Multimodal profiling of inflammatory bowel disease (IBD) patient tissue and blood samples has revealed the disease spectrum in unprecedented detail, and cellular and molecular correlates of disease severity and outcome in IBD have been elaborated. Incorporating these in the clinical setting would offer a unique opportunity to increase the granularity of current clinical measures and to better assess treatment response. Remission and healing at a cellular/molecular level are also likely to have predictive value for long-term outcomes. Here, we outline a path forward to implementing the most promising molecular disease descriptors as future clinical treatment targets in IBD. We focus on the concept of cellular/molecular measures of inflammation, remission, healing, response to therapy, and target pathway engagement. Monitoring mode-of-action-specific pharmacodynamic modules in the context of disease-related resolution pathways will guide assessment of novel and existing therapies. Artificial intelligence-assisted tools will be key to enabling this development, improving reproducibility, limiting costs, and delivering fast detection.

BACKGROUND AND AIMS:Restoration of intestinal barrier integrity and function in inflammatory bowel disease (IBD) has been associated not only with a reduced burden of persistent symptoms but also with improved long-term outcomes, prompting growing interest in intestinal barrier healing as a potential new therapeutic target. To date, no clinical trials have specifically evaluated therapies aimed at restoring intestinal barrier function in IBD, and there is currently no consensus on how such trials should be designed or how the intestinal barrier should be assessed. The aim of this initiative was to develop consensus recommendations on the optimal design of clinical trials and the selection of tools to evaluate therapies targeting the intestinal barrier in IBD. METHODS:A panel of 12 international specialists with recognised expertise in the intestinal barrier and/or IBD clinical trials evaluated statements developed from a systematic literature review. Statements were discussed and anonymously voted on using a modified Delphi methodology. Consensus was predefined as at least 75% agreement among participants. The study was conducted and reported in accordance with the Conducting and REporting of DElphi Studies framework. RESULTS:Fourteen statements reached consensus and were approved. These statements addressed key aspects of clinical trial design, including the role of intestinal barrier assessment as an endpoint, timing of reassessment, protocol requirements and disease-specific considerations. Additional statements focused on the selection and standardisation of tools for intestinal barrier assessment, encompassing imaging-based techniques, functional permeability assays and endogenous biomarkers, as well as considerations for implementation and future research directions. CONCLUSIONS:This international consensus provides a structured framework to guide the design of future clinical trials evaluating efficacies of therapies in restoring intestinal barrier integrity and/or function in IBD.

The intestinal epithelium is a key component of the intestinal barrier, which is the largest and most complex barrier of the human body, regulating nutrient absorption while restricting the entry of harmful antigens. Breakdown of this barrier facilitates microbial and dietary antigenic translocation, triggering local immune system activation and inflammation. Although barrier alteration alone may not be sufficient to initiate disease, accumulating evidence highlights its critical role in the pathogenesis and progression of a wide range of gastrointestinal and systemic disorders. Early identification of intestinal epithelium and barrier alterations could enable timely therapeutic approaches. This systematic review provides an overview of current in vivo (both noninvasive and invasive) and ex vivo/in vitro approaches used to assess intestinal epithelial barrier alterations. Noninvasive in vivo approaches rely mainly on urinary detection of orally ingested probes, but their clinical utility is limited by lack of standardization and specificity. Circulating and fecal constitutive markers derived from the intestinal barrier, which reflect epithelial alterations, together with indicators of microbial translocation, provide complementary insights but remain insufficiently validated. Advanced invasive endoscopic modalities such as confocal laser endomicroscopy enable near-histological, real-time visualization but are costly and largely used as research tools in specialist centers. In vitro, transepithelial electrical resistance assessment remains the reference standard, though novel technologies (including impedance spectroscopy and organic electrochemical transistors) offer enhanced sensitivity and resolution. Despite progress, major gaps remain, including the absence of a standardized definition of epithelial barrier breakdown, the lack of a practical diagnostic tool, methodological heterogeneity, unvalidated thresholds, and limited prospective validation.

BACKGROUND:Neutralizing autoantibodies against interleukin-10 can result in a phenocopy of monogenic defects of interleukin-10 signaling in children and may be associated with inflammatory bowel disease (IBD). The allele HLA-DRB1*01:03 is the strongest genetic risk factor for ulcerative colitis. METHODS:We used a cellular interleukin-10 reporter assay and a confirmatory competitive enzyme-linked immunosorbent assay to assess neutralizing interleukin-10 autoantibodies in serum samples obtained from patients with IBD in the Oxford and U.K. IBD BioResource cohorts and from persons without IBD (controls). An in vitro cytokine-release bioassay was performed in a subgroup of patients to assess interleukin-10, interleukin-23, interleukin-1β, tumor necrosis factor, and interleukin-6. We performed HLA association analysis using imputation and high-resolution sequencing. RESULTS:Interleukin-10-neutralizing autoantibodies were detected in 173 of 4909 patients with IBD (3.5%; 95% confidence interval [CI], 3.0 to 4.1) and in none of 1006 controls (P<0.001). High anti-interleukin-10 activity in serum was associated with a reduction in detectable interleukin-10 and with an exaggerated proinflammatory cytokine response, consistent with functional neutralization of interleukin-10 signaling. Anti-interleukin-10 seropositivity was strongly associated with HLA-DRB1*01:03 on the basis of imputed data from the Oxford cohort (odds ratio, 50.0; 95% CI, 16.4 to 152.3; P = 6.14×10-12) and the U.K. IBD BioResource cohort (odds ratio, 24.7; 95% CI, 14.5 to 42.1; P = 6.20×10-32) and in a high-resolution sequencing analysis of data from the Oxford cohort (odds ratio, 29.5; 95% CI, 12.2 to 71.1; P = 4.85×10-14). CONCLUSIONS:Neutralizing interleukin-10 autoantibodies were present in a subgroup of patients with IBD and were strongly associated with HLA-DRB1*01:03. (Funded by the National Institute for Health and Care Research and others.).

Background Small bowel Crohn’s disease is increasingly treated with biological therapies. Although many patients do not achieve response or remission, this is unpredictable. Motility magnetic resonance imaging reliably measures Crohn’s disease inflammation, but its predictive ability for longer-term response to biologic therapies is unknown. Objectives Primary: to determine if motility magnetic resonance imaging at weeks 12–30 is superior to C-reactive protein for the prediction of response or remission at 1 year in patients commencing biologics for small bowel Crohn’s disease. Secondary: to determine if motility magnetic resonance imaging changes can predict patient quality of life at 1 year; to determine if diffusion-weighted magnetic resonance imaging is predictive of response or remission; to compare the predictive ability of motility magnetic resonance imaging with that of faecal calprotectin; to investigate the effect of body composition on response or remission; to determine the relationship between plasma gut peptide and cytokine levels, patient symptoms and bowel dysmotility. Design and methods Prospective multicentre cohort study. Setting and participants Thirteen National Health Service hospitals with established inflammatory bowel disease and magnetic resonance imaging practices. Participants with active non-stricturing small bowel Crohn’s disease requiring biological therapy. Interventions Motility magnetic resonance imaging (test under evaluation) and C-reactive protein (comparator). Faecal calprotectin as secondary comparator. Diffusion-weighted magnetic resonance imaging and plasma gut peptide/cytokine level measurement in a subset. Main outcome measures Comparative accuracy of motility magnetic resonance imaging, C-reactive protein and faecal calprotectin to predict response or remission at 1 year, defined using a combination of clinical factors and structural magnetic resonance enterography scores, and measures of quality of life at 1 year, using EuroQol-5 Dimensions, five-level version and disease-specific patient-reported outcome measures. Motility magnetic resonance imaging interobserver variability. Post hoc confirmatory analysis of motility magnetic resonance imaging correlation with magnetic resonance enterography-defined disease activity. Results Two hundred and nineteen participants were screened, of whom 199 were treated. Ninety-three participants were excluded prior to their first visit, with a further 20 lost to follow-up subsequently. Eighty-six participants completed all assessments. Stable or improved motility magnetic resonance imaging post induction was more sensitive than normalisation of C-reactive protein for 1-year response or remission (motility magnetic resonance imaging: 71.0%, 95% confidence interval 52.0 to 85.8; C-reactive protein: 45.2%, 95% confidence interval 27.3% to 64.0%; p = 0.008) but less specific (motility magnetic resonance imaging: 30.9%, 95% confidence interval 19.1 to 44.8; C-reactive protein: 67.3%, 95% confidence interval 53.3% to 79.3%; p < 0.001). There was no significant difference in area under the receiver operating characteristic curve (motility magnetic resonance imaging: 0.48; C-reactive protein: 0.53, p = 0.65). Similar results were obtained for faecal calprotectin. None of motility magnetic resonance imaging, C-reactive protein or faecal calprotectin predicted patient quality of life at 1 year. Diffusion-weighted magnetic resonance imaging was also not predictive of response or remission. Interobserver variability of motility magnetic resonance imaging quantified by intraclass correlation coefficients was 0.75–0.83. We confirmed prior work that motility magnetic resonance imaging is negatively correlated with small bowel Crohn’s disease activity (correlation coefficient [rho]= −0.34). Baseline magnetic resonance imaging-measured body composition was not associated with 1-year response or remission. Patient symptoms, gut peptide and cytokine levels and overall small bowel dysmotility were not consistently correlated. Limitations Loss to follow-up was high, mainly due to the coronavirus disease discovered in 2019 (COVID-19) pandemic. Response assessment using ileocolonoscopy was not possible. Conclusions Although improved motility magnetic resonance imaging is more sensitive than C-reactive protein and faecal calprotectin to predict response or remission at 1 year, it is less specific. None of these factors predict patient quality of life. Motility magnetic resonance imaging measurements are reliable between readers, and it remains a marker of disease activity at a given time point. Future work Impact of motility magnetic resonance imaging on therapeutic management decisions and clinician confidence in Crohn’s disease. Utility of motility magnetic resonance imaging in phenotyping stricturing Crohn’s disease. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number 14/201/16. Plain language summary Crohn’s disease is a condition that causes inflammation of the bowels, and this inflammation can eventually lead to irreversible bowel damage. Powerful treatments that suppress inflammation called biologic drugs are now available, but it is not possible to give these to all patients because of side effects, costs and patient inconvenience. Also, they do not always work, but we cannot predict this reliably. In this study, we tested if a novel scanning technique using magnetic resonance imaging that measures bowel motion (called motility magnetic resonance imaging) can help predict which patients are likely to benefit in the longer term from these biologic drugs. The study recruited 86 patients from 13 National Health Service centres, all of whom had motility magnetic resonance imaging before and after starting their biologic treatment. After 1 year, we checked to see if the biologics had worked for each patient. We tested how good motility magnetic resonance imaging was at predicting whether or not the biologics were going to work, and compared this with other simple blood and faeces tests. We also tested some other magnetic resonance imaging techniques called diffusion-weighted imaging and body composition measurements. We found that none of the tests (motility magnetic resonance imaging, blood tests or faeces tests) were better than chance at predicting if biologics were going to work or not. Diffusion-weighted imaging and body composition measurements were not useful either. We did confirm some previous work that motility magnetic resonance imaging is good at telling us if the bowel is inflamed or not, and we also found that many different doctors (not just experts) can measure it reliably. The study means that motility magnetic resonance imaging and diffusion-weighted imaging are not useful ways to predict which patients are likely to benefit from biologic drugs. It can still be used to measure if the bowel is inflamed or not.

Bowel urgency, a burdensome ulcerative colitis symptom, impacts quality of life. It is associated with higher levels of disease severity, corticosteroid use, hospitalization, and colectomy. Despite its prevalence and clinical significance, bowel urgency is under-assessed in clinical practice and infrequently included as a clinical trial endpoint. This review evaluates the strengths and limitations of available patient-reported outcome measures assessing bowel urgency in ulcerative colitis to inform future directions for its assessment. A literature review was conducted using PubMed, Google Scholar, and Embase to identify publications through October 31, 2024, using the key terms “ulcerative colitis assessment” and “bowel urgency.” Publications assessing bowel urgency in ulcerative colitis using patient-reported outcome scales developed according to Food and Drug Administration guidance were included. Five tools met the inclusion criteria. The Urgency Numeric Rating Scale provides a simple and time-efficient tool for clinical use, while multi-item tools such as the Symptoms and Impacts Questionnaire for Ulcerative Colitis and the Ulcerative Colitis-Symptom Questionnaire include comprehensive symptom tracking but impose greater burdens for clinical practice. Diary-based tools, including the Ulcerative Colitis-Patient-Reported Outcomes/Signs and Symptoms Diary and Patient-Reported Outcomes-Ulcerative Colitis Diary, allow detailed symptom monitoring in clinical trials but are less practical for routine clinical use. Some dimensions of bowel urgency are missing from the tools reviewed. Incorporating validated bowel urgency measurement into routine clinical care and research is essential for advancing patient-centered, comprehensive disease management and improving outcomes in patients with ulcerative colitis.

Background:The ability to predict whether patients with a new diagnosis of Crohn's disease will develop disabling disease is an unmet clinical need. Magnetic resonance enterography is a first-line investigation for Crohn's disease, but its role in prognostication is unknown. Objective(s):To improve prediction of disabling Crohn's disease within 5 years of diagnosis by developing and internally evaluating a multivariable prediction model comprising clinical predictors and adding magnetic resonance enterography scores (Magnetic resonance Enterography Global Score, Simplified Magnetic Resonance Index of Activity and Lémann Index). To estimate the healthcare costs incurred within 5 years of Crohn's disease diagnosis and to explore factors driving costs. Design:A multicentre diagnostic inception cohort. Setting:Nine National Health Service hospitals. Participants:Aged ≥ 16 years with newly diagnosed Crohn's disease. Main outcome measures:Comparative predictive ability of prognostic models, including magnetic resonance enterography scores (Magnetic resonance Enterography Global Score, Simplified Magnetic Resonance Index of Activity and Lémann Index) versus a model based on clinical predictors alone for the development of modified Beaugerie disabling Crohn's disease within 5 years of diagnosis. Statistical analysis:We censored development of modified Beaugerie disabling disease ≤ 90 days from diagnosis, and utilised time-to-event models using Royston-Parmar flexible parametric models. Risk group definitions were prespecified; for risk group definition 1, the high-risk patients were the top 40% with the greatest predicted risk, and the high-risk patients had an absolute risk ≥ 10% for risk group definition 2. The absolute risk cut-off was calculated by sorting patients by predicted risk and using the risk of the eighth (10% of 81) patient who developed modified Beaugerie disabling disease. Results:We studied 194 patients, median age 29, interquartile range 22-44 years. Within 5 years from diagnosis, 42% (81/194) developed modified Beaugerie disabling disease. There was a univariable association between initial need for steroid therapy and developing modified Beaugerie disabling disease [hazard ratio 2.11 (95% confidence interval 1.36 to 3.26)]. Using risk group definition 1, the baseline clinical model had 49% (95% confidence interval 39 to 60) sensitivity and 66% (95% confidence interval 57 to 74) specificity for predicting the development of modified Beaugerie disabling disease. There was no difference in sensitivity and specificity between models incorporating Magnetic resonance Enterography Global Score, Simplified Magnetic Resonance Index of Activity and Lémann Index compared to the baseline clinical model. Using risk group definition 2, the model, including magnetic resonance enterography predictors, had 86% (95% confidence interval 77 to 92) sensitivity and 35% (95% confidence interval 27 to 45) specificity for predicting the development of modified Beaugerie disabling disease. There was no difference in sensitivity between the clinical model and models incorporating Magnetic resonance Enterography Global Score, Simplified Magnetic Resonance Index of Activity and Lémann Index, but specificity was significantly lower for models incorporating Magnetic resonance Enterography Global Score [29% (95% confidence interval 22 to 38)] and Lémann Index [29% (95% confidence interval 22 to 38)]. The mean total 5-year per-patient cost of health care was £24,267 (standard deviation £33,108). Mean 5-year costs were £29,763 (standard deviation £38,278) compared to £20,327 (standard deviation £28,368) for those with and without disabling disease, respectively. The largest contributor to costs was biologic use. Age under 40 years, presence of perianal disease and presence of severe endoscopic disease were associated with higher costs. Limitations:Liège and Montreal criteria for disabling disease could not be studied due to an insufficient event rate. Conclusions:Addition of magnetic resonance enterography scores to a multivariable model comprising existing clinical predictors did not improve prediction of modified Beaugerie disabling disease. Healthcare costs were increased in those aged under 40 years and patients with perianal and severe endoscopic disease. Future work:Testing the predictive ability of magnetic resonance enterography against alternative definitions for disabling Crohn's disease. Trial registration:This trial is registered as ISRCTN76899103. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/59/17) and is published in full in Health Technology Assessment; Vol. 30, No. 18. See the NIHR Funding and Awards website for further award information.

Abstract Background Crohn’s disease (CD) and Ulcerative colitis (UC) affect patients’ physical and emotional well-being, posing substantial challenges to daily functioning.1 The CONFIDE study explored patients’ perspectives on the experiences and impact of CD and UC-related symptoms in the US, Europe (France, Germany, Italy, Spain, and UK), and Japan. Here, we assessed the impact of moderate-to-severe CD or UC on self-reported health status using the EQ-5D-5L questionnaire. Methods Online, quantitative, cross-sectional surveys were conducted among patients with moderate-to-severe CD or UC, defined by criteria based on previous treatment, steroid use, and/or hospitalisation. EQ-5D-5L assesses health status across 5 dimensions—mobility, self-care, usual activities, pain/discomfort, and anxiety/depression—rated from 1 (no problems) to 5 (extreme problems). It also includes a visual analogue scale (VAS) to rate current health from 0 (worst) to 100 (best).2 Descriptive statistics were used to summarise data. Results The analysis included 547 European (males [M]=55%, mean age=38 years [yrs]), 215 US (M=55%, 41 yrs), and 99 Japanese (M=68%, 43 yrs) patients with CD and 556 European (M=57%, 39 yrs), 200 US (M=62%, 40 yrs),and 124 Japanese (M=70%, 49 yrs) patients with UC. Of these, 347 (63%) European, 125 (58%) US, and 86 (87%) Japanese patients with CD, and 301 (54%) European, 153 (77%) US, and 52 (42%) Japanese patients with UC were receiving advanced therapies at data collection. Mean EQ-5D VAS scores were 67.9, 65.0, and 70.7 for European, US, and Japanese patients with CD, and 67.2, 67.0, and 73.1 for those with UC. Similar results were observed in patients receiving advanced therapies (Figure 1). Table 1 summarises health status across EQ-5D-5L dimensions. Of the 5 dimensions, most patients reported pain/discomfort and anxiety/depression. Overall, 81% European, 86% US, and 60% Japanese patients with CD reported ‘slight’ to ‘extreme’ pain/discomfort, while 74% European, 70% US, and 52% Japanese patients reported ‘slight’ to ‘extreme’ anxiety/depression. For UC, the percentages were 80% European, 91% US, and 39% Japanese patients for pain/discomfort, and 72% European, 80% US, and 40% Japanese patients for anxiety/depression. Conclusion Despite receiving advanced therapies, patients with CD or UC in Europe, US, and Japan reported impaired overall health by EQ-5D VAS scores. The European and US cohorts reported worse health, with a higher proportion of patients reporting problems across EQ-5D-5L dimensions than the Japanese cohort, possibly resulting from differences in characteristics of survey respondents, environment (e.g., bathroom access) and healthcare. References 1.Popov J, Farbod Y, Chauhan U, et al. Clin Exp Gastroenterol. 2021;14:123-131. 2.Mulhern B, O’Gorman H, Rotherham N, et al. Health Qual Life Outcomes. 2015;13:191.

Chronic pouchitis affects 13% to 17% of patients with ileal pouch-anal anastomosis and ulcerative colitis, and 20% with a history of acute pouchitis. It is classified by antibiotic responsiveness into chronic antibiotic-dependent pouchitis and chronic antibioticrefractory pouchitis. Pathogenesis of chronic pouchitis can range from microbially mediated to more antibiotic-resistant and immune-mediated processes. A diagnostic index combining clinical, endoscopic, and histologic components is essential for clinical practice and research. In chronic antibiotic-dependent pouchitis, remission is managed with microbiota- or immune-targeted therapies. For chronic antibiotic-refractory pouchitis, immune-directed therapy is primary, with vedolizumab recommended for first-line treatment. Other advanced therapies rely on less definitive evidence, and efficacy may be reduced by precolectomy exposure. This article reviews the pathogenesis, diagnosis, and management of chronic pouchitis.

BACKGROUND:Small bowel Crohn's disease (SBCD) is increasingly treated with biological therapies. Predicting response or remission (RoR) for individual patients is difficult and complicates treatment strategy. We aimed to determine if motility magnetic resonance imaging (mMRI) is superior to CRP and fecal calprotectin (FC) for the prediction of RoR at 1 year in patients commencing biologics for SBCD. METHODS:Prospective, multicenter (n = 13) cohort study of patients with active non-stricturing SBCD requiring anti-TNFα or anti-IL-12/23 treatment. We measured mMRI and CRP at baseline and post-induction (visit 2: 12-30 weeks), and FC in a subset. RoR was assessed at 1 year using clinical and structural magnetic resonance enterography parameters. We compared sensitivity, specificity, and area under the receiver operating characteristic curve (ROC-AUC) of changes in mMRI and CRP to predict RoR at 1 year. Secondary outcomes compared mMRI with FC, and prediction of improved quality of life (QoL). RESULTS:Eighty-six participants completed all assessments. Stable or improved mMRI at visit 2 was more sensitive than normalization of CRP for RoR (mMRI:71.0%, 95%CI 52.0-85.8; CRP:45.2%, 95%CI 27.3-64.0%, P = .008) but less specific (mMRI:30.9%, 95%CI 19.1-44.8; CRP:67.3%, 95%CI 53.3-79.3%, P < .001). There was no significant difference in ROC-AUC (mMRI:0.48; CRP:0.53, P = .65). Similar results were obtained for FC. None of mMRI, CRP, or FC predicted patient QoL at 1 year. CONCLUSIONS:Although improved mMRI is more sensitive than CRP and FC to predict RoR at 1 year, it is less specific. No factor predicted patient QoL. Motility MRI remains a marker of disease activity at given timepoints.

Abstract Background Depression is common and costly. First-line antidepressants are ineffective for many and have little impact against cognitive deficits. Stimulating 5-HT4 receptors (5-HT4R) rapidly improves learning and has antidepressant-like effects in rodents 1,2. The highly-selective 5-HT4R agonist, prucalopride (licensed for constipation), had a facilitatory effect on behavioural learning/memory in healthy humans after a single 3 and 6 days' treatment 4,5. Neurally, it also increased hippocampal activity 4 and reduced activation within the default mode network 5, findings supported at a network level by resting state analyses 6. Aims & Objectives Here, we present results from 2 further translational studies, examining 5-HT4R agonists in the context of mental illness. In study 1, we hypothesised that 5-HT4R agonism in participants with un-medicated depression would also increase hippocampal activation during a memory encoding task. In study 2, using a live electronic health record database, we investigated whether a prescription of prucalopride for constipation compared to alternative anti-constipation agents would reduce the future risk of depression. Method For study 1, 57 right-handed un-medicated depressed patients were randomised to a 5-HT4R agonist PF-04995274 (15mg) or placebo in a double-blind design. 53 participants received a 3T scan and fMRI memory task eliciting hippocampal activation 7 on day 6-9. Emotionally-neutral “familiar” pictures were viewed before the scan, and again in the scanner with similar “novel” images. Imaging data were analysed with FSL and corrected for multiple comparisons/sex/perfusion/grey matter. Study 2 was an emulated target trial using anonymised routinely collected data from TriNetX Analytics. We included adults without prior mental illness who received either a prescription of prucalopride (primary cohort) or linaclotide/lubiprostone (comparator cohorts). Cohorts were matched for 118 covariates capturing sociodemographics, comorbidities, and concurrent medications. The primary outcome was a first diagnosis of depressive disorder (ICD-10 F32) within two years of prescription date. Results 5-HT4 versus placebo participants had significantly lower HAM-D scores after study 1 [HAM-D 17: F(1,56)=7.6; p<0.01]. In hippocampal analyses, while processing scenes, the 5-HT4 group had significantly increased activity to novel compared to familiar images, particularly in the left hemisphere [condition*hemisphere*group: F(1,49)=3.56, p=0.04, ηρ2=0.08); novel vs familiar (i) prucalopride L (p=0.035) &R hemisphere (p=0.050); (ii) placebo L (p=0.789) &R hemisphere (p=0.053)]. In study 2, treatment with prucalopride was associated with reduced incidence of depression compared to both lubiprostone [HR 0.84, 95% CI 0.73-0.96, p=0.01, n=7101) and linaclotide (HR 0.85, 95% CI 0.75-0.97, p=0.016, n=6460]. Secondary analyses indicated robustness and specificity of the results. Discussion & Conclusion In participants with un-medicated depression, the 5-HT4R agonist PF-04995274 increased hippocampal activation during a memory task; a replication of previous results in healthy volunteers using another 5-HT4R agonist. The pharmaco-epidemiological findings also suggest 5-HT4R agonists may be novel agents in the prevention of depression. Results from both studies are consistent with preclinical evidence establishing a key role for 5-HT4Rs in mood disorders and cognitive deficits. References 1) Lucas G, Rymar VV, Du J, et al. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 2007; 55(5): 712-25. 2) Murphy SE, de Cates AN, Gillespie AL, et al. Translating the promise of 5HT4 receptor agonists for the treatment of depression. Psychol Med 2021; 51(7): 1111-20. 3) Murphy S, Wright L, Browning M, Cowen P, Harmer C. A role for 5-HT4 receptors in human learning and memory. Psychol Med 2020; 50(16): 2722-30. 4)de Cates AN, Wright LC, Martens MAG, et al. Deja-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task. Trans Psychiatry 2021; 11: 497. 5) de Cates AN, Martens MAG, Wright LC, et al. The effect of the 5-HT4 agonist, prucalopride, on an fMRI faces task in the healthy human brain. Frontiers in Psychiatry 2022; 13(859123). 6) de Cates AN, Martens MAG, Wright LC, et al. 5-HT4 receptor agonist effects on functional connectivity in the human brain; Implications for pro-cognitive action. Biol Psychiatry Cogn Neurosci Neuroimaging 2023. 7) Filippini N, MacIntosh BJ, Hough MG, et al. Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A 2009; 106(17): 7209-14.

BACKGROUND & AIMS: Vedolizumab is indicated for the treatment of chronic pouchitis in the European Union. We assessed whether vedolizumab induced mucosal healing (MH) and if MH was associated with clinical improvements. METHODS: EARNEST, a randomized, double-blind, placebo-controlled study, evaluated vedolizumab effi- cacy and safety in adults with chronic pouchitis. Centrally read endoscopic and histologic evaluation was performed at baseline, Week (W)14, and W34. Ulcer count, adapted Simple Endoscopic Score for Crohn's Disease in the pouch, and Pouchitis Disease Activity Index histologic component were evaluated. Pouchitis Disease Activity Index and Inflammatory Bowel Disease Questionnaire remission at W14 and W34 were compared by MH status at W14. RESULTS: Following treatment, mean (standard deviation) number of ulcers in vedolizumab-treated patients reduced from 15.1 (16.4) to 5.0 (4.9) at W14 and 2.7 (3.2) at W34 versus placebo-treated patients with corresponding values of 11.8 (11.3), 13.4 (18.4), and 9.7 (13.8) (vedolizumab vs placebo difference [95% confidence interval]: W14:- 8.4 [-14.3,- 2.6]; W34:- 7.0 [-12.0,- 2.0]). More patients receiving vedolizumab versus placebo achieved reduction in ulcerated pouch surface area (W14: 52.4% vs 20.0%; difference, 32.4 percentage points [p.p] [9.7, 51.4]; W34: 52.1% vs 12.9%; difference, 40.2p.p [15.6, 60.3]), absence of ulceration (W14: 23.8% vs 7.5%; difference, 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference, 18.8p.p [-2.0, 39.5]), Simple Endoscopic Score for Crohn's Disease remission (W14: 23.8% vs 7.5%; difference, 16.3p.p [1.1, 31.6]; W34: 34.4% vs 15.6%; difference, 18.8p.p [-2.0, 39.5]), and MH (W14: 16.7% vs 2.5%; difference, 14.2p.p [1.9, 26.4]). Patients with MH at W14 had higher rates of Pouchitis Disease Activity Index and Inflammatory Bowel Disease Questionnaire remission at W14 and W34 than those without. CONCLUSIONS: Vedolizumab induced endoscopic improvements in patients with chronic pouchitis, which was associated with improved outcomes at W34, particularly in patients achieving MH at W14. (ClinicalTrials.gov number, NCT02790138.)

Background:Fecal calprotectin (FC) and C-reactive protein (CRP) are noninvasive biomarkers used in ulcerative colitis (UC) clinical trials; however, thresholds defined as "normal" in trials may be higher than "normal" thresholds typically used in clinical practice. We assessed the relationship between FC and CRP improvement in the "normal" range across different cutoff thresholds for patients with moderately to severely active UC treated with mirikizumab. Methods:Patients achieving clinical response to mirikizumab in LUCENT-1 (Weeks 0-12) proceeded to LUCENT-2 (Weeks 12-52 [52 weeks of continuous mirikizumab]). Associations between FC and CRP levels at multiple thresholds and histologic-endoscopic mucosal improvement (HEMI) and histologic-endoscopic mucosal remission (HEMR) at Weeks 12 and 52 were assessed by Fisher's exact test. Least squares means of FC and CRP changes from baseline at Weeks 12 and 52 were calculated using analysis of covariance with HEMI or HEMR status as factors and baseline FC or CRP values as covariates. Results:At Weeks 12 and 52, greater proportions of patients with FC thresholds of ≤250, ≤150, ≤100, and ≤50 µg/g, and CRP thresholds of ≤6 and ≤5 mg/L, achieved HEMI and HEMR compared with those not achieving HEMI and HEMR. Changes from baseline in FC and CRP at Week 12 and FC at Week 52 were greater in patients who achieved HEMI and HEMR compared with those not achieving these endpoints. Conclusions:These results show that FC and CRP analyses may contribute to a noninvasive monitoring strategy in clinical practice.ClinicalTrials.gov numbers: NCT03518086, NCT03524092.

Background:Fatigue is a burdensome symptom of Crohn's disease (CD) and ulcerative colitis (UC). The Communicating Needs and Features of Inflammatory Bowel Disease Experiences (CONFIDE) study investigated how patients and health care professionals (HCPs) in the United States (US) and Europe (France, Germany, Italy, Spain, and the United Kingdom) perceived the experiences and impact of CD/UC-related symptoms. Methods:Online, quantitative, cross-sectional surveys were conducted separately among patients with moderate-to-severe CD/UC (defined based on previous treatment, steroid use, and/or hospitalization) and HCPs who treated patients with CD/UC. US and Europe data are presented as descriptive statistics. Results:Surveys were completed by 215 US and 547 European patients with CD, 200 US and 556 European patients with UC, and 200 US and 503 European HCPs. Overall, 35.8% US and 34.2% European patients with CD and 27.5% US and 20.9% European patients with UC reported currently experiencing fatigue (in past month). Most of these patients reported severe fatigue and indicated that CD/UC negatively affected their sleep, energy levels, and quality of life (QoL). The majority of patients currently experiencing but not discussing fatigue with their HCPs at every appointment wished they discussed it more frequently. However, most HCPs reported proactively discussing fatigue at routine appointments. Approximately 20% patients with CD/UC reported declining participation in work/school, social activities, and sports/physical exercise, and avoiding sexual activities due to fatigue. Conclusions:US and European patients with CD/UC experienced severe burden of fatigue, which negatively affected their QoL. Assessing and discussing fatigue in routine appointments is critical for effectively managing this debilitating symptom.

BACKGROUND:Ulcerative colitis (UC) and Crohn's disease (CD) negatively affect patients' quality-of-life, and their impact on patients' sexual health is rarely addressed. This study assessed the impact of moderate-to-severe UC and CD on sexual activity using United States (US) and European data from the Communicating Needs and Features of IBD Experiences (CONFIDE) survey. METHODS:Online, quantitative, cross-sectional surveys were conducted among patients with moderate-to-severe UC or CD and health care professionals (HCPs). Moderate-to-severe UC or CD were defined using criteria based on previous treatment, steroid use, and/or hospitalization. The surveys were developed with input from HCPs and patient advisors and included questions on demographics, UC- or CD-related symptoms, and the impact of UC or CD on sexual health. Patients were asked whether they had avoided/decreased sexual activity in the past 3 months and their UC- or CD-related reasons. Patients and HCPs rated levels of impact of UC or CD on sex life/sexual intimacy and patients rated how bowel urgency interferes with their relationship with spouse/partner. Additionally, questions assessing the psychosocial health of patients and identifying gaps and barriers in HCP-patient communication were also included. Descriptive statistics were used to summarize the data. RESULTS:Surveys were completed by 200 US and 556 European patients with UC and 215 US and 547 European patients with CD. Of these, most US (UC: 63%, CD: 69%) and European (UC: 53%, CD: 56%) patients reported avoiding or decreasing sexual activity due to UC or CD in the past 3 months; however, the proportion was significantly greater among US patients (p <.05). Among patients with UC, a significantly greater proportion of female patients reported altered sexual activity due to their disease. A similar proportion of male and female patients with CD reported impaired sexual activity. Most common UC-related reasons for avoidance of sexual activity were bowel urgency among US patients and fear of faecal seepage among European patients. Among patients with CD, the most common reason was fear of bowel urgency-related accidents in both US and European patients. Patients reported a negative impact of bowel urgency on their relationship with spouse/partner. CONCLUSIONS:In the US and Europe, most patients reported avoiding or decreasing sexual activity due to moderate-to-severe UC or CD, with bowel urgency and bowel urgency-related accidents being common reasons. Assessing and addressing sexual health in routine clinical care should be considered when treating UC and CD.