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Populin LC, Rajala AZ, Matkowskyj KA, Saha S, Zeng W, Christian B, McVea A, Tay EX, Mueller EM, Malone ME, Brust-Mascher I, McMillan AB, Ludwig KA, Suminski AJ, Reardon C, Furness JB. Characterization of idiopathic chronic diarrhea and associated intestinal inflammation and preliminary observations of effects of vagal nerve stimulation in a non-human primate. Neurogastroenterol Motil 2024; 36:e14876. [PMID: 39072841 PMCID: PMC11321913 DOI: 10.1111/nmo.14876] [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: 03/20/2024] [Revised: 05/26/2024] [Accepted: 07/11/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Diarrhea is commonly associated with irritable bowel syndrome, inflammatory bowel disease, microscopic colitis, and other gastrointestinal dysfunctions. Spontaneously occurring idiopathic chronic diarrhea is frequent in rhesus macaques, but has not been used as a model for the investigation of diarrhea or its treatment. We characterized this condition and present preliminary data demonstrating that left vagal nerve stimulation provides relief. METHODS Stool consistency scores were followed for up to 12 years. Inflammation was assessed by plasma C-reactive protein, [18F]fluorodeoxyglucose (FDG) uptake, measured by positron emission tomography (PET), multiplex T cell localization, endoscopy and histology. The vagus was stimulated for 9 weeks in conscious macaques, using fully implanted electrodes, under wireless control. KEY RESULTS Macaques exhibited recurrent periods of diarrhea for up to 12 years, and signs of inflammation: elevated plasma C-reactive protein, increased bowel FDG uptake and increased mucosal T helper1 T-cells. The colon and distal ileum were endoscopically normal, and histology revealed mild colonic inflammation. Application of vagal nerve stimulation to conscious macaques (10 Hz, 30 s every 3 h; 24 h a day for 9 weeks) significantly reduced severity of diarrhea and also reduced inflammation, as measured by FDG uptake and C-reactive protein. CONCLUSIONS AND INFERENCES These macaques exhibit spontaneously occurring diarrhea with intestinal inflammation that can be reduced by VNS. The data demonstrate the utility of this naturally occurring primate model to study the physiology and treatments for chronic diarrhea and the neural control circuits influencing diarrhea and inflammation that are not accessible in human subjects.
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Affiliation(s)
- Luis C Populin
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Abigail Z Rajala
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Kristina A Matkowskyj
- Department of Pathology & Laboratory Medicine, University of Wisconsin-Madison, Madison, WI
| | - Sumona Saha
- Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Weifeng Zeng
- Department of Surgery, Dental and Plastic Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Bradley Christian
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Andrew McVea
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Emmy Xue Tay
- Department of Anatomy, Physiology and Cell Biology, UC Davis
| | - Ellie M Mueller
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Margaret E Malone
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | | | - Alan B McMillan
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
- Department of Radiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Kip A Ludwig
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Aaron J Suminski
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Colin Reardon
- Department of Anatomy, Physiology and Cell Biology, UC Davis
| | - John B Furness
- Department of Anatomy & Physiology, University of Melbourne, Parkville, VIC 3010, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
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Tang LQ, Fraebel J, Jin S, Winesett SP, Harrell J, Chang WH, Cheng SX. Calcium/calcimimetic via calcium-sensing receptor ameliorates cholera toxin-induced secretory diarrhea in mice. World J Gastroenterol 2024; 30:268-279. [PMID: 38314127 PMCID: PMC10835527 DOI: 10.3748/wjg.v30.i3.268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/01/2023] [Accepted: 01/02/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system. Calcium-sensing receptor (CaSR) inhibits both actions. The latter has been well documented in vitro but not in vivo. The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo. AIM To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin (CTX) in mice. METHODS CTX was given orally to C57BL/6 mice to induce diarrhea. Calcium and calcimimetic R568 were used to activate CaSR. To maximize their local intestinal actions, calcium was administered luminally via oral rehydration solution (ORS), whereas R568 was applied serosally using an intraperitoneal route. To verify that their actions resulted from the intestine, effects were also examined on Cre-lox intestine-specific CaSR knockouts. Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl- or clinically by assessing stool consistency and weight loss. RESULTS CTX induced secretory diarrhea, as evidenced by increases in fecal Cl-, stool consistency, and weight loss following CTX exposure, but did not alter CaSR, neither in content nor in function. Accordingly, calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines. Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts (villinCre/Casrflox/flox) and neuronal CaSR knockouts (nestinCre/Casrflox/flox). CONCLUSION Treatment of acute secretory diarrheas remains a global challenge. Despite advances in diarrhea research, few have been made in the realm of diarrhea therapeutics. ORS therapy has remained the standard of care, although it does not halt the losses of intestinal fluid and ions caused by pathogens. There is no cost-effective therapeutic for diarrhea. This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases.
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Affiliation(s)
- Lie-Qi Tang
- Department of Pediatrics, University of Florida, Gainesville, FL 32610, United States
| | - Johnathan Fraebel
- Department of Pediatrics, University of Florida, Gainesville, FL 32610, United States
- College of Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Shi Jin
- Department of Pediatrics, University of Florida, Gainesville, FL 32610, United States
| | - Steven P Winesett
- Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32610, United States
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, Gainesville, FL 32610, United States
| | - Jane Harrell
- Department of Pediatrics, University of Florida, Gainesville, FL 32610, United States
| | - Wen-Han Chang
- Department of Medicine, Endocrine Research Unit, Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA 94121, United States
| | - Sam Xianjun Cheng
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Florida Shands Children’s Hospital, Gainesville, FL 32608, United States
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Panther EJ, Dodd W, Clark A, Lucke-Wold B. Gastrointestinal Microbiome and Neurologic Injury. Biomedicines 2022; 10:biomedicines10020500. [PMID: 35203709 PMCID: PMC8962360 DOI: 10.3390/biomedicines10020500] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/16/2022] [Accepted: 02/18/2022] [Indexed: 02/05/2023] Open
Abstract
Communication between the enteric nervous system (ENS) of the gastrointestinal (GI) tract and the central nervous system (CNS) is vital for maintaining systemic homeostasis. Intrinsic and extrinsic neurological inputs of the gut regulate blood flow, peristalsis, hormone release, and immunological function. The health of the gut microbiome plays a vital role in regulating the overall function and well-being of the individual. Microbes release short-chain fatty acids (SCFAs) that regulate G-protein-coupled receptors to mediate hormone release, neurotransmitter release (i.e., serotonin, dopamine, noradrenaline, γ-aminobutyric acid (GABA), acetylcholine, and histamine), and regulate inflammation and mood. Further gaseous factors (i.e., nitric oxide) are important in regulating inflammation and have a response in injury. Neurologic injuries such as ischemic stroke, spinal cord injury, traumatic brain injury, and hemorrhagic cerebrovascular lesions can all lead to gut dysbiosis. Additionally, unfavorable alterations in the composition of the microbiota may be associated with increased risk for these neurologic injuries due to increased proinflammatory molecules and clotting factors. Interventions such as probiotics, fecal microbiota transplantation, and oral SCFAs have been shown to stabilize and improve the composition of the microbiome. However, the effect this has on neurologic injury prevention and recovery has not been studied extensively. The purpose of this review is to elaborate on the complex relationship between the nervous system and the microbiome and to report how neurologic injury modulates the status of the microbiome. Finally, we will propose various interventions that may be beneficial in the recovery from neurologic injury.
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Affiliation(s)
- Eric J. Panther
- Department of Neurosurgery, University of Florida, Gainesville, FL 32601, USA;
- Correspondence:
| | - William Dodd
- College of Medicine, University of Central Florida, Orlando, FL 32816, USA; (W.D.); (A.C.)
| | - Alec Clark
- College of Medicine, University of Central Florida, Orlando, FL 32816, USA; (W.D.); (A.C.)
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32601, USA;
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Enteric neuroimmune interactions coordinate intestinal responses in health and disease. Mucosal Immunol 2022; 15:27-39. [PMID: 34471248 PMCID: PMC8732275 DOI: 10.1038/s41385-021-00443-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 08/02/2021] [Accepted: 08/05/2021] [Indexed: 02/04/2023]
Abstract
The enteric nervous system (ENS) of the gastrointestinal (GI) tract interacts with the local immune system bidirectionally. Recent publications have demonstrated that such interactions can maintain normal GI functions during homeostasis and contribute to pathological symptoms during infection and inflammation. Infection can also induce long-term changes of the ENS resulting in the development of post-infectious GI disturbances. In this review, we discuss how the ENS can regulate and be regulated by immune responses and how such interactions control whole tissue physiology. We also address the requirements for the proper regeneration of the ENS and restoration of GI function following the resolution of infection.
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Beopoulos A, Gea M, Fasano A, Iris F. Autonomic Nervous System Neuroanatomical Alterations Could Provoke and Maintain Gastrointestinal Dysbiosis in Autism Spectrum Disorder (ASD): A Novel Microbiome-Host Interaction Mechanistic Hypothesis. Nutrients 2021; 14:65. [PMID: 35010940 PMCID: PMC8746684 DOI: 10.3390/nu14010065] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/08/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022] Open
Abstract
Dysbiosis secondary to environmental factors, including dietary patterns, antibiotics use, pollution exposure, and other lifestyle factors, has been associated to many non-infective chronic inflammatory diseases. Autism spectrum disorder (ASD) is related to maternal inflammation, although there is no conclusive evidence that affected individuals suffer from systemic low-grade inflammation as in many psychological and psychiatric diseases. However, neuro-inflammation and neuro-immune abnormalities are observed within ASD-affected individuals. Rebalancing human gut microbiota to treat disease has been widely investigated with inconclusive and contradictory findings. These observations strongly suggest that the forms of dysbiosis encountered in ASD-affected individuals could also originate from autonomic nervous system (ANS) functioning abnormalities, a common neuro-anatomical alteration underlying ASD. According to this hypothesis, overactivation of the sympathetic branch of the ANS, due to the fact of an ASD-specific parasympathetic activity deficit, induces deregulation of the gut-brain axis, attenuating intestinal immune and osmotic homeostasis. This sets-up a dysbiotic state, that gives rise to immune and osmotic dysregulation, maintaining dysbiosis in a vicious cycle. Here, we explore the mechanisms whereby ANS imbalances could lead to alterations in intestinal microbiome-host interactions that may contribute to the severity of ASD by maintaining the brain-gut axis pathways in a dysregulated state.
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Affiliation(s)
- Athanasios Beopoulos
- Bio-Modeling Systems, Tour CIT, 3 Rue de l’Arrivée, 75015 Paris, France; (A.B.); (M.G.)
| | - Manuel Gea
- Bio-Modeling Systems, Tour CIT, 3 Rue de l’Arrivée, 75015 Paris, France; (A.B.); (M.G.)
| | - Alessio Fasano
- Mucosal Immunology and Biology Research Center, Center for Celiac Research and Treatment, Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, MA 022114, USA;
| | - François Iris
- Bio-Modeling Systems, Tour CIT, 3 Rue de l’Arrivée, 75015 Paris, France; (A.B.); (M.G.)
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Sousa FBM, Pacheco G, Oliveira AP, Nicolau LAD, Lopes ALF, Ferreira-Fernandes H, Pinto GR, Medeiros JVR. Mechanism of preservation of the intestinal mucosa architecture and NF-κB/PGE2 reduction by hydrogen sulfide on cholera toxin-induced diarrhea in mice. Life Sci 2021; 284:119869. [PMID: 34358552 DOI: 10.1016/j.lfs.2021.119869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/29/2021] [Accepted: 07/29/2021] [Indexed: 11/29/2022]
Abstract
AIMS Investigate the involvement of Hydrogen sulfide (H2S) in inflammatory parameters and intestinal morphology caused by cholera toxin (CT) in mice. MAIN METHODS Mice were subjected to the procedure of inducing diarrhea by CT in the isolated intestinal loop model. The intestinal loops were inoculated with H2S donor molecules (NaHS and GYY 4137) or saline and CT. To study the role of EP2 and EP4 prostaglandin E2 (PGE2) receptors in the H2S antisecretory effect, PAG (DL-propargylglycine - inhibitor of cystathionine-γ-lyase (CSE)), PF-04418948 (EP2 antagonist) and ONO-AE3-208 (EP4 antagonist) were used. The intestinal loops were evaluated for intestinal secretion, relation of the depth of villi and intestinal crypts, and real-time PCR for the mRNA of the CXCL2, IL-6, NOS-2, IL-17, NF-κB1, NF-κBIA, SLC6A4 and IFN-γ genes. KEY FINDINGS H2S restored the villus/crypt depth ratio caused by CT. NaHS and GYY 4137 increased the expression of NF-κB1 and for the NF-κBIA gene, only GYY 4137 increased the expression of this gene. The increased expression of NF-κB inhibitors, NF-κB1 and NF-κBIA by H2S indicates a possible decrease in NF-κB activity. The pretreatment with PAG reversed the protective effect of PF-04418948 and ONO-AE3-208, indicating that H2S probably decreases PGE2 because in the presence of antagonists of this pathway, PAG promotes intestinal secretion. SIGNIFICANCE Our results point to a protective activity of H2S against CT for promoting a protection of villus and crypt intestine morphology and also that its mechanism occurs at least in part due to decreasing the activity of NF-κB and PGE2.
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Affiliation(s)
- Francisca B M Sousa
- Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (LAFIDG), Post-graduation Program in Biotechnology, Parnaiba Delta Federal University, Parnaíba, PI, Brazil; Northeast Biotechnology Network (RENORBIO), Federal University of Piauí, Teresina, PI, Brazil
| | - Gabriella Pacheco
- Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (LAFIDG), Post-graduation Program in Biotechnology, Parnaiba Delta Federal University, Parnaíba, PI, Brazil
| | - Ana P Oliveira
- Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (LAFIDG), Post-graduation Program in Biotechnology, Parnaiba Delta Federal University, Parnaíba, PI, Brazil; Northeast Biotechnology Network (RENORBIO), Federal University of Piauí, Teresina, PI, Brazil
| | - Lucas A D Nicolau
- Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (LAFIDG), Post-graduation Program in Biotechnology, Parnaiba Delta Federal University, Parnaíba, PI, Brazil
| | - André L F Lopes
- Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (LAFIDG), Post-graduation Program in Biotechnology, Parnaiba Delta Federal University, Parnaíba, PI, Brazil
| | - Hygor Ferreira-Fernandes
- Laboratory of Genetics and Molecular Biology, Parnaiba Delta Federal University, Parnaíba, PI, Brazil
| | - Giovanny R Pinto
- Northeast Biotechnology Network (RENORBIO), Federal University of Piauí, Teresina, PI, Brazil; Laboratory of Genetics and Molecular Biology, Parnaiba Delta Federal University, Parnaíba, PI, Brazil
| | - Jand V R Medeiros
- Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (LAFIDG), Post-graduation Program in Biotechnology, Parnaiba Delta Federal University, Parnaíba, PI, Brazil; Northeast Biotechnology Network (RENORBIO), Federal University of Piauí, Teresina, PI, Brazil.
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Li ZS, Hung LY, Margolis KG, Ambron RT, Sung YJ, Gershon MD. The α isoform of cGMP-dependent protein kinase 1 (PKG1α) is expressed and functionally important in intrinsic primary afferent neurons of the guinea pig enteric nervous system. Neurogastroenterol Motil 2021; 33:e14100. [PMID: 33655600 PMCID: PMC8681866 DOI: 10.1111/nmo.14100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 01/18/2021] [Accepted: 01/26/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Intrinsic primary afferent neurons (IPANs) enable the gut to manifest reflexes in the absence of CNS input. PKG1α is selectively expressed in a subset of neurons in dorsal root ganglia (DRG) and has been linked to nociception and long-term hyperexcitability. METHODS We used immunoblotting, immunocytochemistry, and in vitro assays of IPAN-dependent enteric functions to test hypotheses that subsets of primary neurons of the ENS and DRG share a reliance on PKG1α expression. KEY RESULTS PKG1α immunoreactivity was demonstrated in immunoblots from isolated myenteric ganglia. PKG1α, but not PKG1β, immunoreactivity, was coincident with that of neuronal markers (HuC/D; β3-tubulin) in both enteric plexuses. PKG1α immunoreactivity also co-localized with the immunoreactivities of the IPAN markers, calbindin (100%; myenteric plexus) and cytoplasmic NeuN (98 ± 1% submucosal plexus). CGRP-immunoreactive DRG neurons, identified as visceral afferents by retrograde transport, were PKG1α-immunoreactive. We used intraluminal cholera toxin to determine whether PKG1α was necessary to enable stimulation of the mucosa to activate Fos in enteric neurons. Tetrodotoxin (1.0 µM), low Ca2+ /high Mg2+ media, and the PKG inhibitor, N46 (100 µM), all inhibited Fos activation in myenteric neurons. N46 also concentration dependently inhibited peristaltic reflexes in isolated preparations of distal colon (IC50 = 83.3 ± 1.3 µM). CONCLUSIONS & INFERENCES These data suggest that PKG1α is present and functionally important in IPANs and visceral afferent nociceptive neurons.
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Affiliation(s)
- Zhi S. Li
- Departments of Pathology & Cell Biology, Columbia University, New York, NY, USA
| | - Lin Y. Hung
- Departments of Pediatrics, Columbia University, New York, NY, USA
| | - Kara G. Margolis
- Departments of Pediatrics, Columbia University, New York, NY, USA
| | - Richard T. Ambron
- Departments of Pathology & Cell Biology, Columbia University, New York, NY, USA
| | - Ying J. Sung
- Departments of Basic Science, The Commonwealth Medical College, Scranton, PA, USA
| | - Michael D. Gershon
- Departments of Pathology & Cell Biology, Columbia University, New York, NY, USA
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Giuffrè M, Moretti R, Campisciano G, da Silveira ABM, Monda VM, Comar M, Di Bella S, Antonello RM, Luzzati R, Crocè LS. You Talking to Me? Says the Enteric Nervous System (ENS) to the Microbe. How Intestinal Microbes Interact with the ENS. J Clin Med 2020; 9:E3705. [PMID: 33218203 PMCID: PMC7699249 DOI: 10.3390/jcm9113705] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/13/2020] [Accepted: 11/16/2020] [Indexed: 12/12/2022] Open
Abstract
Mammalian organisms form intimate interfaces with commensal and pathogenic gut microorganisms. Increasing evidence suggests a close interaction between gut microorganisms and the enteric nervous system (ENS), as the first interface to the central nervous system. Each microorganism can exert a different effect on the ENS, including phenotypical neuronal changes or the induction of chemical transmitters that interact with ENS neurons. Some pathogenic bacteria take advantage of the ENS to create a more suitable environment for their growth or to promote the effects of their toxins. In addition, some commensal bacteria can affect the central nervous system (CNS) by locally interacting with the ENS. From the current knowledge emerges an interesting field that may shape future concepts on the pathogen-host synergic interaction. The aim of this narrative review is to report the current findings regarding the inter-relationships between bacteria, viruses, and parasites and the ENS.
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Affiliation(s)
- Mauro Giuffrè
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
- Italian Liver Foundation, 34129 Trieste, Italy
| | - Rita Moretti
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
| | - Giuseppina Campisciano
- Department of Advanced Microbiology Diagnosis and Translational Research, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (G.C.); (M.C.)
| | | | | | - Manola Comar
- Department of Advanced Microbiology Diagnosis and Translational Research, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (G.C.); (M.C.)
| | - Stefano Di Bella
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
| | - Roberta Maria Antonello
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
| | - Roberto Luzzati
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
| | - Lory Saveria Crocè
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (M.G.); (R.M); (R.M.A.); (R.L.); (L.S.C.)
- Italian Liver Foundation, 34129 Trieste, Italy
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de Jonge HR, Ardelean MC, Bijvelds MJC, Vergani P. Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas. FEBS Lett 2020; 594:4085-4108. [PMID: 33113586 PMCID: PMC7756540 DOI: 10.1002/1873-3468.13971] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/22/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023]
Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) is an unusual ABC transporter. It acts as an anion‐selective channel that drives osmotic fluid transport across many epithelia. In the gut, CFTR is crucial for maintaining fluid and acid‐base homeostasis, and its activity is tightly controlled by multiple neuro‐endocrine factors. However, microbial toxins can disrupt this intricate control mechanism and trigger protracted activation of CFTR. This results in the massive faecal water loss, metabolic acidosis and dehydration that characterize secretory diarrhoeas, a major cause of malnutrition and death of children under 5 years of age. Compounds that inhibit CFTR could improve emergency treatment of diarrhoeal disease. Drawing on recent structural and functional insight, we discuss how existing CFTR inhibitors function at the molecular and cellular level. We compare their mechanisms of action to those of inhibitors of related ABC transporters, revealing some unexpected features of drug action on CFTR. Although challenges remain, especially relating to the practical effectiveness of currently available CFTR inhibitors, we discuss how recent technological advances might help develop therapies to better address this important global health need.
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Affiliation(s)
- Hugo R. de Jonge
- Department of Gastroenterology & HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Maria C. Ardelean
- Department of Neuroscience, Physiology and PharmacologyUniversity College LondonUK
- Department of Natural SciencesUniversity College LondonUK
| | - Marcel J. C. Bijvelds
- Department of Gastroenterology & HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Paola Vergani
- Department of Neuroscience, Physiology and PharmacologyUniversity College LondonUK
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Budnik AF, Aryaeva D, Vyshnyakova P, Masliukov PM. Age related changes of neuropeptide Y-ergic system in the rat duodenum. Neuropeptides 2020; 80:101982. [PMID: 31708113 DOI: 10.1016/j.npep.2019.101982] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 11/02/2019] [Accepted: 11/04/2019] [Indexed: 12/31/2022]
Abstract
Neuropeptide Y (NPY) is widely distributed in the autonomic nervous system and acts as a neurotransmitter and a trophic factor. However, there is no report concerning the expression of NPY and its receptors in the intestine during postnatal ontogenesis. In the current study, immunohistochemistry and western blot analysis was used to label NPY, Y1R, Y2R and Y5R receptors in the duodenum from rats of different ages (1-, 10-, 20-, 30-, 60-day-old and 2-year-old). The obtained data suggest age-dependent changes of NPY-mediated gut innervation. NPY-immunoreactive (IR) neurons were observed in the myenteric (MP) and submucous (SP) plexus from the moment of birth. In the MP, the percentage of NPY-IR neurons was low and varied from 4.1 ± 0.32 in 1-day-old to 2.9 ± 0.62 in 2-year-old rats. The proportion of NPY-IR myenteric neurons did not change significantly through the senescence (p > .05). In the SP, the proportion of NPY-IR neurons significantly increased in the first month of life from 56.3 ± 2.4% in 1-day-old to 78.1 ± 5.18% in 20-day-old and significantly decreased from 75.6 ± 4.62% in 30-day-old rats to 59.8 ± 4.24% in 2-year-old rats. The expression of NPY in the duodenum did not change significantly during the development by western blot analysis. The expression of Y1R and Y2R was low in newborns and upregulated in the first ten days of life. The expression of Y5R was maximal in newborn pups and significantly decreased in in the first 20 days. Thus, there are some fluctuation of the percentage of NPY-IR neurons accompanies changes in relation of different subtypes of NPY receptors in the small intestine during postnatal ontogenesis.
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Affiliation(s)
- Antonina F Budnik
- Department of Normal and Pathological Anatomy, Kabardino-Balkarian State University named after H.M. Berbekov, Nalchik, Russia
| | - Daria Aryaeva
- Department of Normal Physiology, Yaroslavl State Medical University, Yaroslavl, Russia
| | - Polina Vyshnyakova
- Department of Normal Physiology, Yaroslavl State Medical University, Yaroslavl, Russia
| | - Petr M Masliukov
- Department of Normal Physiology, Yaroslavl State Medical University, Yaroslavl, Russia; Petrozavodsk State University, Petrozavodsk, Russia.
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11
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Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis. Cell Mol Gastroenterol Hepatol 2019; 7:709-728. [PMID: 30716420 PMCID: PMC6462823 DOI: 10.1016/j.jcmgh.2019.01.004] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 01/03/2019] [Accepted: 01/07/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Serotonin (5-hydroxytryptamine [5-HT]) is synthesized mainly within enterochromaffin (EC) cells in the gut, and tryptophan hydroxylase 1 (Tph1) is the rate-limiting enzyme for 5-HT synthesis in EC cells. Accumulating evidence suggests the importance of gut microbiota in intestinal inflammation. Considering the close proximity of EC cells and the microbes, we investigated the influence of gut-derived 5-HT on the microbiota and the susceptibility to colitis. METHODS Gut microbiota of Tph1-/- and Tph1+/- mice were investigated by deep sequencing. Direct influence of 5-HT on bacteria was assessed by using in vitro system of isolated commensals. The indirect influence of 5-HT on microbiota was assessed by measuring antimicrobial peptides, specifically β-defensins, in the colon of mice and HT-29 colonic epithelial cells. The impact of gut microbiota on the development of dextran sulfate sodium-induced colitis was assessed by transferring gut microbiota from Tph1-/- mice to Tph1+/- littermates and vice versa, as well as in germ-free mice. RESULTS A significant difference in microbial composition between Tph1-/- and Tph1+/- littermates was observed. 5-HT directly stimulated and inhibited the growth of commensal bacteria in vitro, exhibiting a concentration-dependent and species-specific effect. 5-HT also inhibited β-defensin production by HT-29 cells. Microbial transfer from Tph1-/- to Tph1+/- littermates and vice versa altered colitis severity, with microbiota from Tph1-/- mice mediating the protective effects. Furthermore, germ-free mice colonized with microbiota from Tph1-/- mice exhibited less severe dextran sulfate sodium-induced colitis. CONCLUSIONS These findings demonstrate a novel role of gut-derived 5-HT in shaping gut microbiota composition in relation to susceptibility to colitis, identifying 5-HT-microbiota axis as a potential new therapeutic target in intestinal inflammatory disorders.
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12
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Neuroepithelial control of mucosal inflammation in acute cystitis. Sci Rep 2018; 8:11015. [PMID: 30030504 PMCID: PMC6054610 DOI: 10.1038/s41598-018-28634-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 05/03/2018] [Indexed: 12/18/2022] Open
Abstract
The nervous system is engaged by infection, indirectly through inflammatory cascades or directly, by bacterial attack on nerve cells. Here we identify a neuro-epithelial activation loop that participates in the control of mucosal inflammation and pain in acute cystitis. We show that infection activates Neurokinin-1 receptor (NK1R) and Substance P (SP) expression in nerve cells and bladder epithelial cells in vitro and in vivo in the urinary bladder mucosa. Specific innate immune response genes regulated this mucosal response, and single gene deletions resulted either in protection (Tlr4−/− and Il1b−/− mice) or in accentuated bladder pathology (Asc−/− and Nlrp3−/− mice), compared to controls. NK1R/SP expression was lower in Tlr4−/− and Il1b−/− mice than in C56BL/6WT controls but in Asc−/− and Nlrp3−/− mice, NK1R over-activation accompanied the exaggerated disease phenotype, due, in part to transcriptional de-repression of Tacr1. Pharmacologic NK1R inhibitors attenuated acute cystitis in susceptible mice, supporting a role in disease pathogenesis. Clinical relevance was suggested by elevated urine SP levels in patients with acute cystitis, compared to patients with asymptomatic bacteriuria identifying NK1R/SP as potential therapeutic targets. We propose that NK1R and SP influence the severity of acute cystitis through a neuro-epithelial activation loop that controls pain and mucosal inflammation.
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Deng Y, Han X, Tang S, Li C, Xiao W, Tan Z. Magnolol and Honokiol Attenuate Apoptosis of Enterotoxigenic Escherichia Coli-Induced Intestinal Epithelium by Maintaining Secretion and Absorption Homeostasis and Protecting Mucosal Integrity. Med Sci Monit 2018; 24:3348-3356. [PMID: 29782483 PMCID: PMC5990993 DOI: 10.12659/msm.910350] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 05/07/2018] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The cortex of Magnolia officinalis has long been used as an element of traditional Chinese medicine for the treatment of anxiety, chronic bronchitis, and gastrointestinal dysfunction. This study aimed to elucidate the underlying mechanism of its functional ingredients (magnolol and honokiol) in modifying the secretion and absorption homeostasis and protecting mucosal integrity in an Enterotoxigenic Escherichia coli (ETEC)-induced diarrhea mouse model. MATERIAL AND METHODS This study established a diarrhea mouse model infected by ETEC at a dosage of 0.02 ml/g live body weight (BW) in vivo. Magnolol or honokiol was followed by an intraperitoneal administration at dosages of 100, 300, and 500 mg/kg BW according to a 3×3 factorial arrangement. The useful biomarkers for evaluating the integrity of intestinal tract and histologic injury were analyzed and morphological development (including villus height, crypt depth, and ratio of villus height to crypt depth) and the expressions of inflammatory cytokines were determined by real-time PCR. RESULTS The results showed that magnolol and honokiol (500 mg/kg BW) reduced the concentrations of NO, DAO, and DLA, and iNOS activity, and the mRNA expressions of the interferon gamma (IFN-γ) and interleukin 10 (IL-10), and inhibited intestinal epithelial cell apoptosis. Magnolol and honokiol (300 mg/kg BW) elongated the villus height and crypt depth and decreased the number of goblet cells and the ratio of villus height to crypt depth. CONCLUSIONS The current results indicate that magnolol and honokiol enhance the intestinal anti-inflammatory capacities, elongate the villus height and crypt depth, and reduce goblet cell numbers to inhibit the intestinal epithelium apoptosis and effectively protect the intestinal mucosa. These results show that magnolol and honokiol protect the intestinal mucosal integrity and regulate gastrointestinal dysfunction.
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Affiliation(s)
- Yanli Deng
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Hunan Collaborative Innovation Center for Utilization of Botanical Functional Ingredients, Changsha, Hunan, P.R. China
- Tea College of Guizhou University, Guiyang, Guizhou, P.R. China
| | - Xuefeng Han
- Key Laboratory for Agro-Ecological Processes in Subtropical Region, and South-Central Experimental Station of Animal Nutrition and Feed Science in Ministry of Agriculture, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, P.R. China
| | - Shaoxun Tang
- Key Laboratory for Agro-Ecological Processes in Subtropical Region, and South-Central Experimental Station of Animal Nutrition and Feed Science in Ministry of Agriculture, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, P.R. China
| | - Chengjian Li
- Department of Pharmacy, Yongzhou Vocational Technical College, Yongzhou, Hunan, P. R. China
| | - Wenjun Xiao
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Hunan Collaborative Innovation Center for Utilization of Botanical Functional Ingredients, Changsha, Hunan, P.R. China
| | - Zhiliang Tan
- Key Laboratory for Agro-Ecological Processes in Subtropical Region, and South-Central Experimental Station of Animal Nutrition and Feed Science in Ministry of Agriculture, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, P.R. China
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Tang L, Jiang L, McIntyre ME, Petrova E, Cheng SX. Calcimimetic acts on enteric neuronal CaSR to reverse cholera toxin-induced intestinal electrolyte secretion. Sci Rep 2018; 8:7851. [PMID: 29777154 PMCID: PMC5959902 DOI: 10.1038/s41598-018-26171-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 05/08/2018] [Indexed: 01/19/2023] Open
Abstract
Treatment of acute secretory diarrheal illnesses remains a global challenge. Enterotoxins produce secretion through direct epithelial action and indirectly by activating enteric nervous system (ENS). Using a microperfused colonic crypt technique, we have previously shown that R568, a calcimimetic that activates the calcium-sensing receptor (CaSR), can act on intestinal epithelium and reverse cholera toxin-induced fluid secretion. In the present study, using the Ussing chamber technique in conjunction with a tissue-specific knockout approach, we show that the effects of cholera toxin and CaSR agonists on electrolyte secretion by the intestine can also be attributed to opposing actions of the toxin and CaSR on the activity of the ENS. Our results suggest that targeting intestinal CaSR might represent a previously undescribed new approach for treating secretory diarrheal diseases and other conditions with ENS over-activation.
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Affiliation(s)
- Lieqi Tang
- Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA
| | - Lingli Jiang
- Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA
| | - Megan E McIntyre
- Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA
| | - Ekaterina Petrova
- Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA
| | - Sam X Cheng
- Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA. .,Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, FL, 32610, USA.
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15
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Sheikh IA, Ammoury R, Ghishan FK. Pathophysiology of Diarrhea and Its Clinical Implications. PHYSIOLOGY OF THE GASTROINTESTINAL TRACT 2018:1669-1687. [DOI: 10.1016/b978-0-12-809954-4.00068-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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16
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Moeser AJ, Pohl CS, Rajput M. Weaning stress and gastrointestinal barrier development: Implications for lifelong gut health in pigs. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2017; 3:313-321. [PMID: 29767141 PMCID: PMC5941262 DOI: 10.1016/j.aninu.2017.06.003] [Citation(s) in RCA: 252] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 06/15/2017] [Accepted: 06/20/2017] [Indexed: 12/14/2022]
Abstract
The gastrointestinal (GI) barrier serves a critical role in survival and overall health of animals and humans. Several layers of barrier defense mechanisms are provided by the epithelial, immune and enteric nervous systems. Together they act in concert to control normal gut functions (e.g., digestion, absorption, secretion, immunity, etc.) whereas at the same time provide a barrier from the hostile conditions in the luminal environment. Breakdown of these critical GI functions is a central pathophysiological mechanism in the most serious GI disorders in pigs. This review will focus on the development and functional properties of the GI barrier in pigs and how common early life production stressors, such as weaning, can alter immediate and long-term barrier function and disease susceptibility. Specific stress-related pathophysiological mechanisms responsible for driving GI barrier dysfunction induced by weaning and the implications to animal health and performance will be discussed.
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Affiliation(s)
- Adam J. Moeser
- Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
- Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
- Corresponding author.
| | - Calvin S. Pohl
- Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Mrigendra Rajput
- Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
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17
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Clemens JD, Nair GB, Ahmed T, Qadri F, Holmgren J. Cholera. Lancet 2017; 390:1539-1549. [PMID: 28302312 DOI: 10.1016/s0140-6736(17)30559-7] [Citation(s) in RCA: 267] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 11/01/2016] [Accepted: 12/15/2016] [Indexed: 12/30/2022]
Abstract
Cholera is an acute, watery diarrhoeal disease caused by Vibrio cholerae of the O1 or O139 serogroups. In the past two centuries, cholera has emerged and spread from the Ganges Delta six times and from Indonesia once to cause global pandemics. Rational approaches to the case management of cholera with oral and intravenous rehydration therapy have reduced the case fatality of cholera from more than 50% to much less than 1%. Despite improvements in water quality, sanitation, and hygiene, as well as in the clinical treatment of cholera, the disease is still estimated to cause about 100 000 deaths every year. Most deaths occur in cholera-endemic settings, and virtually all deaths occur in developing countries. Contemporary understanding of immune protection against cholera, which results from local intestinal immunity, has yielded safe and protective orally administered cholera vaccines that are now globally stockpiled for use in the control of both epidemic and endemic cholera.
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Affiliation(s)
- John D Clemens
- International Centre for Diarrhoeal Disease Research, Bangladesh, Centre for Health and Population Research, Dhaka, Bangladesh; UCLA Fielding School of Public Health, Los Angeles, CA, USA; Korea University School of Medicine, Seoul, Korea.
| | | | - Tahmeed Ahmed
- International Centre for Diarrhoeal Disease Research, Bangladesh, Centre for Health and Population Research, Dhaka, Bangladesh
| | - Firdausi Qadri
- International Centre for Diarrhoeal Disease Research, Bangladesh, Centre for Health and Population Research, Dhaka, Bangladesh
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18
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Integrated Neural and Endocrine Control of Gastrointestinal Function. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 891:159-73. [PMID: 27379644 DOI: 10.1007/978-3-319-27592-5_16] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The activity of the digestive system is dynamically regulated by external factors, including body nutritional and activity states, emotions and the contents of the digestive tube. The gut must adjust its activity to assimilate a hugely variable mixture that is ingested, particularly in an omnivore such as human for which a wide range of food choices exist. It must also guard against toxins and pathogens. These nutritive and non-nutritive components of the gut contents interact with the largest and most vulnerable surface in the body, the lining of the gastrointestinal tract. This requires a gut sensory system that can detect many classes of nutrients, non-nutrient components of food, physicochemical conditions, toxins, pathogens and symbionts (Furness et al., Nat Rev Gastroenterol Hepatol 10:729-740, 2013). The gut sensors are in turn coupled to effector systems that can respond to the sensory information. The responses are exerted through enteroendocrine cells (EEC), the enteric nervous system (ENS), the central nervous system (CNS) and the gut immune and tissue defence systems. It is apparent that the control of the digestive organs is an integrated function of these effectors. The peripheral components of the EEC, ENS and CNS triumvirate are extensive. EEC cells have traditionally been classified into about 12 types (disputed in this review), releasing about 20 hormones, together making the gut endocrine system the largest endocrine organ in the body. Likewise, in human the ENS contains about 500 million neurons, far more than the number of neurons in the remainder of the peripheral autonomic nervous system. Together gut hormones, the ENS and the CNS control or influence functions including satiety, mixing and propulsive activity, release of digestive enzymes, induction of nutrient transporters, fluid transport, local blood flow, gastric acid secretion, evacuation and immune responses. Gut content receptors, including taste, free fatty acid, peptide and phytochemical receptors, are primarily located on EEC. Hormones released by EEC act via both the ENS and CNS to optimise digestion. Toxic chemicals and pathogens are sensed and then avoided, expelled or metabolised. These defensive activities also involve the EEC and signalling from EEC to the ENS and the CNS. A major challenge is to develop a comprehensive understanding of the integrated responses of the gut, via its effector systems, the ENS, extrinsic innervation, EEC and the gut immune system, to the sensory information it receives.
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19
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Koussoulas K, Gwynne RM, Foong JPP, Bornstein JC. Cholera Toxin Induces Sustained Hyperexcitability in Myenteric, but Not Submucosal, AH Neurons in Guinea Pig Jejunum. Front Physiol 2017; 8:254. [PMID: 28496413 PMCID: PMC5406514 DOI: 10.3389/fphys.2017.00254] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 04/10/2017] [Indexed: 01/04/2023] Open
Abstract
Background and Aims: Cholera toxin (CT)-induced hypersecretion requires activation of secretomotor pathways in the enteric nervous system (ENS). AH neurons, which have been identified as a population of intrinsic sensory neurons (ISNs), are a source of excitatory input to the secretomotor pathways. We therefore examined effects of CT in the intestinal lumen on myenteric and submucosal AH neurons. Methods: Isolated segments of guinea pig jejunum were incubated for 90 min with saline plus CT (12.5 μg/ml) or CT + neurotransmitter antagonist, or CT + tetrodotoxin (TTX) in their lumen. After washing CT away, submucosal or myenteric plexus preparations were dissected keeping circumferentially adjacent mucosa intact. Submucosal AH neurons were impaled adjacent to intact mucosa and myenteric AH neurons were impaled adjacent to, more than 5 mm from, and in the absence of intact mucosa. Neuronal excitability was monitored by injecting 500 ms current pulses through the recording electrode. Results: After CT pre-treatment, excitability of myenteric AH neurons adjacent to intact mucosa (n = 29) was greater than that of control neurons (n = 24), but submucosal AH neurons (n = 33, control n = 27) were unaffected. CT also induced excitability increases in myenteric AH neurons impaled distant from the mucosa (n = 6) or in its absence (n = 5). Coincubation with tetrodotoxin or SR142801 (NK3 receptor antagonist), but not SR140333 (NK1 antagonist) or granisetron (5-HT3 receptor antagonist) prevented the increased excitability induced by CT. Increased excitability was associated with a reduction in the characteristic AHP and an increase in the ADP of these neurons, but not a change in the hyperpolarization-activated inward current, Ih. Conclusions: CT increases excitability of myenteric, but not submucosal, AH neurons. This is neurally mediated and depends on NK3, but not 5-HT3 receptors. Therefore, CT may act to amplify the secretomotor response to CT via an increase in the activity of the afferent limb of the enteric reflex circuitry.
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Affiliation(s)
- Katerina Koussoulas
- Enteric Neuroscience Laboratory, Department of Physiology, University of MelbourneParkville, VIC, Australia
| | - Rachel M Gwynne
- Enteric Neuroscience Laboratory, Department of Physiology, University of MelbourneParkville, VIC, Australia
| | - Jaime P P Foong
- Enteric Neuroscience Laboratory, Department of Physiology, University of MelbourneParkville, VIC, Australia
| | - Joel C Bornstein
- Enteric Neuroscience Laboratory, Department of Physiology, University of MelbourneParkville, VIC, Australia
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20
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Yang NJ, Chiu IM. Bacterial Signaling to the Nervous System through Toxins and Metabolites. J Mol Biol 2017; 429:587-605. [PMID: 28065740 PMCID: PMC5325782 DOI: 10.1016/j.jmb.2016.12.023] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 12/21/2016] [Accepted: 12/29/2016] [Indexed: 12/31/2022]
Abstract
Mammalian hosts interface intimately with commensal and pathogenic bacteria. It is increasingly clear that molecular interactions between the nervous system and microbes contribute to health and disease. Both commensal and pathogenic bacteria are capable of producing molecules that act on neurons and affect essential aspects of host physiology. Here we highlight several classes of physiologically important molecular interactions that occur between bacteria and the nervous system. First, clostridial neurotoxins block neurotransmission to or from neurons by targeting the SNARE complex, causing the characteristic paralyses of botulism and tetanus during bacterial infection. Second, peripheral sensory neurons-olfactory chemosensory neurons and nociceptor sensory neurons-detect bacterial toxins, formyl peptides, and lipopolysaccharides through distinct molecular mechanisms to elicit smell and pain. Bacteria also damage the central nervous system through toxins that target the brain during infection. Finally, the gut microbiota produces molecules that act on enteric neurons to influence gastrointestinal motility, and metabolites that stimulate the "gut-brain axis" to alter neural circuits, autonomic function, and higher-order brain function and behavior. Furthering the mechanistic and molecular understanding of how bacteria affect the nervous system may uncover potential strategies for modulating neural function and treating neurological diseases.
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Affiliation(s)
- Nicole J Yang
- Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Isaac M Chiu
- Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115, USA.
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21
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Tang L, Cheng CY, Sun X, Pedicone AJ, Mohamadzadeh M, Cheng SX. The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity. Front Physiol 2016; 7:245. [PMID: 27458380 PMCID: PMC4914593 DOI: 10.3389/fphys.2016.00245] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 06/03/2016] [Indexed: 12/14/2022] Open
Abstract
Different from other epithelia, the intestinal epithelium has the complex task of providing a barrier impeding the entry of toxins, food antigens, and microbes, while at the same time allowing for the transfer of nutrients, electrolytes, water, and microbial metabolites. These molecules/organisms are transported either transcellularly, crossing the apical and basolateral membranes of enterocytes, or paracellularly, passing through the space between enterocytes. Accordingly, the intestinal epithelium can affect energy metabolism, fluid balance, as well as immune response and tolerance. To help accomplish these complex tasks, the intestinal epithelium has evolved many sensing receptor mechanisms. Yet, their roles and functions are only now beginning to be elucidated. This article explores one such sensing receptor mechanism, carried out by the extracellular calcium-sensing receptor (CaSR). In addition to its established function as a nutrient sensor, coordinating food digestion, nutrient absorption, and regulating energy metabolism, we present evidence for the emerging role of CaSR in the control of intestinal fluid homeostasis and immune balance. An additional role in the modulation of the enteric nerve activity and motility is also discussed. Clearly, CaSR has profound effects on many aspects of intestinal function. Nevertheless, more work is needed to fully understand all functions of CaSR in the intestine, including detailed mechanisms of action and specific pathways involved. Considering the essential roles CaSR plays in gastrointestinal physiology and immunology, research may lead to a translational opportunity for the development of novel therapies that are based on CaSR's unique property of using simple nutrients such as calcium, polyamines, and certain amino acids/oligopeptides as activators. It is possible that, through targeting of intestinal CaSR with a combination of specific nutrients, oral solutions that are both inexpensive and practical may be developed to help in conditioning the gut microenvironment and in maintaining digestive health.
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Affiliation(s)
- Lieqi Tang
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida Gainesville, FL, USA
| | - Catherine Y Cheng
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida Gainesville, FL, USA
| | - Xiangrong Sun
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida Gainesville, FL, USA
| | - Alexandra J Pedicone
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida Gainesville, FL, USA
| | - Mansour Mohamadzadeh
- Department of Medicine, Center for Inflammation and Mucosal Immunology, University of Florida Gainesville, FL, USA
| | - Sam X Cheng
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida Gainesville, FL, USA
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22
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Balasuriya GK, Hill-Yardin EL, Gershon MD, Bornstein JC. A sexually dimorphic effect of cholera toxin: rapid changes in colonic motility mediated via a 5-HT3 receptor-dependent pathway in female C57Bl/6 mice. J Physiol 2016; 594:4325-38. [PMID: 26990461 DOI: 10.1113/jp272071] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 03/11/2016] [Indexed: 12/19/2022] Open
Abstract
KEY POINTS Cholera causes more than 100,000 deaths each year as a result of severe diarrhoea, vomiting and dehydration due to the actions of cholera toxin; more females than males are affected. Cholera toxin induces hypersecretion via release of mucosal serotonin and over-activation of enteric neurons, but its effects on gastrointestinal motility are not well characterized. We found that cholera toxin rapidly and reversibly reduces colonic motility in female mice in oestrus, but not in males or females in prooestrus, an effect mediated by 5-HT in the colonic mucosa and by 5-HT3 receptors. We show that the number of mucosal enterochromaffin cells containing 5-HT changes with the oestrous cycle in mice. These findings indicate that cholera toxin's effects on motility are rapid and depend on the oestrous cycle and therefore can help us better understand differences in responses in males and female patients. ABSTRACT Extensive studies of the mechanisms responsible for the hypersecretion produced by cholera toxin (CT) have shown that this toxin produces a massive over-activation of enteric neural secretomotor circuits. The effects of CT on gastrointestinal motility, however, have not been adequately characterized. We investigated effects of luminal CT on neurally mediated motor activity in ex vivo male and female mouse full length colon preparations. We used video recording and spatiotemporal maps of contractile activity to quantify colonic migrating motor complexes (CMMCs) and resting colonic diameter. We compared effects of CT in female colon from wild-type and mice lacking tryptophan hydroxylase (TPH1KO). We also compared CMMCs in colons of female mice in oestrus with those in prooestrus. In female (but not male) colon, CT rapidly, reversibly and concentration-dependently inhibits CMMC frequency and induces a tonic constriction. These effects were blocked by granisetron (5-HT3 antagonist) and were absent from TPH1KO females. CT effects were prominent at oestrus but absent at prooestrus. The number of EC cells containing immunohistochemically demonstrable serotonin (5-HT) was 30% greater in female mice during oestrus than during prooestrus or in males. We conclude that CT inhibits CMMCs via release of mucosal 5-HT, which activates an inhibitory pathway involving 5-HT3 receptors. This effect is sex- and oestrous cycle-dependent and is probably due to an oestrous cycle-dependent change in the number of 5-HT-containing EC cells in the colonic mucosa.
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Affiliation(s)
| | - Elisa L Hill-Yardin
- Department of Physiology, University of Melbourne, Parkville Vic, 3010, Australia
| | - Michael D Gershon
- Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Joel C Bornstein
- Department of Physiology, University of Melbourne, Parkville Vic, 3010, Australia
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Interactions Between Bacteria and the Gut Mucosa: Do Enteric Neurotransmitters Acting on the Mucosal Epithelium Influence Intestinal Colonization or Infection? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 874:121-41. [DOI: 10.1007/978-3-319-20215-0_5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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The enteric nervous system and gastrointestinal innervation: integrated local and central control. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 817:39-71. [PMID: 24997029 DOI: 10.1007/978-1-4939-0897-4_3] [Citation(s) in RCA: 511] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The digestive system is innervated through its connections with the central nervous system (CNS) and by the enteric nervous system (ENS) within the wall of the gastrointestinal tract. The ENS works in concert with CNS reflex and command centers and with neural pathways that pass through sympathetic ganglia to control digestive function. There is bidirectional information flow between the ENS and CNS and between the ENS and sympathetic prevertebral ganglia.The ENS in human contains 200-600 million neurons, distributed in many thousands of small ganglia, the great majority of which are found in two plexuses, the myenteric and submucosal plexuses. The myenteric plexus forms a continuous network that extends from the upper esophagus to the internal anal sphincter. Submucosal ganglia and connecting fiber bundles form plexuses in the small and large intestines, but not in the stomach and esophagus. The connections between the ENS and CNS are carried by the vagus and pelvic nerves and sympathetic pathways. Neurons also project from the ENS to prevertebral ganglia, the gallbladder, pancreas and trachea.The relative roles of the ENS and CNS differ considerably along the digestive tract. Movements of the striated muscle esophagus are determined by neural pattern generators in the CNS. Likewise the CNS has a major role in monitoring the state of the stomach and, in turn, controlling its contractile activity and acid secretion, through vago-vagal reflexes. In contrast, the ENS in the small intestine and colon contains full reflex circuits, including sensory neurons, interneurons and several classes of motor neuron, through which muscle activity, transmucosal fluid fluxes, local blood flow and other functions are controlled. The CNS has control of defecation, via the defecation centers in the lumbosacral spinal cord. The importance of the ENS is emphasized by the life-threatening effects of some ENS neuropathies. By contrast, removal of vagal or sympathetic connections with the gastrointestinal tract has minor effects on GI function. Voluntary control of defecation is exerted through pelvic connections, but cutting these connections is not life-threatening and other functions are little affected.
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Welch MG, Margolis KG, Li Z, Gershon MD. Oxytocin regulates gastrointestinal motility, inflammation, macromolecular permeability, and mucosal maintenance in mice. Am J Physiol Gastrointest Liver Physiol 2014; 307:G848-62. [PMID: 25147234 PMCID: PMC4200316 DOI: 10.1152/ajpgi.00176.2014] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 08/18/2014] [Indexed: 01/31/2023]
Abstract
Enteric neurons express oxytocin (OT); moreover, enteric neurons and enterocytes express developmentally regulated OT receptors (OTRs). Although OT (with secretin) opposes intestinal inflammation, physiological roles played by enteric OT/OTR signaling have not previously been determined. We tested hypotheses that OT/OTR signaling contributes to enteric nervous system (ENS)-related gastrointestinal (GI) physiology. GI functions and OT effects were compared in OTR-knockout (OTRKO) and wild-type (WT) mice. Stool mass and water content were greater in OTRKO mice than in WT. GI transit time in OTRKO animals was faster than in WT; OT inhibited in vitro generation of ENS-dependent colonic migrating motor complexes in WT but not in OTRKO mice. Myenteric neurons were hyperplastic in OTRKO animals, and mucosal exposure to cholera toxin (CTX) in vitro activated Fos in more myenteric neurons in OTRKO than WT than in WT mice; OT inhibited the CTX response in WT but not in OTRKO mice. Villi and crypts were shorter in OTRKO than in WT mice, and transit-amplifying cell proliferation in OTRKO crypts was deficient. Macromolecular intestinal permeability in OTRKO was greater than WT mice, and experimental colitis was more severe in OTRKO mice; moreover, OT protected WT animals from colitis. Observations suggest that OT/OTR signaling acts as a brake on intestinal motility, decreases mucosal activation of enteric neurons, and promotes enteric neuronal development and/or survival. It also regulates proliferation of crypt cells and mucosal permeability; moreover OT/OTR signaling is protective against inflammation. Oxytocinergic signaling thus appears to play an important role in multiple GI functions that are subject to neuronal regulation.
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Affiliation(s)
- Martha G Welch
- Department of Psychiatry, Pediatrics, and Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York
| | - Kara G Margolis
- Department of Psychiatry, Pediatrics, and Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York
| | - Zhishan Li
- Department of Psychiatry, Pediatrics, and Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York
| | - Michael D Gershon
- Department of Psychiatry, Pediatrics, and Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York
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Gwynne RM, Clarke AJ, Furness JB, Bornstein JC. Both exogenous 5-HT and endogenous 5-HT, released by fluoxetine, enhance distension evoked propulsion in guinea-pig ileum in vitro. Front Neurosci 2014; 8:301. [PMID: 25285066 PMCID: PMC4168689 DOI: 10.3389/fnins.2014.00301] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 09/03/2014] [Indexed: 12/11/2022] Open
Abstract
The roles of 5-HT3 and 5-HT4 receptors in the modulation of intestinal propulsion by luminal application of 5-HT and augmentation of endogenous 5-HT effects were studied in segments of guinea-pig ileum in vitro. Persistent propulsive contractions evoked by saline distension were examined using a modified Trendelenburg method. When 5-HT (30 nM), fluoxetine (selective serotonin reuptake inhibitor; 1 nM), 2-methyl-5-HT (5-HT3 receptor agonist; 1 mM), or RS 67506 (5-HT4 receptor agonist, 1 μM) was infused into the lumen, the pressure needed to initiate persistent propulsive activity fell significantly. A specific 5-HT4 receptor antagonist, SB 207266 (10 nM in lumen), abolished the effects of 5-HT, fluoxetine, and RS 67506, but not those of 2-methyl-5-HT. Granisetron (5-HT3 receptor antagonist; 1 μM in lumen) abolished the effect of 5-HT, fluoxetine, RS 67506, and 2-methyl-5-HT. The NK3 receptor antagonist SR 142801 (100 nM in lumen) blocked the effects of 5-HT, fluoxetine, and 2-methyl-5-HT. SB 207266, granisetron, and SR 142801 had no effect by themselves. Higher concentrations of fluoxetine (100 and 300 nM) and RS 67506 (3 and 10 μM) had no effect on the distension threshold for propulsive contractions. These results indicate that luminal application of exogenous 5-HT, or increased release of endogenous mucosal 5-HT above basal levels, acts to lower the threshold for propulsive contractions in the guinea-pig ileum via activation of 5-HT3 and 5-HT4 receptors and the release of tachykinins. The results further indicate that basal release of 5-HT is insufficient to alter the threshold for propulsive motor activity.
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Affiliation(s)
- Rachel M Gwynne
- Department of Physiology, University of Melbourne Parkville, VIC, Australia
| | - Amanda J Clarke
- Department of Physiology, University of Melbourne Parkville, VIC, Australia
| | - John B Furness
- Departments of Anatomy and Cell Biology, University of Melbourne Parkville, VIC, Australia
| | - Joel C Bornstein
- Department of Physiology, University of Melbourne Parkville, VIC, Australia
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Ochoa-Cortes F, Liñán-Rico A, Jacobson KA, Christofi FL. Potential for developing purinergic drugs for gastrointestinal diseases. Inflamm Bowel Dis 2014; 20:1259-87. [PMID: 24859298 PMCID: PMC4340257 DOI: 10.1097/mib.0000000000000047] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Treatments for inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), functional dyspepsia, or motility disorders are not adequate, and purinergic drugs offer exciting new possibilities. Gastrointestinal symptoms that could be targeted for therapy include visceral pain, inflammatory pain, dysmotility, constipation, and diarrhea. The focus of this review is on the potential for developing purinergic drugs for clinical trials to treat gastrointestinal symptoms. Purinergic receptors are divided into adenosine P1 (A(1), A(2A), A(2B), A(3)), ionotropic ATP-gated P2X ion channel (P2X(1-7)), or metabotropic P2Y(1,2,4,6,11-14) receptors. There is good experimental evidence for targeting A(2A), A(2B), A(3), P2X(7), and P2X(3) receptors or increasing endogenous adenosine levels to treat IBD, inflammatory pain, IBS/visceral pain, inflammatory diarrhea, and motility disorders. Purine genes are also potential biomarkers of disease. Advances in medicinal chemistry have an accelerated pace toward clinical trials: Methotrexate and sulfasalazine, used to treat IBD, act by stimulating CD73-dependent adenosine production. ATP protects against NSAID-induced enteropathy and has pain-relieving properties in humans. A P2X(7)R antagonist AZD9056 is in clinical trials for Crohn's disease. A(3) adenosine receptor drugs target inflammatory diseases (e.g., CF101, CF102). Dipyridamole, a nucleoside uptake inhibitor, is in trials for endotoxemia. Drugs for pain in clinical trials include P2X(3)/P2X(2/3) (AF-219) and P2X(7) (GSK1482160) antagonists and A(1) (GW493838) or A(2A) (BVT.115959) agonists. Iberogast is a phytopharmacon targeting purine mechanisms with efficacy in IBS and functional dyspepsia. Purinergic drugs have excellent safety/efficacy profile for prospective clinical trials in IBD, IBS, functional dyspepsia, and inflammatory diarrhea. Genetic polymorphisms and caffeine consumption may affect susceptibility to treatment. Further studies in animals can clarify mechanisms and test new generation drugs. Finally, there is still a huge gap in our knowledge of human pathophysiology of purinergic signaling.
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Affiliation(s)
- Fernando Ochoa-Cortes
- Department of Anesthesiology, The Wexner Medical Center at The Ohio State University, Columbus, Ohio
| | - Andromeda Liñán-Rico
- Department of Anesthesiology, The Wexner Medical Center at The Ohio State University, Columbus, Ohio
| | - Kenneth A. Jacobson
- Laboratory of Bioorganic Chemistry & Molecular Recognition Section, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health
| | - Fievos L. Christofi
- Department of Anesthesiology, The Wexner Medical Center at The Ohio State University, Columbus, Ohio
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Foulke-Abel J, In J, Kovbasnjuk O, Zachos NC, Ettayebi K, Blutt SE, Hyser JM, Zeng XL, Crawford SE, Broughman JR, Estes MK, Donowitz M. Human enteroids as an ex-vivo model of host-pathogen interactions in the gastrointestinal tract. Exp Biol Med (Maywood) 2014; 239:1124-34. [PMID: 24719375 DOI: 10.1177/1535370214529398] [Citation(s) in RCA: 148] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Currently, 9 out of 10 experimental drugs fail in clinical studies. This has caused a 40% plunge in the number of drugs approved by the US Food and Drug Administration (FDA) since 2005. It has been suggested that the mechanistic differences between human diseases modeled in animals (mostly rodents) and the pathophysiology of human diseases might be one of the critical factors that contribute to drug failure in clinical trials. Rapid progress in the field of human stem cell technology has allowed the in-vitro recreation of human tissue that should complement and expand upon the limitations of cell and animal models currently used to study human diseases and drug toxicity. Recent success in the identification and isolation of human intestinal epithelial stem cells (Lgr5(+)) from the small intestine and colon has led to culture of functional intestinal epithelial units termed organoids or enteroids. Intestinal enteroids are comprised of all four types of normal epithelial cells and develop a crypt-villus differentiation axis. They demonstrate major intestinal physiologic functions, including Na(+) absorption and Cl(-) secretion. This review discusses the recent progress in establishing human enteroids as a model of infectious diarrheal diseases such as cholera, rotavirus, and enterohemorrhagic Escherichia coli, and use of the enteroids to determine ways to correct the diarrhea-induced ion transport abnormalities via drug therapy.
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Affiliation(s)
- Jennifer Foulke-Abel
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Julie In
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Olga Kovbasnjuk
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Nicholas C Zachos
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Khalil Ettayebi
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sarah E Blutt
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Joseph M Hyser
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xi-Lei Zeng
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sue E Crawford
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - James R Broughman
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mary K Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mark Donowitz
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Guichard A, Cruz-Moreno B, Cruz-Moreno BC, Aguilar B, van Sorge NM, Kuang J, Kurkciyan AA, Wang Z, Hang S, Pineton de Chambrun GP, McCole DF, Watnick P, Nizet V, Bier E. Cholera toxin disrupts barrier function by inhibiting exocyst-mediated trafficking of host proteins to intestinal cell junctions. Cell Host Microbe 2014; 14:294-305. [PMID: 24034615 DOI: 10.1016/j.chom.2013.08.001] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 06/21/2013] [Accepted: 07/25/2013] [Indexed: 12/21/2022]
Abstract
Cholera toxin (CT), a virulence factor elaborated by Vibrio cholerae, is sufficient to induce the severe diarrhea characteristic of cholera. The enzymatic moiety of CT (CtxA) increases cAMP synthesis in intestinal epithelial cells, leading to chloride ion (Cl(-)) efflux through the CFTR Cl(-) channel. To preserve electroneutrality and osmotic balance, sodium ions and water also flow into the intestinal lumen via a paracellular route. We find that CtxA-driven cAMP increase also inhibits Rab11/exocyst-mediated trafficking of host proteins including E-cadherin and Notch signaling components to cell-cell junctions in Drosophila, human intestinal epithelial cells, and ligated mouse ileal loops, thereby disrupting barrier function. Additionally, CtxA induces junctional damage, weight loss, and dye leakage in the Drosophila gut, contributing to lethality from live V. cholerae infection, all of which can be rescued by Rab11 overexpression. These barrier-disrupting effects of CtxA may act in parallel with Cl(-) secretion to drive the pathophysiology of cholera.
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Affiliation(s)
- Annabel Guichard
- Section of Cell and Developmental Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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Zhang J, Halm ST, Halm DR. Role of the BK channel (KCa1.1) during activation of electrogenic K+ secretion in guinea pig distal colon. Am J Physiol Gastrointest Liver Physiol 2012; 303:G1322-34. [PMID: 23064759 PMCID: PMC3532550 DOI: 10.1152/ajpgi.00325.2012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Secretagogues acting at a variety of receptor types activate electrogenic K(+) secretion in guinea pig distal colon, often accompanied by Cl(-) secretion. Distinct blockers of K(Ca)1.1 (BK, Kcnma1), iberiotoxin (IbTx), and paxilline inhibited the negative short-circuit current (I(sc)) associated with K(+) secretion. Mucosal addition of IbTx inhibited epinephrine-activated I(sc) ((epi)I(sc)) and transepithelial conductance ((epi)G(t)) consistent with K(+) secretion occurring via apical membrane K(Ca)1.1. The concentration dependence of IbTx inhibition of (epi)I(sc) yielded an IC(50) of 193 nM, with a maximal inhibition of 51%. Similarly, IbTx inhibited (epi)G(t) with an IC(50) of 220 nM and maximal inhibition of 48%. Mucosally added paxilline (10 μM) inhibited (epi)I(sc) and (epi)G(t) by ∼50%. IbTx and paxilline also inhibited I(sc) activated by mucosal ATP, supporting apical K(Ca)1.1 as a requirement for this K(+) secretagogue. Responses to IbTx and paxilline indicated that a component of K(+) secretion occurred during activation of Cl(-) secretion by prostaglandin-E(2) and cholinergic stimulation. Analysis of K(Ca)1.1α mRNA expression in distal colonic epithelial cells indicated the presence of the ZERO splice variant and three splice variants for the COOH terminus. The presence of the regulatory β-subunits K(Ca)β1 and K(Ca)β4 also was demonstrated. Immunolocalization supported the presence of K(Ca)1.1α in apical and basolateral membranes of surface and crypt cells. Together these results support a cellular mechanism for electrogenic K(+) secretion involving apical membrane K(Ca)1.1 during activation by several secretagogue types, but the observed K(+) secretion likely required the activity of additional K(+) channel types in the apical membrane.
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Affiliation(s)
- Jin Zhang
- Department of Neuroscience, Cell Biology and Physiology, Wright State University Boonshoft School of Medicine, Dayton, Ohio
| | - Susan T. Halm
- Department of Neuroscience, Cell Biology and Physiology, Wright State University Boonshoft School of Medicine, Dayton, Ohio
| | - Dan R. Halm
- Department of Neuroscience, Cell Biology and Physiology, Wright State University Boonshoft School of Medicine, Dayton, Ohio
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Cheng SX. Calcium-sensing receptor inhibits secretagogue-induced electrolyte secretion by intestine via the enteric nervous system. Am J Physiol Gastrointest Liver Physiol 2012; 303:G60-70. [PMID: 22517767 PMCID: PMC3404579 DOI: 10.1152/ajpgi.00425.2011] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Bacterial toxins such as cholera toxin induce diarrhea by both direct epithelial cell generation of cyclic nucleotides as well as stimulation of the enteric nervous system (ENS). Agonists of the extracellular calcium-sensing receptor (CaSR) can reduce toxin-stimulated fluid secretion in ENS-absent colonic epithelial crypts by increasing phosphodiesterase-dependent cyclic-nucleotide degradation. Here we show that the CaSR is also highly expressed in tetrodotoxin (TTX)-sensitive neurons comprising the ENS, suggesting that CaSR agonists might also function through neuronal pathways. To test this hypothesis, rat colon segments containing intact ENS were isolated and mounted on Ussing chambers. Basal and cyclic nucleotide-stimulated electrolyte secretions were monitored by measuring changes in short-circuit current (I(sc)). CaSR was activated by R-568 and its effects were compared in the presence and absence of TTX. Consistent with active regulation of anion secretion by the ENS, a significant proportion of I(sc) in the proximal and distal colon was inhibited by serosal TTX, both at basal and under cyclic AMP-stimulated conditions. In the absence of TTX, activation of CaSR with R-568 significantly reduced basal I(sc) and cyclic AMP-stimulated I(sc); it also completely reversed the cAMP-stimulated secretory responses if the drug was applied after the forskolin stimulation. Such inhibitory effects of R-568 were either absent or significantly reduced when serosal TTX was present, suggesting that this agonist exerts its antisecretory effect on the intestine by inhibiting ENS. The present results suggest a new model for regulating intestinal fluid transport in which neuronal and nonneuronal secretagogue actions are modulated by the inhibitory effects of CaSR on the ENS. The ability of a CaSR agonist to reduce secretagogue-stimulated Cl(-) secretion might provide a new therapeutic approach for secretory and other ENS-mediated diarrheal conditions.
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Affiliation(s)
- Sam X. Cheng
- 1Department of Pediatrics, School of Medicine, Yale University, New Haven, Connecticut; and ,2Department of Pediatrics, School of Medicine, University of Florida, Gainesville, Florida
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Furness JB, Poole DP. NONRUMINANT NUTRITION SYMPOSIUM: Involvement of gut neural and endocrine systems in pathological disorders of the digestive tract1,2. J Anim Sci 2012; 90:1203-12. [DOI: 10.2527/jas.2011-4825] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Abstract
Neurogastroenterology is defined as neurology of the gastrointestinal tract, liver, gallbladder and pancreas and encompasses control of digestion through the enteric nervous system (ENS), the central nervous system (CNS) and integrative centers in sympathetic ganglia. This Review provides a broad overview of the field of neurogastroenterology, with a focus on the roles of the ENS in the control of the musculature of the gastrointestinal tract and transmucosal fluid movement. Digestion is controlled through the integration of multiple signals from the ENS and CNS; neural signals also pass between distinct gut regions to coordinate digestive activity. Moreover, neural and endocrine control of digestion is closely coordinated. Interestingly, the extent to which the ENS or CNS controls digestion differs considerably along the digestive tract. The importance of the ENS is emphasized by the life-threatening effects of certain ENS neuropathies, including Hirschsprung disease and Chagas disease. Other ENS disorders, such as esophageal achalasia and gastroparesis, cause varying degrees of dysfunction. The neurons in enteric reflex pathways use a wide range of chemical messengers that signal through an even wider range of receptors. These receptors provide many actual and potential targets for modifying digestive function.
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Affiliation(s)
- John B Furness
- Department of Anatomy and Neuroscience, University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia.
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Enteroendocrine and neuronal mechanisms in pathophysiology of acute infectious diarrhea. Dig Dis Sci 2012; 57:19-27. [PMID: 22001941 PMCID: PMC3809758 DOI: 10.1007/s10620-011-1939-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 09/30/2011] [Indexed: 12/30/2022]
Abstract
BACKGROUND While enterocyte secretion is the predominant mechanism considered responsible for secretory diarrhea in response to acute enteric infections, there are several lines of evidence that support alternative mechanisms controlling fluid and electrolyte secretion in diarrhea. AIM To review enteroendocrine and neuronal mechanisms that participate in the development of acute infectious diarrhea. RECENT ADVANCES Acute infectious diarrheas due to bacterial toxins (e.g., cholera, E. coli heat-stable enterotoxin, C. difficile) and rotavirus are all associated with secretion of transmitters from enteroendocrine cells (e.g., 5-HT) and activation of afferent neurons that stimulate submucosal secretomotor neurons. The latter secrete acetylcholine (which binds to muscarinic receptors on epithelial cells) and VIP. Involvement of nerves was demonstrated by inhibition of bacterial toxin-induced secretion by hexamethonium (nicotinic), tetrodotoxin (Na(+) channel blocker), and lidocaine (visceral/mucosal afferents). Nicotinic receptors are present on secretomotoneurons and these are activated by release of acetylcholine from enteric interneurons or extrinsic efferent fibers. Specific organisms also modify other mechanisms that may contribute to development of acute diarrhea. Thus, mucin secretion, activation of motor mechanisms, increased mucosal permeability and inhibition of bile acid absorption have been reported in specific types of acute infectious diarrhea. CONCLUSION New therapies targeting neural and transmitter mediation including 5-HT, VIP, NPY, as well as toxin receptors and channels activated during acute infectious diarrhea could usher in a novel approach to enhancing glucose-electrolyte solutions used in the treatment of acute diarrhea.
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Ammoury RF, Ghishan FK. Pathophysiology of Diarrhea and its Clinical Implications. PHYSIOLOGY OF THE GASTROINTESTINAL TRACT 2012:2183-2197. [DOI: 10.1016/b978-0-12-382026-6.00082-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Chen M, Sultan A, Cinar A, Yeruva S, Riederer B, Singh AK, Li J, Bonhagen J, Chen G, Yun C, Donowitz M, Hogema B, de Jonge H, Seidler U. Loss of PDZ-adaptor protein NHERF2 affects membrane localization and cGMP- and [Ca2+]- but not cAMP-dependent regulation of Na+/H+ exchanger 3 in murine intestine. J Physiol 2011; 588:5049-63. [PMID: 20962002 DOI: 10.1113/jphysiol.2010.198721] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Trafficking and regulation of the epithelial brush border membrane (BBM) Na+/H+ exchanger 3 (NHE3) in the intestine involves interaction with four different members of the NHERF family in a signal-dependent and possibly segment-specific fashion. The aim of this research was to study the role of NHERF2 (E3KARP) in intestinal NHE3 BBM localization and second messenger-mediated and receptor-mediated inhibition of NHE3. Immunolocalization of NHE3 in WT mice revealed predominant microvillar localization in jejunum and colon, a mixed distribution in the proximal ileum but localization near the terminal web in the distal ileum. The terminal web localization of NHE3 in the distal ileum correlated with reduced acid-activated NHE3 activity (fluorometrically assessed). NHERF2 ablation resulted in a shift of NHE3 to the microvilli and higher basal fluid absorption rates in the ileum, but no change in overall NHE3 protein or mRNA expression. Forskolin-induced NHE3 inhibition was preserved in the absence of NHERF2, whereas Ca2+ ionophore- or carbachol-mediated inhibition was abolished. Likewise, Escherichia coli heat stable enterotoxin peptide (STp) lost its inhibitory effect on intestinal NHE3. It is concluded that in native murine intestine, the NHE3 adaptor protein NHERF2 plays important roles in tethering NHE3 to a position near the terminal web and in second messenger inhibition of NHE3 in a signal- and segment-specific fashion, and is therefore an important regulator of intestinal fluid transport.
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Affiliation(s)
- Mingmin Chen
- Department of Gastroenterology, Hannover Medical School, Hannover 30625, Germany
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Pfannkuche H, Mauksch A, Gäbel G. Modulation of electrogenic transport processes in the porcine proximal colon by enteric neurotransmitters. J Anim Physiol Anim Nutr (Berl) 2011; 96:482-93. [PMID: 21623932 DOI: 10.1111/j.1439-0396.2011.01168.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The aim of our study was to evaluate the involvement of essential pro- and antisecretory neurotransmitters in regulation of secretion in porcine proximal colon. Choline acetyltransferase (ChAT), nitric oxide synthase (NOS), vasoactive intestinal peptide (VIP), substance P (SP), somatostatin (SOM) and neuropeptide Y (NPY) were located immunohistochemically in the epithelium and subepithelial layer. Modulation of epithelial secretion was studied in Ussing chambers. Application of carbachol (CA), sodium nitroprussid (SNP), VIP and SP but not of NPY or SOM resulted in a chloride dependent increase in short circuit current (I(sc) ). I(sc) increase induced by CA, VIP or SNP was not altered by preincubation with tetrodotoxin or indomethacin. In contrast, SP-induced I(sc) increase was diminished by preincubation with tetrodotoxin, indomethacin, L-nitro-arginin-methyl-ester, and atropine but not hexamethonium. Simultaneous application of CA and VIP, or CA and SNP increased the I(sc) stronger as expected. Applying SP/CA led to a smaller increase in I(sc) as calculated. It is concluded that mainly prosecretory neurotransmitters are involved in regulation of colonic secretion. Cross-potentiations of acetylcholine and nitric oxide and acetylcholine and VIP suggest activation of different intracellular cascades. Similar intracellular pathways may be stimulated by acetylcholine and SP, thus preventing an additive effect of the transmitters.
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Affiliation(s)
- H Pfannkuche
- Institute for Veterinary-Physiology, Leipzig University, Leipzig, Germany.
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Lundgren O, Jodal M, Jansson M, Ryberg AT, Svensson L. Intestinal epithelial stem/progenitor cells are controlled by mucosal afferent nerves. PLoS One 2011; 6:e16295. [PMID: 21347406 PMCID: PMC3036584 DOI: 10.1371/journal.pone.0016295] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2010] [Accepted: 12/22/2010] [Indexed: 01/07/2023] Open
Abstract
Background The maintenance of the intestinal epithelium is of great importance for the survival of the organism. A possible nervous control of epithelial cell renewal was studied in rats and mice. Methods Mucosal afferent nerves were stimulated by exposing the intestinal mucosa to capsaicin (1.6 mM), which stimulates intestinal external axons. Epithelial cell renewal was investigated in the jejunum by measuring intestinal thymidine kinase (TK) activity, intestinal 3H-thymidine incorporation into DNA, and the number of crypt cells labeled with BrdU. The influence of the external gut innervation was minimized by severing the periarterial nerves. Principal Findings Luminal capsaicin increased all the studied variables, an effect nervously mediated to judge from inhibitory effects on TK activity or 3H-thymidine incorporation into DNA by exposing the mucosa to lidocaine (a local anesthetic) or by giving four different neurotransmitter receptor antagonists i.v. (muscarinic, nicotinic, neurokinin1 (NK1) or calcitonin gene related peptide (CGRP) receptors). After degeneration of the intestinal external nerves capsaicin did not increase TK activity, suggesting the involvement of an axon reflex. Intra-arterial infusion of Substance P (SP) or CGRP increased intestinal TK activity, a response abolished by muscarinic receptor blockade. Immunohistochemistry suggested presence of M3 and M5 muscarinic receptors on the intestinal stem/progenitor cells. We propose that the stem/progenitor cells are controlled by cholinergic nerves, which, in turn, are influenced by mucosal afferent neuron(s) releasing acetylcholine and/or SP and/or CGRP. In mice lacking the capsaicin receptor, thymidine incorporation into DNA and number of crypt cells labeled with BrdU was lower than in wild type animals suggesting that nerves are important also in the absence of luminal capsaicin, a conclusion also supported by the observation that atropine lowered thymidine incorporation into DNA by 60% in control rat segments. Conclusion Enteric nerves are of importance in maintaining the intestinal epithelial barrier.
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Affiliation(s)
- Ove Lundgren
- Section of Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
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Immunohistochemical analysis of substance P-containing neurons in rat small intestine. Cell Tissue Res 2010; 343:331-41. [DOI: 10.1007/s00441-010-1080-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Accepted: 10/18/2010] [Indexed: 10/18/2022]
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Schröder B, Hoppe S, Breves G. Evidence for down-regulation of neurogenic secretion in small intestinal epithelium from weaned piglets suffering from diarrhea. Livest Sci 2010. [DOI: 10.1016/j.livsci.2010.06.068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Abstract
Antisecretory factor (AF) is a protein secreted in plasma and other tissue fluids in mammals with proven antisecretory and anti-inflammatory activity; its immunohistological distribution suggests a role in the immune system. The expression level and the distribution of AF protein are altered during an immunological response. Exposure to bacterial toxins induces secretion of AF in plasma, probably reflecting a natural defence mechanism to agents causing diarrhoea, thereby contributing to a favourable clinical outcome and disease termination. An increase of AF levels in plasma by dietary means, such as specially processed cereals (SPC), has been demonstrated in human subjects and animals. Administration of SPC to patients affected by inflammatory bowel disease, gastroenteritis and Ménière's disease relieved symptoms and improved quality of life. A recent study showed the positive effect of SPC diet supplementation on prevention of the effects of exposure to low levels of blast overpressure in rats, reducing the extent of intracranial pressure increase and cognitive function impairment. AF-rich egg yolk powder improved health status in children suffering acute and chronic diarrhoea, reducing the frequency and increasing the consistency of stools. This kind of functional food could be used for prophylaxis in populations exposed to a high risk of morbidity and mortality caused by diarrhoea and as a complementary therapy in patients affected by chronic intestinal inflammatory disease to improve well-being. In pig husbandry AF-inducing diets, owing to their antisecretory activity and anti-inflammatory action, are a suitable option as an alternative to antibiotic growth promoters to counteract post-weaning diarrhoea.
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Popoff MR, Poulain B. Bacterial toxins and the nervous system: neurotoxins and multipotential toxins interacting with neuronal cells. Toxins (Basel) 2010; 2:683-737. [PMID: 22069606 PMCID: PMC3153206 DOI: 10.3390/toxins2040683] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2010] [Revised: 03/18/2010] [Accepted: 04/07/2010] [Indexed: 12/13/2022] Open
Abstract
Toxins are potent molecules used by various bacteria to interact with a host organism. Some of them specifically act on neuronal cells (clostridial neurotoxins) leading to characteristics neurological affections. But many other toxins are multifunctional and recognize a wider range of cell types including neuronal cells. Various enterotoxins interact with the enteric nervous system, for example by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, in amplification of the diarrhea, or in intestinal inflammation process. Other toxins can pass the blood brain barrier and directly act on specific neurons.
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Affiliation(s)
- Michel R. Popoff
- Neurotransmission et Sécrétion Neuroendocrine, CNRS UPR 2356 IFR 37 - Neurosciences, Centre de Neurochimie, 5, rue Blaise Pascal, F-67084 STRASBOURG cedex, France;
- Author to whom correspondence should be addressed;
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Abstract
Gut inflammation is characterized by mucosal recruitment of activated cells from both the innate and adaptive immune systems. In addition to immune cells, inflammation in the gut is associated with an alteration in enteric endocrine cells and various biologically active compounds produced by these cells. Although the change in enteric endocrine cells or their products is considered to be important in regulating gut physiology (motility and secretion), it is not clear whether the change plays any role in immune activation and in the regulation of gut inflammation. Due to the strategic location of enteric endocrine cells in gut mucosa, these gut hormones may play an important role in immune activation and promotion of inflammation in the gut. This review addresses the research on the interface between immune and endocrine systems in gastrointestinal (GI) pathophysiology, specifically in the context of two major products of enteric endocrine systems, namely serotonin (5-hydroxytryptamine: 5-HT) and chromogranins (Cgs), in relation to immune activation and generation of inflammation. The studies reviewed in this paper demonstrate that 5-HT activates the immune cells to produce proinflammatory mediators and by manipulating the 5-HT system it is possible to modulate gut inflammation. In the case of Cgs the scenario is more complex, as this hormone has been shown to play both proinflammatory and anti-inflammatory functions. It is also possible that interaction between 5-HT and Cgs may play a role in the modulation of immune and inflammatory responses. In addition to enhancing our understanding of immunoendocrine interaction in the gut, the data generated from the these studies may have implications in understanding the role of gut hormone in the pathogenesis of both GI and non-GI inflammatory diseases which may lead ultimately to improved therapeutic strategies in inflammatory disorders.
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Affiliation(s)
- W I Khan
- Farncombe Family Digestive Health Research Institute, Department of Pathology and Molecular Medicine, McMaster University, ON, Canada.
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The effects of cholera toxin on cellular energy metabolism. Toxins (Basel) 2010; 2:632-48. [PMID: 22069603 PMCID: PMC3153216 DOI: 10.3390/toxins2040632] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2010] [Revised: 03/31/2010] [Accepted: 04/06/2010] [Indexed: 11/27/2022] Open
Abstract
Multianalyte microphysiometry, a real-time instrument for simultaneous measurement of metabolic analytes in a microfluidic environment, was used to explore the effects of cholera toxin (CTx). Upon exposure of CTx to PC-12 cells, anaerobic respiration was triggered, measured as increases in acid and lactate production and a decrease in the oxygen uptake. We believe the responses observed are due to a CTx-induced activation of adenylate cyclase, increasing cAMP production and resulting in a switch to anaerobic respiration. Inhibitors (H-89, brefeldin A) and stimulators (forskolin) of cAMP were employed to modulate the CTx-induced cAMP responses. The results of this study show the utility of multianalyte microphysiometry to quantitatively determine the dynamic metabolic effects of toxins and affected pathways.
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Bajor A, Ung KA, Ohman L, Simren M, Thomas EA, Bornstein JC, Sjövall H. Indirect evidence for increased mechanosensitivity of jejunal secretomotor neurones in patients with idiopathic bile acid malabsorption. Acta Physiol (Oxf) 2009; 197:129-37. [PMID: 19432585 DOI: 10.1111/j.1748-1716.2009.01993.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIM The interdigestive motor rhythm, the migrating motor complex (MMC), is accompanied by active secretion of chloride during periods of distally propagating maximal motor activity (MMC phase III). We studied the behaviour of this system in bile acid malabsorption (BAM), a relative common cause of chronic diarrhoea. We measured motor activity and transmucosal potential difference (PD, reflecting active chloride secretion), in the proximal jejunum in healthy controls (n = 18) and in a group of patients with BAM (n = 11). The phase III-generated voltage was related to the degree of BAM quantified by the (75)SeHCAT test. METHODS We used a multi-channel intestinal infusion system to simultaneously measure jejunal pressure and PD. Saline passing calomel half-cells was infused into the jejunum and subcutaneously. Pressure and PD were recorded in the fasting state and after a test meal. RESULTS In the absence of motor activity, jejunal PD was not significantly different from zero in either group. During MMC phase III, PD reached significantly higher mean and peak levels in BAM patients. The product of MMC phase III length multiplied by voltage, over 3 h, was also significantly higher in BAM patients (controls: median 307 mV x cm, range 70-398; BAM: median 511, range 274-2271, P < 0.01). This value was also significantly correlated with the degree of BAM as reflected by the (75)SeHCAT test (P < 0.05). CONCLUSION Phase III induced jejunal secretion may be upregulated in BAM patients, resulting in overload of colonic reabsorption capacity.
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Affiliation(s)
- A Bajor
- Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Identification of neuron types in the submucosal ganglia of the mouse ileum. Cell Tissue Res 2009; 336:179-89. [PMID: 19326148 DOI: 10.1007/s00441-009-0773-2] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2008] [Accepted: 01/28/2009] [Indexed: 12/20/2022]
Abstract
The continuing and even expanding use of genetically modified mice to investigate the normal physiology and development of the enteric nervous system and for the study of pathophysiology in mouse models emphasises the need to identify all the neuron types and their functional roles in mice. An investigation that chemically and morphologically defined all the major neuron types with cell bodies in myenteric ganglia of the mouse small intestine was recently completed. The present study was aimed at the submucosal ganglia, with the purpose of similarly identifying the major neuron types with cell bodies in these ganglia. We found that the submucosal neurons could be divided into three major groups: neurons with vasoactive intestinal peptide (VIP) immunoreactivity (51% of neurons), neurons with choline acetyltransferase (ChAT) immunoreactivity (41% of neurons) and neurons that expressed neither of these markers. Most VIP neurons contained neuropeptide Y (NPY) and about 40% were immunoreactive for tyrosine hydroxylase (TH); 22% of all submucosal neurons were TH/VIP. VIP-immunoreactive nerve terminals in the mucosa were weakly immunoreactive for TH but separate populations of TH- and VIP-immunoreactive axons innervated the arterioles in the submucosa. Of the ChAT neurons, about half were immunoreactive for both somatostatin and calcitonin gene-related peptide (CGRP). Calretinin immunoreactivity occurred in over 90% of neurons, including the VIP neurons. The submucosal ganglia and submucosal arterioles were innervated by sympathetic noradrenergic neurons that were immunoreactive for TH and NPY; no VIP and few calretinin fibres innervated submucosal neurons. We conclude that the submucosal ganglia contain cell bodies of VIP/NPY/TH/calretinin non-cholinergic secretomotor neurons, VIP/NPY/calretinin vasodilator neurons, ChAT/CGRP/somatostatin/calretinin cholinergic secretomotor neurons and small populations of cholinergic and non-cholinergic neurons whose targets have yet to be identified. No evidence for the presence of type-II putative intrinsic primary afferent neurons was found.
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Gwynne RM, Ellis M, Sjövall H, Bornstein JC. Cholera toxin induces sustained hyperexcitability in submucosal secretomotor neurons in guinea pig jejunum. Gastroenterology 2009; 136:299-308.e4. [PMID: 19026646 DOI: 10.1053/j.gastro.2008.09.071] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2008] [Revised: 09/16/2008] [Accepted: 09/25/2008] [Indexed: 02/01/2023]
Abstract
BACKGROUND & AIMS Neural mechanisms underlying cholera toxin (CT)-induced intestinal hypersecretion remain unclear. We investigated long-term excitability changes in vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) secretomotor neurons after prolonged luminal exposure to CT. METHODS Isolated segments of guinea pig jejunum were incubated with saline or CT +/- neurotransmitter antagonist in the lumen; the submucosal plexus was then dissected clear, circumferentially adjacent to intact mucosa. Synaptic inputs and firing properties of S neurons in ganglia next to the mucosa in control saline were studied using intracellular recording. Neurons were processed for VIP and NPY immunoreactivity. RESULTS Thirty S neurons (20 VIP(+), 7 NPY(+), 3 VIP(-)/NPY(-)) from CT-treated preparations and 27 control S neurons (19 VIP(+), 4 NPY(+), 4 VIP(-)/NPY(-)) in ganglia adjacent to intact mucosa were analyzed. VIP(+) and NPY(+) neurons in CT-treated preparations fired significantly more action potentials and for longer periods during injected depolarizing current pulses (50-350 pA) than control neurons. Addition of tetrodotoxin, hexamethonium, granisetron, or the neurokinin-1 (NK1) antagonist SR140333 during the CT incubation blocked CT-induced effects in both neuron types. The NK3 antagonist SR142801 blocked CT-induced effects in NPY(+) neurons and reduced the number of action potentials in VIP(+) neurons. Synaptic activity was unaffected by CT. CONCLUSIONS CT induces specific and sustained hyperexcitability of secretomotor neurons in enteric pathways. CT acts in the mucosa. Its effect is neurally mediated and depends on 5-hydroxytryptamine-3, nicotinic, and NK1 receptors. This system represents a unique model to understand the neural mechanisms of action of CT and to identify therapeutic targets.
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Affiliation(s)
- Rachel M Gwynne
- Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
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Physiological changes in the gastrointestinal tract and host protective immunity: learning from the mouse-Trichinella spiralis model. Parasitology 2008; 135:671-82. [PMID: 18501042 DOI: 10.1017/s0031182008004381] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Infection and inflammation in the gastrointestinal (GI) tract induces a number of changes in the GI physiology of the host. Experimental infections with parasites represent valuable models to study the structural and physiological changes in the GI tract. This review addresses research on the interface between the immune system and GI physiology, dealing specifically with 2 major components of intestinal physiology, namely mucin production and muscle function in relation to host defence, primarily based on studies using the mouse-Trichinella spiralis system. These studies demonstrate that the infection-induced T helper 2 type immune response is critical in generating the alterations of infection-induced mucin production and muscle function, and that this immune-mediated alteration in gut physiology is associated with host defence mechanisms. In addition, by manipulating the host immune response, it is possible to modulate the accompanying physiological changes, which may have clinical relevance. In addition to enhancing our understanding of immunological control of GI physiological changes in the context of host defence against enteric infections, the data acquired using the mouse-T. spiralis model provide a basis for understanding the pathophysiology of a wide range of GI disorders associated with altered gut physiology.
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Antonioli L, Fornai M, Colucci R, Ghisu N, Tuccori M, Del Tacca M, Blandizzi C. Regulation of enteric functions by adenosine: pathophysiological and pharmacological implications. Pharmacol Ther 2008; 120:233-53. [PMID: 18848843 DOI: 10.1016/j.pharmthera.2008.08.010] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2008] [Accepted: 08/04/2008] [Indexed: 12/20/2022]
Abstract
The wide distribution of ATP and adenosine receptors as well as enzymes for purine metabolism in different gut regions suggests a complex role for these mediators in the regulation of gastrointestinal functions. Studies in rodents have shown a significant involvement of adenosine in the control of intestinal secretion, motility and sensation, via activation of A1, A2A, A2B or A3 purinergic receptors, as well as the participation of ATP in the regulation of enteric functions, through the recruitment of P2X and P2Y receptors. Increasing interest is being focused on the involvement of ATP and adenosine in the pathophysiology of intestinal disorders, with particular regard for inflammatory bowel diseases (IBDs), intestinal ischemia, post-operative ileus and related dysfunctions, such as gut dysmotility, diarrhoea and abdominal discomfort/pain. Current knowledge suggests that adenosine contributes to the modulation of enteric immune and inflammatory responses, leading to anti-inflammatory actions. There is evidence supporting a role of adenosine in the alterations of enteric motor and secretory activity associated with bowel inflammation. In particular, several studies have highlighted the importance of adenosine in diarrhoea, since this nucleoside participates actively in the cross-talk between immune and epithelial cells in the presence of diarrhoeogenic stimuli. In addition, adenosine exerts complex regulatory actions on pain transmission at peripheral and spinal sites. The present review illustrates current information on the role played by adenosine in the regulation of enteric functions, under normal or pathological conditions, and discusses pharmacological interventions on adenosine pathways as novel therapeutic options for the management of gut disorders and related abdominal symptoms.
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Affiliation(s)
- Luca Antonioli
- Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy
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Heitzmann D, Warth R. Physiology and pathophysiology of potassium channels in gastrointestinal epithelia. Physiol Rev 2008; 88:1119-82. [PMID: 18626068 DOI: 10.1152/physrev.00020.2007] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Epithelial cells of the gastrointestinal tract are an important barrier between the "milieu interne" and the luminal content of the gut. They perform transport of nutrients, salts, and water, which is essential for the maintenance of body homeostasis. In these epithelia, a variety of K(+) channels are expressed, allowing adaptation to different needs. This review provides an overview of the current literature that has led to a better understanding of the multifaceted function of gastrointestinal K(+) channels, thereby shedding light on pathophysiological implications of impaired channel function. For instance, in gastric mucosa, K(+) channel function is a prerequisite for acid secretion of parietal cells. In epithelial cells of small intestine, K(+) channels provide the driving force for electrogenic transport processes across the plasma membrane, and they are involved in cell volume regulation. Fine tuning of salt and water transport and of K(+) homeostasis occurs in colonic epithelia cells, where K(+) channels are involved in secretory and reabsorptive processes. Furthermore, there is growing evidence for changes in epithelial K(+) channel expression during cell proliferation, differentiation, apoptosis, and, under pathological conditions, carcinogenesis. In the future, integrative approaches using functional and postgenomic/proteomic techniques will help us to gain comprehensive insights into the role of K(+) channels of the gastrointestinal tract.
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Affiliation(s)
- Dirk Heitzmann
- Institute of Physiology and Clinic and Policlinic for Internal Medicine II, Regensburg, Germany
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