Inhibiting Inducible Nitric Oxide Synthase in Enteric Glia Restores Electrogenic Ion Transport in Mice With Colitis.
BACKGROUND & AIMS
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.
['MacEachern|Sarah J|SJ|', 'Patel|Bhavik A|BA|', 'Keenan|Catherine M|CM|', 'Dicay|Michael|M|', 'Chapman|Kevin|K|', 'McCafferty|Donna-Marie|DM|', 'Savidge|Tor C|TC|', 'Beck|Paul L|PL|', 'MacNaughton|Wallace K|WK|', 'Sharkey|Keith A|KA|']
D000818:Animals D018988:Bacterial Translocation D003092:Colitis D004195:Disease Models, Animal D004558:Electric Stimulation D017615:Enteric Nervous System D005463:Fluoroacetates D016753:Interleukin-10 D017136:Ion Transport D008297:Male D051379:Mice D057507:Mice, 129 Strain D018345:Mice, Knockout D009197:Myenteric Plexus D009457:Neuroglia D009569:Nitric Oxide D052248:Nitric Oxide Synthase Type I D052247:Nitric Oxide Synthase Type II
Myenteric Plexus Enteric Glial Cells IBD Inflammation