucosal plexus. The progeny of choline acetyltransferase (ChAT)-Cre × ROSA26(YFP) reporter mice, ChAT-Cre;R26R-yellow fluorescent protein (YFP) mice, express YFP in every neuron that has ever expressed ChAT. With the aid of the robust YFP staining in these mice, we correlated the neurochemistry, morphology and electrophysiology of submucosal neurons in distal colon. We also examined whether there are differences in neurochemistry along the colon and in neurally mediated vectorial ion transport between the proximal and distal colon. All YFP(+) submucosal neurons also contained ChAT. Two main neurochemical but not electrophysiological groups of neurons were identified: cholinergic (containing ChAT) or non-cholinergic. The vast majority of neurons in the middle and distal colon were non-cholinergic but contained vasoactive intestinal peptide. In the distal colon, non-cholinergic neurons had one or two axons, whereas the cholinergic neurons examined had only one axon. All submucosal neurons exhibited S-type electrophysiology, shown by the lack of long after-hyperpolarizing potentials following their action potentials and fast excitatory postsynaptic potentials (EPSPs). Fast EPSPs were predominantly nicotinic, and somatic action potentials were mediated by tetrodotoxin-resistant voltage-gated channels. The size of submucosal ganglia decreased but the proportion of cholinergic neurons increased distally along the colon. The distal colon had a significantly larger nicotinic ion transport response than the proximal colon. This work shows that the properties of murine submucosal neurons and their control of epithelial ion transport differ between colonic regions. There are several key differences between the murine submucous plexus and that of other animals, including a lack of conventional intrinsic sensory neurons, which suggests there is an incomplete neuronal circuitry within the murine submucous plexus.
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Affiliation(s)
- Jaime Pei Pei Foong
- Department of Physiology, University of Melbourne, Parkville, Vic. 3010, Australia.
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Fairbrother SE, Smith JE, Borman RA, Cox HM. EP4 receptors mediate prostaglandin E2, tumour necrosis factor alpha and interleukin 1beta-induced ion secretion in human and mouse colon mucosa. Eur J Pharmacol 2012; 694:89-97. [DOI: 10.1016/j.ejphar.2012.06.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Revised: 05/29/2012] [Accepted: 06/09/2012] [Indexed: 01/12/2023]
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Foong JPP, Parry LJ, Bornstein JC. Activation of neuronal SST₁ and SST₂ receptors decreases neurogenic secretion in the guinea-pig jejunum. Neurogastroenterol Motil 2010; 22:1209-16, e317. [PMID: 20626789 DOI: 10.1111/j.1365-2982.2010.01566.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Vasoactive intestinal peptide (VIP) submucosal neurons, the main regulators of gut secretion, display inhibitory postsynaptic potentials mediated by somatostatin (SOM) acting on SST(1) and SST(2) receptors (SSTR(1), SSTR(2)) in the guinea-pig small intestine. We investigated the implications of this for neurally-evoked mucosal secretion. METHODS Mucosal-submucosal preparations from guinea-pig jejunum were mounted in Ussing chambers to measure Cl(-) secretion, measured by short circuit current (I(sc)). All drugs were added serosally. Veratridine (1 μmol L(-1)) was used to stimulate neurons and provide a robust secretory response for pharmacological testing.5-hydroxytrptamine (5-HT, 300 nmol L(-1)) was used to specifically activate non-cholinergic secretomotor neurons, while 1,1-dimethyl-4-phenylpiperazinium (DMPP, 10 μmol L(-1)) was used to stimulate all secretomotor neurons. KEY RESULTS Somatostatin (50 nmol L(-1)) induced a tetrodotoxin (TTX, 1 μmol L(-1))-sensitive decrease in secretion. Somatostatin also reduced the veratridine-induced increase in I(sc). The effects of SOM were significantly reduced by blocking SSTR(1) and SSTR(2) individually or together. Blocking SSTR(1) abolished the inhibition produced by SOM. Quantitative PCR demonstrated that SSTR(1) and SSTR(2) were much more highly expressed in the submucosa than the mucosa. Submucosal SSTR(1) expression was several fold higher than SSTR(2). Responses to DMPP (biphasic) and 5-HT (monophasic) were TTX-sensitive. Somatostatin significantly reduced the 5-HT-induced increase in I(sc), and the second, more sustained phase evoked by DMPP. CONCLUSIONS & INFERENCES These data suggest that SOM exerts its antisecretory effects by suppressing firing of VIP secretomotor neurons, rather than via a direct action on mucosal enterocytes.
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Affiliation(s)
- J P P Foong
- Department of Anatomy & Cell Biology, University of Melbourne, Parkville, Victoria, Australia.
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Antisecretory effects of neuropeptide Y in the mouse colon are region-specific and are lost in DSS-induced colitis. ACTA ACUST UNITED AC 2010; 165:138-45. [PMID: 20561896 DOI: 10.1016/j.regpep.2010.05.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Revised: 05/20/2010] [Accepted: 05/30/2010] [Indexed: 12/13/2022]
Abstract
Regulation of water movement in the gut is an important homeostatic event that is critical to normal intestinal function. We assessed the effect of neuropeptide Y (NPY) on epithelial ion transport in the normal and inflamed mouse colons. Colitis was induced by dextran sodium sulfate (DSS, 4% wt./vol.) administered in the drinking water for 5 days followed by 3 days of regular water. Segments of proximal and distal colons were excised and short-circuit current (I(SC)) was measured in Ussing chambers to assess net electrogenic active ion transport. NPY Y(1) receptor (Y(1)R) expression was measured by quantitative real-time PCR and immunohistochemistry. Challenge of distal colon from normal mice with NPY (10(-7)M) evoked a drop in I(SC) (51.4±9.1 μA/cm(2)), which was dependent on Cl(-) flux, was insensitive to neural blockade with tetrodotoxin and was mediated primarily through the Y(1)R. In contrast, the proximal colon was largely unresponsive to NPY, expressing ~ten-fold less Y(1)R mRNA compared to the distal colon. These findings confirm that specific regional regulation of ion transport occurs in the colon. Segments of proximal and distal colons from mice with DDS-induced colitis were virtually unresponsive to NPY, expressed less Y(1)R mRNA than tissues from control mice and displayed loss of Y(1)R protein expression in the colonic epithelium. This hypo-responsiveness to an antisecretory stimulus adds to the well-documented loss of responsiveness to pro-secretory agents during inflammation, attesting to a profound loss of control of active ion transport during enteric inflammatory disease.
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Julio-Pieper M, Hyland NP, Bravo JA, Dinan TG, Cryan JF. A novel role for the metabotropic glutamate receptor-7: modulation of faecal water content and colonic electrolyte transport in the mouse. Br J Pharmacol 2010; 160:367-75. [PMID: 20423346 DOI: 10.1111/j.1476-5381.2010.00713.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND AND PURPOSE Increasing evidence implicates metabotropic glutamate receptor mGlu(7) in the pathophysiology of stress-related disorders such as depression and anxiety. Mood disorders are frequently associated with gastrointestinal (GI) dysfunction; however, the role of mGlu(7) receptors outside the CNS is unknown. This present study investigated the expression and possible functional role of mGlu(7) receptors in the mouse colon. EXPERIMENTAL APPROACH Expression of mGlu(7) receptor mRNA and protein was studied in mouse colon by in situ hybridization and Western blotting. Effects of the selective mGlu(7) receptor agonist AMN082 on defecation and faecal parameters were studied in an isolation-induced stress model. AMN082 effects on ion transport and neuronal intracellular signalling were examined via Ussing chambers and calcium imaging. KEY RESULTS mGlu(7) receptor mRNA and protein were highly expressed in colon mucosa. Stress-induced faecal output was unaffected by AMN082, although faecal water content was increased. In mucosa/submucosa preparations, 100 nM and 1 microM AMN082 increased bethanechol-induced changes in short-circuit current in the Ussing chamber. This was sensitive to tetrodotoxin. Also, 100 nM AMN082 significantly increased calcium signalling in a subset of submucosal neurons. CONCLUSIONS AND IMPLICATIONS Activating mGlu(7) receptors increased colonic secretory function in vivo and ex vivo. In a group of submucosal neurons, AMN082 strongly induced calcium signalling and the presence of submucosal nerves was required for the AMN082-dependent increase in secretion. These data suggest that targeting mGlu(7) receptors may be useful in the treatment of central components of stress disorders and also stress-associated GI dysfunction such as diarrhoea or constipation.
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Affiliation(s)
- M Julio-Pieper
- Alimentary Pharmabiotic Centre, University College Cork, Ireland
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Wang L, Gourcerol G, Yuan PQ, Wu SV, Million M, Larauche M, Taché Y. Peripheral peptide YY inhibits propulsive colonic motor function through Y2 receptor in conscious mice. Am J Physiol Gastrointest Liver Physiol 2010; 298:G45-56. [PMID: 19892938 PMCID: PMC2806102 DOI: 10.1152/ajpgi.00349.2009] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Peptide YY (PYY) antisecretory effect on intestinal epithelia is well established, whereas less is known about its actions to influence colonic motility in conscious animals. We characterized changes in basal function and stimulated colonic motor function induced by PYY-related peptides in conscious mice. PYY(3-36), PYY, and neuropeptide Y (NPY) (8 nmol/kg) injected intraperitoneally inhibited fecal pellet output (FPO) per hour during novel environment stress by 90%, 63%, and 57%, respectively, whereas the Y(1)-preferring agonists, [Pro(34)]PYY and [Leu(31),Pro(34)]NPY, had no effect. Corticotrophin-releasing factor 2 receptor antagonist did not alter PYY(3-36) inhibitory action. PYY and PYY(3-36) significantly reduced restraint-stimulated defecation, and PYY(3-36) inhibited high-amplitude distal colonic contractions in restrained conscious mice for 1 h, by intraluminal pressure with the use of a microtransducer. PYY suppression of intraperitoneal 5-hydroxytryptophan induced FPO and diarrhea was blocked by the Y(2) antagonist, BIIE0246, injected intraperitoneally and mimicked by PYY(3-36), but not [Leu(31),Pro(34)]NPY. PYY(3-36) also inhibited bethanechol-stimulated FPO and diarrhea. PYY(3-36) inhibited basal FPO during nocturnal feeding period and light phase in fasted/refed mice for 2-3 h, whereas the reduction of food intake lasted for only 1 h. PYY(3-36) delayed gastric emptying after fasting-refeeding by 48% and distal colonic transit time by 104%, whereas [Leu(31),Pro(34)]NPY had no effect. In the proximal and distal colon, higher Y(2) mRNA expression was detected in the mucosa than in muscle layers, and Y(2) immunoreactivity was located in nerve terminals around myenteric neurons. These data established that PYY/PYY(3-36) potently inhibits basal and stress/serotonin/cholinergic-stimulated propulsive colonic motor function in conscious mice, likely via Y(2) receptors.
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Affiliation(s)
- Lixin Wang
- CURE/Digestive Diseases Research Center, and Center for Neurobiology of Stress, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.
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Fichna J, Schicho R, Andrews CN, Bashashati M, Klompus M, McKay DM, Sharkey KA, Zjawiony JK, Janecka A, Storr MA. Salvinorin A inhibits colonic transit and neurogenic ion transport in mice by activating kappa-opioid and cannabinoid receptors. Neurogastroenterol Motil 2009; 21:1326-e128. [PMID: 19650775 DOI: 10.1111/j.1365-2982.2009.01369.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The major active ingredient of the plant Salvia divinorum, salvinorin A (SA) has been used to treat gastrointestinal (GI) symptoms. As the action of SA on the regulation of colonic function is unknown, our aim was to examine the effects of SA on mouse colonic motility and secretion in vitro and in vivo. The effects of SA on GI motility were studied using isolated preparations of colon, which were compared with preparations from stomach and ileum. Colonic epithelial ion transport was evaluated using Ussing chambers. Additionally, we studied GI motility in vivo by measuring colonic propulsion, gastric emptying, and upper GI transit. Salvinorin A inhibited contractions of the mouse colon, stomach, and ileum in vitro, prolonged colonic propulsion and slowed upper GI transit in vivo. Salvinorin A had no effect on gastric emptying in vivo. Salvinorin A reduced veratridine-, but not forskolin-induced epithelial ion transport. The effects of SA on colonic motility in vitro were mediated by kappa-opioid receptors (KORs) and cannabinoid (CB) receptors, as they were inhibited by the antagonists nor-binaltorphimine (KOR), AM 251 (CB(1) receptor) and AM 630 (CB(2) receptor). However, in the colon in vivo, the effects were largely mediated by KORs. The effects of SA on veratridine-mediated epithelial ion transport were inhibited by nor-binaltorphimine and AM 630. Salvinorin A slows colonic motility in vitro and in vivo and influences neurogenic ion transport. Due to its specific regional action, SA or its derivatives may be useful drugs in the treatment of lower GI disorders associated with increased GI transit and diarrhoea.
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Affiliation(s)
- J Fichna
- Division of Gastroenterology, Department of Medicine, Snyder Institute of Infection, Immunity and Inflammation (III), Alberta, Canada
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Hons IM, Burda JE, Grider JR, Mawe GM, Sharkey KA. Alterations to enteric neural signaling underlie secretory abnormalities of the ileum in experimental colitis in the guinea pig. Am J Physiol Gastrointest Liver Physiol 2009; 296:G717-26. [PMID: 19221017 PMCID: PMC2670664 DOI: 10.1152/ajpgi.90472.2008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Inflammatory bowel diseases (IBD) can involve widespread gastrointestinal dysfunction, even in cases in which inflammation is localized to a single site. The underlying pathophysiology of dysfunction in noninflamed regions is unclear. We examined whether colitis is associated with altered electrogenic ion transport in the ileal mucosa and/or changes in the properties of ileal submucosal neurons. Colitis was induced by administration of trinitrobenzene sulfonic acid (TNBS), and the uninflamed ileum from animals was examined 3, 7, and 28 days later. Electrogenic ion transport was assessed in Ussing chambers. Intracellular microelectrode recordings were used to examine the neurophysiology of the submucosal plexus of the ileum in animals with colitis. Noncholinergic secretion was reduced by 33% in the ileum from animals 7 days after the induction of colitis. The epithelial response to vasoactive intestinal peptide (VIP) was unaltered in animals with colitis, but the response to carbachol was enhanced. Slow excitatory synaptic transmission was dramatically reduced in VIP-expressing, noncholinergic secretomotor neurons. This change was detected as early as 3 days following TNBS treatment. No changes to fast synaptic transmission or the number of VIP neurons were observed. In addition, cholinergic secretomotor neurons fired more action potentials during a given stimulus, and intrinsic primary afferent neurons had broader action potentials in animals with colitis. These findings implicate changes to enteric neural circuits as contributing factors in inflammation-induced secretory dysfunction at sites proximal to a localized inflammatory insult.
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Affiliation(s)
- Ian M. Hons
- Snyder Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; and Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont
| | - Joshua E. Burda
- Snyder Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; and Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont
| | - John R. Grider
- Snyder Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; and Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont
| | - Gary M. Mawe
- Snyder Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; and Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont
| | - Keith A. Sharkey
- Snyder Institute of Infection, Immunity and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Internal Medicine, Virginia Commonwealth University, Richmond, Virginia; and Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont
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Feighery LM, Cochrane SW, Quinn T, Baird AW, O'Toole D, Owens SE, O'Donoghue D, Mrsny RJ, Brayden DJ. Myosin light chain kinase inhibition: correction of increased intestinal epithelial permeability in vitro. Pharm Res 2008; 25:1377-86. [PMID: 18163202 DOI: 10.1007/s11095-007-9527-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2007] [Accepted: 12/10/2007] [Indexed: 01/12/2023]
Abstract
PURPOSE To examine whether myosin light chain kinase (MLCK) inhibitors can reduce intestinal epithelial permeability increases in vitro. MATERIALS AND METHODS Isolated rat, mouse and human colonic tissue mucosae and Caco-2 monolayers were exposed to cytochalasin D (cD) and sodium caprate (C10), in the absence and presence of the MLCK inhibitors, ML-9 and D PIK. Transepithelial electrical resistance (TEER) and Papp of [14C]-mannitol or FITC-dextran 4000 (FD-4) were measured. Western blots were used to measure MLC phosphorylation. RESULTS Increases in Papp of [14C]-mannitol and decreases in TEER were induced by tight junction openers. These changes were attenuated by ML-9. D-PIK offset the FD-4 Papp increase induced by C10 in Caco-2 only, while ML-9 and PIK inhibited MLC directly, cD induced constriction of peri-junctional actin in Caco-2 monolayers, but this was prevented by ML-9. Although mannitol fluxes across colonic mucosae from dextran-sulphate (DSS)-treated mice were higher than control, they were not ameliorated by either ML-9 or PIK in vitro. CONCLUSIONS ML-9 inhibits paracellular permeability increases in several intestinal epithelial models. D-PIK reduced stimulated paracellular fluxes in Caco-2 monolayers, but not in tissue. Pre-established increases were not modified by two MLCK inhibitors in a mouse model of IBD.
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Affiliation(s)
- Linda M Feighery
- School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland
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Cox HM. Endogenous PYY and NPY mediate tonic Y1- and Y2-mediated absorption in human and mouse colon. Nutrition 2008; 24:900-6. [PMID: 18662856 PMCID: PMC2572019 DOI: 10.1016/j.nut.2008.06.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2008] [Accepted: 06/13/2008] [Indexed: 02/07/2023]
Abstract
Objective To establish the functional significance of endogenous peptide YY (PYY) and neuropeptide Y (NPY) as mediators of Y1 and Y2 absorptive tone in colonic mucosa. Methods Functional studies utilized descending colon from adult mice (wild type [WT] and peptide nulls) and ex vivo human colonic tissue (from patients undergoing bowel resections) measuring changes in basal ion transport. Peak increases in ion transport to Y1 or Y2 antagonists (BIBO3304 300 nM; BIIE0246 1 μM) were pooled (mean ± SEM) and compared using Student's unpaired t test (P ≤ 0.05); some tissues received tetrodotoxin (TTX; 100 nM). PYY-positive L-cell numbers and NPY innervation were also compared. Results Y1 and Y2 tones were present in human and WT mouse colon mucosa and only the latter was TTX sensitive. Y1 tone was unchanged in NPY−/− but was ∼90% inhibited in PYY−/− and abolished in PYYNPY−/− colon mucosa. Y2 tone was reduced ∼50% in NPY−/− and PYY−/− tissues and was absent from PYYNPY−/− colon. Residual Y2 and Y1 tones present in PYY−/− mucosa were abolished by TTX. PYY ablation had no apparent effect on NPY innervation and PYY-positive cells were observed at the same frequency in NPY−/− (56.7 ± 6.8 cells/section) and WT (55.0 ± 4.6 cells/section) colons. Double knockouts lacked PYY and NPY expression, but endocrine cells and enteric nerves were present with similar frequencies to those of WT mice. Conclusion Endogenous PYY mediates Y1 absorptive tone that is epithelial in origin, whereas Y2 tone is a combination of PYY and NPY mediation.
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Affiliation(s)
- Helen M Cox
- King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London, United Kingdom.
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Lomax AE, O'Hara JR, Hyland NP, Mawe GM, Sharkey KA. Persistent alterations to enteric neural signaling in the guinea pig colon following the resolution of colitis. Am J Physiol Gastrointest Liver Physiol 2007; 292:G482-91. [PMID: 17008554 DOI: 10.1152/ajpgi.00355.2006] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Functional changes induced by inflammation persist following recovery from the inflammatory response, but the mechanisms underlying these changes are not well understood. Our aim was to investigate whether the excitability and synaptic properties of submucosal neurons remained altered 8 wk post-trinitrobenzene sulfonic acid (TNBS) treatment and to determine whether these changes were accompanied by alterations in secretory function in submucosal preparations voltage clamped in Ussing chambers. Mucosal serotonin (5-HT) release measurements and 5-HT reuptake transporter (SERT) immunohistochemistry were also performed. Eight weeks after TNBS treatment, colonic inflammation resolved, as assessed macroscopically and by myeloperoxidase assay. However, fast excitatory postsynaptic potential (fEPSP) amplitude was significantly increased in submucosal S neurons from previously inflamed colons relative to those in control tissue. In addition, fEPSPs from previously inflamed colons had a hexamethonium-insensitive component that was not evident in age-matched controls. AH neurons were hyperexcitable, had shorter action potential durations, and decreased afterhyperpolarization 8 wk following TNBS adminstration. Neuronally mediated colonic secretory function was significantly reduced after TNBS treatment, although epithelial cell signaling, as measured by responsiveness to both forskolin and bethanecol in the presence of tetrodotoxin, was comparable with control tissue. 5-HT levels and SERT immunoreactivity were comparable to controls 8 wk after the induction of inflammation, but there was an increase in glucagon-like peptide 2-immunoreactive L cells. In conclusion, sustained alterations in enteric neural signaling occur following the resolution of colitis, which are accompanied by functional changes in the absence of active inflammation.
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Affiliation(s)
- Alan E Lomax
- Gastrointestinal Diseases Research Unit, Department of Medicine, Queen's University, Kingston, Ontario, Canada
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Abstract
Endocrine cells, enteric neurons and enterocytes provide an integrated functional defense against luminal factors, including nutrients, microbes and toxins. Prominent among intrinsic mediators is peptide YY (PYY) which is present in approximately 50% of colorectal endocrine cells and neuropeptide Y (NPY), a neurotransmitter expressed in submucous and myenteric nerves. Both peptides and their long fragments (PYY(3-36) and NPY(3-36)) are potent, long-lasting anti-secretory agents in vitro and in vivo and, they provide significant Y receptor-mediated absorptive tone in human and mouse colon mucosa. The main function of the colon is to absorb 90% of approximately 2l of daily ileal effluent (in adult humans) and Y-absorptive tone can contribute significantly to this electrolyte absorption. Blockade or loss of this mucosal Y-absorptive tone (i.e. with Y(1) or Y(2) antagonists) leads to hypersecretion and potentially to diarrhea, so Y agonists are predicted to rescue absorption by mimicking endogenous neuroendocrine PYY or neuronal NPY.
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Affiliation(s)
- Helen M Cox
- Wolfson Centre for Age-Related Diseases, King's College London, School of Biomedical and Health Sciences, Guy's Campus, Hodgkin Building, London SE1 1UL, UK.
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Abstract
BACKGROUND AND AIMS Intestinal inflammation alters neuronal and enteroendocrine signalling, leading to functional adaptations in the inflamed bowel. Human studies have reported functional alterations at sites distant from active inflammation. Our aims were to determine whether neuronal and enteroendocrine signalling are altered in the uninflamed colon during ileitis. METHODS We used neurophysiological, immunohistochemical, biochemical and Ussing chamber techniques to examine the effect of 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced ileitis on the properties of submucosal neurones, enteroendocrine cells and epithelial physiology of the distal colon of guinea pigs. RESULTS Three days after TNBS administration, when inflammation was restricted to the ileum, the properties of colonic enteric neurones were altered. Submucosal AH neurones were hyperexcitable and had reduced after hyperpolarisations. S neurones received larger fast and slow excitatory postsynaptic potentials, due to an increase in non-cholinergic synaptic transmission. Despite the absence of inflammation in the colon, we found increased colonic prostaglandin E(2) content in animals with ileitis. Ileitis also increased the number of colonic 5-hydroxytryptamine (5-HT)- and GLP-2-immunoreactive enteroendocrine cells. This was accompanied by an increase in stimulated 5-HT release. Functional alterations in epithelial physiology occurred such that basal short circuit current was increased and veratridine-stimulated ion transport was reduced in the colon of animals with ileitis. CONCLUSION Our data suggest that inflammation at one site in the gut alters the cellular components of enteric reflex circuits in non-inflamed regions in ways similar to those at sites of active inflammation. These changes underlie altered function in non-involved regions during episodes of intestinal inflammation.
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Affiliation(s)
- Jennifer R O'Hara
- Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada
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Cox HM. Neuropeptide Y receptors; antisecretory control of intestinal epithelial function. Auton Neurosci 2006; 133:76-85. [PMID: 17140858 DOI: 10.1016/j.autneu.2006.10.005] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2006] [Revised: 09/12/2006] [Accepted: 10/23/2006] [Indexed: 12/11/2022]
Abstract
This paper reviews the cellular localisation, mechanisms of release and intestinal absorptive actions of neuropeptide Y and its related peptides, peptide YY, pancreatic polypeptide and major fragments NPY(3-36) and PYY(3-36). While NPY is commonly found in inhibitory enteric neurons that can be interneurons, motor neurons or secretomotor-nonvasodilator in nature, its analogue, peptide YY in contrast, is located in neuroendocrine L-cells that predominate in the colorectal mucosa. Peptide YY is released from these cells when nutrients arrive in the small or large bowel, exerting paracrine as well as hormonal actions. Pancreatic polypeptide is found in relatively few, scattered intestinal endocrine cells, the majority of this peptide being produced by, and released from pancreatic islet F-cells in response to food intake. An introduction to the current pharmacology of this family of peptides is provided and the different types of neuropeptide Y (termed Y) receptors, their agonist preferences, antagonism, and preferred signalling pathways, are described. Our current understanding of specific Y receptor localisation within the intestine as determined by immunohistochemistry, is presented as a prelude to an assessment of functional studies that have monitored ion transport across isolated mucosal preparations. It is becoming clear that three Y receptor types are significant functionally in human colon, as well as particular rodent models (e.g. mouse) and these, namely the Y(1), Y(2) and Y(4) receptors, are discussed in detail. Their presence within the basolateral aspect of the epithelial layer (Y(1) and Y(4) receptors) or on enteric neurons (Y(1) and Y(2) receptors) and their activation by endogenous neuropeptide Y, peptide YY (Y(1) and Y(2) receptors) or pancreatic polypeptide (which prefers Y(4) receptors) results consistently in antisecretory/absorptive responses. The recent use of novel mouse knockouts has helped establish loss of specific intestinal functions including Y(1) and Y(2) receptor-mediated absorptive tone in colon mucosa. Progress in this field has been rapid recently, aided by the availability of selective antagonists and mutant mice lacking either one (e.g. Y(4)-/-, for which no antagonists exist at present) or more Y receptor types. It is therefore timely to review this work and present a rational basis for developing stable synthetic Y receptor agonists as novel anti-diarrhoeals.
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Affiliation(s)
- Helen M Cox
- Wolfson Centre for Age-Related Diseases, King's College London, Hodgkin Building, Guy's Campus, London, SE1 1UL, United Kingdom.
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Tough IR, Holliday ND, Cox HM. Y(4) receptors mediate the inhibitory responses of pancreatic polypeptide in human and mouse colon mucosa. J Pharmacol Exp Ther 2006; 319:20-30. [PMID: 16807358 DOI: 10.1124/jpet.106.106500] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The antisecretory effects of several Y agonists, including pancreatic polypeptide (PP), indicate the presence of Y(1), Y(2), and Y(4) receptors in mouse and human (h) colon mucosae. Here, we used preparations from human and from wild-type (WT), Y(4), and Y(1) receptor knockout ((-/-)) mice, alongside Y(4) receptor-transfected cells to define the relative functional contribution of the Y(4) receptor. First, rat (r) PP antisecretory responses were lost in murine Y(4)(-/-) preparations, but hPP and Pro(34) peptide YY (PYY) costimulated Y(4) and Y(1) receptors in WT mucosa. The Y(1) antagonist/Y(4) agonist GR231118 [(Ile,Glu,Pro,Dpr,Tyr,Arg,Leu,Arg,Try-NH(2))-2-cyclic(2,4'),(2',4)-diamide] elicited small Y(4)-mediated antisecretory responses in human tissues pretreated with the Y(1) antagonist, BIBO3304 [(R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N(2)-(diphenylacetyl)-argininamide trifluoroacetate)], and attenuated Y(4)-mediated hPP responses in mouse and human mucosa. GR231118 and rPP were also antisecretory in hY(4)-transfected epithelial monolayers but were partial agonists compared with hPP at this receptor. In Y(4)-transfected human embryonic kidney (HEK) 293 cells, Y(4) ligands displaced [(125)I]hPP binding with orders of affinity (pK(i)) at human (hPP = rPP > GR231118 > Pro(34)PYY = PYY) and mouse (rPP = hPP > GR231118 > Pro(34)PYY > PYY) Y(4) receptors. GR231118- and rPP-stimulated guanosine 5'-3-O-(thio)triphosphate binding through hY(4) receptors with significantly lower efficacy than hPP. GR231118 marginally increased basal but abolished further PP-induced hY(4) internalization to recycling (transferrin-labeled) pathways in HEK293 cells. Taken together, these findings show that Y(4) receptors play a definitive role in attenuating colonic anion transport and may be useful targets for novel antidiarrheal agents due to their limited peripheral expression.
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Affiliation(s)
- Iain R Tough
- Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK
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Jonz MG, Nurse CA. Epithelial mitochondria-rich cells and associated innervation in adult and developing zebrafish. J Comp Neurol 2006; 497:817-32. [PMID: 16786554 DOI: 10.1002/cne.21020] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Studies of ion regulation by mitochondria-rich cells (MRCs) of transport epithelia in fish have revealed many processes by which ion homeostasis is achieved. However, the control of these mechanisms and, particularly, the extent of nervous system involvement are not completely understood. We characterized the potential innervation of MRCs in various gill and extrabranchial tissues involved in ion transport in the model vertebrate the zebrafish. Confocal and conventional microscopy of whole-mount preparations were combined with immunofluorescence techniques to label MRCs with antibodies against a subunit of the enzyme Na(+)/K(+)-ATPase and nerve fibers with a zebrafish neuronal marker, zn-12. MRCs of the gill filaments were identified by their morphology and migration out to the lamellae in response to ion-poor water acclimation. Gill MRCs were intimately associated with nerve fibers originating from outside the filaments. MRCs of the opercular epithelium resembled those of the gill and were also located adjacent to nerve fibers. Mitochondria-rich "pseudobranch cells" were identified in the pseudobranch by immunofluorescence and labeling of dissociated cells with the mitochondrial marker DASPEI. Pseudobranch MRCs resembled gill MRCs and received innervation from a dense network of nerve fibers. In larvae, MRCs were distributed across the surface of the skin. These cells were situated among a dense network of varicose nerve fibers, and some MRCs of the skin displayed extensive cytoplasmic processes. Evidence is presented suggestive of widespread association of MRCs with the nervous system in transport epithelia and the neural control of MRC-mediated ion regulation in teleost fish.
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Affiliation(s)
- Michael G Jonz
- Department of Biology, McMaster University, Hamilton, Ontario, Canada L8S 4K1.
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