title: Role of enteric glia in intestinal physiology: effects of the gliotoxin fluorocitrate on motor and secretory function.
abstract: The role of enteric glia in gastrointestinal physiology remains largely unexplored. We examined the actions of the gliotoxin fluorocitrate (FC) on intestinal motility, secretion, and inflammation after assessing its efficacy and specificity in vitro. FC (100 microM) caused a significant decrease in the phosphorylation of the glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diaz-4-yl)amino]-2-deoxyglucose in enteric glial cultures and a reduction in glial uptake of the fluorescent dipeptide Ala-Lys-7-amino-4-methylcoumarin-3-acetic acid in both the ileum and colon. Dipeptide uptake by resident murine macrophages or guinea pig myenteric neurons was unaffected by FC. Incubation of isolated guinea pig ileal segments with FC caused a specific and significant increase in glial expression of the phosphorylated form of ERK-1/2. Disruption of enteric glial function with FC in mice reduced small intestinal motility in vitro, including a significant decrease in basal tone and the amplitude of contractility in response to electrical field stimulation. Mice treated with 10 or 20 micromol/kg FC twice daily for 7 days demonstrated a concentration-dependent decrease in small intestinal transit. In contrast, no changes in colonic transit or ion transport in vitro were observed. There were no changes in glial or neuronal morphology, any signs of inflammation in the FC-treated mice, or any change in the number of myenteric nitric oxide synthase-expressing neurons. We conclude that FC treatment causes enteric glial dysfunction, without causing intestinal inflammation. Our data suggest that enteric glia are involved in the modulation of enteric neural circuits underlying the regulation of intestinal motility.
authors.affiliation: Institute for Infection, Immunity and Inflammation, University of Calgary, Alberta, Canada.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Nasser
authors.forename: Ester
authors.initials: E
authors.lastname: Fernandez
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Keenan
authors.forename: Winnie
authors.initials: W
authors.lastname: Ho
authors.forename: Lorraine D
authors.initials: LD
authors.lastname: Oland
authors.forename: Lee Anne
authors.initials: LA
authors.lastname: Tibbles
authors.forename: Michael
authors.initials: M
authors.lastname: Schemann
authors.forename: Wallace K
authors.initials: WK
authors.lastname: MacNaughton
authors.forename: Anne
authors.initials: A
authors.lastname: Rühl
authors.forename: Keith A
authors.initials: KA
authors.lastname: Sharkey
mesh_terms: D009327:4-Chloro-7-nitrobenzofurazan / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002951:Citrates / Q000633:toxicity*; D003092:Colitis / Q000139:chemically induced; D003847:Deoxyglucose / Q000031:analogs & derivatives / Q000494:pharmacology; D017615:Enteric Nervous System / Q000166:cytology / Q000187:drug effects*; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000473:pathology; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D005772:Gastrointestinal Transit / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007422:Intestines / Q000166:cytology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000201:enzymology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002951:Citrates; C007744:fluorocitrate; D003847:Deoxyglucose; D052250:Nitric Oxide Synthase Type III; D009327:4-Chloro-7-nitrobenzofurazan; C098340:2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose