Skip to main content

The relationship between preoperative T helper cytokines in the ileal mucosa and the pathogenesis of pouchitis

Abstract

Background

Although the etiology of pouchitis remains unknown, inflammatory cytokines are significantly associated with the pathogenesis of pouchitis. The cytokine responses that characterize inflammatory bowel diseases (IBD) are key pathogenic components of the disease. Although cytokine profiles in the colonic mucosa have been investigated in experimental colitis models or IBD patients, cytokine profiles in the ileal mucosa at colectomy have been rarely assessed.

Aim

To assess the relationship between pouchitis and T helper (Th) cytokines in the ileal mucosa collected at the time of colectomy and pouch construction.

Methods

This retrospective study involved 68 consecutive patients from January 2004 to May 2011 who underwent ileal pouch–anal anastomosis for ulcerative colitis. Samples were obtained from the terminal ileum of resected specimens at time of total colectomy or subtotal colectomy. mRNA expression levels of Th cytokines (IFN-γ, IL-23A, IL-5, IL-13 and IL-17A) were determined.

Results

Forty of 68 patients (58.8%) developed pouchitis. There was no association between IL-23A expression levels and incidence of pouchitis (p = 0.301). Patients with elevated IFN-γ had a significantly higher incidence of pouchitis compared with low IFN-γ patients (p = 0.043). Univariate analysis demonstrated a total dose of prednisolone > 7000 mg administered before colectomy (p = 0.04) and high IFN-γ expression (p = 0.02) were significant risk factors for pouchitis onset. In multivariate analysis, elevated IFN-γ messenger(m)RNA levels were significantly associated with pouchitis onset (p = 0.03).

Conclusion

IFN-γ expression in the normal ileal mucosa at the time of colectomy may be an important factor in the pathophysiology of pouchitis.

Peer Review reports

Background

Restorative proctocolectomy and ileal pouch anal anastomosis (IPAA) have been established as standard surgical treatment methods for the management of ulcerative colitis (UC). Pouchitis, a nonspecific inflammatory condition of the ileal pouch, is a well-known complication in patients who undergo IPAA. Pouchitis is defined as nonspecific inflammation developing after intestinal continuity of IPAA. The incidence of pouchitis is 40–70% in UC patients who receive IPAA [1,2,3]. Although the immunopathogenesis of pouchitis is unclear, there are two major mechanisms associated with pouchitis: microbial dysbiosis and abnormal immune responses [4]. Whether inflammation of the pouch mucosa represents a recurrence of immune mechanisms in UC or a new form of inflammatory bowel disease (IBD) remains a topic of discussion.

Cytokine responses that characterize IBD are key pathogenic components of the disease. Cytokine responses play key roles in the initiation, evolution, maintenance, and resolution of inflammation. Classically, two types of cytokine responses, determined by T-cell differentiation, have been described [5]: T-helper cell (Th)1 and Th2. Th1, characterized by the production of interferon (IFN)-γ mediates Crohn’s disease (CD) [6]. Th2 responses, characterized by the production of interleukin (IL)-5 and IL-13 as well as normal IFN-γ, mediate UC [7, 8]. In addition to these two Th cell types, the recently described Th17 cells, producing IL-17 and IL-23, were reported as a third component of Th cells in various autoimmune disease models [9,10,11]. IL-23 is a newly discovered cytokine that has a role in the maintenance and/or expansion of Th17 cells [12, 13]. In the mucosa of IBD, Th17 cells have been proposed to play a key role in intestinal inflammation [14, 15]. Th1 cytokines as well as those secreted from Th17 cells might be associated with CD [14]. Olsen et al. reported that the gene expression levels of IL-17A, IL-23 and IFN-γ correlated with the grade of inflammation in UC, and that IL-17A and IL-23 had a role in mediating inflammation in both forms of IBD [16]. Clarification of these complex networks of Th cytokines might lead to the identification of novel targets for the diagnosis and treatment of CD and UC.

Mucosal concentrations of proinflammatory cytokines including IL-1ß, IL-6 and IL-8 were increased in pouchitis similar to UC [17, 18]. However, cytokine profiles in the ileal mucosa at the time of colectomy have been rarely assessed. Investigating these cytokines in the ileal mucosa might help diagnose the subsequent onset of pouchitis. To the best of our knowledge, no study has examined Th cytokine profiles in ileal mucosa obtained at the time of total colectomy in patients with UC. This study evaluated Th cytokines in the ileal mucosa from UC patients at the time of total colectomy, and tested the predictive value of these cytokines for the onset of pouchitis.

Methods

Patients and specimens

From 2004 to 2011, this study included 183 patients who underwent IPAA in our institution. One hundred fifteen patients excluded for the following reasons: unable to obtain the frozen tissue samples of ileal mucosa because of emergency surgery (subtotal colectomy) (n = 65), poor quality of samples(n = 12) and lost to follow-up(n = 38). In total, frozen tissue samples of ileal mucosa were obtained from 68 patients who underwent IPAA in our institution. Samples were obtained from the terminal ileum of resected specimens at time of total colectomy or subtotal colectomy. Patients with obvious backwash ileitis were excluded. Samples were soaked in RNA later and stored at − 80 °C until RNA extraction. The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution and it conforms to the provisions of the Declaration of Helsinki. All informed consent was obtained from the subjects and guardians.

Surgical procedure and diagnosis of pouchitis

All patients underwent IPAA and routinely performed endoscopy each year after stoma closure. In addition, patients with suspected pouchitis were assessed by endoscopic assessments. Patients with pouchitis were diagnosed by a modified Pouchitis Disease Activity Index (mPDAI) score ≥ 5 [19]. Patients with CD of pouch were diagnosed with granulomas, stenosing, fistulising and inflammatory during follow-up [20, 21] . Patients with CD of the pouch and Secondary pouchitis (pouch ischemia, anastomotic stricture, pelvic sepsis, Cytomegalovirus infection, Clostridium difficile infection, and regular use of nonsteroidal anti-inflammatory drugs) were excluded. The onset of pouchitis was defined as the time from stoma closure to clinical and endoscopic diagnosis at the first episode. Acute antibiotic-responsive pouchitis (ADP) was defined as episodes of symptomatic pouch inflammation occurring fewer than 4 times per year with symptomatic response to a 2-week course of a single antibiotic such as ciprofloxacin. Chronic antibiotic-refractory pouchitis (CARP) included patients with greater than 4 episodes of symptomatic pouch inflammation per year, individuals who require continuous antibiotic therapy to maintain symptom remission, or patients whose symptoms were refractory to antibiotic therapy [22].

RNA extraction and cDNA synthesis

Ileal mucosa was homogenized with a Mixer Mill MM 300 homogenizer (Qiagen, Chatsworth, CA, USA). Total RNA was isolated using a RNeasy Mini Kit (Qiagen) according to the manufacturer’s instructions. Then, purity and concentration of RNA was estimated with Nano-Drop. Pure RNA was obtained with a A260/A280 ratio of 2.0–2.2. Degraded RNA could be detected with different ratio. cDNA was synthesized from 5.0 mg total RNA with random hexamer primers and Superscript III reverse transcriptase (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions.

Quantitative reverse transcription-polymerase chain reaction (qRT-PCR)

qRT-PCR analysis was performed using the TaqMan universal PCR Master Mix (Applied Biosystems, Foster City, CA, USA). We investigated the mRNA expression of 5 cytokines in the terminal ileum focusing on Th2 responses (IL-5, IL-6, IL-13, IL-17A and IL-23), and IFN-γ. The relative abundance of target transcripts was measured using TaqMan probes (Applied Biosystems, Foster City, CA, USA) for IFN-γ (Assay ID: Hs00989291_m1), IL-5 (Assay ID: Hs01548712_g1), IL-13 (Assay ID: Hs00174379_m1), IL-17A (Assay ID: Hs001743883_m1), and IL-23A (Assay ID: Hs00900828_g1). Glyceraldehyde-3-phosphate dehydrogenase: GAPDH (Assay ID, Hs02758991_g1; Applied Biosystems) was measured as an internal housekeeping gene. cDNA was amplified and quantified using Applied Biosystems StepOne Plus Real-Time PCR System and analyzed by Software version 2.2.2 (Applied Biosystems).

Quantification of the relative expression levels of Th cytokines

Relative gene expression was determined using the standard curve method. Standard curves and line equations were generated using five-fold serially diluted solutions of cDNA generated by the reverse transcription of qPCR Human Reference Total RNA (Clontech, Mountain View, CA, USA). All standard curves were linear in the analyzed range with an acceptable correlation coefficient (R2). Target gene expression was calculated from the standard curve followed by the quantitative normalization of cDNA in each sample using GAPDH as an internal control. Assays were performed in duplicate for each sample and the mean value was used for analysis.

Statistical analysis

Results were expressed as median values (interquartile range). The cutoff value of each continuous variable was determined by the median value. Comparisons were performed using non-parametric Wilcoxon signed-rank test for continuous variables. Cumulative incidence of pouchitis was evaluated by the Kaplan-Meier method. Differences between two groups were determined by the log-rank test. Cox proportional hazard regression analysis was used to evaluate the independent influence of factors on the onset of pouchitis. All statistical analyses were carried out using JMP 10 for Windows software (SAS Institute, Cary, NC, USA). Two-sided p-values < 0.05 were considered statistically significant.

Results

Patient characteristics

Sixty-eight patients (male/female; 39/29, median age; 32 years (11–62 years)) were enrolled in this study. The median follow-up period was 40 months (0–117 months). Among these patients, 40 (58.8%) developed pouchitis (Fig. 1). Patient characteristics are shown in Table 1.

Fig. 1
figure1

Cumulative risk of developing pouchitis. Cumulative risk of developing pouchitis was 58.8% at the follow-up period (median 40 months (0–117 months))

Table 1 Clinicopathological factors of 68 patients with pouchitis

Expression levels of Th cytokines

The mRNA expression levels of Th cytokines (IFN-γ, IL-23A, IL-5, IL-13 and IL-17A) were calculated. More than half of the samples were below the level of detection in IL-5, IL-13 and IL-17A assays. These cytokines were excluded from further analysis.

Cumulative incidence of pouchitis after IPAA according to mRNA levels of Th cytokines

The cumulative incidence of pouchitis according to the expression levels of IFN-γ and IL-23A are shown in Fig. 2. Although there was no association between IL-23A expression levels and the incidence of pouchitis (p = 0.301), patients with elevated IFN-γ had a significantly higher incidence of pouchitis than those with low levels of IFN-γ (p = 0.043). Because only IFN-γ was associated with the onset of pouchitis, we focused the rest of our study on IFN-γ.

Fig. 2
figure2

The relationship between the cumulative incidence of pouchitis and IL-23A (a) and IFN-γ (b). There was no association between IL-23A expression levels and the incidence of pouchitis (p = 0.301) (a). However, the patients with elevated IFN-γ had a significantly higher incidence of pouchitis than those with low levels of IFN-γ (p = 0.043)

Relationship between IFN-γ and preoperative clinicopathologic data

The relationship between pouchitis and preoperative clinicopathologic factors is shown in Table 2. There was a significant difference between IFN-γ level and severity of colitis, and patients with elevated C-reactive protein had a trend for higher IFN-γ mRNA levels. However, there was no correlation between IFN-γ and type of pouchitis. According to univariate analysis, a total dose of prednisolone > 7000 mg administered before colectomy and IFN-γ were identified as significant risk factors for the onset of pouchitis (Table 3). In addition, multivariate analysis showed that elevated IFN-γ mRNA levels were significantly associated with the onset of pouchitis.

Table 2 Relationship between IFN-γ mRNA expression and preoperative clinicopathologic factors
Table 3 Univariate and multivariate analysis of factors influencing pouchitis

Discussion

The etiology of pouchitis is unknown, but numerous risk factors have been identified. Increased incidence of pouchitis in patients with extraintestinal manifestations [23,24,25,26,27], younger age [27], shorter disease duration [2], extent of disease [2, 27], more severe preoperative clinical course, steroid dependency [28] and primary sclerosing cholangitis [29,30,31] have been reported. Other studies have reported that even pre- and postoperative use of biologics [32], steroid use before colectomy [26, 27], and postoperative use of nonsteroidal anti-inflammatory drugs [25], have significantly correlated with pouchitis. However, in our study, these factors are no statistical difference between the pouchitis and no pouchitis groups. Therefore, additional risk factors or aetiologic factors are needed to help predict which patients are at risk of pouchitis. In our study, only IFN-γ mRNA expressions in patients who developed pouchitis were significantly higher than in patients without pouchitis (p = 0.043). In addition, multivariate analysis demonstrated that elevated IFN-γ mRNA levels was an independent risk factor for the onset of pouchitis.

Pouchitis is a heterogeneous disorder with a combination of various underlying case. Acute pouchitis may be more attributable to dysbiosis in the ileal pouch. ADP, which is predominately microbially mediated, requires antibiotic therapy to maintain symptom remission. On the other hands, CARP may be a result of abnormal host immune response. Thus, a subgroup of patients with CARP does not respond to standard antibiotic therapy [4, 33,34,35]. The treatment of choice is immunosuppressive therapy with a good response in the treatment of CARP and Crohn’s pouchitis [36,37,38]. Therefore, when discussing risk factors or predicting factors for pouchitis, it is important to accurately phenotype patients with pouchitis. Our data suggest that IFN-γ expression in ileal mucosa is slightly lower in patients with CARP than those with ADP, although not significant, since Crohn’s pouchitis excluded in this study. Further large number study are needs to confirm the accurate correlation between IFN-γ and immune mediated pouchitis.

IFN-γ, a cytokine secreted by activated T cells and natural killer (NK) cells, promotes inflammation by activating macrophages and upregulating the expression of cell adhesion molecules [39]. Furthermore, increased IFN-γ production might be responsible for the tissue damage observed in pouchitis because IFN-γ sustains cytotoxic reactions [40]. Signal transducer and activator of transcription (STAT)1 is part of the signaling pathway of other cytokines/growth factor receptors as well as be a hallmark of IFN-γ receptor signal transduction [41,42,43]. Previous studies investigating activation and expression of nuclear factor-kappa B (NF-κB) and members of the STAT family has positive correlation with the activation of cytokine transcription factors in IBD [41,42,43]. Although increased NF-κB activation was more predominant in CD than in UC, activation and expression of STAT1 were increased in UC compared with CD and normal controls [43,44,45]. A study investigating intracellular cytokine data reported that the pathophysiology of small-intestinal inflammation occurring after colectomy in patients with UC might be associated with a Th2 cytokine phenotype [46]. Additionally, there was a significant increase in the number of IFN-γ producing mononuclear cells in patients with UC with pouchitis compared with UC patients without pouchitis [47]. Furthermore, there was a tendency towards increased levels of IFN-γ and STAT1 in patients with UC, even without clinical and endoscopic evidence of pouchitis [48]. Of note, the normal pouch already indicated high levels of STAT1 expression and activation compared with normal preoperative ileum [44].

There are some limitations in this cohort. First, this retrospective study included a limited number of patients with geographical reason from a single cohort. We were unable to detect the genuine number of the patients with pouchitis. Therefore, the finding needs to be validated in a larger prospective cohort. Second, the short follow-up time duration was insufficient to evaluate incidence of pouchitis. Third, we analyzed specific 5 cytokines which might be suggested with incidence of pouchitis in this study. Therefore, further comprehensive analyses of ileal mucosal cytokines related with pouchitis are needed. Nevertheless, our findings suggest that IFN-γ expression in the normal ileal mucosa at the time of colectomy may be an important factor in the pathophysiology of pouchitis. However, further proteomics approach such as ELISA, immunohistochemical analysis or Western blot are needed to confirm the real IFN-γ expression in the ileal mucosa.

Conclusions

Our data suggest that IFN-γ expression in the normal ileal mucosa at the time of colectomy may be an important factor in the pathophysiology of pouchitis. Further research is required to determine the physiological role of IFN-γ.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

IBD:

Inflammatory bowel diseases

Th:

T helper

mRNA:

Messenger RNA

IPAA:

Ileal pouch anal anastomosis

UC:

Ulcerative colitis

IFN:

Interferon

CD:

Crohn’s disease

IL:

Interleukin

ADP:

Antibiotic dependent pouchitis

CARP:

Chronic antibiotic refractory pouchitis

NF-κB:

Nuclear factor-kappa B

STAT:

Signal transducer and activator of transcription

References

  1. 1.

    Coffey JC, Rowan F, Burke J, Dochery NG, Kirwan WO, O’Connel RP. Pathogenesis of and unifying hypothesis for idiopathic pouchitis. Am J Gastroenterol. 2009;104:1013–23..

  2. 2.

    Hashavia E, Dotan I, Rabau M, Klausner JM, Halpern Z, Tulchinsky H. Risk factors for chronic pouchitis after ileal pouch-anal anastomosis: a prospective cohort study. Colorectal Dis. 2012;14:1365–71.

    CAS  PubMed  Google Scholar 

  3. 3.

    Araki T, Kawamura M, Tanaka K, et al. FK506-binding protein 5 mRNA levels in Ileal mucosa are associated with Pouchitis in patients with ulcerative colitis. Dig Dis Sci. 2015;60(6):1617–23.

    CAS  PubMed  Google Scholar 

  4. 4.

    Hata K, Ishihara S, Nozawa H, et al. Pouchitis after ileal pouch-anal anastomosis in ulcerative colitis: diagnosis, management, risk factors, and incidence. Dig Endosc. Jan 2017;29(1):26–34.

    PubMed  Google Scholar 

  5. 5.

    Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 2005;175(1):5–14.

    CAS  PubMed  Google Scholar 

  6. 6.

    Parronchi P, Romagnani P, Annunziato F, et al. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease. Am J Pathol. 1997;150(3):823–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Breese E, Braegger CP, Corrigan CJ, Walker-Smith JA. TT. M. Interleukin-2- and interferon-y-secreting T cells in normal and diseased human intestinal mucosa. Immunology. 1993;78(1):127–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Fuss IJ, Neurath M, Boirivant M, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996;157(3):1261–70.

    CAS  PubMed  Google Scholar 

  9. 9.

    Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13(5):715–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003;278(3):1910–4.

    CAS  PubMed  Google Scholar 

  11. 11.

    Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116(5):1310–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8(4):345–50..

    CAS  PubMed  Google Scholar 

  13. 13.

    Maloy KJ. The Interleukin-23 / Interleukin-17 axis in intestinal inflammation. J Intern Med. 2008;263(6):584–90.

    CAS  PubMed  Google Scholar 

  14. 14.

    Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52(1):65–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Nielsen OH, Kirman I, Rüdiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol. 2003;38(2):180–5.

    CAS  PubMed  Google Scholar 

  16. 16.

    Olsen T, Rismo R, Cui G, Goll R, Christiansen I, Florholmen J. TH1 and TH17 interactions in untreated inflamed mucosa of inflammatory bowel disease, and their potential to mediate the inflammation. Cytokine. 2011;56(3):633–40.

    CAS  PubMed  Google Scholar 

  17. 17.

    Paolo G, Massimo C, Andrea B, et al. Macrophage subpopulations and interleukin-1ß tissue levels in pelvic ileal pouch pouches. Eur J Gastroenterol Hepatol. 1994;6:217–22.

    Google Scholar 

  18. 18.

    Reinecker HC, Steffen M, Witthoeft T, et al. Enhanced secretion of tumor necrosis factor alpha, IL-6 and Il-1ß by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol. 1993;94:174–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Shen B, Achkar JP, Connor JT, et al. Modified pouchitis disease activity index: a simplified approach to the diagnosis of pouchitis. Dis Colon Rectum. 2003;46(6):748–53.

    PubMed  Google Scholar 

  20. 20.

    Gasche C, Scholmerich J, Brynskov J, et al. A simple classification of Crohn's disease: report of the working Party for the World Congresses of gastroenterology, Vienna 1998. Inflamm Bowel Dis. Feb 2000;6(1):8–15.

    CAS  PubMed  Google Scholar 

  21. 21.

    Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 montreal world congress of gastroenterology. Can J Gastroenterol. 2005;19(Suppl A):5A–36A.

    PubMed  Google Scholar 

  22. 22.

    Seril DN, Yao Q, Lashner BA, Shen B. Autoimmune features are associated with chronic antibiotic-refractory pouchitis. Inflamm Bowel Dis. 2015;21(1):110–20.

    PubMed  Google Scholar 

  23. 23.

    Lohmuller JL, Pemberton JH, Dozois RR, Ilstrup D. Heerden Jv. Pouchitis and extraintestinal manifestations of inflammatory bowel disease after ileal pouch-anal anastomosis. Ann Surg. 1990;211:622–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Hata K, Watanabe T, Shinozaki M, Nagawa H. Patients with extraintestinal manifestations have a higher risk of developing pouchitis in ulcerative colitis: multivariate analysis. Scand J Gastroenterol. 2003;38:1055–8.

    CAS  PubMed  Google Scholar 

  25. 25.

    Achkar JP, Al-Haddad M, Lashner B, et al. Differentiating risk factors for acute and chronic pouchitis. Clin Gastroenterol Hepatol. 2005;3:60–6.

    PubMed  Google Scholar 

  26. 26.

    Fleshner P, Ippoliti A, Dubinsky M, et al. A prospective multivariate analysis of clinical factors associated with pouchitis after ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol. 2007;5:952–8.

    PubMed  Google Scholar 

  27. 27.

    Lipman JM, Kiran RP, Shen B, Remzi F, Fazio VW. Perioperative factors during ileal pouch-anal anastomosis predict pouchitis. Dis Colon Rectum. 2011;54:311–7.

    PubMed  Google Scholar 

  28. 28.

    Kalkan IH, Dağli Ü, Önder FO, et al. Evaluation of preoperative predictors of development of pouchitis after ileal-pouch-anastomosis in ulcerative colitis. Clin Res Hepatol Gastroenterol. 2012;36:622–7.

    CAS  PubMed  Google Scholar 

  29. 29.

    Penna C, Dozois R, Tremaine W, et al. Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis. Gut. 1996;38:234–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Hoda KM, Collins JF, Knigge KL, Deveney KE. Predictors of pouchitis after ileal pouch-anal anastomosis: a retrospective review. Dis Colon rectum. 2008;51:554–60.

    PubMed  Google Scholar 

  31. 31.

    Wasmuth HH, Tranø G, Endreseth BH, Wibe A, Rydning A, Myrvold HE. Primary sclerosing cholangitis and extraintestinal manifestations in patients with ulcerative colitis and ileal pouch-anal anastomosis. J Gastrointest Surg. 2010;14:1099–104.

    PubMed  Google Scholar 

  32. 32.

    Shen B, Yu C, Lian L, et al. Prediction of late-onset pouch failure in patients with restorative proctocolectomy with a nomogram. J Crohns Colitis. 2012;6:198–206.

    PubMed  Google Scholar 

  33. 33.

    Hurst RD, Chung TP, Rubin M, Michelassi F. The implications of acute pouchitis on the long-term functional results after restorative proctocolectomy. Inflamm Bowel Dis. Nov 1998;4(4):280–4.

    CAS  PubMed  Google Scholar 

  34. 34.

    Mowschenson PM, Critchlow JF, Peppercorn MA. Ileoanal pouch operation: long-term outcome with or without diverting ileostomy. Arch Surg. 2000;135(4):463–5 discussion 465-466.

    CAS  PubMed  Google Scholar 

  35. 35.

    Shen B. Diagnosis and treatment of patients with pouchitis. Drugs. 2003;63(5):453–61.

    PubMed  Google Scholar 

  36. 36.

    Haveran LA, Sehgal R, Poritz LS, McKenna KJ, Stewart DB, Koltun WA. Infliximab and/or azathioprine in the treatment of Crohn's disease-like complications after IPAA. Dis Colon rectum. Jan 2011;54(1):15–20.

    PubMed  Google Scholar 

  37. 37.

    Sedano R, Nuñez P, Quera R. Diagnostic and management approach to pouchitis in inflammatory bowel disease. Arq Gastroenterol. 2020;57(1):100–6.

    PubMed  Google Scholar 

  38. 38.

    Shen B. Crohn's disease of the ileal pouch: reality, diagnosis, and management. Inflamm Bowel Dis. 2009;15(2):284–94.

    PubMed  Google Scholar 

  39. 39.

    Dijkmans R, Billiau A. Interferon gamma: a master key in the immune system. Curr Opin Immunol. 1998;1(2):269–74.

    Google Scholar 

  40. 40.

    Fink S, de la Barrera S, Minnucci F, Valdez R, Baliña LM, Sasiain MC. IFN-γ, IL-6 and IL-4 modulate M. leprae- or PPD-specific cytotoxic T cells in leprosy patients. Scand J Immunol. 1993;38:551–8.

    CAS  PubMed  Google Scholar 

  41. 41.

    Nikolaus S, Bauditz J, Gionchetti P, Witt C, Lochs H, Schreiber S. Increased Secrection of proinflammatory cytokines by polymorphonuclear neutrophils regulation by Interleukin 10 in inflammatory bowel disease. Gut. 1998;42:470–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Rogler G, Brand K, Vogl D, et al. Nuclear factor kappa B is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology. 1998;115:357–69.

    CAS  PubMed  Google Scholar 

  43. 43.

    Schreiber S, Nikolaus S, Hampe J. Activation of Nuclear Factor kappa B in inflammatory bowel disease. Gut. 1998;42:477–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Kühbacher T, Gionchetti P, Hampe J, et al. Activation of signal-transducer and activator of transcription 1 (STAT1) in pouchitis. Clin Exp Immunol. 2001;123(3):395–401.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Schreiber S, Rosenstiel P, Hampe J, et al. Activation of signal transducer and activator of transcription (STAT) 1 in human chronic inflammatory bowel disease. Gut. 2002;51(3):379–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Akitake R, Nakase H, Tamaoki M, Ueno S, Mikami S, Chiba T. Modulation of Th1/Th2 balance by infliximab rescues postoperative occurrence of small-intestinal inflammation associated with ulcerative colitis. Dig Dis Sci. 2010;55(6):1781–4..

    PubMed  Google Scholar 

  47. 47.

    Stallmach A, Schäfer F, Hoffmann S, et al. Increased state of activation of CD4 positive T cells and elevated interferon gamma production in pouchitis. Gut. 1998;43(4):499–505.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Leal RF, Ayrizono ML, Milanski M, et al. Activation of signal transducer and activator of transcription-1 (STAT-1) and differential expression of interferon-gamma and anti-inflammatory proteins in pelvic ileal pouches for ulcerative colitis and familial adenomatous polyposis. Clin Exp Immunol. 2010;160(3):380–5.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This study has received a research grant from Japanese Society for Palliative Medicine and Mie Medical Research Foundation.

Author information

Affiliations

Authors

Contributions

Conception: TK, MK, KU; design of the work: TK, MK, YO; the acquisition of data: YO, SK, KU; analysis of data: TK, MK; interpretation of data: TK, MK, YT; drafting of the work: TK, YT, KU, MK. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Takahito Kitajima.

Ethics declarations

Ethics approval and consent to participate

The protocol for this research project has been approved by a suitably constituted Ethics Committee of the Institutional Review Board of Mie University Hospital, and it conforms to the provisions of the Declaration of Helsinki. All informed consent was obtained from the subjects and respective guardians with written.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kitajima, T., Okita, Y., Kawamura, M. et al. The relationship between preoperative T helper cytokines in the ileal mucosa and the pathogenesis of pouchitis. BMC Gastroenterol 20, 277 (2020). https://doi.org/10.1186/s12876-020-01421-w

Download citation

Keywords

  • Ulcerative colitis
  • Pouchitis
  • Cytokine
  • IFN-γ
  • IBD