Inflammatory Bowel Disease Phenotype Research Articles

The TNFSF12/TWEAK Modulates Colonic Inflammatory Fibroblast Differentiation and Promotes Fibroblast-Monocyte Interactions.

Fibroblasts acquire a proinflammatory phenotype in inflammatory bowel disease, but the factors driving this process and how fibroblasts contribute to mucosal immune responses are incompletely understood. TNF superfamily member 12 (TNFSF12, or TNF-like weak inducer of apoptosis [TWEAK]) has gained interest as a mediator of chronic inflammation. In this study, we explore its role as a driver of inflammatory responses in fibroblasts and its contribution to fibroblast-monocyte interaction using human primary colonic fibroblasts, THP-1 and primary monocytes. Recombinant human TWEAK induced the expression of cytokines, chemokines, and immune receptors in primary colonic fibroblasts. The TWEAK upregulated transcriptome shared 29% homology with a previously published transcriptional profile of inflammatory fibroblasts from ulcerative colitis. TWEAK elevated surface expression of activated fibroblast markers and adhesion molecules (podoplanin [PDPN], ICAM-1, and VCAM-1) and secretion of IL-6, CCL2, and CXCL10. In coculture, fibroblasts induced monocyte adhesion and secretion of CXCL1 and IL-8, and they promoted a CD14high/ICAM-1high phenotype in THP-1 cells, which was enhanced when fibroblasts were prestimulated with TWEAK. Primary monocytes in coculture with TWEAK-treated fibroblasts had altered surface expression of CD16 and triggering receptor expressed on myeloid cells-1 (TREM-1) as well as increased CXCL1 and CXCL10 secretion. Conversely, inhibition of the noncanonical NF-κB pathway on colonic fibroblasts with a NF-κB-inducing kinase small molecule inhibitor impaired their ability to induce a CD14high phenotype on monocytes. Our results indicate that TWEAK promotes an inflammatory fibroblast-monocyte crosstalk that may be amenable for therapeutic intervention.

The Impact of Phenotype of Inflammatory Bowel Diseases, Inflammation Activity and Therapy on Mucosal Mature Cd83+ Dendritic Cell.

Background: Crohn's disease (CD) and ulcerative colitis (UC) are well-defined phenotypes of chronic inflammatory bowel diseases (IBDs). A mechanism of inflammation in these diseases is partially controlled by the intestinal dendritic cell (DC). In this study, we observed a mature CD83+ DC in colonic bioptic samples, and its correlation with disease phenotype and activity. Methods: The study included 219 subjects: 100 with UC, 44 with CD and 75 healthy subjects. Colonic biopsy specimens were incubated with the primary antibody Anti-CD83. Intraepithelial CD83+ DCs were counted per 100 enterocytes. The presence of CD83+ DC was analysed according to the type of IBD, histopathologic inflammation activity and treatment outcome. Results: The presence of mature CD83+ DCs (0, ≥1) differed according to disease types of IBD (p = 0.001), histologic inflammation activity (p = 0.049) and applied therapy (p = 0.001). The odds for CD83+ DC presence were 5.2 times higher in the CD group than in the control/UC group. The odds for CD83+ DC presence were 2.6 times higher in subjects without inflammation or chronic inflammation than with acute inflammation. They were also 3.7 times higher in subjects without therapy. The cut-off value 0.5 CD83+ DC (Rock analysis area = 0.699; SE 0.046; p < 0.001; 95% CI: 0.609-0.788) had been assessed as a differentiation marker between UC and CD. Conclusion: Presence of CD83+ DC could be used as a possible parameter in distinction between UC and CD, as well as a predictor of inflammation activity and treatment outcome.

Clinical Phenotype and Disease Course of Inflammatory Bowel Disease in Iran: Results of the Iranian Registry of Crohn's and Colitis (IRCC).

Data on the epidemiology of inflammatory bowel disease (IBD) in the Middle East are scarce. We aimed to describe the clinical phenotype, disease course, and medication usage of IBD cases from Iran in the Middle East. We conducted a cross-sectional study of registered IBD patients in the Iranian Registry of Crohn's and Colitis (IRCC) from 2017 until 2022. We collected information on demographic characteristics, past medical history, family history, disease extent and location, extra-intestinal manifestations, IBD medications, and activity using the IBD-control-8 questionnaire and the Manitoba IBD index, admissions history, history of colon cancer, and IBD-related surgeries. In total, 9746 patients with ulcerative colitis (UC) (n=7793), and Crohn's disease (CD) (n=1953) were reported. The UC to CD ratio was 3.99. The median age at diagnosis was 29.2 (IQR: 22.6,37.6) and 27.6 (IQR: 20.6,37.6) for patients with UC and CD, respectively. The male-to-female ratio was 1.28 in CD patients. A positive family history was observed in 17.9% of UC patients. The majority of UC patients had pancolitis (47%). Ileocolonic involvement was the most common type of involvement in CD patients (43.7%), and the prevalence of stricturing behavior was 4.6%. A prevalence of 0.3% was observed for colorectal cancer among patients with UC. Moreover,15.2% of UC patients and 38.4% of CD patients had been treated with anti-tumor necrosis factor (anti-TNF). In this national registry-based study, there are significant differences in some clinical phenotypes such as the prevalence of extra-intestinal manifestations and treatment strategies such as biological use in different geographical locations.

Prevalence of metabolic syndrome in patients with inflammatory bowel disease: a systematic review and meta-analysis

ObjectivesPatients with inflammatory bowel disease (IBD) may experience comorbidities involving metabolic syndrome (MetS). However, this association remains controversial. Our objective was to estimate the prevalence of MetS in patients with...

Structural brain morphometry differences and similarities between young patients with Crohn's disease in remission and healthy young and old controls.

Crohn's disease (CD), one of the main phenotypes of inflammatory bowel disease (IBD), can affect any part of the gastrointestinal tract. It can impact the function of gastrointestinal secretions, as well as increasing the intestinal permeability leading to an aberrant immunological response and subsequent intestinal inflammation. Studies have reported anatomical and functional brain changes in Crohn's Disease patients (CDs), possibly due to increased inflammatory markers and microglial cells that play key roles in communicating between the brain, gut, and systemic immune system. To date, no studies have demonstrated similarities between morphological brain changes seen in IBD and brain morphometry observed in older healthy controls.. For the present study, twelve young CDs in remission (M = 26.08 years, SD = 4.9 years, 7 male) were recruited from an IBD Clinic. Data from 12 young age-matched healthy controls (HCs) (24.5 years, SD = 3.6 years, 8 male) and 12 older HCs (59 years, SD = 8 years, 8 male), previously collected for a different study under a similar MR protocol, were analyzed as controls. T1 weighted images and structural image processing techniques were used to extract surface-based brain measures, to test our hypothesis that young CDs have different brain surface morphometry than their age-matched young HCs and furthermore, appear more similar to older HCs. The phonemic verbal fluency (VF) task (the Controlled Oral Word Association Test, COWAT) (Benton, 1976) was administered to test verbal cognitive ability and executive control. On the whole, CDs had more brain regions with differences in brain morphometry measures when compared to the young HCs as compared to the old HCs, suggesting that CD has an effect on the brain that makes it appear more similar to old HCs. Additionally, our study demonstrates this atypical brain morphometry is associated with function on a cognitive task. These results suggest that even younger CDs may be showing some evidence of structural brain changes that demonstrate increased resemblance to older HC brains rather than their similarly aged healthy counterparts.

P710 Prevalence, Characteristics and Management of Patients with Difficult-To-Treat Inflammatory Bowel Disease: A Cross-Sectional Study From a Tertiary Referral Center

Abstract Background Difficult-to-treat (D2T) inflammatory bowel disease (IBD) is defined by lack or loss of response to advanced treatments with 2 or more mechanisms of action (MoA), Crohn’s (CD) recurrence after 2 resections, chronic antibiotic refractory pouchitis, complex perianal CD or by the presence of psychiatric comorbidities impairing IBD management.1 We aimed to assess the prevalence, characteristics, management, and outcomes of D2T-IBD. Methods We retrospectively searched the electronic medical records of patients with IBD followed at San Raffaele Hospital (Milan, Italy) as of October 1st, 2023. Patients enrolled in clinical trials altering disease management were excluded. Results In total 679 patients with moderate-to-severe IBD were included (350 CD, 326 UC, 3 IBD-U). 163 patients (24%) met at least one criterion of D2T (25% CD, 23% UC). Of these, 75% did not respond or lost response to 2 or more biologics/small molecules with different MoA, 18% had complex perianal CD, 17% had CD recurrence after 2 or more resections for active CD, the remaining had antibiotic refractory pouchitis or psychiatric comorbidities impairing IBD management. Multiple criteria can coexist. Figure 1. Drug-wise, 54% of patients with D2T-IBD failed 2 MoA, 26% 3 MoA, and 3% 4 MoA, the remaining had other causes of D2T-IBD. Prevalence of D2T varied across phenotypes of CD. The presence of perianal disease doubled the probability of D2T-CD (48 vs 24%); stricturing (B2), fistulizing (B3), and upper gastrointestinal involvement (L4) also increased risk. In UC, 22% of left-sided colitis (E2) and 27% of pancolitis (E3) were D2T, no proctitis was D2T. Patients with D2T-CD had a longer mean disease duration (14 vs 8.7 years; p&amp;lt;0.05) and time on advanced treatments (78 vs 63 months; p&amp;lt;0.05). The same two analyses showed no significant difference for UC (11.6 vs 11.2 years; and 41 vs 50 months; both p&amp;gt;0.05). Differently from bio-naive patients (Figure 2A), patients with D2T-IBD were mostly on ustekinumab, followed by infliximab and adalimumab in CD, and by upadacitinib, infliximab and tofacitinib in UC. Notably, 11 patients with D2T-CD received a combination of advanced therapies. Figure 2B Overall, 61% of patients with D2T-IBD were in clinical remission, 43% in biochemical remission (calprotectin &amp;lt;150 μg/g), and 13% in endoscopic remission (Mayo≤1; or SES-CD≤3 or Rutgeerts i0-i1). Conclusion D2T-IBD is heterogeneous but most commonly due to multidrug failure and associated with certain phenotypes of IBD. Ustekinumab was the most common treatment choice for D2T-IBD. The majority of patients with D2T-IBD achieved clinical remission but failed to achieve biochemical or endoscopic remission. 1. Parigi et al. Lancet Gastroenterol. &amp; Hep. 2023

Altered resting-state brain functional activities and networks in Crohn’s disease: a systematic review

BackgroundCrohn’s disease (CD) is a non-specific chronic inflammatory disease of the gastrointestinal tract and is a phenotype of inflammatory bowel disease (IBD). The current study sought to compile the resting-state functional differences in the brain between CD patients and healthy controls.MethodsThe online databases PubMed, Web of Science Core, and EMBASE were used to find the published neuroimage studies. The search period was from the beginning through December 15, 2023. The predetermined inclusion and exclusion criteria allowed for the identification of the studies. The studies were assembled by two impartial reviewers, who also assessed their quality and bias.ResultsThis review comprised 16 resting-state fMRI studies in total. The included studies generally had modest levels of bias. According to the research, emotional processing and pain processing were largely linked to increased or decreased brain activity in patients with CD. The DMN, CEN, and limbic systems may have abnormalities in patients with CD, according to research on brain networks. Several brain regions showed functional changes in the active CD group compared to the inactive CD group and the healthy control group, respectively. The abnormalities in brain areas were linked to changes in mood fluctuations (anxiety, melancholy) in patients with CD.ConclusionFunctional neuroimaging helps provide a better understanding of the underlying neuropathological processes in patients with CD. In this review, we summarize as follows: First, these findings indicate alterations in brain function in patients with CD, specifically affecting brain regions associated with pain, emotion, cognition, and visceral sensation; second, disease activity may have an impact on brain functions in patients with CD; and third, psychological factors may be associated with altered brain functions in patients with CD.

P1101 Patient-reported physical activity of IBD patients is of concern when weighed with the international physical activity questionnaire regardless of disease activity and IBD phenotype: barriers and facilitators emerged from the extended "BE-FIT-IBD" cross-sectional study

Abstract Background As the World Health Organization recommends, regular physical activity (PA) determines quality of life. The qualitative/quantitative characteristics of ideal PA to be suggested for inflammatory bowel diseases (IBD) nor the relationship with disease activity are not yet well defined. This study aimed to weigh PA levels and barriers/facilitators to PA in a cross-sectional group of patients with IBD. Methods Consecutive Italian non-severe IBD patients (assessed with partial Mayo score for and Harvey-Bradshaw index) received an anonymous online questionnaire to assess PA levels using the International Physical Activity Questionnaire (IPAQ), disease activity as Patient-Reported Outcomes 2 (PRO-2), and finally habits, beliefs, and barriers in conducting regular PA. Clinical, anthropometric, and demographic data were also collected. PA was processed as continuous units of resting metabolic rate in minutes/week (Met min/wk). Three PA groups were identified: inactive (&amp;lt; 700 Met min/wk), sufficiently active (700-2500 Met min/wk) and Health Enhancing PA (i.e., HEPA active, &amp;gt; 2500 Met min/wk) patients. Results The 219 patients enrolled exhibited overall PA levels of 834.5 Met min/wk, with a large proportion (94, 42.9%) classified as inactive. Only a minority (9, 4.1%) resulted as health-enhancing PA. Patients with a non-dyslipidaemia metabolic profile (p &amp;lt; 0.0001) or on biologics therapy (p=0.022) showed better IPAQ scores in moderate activities. PRO-2 correlated negatively with IPAQ intense activities scores (τ= -0.156, p=0.038) in ulcerative colitis patients. PRO-2 did not show notable sensitivity/specificity in predicting IPAQ inactivity (AUC &amp;lt; 0.6). IPAQ showed no notable differences when related to disease activity categories according to PRO-2 (p &amp;gt; 0.05). Physically active patients were more willing to discuss their PA with their IBDologists. Several barriers (e.g., diagnosis of IBD and fear of flare-ups after PA) are firmly rooted in physically inactive patients. Evacuation urgency (rectal syndrome) is the IBD-related barrier most physically inactive patients reported. Some fears about PA were worse felt in the absence of a stable partner (i.e., fear of worsening or recurrence of IBD, p &amp;lt; 0.05). Conclusion Many Italian IBD patients show a worrying rate of physical inactivity, depriving themselves of the multidimensional benefits that regular PA can bring. There is a need for IBDologists to act by removing barriers to PA and engaging in a regular discussion on the importance of PA with IBD patients. IPAQ has shown good feasibility and patient acceptance in this setting.

P427 Inflammatory bowel disease after liver transplantation: a retrospective cohort study from Latin America

Abstract Background The management of inflammatory bowel disease (IBD) in the setting of liver transplantation (LT) is a significant challenge. Previous data have described conflicting results on the incidence of relapses, risk of colectomy and post-transplant prognosis. In addition, there is no guidelines to recommend specific immunosuppressive regimens in this scenario. Our aim is to describe the IBD course in a cohort of liver transplanted patients in Latin America. Methods Medical records from two quaternary centers were reviewed using informatics tools to identify patients with Crohn’s Disease (CD) and Ulcerative Colitis (UC), associated with LT, from January 2010 and July 2023. Data on demographics, IBD phenotype, immunosuppressive therapy and infections were extracted. Results Among 1,683 patients that underwent LT, 45 had concomitant IBD diagnosis. Most for them (55%) were diagnosed with IBD prior to the LT. The median age at IBD diagnosis was 45 years and 57% were male. The majority had UC (80%). The causes of LT were primary sclerosing cholangitis in 24 (53.3%) patients, overlapping with autoimmune hepatitis (AIH) in 15 (33.3%), isolated AIH in 9 (20%), AIH with or without primary biliary cholangitis (PBC) in 4 (8.8%), viral hepatitis in 3 (6,6%) and other causes in 2 (4.4%) patients. Regarding immunosuppression, 19 (42.2%) patients were treated with tacrolimus, 10 (22.2%) with tacrolimus and mycophenolate mofetil, 8 (17.7%) with tacrolimus and azathioprine, 3 (6.6%) tacrolimus and everolimus, 3 (6.6%) with mycophenolate mofetil and cyclosporine, 2 (4.4%) patients with cyclosporine monotherapy. Before LT, 13 (28.8%) patients were treated with aminosalicylates and/or thiopurines, while 2 (4.4%) of them were on biologics. After LT, 20 (44.4%) patients required biological therapy, 11 (24.4%) were treated with anti-TNF (infliximab and adalimumab), 5 (11.1%) with vedolizumab, 3 (6.6%) with ustekinumab and 1 with tofacitinib. Seven (15.5%) patients required total colectomy for refractory disease, 75% after LT. Sixteen (35.5%) patients developed serious infections and the most frequent were cholangitis and cytomegalovirus (68.7%). Two patients developed adverse events, such as infliximab-induced autoimmune hepatitis and thrombocytopenic purpura related to the tacrolimus. Eight (17.7%) patients had malignancies, 3 of them related to the baseline conditions such as hepatocellular, gallbladder carcinoma, colorectal cancer, while 4 patients died during the follow-up. Conclusion In our experience, IBD patients undergoing LT exhibited an aggressive disease course and required concomitant biological therapy, despite the ongoing immunosuppressive regimens.

P1176 The Influence of positive family history on the phenotype and clinical course of inflammatory bowel disease: A Systematic review and meta-Analysis

Abstract Background The phenotypes and clinical course of familial and sporadic inflammatory bowel disease (IBD) are not yet well-established. We sought to perform a systematic review and meta-analysis to assess the pooled influences of positive family history on disease characteristics and clinical outcomes in IBD. Methods We searched MEDLINE, EMBASE, and the COCHRANE library to identify full text articles analyzing disease phenotypes and clinical courses in IBD based on the presence or absence of a family history of IBD. A meta-analysis was performed using a random-effects model to pool estimates and report odds ratios [ORs]. Results A total of 14 studies were identified as eligible for the meta-analysis. A positive family history (of any degree) of IBD was associated with a lower prevalence of extensive colitis in ulcerative colitis (OR 0.83, 95% confidence interval [CI] 0.72-0.94) but was not associated with most phenotype features including male gender (OR 0.89, 95% CI 0.74-1.07), small intestine involvement (OR 1.11, 95% CI 0.81-1.52), and stricturing or penetrating disease behavior (OR 0.99, 95% CI 0.76-1.29) in Crohn's disease, extraintestinal manifestations (OR 1.26, 95% CI 0.89-1.78), or perianal fistula (OR 1.02, 95% CI 0.84-1.23). Additionally, various clinical outcomes of IBD including IBD-related hospitalization (OR 1.52, 95% CI 0.93-2.47), corticosteroid use (OR 0.91, 95% CI 0.58-1.44), immunomodulator use (OR 1.07, 95% CI 0.98-1.17), biologics use (OR 1.13, 95% CI 0.91-1.42), and intestinal resection surgery (OR 1.01, 95% CI 0.83-1.23) were not associated with family history. In the subgroup analysis of studies analyzing first-degree family history alone, family history was also not associated with small intestine involvement, stricturing or penetrating behavior, perianal fistula, corticosteroid use, immunomodulator use, biologics use, or intestinal resection surgery. Conclusion Familial cases with IBD exhibited a lower prevalence of extensive colitis compared to sporadic cases, but the overall disease phenotype and clinical course were similar in both types of IBD.

P448 The role of SARS-CoV2 infection in the clinical outcomes of patients with Inflammatory Bowel Disease

Abstract Background Immunosuppression has been identified as one of the main risk factors for complications and clinical outcomes in SARS-CoV2 infection, this takes special interest in patients with Inflammatory Bowel Disease (IBD), where there are a significant proportion of patients under immunosuppressant treatment such as biologics and steroids. On the other hand, SARS-CoV2 infection has been associated with recurrence or new onset of immune-mediated diseases like IBD. Methods This is a transversal, descriptive and observational study that included patients with IBD and history of SARS-CoV2 infection detected by laboratory tests and accepted to answer the questionary. Analyzed variables: sex, type of IBD (phenotype and localization), COVID-19 symptoms, treatment and severity, exacerbations, and its symptoms. Statics: we used SPSS software version 25 for the descriptive analysis and frequencies. Results We interviewed 186 patients, 105 women (56.5%) and 81 men (43.5%); 146 (78.5%) had Ulcerative Colitis (UC) and 40 (21.5%) Crohn´s disease (CD). Of the total of interviewed patients 82 (44.3%) had history of SARS-CoV2 infection, 16 (19.3%) were asymptomatic, 59 (71.1%) had a mild course of the infection, 8 (9.6%) moderate and no one had severe disease. The most common clinical manifestations were asthenia/adynamia (61.2%), cough (50.7%) headache (44.8%), rhinorrhea (44.8%) and fever (43.3%). Gastrointestinal manifestations were presented in less than 10%. For the infection treatment 69.1% patients used acetaminophen, 13.2% nonesteroideal anti inflammatory drugs (NSAIDs), 1.5% steroids and 4.4% antiviral therapy. Of the 82 patients who presented the infection, 24 (29.3%) had at least one clinical manifestation of disease flare. The most common one was diarrhea in 15 patients (62.5%),10 (41.6%) had abdominal pain, 7 (20.1%) patients had arthralgia and one patient (4.1%) required hospitalization due to disease flare. Of the 24 patients that had disease flare, only 10 (41.6%) received treatment optimization. Conclusion SARS-CoV2 infection prevalence in patients with IBD were 44.2% in this study. The most common clinical course of the infection was mild and moderate disease, no severe cases were reported. The infection caused mild to moderate exacerbation in 28% patients and one patient had severe exacerbation that required hospitalization.

DOP30 Cross-ethnic microbiome analyses identify shared and specific signals for Northern Indian IBD patients

Abstract Background Clinical manifestation of the inflammatory bowel disease (IBD) shows considerable variation across the world. We hypothesized these differences may be influenced by geographical differences in gut microbiome. To test this, we investigated the correlation between gut microbiota and the disease phenotypes of IBD in a cohort form the Northern part of India. Methods Stool samples and clinical metadata were collected from 226 IBD patients (198 ulcerative colitis and 28 Crohn’s disease) and 66 controls from a population cohort from the Northern India. We used metagenomic shotgun sequencing to determine diversity, composition and function of the gut microbiota of the participants. Microbiome was then associated to IBD and its subtypes and clinical metadata (e.g. medication use, drug response, and disease activity). We replicated our results in 436 IBD patients and 903 population controls from the Netherlands analyzed using an identical workflow and used machine learning to assess how well do the Indian IBD signals generalize to Dutch IBD. Results We identified reduction in microbiome diversity and changes in beta diversity in Indian IBD patients (FDR &amp;lt; 0.05, replicated in Dutch population) and identified that 319 taxa and 71 biochemical pathways are altered in Indian patients (FDR &amp;lt; 0.05). Of note, 39% of these signals were replicated in the Dutch cohort (at FDR &amp;lt; 0.05 level). We identified strong dysbiosis shared across Indian and Dutch IBD patients, characterized by expansion of opportunistic pathogens (e.g. Genera Clostridium, Streptococcus and Lactobacilli) and oral bacteria (e.g. Streptococcus oralis and Bifidobacterium dentium) as well as reduction in butyrate producers such as Faecalibacterium prausnitzii, Roseburia hominis and Blautia massiliensis. In addition, we found novel pathobionts specific to the Indian cohort (including oral bacteria from Genus Scardovia and Oribacterium; Actinomyces dentalis and Klebsiella pneumoniae). Machine-learning models trained on the Indian cohort were highly predictive in the Indian test set (Sensitivity 0.84, Specificity 0.95) and generalized to Dutch cohort (Sensitivity 0.77, Specificity 0.69). In addition to IBD-associated dysbiosis, we identified links between medication use and gut microbiota independent of the disease activity: use of Tofacitinib (used by 26 UC patients) was linked to decrease in Lactobacilliales and increase in Clostridia, while Prednisolone and Azathioprine associated to reduction in Roseburia and increase in Streptococcus and Granulicatella. Conclusion The IBD patients from Northern India show gut dysbiosis similar to European patients, but also show enrichment in India-specific pathobionts. The microbiome-based diagnostic models generalize across these populations.

P037 Modelling gut complexity and disease: development of a next-generation adult stem cell based tubular gut-on-a-chip model

Abstract Background Developing effective therapies for Inflammatory Bowel Disease (IBD) necessitates advanced in vitro models that faithfully replicate the intricacies of the gut. The current challenge is to create models that encompass the 3D morphology, heterogeneity, and boundary characteristics of intestinal tissue while also being amenable to high-throughput screening. Microfluidic techniques are emerging as vital tools to introduce physiologically relevant cues into conventional cell cultures. Methods We present an innovative in vitro model employing human adult stem cell-derived colon organoids cultivated as perfused epithelial tubules within the MIMETAS OrganoPlate®. This microfluidic platform facilitates the simultaneous culture of up to 64 independent gut tubules on an extracellular matrix, offering continuous media perfusion without artificial membrane interference. The barrier function of the epithelial tubules is assessed in real-time through transepithelial electrical resistance (TEER) measurements. Immunostaining and 3D reconstruction of confocal images evaluate the expression of relevant epithelial markers. Results The tubular epithelial model of the intestinal tract demonstrated rapid cell polarization, expression of cell-specific markers, tight junction formation, and the presence of functional transporters. TEER measurements indicated functional and reproducible barrier integrity across tubules generated from different organoid donors for at least 10 days. Incorporation of additional cell types, such as patient-derived immune cells and endothelium, marks a groundbreaking advancement in understanding disease pathogenesis. The plug-and-play modularity of these models allows for flexibility in incorporating specific cell types based on the biological pathway of interest. Conclusion Our next-generation gut-on-a-chip model faithfully mimics the IBD phenotype and facilitates screening for potential drug targets. Combining adult human stem cell-derived intestinal organoids with microfluidic technology provides a robust platform to study physiology and disease mechanisms in patient-specific gut models. The inclusion of IBD patient-derived cells promises further refinement, enabling a more profound exploration of disease phenotypes and treatment responsiveness. Moreover, organoids, as one of the most physiologically relevant cell sources, authentically represent patient biology, enhancing the translational potential of our findings.

P370 Quality of life in inflammatory bowel diseases – is the flare all that matters?

Abstract Background Burden in inflammatory bowel diseases (IBD) is high and affects both physical and psychological status. Short inflammatory bowel disease questionnaire (SIBDQ) is a self-administered health-related quality of life questionnaire that evaluates social, bowel, emotional and systemic dimension. Our aim is to evaluate the impact of IBD status on patients’ daily life. Methods We analysed 82 patients diagnosed with Crohn’s disease or ulcerative colitis or that were admitted between March 2021 and April 2022 in Fundeni Clinical Institute, Bucharest. SIBDQ consists of ten questions, with score ranging from 10 (poor) to 70 (optimal). Patients completed SIBDQ and we assessed disease status and determined biological and clinical markers. Results 51% of patients were diagnosed with Crohn’s Disease. 79% were in clinical remission. The mean age was 39.53±12.9 years old and 52.4% were men. Mean illness duration was 8.03±7.18 years. Mean SIBDQ score was 50.25±14.51, with significantly higher scores in the remission subgroup (55.26±10.30 vs. 31.11±12.24, p&amp;lt;0.001) and it correlated with faecal calprotectin level (ρ=-0,502) and C-reactive protein level (ρ=- 0,531), without regard to disease type or sex. There were no correlations between SIBDQ score and Crohn’s disease or ulcerative colitis phenotype, duration since diagnosis, presence of extraintestinal manifestations or history of abdominal surgery related to IBD. Conclusion Patients with IBD flares have low quality of life and SIBDQ scores correlate with markers of disease severity, comparable to previously-published literature. Patients in clinical remission presented with higher SIBDQ scores, independently of IBD phenotype or previous surgery. Acute flares of IBD have a major impact on daily life, additional psychological and social support is needed in order to improve management.

P462 The burden of mental health disease in people with inflammatory bowel disease - Crohn's Colitis Cure (CCC) Data Insights Program

Abstract Background The impact of Inflammatory Bowel Disease (IBD) on individuals’ quality of life is well reported. Recent studies have shown that depression or anxiety affect almost 1 in 5 people with IBD and may be a predictor of active disease. We aimed to explore the burden of MHI in the Australasian IBD population and examine the real-world variation in screening and care across different sites and care settings Methods Crohn’s Colitis Care’s (CCCare) clinical quality registry (CQR) is created by deidentified data flowing across from routine care encounters. Data in the CQR for all individuals with a clinical encounter since August 2018 were interrogated in April 2023. Mental health data were collected from documentation during routine care or through patient consumer completion of embedded questionnaires, namely Depression Anxiety and Stress Scale 21 [DASS-21] and Kessler Psychological Distress Scale [K10] Results The CQR contained 6614 people with IBD with a mean age of 44.4 (SD +/- 22.09) and even gender distribution (50.9% female). 79.5% of people were from Australia and 20.5% from New Zealand. 57.1% of people had Crohn’s disease (CD), 40.4% ulcerative colitis (UC) and 2.5% IBDU with a mean disease duration of 13.3 years (SD +/-23.0). Anxiety was the 4th most listed comorbidity affecting 17.8% of individuals, depression 7th affecting 13.7% of people and both depression and anxiety 13th affecting 9.1% of people with IBD. In total 40.8% or 2 in 5 people with IBD in Australasia had received a formal diagnosis of a MHI. 2,928 consumers had been invited to complete the DASS-21 and 2,340 the K10 (44% &amp; 35% respectively). Of the questionnaires sent, 32% of DASS-21s and 33% of K10s were completed. Rates of both invitation and completion varied significantly between centres. Invitation rates varied from 11% - 90% (p&amp;lt;0.001) while questionnaire completion rates varied from 26% to 46.8% (p&amp;lt;0.001). The mean DASS-21 score for all people with IBD was 8.1 for depression (7-10 indicating moderate disease), 6.6 for anxiety (6-7 suggests moderate disease) and 11.2 for stress (10-12 indicates moderate disease). Individuals with current fistulising CD (representing severe IBD phenotype) mean DASS-21 scores were higher than the wider IBD population, averaging 9.9 for depression (p&amp;lt;0.001), 7.4 for anxiety (p&amp;lt;0.001) &amp; 12.9 for stress (p&amp;lt;0.001) Conclusion Individuals with IBD suffer from high rates of MHIs, with those suffering more severe disease phenotypes scoring worse on mental health assessment tools. Despite the availability of screening and monitoring tools, healthcare providers use these variably and insufficiently. This may result in unmet care needs. Standardisation of care addressing the psychosocial care needs of people with IBD is needed

Corin deficiency alleviates mucosal lesions in a mouse model of colitis induced by dextran sulfate sodium

AimsHigh dietary salt consumption is a risk factor for inflammatory bowel disease (IBD). Corin is a protease that activates atrial natriuretic peptide (ANP), thereby regulating sodium homeostasis. Corin acts in multiple tissues, including the intestine. In mice, corin deficiency impairs intestinal sodium excretion. This study aims to examine if reduced intestinal sodium excretion alters the pathophysiology of IBD. Main methodsWild-type (WT), Corin knockout (KO), and Corin kidney conditional KO (kcKO) mice were tested in a colitis model induced by dextran sulfide sodium (DSS). Effects of ANP on DSS-induced colitis were tested in WT and Corin KO mice. Body weight changes in the mice were monitored. Necropsy, histological analysis, and immunostaining studies were conducted to examine colon length and mucosal lesions. Fecal sodium levels were measured. RT-PCR was done to analyze proinflammatory genes in colon samples. Key findingsDSS-treated Corin KO mice had an ameliorated colitis phenotype with less body weight loss, longer colon lengths, smaller mucosal lesions, lower disease scores, more preserved goblet cells, and suppressed proinflammatory genes in the colon. In longitudinal studies, the DSS-treated Corin KO mice had delayed onset of colon mucosal lesions. ANP administration lessened the colitis in WT, but not Corin KO, mice. Analyses of WT, Corin KO, and Corin kcKO mice indicated that fecal sodium excretion, controlled by intestinal corin, may regulate inflammatory responses in DSS-induced colitis in mice. SignificanceOur findings indicate a role of corin in intestinal pathophysiology, suggesting that reduced intestinal sodium level may offer protective benefits against IBD.

T Cell-Induced Colitis Is Exacerbated by Prolonged Stress: A Comparison in Male and Female Mice.

Psychological stress exposure is well recognized to exacerbate inflammatory bowel disease (IBD) but the mechanisms involved remain poorly understood. In this study, chronic T cell-mediated colitis was induced by adoptively transferring CD4+CD45RBhigh splenic T cells from C57BL/6 WT donor mice into Rag1tm1Mom mice. Two weeks after T cell transfer, mice were exposed to a prolonged restraint stressor (RST) for 8 h per day for 6 consecutive days. The colitis phenotype was assessed via histopathology and semi-quantitative rt-PCR at humane endpoints or 10 weeks post-T-cell transfer. Mice that received the T cell transplant developed chronic colitis marked by increases in colonic histopathology and inflammatory cytokines. Colonic histopathology was greater in males than females regardless of RST exposure but RST exposure increased histopathology scores in females such that they reached scores observed in the males. This pattern was consistent with cytokine gene expression and protein levels in the colon (especially for IFN-γ, IL-17A, and TNF-α). Serum cytokine levels were not strongly affected by exposure to the stressor. Using a murine model of chronic T cell-mediated colitis, this study demonstrates that biological sex strongly influences colonic inflammation and exposure to chronic stress has a more pronounced effect in females than in males.

New resource food-arabinogalactan improves DSS-induced acute colitis through intestinal flora and NLRP3 signaling pathway

Colitis can significantly impact daily life. This study utilized DSS to induce acute colitis in mice and examined the regulatory effect of arabinogalactan (AG). The findings demonstrated that AG intake effectively alleviated the phenotype of DSS-induced colitis in mice and protected against small intestine damage. Furthermore, AG suppressed the secretion of pro-inflammatory factors TNF-α and IL-1β, while promoting the secretion of anti-inflammatory factor IL-10. It also inhibited the secretion of LPS in serum and MPO in colon tissue. Additionally, AG regulated the NF-κB/MAPK/PPARγ signaling pathway and inhibited the NLRP3 inflammasome signaling pathway, thereby ameliorating DSS-induced colitis inflammation in mice. AG also influenced the metabolism of short-chain fatty acids, particularly butyrate, in the intestinal tract of mice. Moreover, AG modulated and enhanced the composition of intestinal flora in mice with colitis, increasing the diversity of dominant flora and promoting the growth of beneficial bacteria. These results highlight the protective effects of arabinogalactan against colitis and its potential applications in the food industry.

Excessive nucleic acid R-loops induce mitochondria-dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation.

Oxidative stress, which can be activated by a variety of environmental risk factors, has been implicated as an important pathogenic factor for inflammatory bowel disease (IBD). However, how oxidative stress drives IBD onset remains elusive. Here, we found that oxidative stress was strongly activated in inflamed tissues from both ulcerative colitis patients and Crohn's disease patients, and it caused nuclear-to-cytosolic TDP-43 transport and a reduction in the TDP-43 protein level. To investigate the function of TDP-43 in IBD, we inducibly deleted exons 2 to 3 of Tardbp (encoding Tdp-43) in mouse intestinal epithelium, which disrupted its nuclear localization and RNA-processing function. The deletion gave rise to spontaneous intestinal inflammation by inducing epithelial cell necroptosis. Suppression of the necroptotic pathway with deletion of Mlkl or the RIP1 inhibitor Nec-1 rescued colitis phenotypes. Mechanistically, disruption of nuclear TDP-43 caused excessive R-loop accumulation, which triggered DNA damage and genome instability and thereby induced PARP1 hyperactivation, leading to subsequent NAD+ depletion and ATP loss, consequently activating mitochondrion-dependent necroptosis in intestinal epithelial cells. Importantly, restoration of cellular NAD+ levels with NAD+ or NMN supplementation, as well as suppression of ALKBH7, an α-ketoglutarate dioxygenase in mitochondria, rescued TDP-43 deficiency-induced cell death and intestinal inflammation. Furthermore, TDP-43 protein levels were significantly inversely correlated with γ-H2A.X and p-MLKL levels in clinical IBD samples, suggesting the clinical relevance of TDP-43 deficiency-induced mitochondrion-dependent necroptosis. Taken together, these findings identify a unique pathogenic mechanism that links oxidative stress to intestinal inflammation and provide a potent and valid strategy for IBD intervention.

Is the Mediterranean Diet in Inflammatory Bowel Diseases Ready for Prime Time?

The rising incidence of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), specifically in the developing world, suggests an important environmental effect. Amongst environmental influences, dietary factors, particularly the adoption of a westernized diet, have been specifically noticed. In contrast, the Mediterranean diet (MED), characterized by high intake of fruits, vegetables, whole grains, legumes, nuts, olive oil, and moderate consumption of animal and ultra processed foods, has shown potential positive effects in IBD. Here we conducted a narrative review focusing on the evidence regarding the role of MED in IBD prevention and management. Epidemiological studies suggest inverse association of MED with CD development. Furthermore, adherence to MED has been associated with clinical improvement in active CD and maintenance of lower levels of inflammatory markers in UC, along with improved quality of life and lower mortality rates in IBD patients. Mechanistically, MED promotes a diverse and beneficial gut microbiota, possesses anti-inflammatory properties through polyphenols and dietary fats, and may modulate oxidative stress. In clinical practice, MED may be adapted to diverse disease phenotypes and cultural preferences, and is a sustainable, easy to maintain dietary approach. Current evidence may support the integration of MED into clinical practice in IBD care. In future research, the efficacy of MED in specific IBD phenotypes should be assessed.