Total abdominal colectomy (TAC) with a staged ileal pouch-anal anastomosis (IPAA) is a common surgical treatment for ulcerative colitis (UC). However, a significant percentage of patients experience pouch failure, leading to morbidity. This retrospective case-control study identified histopathological features of the TAC specimen associated with pouch failure and investigated the molecular mechanisms of this susceptibility using single-cell spatial transcriptomics.

We analyzed a cohort of 417 patients who underwent IPAA between 2000-2010 at the University of Chicago Medical Center for up to 18 years. Histological examination of TAC specimens focused on disease activity, depth of inflammation, and specific features, including granulomas and deep ulcers. A subset of patients was profiled using single-cell spatial transcriptomics to map gene expression and immune cell interactions in relation to the risk of pouch failure.

The 18-year pouch failure risk was 23%, with post-procedure diagnosis of CD as a major risk factor (HR = 4.3, 95% CI: 2.3-8.1) as well as high-risk histologic features, including deep chronic inflammation (HR = 21, 95% CI: 11-41) and severe disease activity (HR = 14, 95% CI: 5.7-32) in TAC specimens. Spatial transcriptomics showed immune infiltration of T and myeloid cells, reduced myocyte-glial interactions, and cytokine signaling pathways such as IL-10, IL-1β, and type I/II interferons, associated with an increased risk of pouch failure.

Histological features and spatial molecular profiling are predictive of IPAA failure. These findings support the use of histologic evaluation and targeted molecular analysis of the TAC specimen to identify high-risk patients and improve IPAA outcomes.

Pouchitis is the most common complication among patients with ulcerative colitis who have undergone restorative proctocolectomy with ileal pouch-anal anastomosis. Pouchitis is actually a spectrum of diseases that vary in etiology, pathogenesis, phenotype, and clinical course. Although initial acute episodes typically respond to antibiotic therapy, patients can become dependent on antibiotics or develop refractory disease. Many factors contribute to the course of refractory pouchitis, such as the use of nonsteroidal anti-inflammatory drugs, infection with Clostridium difficile, pouch ischemia, or concurrent immune-mediated disorders. Identification of these secondary factors can help direct therapy.

Restorative proctocolectomy with ileal-pouch anal anastomosis (RPC) is the operation of choice for ulcerative colitis (UC) patients requiring surgery. It is also used for patients with familial adenomatous polyposis (FAP). Pouchitis accounts for 10% of pouch failures. It is an idiopathic inflammatory condition that may occur in up to 50% of patients after RPC for UC. It is rarely seen in FAP patients after RPC. The etiology of pouchitis remains unclear. An overlap with UC is suggested by the frequency with which pouchitis affects patients with UC compared with FAP patients. There is significant clinical evidence implicating bacteria in the pathogenesis of pouchitis. Studies using culture and molecular methods demonstrate a dysbiosis of the pouch microbiota in pouchitis. Risk factors, genetic associations, and serological markers of pouchitis suggest that the interactions between the host immune responses and the pouch microbiota underlie the etiology of this idiopathic inflammatory condition. Here we present a detailed review of the data focusing on the pouch microbiota and the immune responses that support this hypothesis. We also discuss the contribution of luminal metabolic factors and the epithelial membrane in the etiology of this inflammatory process. The ileoanal pouch offers a unique opportunity to study the inter-relationships between the gut microbiota and host immune responses from before the onset of disease. For this reason the study of pouchitis could serve as a human model that significantly enhances our understanding of inflammatory bowel diseases in general.

Restorative proctocolectomy with ileal pouch-anal anastomosis has become the procedure of choice for the majority of patients with ulcerative colitis who require surgical treatment. Pouchitis, the most common long-term complication of the procedure, involves a spectrum of disease processes with heterogeneous risk factors, clinical features, disease courses and prognoses. In addition, clinical symptoms of pouchitis are not specific and often overlap with those of other inflammatory and functional pouch disorders, such as Crohn's disease of the pouch and irritable pouch syndrome. Pouchoscopy and biopsy, along with laboratory and radiographic evaluations, are often required for accurate diagnosis in patients with symptoms indicative of pouchitis. Dysbiosis has been implicated as a triggering factor for pouchitis, and concurrent infection with pathogens, such as Clostridium difficile, might contribute to disease relapse and exacerbation. Antibiotic therapy is the main treatment modality. However, the management of antibiotic-dependent and antibiotic-refractory pouchitis remains challenging. Secondary causes of pouchitis, such as ischaemia, NSAID use, the presence of concurrent primary sclerosing cholangitis and other systemic immune-mediated disorders, should be evaluated and properly managed.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the surgical treatment of choice for patients with medically refractory ulcerative colitis (UC) or UC with dysplasia and for the majority of patients with familial adenomatous polyposis. However, UC patients with IPAA are susceptible to inflammatory and noninflammatory sequelae, such as pouchitis, Crohn's disease of the pouch, cuffitis, and irritable pouch syndrome, in addition to common surgery-associated complications, which adversely affect the surgical outcome and compromise health-related quality of life. Pouchitis is the most frequent long-term complication of IPAA in patients with UC, with a cumulative prevalence of up to 50%. Pouchitis may be classified based on the etiology into idiopathic and secondary types, and the management is often different. Pouchoscopy is the most important tool for the diagnosis and differential diagnosis in patients with pouch dysfunction. Antibiotic therapy is the mainstay of treatment for active pouchitis. Some patients may develop dependency on antibiotics, requiring long-term maintenance therapy. Although management of antibiotic-dependent or antibiotic-refractory pouchitis has been challenging, secondary etiology for pouchitis should be evaluated and modified, if possible.

Restorative proctocolectomy with ileal pouch-anal anastomosis has become the surgical treatment of choice for most patients with ulcerative colitis who require surgery. Although the surgical procedure offers a cure in some patients, postoperative inflammatory and noninflammatory complications are common. Pouchitis is the most common long-term complication of the procedure. Pouchitis represents a spectrum of disease processes with heterogeneous risk factors, clinical phenotypes, natural history, and prognosis. Accurate diagnosis and classification are important for proper treatment and prognosis.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical treatment of choice for the majority of patients with medically refractory ulcerative colitis (UC) or UC with dysplasia, or familial adenomatous polyposis. Various forms of pouchitis frequently occur after surgery. In fact, pouchitis is the most frequent long-term complication of IPAA in patients with UC, with a cumulative prevalence of up to 50%. The etiology and pathogenesis of pouchitis are not entirely clear. It is generally believed that the initiation and development of the disease process of pouchitis is associated with dysbiosis of pouch reservoir, as evidenced by a favorable response to antibiotic therapy. However, the majority of the patients do not show identifiable etiopathogenetic or triggering factors, therefore being labeled to have idiopathic pouchitis. In contrast, a subgroup of patients, particularly those with antibiotic-refractory pouchitis, may have obvious triggering factors for disease flare-up and progression and may be considered to have secondary pouchitis. Therefore, pouchitis can be classified on the basis of etiology into idiopathic and secondary causes. Approximately 20-30% of patients who present with chronic pouchitis have secondary identifiable and triggering factors, including cytomegalovirus or Clostridium difficile infection, ischemia, concurrent immune-mediated disorders, radiation, collagen deposition, and use of nonsteroidal anti-inflammatory drugs. Careful evaluation of these secondary causes of pouchitis that may contribute to resistance to antibiotics should be performed before the introduction of next-line medical therapy.

Restorative proctocolectomy with ileal pouch-anal anastomosis has become the surgical treatment of choice for most patients with ulcerative colitis who require surgery. Although the surgical procedure offers a cure in some patients, postoperative inflammatory and noninflammatory complications are common. Pouchitis is the most common long-term complication of the procedure. Pouchitis represents a spectrum of disease processes with heterogeneous risk factors, clinical phenotypes, natural history, and prognosis. Accurate diagnosis and classification are important for proper treatment and prognosis.

One of the significant limitations to the investigation of inflammatory bowel disease (IBD) in humans is the impossibility of studying this condition from the beginning of the disease process to understand the individual contribution of the various microbiological and immunological components to its pathogenesis. Pouchitis can serve as a human model for IBD, as the time of the pouch creation is known, which allows to prospectively study the events that might eventually lead to the development of a form of intestinal inflammation (i.e., pouchitis) that mimics IBD.

A considerable amount of progress has been made in the last few years on the mechanisms underlying the pathogenesis of pouchitis. Recent literature suggests that pouchitis may present a spectrum of disease processes, with a wide range of causes, risk factors, clinical phenotypes, disease courses, and prognoses. Genetic, microbiological, and immunological profiles in pouchitis were evaluated.

Ileal pouch and pouchitis represent a valuable human model to study the evolution of bacterial communities and host-bacteria interactions in IBD by sequentially monitoring microbiological and immunological profile before, during, and after pouch construction and before and after development and treatment of pouchitis.

Ileal pouch-anal anastomosis is the procedure of choice in the surgical management of refractory ulcerative colitis. Pouchitis affects up to 60% of patients following ileal pouch-anal anastomosis for ulcerative colitis. It overlaps significantly with ulcerative colitis such that improvements in our understanding of one will impact considerably on the other. The symptoms are distressing and impinge significantly on patients' quality of life. Despite 30 years of scientific and clinical investigation, the pathogenesis of pouchitis is unknown; however, recent advances in molecular and cell biology make a synergistic hypothesis possible. This hypothesis links interaction between epithelial metaplasia, changes in luminal bacteria (in particular sulfate-reducing bacteria), and altered mucosal immunity. Specifically, colonic metaplasia supports colonization by sulfate-reducing bacteria that produce hydrogen sulfide. This causes mucosal depletion and subsequent inflammation. Although in most cases antibiotics lead to bacterial clearance and symptom resolution, immunogenetic subpopulations can develop a chronic refractory variant of pouchitis. The aims of this paper are to discuss proposed pathogenic mechanisms and to describe a novel mechanism that combines many hypotheses and explains several aspects of pouchitis. The implications for the management of both pouchitis and ulcerative colitis are discussed.

Autoimmune disorders (ADs) frequently coexist with inflammatory bowel disease. The aim of the study was to determine whether coexisting AD in patients with ileal pouches increases the risk for chronic antibiotic-refractory pouchitis (CARP) and other inflammatory conditions of the pouch.

A total of 622 patients seen in our Pouchitis Clinic were enrolled. We compared the prevalence of adverse outcomes of the pouch (including CARP, Crohn's disease of the pouch, and pouch failure) in patients with or without concurrent AD and assessed the factors for these adverse outcomes.

There were seven pouch disease categories: normal (N=60), irritable pouch syndrome (N=112), active pouchitis (N=131), CARP (N=67), Crohn's disease (N=131), cuffitis (N=83), surgical complications (N=36), and anismus (N=2). The prevalence of AD in these pouch disease categories was 4.5%, 12.5%, 9.2%, 13.4%, 10.7%, 3.8%, 1.5%, and 0%, respectively. The presence of at least one AD at time of pouch surgery was shown to be associated with a twofold increase in the risk for CARP (hazard ratio=2.29; 95% CI: 1.52, 3.46; P<0.001) and for pouch-associated hospitalization (hazard ratio=2.39; 95% CI: 1.59, 3.58; P<0.001). The presence of AD was not associated with increased risk for irritable pouch syndrome, active pouchitis, Crohn's disease, cuffitis, surgical complications, or pouch failure. Patients with Crohn's disease of the pouch had a 2.42 times higher risk for pouch failure (P=0.042) than these without. Active smoking or a history of smoking was shown to be associated with an increased risk for pouch-associated hospitalization and pouch failure.

AD appears to be associated with an increased risk for CARP, and the presence of the association between these AD and pouch disorders may stimulate further research on the link of these organ systems on an immunological basis.

Ileal pouch-anal anastomosis following total proctocolectomy has become part of the standard surgical treatment for patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although this surgery has improved patient quality of life and significantly reduced the risk of dysplasia or neoplasia in ulcerative colitis patients, complications are common. Pouchitis is the most common long-term complication of ileal pouch surgery and has a significant adverse impact on patient quality of life. The diagnosis and differential diagnosis of pouchitis are not straightforward, and the management of pouchitis, particularly chronic antibiotic-refractory pouchitis, which is one of the leading causes of pouch failures, can be challenging.

While restorative proctocolectomy with ileal pouch-anal anastomosis has significantly improved the quality of life in patients with underlying ulcerative colitis who require surgery, complications can occur. Pouchitis as the most common long-term complication represents a spectrum of disease processes ranging from acute, antibiotic-responsive type to chronic antibiotic-refractory entity. Accurate diagnosis using a combined assessment of symptoms, endoscopy and histology and the stratification of clinical phenotypes is important for treatment and prognosis the disease. The majority of patients respond favorably to antibiotic therapy. However, management of chronic antibiotic-refractory pouchitis remains a challenge.

After ileopouch anal anastomosis (IPAA), 10-40% of patients with ulcerative colitis (UC) but only 5% of patients with familial adenomatous polyposis (FAP) develop pouchitis. Immunoregulatory abnormalities might be of importance in the pathogenesis of the disease. Therefore, we characterized cytokine and chemokine transcripts in inflamed and non-inflamed pouches in patients with UC compared to those with FAP and Crohn's disease (CD).

Mucosal biopsies were taken from 87 patients with IPAA [UC (n=70), CD (n=8) or FAP (n=9)]. Patients with active ileal CD (n=14), active UC (n=17) and non-inflammatory conditions (n=12) served as controls. The expression of 20 gene transcripts was quantified using real-time polymerase chain reaction.

Pro-inflammatory cytokines and chemokines are significantly increased in IPAA patients with acute pouchitis. This increase is independent of the underlying disease (UC or CD) and reflects the degree of inflammation. A good correlation between pouchitis activity (using the Pouchitis Disease Activity Index) and the MRP-14, interleukin-8, macrophage inflammatory protein-2alpha and matrix metalloproteinase-1 transcripts was observed.

Our data support the view that pouchitis reflects an inflammatory process that is different from that of underlying inflammatory bowel diseases, as the cytokine and chemokine patterns in pouchitis are neither typical of CD nor of UC, but maybe due to bacterial intestinal microflora overgrowth in the pouch lumen. Quantification of transcript levels allows an estimation of the extent of mucosal inflammation and may become helpful in the evaluation of the disease, especially in clinical trials.

The intestinal microbiota plays a critical role in the pathophysiology of pouchitis, a major complication after ileal pouch anal anastomosis in patients with ulcerative colitis. Recently, controlled trials have demonstrated that probiotics are effective in maintenance of remission in pouchitis patients. However, the mechanism by which therapy with probiotics works remains elusive. This study explores the role of the bacterial and fungal flora in a controlled trial for maintenance of remission in pouchitis patients with the probiotic VSL#3 compound.

The mucosa associated pouch microbiota was investigated before and after therapy with VSL#3 by analysis of endoscopic biopsies using ribosomal DNA/RNA based community fingerprint analysis, clone libraries, real time polymerase chain reaction (PCR), and fluorescence in situ hybridisation. Patients were recruited from a placebo controlled remission maintenance trial with VSL#3.

Patients who developed pouchitis while treated with placebo had low bacterial and high fungal diversity. Bacterial diversity was increased and fungal diversity was reduced in patients in remission maintained with VSL#3 (p = 0.001). Real time PCR experiments demonstrated that VSL#3 increased the total number of bacterial cells (p = 0.002) and modified the spectrum of bacteria towards anaerobic species. Taxa specific clone libraries for Lactobacilli and Bifidobacteria showed that the richness and spectrum of these bacteria were altered under probiotic therapy.

Probiotic therapy with VSL#3 increases the total number of intestinal bacterial cells as well as the richness and diversity of the bacterial microbiota, especially the anaerobic flora. The diversity of the fungal flora is repressed. Restoration of the integrity of a "protective" intestinal mucosa related microbiota could therefore be a potential mechanism of probiotic bacteria in inflammatory barrier diseases of the lower gastrointestinal tract.

This review summarizes some of the common diagnostic problems encountered by pathologists when evaluating patients with chronic colitis and in whom inflammatory bowel disease (IBD) is either suspected or within the differential diagnosis. Both ulcerative colitis (UC) and Crohn's disease (CD) show characteristic, but non-specific, pathological features that may overlap and result in a diagnosis of 'indeterminate colitis' (IC). However, other reasons why pathologists may entertain a diagnosis of IC include failure to recognize or accept certain 'hardcore' histological features as indicative of CD, an attempt to classify cases of chronic colitis based on mucosal biopsy material or in the absence of adequate clinical and radiographic information, and the presence of other disease processes that mask, or mimic, IBD. In addition, some cases of UC may show unusual CD-like features, such as discontinuous or patchy disease, ileal inflammation, extracolonic inflammation, granulomatous inflammation in response to ruptured crypts, aphthous ulcers, or transmural inflammation. Furthermore, other forms of colitis, such as microscopic colitis, diverticulitis and diversion colitis may, on occasion, also show IBD-like changes. The clinical and pathological features that aid in the distinction between these entities, and others, are covered in detail in this review.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical treatment of choice for ulcerative colitis and familial adenomatous polyposis patients who require surgery. Pouchitis is the most common long-term complication after IPAA. Patients with pouchitis represent a heterogeneous group in terms of pathogenesis, clinical presentation, disease course, and prognosis, suggesting a wide range of disease mechanisms. Before the diagnosis of pouchitis is made, other inflammatory and non-inflammatory disease conditions, such as Crohn's disease, cuffitis, and irritable pouch syndrome, should be ruled out. Pouch endoscopy is the most important tool for diagnosis and differential diagnosis. Accurate diagnosis and classification are essential for appropriate management. Although the majority of patients with pouchitis respond to antibiotic therapy, a subset of these patients cannot achieve remission by means of antibiotics and thus require anti-inflammatory or immunosuppressive treatment.

Pouchitis is one of the commonest and most debilitating complications of a restorative proctocolectomy. The cause remains elusive, though a number of approaches have been shown to alleviate the condition. This review outlines current evidence relating to pouchitis, obtained from randomised and nonrandomised studies. Medline, the Bath Information Data Service (BIDS) and PubMed were searched using the keywords 'pouchitis' and 'inflammatory bowel disease'. In addition, articles were cross-referenced, and the abstracts of recent colorectal meetings studied.

Pouchitis is an unfortunate common complication of the ileal pouch-anal anastomosis procedure, an otherwise very attractive surgical option in patients with ulcerative colitis (UC). The fact that the same pouch in familial polyposis is hardly complicated by pouchitis suggests that the basic inflammatory process in UC might participate in the pathophysiology. We review the clinical features of pouchitis, the diagnostic approach, and the many therapeutic considerations, including more recent data on prebiotics and probiotics.

Endothelial-bound cell adhesion molecules are important in recruiting inflammatory cells to the mucosa in inflammatory bowel disease (IBD). Little is known of the expression of these molecules in relation to the recruitment of particular cell subtypes in the early course of mucosal inflammation. We therefore studied the expression of several adhesion molecules to examine their potential correlation with the cellular infiltrate in the inflamed ileal pouch, a possible disease model for ulcerative colitis.

Eleven patients (group 1) with familial adenomatous polyposis (FAP) with no evidence of ileal pouch inflammation and 14 patients (group 2) with ileal pouch inflammation (all with a prior diagnosis of ulcerative colitis) underwent pouch endoscopy with biopsy. Cryostat sections of biopsies were immunostained using a three-stage immunoperoxidase method for the adhesion molecules intercellular adhesion molecule (ICAM-1), vascular cellular adhesion molecule (VCAM-1), E-selectin and mucosal addressin cell adhesion molecule 1 (MAdCAM-1). These results were correlated with immunostaining for the cell markers CD3, CD4, CD8, CD45RO, CD14 and CD15, which were quantified by computer image analysis.

MAdCAM-1, ICAM-1 and VCAM-1 were expressed to similar degrees on the endothelia of groups 1 and 2. In contrast, E-selectin was significantly increased in group 2 (P = 0.003) and correlated with immunostaining for CD15 (r = 0.72), CD4 (r = 0.55) and CD14 (r = 0.53). MAdCAM-1 expression did not correlate with any cell subset. CD15 was the only cell marker to be altered significantly, being increased in group 2 (P = 0.002).

The inflammatory process seen in ileal pouch inflammation is characterized by up-regulation of E-selectin and recruitment of CD15-positive cells, emphasizing the role of neutrophil recruitment and migration to the epithelium in the pathogenesis of this condition.

Pouchitis has been suggested to be a recurrence of ulcerative colitis in a colon-like mucosa. Topical steroids are a valid therapeutic alternative for distal forms of ulcerative colitis.

To investigate the efficacy and tolerability of budesonide enema in the treatment of pouchitis compared with oral metronidazole.

Twenty-six patients with an active episode of pouchitis (defined as a pouchitis disease activity index score >or= 7) and no treatment during the previous month were randomized to receive either budesonide enema (2 mg/100 mL at bedtime) plus placebo tablets or oral metronidazole (0.5 g b.d.) plus placebo enema in a prospective, double-blind, double-dummy, 6-week, controlled trial.

Based on the intention-to-treat principle, we detected a significant improvement in disease activity at the end of the first week with both drugs (P < 0.01). After that, improvement was moderated until stabilization at 4 weeks in both treatments. The per protocol analysis showed that both drugs had similar efficacy in terms of disease activity, clinical and endoscopic findings. Fifty-eight per cent and 50% of patients improved (decrease in pouchitis disease activity index >or= 3) with budesonide enema and metronidazole, respectively (odds ratio, 1.4; confidence interval, 0.2-8.9). Adverse effects were observed in 57% of patients given metronidazole and in 25% of patients given budesonide.

Budesonide enemas are an alternative treatment for active pouchitis, with similar efficacy but better tolerability than oral metronidazole.

Dendritic cells (DC) in the colon may regulate intestinal immunity but remain poorly characterized. In this study a CD11c(+)HLA-DR(+)lin(-) (CD3(-)CD14(-)CD16(-)CD19(-)CD34(-)) population has been identified by flow cytometry in cells obtained by rapid collagenase digestion of human colonic and rectal biopsies. These day 0 (d0) CD11c(+)HLA-DR(+)lin(-) cells comprised approximately 0.6% of the mononuclear cells obtained from the lamina propria, were endocytically active, and had the phenotype of immature DC; they were CD40(+) and expressed low levels of CD83 and CD86, but little or no CD80 or CD25. Similar d0 DC populations were isolated from the colonic mucosa of healthy controls and from both inflamed and noninflamed tissue from patients with Crohn's disease. The lamina propria also contained a population of cells capable of migrating out of biopsies during an overnight culture and differentiating into mature DC with lower levels of endocytic activity and high cell surface expression of CD40, CD80, CD86, CD83, and CD25. This mature DC population was a potent stimulator of an allogeneic mixed leukocyte (MLR). Overnight culture of cells isolated by enzymatic digestion on d0 yielded DC with a phenotype intermediate between that of the d0 cells and that of the cells migrating out overnight. Overnight culture of colonic cells in which DC and HLA-DR(+)lin(+) cells were differentially labeled with FITC-dextran suggested that some of the maturing DC might differentiate from HLA-DR(+)lin(+) progenitors. This study presents the first analysis of the phenotype, maturational status, and migratory activity of human gut DC.

Activation of signal transducer and activator of transcription 1 (STAT1) is a hallmark of IFN-gamma receptor signal transduction but is also part of the signalling pathway of other cytokines/growth factor receptors. In ulcerative colitis, high levels of activation and expression of STAT1 have been observed in comparison with both Crohn's Disease and normal controls. Pouchitis develops in some patients after Ileal-Pouch-Anal-Anastomosis (IPAA). The pathophysiology and aetiology of pouchitis is still unclear. Recent studies have shown an increased production of proinflammatory cytokines including IFN-gamma. To investigate the expression and activation of STAT1 in pouchitis and the influence of treatment, patients were followed longitudinally from pouch operation. Diagnosis of pouchitis was made by clinical, endoscopic and histological criteria. Biopsies were obtained during routine endoscopy and snap frozen in liquid nitrogen. Nuclear and cytosolic extracts were prepared and the expression and activation of specific transcription factors were assessed by Western blot, electrophoretic mobility shift assay and immunofluorescence. Patients who develop pouchitis show highly increased levels of STAT1 alpha as well as STAT1 beta expression and activation in comparison with both normal pouch and normal ileal mucosa. Improvement of pouchitis during antibiotic therapy relates to a normalization of STAT1 expression and activation. We conclude that activation of STAT1 correlates to clinical disease activity and therefore STAT1 could play an important role in the pathophysiology of pouchitis. Similarities in the pattern of activation of STAT1 in pouchitis and ulcerative colitis may suggest a common pathway in the immunopathophysiology of both diseases.

Gut protein loss is a characteristic of inflammatory bowel disease (IBD), and immunoglobulin (Ig) G, albumin and alpha1-antitrypsin concentrations in whole gut lavage fluid (WGLF) correlate with clinical disease activity. If inflammation in ileoanal pouches is similar to IBD, then measurement of protein-losing enteropathy by analysis of WGLF may provide an objective assessment of disease activity in pouches.

Forty-two patients who had restorative proctocolectomy for ulcerative colitis underwent whole gut lavage with a polyethylene glycol-electrolyte solution. The first clear effluent was filtered, processed by the addition of protease inhibitors and stored at - 70 degrees C. IgG, albumin and alpha1-antitrypsin were assayed in WGLF. The Pouchitis Disease Activity Index (PDAI) was calculated after pouchoscopy and biopsy; the Moskowitz criteria for pouchitis were also applied.

There was a significant correlation of the pouchoscopy score and the PDAI with the concentration of WGLF IgG. All patients with 'pouchitis' according to the Moskowitz criteria had a WGLF IgG concentration greater than 10 microg/ml. The WGLF albumin level also showed a significant correlation with the PDAI, but alpha1-antitrypsin concentration did not.

Analysis of WGLF for IgG and albumin may be useful in the assessment of disease activity in pouch inflammation.

Macrophages are important in the host's immunological and inflammatory responses. There is a large population of these cells in the normal intestinal mucosa where they represent the major antigen presenting cell population capable of determining the type of T cell responses that develop to luminal antigens. Studies suggest that the normal intestinal macrophages cannot be easily induced to mediate acute inflammatory responses. In active inflammatory bowel disease there is an increase in the mucosal macrophage population, derived from circulating monocytes. These recruited macrophages are phenotypically different from the resident population of cells and play a major role in mediating the chronic mucosal inflammation seen in patients with ulcerative colitis and Crohn's disease. They secrete many cytokines that are important in the proinflammatory responses, such as interleukin (IL)-1, IL-6, IL-8, IL-12, IL-18, and tumor necrosis factor-alpha. They also release reactive metabolites of oxygen and nitrogen and proteases that degrade the extracellular matrix. Macrophages also appear to be important during resolution of inflammation and repair of the intestinal mucosa that occurs during disease remission.

Immunoregulatory abnormalities of T cells might be of importance in the pathogenesis of pouchitis after ileoanal pouch anastomosis (IAP).

To characterise T cell subsets, their state of activation, and production of cytokines in inflamed and non-inflamed pouches in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). The influence of T cell activation on mucosal transformation was also studied.

Mucosal biopsy specimens were taken from 42 patients with IAP (33 with UC and nine with FAP).

Mononuclear cells were isolated by standard techniques and characterised by three colour flow cytometry. Interferon gamma (IFN-gamma) production was studied using the ELISPOT technique.

In patients with UC with pouchitis there was a significant increase in the CD4:CD8 ratio, expression of activation markers on CD3+ cells, and number of IFNgamma producing mononuclear cells compared with patients with UC without pouchitis (CD4:CD8 ratio 1.3 (range 0.7-2.7) versus 0.6 (0. 1-1.0), p=0.012). In addition, a positive correlation between increased crypt depth and the number of CD4+ cells (r=0.57) was shown.

The observed increase in activated mucosal CD4+ T cells and IFN-gamma production might lead to mucosal destruction and crypt hyperplasia as seen in pouchitis.

Pouchitis is a major long-term complication of the continent ileostomy as well as the ileoanal pouch anastomosis. When diagnosed on the basis of clinical, endoscopic and histologic features, this syndrome has been demonstrated almost exclusively in patients with ulcerative colitis. The clinical course, the endoscopic findings and the histologic abnormalities resemble those of ulcerative colitis. The association with extra-intestinal manifestations further supports the hypothesis that pouchitis represents ulcerative colitis in the small bowel. All ileal reservoirs show bacterial overgrowth, especially of anaerobes. As a response to this altered intraluminal environment chronic inflammation and incomplete colonic metaplasia occur. The efficiency of metronidazole does suggest that bacteriological factors play an important role in the pathogenesis of pouchitis.

Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become an established surgical procedure for ulcerative colitis. Occasional patients who have undergone IPAA develop persistent or recurrent episodes of pouchitis (chronic pouchitis), from which a subset also develop gastrointestinal and systemic complications that are identical to those seen in Crohn's disease. These complications include enteric stenoses or fistulas in the pouch or pouch inlet segment, perianal fistulas or abscesses, pouch fistulas, arthritis, iridocyclitis, and pyoderma gangrenosum. The development of Crohn's-like gastrointestinal complications in a patient with chronic pouchitis frequently engenders concern that the pathologist misinterpreted the proctocolectomy specimen as ulcerative colitis instead of Crohn's disease. We describe eight patients who developed chronic pouchitis and Crohn's-like complications after IPAA and total proctocolectomy. In each case, concern was voiced about misinterpretation of the proctocolectomy specimen as ulcerative colitis instead of Crohn's disease after the development of the Crohn's-like complications. Preoperatively, all eight patients had characteristic clinical, radiographic, and pathologic features of ulcerative colitis. Review of the pathology specimens indicated that all eight had ulcerative colitis. Crohn's-like complications are most likely related to chronic pouchitis, which probably is a form of recrudescent ulcerative colitis within the novel environment of the pouch. A diagnosis of Crohn's disease after IPAA surgery should only be made when reexamination of the original proctocolectomy specimen shows typical pathologic features of Crohn's disease, Crohn's disease arises in parts of the gastrointestinal tract distant from the pouch, pouch biopsies contain active enteritis with granulomas, or excised pouches show the characteristic features of Crohn's disease, including granulomas. There were no histologic differences in the total colectomy specimens between the eight ulcerative colitis study patients and 16 control ulcerative colitis patients who had a favorable clinical outcome after IPAA surgery groups. Crohn's-like complications and chronic pouchitis does not necessarily imply an incorrect original interpretation of ulcerative colitis by the pathologist.

This study aimed to examine the incidence and cumulative risk of pouchitis after restorative proctocolectomy for ulcerative colitis and to evaluate the clinical and functional results in patients with pouchitis.

A total of 291 patients had proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis between January 1985 and January 1996. During follow-up, 65 patients had one or more episodes of pouchitis based on clinical, histologic, and endoscopic criteria. Functional results and patient satisfaction in these patients were compared with those of 65 matched control patients who had experienced no episodes of pouchitis.

Pouchitis developed in 65 patients (22 percent), giving rise to a cumulative frequency of 28 percent at 11 years after the operation. Only 13 patients (4.5 percent) had chronic pouchitis that required long-lasting treatment. A permanent ileostomy had to be constructed in one patient (0.3 percent) because of pouchitis. During the last year (1995), 60 percent of patients with pouchitis had medication, most often metronidazole and/or corticosteroids. Defecation frequency per 24 hours was 6.7 for all patients with pouchitis, 8.2 for those with chronic pouchitis (P < 0.05), and 6.3 for patients without pouchitis. Nighttime defecation occurred in 44 (80 percent) patients with pouchitis, compared with 37 (67 percent) of those without pouchitis (P > 0.05). Frequencies of soiling or flatus incontinence did not differ between the two groups. During the last year, 43 (80 percent) of the pouchitis patients, who answered the questionnaire, were working all the year or were on sick-leave less than one month.

Episodic pouchitis is easily treated and causes minimum functional consequences, whereas chronic pouchitis increases defecation frequency and needs prolonged medication. Pouchitis seems not to be a major threat to preventing the use of restorative proctocolectomy in ulcerative colitis, but still the small group of chronic pouchitis patients remains a problem.

Conventional histopathology, leucocyte typing, cytokine mRNA expression, and crypt cell turnover were compared in ileal pouch biopsy specimens from patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP).

Biopsy specimens were taken from 17 patients with UC and seven with FAP at a median interval of 19 months (range 2-120) after ileostomy closure. All contained both epithelium and lamina propria. Cryostat sections were stained for lymphocyte subtypes (CD3, CD4, CD8), macrophages (CD68), common leucocyte antigen (CD45), and Ki-67, using a three stage immunoperoxidase reaction. Cytokine mRNA expression for interleukins 2 and 6, tumour necrosis factor alpha, and interferon gamma was studied using an in situ hybridisation technique.

Lymphocyte subtype and macrophage populations in epithelium and lamina propria were similar in UC and FAP. The labelling index (Ki-67) was significantly increased in biopsy specimens from patients with UC (UC median = 43.3 (interquartile range (IQR) 38.9-48.2) v FAP 34.9 (29.9-35.2), p < 0.05). There was little or no epithelial mRNA expression for any cytokine in any of the specimens. Lamina propria mRNA expression for interleukin 2 was significantly increased in UC (UC median (IQR) 10.7 (5.4-14.2) cells per unit area v FAP 2.8 (1.5-6.6) p < 0.05) but not for tumour necrosis factor alpha, interleukin 6, and interferon gamma.

While static morphological assessment (leucocyte type, conventional histopathological examination) was similar, tests of cell function (mRNA expression and labelling index) were different in ileal pouches in patients with UC compared with FAP. The study also showed that mRNA expression occurred almost entirely in the lamina propria.

Construction of an ileal reservoir changes the fecal bacterial flora and the fecal composition of bile acids and short-chain fatty acids. We examined the relationships between pouch inflammation (pouchitis) and pouch content, as assessed by analysis of fecal bacteria, bile acids, and short chain fatty acids. Four groups were studied: ileal pouch-anal anastomosis (IPAA) for ulcerative colitis with pouchitis (N = 10), IPAA without pouchitis (N =5), IPAA for familial adenomatous polyposis without pouchitis (N = 5); and Brooke ileostomy for ulcerative colitis, which served as controls (N = 5). Pouchitis was defined as > or = 7 points on an 18-point pouchitis disease activity index. Aerobic and anaerobic bacteria were quantitatively cultured. Total aqueous-phase bile acids were measured by thin-layer chromatography and an enzymatic 3 alpha-OH hydroxysteroid dehydrogenase method. Fecal short chain fatty acids were measured by gas liquid chromatography. All patients with an IPAA had higher ratios of anaerobes/aerobes and concentrations of anaerobic gram-negative rods than did patients with an ileostomy. There were no other differences between patient groups with respect to bacteria, aqueous-phase total bile acids, or fecal short-chain fatty acids. Fecal concentrations of bacteria, bile acids, and short-chain fatty acids were similar in patients with and without pouchitis, indicating that these factors can not be the sole cause of pouchitis.

To determine whether there are characteristic immunohistological changes in the colonic mucosa in acute graft versus host disease (GvHD).

Consecutive allogeneic (n = 11) and autologous (n = 11) bone marrow transplant recipients underwent endoscopic biopsy of sigmoid mucosa before transplant and on day 30 post-transplant. Immunohistochemical staining and quantitation of intraepithelial and lamina propria mononuclear cells were undertaken using a panel of monoclonal antibodies and a Streptavidin-biotin alkaline phosphatase staining technique.

In the allogeneic group (nine of whom had clinical acute GvHD) there was a fivefold increase in lamina propria CD16+ mononuclear cells (3.1 +/- 4.3 to 17.0 +/- 12.2 per 100 lamina propria nucleated cells), compared with autologous transplant recipients in whom this rise was twofold (5.5 +/- 4.6 to 10.6 +/- 7.1 per 100 lamina propria nucleated cells). The CD16+ mononuclear cells had morphological appearances of tissue macrophages, but in neither the allogeneic nor autologous groups was there an increase in total macrophage numbers (CD14+). In patients with acute GvHD the lamina propria CD4+:CD8+ lymphocyte ratio fell (1.97 +/- 1.12 to 1.07 +/- 1.01), primarily because of a fall in the number of lamina propria CD4+ lymphocytes. In both allogeneic and autologous groups there was a fall in intraepithelial lymphocyte numbers, but there was no change in CD19+ (B cell), CD25+ (interleukin-2 receptor positive) or CD56+ (natural killer) cell numbers.

Following bone marrow transplantation, there appears to be upregulation of lamina propria tissue macrophage CD16 (an Fc receptor for IgG), a change which is more noticeable after allogeneic transplantation and which may be related to the development of acute GvHD. In patients with acute GvHD there was a fall in the lamina propria CD4+:CD8+ lymphocyte ratio. If these changes are functionally important, they may have significant implications for understanding the pathogenesis of GvHD.

The rate of oxidation of butyrate, glutamine and glucose was investigated in terminal ileal mucosal biopsy samples from nine patients with ulcerative colitis undergoing restorative proctocolectomy and from 12 patients undergoing laparotomy for reasons other than ulcerative colitis. Substrate oxidation was assayed using a radiolabelled isotope technique. Butyrate was the preferred fuel substrate, followed by glutamine and then glucose (median (95 per cent confidence interval) 567 (262-894), 63 (35-123) and 8.1 (5.1-18) pmol micrograms-1 h-1 respectively; P < 0.01, Mann-Whitney U test) in normal terminal ileal mucosa. The patients with ulcerative colitis had a significantly reduced rate of butyrate oxidation compared with the control group (194 (81-321) versus 567 (262-894) pmol micrograms-1 h-1, P < 0.05). Normal terminal ileal mucosa oxidized butyrate in greater quantities than glucose and glutamine. Ulcerative colitic terminal ileal mucosa exhibited an impaired rate of butyrate oxidation.

Pouchitis is an increasing drawback to patients who undergo ileal pouch-anal anastomosis for ulcerative colitis; complication overshadows the overall good functional results of this sphincter-saving operation. There is a need for cooperative, multicenter, and longitudinal studies of patients undergoing ileal pouch-anal anastomosis, to unravel the etiology and pathophysiology of pouchitis. Because of the absence of a mucosal inflammation before pouch construction, patients operated on for familial adenomatous polyposis are the perfect control group. Thus, it may be possible to elucidate and define the sequence that leads to pouchitis, including overgrowth of a colonic type flora, transformation of the histology to an epithelium with colonic features, an altered biochemical milieu in the lumen (volatile fatty acids, secondary bile acids), and changes in mucosal defense mechanisms.

Proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice for severe chronic ulcerative colitis and familial polyposis coli because the entire colonic mucosa is removed while anal function can be preserved and the necessity for permanent ileostomy is eliminated. Long-term functional results are generally gratifying, as defecation frequency and degree of incontinence are acceptable in most patients. Pouchitis, however, a non-specific inflammation of the ileal reservoir, is a major long-term complication occurring in a considerable number of patients. The etiology of pouchitis is unknown. Since pouchitis occurs more frequently or even exclusively in ulcerative colitis patients it is assumed that pouchitis is a novel manifestation of inflammatory bowel disease. However, bacterial overgrowth in the ileal pouch may also play a pathogenetic role. Chronic inflammation and villous atrophy of varying severity is found in virtually all pouches. Acute inflammatory changes and ulceration are associated with pouchitis.

Little is known about the evolution of morphological changes in pelvic ileal-pouch mucosa. This study evaluates prospectively the sequence of early morphological, histochemical, and phenotypic features in pouch mucosal biopsy specimens.

Twenty-two patients with pelvic ileal pouches constructed after total colectomy for chronic ulcerative colitis had biopsies performed at the time of ileostomy closure and after 6 weeks and 6 months of pouch function and were evaluated to assess the type and degree of inflammation, villus atrophy, Paneth's cell hyperplasia, mucin histochemical changes, the mucosal proliferative activity using the murine monoclonal antibody 1 (MIB-1), and the expression of the enzyme sucrase-isomaltase.

Early changes (6 weeks) were characterized by neutrophilic and eosinophilic inflammation, mild villus atrophy, Paneth's cell hyperplasia, a partial transition to colonic mucin phenotype, and an increased MIB-1 proliferation index. These features remained relatively stable after 6 months, except for a greater degree of mononuclear infiltration, a progressive increase in the degree of eosinophilic inflammation and a new higher steady state level of crypt epithelial kinetics. Expression of sucrase-isomaltase remained stable.

Pelvic ileal pouches develop inflammatory, phenotypic, and kinetic changes early in the course of function but have only a limited potential for colonic type metaplasia. The persistence of these changes is evidence in support of an adaptive response to a new luminal environment.

Concentrations of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha) were determined by solid-phase ELISA in tissue homogenates of mucosal biopsy specimens obtained from pelvic ileal pouches in 13 patients with pouchitis (reservoir ileitis) and 17 with pouches without pouchitis. Normal ileal mucosa was used as a control. IL-1 beta was detected in all tissue homogenates from patients with pouchitis compared with only 29% from pouches without pouchitis and none from controls. IL-6 and IL-8 were present in all pouchitis specimens, in 70% of the specimens from nonpouchitis and only 30% of specimens from controls. TNF-alpha was undetectable in all specimens examined. The concentrations of IL-1 beta, IL-6, and IL-8 were significantly greater (P < 0.001) in biopsy specimens from pouchitis compared to those from pouches without pouchitis or normal ileal mucosa and in patients with pouchitis tissue levels of IL-1 beta significantly correlated with IL-6 (P < 0.05) and IL-8 (P < 0.01). Furthermore IL-1 and IL-8 levels were significantly higher in tissue specimens from nonpouchitis pouches than in those from normal ileal mucosa (P < 0.02). These results suggest that an enhanced cellular immunity operates in vivo at the mucosal level in pouchitis as in the case of ulcerative colitis.

Various mechanisms have been proposed for the aetiology of inflammation in ileal pouches following restorative proctocolectomy. It is proposed that many of these processes may be involved in the pathogenesis of ulcerative colitis, and therefore pouchitis may be used to study pathogenesis and treatment of inflammatory bowel disease in general and, in particular, ulcerative colitis.

The aim of this study was to evaluate the use of cyclosporin enemas in patients with distal ulcerative colitis and 'pouchitis' resistant to all conventional medical therapy. In an trial 12 patients with distal ulcerative colitis unresponsive to treatment with topical and oral corticosteroids, 5-aminosalicylic acid, and oral immunosuppressive therapy together with 1 patient with 'pouchitis' unresponsive to repeated courses of antibiotics, topical corticosteroids, and oral mesalazine received 250 mg cyclosporin administered daily as a retention enema. Changes in symptoms and the sigmoidoscopic/histologic appearances of the rectal mucosa were assessed at monthly intervals. Seven of 12 patients with ulcerative colitis improved. There was a strong correlation between clinical and histologic improvement (p < 0.005). Four of 12 patients showed no response. Three of these required colectomy, two of whom had more extensive disease than had previously been documented. The patient with pouchitis showed improvement in symptoms and 'pouchoscopy' appearance but not in histologic score. Cyclosporin blood concentrations were very low and side effects negligible. Cyclosporin A retention enemas are safe and may be useful in the treatment of severe refractory distal ulcerative colitis. A controlled trial would now seem warranted.