title: Inhibiting Inducible Nitric Oxide Synthase in Enteric Glia Restores Electrogenic Ion Transport in Mice With Colitis.
abstract: OBJECTIVE
  Disturbances in the control of ion transport lead to epithelial barrier dysfunction in patients with colitis. Enteric glia regulate intestinal barrier function and colonic ion transport. However, it is not clear whether enteric glia are involved in epithelial hyporesponsiveness. We investigated enteric glial regulation of ion transport in mice with trinitrobenzene sulfonic acid- or dextran sodium sulfate-induced colitis and in Il10(-/-) mice.
  
  
  METHODS
  Electrically evoked ion transport was measured in full-thickness segments of colon from CD1 and Il10(-/-) mice with or without colitis in Ussing chambers. Nitric oxide (NO) production was assessed using amperometry. Bacterial translocation was investigated in the liver, spleen, and blood of mice.
  
  
  RESULTS
  Electrical stimulation of the colon evoked a tetrodotoxin-sensitive chloride secretion. In mice with colitis, ion transport almost completely disappeared. Inhibiting inducible NO synthase (NOS2), but not neuronal NOS (NOS1), partially restored the evoked secretory response. Blocking glial function with fluoroacetate, which is not a NOS2 inhibitor, also partially restored ion transport. Combined NOS2 inhibition and fluoroacetate administration fully restored secretion. Epithelial responsiveness to vasoactive intestinal peptide was increased after enteric glial function was blocked in mice with colitis. In colons of mice without colitis, NO was produced in the myenteric plexus almost completely via NOS1. NO production was increased in mice with colitis, compared with mice without colitis; a substantial proportion of NOS2 was blocked by fluoroacetate administration. Inhibition of enteric glial function in vivo reduced the severity of trinitrobenzene sulfonic acid-induced colitis and associated bacterial translocation.
  
  
  CONCLUSIONS
  Increased production of NOS2 in enteric glia contributes to the dysregulation of intestinal ion transport in mice with colitis. Blocking enteric glial function in these mice restores epithelial barrier function and reduces bacterial translocation.
authors: Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Sarah J
authors: SJ
authors: MacEachern
authors: School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Brighton, United Kingdom.
authors: Bhavik A
authors: BA
authors: Patel
authors: Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Catherine M
authors: CM
authors: Keenan
authors: Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Michael
authors: M
authors: Dicay
authors: Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Kevin
authors: K
authors: Chapman
authors: Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Donna-Marie
authors: DM
authors: McCafferty
authors: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors: Tor C
authors: TC
authors: Savidge
authors: Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Paul L
authors: PL
authors: Beck
authors: Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Wallace K
authors: WK
authors: MacNaughton
authors: Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address: ksharkey@ucalgary.ca.
authors: Keith A
authors: KA
authors: Sharkey
mesh_terms: D000818:Animals; D018988:Bacterial Translocation; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D017615:Enteric Nervous System / Q000166:cytology*; D005463:Fluoroacetates / Q000008:administration & dosage; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D017136:Ion Transport; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009197:Myenteric Plexus / Q000166:cytology; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*
chemical_list: D005463:Fluoroacetates; D016753:Interleukin-10; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse
keywords: Enteric Glial Cells; IBD; Inflammation; Myenteric Plexus