Innate immune environment in ileal pouch mucosa: α5 defensin up-regulation as predictor of chronic/relapsing pouchitis.

Abstract

Defensins are small cationic peptides with antibacterial activity expressed in Paneth cells (α-defensins) or generally in intestinal epithelial cells (β-defensins) that have a profound effect on gut microbiota. Chronic pouchitis, which occurs in 5% of patients after restorative proctocolectomy and can cause pouch failure, is associated to a significant increase of Clostridiaceae spp. The aim of this study was to gain further insight in the pathogenesis of pouch dysbiosis by exploring defensin expression. Thirty-two consecutive patients coming for follow-up endoscopy were recruited. On pouch biopsies, we cultured bacteria adherent to the mucosa and determined α- and β-defensins and toll-like receptor-4 and -2 mRNA by quantitative real-time RT-PCR. Serum and mucosal levels of IL-1β, IL-6 and TNF-α were measured with immunometric assays. Faecal lactoferrin was analysed by quantitative ELISA. After a median follow-up of 23 (IQR 20-24) months, the patients were contacted for a reassessment of current and past disease activity. During the follow-up, chronic/relapsing pouchitis was diagnosed in six patients. The mucosal level of α-5 and α-6 defensins correlated with chronic/relapsing pouchitis onset (τ = 0.30, p = 0.034 and τ = 0.28, p = 0.053, respectively). High levels of α-5 defensin resulted to be predictive of chronic/relapsing pouchitis [AUC = 74% (95% CI = 53-89%), p = 0.052]. Patients with high levels of α-5 and α-6 defensins had earlier pouchitis relapses (p = 0.009 and p = 0.034, respectively). High levels of α-5 defensin were associated to a significant risk of chronic/relapsing pouchitis [OR = 10.6 (95% CI = 1.2-97.6), p = 0.027]. At multivariate analysis, the mucosal levels of α-5 defensin and the number of CFU of mucosa-associated Clostridiaceae spp resulted to be independent predictors of chronic/relapsing pouchitis [β = 0.46 (0.18), p = 0.024 and β = 0.44 (0.18), p = 0.027, respectively]. In conclusion, chronic/relapsing pouchitis is associated to increased expression of mucosal HD-5 and to increased antimicrobial activity against Escherichia coli. In patients with chronic/relapsing pouchitis, HD-5 and TLR-4 over-expression is likely to create a hostile environment against Enterobacteriaceae, thus favouring Clostridiaceae spp by decreasing competing bacteria families.

• Authors: Marco Scarpa, Alessia Grillo, Melania Scarpa, Paola Brun, Carlo Castoro, Anna Pozza, Donatella Cavallo, Diego Faggian, Cesare Ruffolo, Renata D'Incà, Romeo Bardini, Ignazio Castagliuolo, Imerio Angriman
• Journal: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract (J Gastrointest Surg) Vol. 16 Issue 1 Pg. 188-201; discussion 201-2 (Jan 2012) ISSN: 1873-4626 [Electronic] United States
• PMID: 21983950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DEFA5 protein, human
• DEFA6 protein, human
• Interleukin-1beta
• Interleukin-6
• RNA, Messenger
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• alpha-Defensins
• beta-Defensins
• Lactoferrin

Topics

• Adult
• Aged
• Chronic Disease
• Clostridioides difficile (growth & development)
• Colonic Pouches (immunology, microbiology)
• Colony Count, Microbial
• Escherichia coli (growth & development)
• Feces (chemistry)
• Female
• Follow-Up Studies
• Humans
• Immunity, Innate
• Interleukin-1beta (metabolism)
• Interleukin-6 (metabolism)
• Intestinal Mucosa (immunology, metabolism, microbiology)
• Lactoferrin (analysis)
• Male
• Middle Aged
• Multivariate Analysis
• Pouchitis (immunology, metabolism, microbiology)
• Predictive Value of Tests
• RNA, Messenger (metabolism)
• Recurrence
• Toll-Like Receptor 2 (metabolism)
• Toll-Like Receptor 4 (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation
• alpha-Defensins (immunology, metabolism)
• beta-Defensins (metabolism)