Pouchitis: pathophysiology and management.

Pouchitis is an acute or chronic inflammatory disease of the ileal reservoir. It is common after restorative proctocolectomy with ileal pouch-anal anastomosis, and treatment of chronic antibiotic-refractory pouchitis has proven challenging. Most cases of acute pouchitis evolve into chronic pouchitis. The aetiology of acute pouchitis is likely to be partly related to the gut microbiota, whereas the pathophysiology of chronic pouchitis involves abnormal interactions between genetic disposition, faecal stasis, the gut microbiota, dysregulated host immunity, surgical techniques, ischaemia and mesentery-related factors. Pouchoscopy with biopsy is the most valuable modality for diagnosis, disease monitoring, assessment of treatment response, dysplasia surveillance and delivery of endoscopic therapy. Triggering or risk factors, such as Clostridioides difficile infection and use of non-steroidal anti-inflammatory drugs, should be modified or eradicated. In terms of treatment, acute pouchitis usually responds to oral antibiotics, whereas chronic antibiotic-refractory pouchitis often requires induction and maintenance therapy with integrin, interleukin or tumour necrosis factor inhibitors. Chronic pouchitis with ischaemic features, fistulae or abscesses can be treated with hyperbaric oxygen therapy.

Greater Peripouch Fat Area on CT Image Is Associated with Chronic Pouchitis and Pouch Failure in Inflammatory Bowel Diseases Patients.

BACKGROUND: The causes of chronic antibiotic refractory pouchitis (CARP) and pouch failure in inflammatory bowel disease (IBD) patients remain unknown. Our previous small study showed peripouch fat area measured by MRI was associated with pouchitis. AIMS: To explore the relationship between peripouch fat area on CT imaging and pouch outcomes. METHODS: This is a historical cohort study. Demographic, clinical, and radiographic data of IBD patients with abdominal CT scans after pouch surgery between 2002 and 2017 were collected. Peripouch fat areas and mesenteric peripouch fat areas were measured on CT images at the middle pouch level. RESULTS: A total of 435 IBD patients were included. Patients with higher peripouch fat areas had a higher prevalence of CARP. Univariate analyses demonstrated that long duration of the pouch, high weight or body mass index, the presence of primary sclerosing cholangitis or other autoimmune disorders, and greater peripouch fat area or mesenteric peripouch fat area were risk factors for CARP. Multivariable analyses demonstrated that the presence of primary sclerosing cholangitis or autoimmuned disorders, and greater peripouch fat area (odds ratio [OR] 1.031; 95% confidence interval [CI] 1.016-1.047, P < 0.001) or mesenteric peripouch fat area were independent risk factors for CARP. Of the 435 patients, 139 (32.0%) had two or more CT scans. Multivariable Cox proportional hazard analyses showed that "peripouch fat area increase ≥ 15%" (OR 3.808, 95%CI 1.703-8.517, P = 0.001) was an independent predictor of pouch failure. CONCLUSIONS: A great peripouch fat area measured on CT image is associated with a higher prevalence of CARP, and the accumulation of peripouch fat is a risk factor for pouch failure. The assessment of peripouch fat may be used to monitor the disease course of the ileal pouch.

The Structure and Function of the Human Small Intestinal Microbiota: Current Understanding and Future Directions.

Despite growing literature characterizing the fecal microbiome and its association with health and disease, few studies have analyzed the microbiome of the small intestine. Here, we examine what is known about the human small intestinal microbiota in terms of community structure and functional properties. We examine temporal dynamics of select bacterial populations in the small intestine, and the effects of dietary carbohydrates and fats on shaping these populations. We then evaluate dysbiosis in the small intestine in several human disease models, including small intestinal bacterial overgrowth, short-bowel syndrome, pouchitis, environmental enteric dysfunction, and irritable bowel syndrome. What is clear is that the bacterial biology, and mechanisms of bacteria-induced pathophysiology, are enormously broad and elegant in the small intestine. Studying the small intestinal microbiota is challenged by rapidly fluctuating environmental conditions in these intestinal segments, as well as the complexity of sample collection and bioinformatic analysis. Because the functionality of the digestive tract is determined primarily by the small intestine, efforts must be made to better characterize this unique and important microbial ecosystem.

Alicaforsen for the treatment of inflammatory bowel disease.

INTRODUCTION: Intracellular adhesion molecule-1 (ICAM-1), is a transmembrane glycoprotein of the immunoglobulin family, constitutively expressed on vascular endothelial cells and upregulated in inflamed colonic tissue. Alicaforsen, a 20 base ICAM-1 anti-sense oligonucleotide and highly selective ICAM-1 inhibitor, down-regulates ICAM-1 mRNA. Areas covered: We review mechanism of action, pharmacokinetics, pre-clinical, clinical and safety data of alicaforsen for the treatment of ulcerative colitis (UC), pouchitis and Crohn's disease (CD). Expert opinion: After 6 weeks of treatment, topical alicaforsen was significantly more effective than placebo in inducing remission in patients with moderate-severe distal UC, with treatment effects lasting up to 30 weeks. No difference was observed in head-head comparison with mesalamine topical enema, although alicaforsen appeared to have more durable treatment effect. Clinical trials of an intravenous formulation in Crohn's disease showed no significant treatment effect compared to placebo. An open-label trial in alicaforsen for pouchitis demonstrated encouraging results, now being assessed in a multi-national phase 3 trial. No major safety signals have been observed in UC patients treated with alicaforsen enemas. The potential as a novel therapy for pouchitis has led to orphan designation for this indication by the FDA and European Medicines Agency.

De novo Crohn's Disease after Ileal Pouch-Anal Anastomosis for Ulcerative Colitis and Inflammatory Bowel Disease Unclassified: Long-Term Follow-Up of a Prospective Inflammatory Bowel Disease Registry.

The risk of de novo Crohn's disease (CD) after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) versus inflammatory bowel disease unclassified (IBDU) or indeterminate colitis (IC) remains debatable. Here, we present updated results after long-term follow-up of a previously studied cohort of 334 patients with UC, IBDU, or IC who underwent IPAA during a 10-year period ending 2007. Of 334 study patients, 56 per cent were male and median age was 38 years (range: 8-81). Patients were classified as UC (n = 237) or IBDU (n = 97) preoperatively and UC (n = 236) or IC (n = 98) postoperatively. After a median follow-up of 76 months (range: 3-236), 63 patients (19%) developed CD within a median of 22 months (range: 1-213) from ileostomy closure compared with the previously published 40 patients (12%) with 26-month follow-up (P = 0.01). The development of de novo CD was similar for patients undergoing IPAA for UC (n = 40; 17%), IBDU (n = 21; 22%) or those classified as having UC (n = 42; 18%) or IC (n = 19; 19%) postoperatively; P > 0.05. Thus, patients with IBDU and IC can expect equivalent long-term outcome to patients with UC after IPAA. Pouch failure occurred in 13 (4%) study patients and was equal among all four groups.

Effect of probiotics (Lactobacillus plantarum 299 plus Bifidobacterium Cure21) in patients with poor ileal pouch function: a randomised controlled trial.

OBJECTIVE: Poor pouch function after restorative proctocolectomy for ulcerative colitis is a considerable problem. Pouchitis and functional disorders are the most common reasons. Probiotics seem to have a beneficial effect in pouchitis but have not been assessed in functional pouch disorders. The aim was to analyse the effects of probiotics in patients with poor pouch function. METHODS: Thirty-three patients were randomized to probiotics (Lactobacillus plantarum 299 and Bifidobacterium infantis Cure 21) or placebo in a double blinded, 1:1 fashion. The treatment effect was assessed by the pouch functional score (PFS; 0-15, 15 worst), pouchitis disease activity index (PDAI; 0-18, 18 worst), and levels of four faecal biomarkers of inflammation (calprotectin, lactoferrin, myeloperoxidase [MPO] and eosinophilic cationic protein [ECP]). RESULTS: Thirty-two patients were included (probiotics = 17, placebo = 16). There was no difference in change in the PFS from before to after treatment between the groups (median difference: -1.00, 95% C.I. -3.00 to 0.00, p = 0.119). Furthermore, probiotics had no effect on PDAI (median difference: 0.00, 95% C.I. 0.00-1.00, p = 0.786), or on faecal biomarkers. Significant correlations were observed between PDAI and each of the faecal biomarkers at study start. There were no correlations between PFS or PDAI symptom subscore and the biomarkers. PDAI endoscopic and histologic subscores correlated significantly to each of the biomarkers. CONCLUSION: The hypothesis that probiotics improves pouch-related dysfunction was not confirmed. Faecal biomarkers could play a future role in the management of pouch patients.

Pathobiology and potential therapeutic value of intestinal short-chain fatty acids in gut inflammation and obesity.

BACKGROUND: The lumen of the gastrointestinal tract contains many substances produced from the breakdown of foodstuffs, from salivary, esophageal, intestinal, hepatic, and pancreatic secretions, and from sloughed cells present in the gastrointestinal lumen. Although these substances were traditionally regarded as waste products, there is increasing realization that many can be biologically active, either as signalling compounds or as nutrients. For example, proteins are broken down into amino acids, which are then sensed by nutrient receptors. The gut microbiome, which is at highest abundance in the ileocecum, has powerful metabolic activity, digesting and breaking down unabsorbed carbohydrates, proteins, and other ingested nutrients into phenols, amines, volatile organic compounds, methane, carbon dioxide, hydrogen, and hydrogen sulfide into volatile fatty acids, also called short-chain fatty acids (SCFAs). CONCLUSION: These latter substances are the topic of this review. In this review, we will briefly discuss recent advances in the understanding SCFA production, signalling, and absorption, followed by a detailed description and discussion of trials of SCFAs, probiotics, and prebiotics in the treatment of gastrointestinal disease, in particular ulcerative colitis (UC), pouchitis, short bowel syndrome, and obesity.

ASCA IgG and CBir antibodies are associated with the development of Crohn's disease and fistulae following ileal pouch-anal anastomosis.

BACKGROUND: For ulcerative colitis (UC) patients undergoing ileal pouch-anal anastomosis (IPAA), postoperative complications include chronic pouchitis and development of Crohn's disease (CD) of the pouch. AIMS: The aim of this study was to determine if serologic markers obtained postoperatively are associated with the development of complications in UC patients after IPAA. METHODS: A retrospective chart review was conducted of UC patients with IPAA were tested for expression of serologic markers. Complications abstracted from medical records included postoperative fistula, CD of the pouch, chronic pouchitis, and diversion or excision of the pouch. RESULTS: 142 patients were enrolled, 44 of whom developed complications. Positive serologic profiles for ASCA IgG and anti-CBir1 markers were found to be associated with the development of any complication, (P = 0.017 and P = 0.002, respectively). A positive anti-CBir1 test was also found to be associated with CD of the pouch and/or fistula formation (P < 0.001). Similarly, both ASCA IgG and anti-CBir1 titers were significantly associated with postoperative IPAA complications (P = 0.034 and P = 0.001, respectively), and anti-CBir1 titers were associated with CD of the pouch and/or fistula formation (P < 0.001). Complications developed after a median follow-up of 216 months (range 1-264). CONCLUSIONS: ASCA IgG and anti-CBir1 markers were associated with the development of complications after IPAA, specifically fistulae and/or CD of the pouch. The ability to identify patients at high risk for adverse outcomes may allow for early aggressive therapy, which may decrease the rate of pouch failure. A prospective study of patients with preoperative serology is ongoing.

Stasis predisposes ileal pouch inflammation in a rat model of ileal pouch-anal anastomosis.

BACKGROUND: While restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the definitive surgical treatment for patients suffering from chronic ulcerative colitis (CUC), pouchitis still remains a major late complication. Fecal stasis has been implicated in the etiology of ileal inflammation; however, the mechanism(s) remain unclear, in part due to the lack of an animal model. Our goal was to surgically mimic the IPAA procedure in a rat to investigate the hypothesis that stasis leads to biochemical changes that predispose the ileal pouch to inflammation. MATERIALS AND METHODS: Thirty-two Sprague-Dawley rats underwent total colectomy with either straight ileorectal (IRA) or IPAA, and 11 nonoperated rats served as controls (Controls). Twenty-one d postoperatively, 48 h serial barium radiographs and 12 h charcoal transit follow-through studies were performed. Following sacrifice, ileal tissue was harvested for the measurement of myeloperoxidase activity (MPO) activity, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) mRNA levels, and histology. RESULTS: Serial barium radiographs showed stasis in the ileal pouch compared with IRA animals, and charcoal transit times that were two times longer (P ≤ 0.05) than that in the straight IRA rats. Ileal pouch MPO levels were significantly elevated in the IPAA rats compared with the straight IRA rats. ICAM-1 and VCAM-1 mRNA levels were not associated with neutrophil infiltration. CONCLUSIONS: These studies showed that ileal pouch stasis predisposes biochemical and histological evidence of ileal pouch mucosal inflammation. Studies such as this may provide the rationale for novel, adjunct therapies for the management of pouchitis in patients having undergone IPAA for CUC.

Inflamed pouch mucosa possesses altered tight junctions indicating recurrence of inflammatory bowel disease.

BACKGROUND AND AIMS: The etiology of pouchitis after coloproctomucosectomy with ileal pouch-anal anastomosis in patients with ulcerative colitis is still unknown. Beside changes in luminal antigens, the immunological predisposition is assumed to be responsible. In previous electrophysiological studies, we showed that mucosal barrier and transport function in pouchitis is markedly reduced. Thus, the aim of the present study was to analyze barrier function on the molecular level. MATERIAL AND METHODS: Pouch biopsies of 36 ulcerative colitis patients were analyzed. Time points were (1) intraoperative immediately prior to ileal pouch-anal anastomosis (n = 13), (2) >1 year after ileostomy closure (pouch, n = 12), and (3) during pouchitis (n = 11). Control terminal ileum biopsies were obtained from eight patients undergoing hemicolectomy due to carcinoma. Expression of tight junction proteins was analyzed by Western blotting and confocal laser-scanning microscopy. To elucidate effects on epithelial barrier properties, impedance spectroscopy was performed in miniaturized Ussing chambers. RESULTS: In pouchitis, epithelial resistance was markedly reduced compared to non-inflamed pouch and control ileum. Expression of tight junction proteins claudin-1, 3, 4, 5, and 7 and occludin revealed differential expression regulation with the tightening tight junction protein claudin-1 being decreased and an increase of the pore-forming claudin-2, whereas other claudins remained constant. Morphometry indicated the mucosal surface to be unchanged. CONCLUSION: Pouchitis is characterized by a selective change of tight junction proteins in favor of opening the epithelial tight junction and, thus, the paracellular pathway, which contributes to the inflammatory process. This resembles changes in inflammatory bowel disease (IBD) and indicates IBD recurrence in pouchitis.

Pouchitis: an evolving clinical enigma--a review.

While the overall incidence of pouchitis is low, extensive research continues at clinical and experimental levels in attempts to unravel its etiology. The ileal pouch and pouchitis together represent a unique in vivo opportunity to study mucosal adaptation and inflammation in depth. In the recent past, molecular data relating to pouchitis has significantly expanded. These data provide invaluable insight into intracellular and extracellular events that underpin mucosal adaptation and inflammation. Advances in classification, risk factor evaluation, and prevention have meant that a review of this data, as well as its relationship to our current understanding of pouchitis, is both timely and warranted. Therefore, the aim of this review is to summarize recent data in the context of the established literature.

Ostomy options for clients with ileostomies.

Quality of life with an external appliance has a significant impact on decision making when considering an incontinent or continent ostomy. A majority of clients with external pouches are content with their pouches and enjoy a good quality of life. For others, not having to deal with an external appliance is reason enough to consider surgery. Major physical and psychological lifestyle changes occur with the ileostomy, particularly with body image and self-concept (Reynaud & Meeker, 2002). Having an external appliance can lead to depression for the client because of skin irritation, leakage of stool, and difficulty securing the appliance. Other issues include moving wrong while sleeping, which can create an uncomfortable feeling of warmth across the abdomen, and putting on a seatbelt can be a challenge.

Permanently increased mucosal permeability in patients with backwash ileitis after ileoanal pouch for ulcerative colitis.

OBJECTIVE: Backwash ileitis (BI) has not been identified as a risk factor for pouchitis. The aim of this study was to investigate the barrier function of the ileoanal pouch depending on the presence of BI. The incidence of pouchitis in a population of ulcerative colitis patients with BI is also reported. MATERIAL AND METHODS: Biopsies were taken from 80 patients with ulcerative colitis: a) terminal ileum prior to pouch creation (pre-IAP); b) 16 months after ileostomy closure (intact pouch); and c) during pouchitis. Patients were stratified into the BI group and the non-BI (ØBI) group. Barrier function was determined in Ussing-chambers as epithelial resistance by impedance analysis and as mannitol permeability from (3)H-mannitol fluxes. Na(+)-glucose co-transport was measured as a change in short-circuit current (I(SC)) after addition of glucose. Relative risk of developing pouchitis was calculated by corrected chi(2) test. RESULTS: In 13/21 (BI/ØBI) pre-IAP patients, 23/37 (BI/ØBI) with an intact pouch, and 35/7 (BI/ØBI) with pouchitis, epithelial resistance in BI/ØBI was 13.5+/-1.6/14.3+/-0.9 Omega.cm(2) for pre-IAP, 12.7+/-1.3/16.8+/-1.2 Omega x cm(2) (p<0.05 BI versus ØBI) for the intact pouch, and 10.1+/-1.1/9.9+/-1.8 Omega x cm(2) for pouchitis (p<0.05 BI versus ØBI with an intact pouch). No differences were found for electrogenic chloride secretion and active Na(+)-glucose co-transport between BI/ØBI in the three groups. In patients with BI, pouchitis was more common (35 versus 7 patients, odds ratio 33.0 (95% CI 8.3-143.9; p<0.0001)). CONCLUSIONS: Ulcerative colitis patients with BI show impaired barrier function in the further course of the ileoanal pouch. Thus, BI has a long-term impact on epithelial barrier function.

Predictors for acute and chronic pouchitis following restorative proctocolectomy for ulcerative colitis.

OBJECTIVE: This study was undertaken to evaluate the cumulative incidence, onset and risk predicting factors for acute and chronic pouchitis. METHOD: A consecutive series of patients (n = 210), who underwent restorative proctocolectomy (RPC) and had a minimum follow-up of 12 months was reviewed. The cumulative incidence and onset of pouchitis was determined. Univariate analysis, followed by logistic regression analysis was used to evaluate the association of various demographic, clinical and histopathologic variables with the subsequent development of acute and chronic pouchitis. RESULTS: A total of 198 patients were included. The mean follow-up was 64 months (range, 12-180). Sixty-four patients (32%) developed pouchitis, 35 acute and 29 chronic. The first episode of pouchitis occurred within the first year in 70% of cases. The presence of backwash ileitis (OR, 2.6; P = 0.015), primary sclerosing cholangitis (PSC; OR, 2; P = 0.018) and the duration of follow-up (OR, 1.1; P = 0.043) were associated with a higher incidence of pouchitis. The duration of follow-up was the only variable associated with acute pouchitis (P = 0.007). The presence of backwash ileitis and PSC were independent risk factors for chronic pouchitis (OR, 5.9; P < 0.001; OR, 2.8; P = 0.001 respectively). CONCLUSION: Pouchitis is a heterogeneous disease which tends to occur early after restoration of gastrointestinal continuity. Patients with backwash ileitis and/or PSC are at considerable risk of developing chronic pouchitis. The strong association between backwash ileitis, PSC and chronic pouchitis suggests a common link in their pathogenesis.

Pouch-ouch.

PURPOSE OF REVIEW: For patients who require colectomy, the ileal pouch anal anastomosis operation has alleviated the need for permanent ileostomy and has improved associated self-esteem issues. The most common complication of this surgery, however, is pouchitis. This review highlights the most recent research in the pathophysiology, risk factors, diagnosis and management of pouchitis, and pouch surveillance for neoplasia in patients who had ulcerative colitis. RECENT FINDINGS: Markers of inflammation, including fecal lactoferrin and mucosal cytokines, have been reported as useful in differentiating between irritable pouch syndrome and pouchitis. Numerous risk factors for the development of pouchitis have been identified. They include the presence of perinuclear antinuclear cytoplasmic antibodies, steroid use prior to colectomy, dysplasia as the indication for colectomy, the presence of extraintestinal manifestations, and an elevated platelet count. Therapy for acute pouchitis remains a short course of antibiotics. For chronic pouchitis, studies found success with rifaximin, tinidazole, and oral budesonide. Cancer in the residual rectal mucosa, in the ileal mucosa, and in pouch polyps occurs frequently enough to warrant surveillance. SUMMARY: Risk factors for the development of pouchitis should be discussed with patients. Less invasive diagnostic strategies have been proposed and antibiotics are still the mainstay of therapy.

High-dose probiotics for the treatment of active pouchitis.

PURPOSE: Pouchitis is the major long-term complication after ileal-pouch anal anastomosis for ulcerative colitis. Broad-spectrum antibiotics are the mainstay of treatment in this condition. Recently, we have shown the efficacy of a highly concentrated probiotic preparation (VSL#3, 900 billions/sachet lyophilized viable bacteria) in preventing relapses of chronic pouchitis and in preventing pouchitis onset. This study was designed to evaluate the efficacy of high-dose VSL#3 in the treatment of mildly active pouchitis. METHODS: Twenty-three consecutive patients with mild pouchitis, defined as a score of between 7 and 12 in the Pouchitis Disease Activity Index, which includes clinical, endoscopic, and histological criteria, were treated with VSL#3, 2 sachets b.i.d. (3,600 billion bacteria/day) for four weeks. Symptomatic, endoscopic, and histologic evaluations were undertaken before and after treatment according to Pouchitis Disease Activity Index. Remission was defined as a combination of a Pouchitis Disease Activity Index clinical score of

Dysbiosis in pouchitis: evidence of unique microfloral patterns in pouch inflammation.

BACKGROUND & AIMS: Pouch inflammation after surgery for ulcerative colitis can significantly alter quality of life and thus ideally should be prevented. Dysbiosis or altered microflora is suspected to be the key pathogenic factor for pouchitis. However, dysbiosis in pouchitis has not been characterized carefully because of a lack of available sensitive microbiological technology suitable for in vivo studies in human beings. Thus, the aims of our study were as follows: (1) to show the use of the length heterogeneity polymerase chain reaction (LH-PCR) technique for studying microflora in human beings, and (2) to use the technique to characterize the microfloral patterns in the ileal pouch of patients with pouchitis. METHODS: Microfloral patterns initially were assessed using a 16S ribosomal RNA technique (LH-PCR) to determine the qualitative changes in the luminal and mucosal intestinal flora. We subsequently cloned and sequenced the LH-PCR amplification products from the community 16S ribosomal RNA found in patients with pouchitis and in control pouch to identify the microbial species involved in pouchitis. RESULTS: We have shown unique microfloral patterns in pouchitis. Through cloning and sequencing of the LH-PCR amplicons, we have shown the persistence of Fusobacter and Enteric species associated with the disease state and the absence of specific bacteria such as Streptococcus species in the inflamed pouch. CONCLUSIONS: We have shown that the LH-PCR technique is suitable for studying microflora in human beings. By using this technique and the clone sequences, we have shown dysbiosis in the microbial biofilm adherent to the mucosa in pouchitis. Our data provide direct evidence of the role of bacteria in the pathogenesis of pouchitis.