Treatment Of Colitis Research Articles

Body Mass Index Did Not Impact Efficacy and Safety of Etrasimod: A Post Hoc Analysis of the ELEVATE UC Clinical Program.

High body mass index (BMI) may reduce ulcerative colitis (UC) treatment efficacy. Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. This post hoc analysis assessed treatment outcomes according to BMI in ELEVATE UC 52 and ELEVATE UC 12. Patients receiving etrasimod 2 mg QD or placebo were stratified by BMI: <25, 25-‍30, and >30 kg/m2. Efficacy and safety were assessed at Weeks 12 (pooled data) and 52 (ELEVATE UC 52 only) in addition to biomarkers assessments from Week 0-12. For BMI <25 (N = 443) and 25-30 kg/m2 (N = 217) subgroups, more patients receiving etrasimod vs placebo achieved clinical remission at Weeks 12 (BMI <25 kg/m2: 27.9% vs 13.3%; 25-30 kg/m2: 28.5% vs 10.0%; all P<0.001) and 52 (BMI <25 kg/m2: 30.8% vs 10.0%; 25-30 kg/m2: 33.3% vs 6.3%; all P<0.0001); and also for all other efficacy endpoints (P<0.05). In the BMI >30 kg/m2 subgroup (N = 127), more patients receiving etrasimod vs placebo achieved clinical remission at Week 52 (36.5% vs 3.9%; P<0.0001) and most other efficacy endpoints at Weeks 12 and 52 (all P<0.05). Overall, regardless of baseline BMI, numerically lower fecal calprotectin levels were observed with etrasimod vs placebo in treatment responders. The safety profile of etrasimod was consistent between BMI subgroups. A high BMI did not significantly impact efficacy and safety outcomes of etrasimod. (NCT03945188; NCT03996369).

Identification of DDR1 Inhibitors from Marine Compound Library Based on Pharmacophore Model and Scaffold Hopping

Ulcerative colitis (UC) is a chronic inflammatory condition that affects the intestines. Research has shown that reducing the activity of DDR1 can help maintain intestinal barrier function in UC, making DDR1 a promising target for treatment. However, the development of DDR1 inhibitors as drugs has been hindered by issues such as toxicity and poor binding stability. As a result, there are currently no DDR1-targeting drugs available for clinical use, highlighting the need for new inhibitors. In a recent study, a dataset of 85 DDR1 inhibitors was analyzed to identify key characteristics for effective inhibition. A pharmacophore model was constructed and validated to screen a library of marine natural products for potential DDR1 inhibitors. Through high-throughput virtual screening and precise docking, 17 promising compounds were identified from a pool of over 52,000 molecules in the marine database. To improve binding affinity and reduce potential toxicity, scaffold hopping was employed to modify the 17 compounds, resulting in the generation of 1070 new compounds. These new compounds were further evaluated through docking and ADMET analysis, leading to the identification of three compounds—39713a, 34346a, and 34419a—with superior predicted activity and drug-like properties compared to the original 17 compounds. Further analysis showed that the binding free energy values of the three candidate compounds were less than −12.200 kcal/mol, which was similar to or better than −12.377 kcal/mol of the known positive compound VU6015929, and the drug-like properties were better than those of the positive compounds. Molecular dynamics simulations were then conducted on these three candidate compounds, confirming their stable interactions with the target protein. In conclusion, compounds 39713a, 34346a, and 34419a show promise as potential DDR1 inhibitors for the treatment of ulcerative colitis.

Clinical evidence on nutrological management and gut microbiota in inflammatory bowel diseases: a systematic review

Introduction: The main risk factor for inflammatory bowel disease (IBD) is a positive family history. Crohn's disease (CD) can affect individuals aged 15 to 40 and 50 to 80 years, with a higher percentage in women. Ulcerative colitis (UC) can start at any age. Metabolism encompasses the interactions between diet, the microbiome, and cellular enzymatic processes that generate the chemical pathways necessary to sustain life. Endogenous metabolites and dietary nutrients can directly influence epigenetic enzymes. Epigenetic modifications to DNA and histone proteins alter cell fate by controlling chromatin accessibility and downstream gene expression patterns. Objective: It was to highlight the main interactions between nutrition and gut microbiota in the treatment of inflammatory bowel diseases. Methods: The present study followed the international systematic review model (PRISMA). This study was carried out from July to September 2024. It included randomized controlled, prospective, and retrospective studies published from 2013 to 2023. The Cohen test was performed to calculate the Effect Size and the inverse error standard (precision or sample size) for the risk of bias (Funnel Plot). Results and Conclusion: A total of 30 articles were found, and 17 clinical studies on the modulation of diet to control IBD were included in this study. These studies have shown reductions in persistent gut symptoms, improved gut microbiota, reduced markers of inflammation, and improved quality of life. Diet has an important role in controlling and even remitting IBD. The studies were homogeneous in results, with X2 = 82.5%, which increases the reliability of clinical results on the importance of diet in modulating IBD.

Treatment Patterns and Economic Burden of Ulcerative Colitis in Japan: A Retrospective Claims Analysis.

This retrospective claims analysis characterized contemporary ulcerative colitis (UC) treatment patterns and investigated the economic burden of UC in Japan. This study used anonymized claims data in the Medical Data Vision database. Patients were included if they had a confirmed UC diagnosis and ≥ 1 claim of systemic treatment for UC (index date) between June 2018 and December 2022, in addition to continuous enrollment for ≥ 6months before and ≥ 12months after the index date. Patients were excluded if they were aged < 18years at index or if they had claimed systemic UC treatmentduring the pre-index period, had a confirmed diagnosis of Crohn's or Behçet's disease, or had a record of colectomy during the pre-index period. Outcomes of interest were treatment patterns, healthcare resource utilization (HCRU), and UC-related costs per person per month (PPPM). Further exploratory analyses were conducted to understand whether real-world treatment patterns with conventional therapy were optimally aligned with guideline recommendations. Two definitions of suboptimal treatment with conventional therapies were identified: prolonged treatment with corticosteroids (i.e., consecutive use for > 90days) and corticosteroid cycling (i.e., three or more ≥ 30-day corticosteroid courses over 1year, with a ≥ 60-day gap between courses). Overall, 15,429 patients were included. The most frequently observed class of first-line treatment was 5-aminosalicylic acid monotherapy (75.0%); treatment modification was observed in 39.7% of patients. Within 1year of follow-up, patients had a mean (SD) of 9.8 (6.8) outpatient visits, and a hospital stay was reported in 23.9% of patients. Mean total cost PPPM was ¥76,374. Of patients with ≥ 1 course of corticosteroids, 39.8% received suboptimal treatment with conventional therapies. HCRU and total costs were higher for patients with versus without suboptimal treatment with conventional therapies. Japanese patients with UC would benefit from treatment options that can reduce costs, HCRU, and suboptimal treatment with conventional therapies.

Neutrophil-macrophage hybrid membrane-coated prussian blue nanozyme for ulcerative colitis treatment and mechanistic insights

BackgroundUlcerative colitis (UC) is a chronic and recurrent digestive tract disease that can lead to significant morbidity and mortality. The pathogenesis of UC is intricately associated with the presence of reactive oxygen species (ROS). Prussian blue (PB), an inorganic nanozyme with potent antioxidant properties, has been extensively applied in the treatment of various inflammatory conditions and tumors. However, despite the explicit antioxidant properties, the underlying molecular mechanism of PB nanozyme in the treatment of UC remains poorly understood. Furthermore, there is a deficiency in antioxidants that possess specific targeting capabilities towards UC lesions. The present study pioneered the fabrication of neutrophil (N)-macrophage (M) hybrid membrane-coated PB (NM-PB) nanozyme for the treatment of UC and investigated its underlying molecular mechanism.ResultsWe have successfully constructed PB, N-PB, M-PB, and NM-PB nanozymes. In both the colitis cell model and UC mouse model, compared with PB, N-PB, and M-PB nanozymes, NM-PB nanozymes exhibited remarkable targeting capabilities, significantly enhancing the localization and uptake of PB nanozymes at the lesion site. NM-PB nanozymes significantly reduced levels of ROS (•OH, •OOH, and H2O2) and decreased the production of proinflammatory cytokines (TNF-α, IL-6, IL-1β). Meanwhile, these nanozymes regulated the expression of intestinal mucosal barrier-related proteins (ZO-1, E-cadherin, and Occludin) and apoptosis-related proteins (Bcl2, Bax). Furthermore, NM-PB nanozymes facilitated the polarization of proinflammatory M1-phenotype macrophage towards an anti-inflammatory M2-phenotype. The mechanistic studies demonstrated that NM-PB nanozymes mitigated the progression of UC by inhibiting the pathway of cytokine-cytokine receptor interaction.ConclusionThe NM-PB nanozymes provide a promising and innovative alternative for the treatment of UC, offering enhanced targeting and efficacy through their unique design and mechanism of action.Graphical

Fluorescent Properties of Mesalazine-Loaded Hydrogel Nanocomposites for the Treatment of Ulcerative Colitis.

This study synthesizes a novel three-dimensional (3D) porous coordination polymer (CP), {[Co(L)₀.₅(H₂O)]·NMP·H₂O}n (1), via a solvothermal method in a mixed solvent of water and NMP (1-methyl-2-pyrrolidinone), reacting Co(II) ions with H₄L (1,4-bis(5,6-carboxybenzimidazolylmethyl)benzene). The CP exhibits unique fluorescence properties, emitting at 420nm under UV light excitation at 350nm, and serves as a carrier for Mesalazine (MSZ) in therapeutic applications. To enhance biocompatibility, MSZ-loaded fluorescent metal particles were encapsulated with chitosan (CMCS) and hyaluronic acid (HA), forming a bio-friendly drug delivery system, HA/CMCS-CP1@MSZ. The system was extensively characterized, confirming its stability and fluorescence properties, which facilitate drug tracking and controlled release. In vitro tests in ulcerative colitis (UC) models demonstrated that the HA/CMCS-CP1@MSZ system significantly reduced LPS-induced TNF-α and IL-6 levels, indicating its potential to effectively downregulate UC-associated inflammatory factors and be developed as a clinical treatment for UC. Furthermore, the fluorescence sensitivity of the system was explored, revealing its broad application potential beyond Fe³⁺ sensing, including drug release monitoring and tracking biological processes. This feature not only supports UC treatment but also presents new possibilities for iron ion monitoring in various iron metabolism-related diseases, such as anemia and cancer. Molecular docking simulations suggest that the carboxyl functional groups on the cobalt metal complex play a crucial role in the bioactivity, while the benzimidazole groups, serving as ligands, have a minimal direct impact on the bioactivity.

P0237 Opportunity for action in Spanish IBD patients with Sub-optimal Disease Control: Subanalysis of IBD-PODCAST Study

Abstract Background Timely, effective management of inflammatory bowel diseases (IBD) is crucial to achieve sustained clinical remission, and prevent bowel damage and disease progression and complications, as demonstrated by the PROFILE trial and reinforced by ECCO guidelines on therapeutics of Crohn’s disease (CD)1. Endoscopic activity and consecutive elevated fecal calprotectin values are predictive of worse IBD outcomes2,3. Methods The IBD-PODCAST was a non-interventional, cross-sectional, multicounty study, including 396 patients from 14 Spanish hospitals, recruited from February to June 20224. The objective was to determine the percentage of CD and ulcerative colitis (UC) patients with sub-optimal disease control (SDC) in a real-world setting, according to STRIDE-II criteria refined by experts. SDC in 53% of CD and 41% of UC Spanish patients was previously reported4. The aim of this analysis was to evaluate the proportion of these patients with sustained abnormal parameters, and the treatment pattern in patients with SDC. Results A total of 104 CD and 83 UC patients with SDC were analyzed. Data on sustained abnormal parameters over 12 months is summarized in Table 1. Among CD patients reporting abdominal pain, 23% experienced this symptom for a duration exceeding 12 months; and 7% of UC patients experiencing rectal bleeding reported this symptom over 12 months. Positively, sustained use of prednisolone at ≥10 mg/day was not reported for longer than 12 months. However, percentages of sustained abnormal parameters were higher for outcomes related to intermediate and long-term targets from STRIDE II. Fecal calprotectin remained above 250 μg/g for more than 12 months in 35% of CD and 26% of UC patients with elevated levels. Endoscopic findings were maintained over 12 months in 29% of CD patients and 18% of UC patients with any endoscopic finding. Additionally, clinicians reported sustained SDC for 18% of CD patients, and 30% UC patients among the overall group with clinician-reported SDC. Over 35% of IBD patients with self-assessed SDC reported this condition for longer than 12 months. Remarkably, more than 70% of patients with SDC were either naïve to targeted immunomodulators (TIMs) or were treated with them as first-line therapy (Figure 1), indicating scope for further management. Conclusion Although the cohort of Spanish patients with SDC had limited exposure to TIMs, up to one third of patients presented sustained abnormal parameters for over 12 months. These results highlight the opportunity for early intervention with effective treatment in IBD, considering the advancements in therapeutic options in the last three years.

P0194 Osteoporosis and osteopenia as extraintestinal manifestations in ulcerative colitis

Abstract Background Inflammatory bowel diseases (IBD) are often characterized by associated conditions with extraintestinal manifestations that can make diagnosis and treatment difficult. It is known that chronic inflammation, nutritional deficiencies and corticosteroid treatment in IBD are the main risk factors for developing metabolic bone diseases. This study aims to evaluate ulcerative colitis (UC) patients with osteoporosis and osteopenia as extraintestinal manifestation. Methods We analyzed 79 patients (mean age 42 years) with UC and we measured bone mineral density by dual energy X-ray absorptiometry (DXA). Patients who received treatment with corticosteroids were not included in the study. 25(OH)D levels were also measured in all patients enrolled in the study. The patients did not follow vitamin D supplementation treatment. Disease remission was defined with partial Mayo score ≤2. Among the patients included in the study, 52 were under biologic therapy. Results Among the patients included in the study 55 patients (69%) were in remission and 49 patients (62%) with low vitamin D levels &amp;lt;20 ng/ml. Osteoporosis (T score &amp;lt;-2.5) was found in 24% of patients at the lumbar-sacral spine and in 13.9% of patients at the femoral neck; osteopenia (T score between -1.0 and -2.5) was also found in 40.5% of patients at the lumbar-sacral spine and in 35.5% of patients at the femoral neck. All patients with osteoporosis had vitamin D deficiency (p=0.01) and osteopenia was present in 61% of patients with vitamin D deficiency (p=0.05). Regarding disease activity, 23.6% patients in remission and 29.1% patients with active ulcerative colitis were diagnosed with osteoporosis (p=0.69), meanwhile in the osteopenia group, 38.1% patients were in remission and 41.6% patients were with active disease (p=0.84). From the patients included in the study, 65.8% were following biological therapy of which only 3.8% were diagnosed with osteoporosis (p=0.007) and 11.5% were diagnosed with osteopenia (p=0.006). Conclusion Our data confirm that osteoporosis and osteopenia are common extraintestinal manifestations in ulcerative colitis. Patients with vitamin D deficiency were more likely to develop metabolic bone diseases without statistically significant differences between ulcerative colitis patients with active disease or those in remission. Patients who follow biological therapy have a lower risk of developing metabolic bone disease. Screening for osteoporosis and osteopenia is indicated in UC patients and vitamin D supplements are mandatory.

P0180 Bifidobacterium longum alleviates dextran sulfate sodium-induced colitis through the differential regulation of Toll-like receptor 5 on enteric glial cells

Abstract Background Inflammatory bowel disease (IBD) is a chronic immune-associated disease arising from gastrointestinal dysbiosis and subsequent immunological dysfunction. Numerous studies have reported the beneficial effects of probiotics, such as Bifidobacterium longum (BL), on IBD, while the related mechanism behind these effects have not been fully elucidated. Enteric nervous system abnormalities have increasingly been tied to the pathogenesis of IBD, with a particular focus on the role of enteric glial cells (EGC) in this context. In this study, we aim to explore the mechanism of probiotics in the treatment of IBD from the perspective of EGC. Methods On base of C57BL/6 mouse, TLR5 of EGC knockdown mouse model (TLR5 KD mouse) was constructed by adeno-associated virus (serum type 6) (AAV6) which carried the interference sequence of TLR5 gene (AAV6-TLR5-RNAi). Experimental colitis was induced by dextran sulfate sodium (DSS). Mice were treated with phosphate buffer solution (PBS) or BL. Disease activity index (DAI) and histological score were applied to assess the severity of colitis. The level of GDNF、IL-1β of colonic tissue were measured by ELISA. The expression of glial fibrillary acidic protein (GFAP)、toll-like receptor 5 (TLR5)、cleaved caspase-3 of colonic tissue were tested by immunofluorescence staining and quantitative PCR (qPCR). EGC cell line, EGC CRL2690, was exposed to probiotic (Bifidobacterium longum; BL) bacteria and pathogenic (Enterohemorrhagic Escherichia coli; EHEC). Cell apoptosis rate was assessed by flow cytometry. TLRs expression in EGC CRL2690 were evaluated at both baseline and after exposure to bacteria by qPCR and western blot analysis. GDNF and IL-1β release from EGC CRL2690, following exposure to bacteria, were measured in the presence or absence of specific TLR and pathway inhibitors. Results The results showed that BL ameliorated DSS-induced colitis accompanied by increased expression of GDNF, while pathogenic EHEC aggravated DSS-induced colitis combined with decreased expression of GDNF. Mechanistically, BL could up-regulate the secretion of GDNF via TLR5/p38 MAPK pathway in EGC, which was different from EHEC, which could up-regulate the secretion of IL-1β through TLR2/NF-κB pathway. Conclusion Our results suggested a new possible mechanism whereby probiotics ameliorate DSS-induced colitis in mice by regulating EGC via TLR5, namely, BL promotes GDNF secretion in EGC through activation of p38 MAPK signaling pathway by TLR5. Meanwhile, our results suggested that probiotic, pathogenic bacteria appeared to influence the development of intestinal inflammation by differentially modulating the secretion function of EGC via different TLRs.

DOP103 Optimization of Ustekinumab Treatment Induction Using a Pharmacokinetic Model in Inflammatory Bowel Disease Patients

Abstract Background Therapeutic drug monitoring and pharmacokinetic modeling, implemented in the treatment of patients with inflammatory bowel disease (IBD), improve drug efficacy and reduce side effects. Recently, Ustekinumab (UST) levels associated with therapeutic targets have been established, principally during induction, highlighting the need for appropriate optimization of this phase to improve response to UST treatment. Objectives To evaluate the effectiveness of proactive dose optimization of UST using pharmacokinetic modeling during induction (target concentration at week 8) in the treatment of IBD with UST. Methods A prospective comparative study was conducted on IBD patients initiating UST treatment, divided into two groups: standard induction protocol (initial intravenous UST dose adjusted to weight) or optimized induction protocol (following the initial weight-adjusted intravenous UST dose, UST levels were measured at 4 weeks and, using a pharmacokinetic model—including weight, height, and serum albumin levels—induction dosing was adjusted). UST plasma concentration was measured by FIA at 4 weeks in the optimized group and at 8 weeks from treatment initiation in all patients. Data on IBD and the clinical status of patients at UST treatment initiation were reviewed. Results A total of 88 patients were included: 72 in the standard protocol group (male 52.8%; Crohn's disease 59.2%; prior biologic use 95.8%; fecal calprotectin &amp;gt;150 g/kg 61.5%) and 16 in the optimized group (male 56.3%; Crohn's disease 68.8%; prior biologic use 93.88%; fecal calprotectin &amp;gt;150 g/kg 68.8%), with no significant differences in baseline characteristics between groups. The mean UST concentration at the end of induction (8 weeks) was significantly higher in patients with optimization via pharmacokinetic model compared to the standard protocol (15.4 [10.4-20.3] µg/ml vs 9.2 [7.7-10.7] µg/ml; p&amp;gt;0.0018) (Fig. A). In the optimized group, 6 patients (37.5%) received additional intravenous UST doses (3 patients received 1 dose and 3 patients received 2 doses before week 8). The percentage of patients achieving a UST concentration ≥ 6.6 µg/ml (linked to biochemical remission at weeks 12 and 24) and ≥ 9 µg/ml (associated with treatment durability ≥ 12 months) was significantly higher in the optimized group compared to those on the standard protocol (Figs. B and C). Conclusion Optimized UST treatment, through proactive dose adjustment based on pharmacokinetic modeling, achieves a target UST concentration during induction that should ensure treatment efficacy.

P1181 Liver fibrosis predicts response to advanced therapy in inflammatory bowel disease: a new personalized treatment approach?

Abstract Background Crohn's disease (CD) and ulcerative colitis (UC) are chronic and progressive inflammatory bowel diseases (IBD). It is estimated that up to 30-50% of patients with IBD develop intestinal fibrosis leading to complications such as strictures. Liver fibrosis occurs up to 16.7% of patients with IBD. However, the impact of liver fibrosis on the response to therapy in patients with IBD is unknown. Our aim was to investigate the association between liver fibrosis before starting an advanced therapy and response to treatment in IBD. Methods We conducted a retrospective analysis of data that were prospectively gathered from consecutive patients with a confirmed diagnosis of UC or CD, spanning from November 2021 to December 2023. All patients who started an advanced therapy (biological therapy and small molecule drugs) and had transaminase concentrations, body mass index (BMI), history of diabetes, and platelet counts available were eligible. Several scores of liver fibrosis were measured including AST/ALT ratio (AAR), AAR platelet ratio index (AARPRI)1, AST to platelet ratio index (APRI), body mass index AST/ALT ratio and diabetes mellitus score (BARD), fibrosis index based on four factors (FIB -4)2, and modified FIB-4 (m-FIB4)3. All available clinical (partial Mayo score, PMS, for UC and Harvey-Bradshaw index, HBI, for CD), biochemical (fecal calprotectin, FC), and endoscopic (endoscopic Mayo score for UC and simple endoscopic score for Crohn's Disease (SES-CD) and Rutgeert’s score for CD) data at 6 months were collected. A logistic regression multivariate analysis was performed to identify any correlation between scores of liver fibrosis at baseline and response to advanced therapies. Analyses were subjected to correction using the false discovery rate (FDR) method. Results In total, 122 patients were included in the analysis. Patient key demographic and treatment information as well as clinical remission, FC normalization and endoscopic remission at 6 months are summarized in table. Two UC patients (2.7%) were hospitalized. Five patients (4.1%) underwent surgery (2 UC-related and 3 CD related). No cases of neoplasia or death occurred. In the multivariate analysis, mFIB-4 at baseline was a predictor of clinical activity at 6 months in CD (FDR=0.08), while AARPRI at baseline predicted clinical activity at 6 months in UC (FDR=0.08) (Figure). Conclusion Patients with IBD and concomitant liver fibrosis have a lower rate of clinical remission after 6 months of advanced therapy. Scores of liver fibrosis could predict the response to therapy. Further prospective studies are warranted to implement their use in clinical practice

P0996 JAK Inhibitors Open a New Chapter in IBD Treatment: a Monocentric Retrospective Observational Research

Abstract Background The number of new patients with inflammatory bowel disease (IBD) in China continues to increase, the disease burden of patients is increasing, and the efficacy and safety of existing therapies are insufficient. Biologics have gradually become the main treatment for IBD, but more than 40% of patients have non-response or secondary non-response. Current studies have found that JAK-STAT is an important signaling pathway in the pathogenesis of IBD, and small molecule drug JAK inhibitors can block out downstream inflammatory pathways to achieve the purpose of alleviating the disease. Methods To explore the efficacy of the JAK inhibitor Upadacitinib in IBD, active IBD patients who started using Upadacitinib from February 2023 to August 2024 were retrospectively included. The baseline data and data at the end of the 12-week induction period were recorded, including demographic characteristics, symptoms, laboratory results, endoscopy and imaging results, etc. The clinical remission rate and endoscopic remission rate of Upadacitinib in the treatment of IBD were analyzed by statistical methods. Results By August 2024, a total of 75 patients with Crohn’s disease (CD) and 23 patients with ulcerative colitis (UC) had completed 12-week Upadacitinib induction therapy. The duration of the disease ranged from 1 to 12 years, and all of them had a history of non-response or adverse reactions to biologics before Upadacitinib treatment. The disease types of CD patients were mainly A2(16-40 years old)-L3(ileocolon)-B1(non-stricture), and 53% of them were complicated with anal fistula or perianal abscess. 62% of patients showed moderate to severe CD activity under endoscopy. After 12 weeks of use of UPA, the inflammatory indicators such as C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin were significantly decreased, and the SES-CD score as well as the CDAI score was decreased compared with the baseline level. The endoscopic response rate was 73.33%, the endoscopic remission rate was close to 50%, and the mucosal healing rate was 53%. The majority of UC patients were middle-aged and elderly men, and the Mayo scores were mainly in the moderate and severe active stage. The endoscopic subscore of 3 (severe lesions) accounted for 70.83%. At the end of the 12-week induction period, the endoscopic improvement rate reached 80%, the mucosal healing rate was 40%, and the inflammation index basically decreased to normal. Conclusion As a new generation of small-molecule targeted drugs, Upadacitinib has the advantages of convenient use, rapid onset, strong anti-inflammatory effect and high safety, and can significantly alleviate the disease burden of patients whose former biologics treatment has failed.

P0085 Faecalibacterium prausnitzii induces an anti-inflammatory response and a metabolic reprogramming in human monocytes

Abstract Background Faecalibacterium prausnitzii, a highly abundant bacterium in the human gut microbiota, has been linked to overall health and is notably decreased in pathological conditions, such as Inflammatory Bowel Disease (IBD). F. prausnitzii has shown anti-inflammatory properties in human and mouse models, notably through the induction of IL-10 signaling. Here, we investigated which cell types from human blood and intestinal tissue are responsible for producing IL-10 induced by F. prausnitzii, and providing the first mechanistic insights. Methods Immune cells isolated from human blood and intestinal lamina propria of patients with IBD and non-inflamed controls, were stimulated with F. prausnitzii EXL01 strain or Escherichia coli lipopolysaccharide (LPS) and analysed by Legendplex, ELISA, flow cytometry, RNA-sequencing (RNAseq), and Seahorse analyser. Results F. prausnitzii EXL01 strain induced the direct and dose-dependent production of IL-10 in CD14+ monocytes from the systemic circulation and intestinal tissue of IBD patients and non-inflamed controls, without inducing a pro-inflammatory response as compared to LPS stimulation. RNAseq analysis corroborated these results and revealed that F. prausnitzii EXL01 strain differentially affects cell energy metabolism compared to LPS. The anti-inflammatory response induced by F. prausnitzii in monocytes was dependent on mitochondrial respiration. Conclusion F. prausnitzii induces an anti-inflammatory response and rewires energy metabolism in human monocytes, which might explain its beneficial impact on intestinal inflammation and human health in general. These results provide new insight into the mechanisms underlying the anti-inflammatory effects of F. prausnitzii and are crucial for a better understanding of its potential use in the treatment of IBD. The well-characterised F. prausnitzii EXL01 is already in clinical development in Crohn's disease (NCT05542355), and the results of the first phase 1/2A study involving 8 patients will be available in early 2025.

P0043 Fecal extracellular vesicles from healthy individuals: A novel therapeutic approach for patients with Inflammatory Bowel Disease

Abstract Background Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disease that consists of two main types: Crohn's disease and ulcerative colitis. One of the main causes of this disease is the disruption of the diversity of the gut microbiome and dysregulation of the interactions between microbes and the human immune system. So far, no definitive cure has been identified for the disease, and current treatments are only for temporary suppression of severe inflammatory responses. One treatment option currently being investigated in clinical trials is fecal transplants from healthy donors to patients with IBD. Extracellular vesicles (EVs), released by various cell types and microbes residingt in the gastrointestinal tract, can play an important role in the disease progression and treatment of IBD. In this study, we investigate the therapeutic potential of extracellular vesicles extracted from the feces of healthy individuals in the in vitro model of inflammatory bowel disease. Methods An in vitro model of IBD was established using a transwell co-culture system of Caco-2 intestinal epithelial cells and RAW264.7 macrophages. Inflammation was induced in macrophages using lipopolysaccharide (LPS). Stool samples were obtained from healthy donors and IBD patients. Stools were suspended in Tris-EDTA-based buffer in a 1:5 ratio and centrifuged. The supernatant was filtered and centrifuged at 100,000 x g to isolate EVs. Dynamic light scattering (DLS) and Transmission electron microscopy (TEM) were performed to characterize EVs in size and shape. The effects of EVs isolated from healthy individuals and IBD patients on the intestinal cells and expression of epithelial barrier markers were investigated in the in vitro IBD model. Results DLS results revealed that the size of isolated EVs was mainly distributed around 100-200 nm. TEM results showed that the EVs were round- or oval-shaped and their structures did not alter by ultracentrifugation. Inflammation induction using LPS led to changes in the morphology of intestinal cells. However, the shape of cells after treatment with EVs derived from feces of healthy donors was similar to the control group. Intriguingly, the cell shapes shifted toward the inflammatory phase when they were treated with stool-derived EVs of IBD patients. Molecular findings showed that stool-derived EVs of healthy individuals could restore the expression of epithelial cell markers in the inflamed intestinal cells, preserving epithelial barrier function, similar to what was observed in the non-inflamed cells. Conclusion Stool-derived EVs of healthy individuals can be introduced as a new solution for the treatment of IBD patients, although further studies on animal models are needed to enter the clinic.

P0068 Distribution of α4β7 integrin and MAdCAM-1 expression according to the location of intestinal inflammation in a murine model of spontaneous chronic enterocolitis

Abstract Background The selective blockade of α4β7 integrin is a treatment for inflammatory bowel disease (IBD), with different efficacy according to the location of inflammation along the gastrointestinal tract. A more pronounced effect has been reported in patients with predominant colonic inflammation. It may be attributed to differences in the regional expression of adhesion molecules. This study aimed to investigate the expression of α4β7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in colon, ileum, and mesentery, using IL-10 knockout (KO) mice as a model of spontaneous chronic enterocolitis. Methods At 20 weeks, the colon, ileum, and mesentery were extracted from IL-10KO and C57BL/6 wild-type (WT) mice. Protein levels of α4β7 integrin and MAdCAM-1 were determined by Western blot in the different tissues. Additionally, pro-inflammatory cytokines (TNF-α and IFN-γ) and epithelial adhesion molecules (Zonula Occludens-1, ZO-1; E-cadherin and Mucin 2, Muc2) expression in the ileum, as well as adiponectin expression in the mesentery, were analyzed using real-time PCR. Results Analysis demonstrated a significant increase in gene expression of the pro-inflammatory cytokines TNF-α and IFN-γ in the ileum of IL-10 KO mice compared with WT mice (p&amp;lt;0.01). In addition, IL-10KO mice exhibited reduced expression of ZO-1, E-cadherin, and Muc2 in the ileum relative to WT mice (p&amp;lt;0.001). IL-10 deficiency also led to a marked decrease in adiponectin expression in the mesentery (p&amp;lt;0.05). We then analyzed the protein level of MAdCAM-1 and α4β7 integrin according to anatomic region. Remarkably, the protein analysis revealed significantly higher levels of MAdCAM-1 (p&amp;lt;0.01) and α4β7 integrin (p&amp;lt;0.05) in the colon of IL-10 KO mice compared to WT. In the ileum, while MAdCAM-1 levels remained unchanged, α4β7 integrin expression was increased in IL-10KO mice (p&amp;lt;0.01). No significant differences in MAdCAM-1 or α4β7 integrin levels were observed in the mesentery between IL-10KO and WT mice Conclusion IL-10-deficient mice develop inflammation in the ileum, accompanied by a reduction in adiponectin production in the mesentery. In this setting, both α4β7 integrin and MAdCAM-1 showed increased expression in the colon, which was not observed in the ileum or mesentery, despite the inflammation. This differential regional expression pattern of adhesion molecules may explain the variation in the efficacy of anti-integrin therapies. Characterizing these patterns in patients with IBD could help identify those who would benefit most from these treatments.

P0495 Impact of the HLA DQA1*05 allele on the efficacy of vedolizumab treatment in inflammatory bowel disease

Abstract Background Patients with inflammatory bowel disease (IBD) carrying the HLA-DQA1*05 allele have a higher risk of developing immunogenicity and loss of response to anti-TNFs. On the other hand, this association has not been observed with ustekinumab, a fact that could help individualize treatment (J. Guardiola ECCO 2024). We do not have data for vedolizumab. Methods: Objective To evaluate the relationship between the HLA-QA1*05 allele and the loss of response and the persistence of treatment with vedolizumab. Methods Design: Unicentric retrospective cohort study from a tertiary hospital. Population IBD patients who have completed induction with vedolizumab. Loss of response need for intensification, change of treatment, hospitalization or surgery. Analysis univariate (Kaplan Meyer) and multivariate (Cox Regression) analyses. Results We included 67 patients with IBD (24 Crohn’s disease and 43 ulcerative colitis) with an average follow-up of 29±21 months. Both cohorts were comparable in relation to baseline characteristics. 44% were carriers of the risk allele. 74% had previous exposure to biologicals. Mean basal and postinduction calprotectin were 866±1103 and 295±1228, respectively. 28 (46%) of the patients lost response during follow-up. During this period 29%, 25%, 7% and 42% required hospitalization, treatment with corticosteroids, surgery or intensification respectively. We found no differences in relation to clinical or biological remission rates at 6 and 12 months, nor differences in discontinuation rates in relation to the status of carriers of the risk allele. The mean duration free of loss of response was 28 months (95% CI: 9-46) in individuals not carrying the HLA-DQA1*05 allele and 13 months (95% CI: 9-16) in those carriers, without significant differences between both groups (Log Rank p=0.517) (Figure 1). In multivariate analysis, after adjusting for treatment with prior biologics, obesity and type of IBD, the presence of the HLA-DQA1*05 allele was not associated with loss of response to vedolizumab or persistence of the treatment. Conclusion The presence of the HLA-DQA1*05 allele is not associated with loss of response or persistence of vedolizumab treatment.

P0944 Fluorescently labelled adalimumab to visualise drug targeting in Inflammatory Bowel Disease: a safety, feasibility and dose-finding study

Abstract Background Treatment of inflammatory bowel disease (IBD) with biologicals, such as adalimumab, is hampered by high non-response rates and lack of reliable response prediction tools. Therefore, patients are potentially exposed to ineffective treatment and side effects, while clinical deterioration continues. Moreover, it is unclear whether the drug reaches its target site in adequate concentrations to achieve treatment response. We aim to visualise adalimumab distribution and detect adalimumab target cells using quantified fluorescence molecular endoscopy (qFME). Methods Adalimumab was labelled with IRDye 680LT under cGMP conditions, resulting in a fluorescent tracer suitable for human use. This tracer is used in an ongoing, non-randomized, non-blinded, prospective feasibility study. A total of 21 IBD patients scheduled for an endoscopy will be included. Up until now, eight patients received adalimumab-680LT (4.5 mg: n=3, 15 mg: n=3, 25 mg: n=2), and three patients were included as a control. Two to four days after tracer administration, qFME was performed to gather in vivo fluorescence data of inflamed and non-inflamed tissue. Fluorescent signals were quantified by multi-diameter single fibre reflectance/single fibre fluorescence (MDSFR/SFF) spectroscopy. Furthermore, biopsies were taken from inflamed and non-inflamed mucosa for ex vivo analysis. Results To date, 11 patients were included. Tracer administration was well tolerated and no adverse events occurred in any dose group. Real-time in vivo macroscopic imaging showed clear uptake of adalimumab-680LT in inflamed tissue compared to non-inflamed tissue (figure 1A). Spectroscopy revealed a dose-dependent increase in fluorescent signal for adalimumab-680LT in inflamed tissue, with a significant difference between 4.5 and 15 mg (0.016 [0.011-0.021] vs 0.033 [0.021-0.043] (p=0.036)) (figure 1B). The difference between inflamed and non-inflamed tissue is most noticeable in the 25 mg group. Ex vivo Mean Fluorescent Intensity (MFI) quantification of all biopsies showed a significant increase of fluorescent signal in the 15 and 25 mg dose groups compared to control in inflamed tissue (65.0 [54.0-75.7] vs 32.4 [27.1-38.2] (p=0.0040), and 62.1 [44.1-82.8] vs 32.4 [27.1-38.2] (p=0.0286), respectively) (figure 1C). Conclusion Preliminary results show adalimumab-680LT is safe for visualising adalimumab distribution. Doses of at least 15 mg are sufficient for visualisation and quantification of fluorescent signal in vivo. Furthermore, higher MFI’s and spectroscopy results were measured in inflamed tissue compared to healthy tissue, indicating targeting of the tracer to inflamed tissue. Future ex vivo experiments are ongoing to visualise adalimumab target cells.

P0615 Effectiveness and Safety Analysis of Upadacitinib in the Treatment of Inflammatory Bowel Disease: A Multicenter Real-World Study

Abstract Background Inflammatory bowel disease (IBD) requires effective treatment options. Upadacitinib, a Janus kinase 1 (JAK1) inhibitor, has shown effectiveness in trials for Crohn’s disease (CD) and ulcerative colitis (UC). This study evaluates its real-world effectiveness and safety. Methods We conducted a multicenter retrospective cohort study in tertiary care centers, involving patients treated with upadacitinib from January 2023 to September 2024. The study included adult patients aged 18 years or older, diagnosed with UC or CD, who received at least 8 weeks of upadacitinib therapy. Treatment outcomes were evaluated using established clinical, endoscopic, imaging, histological, and laboratory parameters. Results A total of 236 IBD patients received upadacitinib treatment. In 80 UC patients at 8 weeks, 64.0% achieved steroid-free remission (P=0.250), 57.6% clinical remission (P=0.063), and 81.8% response. Endoscopic remission was 35.8% (P=0.039), with 63.3% response and 35.8% mucosal healing (P=0.219). Histological remission reached 29.2% (P=0.009). Mean albumin increased from 37.0 to 40.3 g/L (P&amp;lt;0.001). Normal hemoglobin rates improved from 63.9% to 91.0% (P&amp;lt;0.001), and normal CRP rates from 51.4% to 77.8% (P&amp;lt;0.001).For 156 CD patients at 12 weeks, 76.8% achieved steroid-free remission (P&amp;lt;0.001), 77.8% clinical remission (P&amp;lt;0.001), and 81.0% response. Mean CDAI decreased from 214.9 to 117.5 (P&amp;lt;0.001). Endoscopic remission was 19.4%, with 48.9% response and 4.9% mucosal healing. Radiological remission was 9.1% with 85.7% response. Intestinal ultrasound showed 5.7% remission and 56.7% response. Mean albumin increased from 37.3 to 41.4 g/L (P&amp;lt;0.001). Median CRP decreased from 12.3 to 2.3 mg/L (P&amp;lt;0.001), and ESR from 15.0 to 5.0 mm/h (P=0.025). Normal CRP rates improved from 60.0% to 82.7% (P&amp;lt;0.001). Conclusion Upadacitinib demonstrates significant real-world effectiveness and safety in IBD, suggesting its potential as a treatment for biologic-resistant cases. These results support its use in IBD management, with further research needed to fully define its therapeutic role.

P0200 Evaluating the efficacy of tonsil-derived mesenchymal stem cells and intestinal stem cells-like cells in modulating fibrosis and inflammation in murine colitis models

Abstract Background Current treatments in inflammatory bowel disease (IBD) primarily target inflammation, but effective anti-fibrotic treatments are limited. This study evaluates the therapeutic potential of tonsil derived mesenchymal stem cell (TMSCs) and TMSC induced intestinal stem cell-like cell (T-ISCs) in treating intestinal fibrosis and inflammation using two murine colitis models. Methods Two chronic colitis models were established using dinitrobenzene sulfonic acid (DNBS) and dextran sulfate sodium (DSS) in mice. TMSCs and T-ISCs were administered intraperitoneally, with mice divided into seven groups, including control and treatment groups. Colitis symptoms were assessed using disease activity index (DAI) and colon length. After euthanasia on day 30, colon tissues were collected for analysis. Fibrosis markers and inflammatory cytokines were assessed using real-time PCR, while fibrosis severity was evaluated through Masson’s Trichrome staining. In addition, immunofluorescence and western blotting was performed to confirm the fibrosis-related protein expression. Results The therapeutic effects of TMSCs and T-ISCs were confirmed in both DNBS and DSS colitis models. In the DNBS colitis model, both TMSCs and T-ISCs treatments significantly reduced DAI and restored colon length compared to the PBS group (colitis control group) (all p &amp;lt; 0.05). TMSCs treatment markedly decreased three fibrosis markers, including COL1A1, Vimentin, and TGF-β, with statistical significance (p &amp;lt; 0.01, p &amp;lt; 0.01, and p &amp;lt; 0.05, respectively), while T-ISCs significantly reduced only COL1A1 expression (p &amp;lt; 0.05). Histological analyses using Masson’s Trichrome staining showed decreased fibrosis scores in both TMSCs- and T-ISCs-treated groups, and protein expression analysis via immunofluorescence and western blot also confirmed reductions in a-SMA, Vimentin, COL1A1, and TGF-β in both TMSCs- and T-ISCs-treated groups, with a particularly pronounced reduction observed in the TMSCs-treated group. In the DSS colitis model, both TMSCs and T-ISCs treatments significantly decreased the colon shortening compared to the PBS group (all p &amp;lt; 0.05). Although fibrosis markers and scores showed no significant changes, inflammatory cytokine levels were markedly reduced in the DSS colitis model. Notably, T-ISCs demonstrated significant reductions in both IL-1β (p &amp;lt; 0.01) and IL-6 (p &amp;lt; 0.05). Conclusion TMSCs and T-ISCs demonstrate therapeutic effects in murine colitis models mimicking IBD, with fibrosis reduction in the DNBS model and inflammation reduction in the DSS model. These findings suggest that TMSC-based stem cell therapies are promising strategies for treating fibrosis and inflammation in IBD.

P0680 Upadacitanib in Inflammatory Bowel Disease: Evaluating the risk of neutropenia and impact of thiopurine exposure

Abstract Background Upadacitanib is becoming more prevalent in treatment for inflammatory bowel disease (IBD)1. Upadicinitnib selectively inhibits januse kinase 1 (JAK1), modulating immune and hematopoietic processes, such as neutrophil production. JAK1 inhibition lowers neutrophil count, increasing the risk of neutropenia2. While beneficial for immune control, upadacitinib poses haematological risks3,4. The impact of prior immunomodulator use on upadacitinib’s haematological safety profile remains an area of concern. The aim of the study was to identify the incidence and outcomes of neutropenia during upadacitanib therapy and the impact of prior thiopurine exposure. Methods Data was retrospectively collected using the hospital electronic database, including inpatients and outpatients with IBD initiated on upadacitinib from June 2023-May 2024. Patient demographic and clinical data was collected. Absolute neutrophil count x 109 (ANC) was recorded pre and post upadacinitnib initiation. 57 patients were identified, and of these, 15 were excluded due to inadequate blood tests monitoring. Age adjusted logistic regression assessed the link between thiopurine exposure within one year of upadacitinib and ANC &amp;lt;2 during monitoring post initiation with odds ratios (OR) and 95% confidence intervals (CIs) charted on forest plot. Results Of 42 total patients, demographic data showed 22 males vs 20 females and a mean age 45.95 years (SD=15.14). Ethnicities included 23 white, 16 asian, 3 from other ethnic groups. None had ANC &amp;lt;2 at initiation of upadacitinib. During upadacitinib therapy, 31 patients had ANC which remained &amp;gt;2 (74%) and 11 patients developed ANC &amp;lt;2 (26%), which showed no significance. None of the 11 patients with ANC &amp;lt;2 during upadacitinib therapy were found to develop severe infections or required discontinuation. 3 patients had historical thiopurine induced neutropenia, of these only 1 developed ANC &amp;lt;2, showing no significance. Age adjusted logistic regression showed, prior thiopurine use within the past year increases the odds of developing upadacitinib associated neutropenia ANC &amp;lt;1.5 by 3.833 times (95% CI 0.70-20.97, p = 0.12), neutropenia 1.5-2 by 24.9 times (95% CI 1.20-512.57) p = 0.037), and neutropenia &amp;lt;2 by 7.69 times (95%CI 1.62-36.18, p = 0.01) as compared to the patients with ANC &amp;gt;2. Conclusion Upadacitinib did not significantly increase the risk of neutropenia or present factors limiting its use. Thiopurine exposure within the past year significantly increased the risk of neutropenia &amp;lt;2 whilst on upadacitinib. This heightened risk emphasizes the need for close monitoring of neutrophil counts in thiopurine-exposed patients. Larger cohorts and longer follow-ups are needed to confirm these findings.