Abstract
BackgroundAntimicrobial peptides (AMPs) protect the host intestinal mucosa against microorganisms. Abnormal expression of defensins was shown in inflammatory bowel disease (IBD), but it is not clear whether this is a primary defect. We investigated the impact of anti-inflammatory therapy with infliximab on the mucosal gene expression of AMPs in IBD.Methodology/Principal FindingsMucosal gene expression of 81 AMPs was assessed in 61 IBD patients before and 4–6 weeks after their first infliximab infusion and in 12 control patients, using Affymetrix arrays. Quantitative real-time reverse-transcription PCR and immunohistochemistry were used to confirm microarray data. The dysregulation of many AMPs in colonic IBD in comparison with control colons was widely restored by infliximab therapy, and only DEFB1 expression remained significantly decreased after therapy in the colonic mucosa of IBD responders to infliximab. In ileal Crohn's disease (CD), expression of two neuropeptides with antimicrobial activity, PYY and CHGB, was significantly decreased before therapy compared to control ileums, and ileal PYY expression remained significantly decreased after therapy in CD responders. Expression of the downregulated AMPs before and after treatment (DEFB1 and PYY) correlated with villin 1 expression, a gut epithelial cell marker, indicating that the decrease is a consequence of epithelial damage.Conclusions/SignificanceOur study shows that the dysregulation of AMPs in IBD mucosa is the consequence of inflammation, but may be responsible for perpetuation of inflammation due to ineffective clearance of microorganisms.
Highlights
Inflammatory bowel diseases (IBDs), Crohn’s disease (CD) and ulcerative colitis (UC), are multifactorial diseases of unknown etiology, characterized by chronic relapsing inflammation of the gastro-intestinal tract
Conclusions/Significance: Our study shows that the dysregulation of Antimicrobial peptides (AMPs) in IBD mucosa is the consequence of inflammation, but may be responsible for perpetuation of inflammation due to ineffective clearance of microorganisms
Pairwise comparisons were performed for intestinal mucosal mRNA expression of 81 AMP genes between controls and patients before and after infliximab treatment in UC, CDc, IBDc (UC and CDc) and CDi, using linear models for microarray data (LIMMA)
Summary
Inflammatory bowel diseases (IBDs), Crohn’s disease (CD) and ulcerative colitis (UC), are multifactorial diseases of unknown etiology, characterized by chronic relapsing inflammation of the gastro-intestinal tract. Genetic and environmental factors are thought to contribute to IBD [1]. Many findings suggest that the intestinal flora plays an important role in the pathogenesis of IBD. Several knockout animal models of IBD in a germ-free environment fail to develop intestinal inflammation [2,3,4,5,6]. Antimicrobial peptides (AMPs) protect the host intestinal mucosa against microorganisms. Abnormal expression of defensins was shown in inflammatory bowel disease (IBD), but it is not clear whether this is a primary defect.
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