Target In Ulcerative Colitis Research Articles

DOP001 Endoscopic and histologic outcomes in patients with moderate-to-severe Ulcerative Colitis treated with infliximab: A post hoc analysis of the Phase 3 LIBERTY-UC study

Abstract Background The combined achievement of endoscopic and histologic remission is an emerging therapeutic target in ulcerative colitis (UC) and is associated with lower clinical relapse rates and reduced corticosteroid use.1,2 Here, we present endoscopic and histologic outcomes following maintenance treatment with subcutaneous (SC) infliximab (IFX) using data from the LIBERTY-UC study.3 Methods In the LIBERTY-UC study,3 patients (pts) received induction doses of IFX 5 mg/kg via intravenous infusion at Weeks (W) 0, 2 and 6. Clinical responders at W10 were randomised 2:1 to receive either IFX SC every other week or a placebo (PBO) during maintenance therapy. All pts randomised at W10 were included in this post hoc analysis. Endoscopic and histologic assessments were performed at screening, W8, W22 and W54 (centrally evaluated). Endoscopic improvement (Mayo endoscopic subscore [MES] ≤1), endoscopic normalisation (MES=0), histologic remission (Robarts Histopathology Index [RHI] <3 without neutrophils in the epithelium or lamina propria) and the combination of histologic remission and endoscopic normalisation were assessed. Non-responder imputation was used for pts who underwent dose adjustment or had missing data. Data were analysed descriptively with nominal p-values. Results Baseline characteristics were similar between IFX SC and PBO groups, with 48.6% and 53.5% of pts having severe disease (MES=3); and mean histologic activity (RHI) of 17.0 and 18.0, respectively (Table). At W8, half of the pts achieved endoscopic improvement in both groups (IFX SC: 53.1%; PBO: 50.0%). From W22 onwards, the difference in rates of endoscopic improvement between the two groups was statistically significant (50.7% vs 34.0%; p=0.0011) up to W54 (43.9% vs 22.2%; p<0.0001). Similar findings were observed for histologic remission. Endoscopic normalisation rate in the IFX SC group increased with continued treatment (23.8% at W8, 26.9% at W22 and 32.7% at W54), while it declined in the PBO group (21.5% at W8, 18.8% at W22 and 11.1% at W54). Furthermore, a greater proportion of pts in the IFX SC group achieved combined histologic remission and endoscopic normalisation compared to the PBO group from W22 up to W54 (22.1% vs 16.7% at W22; p=0.2072; 27.9% vs 11.1% at W54; p<0.0001) (Figure). Conclusion Maintenance treatment with IFX SC resulted in significantly greater improvements in endoscopic and histologic outcomes at W54 compared to PBO. Endoscopic improvements were observed as early as W8, along with enhancements in stringent endpoints such as endoscopic normalisation and the combined endpoint of histologic remission and endoscopic normalisation over time, supporting the sustained benefit of a maintenance therapy with IFX SC.

P1130 Real-life histological remission in Ulcerative Colitis patients treated with Ustekinumab: results from the Belgian SULTAN trial

Abstract Background Histological remission is an aspirational therapeutic target in Ulcerative Colitis (UC) associated with lower relapse rates.1Ustekinumab (UST), a monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 has shown in the UNIFI trials to be effective and safe in patients with moderate-to-severe UC. However, real-life data on histological remission rates are sparse. The aim of the study was to assess the real-life histological response and remission rates of UST in patients with UC across Belgian hospitals. Methods In this multicentric, retrospective observational study, patients with UC who initialised UST treatment between September 2020 and July 2023 were included. Histological remission was defined as Nancy score = 0, response as Nancy ≤ 1 and assessed at week 16 and 52 by the local pathologist. Other endpoints included steroid-free clinical remission (partial Mayo ≤ 2 with no subscore >1), endoscopic remission (endoscopic Mayo = 0), endoscopic response (Mayo score ≤ 1) and clinical response (decrease in partial Mayo score ≥ 3 points and ≥ 30% plus a decrease in rectal bleeding score ≥ 1 or an absolute rectal bleeding score ≤ 1). UST drug persistence was analyzed by Cox regression analysis, predictors of other endpoints by logistic regression. Results 120 patients with moderate to severe UC (86% patients with ≥S2 severity) were included across 16 participating centers. Median disease duration was 11 years (IQR 9) and 81 (68%) of patients had previously failed 2 or more biologicals. Histological remission was achieved in 3/37 (8%) and 5/45 (11%) at W16 and W52, while histological response was seen in 10.8% (4/37) and 26.7% (12/45) respectively. Steroid-free clinical remission rates were 41/120 (34%) and 38/85 (44%) while endoscopic remission was seen in 23/120 (19%) and 13/52 (25%) at W16 and 52 respectively. Two patients (40%) in histological remission at W52 had an endoscopic Mayo 0 score, while 3 had a Mayo 1 (60%) at the time of evaluation. Active smoking was a negative predictor for achieving steroid-free remission (OR 0.412, p=0.011). No significant predictors for histological remission or response could be identified. UST drug persistence by week 52 was 70.8%. Active smoking (OR 3.058, p=0.02), vedolizumab non-response (OR 2.592, p=0.03) and a high Nancy baseline score (OR 2.46, p=0.04)) were associated with UST failure Conclusion In this multi-centric, real-life cohort with highly refractory UC patients, UST shows acceptable clinical and endoscopic remission rates, but histological remission rates remain low after one year of treatment.

DOP094 Improvement in biomarkers in patients with ulcerative colitis treated with vedolizumab: Results from the continuing VERDICT trial

Abstract Background Treatment targets in ulcerative colitis (UC) include symptomatic remission, endoscopic remission, and histologic remission. The ongoing VERDICT trial (NCT04259138) aims to determine the optimal treatment target in patients with moderately-to-severely active UC.1,2 Patients follow treatment algorithms involving early use of vedolizumab (VDZ). Here we report biomarker changes (fecal calprotectin [FCP] and C-reactive protein [CRP]) from baseline to weeks 8, 16, 32 and 48. Methods VDZ 300 mg was administered intravenously following a treatment algorithm related to baseline UC treatment until assigned treatment target was reached, with an escalation step between week 16, 32 and 48 as indicated. Treatment targets were as follows: Group 1 (corticosteroid-free [CSF] symptomatic remission), Group 2 (CSF symptomatic remission + CSF endoscopic remission), and Group 3 (CSF symptomatic remission + CSF endoscopic remission + CSF histologic remission, also termed disease clearance). CSF symptomatic remission was defined as Mayo rectal bleeding subscore=0, CSF endoscopic remission was defined as Mayo Endoscopic Score [MES]≤1, and CSF histologic remission was defined as Geboes score<2B.0. Biomarker assessments included FCP and CRP at weeks 8, 16, 32, and 48. Biomarker remission was defined as FCP ≤250 mg/kg and CRP ≤5 mg/l. Results As of 1st October 2024, 672 patients were enrolled, with 185, 222, and 265 patients in Groups 1, 2, and 3, respectively. Biomarkers improved from baseline to Week 16 and incrementally through to Week 48 (Table). Mean changes from baseline to Week 48 in FCP in groups 1, 2, and 3 were: -1268.8 mg/kg, -1515.9 mg/kg, and -1230.1 mg/kg (Table). For CRP, mean changes from baseline to Week 48 were -1.5 mg/l (Group 1), -3.4 mg/l (Group 2), and -1.8 mg/l (Group 3). For FCP, mean changes to Week 48 in all 3 groups were greater in bio-exposed than bionaïve patients, whereas mean change in CRP was greater in bio-exposed patients in Group 1 only (Table). In patients who achieved biomarker remission (FCP≤ 250 mg/kg + CRP ≤5 mg/l) at Week 48, the proportions who had met their treatment target were 51.6% (Group 1), 57.1% (Group 2), and 48.6% (Group 3) [Figure]. Higher baseline FCP was associated with lower odds of histologic remission at Week 16, 32, and 48, with corresponding odds ratios (95% CI) for histologic remission per 100 µg/g increase of baseline FCP of 0.89 (0.86, 0.93), 0.89 (0.86, 0.93), and 0.82 (0.76, 0.87). Conclusion Biomarker data from VERDICT shows improvements in FCP and CRP concentrations from baseline to Week 16, with incremental improvements through to Week 48. Almost half or more of all patients who achieved biomarker remission achieved their assigned treatment target.

P0538 Histologic remission predicts relapse in patients with Ulcerative Colitis

Abstract Background Histologic remission is not currently established as a formal treatment target in ulcerative colitis (UC). However, growing evidence indicates that histologic activity is associated with increased rates of relapse, hospitalization, and colectomy1. We aimed to evaluate the predictive value of histologic remission in UC patients and its potential role in guiding disease management. Methods A unicentric retrospective study was conducted, including all patients with UC who achieved endoscopic remission (Mayo Endoscopic Subscore ≤1) on colonoscopy between January 2020 and June 2023. Histologic remission was defined as the absence of neutrophils in the lamina propria or epithelium. Clinical activity was assessed using patient reported outcomes (PRO-2) for stool frequency or rectal bleeding (PRO-2>0). Clinical relapse was defined as the need for therapy optimization, switching therapy, or corticosteroid use. Factors associated with relapse were assessed using chi-square tests for categorical variables and t-tests for continuous variables. A binary logistic regression model was applied to further evaluate these associations. Results A total of 90 patients were included (58% male; mean age: 55 ± 15 years), with a median disease duration of 15±9 years. Among patients in endoscopic remission, 61% had a Mayo endoscopic subscore of 0, and 39% had a score of 1. Histologic remission was observed in 74% of patients (table 1). During follow-up, 23% (n=21) of patients experienced a relapse. Histologic activity was statistically associated with a higher risk of clinical relapse (p=<0.001). No differences were found in relapse rates between patients with Endoscopic Mayo Subscores of 0 or 1 (p=0.073). Younger age (p=0.009), shorter disease duration (p=0.002), and previous failure of advanced therapies (p=0.049) were also associated with a higher risk of clinical relapse. Multivariate analysis identified histologic remission as the sole independent predictor of relapse (odds ratio: 0.173, 95% CI: 0.053–0.571, p=0.004). Conclusion These observational data suggest that histologic remission may predict clinical relapse in patients with UC. In this cohort, histologic remission was identified as the sole predictor of relapse, outperforming endoscopic remission. References Lobatón T, Bessissow T, Ruiz-Cerulla A, De Hertogh G, Bisschops R, Guardiola J, Van Assche G, Vermeire S, Ferrante M. Prognostic value of histological activity in patients with ulcerative colitis in deep remission: A prospective multicenter study. United European Gastroenterol J. 2018 Jun;6(5):765-772. doi: 10.1177/2050640617752207.

P0073 Evaluation of PYGL as a Biomarker and Therapeutic Target in Ulcerative Colitis

Abstract Background Inflammation begins when innate immune cells recognize and respond to infections or tissue injuries to protect the body. In particular, cells such as macrophages and dendritic cells require more energy to manage these conditions. Glycogen metabolism is a crucial function for cells recruited to the site of inflammation to obtain energy. Within that process, glycogen phosphorylase plays a pivotal role as an enzyme for glycogenolysis. Because ulcerative colitis (UC) is a long-term condition in which the colon and rectum become inflamed, patients with the disease might have high levels of protein or activity of glycogen phosphorylase (PYGL) in the blood. Therefore, this study aims to identify the protein level and activity of PYGL in the serum and peripheral blood mononuclear cells (PBMC) of ulcerative colitis patients. Methods After blood from UC patients was provided by Daejeon St. Mary's Hospital, the PBMCs were isolated using Leucosep tube pre-filled with separation medium (Greiner bio-one, 163288), and the serum was isolated by centrifugation at 1000 x g for 10 minutes in a refrigerated centrifuge (Labogene, 1248R). The PBMCs were stored in an LN2 cell storage tank (ICBiomedical, LS6000), and the serum was stored in a deep freezer (Nihon freezer, CLN-52UW) at -80°C until samples of 60 patients were gathered. To compare with UC patients, normal human PBMCs (STEMCELL Technologies, 70025.1) were used. PYGL levels in serum and PBMCs from normal and UC patients were measured using Human PYGL ELISA Kit (Colorimetric) (Novus, NBP2-82520). PYGL activity in serum and PBMCs from normal and UC patients were measured using Glycogen phosphorylase activity assay kit (Colorimetric) (Abcam, ab273271). Activity Vmax and level from serum and PBMCs were analyzed using an unpaired t-test to determine significant differences (p < 0.05), fitting the standard. Activity reaction curve from serum and PBMCs was anlyzed using an mutiple unpaired t-test to determine significant differences (q < 0.05). GraphPad Prism 10 software was used for all analysis and the data were presented as Mean and SEM. Results Significant differences in PYGL activity were observed between UC patients and healthy controls in both serum and PBMC samples, though PYGL levels did not exhibit notable variation. These findings support the hypothesis that PYGL activity is linked to UC pathology and may serve as a marker for disease severity and progression. Conclusion This study provides initial evidence that PYGL activity could be a predictive biomarker and therapeutic target in UC. Future studies are warranted to further elucidate its role and assess the potential of PYGL inhibitors as a treatment strategy for autoimmune and inflammatory conditions like UC. References Ji Q, Li H, Cai Z, Yuan X et al. Share PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer. Int J Biol Sci. 2023 Mar 21;19(6):1894-1909. Ma J, Wei K, Liu J et al. Glycogen metabolism regulates macrophage-mediated acute inflammatory responses. Nat Commun. 2020 Apr 14;11(1):1769. Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS. Glycogen and its metabolism: some new developments and old themes. Biochem J. 2012 Feb 1;441(3):763-87. Thwe PM, Pelgrom LR, Cooper R et al. Cell-Intrinsic Glycogen Metabolism Supports Early Glycolytic Reprogramming Required for Dendritic Cell Immune Responses. Cell Metab. 2019 Jul 2;30(1):225.

P0754 Extensive disease clearance as a novel composite endpoint to predict long-term relapse in vedolizumab-treated patients with ulcerative colitis: a post-hoc analysis from the VIEWS randomised controlled trial

Abstract Background Disease clearance (DC), defined as combined clinical, endoscopic and histologic remission, has been proposed as the ultimate therapeutic target in ulcerative colitis (UC). However, the addition of faecal calprotectin (FC) remission to DC, now proposed as ‘extensive disease clearance (EDC)’, in predicting for relapse is unknown. We aimed to explore the use of composite therapeutic endpoints, including DC and EDC, in predicting long-term outcomes for UC patients on vedolizumab (VED). Methods The phase IV Vedolizumab Immunomodulator Enforced Withdrawal Study (VIEWS) prospectively recruited UC patients in steroid-free clinical remission on VED 300mg IV q8w. Baseline evaluation (week 0) included FC, endoscopy, histology and serum VED trough levels. Remission definitions were FC<150µg/g, centrally-read Mayo endoscopic score (MES)=0 and Nancy index (NI)=0. FC value differentiated DC and EDC. DC was defined as FC≥150µg/g, MES=0 and NI=0. EDC was defined as FC<150µg/g, MES=0 and NI=0. Clinical relapse, defined as partial Mayo score ≥3 and FC≥150µg/g or MES increase of ≥1, was evaluated for 2 years. Cox regression, Kaplan-Meier curves and log rank statistics were performed to assess the time to clinical relapse. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for dichotomous categorial variables. Multivariate logistic regression models were performed to identify predictive factors of relapse. P<0.05 was deemed statistically significant (SPSS, IBM, USA). Results 62 consecutively recruited UC patients were followed over 24 months. Of 54 patients with endoscopic assessments at baseline, 80% were in endoscopic remission, 76% histologic remission, 68% had DC, and 63% had EDC. Baseline EDC was associated with significantly lower rates of clinical relapse compared with DC and clinical/endoscopic remission alone (log rank P<0.001; HR: 0.17 [95%CI:0.04-0.64], P=0.009) (Figure 1). Baseline EDC had an OR of 0.16 (95%CI:0.04-0.75, P=0.01) in predicting relapse, versus DC (OR: 0.20 [95%CI:0.05-0.89], P=0.03), endoscopic remission (OR:0.91 (95%CI:0.16-5.15), P=0.92), histologic remission (OR: 0.10 [95%CI:0.02-0.50], P=0.002), and neither endoscopic nor histologic remission (OR:4.44 [95%CI:0.55-35.90], P=0.13). Univariate predictors of EDC at baseline were female sex (P=0.03), UC disease duration < 5 years (P=0.01), smoking status (P=0.004) and serum VED concentrations (P=0.03). On multivariate analysis, only female sex (OR: 7.0 [95%CI: 1.17-42.33], P=0.03) predicted for EDC. Conclusion EDC, a novel composite endpoint, predicted for significantly lower rates of relapse compared with DC in UC patients on VED. Female sex was associated with baseline EDC. FC should be incorporated into composite endpoints with endoscopy and histology.

P1124 Disease Clearence after Acute Severe Ulcerative Colitis episode: is it possible ?

Abstract Background Acute severe ulcerative colitis (ASUC) is a critical and potentially life-threatening condition necessitating prompt and effective intervention. Long-term follow-up of these patients is vital for understanding the disease trajectory, therapeutic outcomes, and overall patient management. The concept of disease clearance has been proposed as a potential target in ulcerative colitis (UC). This study aims to report one-year follow up data after patients experienced ASUC. Methods We performed a retrospective analysis of patients diagnosed with ASUC at our Referral IBD center from 2014 to 2024. Inclusion criteria were based on established clinical parameters in accordance with ASUC. Data collected included patient demographics, disease severity, treatment modalities, surgical interventions, and one-year outcome (disease clearance, mucosal healing, colectomy). Treatment comprised intravenous corticosteroids, followed by immunomodulator (Cyclosporine and biologics) in non-responders. Results The study included 109 patients diagnosed with ASUC. The average age at the time of initial presentation with ASUC was 42.1 years, and 47% of the participants (44 out of 109) were male. The mean C-reactive protein (CRP) level recorded was 77.65 mg/L. Among the patients, 36.7% (40 out of 109) were treated with Infliximab, while 14.6% (16 out of 109) received Cyclosporine as rescue therapy. Colectomy was necessary for 12% (14 out of 109) of the patients due to either refractory disease or complications within the first year. The rest of the patients, 44.9 % (49 out of 109) achieved remission on intravenous steroids, and consecutively received either Infliximab (33/49), Vedolizumab (11/49) or Tofacitinib (5/49). Additionally, 7.3% (8 out of 109) achieved clinical remission using intravenous steroids in combination with aminosalycilates. After one year of follow-up, 55% (57 out of 109) of the patients achieved mucosal healing, and disease clearance was observed in 27.5% (30 out of 109) of the cases. 67.5% (27 out of 40) achieving mucosal healing and 45% (18 out of 40) experiencing disease clearance. Conclusion Definition of disease clearance was proposed to provide practical recommendations for its implementation as a therapeutic target in UC. Almost one third of our patients achieved DC after ASUC, majority in Infliximab group with colectomy rate of 12 % in first year.

P0096 Impaired fatty acid oxidation is a hallmark of Ulcerative Colitis: evidence from multi-cohort transcriptomics analysis

Abstract Background Ulcerative colitis (UC) is characterized by persistent colonic mucosal inflammation. Despite available treatments, most patients experience only temporary remission. The lack of universally effective treatments results from our incomplete understanding of UC pathophysiology. While many gene expression studies have provided valuable insights into UC mechanisms, the growing availability of transcriptomics datasets offers a unique opportunity for large-scale, cross-validating analyses. Here, we used multiple independent datasets to identify the most consistently dysregulated pathways in UC mucosal biopsies. Methods We performed an integrative analysis of 10 open transcriptomics datasets from human UC and healthy mucosal biopsies (n=710 samples after selection). Each dataset underwent a separate differential expression analysis followed by gene set enrichment. We used 6 different gene set databases to make the analysis as broad as possible (9962 pathways). The results were aggregated across all datasets to identify consistently altered genes and pathways. Since each dataset has a different number of samples and a different sample distribution between the groups, the aggregation was done purely on the ranking level. The complete workflow of the experiment is in Figure 1. Results Mitochondrial fatty acid oxidation emerged as the most significantly dysregulated pathway with a mean rank 4 (median 2.5) across 6 datasets. The analysis revealed a coordinated pattern of metabolic rewiring: systematic downregulation of the entire mitochondrial transport machinery (CPT1A, SLC25A20, CPT2) and the carnitine transporter SLC22A5, accompanied by decreased expression of β-oxidation enzymes (ACADS, ACADM, ACADVL, HADHA, HADHB, HADH, EHHADH) and consistent downregulation of the medium-chain fatty acid activating enzyme ACSF2. In contrast, ACSL4, which specifically activates polyunsaturated fatty acids, showed consistent upregulation. This metabolic disruption was coupled with coordinated changes in membrane remodeling enzymes, with upregulation of LPCAT1 and downregulation of LPCAT3, suggesting systematic alterations in membrane phospholipid composition. Conclusion Our multi-cohort analysis reveals a specific pattern of metabolic disruption in UC that extends beyond pathway inhibition. The coordinated upregulation of the ferroptosis mediator ACSL4 together with systematic changes in membrane remodeling enzymes suggests active metabolic rewiring that could promote ferroptotic cell death through altered membrane phospholipid composition and increased susceptibility to lipid peroxidation. These findings highlight potential new therapeutic targets in UC focused on specific aspects of lipid metabolism and ferroptosis regulation.

DOP098 Development of BEN8744, a phase 2 ready, peripherally restricted PDE10 inhibitor targeting a new mechanism of action for the treatment of ulcerative colitis.

Abstract Background To identify novel therapeutic targets for ulcerative colitis (UC), a disease-agnostic Knowledge Graph1, comprising multi-modal data sources was used as input to a machine learning gene/protein prioritisation model2. Following in-depth target assessment, phosphodiesterase 10 (PDE10) was selected as a promising novel target for further investigation. Methods Our aim was to develop a novel therapeutic target for UC that will have not just anti-inflammatory properties but improve barrier function. PDE10 hydrolyses both cAMP and cGMP. In UC patients, reduced cAMP levels promote inflammation, while guanylate cyclase-C and its endogenous activators are downregulated in the colon, with lower levels correlating to higher disease severity. Our transcriptional analysis revealed that PDE10 is upregulated in UC patients’ colonic mucosa, correlating with disease severity, suggesting that PDE10 inhibition could potentially restore normal cyclic nucleotide signalling. Following successful experimental target validation, we developed BEN8744 a potent, selective, peripherally restricted oral PDE10 inhibitor. Supporting its therapeutic potential, BEN8744 significantly reduced TNFα, IL-6, and IL-8 in ex vivo inflamed UC patient colonic mucosa biopsy samples, and improved barrier integrity in an in vitro intestinal epithelial cell model. In a Phase 1, randomised, double-blind, placebo-controlled trial with 74 healthy subjects, we assessed the safety, tolerability, pharmacokinetics (PK), and food effect of BEN8744 (NCT06118385). The trial was in 3 parts: Part A investigated single ascending oral doses of BEN8744; Part B was a 2-way crossover assessment of the effect of food on the PK of BEN8744; and Part C investigated multiple ascending oral doses of BEN8744 for 14 days. Results All treatment emergent adverse events (TEASs) were mild or moderate in severity with no clinically significant findings in physical examination, laboratory variables, ECGs, OAAS/S or VAS results, during the study. No class effects previously seen with centrally active PDE10 inhibitors were observed in the present trial. Neither were there any dose dependent nervous system related TEAEs. Conclusion BEN8744 is a potent, peripherally restricted, well tolerated Phase 2 ready PDE10 inhibitor targeting a novel mechanism of action for the treatment of UC. The Phase 1 study showed a favourable safety, tolerability, and PK profile for BEN8744, supporting its further development. We are now planning a study in patients with moderate to severely active ulcerative colitis.

P1104 Endo-histologic outcomes in patients with ulcerative colitis responding to tofacitinib

Abstract Background The therapeutic landscape for ulcerative colitis (UC) has shifted toward deeper disease control. The real-world data on efficacy of tofacitinib in inducing histologic remission (HR) remains limited. We evaluated the real-world efficacy of tofacitinib in achieving endoscopic remission (ER) and HR. Methods A prospective cohort study was conducted from January 2022 to June 2024. Adult patients with moderate-to-severe UC (Mayo score ≥6, endoscopic subscore ≥2), who responded to tofacitinib induction were included. Paired endoscopic and histologic assessments were performed at baseline and week 48. Endoscopic disease activity was graded using the Mayo endoscopic score (MES), while histologic activity was evaluated using the Nancy index. The primary outcome was combined endoscopic-histologic remission (EHR), defined as MES of 0 and a Nancy index of 0, at week 48. The secondary outcomes included ER, HR, histologic endoscopic mucosal improvement (HEMI) and endoscopic improvement histologic remission (EIHR). Results Seventy-seven patients were analyzed. Clinical response at week 8 was seen in 66 (85.7%) patients, with 43 (65.2%) of these patients maintaining clinical response through week 48. At week 48, combined EHR was achieved in 22 (28.6%) patients, while ER and HR were observed in 30 (38.9%) and 29 (37.6%) patients, respectively. HEMI was noted in 32 (41.6%) patients, while EIHR was seen in 27 (35.1%) patients. (Figure 1) The endoscopic and histological outcomes did not differ with concomitant administration of corticosteroids during induction, previous exposure to thiopurines and the time of achievement of symptomatic remission (8 weeks vs 16 weeks). (Figure 2) No significant predictors of ER, HR, or combined EHR were identified. No serious adverse effects were reported. Conclusion Tofacitinib is effective in achieving combined HER, ER, and HR. These findings support the potential for histologic healing as a therapeutic target for UC in real world.

P0141 Estrogen receptor β alleviates colitis in intestinal epithelial cells by activating HIF-1α and ATG-9a mediated autophagy

Abstract Background Ulcerative colitis (UC) manifests as excessive inflammation and compromised integrity of the intestinal epithelial barrier. Estrogen receptor β (ERβ) exerts anti-inflammatory effects in the colon. However, the mechanism remains unclear. This study aims to explore the role and mechanism of ERβ in alleviating colitis, and provide a novel therapeutic target for UC. Methods The level of ERβ and autophagy in the inflammatory and non-inflammatory colons of patients with UC were assessed. Mice with dextran sulfate sodium (DSS)-induced colitis were used to establish an in vivo model. The body weight change, colon length, disease activity index (DAI) and histological score of mice in each group were compared. In vitro, HT-29 cell inflammation was induced by lipopolysaccharide (LPS). ERB041, an ERβ specific agonist, was administered to DSS-induced mice and LPS-induced HT-29 cells. Autophagy in vivo and in vitro was evaluated by western blot, transmission electron microscope, and immunofluorescence. Co-immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assay were conducted to further delineate the mechanism between ERβ and autophagy. Results Compared with non-inflammatory mucosa, the expression of ERβ in the inflammatory mucosa in patients with UC was down-regulated, with autophagy inhibited significantly. ERβ activation attenuated the intestinal epithelial barrier disruption, decreased the level of pro-inflammatory cytokines, and significantly attenuated DSS-induced experimental colitis. Mechanically, ERB041 intervention activated autophagy, which was manifested as up-regulation of LC3BII expression, decreased p62 level and increased number of autolysosomes. ERβ interacted with hypoxia-inducible factor 1α (HIF-1α) and activated autophagy. Furthermore, HIF-1α bound to the promoter region of ATG- 9a, and positively regulates its transcription. Conclusion ERβ exerts anti-inflammatory effect by up-regulating HIF-1α and activating ATG-9a mediated autophagy in intestinal epithelial cells, and may be a promising therapeutic target for UC.

P1193 Cross-Disease Analysis Unveils CXCL6 as a Shared Immune Mediator in Ulcerative Colitis and Periodontitis: Novel Insights from Bioinformatics

Abstract Background Emerging evidence underscores a pathological bidirectional relationship between ulcerative colitis (UC) and periodontitis (PD) through the oral-gut axis, highlighting a complex interplay with significant implications for patient health. However, the shared molecular features underlying this interaction have yet to be explored. Methods In this study, we initially established a potential link between periodontitis and ulcerative colitis based on Mendelian randomization. Following this, we analyzed gene expression profiles from the Gene Expression Omnibus (GEO) for both UC and PD, identifying overlapping genes between UC-differentially expressed genes (DEGs) and PD-DEGs. Results Functional enrichment analysis revealed associations with various immune pathways, underscoring the immunological relevance of these genes. Intersection with immune-related genes (IRGs) yielded 25 candidate genes, among which CXCL6 emerged as a central hub gene identified through three machine learning methods: LASSO, RF, and SVM-RFE. Subgroup analysis based on CXCL6 expression demonstrated that the CXCL6-high group exhibited increased immune cell infiltration and enhanced immune function. Moreover, our investigation of CXCL6 in relation to biological therapies in UC patients indicated a reduction in CXCL6 levels following treatment, suggesting potential benefits of biological therapies. Finally, we validated the expression of CXCL6 in a rat model of dual diseases. Conclusion In summary, CXCL6 is identified as a diagnostic biomarker and potential therapeutic target for UC combined with PD, warranting further investigation into its clinical significance and associated mechanisms.

Artificial intelligence-enabled histology exhibits comparable accuracy to pathologists in assessing histological remission in ulcerative colitis: a systematic review, meta-analysis, and meta-regression.

Achieving histological remission is a desirable emerging treatment target in ulcerative colitis (UC), yet its assessment is challenging due to high inter- and intraobserver variability, reliance on experts, and lack of standardization. Artificial intelligence (AI) holds promise in addressing these issues. This systematic review, meta-analysis, and meta-regression evaluated the AI's performance in assessing histological remission and compared it with that of pathologists. We searched Medline/PubMed and Scopus databases from inception to September 2024. We included studies on AI models assessing histological activity in UC, with or without comparison to pathologists. Pooled performance metrics were calculated: sensitivity, specificity, positive and negative predictive value (PPV and NPV), observed agreement, and F1 score. A pairwise meta-analysis compared AI and pathologists, while sub-meta-analysis and meta-regression evaluated heterogeneity and factors influencing AI performance. Twelve studies met the inclusion criteria. AI models exhibited strong performance with a pooled sensitivity of 0.84 (95% CI, 0.80-0.88), specificity 0.87 (0.84-0.91), PPV 0.90 (0.87-0.92), NPV 0.80 (0.71-0.88), observed agreement 0.85 (0.82-0.89), and F1 score 0.85 (0.82-0.89). AI models demonstrated no significant differences with pathologists for specificity, observed agreement, and F1 score, while they were outperformed by pathologists for sensitivity and NPV. AI models for the adult population were linked to reduced heterogeneity and enhanced AI performance at meta-regression. AI shows significant potential for assessing histological remission in UC and performs comparably to pathologists. Future research should focus on standardized, large-scale studies to minimize heterogeneity and support widespread AI implementation in clinical practice.

Revealing therapeutic targets and drugs from Chinese medicine for ulcerative colitis using bioinformatics

Pathogenesis and therapeutic drugs for ulcerative colitis (UC) have plagued researchers worldwide. In this study, therapeutic targets, and drugs from Chinese medicines for UC were screened using bioinformatics. We downloaded five datasets from the GEO database and three machine learning algorithms were used for screening diagnostic biomarkers of UC. Combined with the differential genes for UC, gene sets related to bile acid metabolism, short-chain fatty acids, apoptosis, pyroptosis, G-protein-coupled receptors, mitochondria, and autophagy were collected to screen the core targets, and analyze the association of therapeutic genes (diagnostic biomarkers and core targets) with immune cells. In addition, screening ingredients of Chinese medicines based on UC therapeutic targets was performed. Molecular docking, molecular dynamics simulation, and literature validation were also performed. The screening yielded 37 key therapeutic targets, including 5 diagnostic biomarkers (CCL11, CXCL1, PDZK1IP1, TIMP1, and UGT2A3) and 32 core targets based on hot gene sets. Immune cell infiltration was strongly associated with therapeutic targets in UC, especially neutrophils, macrophages, mast cells, and dendritic cells. Furthermore, a total of 33 compounds with high safety had been recognized as having potential to mitigate UC by reverse prediction from Chinese medicines, and molecular docking, molecular dynamics simulation, and literature reports preliminarily validated the screening results. Although further experimental validation is needed, this work provides some potential therapeutic targets and drugs from Chinese medicines against UC.

METTL14 regulates inflammation in ulcerative colitis via the lncRNA DHRS4-AS1/miR-206/A3AR axis

As a chronic inflammatory bowel disease, the pathogenesis of ulcerative colitis (UC) has not been fully elucidated. N6-methyladenosine (m6A) modification, observed in various RNAs, is implicated in inflammatory bowel diseases. Methyltransferase-like 14 (METTL14) is the major subunit of the methyltransferase complex catalyzing m6A modifications. Here, we designated to examine the regulatory effects and mechanisms of METTL14 on long non-coding RNA (lncRNA) during UC progression. METTL14 knockdown decreased cell viability, promoted apoptosis, increased cleaved PARP and cleaved Caspase-3 levels, while reducing Bcl-2 levels. METTL14 knockdown also led to a significant increase in NF-κB pathway activation and inflammatory cytokine production in the Caco-2 cells treated with TNF-α. Moreover, the suppression of METTL14 aggravated colonic damage and inflammation in our dextran sulfate sodium (DSS)-induced murine colitis model. METTL14 silencing suppressed DHRS4-AS1 expression by reducing the m6A modification of DHRS4-AS1 transcripts. Furthermore, DHRS4-AS1 mitigated inflammatory injury by targeting the miR-206/adenosine A3 receptor (A3AR) axis. DHRS4-AS1 overexpression counteracted the enhancing impact of METTL14 knockdown on TNF-α-induced inflammatory injury in Caco-2 cells. In conclusion, our findings suggest that METTL14 protects against colonic inflammatory injury in UC via regulating the DHRS4-AS1/miR-206/A3AR axis, thus representing a potential therapeutic target for UC.

Treat-to-Target in Inflammatory Bowel Disease: An Updated Survey of Treatment Strategies among Portuguese Gastroenterologists

Background: In 2018, the authors surveyed the clinical practices among Portuguese gastroenterologists (PGEs) regarding treatment targets in Crohn’s disease (CD) and ulcerative colitis (UC). Since then, new evidence has emerged supporting additional targets, such as transmural remission and histological remission. This study provides an updated assessment of treatment practices among PGE with special emphasis on these new targets. Methods: Using the Portuguese Inflammatory bowel disease Study Group (GEDII) physician database, we invited PGE to participate in an anonymous online survey. Results: Fifty-six physicians agreed to participate in the study. Deep remission, steroid-free clinical remission, endoscopic remission, and biomarker remission were ranked among the most important treatment targets in CD (89%, 80%, 89%, and 84%, respectively) and UC (82%, 84%, 79%, and 84%, respectively). In CD, transmural remission was considered a target by 70% of participants, with 48% agreeing to intensify treatment to achieve it. In UC, histological remission was aimed by only 45% of PGE with most (88%) being unwilling to intensify treatment to achieve this goal. Physicians were more likely to seek endoscopic remission in CD and UC in younger and healthier patients, compared to older patients with comorbidities. Conclusion: PGEs are increasingly pursuing tougher treatment targets such as transmural remission in CD and, to a lesser extent, histological remission in UC. Physicians are more willing to escalate treatment to achieve endoscopic remission in younger patients.

Neutrophil extracellular traps induce barrier dysfunction in DSS-induced ulcerative colitis via the cGAS-STING pathway

Peptidyl arginine deiminase 4 (PAD4)-mediated neutrophil extracellular traps (NETs) play a crucial role in the pathogenesis of ulcerative colitis (UC). The cGAS-STING intracellular DNA-sensing pathway has been recognized as a pivotal mediator of inflammation. This study aimed to explore how NETs contribute to intestinal inflammation and barrier dysfunction in UC, focusing on the cGAS-STING pathway. We observed a significant increase of STING expression in UC mouse colons, which was mitigated by blocking NET formation through PAD4 genetic knockout. Moreover, NETs were discovered to activate the cGAS-STING pathway in MC38 cells in a dose and time-dependent manner, leading to the secretion of inflammatory cytokines and impaired barrier function. Additionally, STING deficiency ameliorated the clinical colitis index, intestinal inflammation, and barrier dysfunction. These findings underscore the involvement of cGAS-STING in regulating NET-mediated intestinal inflammation, suggesting its potential as a novel therapeutic target for UC.

Activation of AMPK/SIRT1/FOXO3a signaling by BMS-477118 (saxagliptin) mitigates chronic colitis in rats: uncovering new anti-inflammatory and antifibrotic roles.

Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve long-term remission, underscoring a significant unmet therapeutic need. BMS-477118, a reversible inhibitor of dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical and clinical studies with minimal adverse effects compared to other antidiabetic agents. However, the potential benefits of BMS-477118 in chronic UC have not yet been explored. In this study, we aimed to investigate the effects of BMS-477118 in rats subjected to chronic dextran sodium sulfate (DSS) administration. Our findings indicate that BMS-477118 activates the interconnected positive feedback loop involving AMPK, SIRT1, and FOXO3a, improving histological appearance in injured rat colons. BMS-477118 also reduced fibrotic changes associated with the chronic nature of the animal model, alleviated macroscopic damage and disease severity, and improved the colon weight-to-length ratio. Additionally, BMS-477118 prevented DSS-induced weight loss and enhanced tight junction proteins. These effects, in conjunction with reduced oxidative stress and its potential anti-inflammatory, antiapoptotic, and autophagy-inducing properties, fostered prolonged survival in rats with chronic UC. To conclude, BMS-477118 has the potential to activate the AMPK/SIRT1/FOXO3a signaling pathway in inflamed colons. These results suggest that the AMPK/SIRT1/FOXO3a pathway could be a new therapeutic target for UC. Further research is mandatory to explore the therapeutic possibilities of this pathway. Additionally, continued studies on the therapeutic potential of BMS-477118 and other DPP4 inhibitors are promising for creating new treatments for various conditions, including UC in diabetic patients.

Dynamic changes in the gut microbiota composition during adalimumab therapy in patients with ulcerative colitis: implications for treatment response prediction and therapeutic targets

BackgroundWhile significant research exists on gut microbiota changes after anti-tumor necrosis factor-alpha (anti TNF-α) therapy for ulcerative colitis, little is known about the longitudinal changes related to the effects of anti TNF-α. This study aimed to investigate the dynamics of gut microbiome changes during anti TNF-α (adalimumab) therapy in patients with ulcerative colitis (UC).ResultsThe microbiota composition was affected by the disease severity and extent in patients with UC. Regardless of clinical remission status at each time point, patients with UC exhibited microbial community distinctions from healthy controls. Distinct amplicon sequence variants (ASVs) differences were identified throughout the course of Adalimumab (ADA) treatment at each time point. A notable reduction in gut microbiome dissimilarity was observed only in remitters. Remitters demonstrated a decrease in the relative abundances of Burkholderia-Caballeronia-Paraburkholderia and Staphylococcus as the treatment progressed. Additionally, there was an observed increase in the relative abundances of Bifidobacterium and Dorea. Given the distribution of the 48 ASVs with high or low relative abundances in the pre-treatment samples according to clinical remission at week 8, a clinical remission at week 8 with a sensitivity and specificity of 72.4% and 84.3%, respectively, was predicted on the receiver operating characteristic curve (area under the curve, 0.851).ConclusionsThe gut microbiota undergoes diverse changes according to the treatment response during ADA treatment. These changes provide insights into predicting treatment responses to ADA and offer new therapeutic targets for UC.

The emerging role of neutrophil extracellular traps in ulcerative colitis.

Ulcerative colitis (UC) is characterized by chronic non-recessive inflammation of the intestinal mucosa involving both innate and adaptive immune responses. Currently, new targeted therapies are urgently needed for UC, and neutrophil extracellular traps (NETs) are new therapeutic options. NETs are DNA-based networks released from neutrophils into the extracellular space after stimulation, in which a variety of granule proteins, proteolytic enzymes, antibacterial peptides, histones, and other network structures are embedded. With the deepening of the studies on NETs, their regulatory role in the development of autoimmune and autoinflammatory diseases has received extensive attention in recent years. Increasing evidence indicates that excess NETs exacerbate the inflammatory response in UC, disrupting the structure and function of the intestinal mucosal barrier and increasing the risk of thrombosis. Although NETs are usually assigned a deleterious role in promoting the pathological process of UC, they also appear to have a protective role in some models. Despite such progress, comprehensive reviews describing the therapeutic promise of NETs in UC remain limited. In this review, we discuss the latest evidence for the formation and degradation of NETs, focusing on their double-edged role in UC. Finally, the potential implications of NETs as therapeutic targets for UC will be discussed. This review aims to provide novel insights into the pathogenesis and therapeutic options for UC.