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Innate Immune Environment in Ileal Pouch Mucosa: α5 Defensin Up-regulation as Predictor of Chronic/Relapsing Pouchitis

  • 2011 SSAT Plenary Presentation
  • Published:
Journal of Gastrointestinal Surgery

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.

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Disclosures

This study was partially funded by a grant (ex 60%) provided by the Italian Ministry of Education, University and Research. Preliminary data from this study were presented as an oral presentation at the Digestive Disease 2011 held between May 7 and 10, 2011 in Chicago, IL, USA, and as a poster presentation at the 6th Annual Congress of the European Crohn’s and Colitis Organization held between February 5 and 7, 2010 in Dublin, Ireland.

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Authors and Affiliations

  1. Oncological Surgery Unit, Veneto Institute of Oncology (IOV-IRCCS), via Gattamelata 64, 35128, Padua, Italy

    Marco Scarpa & Carlo Castoro

  2. Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Padua, Italy

    Alessia Grillo, Paola Brun, Donatella Cavallo & Ignazio Castagliuolo

  3. Surgical Oncology Unit, Veneto Institute of Oncology, via Gattamelata 64, 35128, Padua, Italy

    Melania Scarpa

  4. Department of Surgical and Gastroenterological Sciences, University of Padova, Padua, Italy

    Anna Pozza, Renata D’Incà, Romeo Bardini & Imerio Angriman

  5. Department of Diagnostic Sciences and Special Therapy, University of Padova, Padua, Italy

    Diego Faggian

  6. Department of Surgery (Chirurgia IV), Ospedale “Ca’ Foncello”, Treviso, Italy

    Cesare Ruffolo

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  1. Marco Scarpa
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Correspondence to Marco Scarpa.

Additional information

In memory of Prof. A. Cecchetto

Discussant

Dr. Alessandro Fichera (Chicago, IL, USA)

The aetiology of pouchitis and the etiologic factors behind it in UC patients remain unknown. This manuscript clearly opens a whole new avenue of research in the field. The authors have previously extensively published on this topic and they have extensive experience on the relation and assessment of the role of microbiota in pouchitis.

This study would have been more conclusive if biopsies of the ileal mucosa at the time of the pouch construction were obtained and used as a baseline in comparison with those obtained during follow-up with acute, chronic or relapsing pouchitis.

1. In this study, the incidence of pouchitis seems to be high (6/32 patients with a follow-up of 23 months). Were the criteria the authors had established for the inclusion too broad? Specifically, 10/32 patients with clinical diagnosis of acute pouchitis based on a PDAI > 7 early postoperatively raised few questions. Were symptoms correlated with the biopsies? When exactly was the biopsy taken in relation to the surgery? Do the authors have data on the postoperative use of NSAIDs? The use and compliance to prescribed antibiotics, how was that assessed?

2. Do the authors have data on the presence of backwash ileitis preoperatively? The presence of backwash ileitis may explain some of the early symptoms and an analysis of the microbiota in these patients could answer the real question: is HD-5 and TLR4 overexpression driving the changes in microbiota or is it just a consequence of a different microflora present preoperatively in a subset of patients?

Closing Discussant

Dr. Marco Scarpa

Thank you, Dr. Fichera, for your kind comments and for your interesting questions. We completely agree with you that this study would have been much more conclusive if biopsies of the pouch mucosa would have been obtained at the time of the pouch construction and at time of the follow-up with acute, chronic or relapsing pouchitis. However, the expression of defensins in the ileal pouch mucosa at different time after restorative proctocolectomy had already been analysed by Kiehne et al. [1]. In this study, the authors showed the evolution in the expression of the different defensins during the follow up after pouch creation. On the contrary, our goal was to explore the complex interplay between defensins expression and microbiota and inflammatory response, once defensins expression levels were stabilized. For this reason, we chose a cross-sectional design of the study enrolling our patients after a median follow-up of 26 (19–54) months.

The definitions we used for chronic/relapsing pouchitis were strictly those elaborated by Mahadevan and Sandborn [2]. The high rate of patients with chronic and relapsing pouchitis in our study group was probably due to the fact that we consecutively enrolled our patients and those who reported symptoms were those who more likely accepted to have a pouch endoscopy. For this reason, we do not attribute to our acute or chronic/relapsing pouchitis rate any epidemiological value.

As broadly discussed in our first study on this cohort of patients, the histological diagnosis of pouchitis was present in far more patients than the clinical one (PDAI > 7) [3]. However, since all patients with clinical pouchitis had histological pouchitis, our conclusion was that histology could detect subclinical inflammation that in certain cases will never lead to actual symptoms.

No patient was using NSAID at the moment of the enrollment and the use of antibiotic on the previous month was an exclusion criteria.

Unfortunately, we do not have any homogeneous data about backwash ileitis in these patients. As pointed out by Dr. Fichera, these data could have helped us in answering the main question left open about whether HD-5 and TLR4 over-expression can cause the changes in microbiota or it is just a consequence of a different microflora stimulation. However, some data about this are already present in the literature. In effect, Kiehne et al. [1] observed similar levels of α-defensins in ileum of patients with UC and in the ileum of healthy pouch. These levels seemed higher than in normal ileum and much lower than in pouchitis (they do not specify in chronic/relapsing or just acute pouchitis). This over-expression in pouchitis in patients with UC was not observed in patients with pouchitis with FAP. Even if the authors of this study are not too clear in their conclusions, their findings seemed to suggest that there is a specific over-expression of α-defensins in patients with UC who develop pouchitis after restorative proctocolectomy.

Thank you for your consideration.

Yours sincerely,

Marco Scarpa M.D., Ph.D.

Dept of Oncological Surgery, Venetian Oncology Institute (IOV-IRCCS)

Ignazio Castagliuolo M.D.

Dept. of Histology, Microbiology and Medical Biotechnologies, University of Padova

Padova, Italy

References

1. Kiehne K, Brunke G, Wegner F, Banasiewicz T, Fölsch UR, Herzig KH. Defensin expression in chronic pouchitis in patients with ulcerative colitis or familial adenomatous polyposis coli. World J Gastroenterol 2006; 21; 12(7):1056–1062

2. Mahadevan U, Sandborn WJ. Diagnosis and treatment of pouchitis. Gastroenterology 2003;124:1636–50

3. Scarpa M, Grillo A, Faggian D, Ruffolo C, Bonello E, D’Incà R, Scarpa M, Castagliuolo I, Angriman I. Relationship between mucosa-associated microbiota and inflammatory parameters in the ileal pouch after restorative proctocolectomy for ulcerative colitis. Surgery 2011 150:56–67

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Scarpa, M., Grillo, A., Scarpa, M. et al. Innate Immune Environment in Ileal Pouch Mucosa: α5 Defensin Up-regulation as Predictor of Chronic/Relapsing Pouchitis. J Gastrointest Surg 16, 188–202 (2012). https://doi.org/10.1007/s11605-011-1720-6

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