small molecules

2026-09-16 | Antibiotic-Refractory Chronic Pouchitis After Ileal Pouch-Anal Anastomosis: Current and Emerging Therapeutic Strategies.

Chronic inflammatory pouch disorders may affect up to 20% of patients within 5 years after ileal pouch-anal anastomosis and remains a major therapeutic challenge. Within this spectrum, chronic antibiotic-refractory pouchitis is associated with impaired quality of life, long-term pouch-related complications, and potential risk for pouch failure and excision. Current recommendations support the use of probiotics for primary and secondary prevention in selected patients. Increasingly, targeted advanced therapies, including biologics and small molecules approved for the treatment of ulcerative colitis and Crohn's disease, are being used to reduce antibiotic dependence and maintain disease control in patients with pouch inflammation. Vedolizumab is the only advanced therapy approved in Europe for chronic pouchitis, whereas evidence for tumor necrosis factor (TNF) antagonists, ustekinumab, and newer agents, such as interleukin (IL)-23p19 antagonists and Janus kinase (JAK) inhibitors is largely based on observational data from clinical practice and real-world experience. Fecal microbiota transplantation is biologically attractive but remains investigational, with early studies showing inconsistent efficacy. Dietary patterns may modify pouch inflammation; however, most evidence is observational. Overall, current management strategies for chronic pouchitis are limited by incomplete understanding of disease pathogenesis, and by persistent methodological gaps, including poorly standardized treatment outcomes and the lack of validated treat-to-target strategies for this population. Well designed prospective and controlled studies are needed to define appropriate antibiotic-sparing strategies, optimal treatment positioning, and long-term durability of response.

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2026-08-14 | Continued concomitant antibiotic or immunosuppression therapies reduce the risk of pouchitis among patients with ileal pouch-anal anastomosis and primary sclerosing cholangitis.

Complications such as intermittent pouchitis (IP) and chronic inflammatory disorders of the pouch (CP) are common after ileal pouch-anal anastomosis (IPAA), particularly among patients with both ulcerative colitis and primary sclerosing cholangitis (PSC). There are no standardized approaches for prophylaxis against these complications for patients with PSC undergoing IPAA. We compared outcomes among patients with PSC and IPAA who received antibiotic or immunosuppressive therapies to those who did not. We designed a retrospective cohort study that included patients with ulcerative colitis and PSC from 7 tertiary care centers that underwent IPAA between 1994 and 2023. Patients were categorized on whether they received medications following IPAA that may provide primary prophylactic benefit, such as antibiotics, probiotics, immunomodulators, or biologic medications; and the proportion of patients developing IP and CP was evaluated. A total of 172 patients were included in the cohort, and 13 (7.6%) patients received antibiotics or immunosuppressant medications. Antibiotics and probiotics were the most common therapy (5 patients, 2.9%), followed by biologics, small-molecule inhibitors, immunomodulators, or mesalamine (all 1 patient, 0.6%). Compared to patients not receiving antibiotics or immunosuppression, patients receiving antibiotics or immunosuppression were significantly less likely to develop IP (69.2% vs 91.2%; P = .03; odds ratio 0.22; 95% CI, 0.06-0.80) and CP (23.1% vs 56.0%, P = 0.04; OR 0.24, 95% CI, 0.06-0.89). In this retrospective cohort of patients with ulcerative colitis and PSC undergoing IPAA, usage of concomitant antibiotics or immunosuppression was low. However, use of concomitant antibiotics or immunosuppression may decrease the burden of inflammatory conditions of the pouch in these high-risk patients.

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2026-07-18 | Study of TOfacitinib for the treatment of chronic PouchITis (STOPit): a multi-centre open label induction with randomised, double blind, placebo-controlled maintenance trial.

Study of TOfacitinib for the treatment of chronic PouchITis (STOPit) is a national, investigator-led, multicentre, open-label induction with randomised, double-blind, placebo-controlled maintenance trial to determine the effectiveness of tofacitinib to induce and maintain clinical remission in chronic pouchitis patients. The primary objective of STOPit is to evaluate the clinical response to tofacitinib, compared with placebo, using the validated modified Pouchitis Disease Activity Index score. Secondary objectives include clinical response and remission rates, endoscopic response and mucosal healing rates in induction and maintenance phases; rates of flare and recapturing response in open label extension phase; the effect of tofacitinib on clinical biomarkers and quality of life; and safety of tofacitinib use for treatment of chronic pouchitis. Study period is up to ten months, with five visits and three pouchoscopies. Adults with ulcerative colitis who have undergone total proctocolectomy and ileal pouch-anal anastomosis and have chronic pouchitis are eligible. Participants receive open-label 10 mg two times per day tofacitinib for 8 weeks. Clinical responders at the end of week 8 will be randomised to either tofacitinib or placebo in the maintenance phase. Non-responders will receive extended induction dosing for a further 8 weeks. Persistent non-responders exit the study and responders will proceed to maintenance randomisation. Randomised individuals will be followed for 24 weeks. Patients experiencing a flare of symptoms during the maintenance phase will be eligible to receive open-label tofacitinib. Efficacy and safety data will be evaluated at 12 weeks after termination from the study. Target sample size is 72 patients to be randomised into maintenance to achieve sufficient power. Data analysis is planned to commence in October 2026. Ethics approval was granted (Project ID 66809) and the trial was notified (CTN: CT-2020-CTN-04866-1; ANZCTR: 381128) prior to commencement. The study will be conducted in accordance with National Health and Medical Research Council (NHMRC) guidelines, and findings will be published in a peer-reviewed journal. CTN: CT-2020-CTN-04866-1.

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2026-07-10 | Impact of Diet and Body Mass Index on the Development of Pouchitis in the First Year After Ileal Pouch-Anal Anastomosis.

Although pouchitis is the most common complication after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC), the influence of diet on pouchitis is poorly understood. Thus, evidence-based dietary recommendations after IPAA are limited. We evaluated dietary intake in the period after the final stage of IPAA for UC and Body Mass Index (BMI) to identify potential associations with pouchitis. We used the Dietary Screener Questionnaire (DSQ) to assess dietary intake among patients in a prospective cohort enrolled within 2 weeks of the final stage of IPAA for UC. We compared food group and fiber intake of those who developed pouchitis within 12 months of the final stage of IPAA with those who did not. These were also compared to the United States Department of Agriculture (USDA) recommended daily goals. Among 89 patients, there was no significant difference in individual fiber intake when comparing those who developed pouchitis and those who did not. In comparison with USDA guidelines, both groups (pouchitis and no pouchitis) exhibited decreased intake of several food groups, such as fruits, vegetables, fiber, and dairy. Patients who developed pouchitis had a significantly higher median body mass index (BMI) at the time of surgery compared to patients who did not develop pouchitis (median 29.2 vs. 24.8, P = 0.022). In a prospective cohort, we identified no association between dietary intake and development of pouchitis within the first year after IPAA. However, elevated BMI may represent a unique target for intervention to prevent pouchitis occurrence.

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2026-07-01 | The efficacy and safety of hyoscyamine, dicyclomine, and desipramine in the treatment of irritable pouch syndrome-a retrospective cohort study.

Patients with ileal pouch-anal anastomosis (IPAA) frequently experience high bowel frequency and abdominal pain that are disproportionate to endoscopic inflammation, a condition often termed irritable pouch syndrome. Although antispasmodic agents and neuromodulators are widely used in irritable bowel syndrome, real-world data supporting their effectiveness and durability in patients with pouches remain limited. We performed a retrospective cohort study of IPAA patients followed at a pouch clinic between 2014 and 2025. Patients treated with hyoscyamine extended release (ER), dicyclomine, or desipramine for high bowel frequency or abdominal pain were included. Patients could receive multiple therapies sequentially over time. Clinical response was determined by physician-documented symptom improvement. Treatment persistence was assessed using electronic medical record prescription data. Among 219 eligible patients, 329 treatment courses were analyzed: 143 hyoscyamine ER, 80 dicyclomine, and 106 desipramine. In patients with high bowel frequency, 235 treatment courses resulted in clinical improvement in 68.5% of patients receiving hyoscyamine ER, 65.0% of those receiving dicyclomine, and 63.5% of those receiving desipramine. For abdominal pain (94 treatment courses), improvement for hyoscyamine ER, dicyclomine, and desipramine was observed in 61.5%, 68.3%, and 76.2% of courses, respectively. Approximately 60% of treatment courses persisted beyond one year. Long-term persistence (≥3 years) was highest with dicyclomine (48.7%), followed by desipramine (38.7%) and hyoscyamine ER (37.8%). Adverse events were infrequent and consistent with known safety profiles. Antispasmodic agents and low-dose neuromodulators are associated with meaningful symptom improvement in patients with irritable pouch syndrome, supporting their role as adjunctive therapies for pouch-related functional symptoms.

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antibodies

2026-07-01 | Risk Factors for Pouch Neoplasia in Patients with Inflammatory Bowel Disease: A Case-Control Study

Background Patients with inflammatory bowel disease (IBD) undergoing total proctocolectomy with ileal pouch-anal anastomosis remain at risk of pouch neoplasia. Prior studies, based on cohorts ending in the 2010s, identified prior colorectal dysplasia and carcinoma as independent risk factors. We aimed to reassess contributors from a contemporary, prospectively maintained registry. Methods Patients with ileal pouch and underlying IBD were identified from tertiary centers (2019- 2026) for a case-control study. Seventeen patients with pouch neoplasia were randomly matched 1:3 to 51 patients without pouch neoplasia. Pediatric patients (<18 years) and non-IBD pouches were excluded. Univariate and multivariable analyses were performed. Results Among 748 patients, 17 (2.3%) had pouch neoplasia, including 1 (5.9%) with anal intraepithelial neoplasia grade 1, 3 (17.6%) with low-grade dysplasia, 4 (23.5%) with high-grade dysplasia, and 10 (58.8%) with cancer. Five patients were diagnosed with anal squamous neoplasia, of whom 4 (80.0%) tested positive for anal human papillomavirus (HPV). On multivariable analysis, dysplasia and carcinoma in the colectomy specimen were identified as independent risk factors for pouch neoplasia (adjusted odds ratio [aOR] 6.2; 95% confidence interval [CI], 1.1 – 36.7; P = .047; and aOR 12.3; 95% CI, 2.5 – 60.8; P = .002, respectively). An older age at pouch construction, a longer duration from IBD diagnosis to pouch construction, and concurrent pouchitis were significantly associated with pouch neoplasia on univariate analysis but did not remain significant on the multivariable model. Conclusion The presence of dysplasia or carcinoma in the colectomy specimen remains the strongest risk factor for pouch neoplasia. An unusual prevalence of anal squamous neoplasia was observed, with a notable presence of HPV infection.

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2026-06-29 | TREATMENT STRATEGIES FOR POUCHITIS: STEP-UP VERSUS EARLY BIOLOGIC THERAPY

Research objectives: This systematic review aims to assess and summarize the available evidence comparing step-up strategies versus early biologic therapy for pouchitis. The goal is to clarify their relative effectiveness, safety profiles, and impact on clinical outcomes to inform evidence-based treatment algorithms and identify gaps for future research. Methods: A systematic review was conducted using PubMed, Google Scholar, and ResearchGate. Eligible studies included clinical trials, observational studies, systematic reviews, meta-analyses, and international guidelines published after 1990. Search terms combined RPC-IPAA, acute pouchitis, chronic pouchitis, step-up therapy, biologic therapy, antibiotics, immunosuppressants, and advanced therapies. Key findings: Most patients with acute pouchitis treated with antibiotics achieved a short-term clinical response, although relapses and progression to chronic disease were common. Chronic combination antibiotic therapy maintained remission in approximately three-quarters of patients but was associated with bacterial resistance and adverse events. Biologic agents achieved response rates of approximately 60%, while remission remained ≤50%. Vedolizumab and ustekinumab showed higher long-term tolerability and treatment persistence than TNF inhibitors. Evidence of early biologic therapy was limited, and no clear association between early initiation and clinical outcomes was identified. Conclusions: Step-up antibiotic therapy remains justified as the first-line treatment for pouchitis due to its high short-term efficacy. Biologic agents represent a valuable option for chronic or refractory disease but do not appear to be superior to antibiotics as initial treatment. Current evidence does not support routine early biologic therapy for all patients, although selected high-risk groups may benefit. Future prospective studies are needed to define optimal timing of biologic therapy.

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2026-06-15 | Demographic Analysis of Patients With Ulcerative Colitis Undergoing Restorative Proctocolectomy With Ileal Pouch-Anal Anastomosis: A Single-Center Retrospective Study

Introduction: Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease limited to the colonic mucosa, with rising incidence and prevalence in many regions of the world, including Latin America. A subset of patients requires colectomy for medically refractory disease, acute severe colitis, dysplasia, or malignancy, for whom restorative proctocolectomy with ileal pouch-anal anastomosis (RPC-IPAA) is the preferred restorative procedure. Pouch-related complications -- including pouchitis, chronic antibiotic-refractory pouchitis (CARP), pouch failure, and diagnostic reclassification to Crohn's disease -- represent major clinical challenges; however, published institutional data on RPC-IPAA outcomes from hospital centers in Mexico and Latin America remain exceptionally scarce. This descriptive single-center study aimed to describe the demographic profile, operative characteristics, and predefined pouch-related complications in patients with UC who underwent RPC-IPAA at a tertiary referral center in Mexico. Methods: A retrospective observational study was conducted at the Inflammatory Bowel Disease Clinic of the Coloproctology Service, Hospital General de México "Dr. Eduardo Liceaga," reviewing medical records of UC patients who underwent RPC-IPAA between 2010 and 2022. Demographic and clinical variables were analyzed using IBM SPSS Statistics, version 29 (IBM Corp., Armonk, NY). Quantitative variables were summarized as mean ± SD and categorical variables as frequencies and percentages. Pouchitis was diagnosed using the Pouchitis Disease Activity Index (PDAI ≥7). CARP was defined as active pouchitis (PDAI ≥7) persisting despite at least four consecutive weeks of antibiotic therapy and failure of at least two sequential antibiotic regimens. Postoperative follow-up was calculated from the date of pouch creation to the last clinical encounter. Results: Fourteen patients were included; 8 (57.1%) were women. Mean age was 34.86 ± 7.94 years. All patients had Montreal E3 pancolitis. The mean interval between UC diagnosis and pouch creation was 3.86 ± 1.81 years. The median postoperative follow-up was 6.2 years (IQR: 3.4-9.1 years; range: 0.5-12.0 years). J-pouch construction was performed in 13 (92.9%) patients and D-pouch in 1 (7.1%). One (7.1%) patient experienced pouch failure and underwent W-pouch reconstruction. One (7.1%) patient originally diagnosed with UC E3 was subsequently reclassified as Crohn's disease (Montreal A2L4B2) and is currently receiving anti-interleukin-12/23 therapy (ustekinumab). Pouchitis occurred in 4 (28.6%) patients; all developed CARP and are currently being treated with anti-integrin therapy (vedolizumab). Conclusions: In this descriptive single-center study, RPC-IPAA was predominantly performed with J-pouch construction, achieving durable pouch preservation over a median follow-up of 6.2 years. Pouch-related complications -- including CARP, pouch failure, and diagnostic reclassification to Crohn's disease -- emerged as important sources of morbidity requiring escalation to advanced biologic therapy and, in selected cases, surgical reintervention. These findings underscore that successful pouch surgery depends on structured individualized surveillance, dedicated multidisciplinary care, and timely access to biologic therapies throughout the postoperative course.

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2026-06-01 | Vedolizumab dose intensification: Is there an endoscopic benefit?

Aims Vedolizumab is an established treatment for inflammatory bowel disease (IBD). Loss of response is occasionally encountered. Data regarding dose intensification are limited 1 . Aim of the study was to evaluate the effectiveness of interval shortening for intravenous vedolizumab (300mg/4 weeks). Methods Data were collected retrospectively from patients’ medical records, in two Greek tertiary centers. All patients received IV vedolizumab every 4 weeks. Endoscopic and biochemical response was evaluated at 12 months. The intervention was considered successful if treatment was maintained, whereas failure was defined as the need to either switch or operate. Results Twenty-one patients [14 (66.7%) men, median age 53 years (range: 25-85 years)] were included. 15 (71.4%) with ulcerative colitis (UC), 4 (19.1%) with Crohn's (CD) and 2 (9.5%) with pouchitis. UC patients: 10 (66.6%) with left-sided colitis (E2) and 5 (33.3%) with extensive disease (E3). All CD patients had ileocolitis (L3), whereas two (50%) had stenotic phenotype and two (50%) perianal involvement. Previous treatments: 5-ASA and corticosteroids (95.2%), immunosuppressants (38.1%) and biologics (57.1%). Vedolizumab was offered as 1 st , 2 nd and 3 rd line treatment in 9, 3 and 9 patients, respectively. Dose intensification was employed after a median duration of 33 months for UC (IQR: 41) and 19.5 months for CD (IQR: 35) (p=0.41). The intensified scheme was applied for a median of 9 months in CD {IQR: 24.5, range 3–48} and 7.5 months in UC {IQR 10, range 3-58, (p=0.98)}. Endoscopic Mayo score decreased from 2.35 to 0.88 and the effect was significant (p=0.001, r=0.79). The mean CRP value decreased significantly from 1.42 to 0.44 (p=0.007). Intensification was successful in fourteen (66.7%) cases (11 UC, 2 CD and one pouchitis). Seven patients failed and switched to another biologic. None underwent surgery. No treatment-related adverse events were observed. Conclusions Vedolizumab intensification scheme was successfully maintained for the majority of IBD patients, beyond six months. The endoscopic and biochemical responses were both significant. Publication History Article published online: 05 June 2026 © 2026. European Society of Gastrointestinal Endoscopy. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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2026-05-21 | Overlapping Cytomegalovirus Infection and Inflammatory Pouchitis After Liver Transplantation: When Antivirals Alone Are Insufficient.

Cytomegalovirus (CMV) is an infrequently reported etiology of secondary pouchitis in patients who have undergone total proctocolectomy with ileal pouch-anal anastomosis. We present the case of a patient with chronic antibiotic-dependent pouchitis, ulcerative pancolitis, primary sclerosing cholangitis, and orthotopic liver transplant who presented with hematochezia. Pouchoscopy showed ulcerated mucosa, and histopathology with immunohistochemistry confirmed CMV pouchitis. The patient was treated with antiviral therapy with improvement in bleeding and viremia. However, persistent refractory pouch inflammation ultimately required guselkumab. This case depicts the importance of considering CMV as a secondary etiology of pouchitis, especially in those with refractory or atypical features.

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cell therapies

2026-06-03 | The effect of fecal microbiota transplantation on quality of life in patients with chronic pouchitis: a post hoc analysis of the MicroPouch trial.

During surgical treatment for ulcerative colitis, an ileal pouch-anal anastomosis is often constructed. Pouchitis, the most common complication after this surgery, substantially reduces patients' quality of life (QoL). In chronic pouchitis, antibiotic treatment often proves ineffective. Fecal microbiota transplantation (FMT) has emerged as a potential treatment for chronic pouchitis. To determine the effect of FMT on QoL in patients with chronic pouchitis. An exploratory post hoc analysis of data from the MicroPouch trial. A double-blinded, placebo-controlled study comprising a 4-week intervention period and 12-month follow-up. Thirty patients with chronic pouchitis were randomized 1:1 to receive either FMT or placebo. Treatment was administered by enema once daily for 2 weeks, then every other day for the following 2 weeks. QoL was assessed using three questionnaires-the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), the Pouch Dysfunction Score (PDS), and the 36-item Short Form Questionnaire (SF-36)-at baseline and at subsequent follow-ups. At the 30-day follow-up, FMT-treated patients showed a significant decrease in QoL from baseline, measured by the SIBDQ (p = 0.03). Within the FMT group, the PDS did not change significantly from baseline to day 30 (p = 0.36). The placebo group reported higher SF-36 QoL scores at both baseline and day 30 (p = 0.02), although neither group showed significant within-group changes over time. In patients with chronic pouchitis, FMT may temporarily worsen symptoms and reduce QoL, as indicated by three QoL questionnaires showing no improvement or poorer outcomes versus placebo. Trial registration: The study is registered at ClinicalTrials.gov (Trial number NCT04100291), date: 12 September 2019.

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2026-01-01 | P0795 Efficacy of Granulocyte and Monocyte Apheresis (GMA) for Pouchitis Following Colectomy in Ulcerative Colitis Patients” Abstract

Abstract Background Despite advances in biologic therapies since the early 2000s, surgery remains necessary for refractory ulcerative colitis (UC) and UC-associated neoplasia (UCAN). After colectomy with ileal pouch–anal anastomosis (IPAA), pouchitis is a common complication. Its pathogenesis involves altered microbiota and immune dysregulation, with neutrophil infiltration in acute cases and lymphocyte/plasma cell infiltration in chronic cases. Antibiotics are first-line therapy, but refractory cases require alternative approaches.This study aimed to evaluate the efficacy and safety of leukocyte apheresis (GMA: granulocyte and monocyte apheresis) in patients who developed pouchitis after colectomy for UC. Methods Between June 2020 and August 2025, 22 patients with UC who developed pouchitis after IPAA and underwent GMA were retrospectively analyzed. The primary endpoint was remission induction rate. Secondary endpoints included comparison of background factors between remission and non-remission groups (sex, age, acute vs. chronic pouchitis, time to onset, ciprofloxacin resistance, prior GMA use, drug allergies, baseline modified Pouchitis Disease Activity Index [mPDAI], hemoglobin, albumin, C-reactive protein levels), improvement in urgency, and adverse events. Results The remission induction rate following GMA was 82%, and improvement in urgency was observed in 91% of cases. Comparison between remission and non-remission groups revealed a significant difference in the presence of extraintestinal complications. Adverse events were minimal: one patient experienced fever and headache, while no other serious events were reported.Although the etiology of pouchitis is multifactorial, histological findings suggest that neutrophil-dominated leukocyte infiltration plays a pivotal role, particularly in the acute phase. The favorable outcomes observed in this study indicate that GMA may exert therapeutic benefit by removing activated inflammatory leukocytes, thereby attenuating mucosal inflammation. Given the high remission and symptom improvement rates, GMA may represent a promising treatment option, especially in patients with antibiotic-refractory pouchitis. The low incidence of adverse events further supports its clinical applicability. Future studies with larger cohorts and prospective designs are warranted to confirm these findings and to clarify the role of GMA in combination with antibiotics or biologic agents. Conclusion Leukocyte apheresis appears to be an effective and safe therapeutic option for pouchitis following colectomy in UC patients. These results suggest that GMA could serve as a valuable adjunctive treatment in the management of postoperative pouchitis, particularly in refractory cases. Conflict of interest: Dr. Ito, Ayumi: No conflict of interest Miki, Koroku: No conflict of interest Yonezawa, Maria: No conflict of interest Nakamura, Shinichi: No conflict of interest Nakai, Yousuke: No conflict of interest

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2025-11-01 | Comment on: Analysis of preoperative predictors for pouchitis after surgery for ulcerative colitis: A multicentre retrospective study of the clinical outcome of surgery for ulcerative colitis in Japan ( COSUC study)

Pouchitis was defined based on clinical and endoscopic criteria, excluding secondary causes such as Crohn's disease or infection. However, the lack of a standardized pouchitis disease activity index (PDAI) may have led to underestimation or inter-centre variability in diagnosis. Prospective validation with uniform diagnostic scoring and inclusion of histologic grading could address this concern [5]. From a translational perspective, the identification of preoperative corticosteroid use as an independent risk factor underscores the need for optimized immunosuppressive tapering before colectomy. Future multicentre trials should consider incorporating steroid-sparing regimens and microbiome-modulating interventions, such as targeted probiotic or FMT therapy, to mitigate postoperative inflammation. Moreover, integrating artificial intelligence-driven prediction tools, which can incorporate nonlinear interactions among variables, may improve predictive performance and clinical usability [6]. Kasashima et al. have provided a valuable contribution by establishing a foundational risk model for pouchitis following IPAA in UC patients. Despite inherent limitations of retrospective design and moderate model discrimination, the study represents an essential step towards individualized perioperative risk stratification. Further prospective and multiethnic validation incorporating biological and microbiome factors will be instrumental in advancing precision surgical care for ulcerative colitis. I congratulate the authors for their important work and hope these comments may contribute constructively to ongoing dialogue and future research in this field. Yanqi Cheng: Writing – original draft. Dongmei Luo: Writing – original draft. Ying Sun: Writing – review and editing. No funding was received to assist with the preparation of this manuscript. All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This study is a commentary article that did not involve human participants, animals or patient data. Therefore, ethical approval and informed consent were not required. The authors declare that all ethical principles have been observed in the preparation of this manuscript. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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2025-05-25 | Fecal microbiota transplantation from a healthy pouch donor for chronic pouchitis: a proof-of-concept study.

Chronic pouchitis is a common complication after ileal pouch-anal anastomosis (IPAA) with limited treatment options. In this case series, we aimed to investigate clinical and microbiome changes, as well as adverse events, associated with using fecal microbiota transplantation (FMT) from a donor with a normal functioning IPAA to induce remission in patients with chronic pouchitis. Methods The study was a case-series including a 4-week intervention period and 12-month follow-up. Patients with chronic pouchitis who met the inclusion criteria were recruited from the Department of Gastrointestinal Surgery at Aalborg University Hospital, Denmark. Participants received FMT derived from a donor with a normal functioning IPAA. Treatment was administered by enema daily for two weeks, then every other day for two more weeks. Disease severity and quality of life (QoL) were accessed at baseline and 30-day follow-up. Clinical remission was defined as Pouchitis Disease Activity Index (PDAI) <7. Fecal samples from participants, healthy donors, and the IPAA donor were analyzed using shotgun metagenomic sequencing. Results Three patients with chronic pouchitis were included and completed the treatment protocol and follow-up visits. At the 30-day follow-up, all participants achieved clinical remission with reduced endoscopic inflammation. The median total PDAI score decreased from 8 (range 10-8) at baseline to 6 (range 6-5) at 30 days. Two participants reported improved QoL, while one reported no change. Few mild, self-limited adverse events were reported by all participants during treatment, with no serious events. Principal component analysis of fecal samples distinguished two clusters: healthy donors and the IPAA donor, with participant samples forming a separate cluster Conclusion We observed that all participants achieved clinical remission with reduced endoscopic inflammation following a 4-week FMT intervention. Adverse events were mild and self-limited. Metagenomic analysis revealed distinct microbiome clusters between IPAA donor and recipients, both of which differed from those of healthy donors.

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2025-05-11 | Optimizing Therapeutic Potential of Fecal Transplant in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract influenced by genetic, environmental, immune, and microbial factors. Reduced gut microbial diversity and elevated proinflammatory bacteria levels in IBD disrupt mucosal immunity, barrier function, and inflammatory pathways. Fecal microbiota transplantation (FMT) is a potential therapy to restore microbial balance. Studies suggest that FMT may induce remission in mild-to-moderate ulcerative colitis but show limited efficacy in Crohn's disease and pouchitis. Donor microbiota colonization correlates with remission, but varied study designs challenge findings. Further research is required to standardize FMT protocols, optimize donor selection, and ensure long-term safety.

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proteins

2026-07-01 | Patients with Ileal Pouch-Anal Anastomosis Have Decreased Bowel Frequency on Glucagon-like Peptide-1 Receptor Agonist Therapy.

High bowel frequency after ileal pouch-anal anastomosis (IPAA) causes significant symptom burden. We aimed to evaluate the impact of GLP-1 receptor agonists (GLP1RAs) in this setting. We conducted a retrospective cohort study of patients with prior IPAA for ulcerative colitis who were treated with a GLP1RA (n=20). Daily bowel frequency at baseline and 12 weeks after GLP1RA initiation was assessed. We also assessed the proportion of patients achieving ≥30% reduction in bowel frequency and ≤8 bowel movements per day. Median daily bowel frequency decreased from 9.0 (IQR, 6.0-12.5) at baseline to 6.0 (IQR, 5.0-8.1) at the 12-week follow-up (p<0.01). Overall, 7 of 20 patients achieved a ≥30% reduction in bowel frequency, and 15 of 20 had ≤8 bowel movements per day. In this retrospective cohort, we provide further evidence for the potential role of GLP1RAs in the management of high bowel frequency after IPAA.

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2025-12-10 | Real-World Outcomes of Glucagon-Like Peptide-1 Receptor Agonist Therapy in Obese Patients With Ulcerative Colitis and IPAA With a History of Pouchitis.

There are limited data on the impact of glucagon-like peptide-1 receptor agonist (GLP-1RA) on the risk of recurrent pouchitis after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). A retrospective cohort study was conducted in the TriNetX Research Network in adult patients with obesity and IPAA for UC with a history of pouchitis in whom a GLP-1RA was initiated compared to those patients in whom a GLP-1RA was not initiated. The primary outcome was the risk of recurrent pouchitis within 12 months. The secondary outcomes were mean number of antibiotic prescriptions, anti-diarrheal medication use, Crohns-like disease of pouch (CLDP), and pouch excision. One-to-one propensity score matching was performed. We identified 43 UC-IPAA patients with obesity and history of pouchitis (mean age 51.7 ± 14.7 years, mean body mass index [BMI] 34.4 ± 6 kg/m2, 60.4% female). After propensity score matching, the GLP-1RA cohort had a significantly decreased risk of recurrent pouchitis (26.3% vs 52.6%; adjusted odds ratio [aOR], 0.32; 95% CI, 0.12-0.84) compared to the control cohort. Mean antibiotic prescriptions were numerically lower in the GLP-1RA cohort (2 vs 4.4, P = .16). Anti-diarrheal medication use was lower in the GLP-1RA cohort (18.4% vs 47.3%; aOR, 0.23; 95% CI, 0.07-0.67). There was no difference in the risk of CLDP. Zero patients required pouch excision in both cohorts. Our study in a small cohort of patients with UC-IPAA and obesity with a history of pouchitis showed that GLP-1RA use was associated with decreased risk of recurrent pouchitis and anti-diarrheal medication use.

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2025-10-01 | S1565 Glucagon-Like Peptide-1 Receptor Agonist Therapy Is Associated With Decreased Risk of Recurrent Pouchitis in Obese Patients With Ulcerative Colitis and IPAA: A Propensity-Matched Cohort Study

Introduction: Obesity is associated with increased pouchitis risk, potentially contributing to chronic intestinal inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) promote weight loss, improve glycemic control, and exhibit anti-inflammatory properties beneficial in inflammatory bowel disease (IBD). However, their role in recurrent pouchitis remains unclear. Methods: We conducted a retrospective cohort study using the TriNetX database to evaluate the risk of recurrent pouchitis in a cohort of patients with obesity and ileal pouch-anal anastomosis (IPAA) with pouchitis history who initiated GLP-1RA compared to those who did not. The primary outcome was risk of repeat antibiotic use (ciprofloxacin and/or metronidazole) after 30 days and within 1 year. Validated case definitions of IPAA and recurrent pouchitis were used. Patients with advanced therapy (AT) use before the index event and after IPAA were excluded. Secondary outcomes included number of antibiotic prescriptions, AT use, anti-diarrheal use, Crohn’s like disease of pouch (CLDP), pouch excision and healthcare utilization. 1:1 propensity score matching was performed. Results: The GLP-1RA cohort included 43 patients (mean age 51.2 ± 14.7; BMI 35.1 ± 6.4 kg/m2; 62.8% women; 72% White; 44.1% T2DM), matched to 509 control patients. 53.4% had pouchitis and 34.8% had ≥2 episodes in the preceding 1 year in the GLP-1RA cohort. GLP-1RA cohort had a significantly decreased risk of recurrent pouchitis (26.3% vs 52.6%; aHR 0.45, 95% CI 0.21-0.96; log rank P = 0.03) compared to the control cohort. Mean antibiotic prescriptions were numerically lower in the GLP-1RA cohort but not statistically significant (2 vs 4.4, P = 0.16). There was no difference in the risk of AT use or CLDP and no patients required pouch excision. Sensitivity analysis excluding antibiotic prescriptions within 1 and 3 months in the control cohort also showed a decreased risk of recurrent pouchitis in the GLP-1RA cohort. Anti-diarrheal use was lower in the GLP1-RA cohort. Within the GLP-1RA cohort, body mass index (BMI) significantly decreased by 3.2 kg/m² within 12 months (95% CI −5.8 to −0.50; P = 0.03). The mean weight loss was 16 lbs (-39.5 to -6.5). Rates of serious adverse events were low in the GLP-1RA cohort. Conclusion: In patients with obesity and IPAA with history of pouchitis, GLP-1RA use was associated with decrease in pouchitis recurrence, BMI, and body weight, suggesting beneficial effects on pouch inflammation.

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2023-11-22 | Pouchitis Is Associated with Paneth Cell Dysfunction and Ameliorated by Exogenous Lysosome in a Rat Model Undergoing Ileal Pouch Anal Anastomosis

Pouchitis is a common complication of restorative proctocolectomy and ileal pouch anal anastomosis (IPAA) for ulcerative colitis (UC), significantly affecting the postoperative quality of life. Paneth cells play an important role in the maintenance of gut homeostasis. This study aimed to investigate the role of Paneth cells in the pathogenesis of pouchitis.Endoscopic biopsies from the pouch body and terminal ileum of UC patients undergoing IPAA with or without pouchitis were obtained to analyze Paneth cell function. Acute pouchitis was induced with 5% dextran sulfate sodium (DSS) for seven consecutive days in a rat model of IPAA. The Paneth cell morphology was examined by immunofluorescence and electron microscopy. The effect of exogenous lysozyme supplementation on pouchitis was also investigated. The fecal microbiota profile after DSS and lysozyme treatment was determined by 16s rRNA ITS2 sequence analysis.Abnormal mucosal lysozyme expression was observed in patients with pouchitis. The rat model of pouchitis showed increased pouch inflammation, increased CD3+ and CD45+ T cell infiltration, and decreased tight junction proteins, including ZO-1 and Occludin. There is a significant deficiency of Paneth cell-derived lysozyme granules in the rat model of pouchitis. Supplementation with exogenous lysozyme significantly ameliorated pouchitis, lowering the levels of inflammatory cytokines such as TNF-α and IL-6 in the pouch tissue. 16s rRNA analysis revealed a higher Lachnospiraceae level after lysosome treatment.Paneth cell dysfunction is prominent in patients and rat models of pouchitis and may be one of its causes. The decrease in Lachnospiraceae, a characteristic of dysbiosis in pouchitis, could be reserved by lysosome treatment. Lysozyme supplementation shows promise as a novel treatment strategy for pouchitis.

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2023-01-30 | P584 Efficacy, safety, and tolerability of AMT-101, a gut selective oral IL-10 fusion, in the Phase 2 FILLMORE trial of patients with chronic pouchitis

Abstract Background Chronic pouchitis can occur in up to half of patients within 10 years of ileal pouch-anal anastomosis (IPAA) after proctocolectomy for ulcerative colitis (UC). There is a large unmet need for medical treatments. Methods This was a phase 2, randomized double-blind, parallel-group, 2 active-arm trial of the combined phase 2/3 trial in adults (18-75 years) with a prior history of UC with proctocolectomy and subsequent IPAA, who presented with chronic or recurrent pouchitis. The trial was conducted in US, Canada, and Western Europe. Approximately 20 patients were planned to be randomized 1:1 to either 3 mg or 10 mg AMT-101 doses administered once daily, orally, for 12 weeks. The key efficacy endpoints were: 1) the proportion of patients with symptomatic improvement, as measured by stool frequency response, and 2) the proportion of patients with histologic healing, as measured by Geboes scores. Histology and endoscopy were centrally read. Results 22 patients were randomized to receive AMT-101 3 mg (n=10) or 10 mg (n=12). The mean (SD) baseline absolute stool frequency was 13.4 (4.5). Overall, 36.4% (8/22) of patients achieved stool frequency response, defined as either a reduction of ≥ 3 stools and a ≥ 30% reduction in number of stools from baseline, or a return to post-IPAA number of stools or lower, at Week 12. 40% (4/10) and 33% (4/12) of patients dosed with 3 mg or 10 mg, respectively, achieved stool frequency response at Week 12. Rapidity of stool frequency response was demonstrated as early as Week 2 in both arms and was substantially maintained through Week 12. Patients had a median (IQR) baseline Geboes score of 5.1 (3.2 to 5.2), representing severe pouchitis with ulceration and tissue destruction. Across both arms, 22.7% (5/22) [20.0% (3 mg) and 25.0% (10 mg)] of patients met the histologic healing response of Geboes score ≤ 3.1, an objective assessment of disease improvement. Endoscopic assessments (SES-CD, ≥50% reduction) were also performed, with modest improvements [10% (3 mg) and 8.3% (10 mg)] at Week 12. There was no systemic AMT-101 PK (by design) nor anti-drug antibodies detected. Translational analysis revealed IL-10 biological responses in both arms. In tissue, IHC results showed increases in anti-inflammatory FOXP3+ (Tregs) and CD163+ (M2-macrophages) cells in the lamina propria. Treatment emergent adverse events were mostly mild to moderate, with only one treatment-unrelated serious adverse event. Conclusion AMT-101 3 mg and 10 mg both appeared to be safe and generally well tolerated. PK and translational data confirmed AMT-101’s gut-restricted profile over the 12-week treatment with tissue-level PD effects and no systemic exposure. The AMT-101 3 mg dose is advancing into a Phase 3 trial for chronic pouchitis.

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2025-03-18 | High Smad7 marks inflammation in patients with chronic pouchitis.

Patients with ulcerative colitis (UC) undergoing colectomy with ileal-anal pouch anastomosis can develop chronic pouchitis (CP). Since treatment options are very limited for patients with CP, identification of factors/mechanisms that amplify the CP-associated inflammatory response could help develop novel treatments. We here assessed the expression of Smad7, an inhibitor of TGF-β1 signaling and positive regulator of gut inflammation, in CP. Mucosal samples were taken from the inflamed pouch of patients with CP, whose activity was evaluated by the modified Pouchitis Disease Activity Index (mPDAI). Controls included mucosal biopsy samples taken from the uninflamed pouch of patients with a history of CP and ileal samples taken from normal/inflamed pre-pouch of patients with CP and normal controls. Smad7 expression was assessed by Western blotting and immunofluorescence, and the Smad7-expressing lamina propria mononuclear cells (LPMCs) were evaluated by flow cytometry. Mucosal samples taken from the inflamed pouch of CP patients were cultured with a Smad7 antisense (AS) or sense oligonucleotide and TNF-α and interleukin (IL)-8 were evaluated by real-time PCR and ELISA. Enhanced Smad7 expression was seen in the inflamed pouch of patients with CP compared to the normal or inflamed ileum of the same patients and the uninflamed pouch of patients with no pouchitis and normal controls. In the inflamed mucosa of patients with CP, Smad7 was more abundant in LPMCs, mainly in T lymphocytes. Knockdown of Smad7 in ex vivo mucosal explants taken from CP patients was associated with a reduction in TNF-α and IL-8 expression. High Smad7 occurs in the inflamed mucosa of patients with CP, further supporting the pathogenic role of Smad7 in the gut.

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2019-04-24 | Oligonucleotides—A Novel Promising Therapeutic Option for IBD

Inflammatory Bowel Diseases (IBD), whose denomination comprehends Crohn's Disease (CD) and Ulcerative Colitis (UC), are intestinal chronic diseases that often require lifelong medical therapy. In the last two decades monoclonal antibodies against the cytokine TNF have become integral parts in the treatment of IBD patients, however there are unwanted side-effects and one third of patients show primary non-response while another subgroup loses response over time. Finding novel drugs which could act as therapies against precise pro-inflammatory molecular targets to avoid unwanted systemic side effects and additionally the process of immunization, represents an important aim for subsequent therapeutic approaches. Oligonucleotide based therapies represent a promising novel concept for the treatment of IBD. The molecular action of oligonucleotides ranges from inhibition of the translational process of mRNA transcripts of pro-inflammatory molecules, to mimicking bacterial DNA which can activate cellular targets for immunomodulation. Alicaforsen, selectively targets ICAM-1 mRNA. ICAM-1 is an adhesion molecule which is upregulated on endothelial cells during IBD, thereby mediating the adhesion and migration of leucocytes from blood to sites of active inflammation. In CD parenteral application of alicaforsen did not show therapeutic efficacy in phase II trials, but it demonstrated an improved efficacy as a topical enema in distal UC. Topical application of alicaforsen might represent a therapeutic perspective for refractory pouchitis as well. SMAD7 is a protein that inhibits the signaling of TGFβ, which is the mainstay of a regulatory counterpart in cellular immune responses. An antisense oligonucleotide against SMAD7 mRNA (mongersen) demonstrated pre-clinical and phase II efficacy in CD, but a phase III clinical trial was stopped due to lack of efficacy. Cobitolimod is a single strand oligonucleotide, which mimics bacterial DNA as its CpG dinucleotide sequences can be recognized by the Toll-like receptor 9 on different immune cells thereby causing induction of different cytokines, for example IL10 and IFNα. Topical application of cobitolimod was studied in UC patients. We will also discuss two other novel oligonucleotides which act on the GATA3 transcription factor (SB012) and on carbohydrate sulfotransferase 15 (STNM01), which could both represent novel promising therapeutic options for the treatment of UC.

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2018-07-04 | Inflammatory bowel disease: new therapies from antisense oligonucleotides

Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract encompassing two main clinical entities: Crohn's disease (CD) and ulcerative colitis (UC). These disorders are characterized by various grades of tissue damage and development of local complications and extra-intestinal manifestations. The cause of IBD remains unknown but accumulating evidence indicates that both CD and UC arise in genetically predisposed individuals as a result of the action of multiple environmental factors, which ultimately trigger excessive and poorly controlled immune response against antigens of the luminal flora. Despite this realization, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. However, in recent years, several pathways of intestinal damage have been delineated and the improved knowledge has contributed to the development of new therapies. Various approaches have been used to either inhibit the expression and/or function of inflammatory molecules or enhance counter-regulatory mechanisms. This review summarizes the available pre-clinical and clinical data for antisense oligonucleotides and oligonucleotide-based therapy to provide a comprehensive understanding of the rationale and mechanism of action of these compounds in IBD. Key messages Preclinical studies and clinical trials show that antisense oligonucleotide (ASO)-based therapy could be of benefit in inflammatory bowel diseases. ASOs have an excellent safety profile. Technical issues emerged from clinical trials suggest that changes in drug formulation and/or route of administration could improve ASO efficacy.

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2017-11-01 | Alicaforsen in the treatment of pouchitis

Alicaforsen is a 20-base antisense oligonucleotide inhibiting ICAM-1 production, which is an important adhesion molecule involved in leukocyte migration and trafficking to the site of inflammation. Hitherto, alicaforsen has been granted orphan drug designation and is prescribed as an unlicensed medicine in accordance with international regulation for the treatment of pouchitis and left-sided ulcerative colitis. Given the positive results evolving from one open-label trial and one case series in patients with chronic refractory pouchitis, US FDA has agreed to a rolling submission for a license application for the treatment of pouchitis, which has been recently initiated. Whether alicaforsen leads to higher endoscopic and clinical remission rates as placebo and whether the response can be maintained in the long-term in larger studies is yet unknown. An ongoing multicenter international Phase III trial will definitely address these unanswered questions.

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2017-07-03 | 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.

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