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

J Gastrointest Surg. 2012 Jan;16(1):188-201; discussion 201-2. doi: 10.1007/s11605-011-1720-6. Epub 2011 Oct 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Chronic Disease
  • Clostridioides difficile / growth & development
  • Colonic Pouches / immunology*
  • Colonic Pouches / 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*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Lactoferrin / analysis
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Pouchitis / immunology*
  • Pouchitis / metabolism
  • Pouchitis / 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*
  • alpha-Defensins / metabolism*
  • beta-Defensins / metabolism

Substances

  • 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