Hyperresponsiveness of the mucosal barrier in Crohn's disease is not tumor necrosis factor-dependent.
BACKGROUND
Crohn's disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti-inflammatory drugs. We studied whether reducing inflammation and restoring gut barrier dysfunction with anti-tumor necrosis factor (TNF) antibody treatment also antagonizes the permeability increase by oral nonsteroidal anti-inflammatory drug intake in patients with CD.


METHODS
Thirty-one healthy control subjects and 25 patients with active CD were studied. The 31 controls performed intestinal permeability testing for Cr-EDTA before (baseline) and after oral intake of indomethacin (50 + 75 mg). Twenty-five patients carried out a baseline and indomethacin-mediated permeability test before infliximab infusion. The patients repeated either the indomethacin test (12/25) or baseline and indomethacin tests (13/25), 1 month after this treatment. Intestinal permeability was studied by measurement of urinary excretion of Cr-EDTA after oral intake.


RESULTS
Increased whole gut permeation before treatment (3.16%; interquartile range [IQR], 2.92-5.72) was restored to normal values (2.47%; IQR, 1.97-2.78) by anti-TNF treatment. Indomethacin increased whole gut permeability significantly more in patients with CD (before anti-TNF: 6.50%; IQR, 4.84-10.38; after anti-TNF: 5.50%; IQR, 3.97-10.09) compared with the healthy subjects (4.66%; IQR, 3.51-5.64). Eleven of 25 patients (44%) had an abnormal whole gut permeability response to indomethacin before anti-TNF, and 9 of them remained hyperresponsive after infusion, despite clinical remission.


CONCLUSIONS
Although anti-TNF treatment suppresses inflammation and restores gut barrier function in patients with CD, it does not antagonize the barrier hyperresponsiveness to indomethacin. These data support the notion of an underlying intestinal mucosal barrier hyperresponsiveness in a subset of patients with CD, independent of inflammation.
Suenaert
Peter
P
Division of Gastroenterology, Montreal General Hospital, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
Bulteel
Veerle
V
Vermeire
Severine
S
Noman
Maja
M
Van Assche
Gert
G
Rutgeerts
Paul
P
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016022:Case-Control Studies; D003424:Crohn Disease / Q000188:drug therapy* / Q000503:physiopathology*; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000503:physiopathology; D016014:Linear Models; D008297:Male; D016555:Matched-Pair Analysis; D008875:Middle Aged; D010539:Permeability; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D007213:Indomethacin