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Impaired anti-inflammatory efficacy of n-butyrate in patients with IBD

Authors


Gerhard J. Zlabinger, Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria. Tel.: 0043 1 4277 64971; fax: 0043 1 4277 64972; e-mail: gerhard.zlabinger@meduniwien.ac.at

Abstract

Eur J Clin Invest 2011; 41 (3): 291–298

Abstract

Background  The intestinal mucosa of patients with inflammatory bowel diseases (IBD) characteristically shows a high degree of inflammation when compared to healthy subjects. This appears to be attributable to an imbalance in local reactivity of inflammatory cells. In the present study, we tested the hypothesis that immune cells from patients with IBD are less sensitive to anti-inflammatory agents in the gut as exemplified by the short-chain fatty acid (SCFA) n-butyrate.

Material and methods  Peripheral blood mononuclear cells (PBMC) of patients with IBD (22 Crohn`s Disease, CD; 9 Ulcerative Colitis, UC) and 20 healthy individuals were stimulated through TLR-4 and TLR-2 engagement, respectively, and the anti-inflammatory activity of n-butyrate (0·06–1 mM) on cytokine production (IL-1β, IL-10, IL-12/23p40, TNF-α) was assessed. Inhibition curves were generated, and effective doses (ED20–ED80) were determined.

Results  Hyperresponsiveness to TLR-2 activation reflected by increased IL-12/23p40 and TNF-α production was observed in patients with IBD. To inhibit the release of IL-12/23p40 from PBMC after activation via TLR2-agonists, higher concentrations of n-butyrate were required in patients with IBD , when compared to healthy subjects. With regard to TLR-4 activation, PBMC from patients with IBD and controls were equally responsive to the immunoregulatory effects of n-butyrate. Further analysis revealed that the impaired sensitivity of PBMC to the anti-inflammatory action of n-butyrate was independent from hyperreactivity of immunocompetent cells.

Conclusions  Impaired sensitivity to the inhibitory action of n-butyrate in IBD may constitute a determinant in the pathogenesis of these inflammatory diseases.

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