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.

Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection

“…Amyloid fibril generation is also important for AMP activities, mediating disruption of microbial cell membranes (Sood et al, 2008), neutralization of bacterial endotoxins (Wang et al, 2014), and pathogen agglutination and entrapment (Chu et al, 2012; Torrent et al, 2012). However, dysregulated AMP oligomerization can also lead to serious pathologies, including inflammation, tissue degeneration (Paulsen et al, 2002; Pereira et al, 1996; Reinholz et al, 2012; Scarpa et al, 2012), and deposition as amyloid in at least three human amyloidopathies (Araki-Sasaki et al, 2005; Ciornei et al, 2006; Kee et al, 2008; Linke et al, 2005; Millucci et al, 2011; Pálffy et al, 2009; Reinholz et al, 2012; Scarpa et al, 2012; Yamaguchi et al, 2007; Zhao et al, 2008). Thus, AMP oligomerization carries a potential for protective/damaging duality in human health.…”

Fecal microbiota transplantation and bacterial consortium transplantation have comparable effects on the re-establishment of mucosal barrier function in mice with intestinal dysbiosis

“…When the intestinal ecosystem is in balance, epithelial cells produce defensins such as α-defensins 5 and 6, and β-defensin 1, as a strong chemomechanical barrier to control the intestinal microbiota and maintain immunological homeostasis. Upregulation of α-defensin 5 is a predictor of chronic/relapsing pouchitis, and can mediate shifts in the composition of the microbiota that favor inflammation (Scarpa et al, 2012 ). During inflammation or infection, additional defensins such as β-defensin 2 and 3 are induced as a type of “demand system” (Semple and Dorin, 2012 ).…”

Upregulated Expression of Intestinal Antimicrobial Peptide HD5 Associated with Renal Function in IgA Nephropathy

“…The antimicrobial, antiviral, and immunomodulatory activities of HD5 are host protective during infection [27,48,49,53,54]. Considering the relationship between the upregulated serum HD5 with clinical-pathological parameters and long-term renal outcome, as well as the expression of HD5 in the damage proximal tubules in IgAN patients, the present study indicated that HD5 as a regulator of intestinal immunology may be a reliable marker of the progression of IgAN and associate with the renal function of IgAN.…”

“…HD5 exhibits high antimicrobial activity against Enterobacteriaceae. Overexpression of HD5 resulted in increased Clostridiaceae by decreasing competing bacteria families, leading to chronic/relapsing pouchitis [48]. Expression balance of HD5 is essential for the intestinal homeostasis [49].…”