Role In Inflammatory Bowel Disease Research Articles

Review Article: Albumin and Its Role in Inflammatory Bowel Disease: The Old, the New, and the Future.

Circulating albumin concentrations are frequently measured in clinical practice. This review explores biochemical properties and physiological roles of albumin, its place in nutritional assessment, current understanding of perturbed circulating concentrations, and role in clinical management, with special focus on patients with inflammatory bowel disease (IBD). A detailed literature search was performed. Albumin is synthesized by hepatocytes and comprises 3% of total body protein. It has a prolonged intravascular half-life (17-19 h) due to neonatal Fc-receptor-mediated salvage and has a multitude of physiological functions. Albumin homeostasis is affected in disease states often resulting in reduced level, which is not a direct marker of malnutrition. In patients with IBD, morbid albumin concentrations provide prognostic information, identification of nonintestinal conditions, guidance to the required aggressiveness of therapy and biologic dosage, monitoring of disease activity, and potential need for therapeutic escalation. Barriers to utilization of morbid albumin levels include the lack of consensus regarding cutoff values and the deficiency of high-quality data in this domain due to the retrospective design of the majority of studies. Serum levels hold greatest clinical potential in prognostication in acute severe ulcerative colitis. The premorbid level in the individual may provide insight into dosing of biologics and potentially enhance interpretation of morbid levels. Understanding the physiology and pathophysiology of albumin is fundamental to interpreting its circulating levels. The clinical value of its measurement in patients with IBD may be undervalued, as it assists in evaluation of disease severity, prognosis, and therapeutic decision-making.

Mitochondrial damage-associated molecular patterns: New perspectives for mitochondria and inflammatory bowel diseases.

Mitochondria are key regulators of inflammatory responses and mitochondrial dysfunction is closely linked to various inflammatory diseases. Increasing genetic and experimental evidence suggests that mitochondria play a critical role in inflammatory bowel disease (IBD). In the complex environment of the intestinal tract, intestinal epithelial cells (IECs) and their mitochondria possess unique phenotypic features, shaping each other and regulating intestinal homeostasis and inflammation through diverse mechanisms. Here, we focus on intestinal inflammation in IBD induced by mitochondrial damage-associated molecular patterns (mtDAMPs), which comprise mitochondrial components and metabolic products. The pathogenic mechanisms of mtDAMP signaling pathways mediated by two major mtDAMPs, mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (mtROS), are discussed.

Inflammatory Bowel Disease and Colorectal Cancer: An Eternal Fire in a Beautiful Garden

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, significantly increases the risk of colitis-associated cancer (CAC). Chronic inflammation, a key contributor to carcinogenesis, disrupts immune surveillance, induces deoxyribonucleic acid (DNA) damage, and alters genetic and epigenetic pathways. Molecular pathways such as STAT3, mTOR, and NF-κB drive CAC progression, while unique microbiome alterations—loss of Faecalibacterium prausnitzii and increases in Escherichia coli and Fusobacterium species—exacerbate the inflammatory milieu. CAC accounts for 2% of all colon cancers and up to 15% of IBD-related deaths. Risk correlates with IBD duration, increasing approximately 1% annually after the first decade. Surveillance via colonoscopy is crucial, with chromoendoscopy recommended for high-risk cases. Preventive drugs, including aminosalicylates, thiopurines, and biologics, offer modest benefits but lack conclusive evidence. Post-CAC diagnosis, immunosuppressants are discontinued in favor of corticosteroids, with 5-aminosalicylates continued as needed. The use of immune checkpoint inhibitors remains controversial due to exacerbation of colitis. Emerging insights into the gut microbiota's role in IBD and CAC may revolutionize prevention and management strategies. Advances in screening, surveillance, and therapeutic approaches have reduced CAC mortality, underscoring the importance of personalized medicine and ongoing research to address these complex conditions.

P0035 Food compounds associated with disease activity in Inflammatory Bowel Disease: a novel approach

Abstract Background Diet plays a disease modifying role in inflammatory bowel disease (IBD), but specific relevant dietary factors have yet to be identified. Previous studies examining the role of diet in IBD have typically analysed food groups or specific macro- and micronutrients. To enhance our understanding, we conducted multivariate analyses on the intake of an extensive range of food compounds, using dietary data from a Dutch IBD cohort. Methods We used dietary and disease status data from IBD patients at the University Medical Center Utrecht, The Netherlands. Dietary data were previously collected using a Food Frequency Questionnaire at baseline. Intake levels for 768 compounds from 135 patients were calculated (Meima et al., 2024, submitted). Hereto, we applied a previously developed tool to translate dietary data into food compounds intake data (Meima et al., 2023). This tool serves as an integrated database, combining compound concentration data from three sources: the Dutch food compounds database NEVO, and international food compounds databases FooDB, and Phenol-Explorer. Using random forest analyses, we explored associations between compound intakes and IBD activity by comparing patients who experienced flares (n=41) or remained in remission during a median follow-up of 29 months (interquartile range 20-48 months). We assessed the potential biological relevance of the most significant compounds (n=35) by examining existing literature on IBD, gut health or immunomodulation. Results Random forest models performed particularly good in predicting remission, with specificities and negative predictive values NPVs up to 77 and 79%, respectively. The intakes of the 35 top-ranked compounds were primarily positively associated with IBD remission (n=29). Most of these were fatty acids (n=24). Other compounds positively associated with remission were 4-hydroxyproline, ethanol, vanillin, heptadecanoyl carnitine, and heme iron. For 11 of the 35 compounds, effects on IBD or the gut were available in literature, most of which aligned with our findings. Among these was butyrate, a short chain fatty acid that has been frequently reported for its beneficial role in IBD and gut health. However, several compounds showed discrepancies with literature. For 11 compounds, immunomodulatory effects were reported in literature. Conclusion With a novel approach, using an integrated food compounds database, we identified several food compounds that may play a modulatory role in IBD. Further research is needed to clarify associations found in our study and validate their possible biological significance. References Meima, M. Y., Westerhout, J., Bijlsma, S., Meijerink, M., & Houben, G. F. (2023). Coupling food compounds data from FooDB and Phenol-Explorer to the Dutch food coding system NEVO: towards a novel approach to studying the role of food in health and disease. Journal of Food Composition and Analysis, 123, 105550. Meima, M. Y., Westerhout, J., Bijlsma, S., van Schaik, F. D. M., Oldenburg, B., Campmans-Kuijpers, M.J.E., Dijkstra G., Meijerink, M., Houben, G.F. (2024, submitted). Calculation of Compound Intake Levels using Integrated Food Compound Databases and Food Intake Data. Journal of Food Composition and Analysis.

P0147 Regulation of Inflammatory Pathways by miR-338-3p and miR-378a-3p: A Novel Approach for Crohn’s Disease Treatment

Abstract Background MicroRNAs (miRNAs), key regulators of gene expression, are promising biomarkers and therapeutic targets in inflammatory bowel disease (IBD) due to their roles in immune response and tissue integrity. This study explores miRNA roles in IBD, focusing on Crohn's disease (CD) pathogenesis and potential therapies. We analyzed epithelial cell-derived miRNA expression in CD patients versus healthy controls and investigated how these miRNAs modulate inflammation in experimental IBD models. Methods Terminal ileum samples were prospectively collected via ileocolonoscopy from non-IBD healthy controls (n=26), CD patients in remission (n=34), and active CD patients (n=42). Clinical remission was defined as a Crohn’s Disease Activity Index score below 150 with endoscopic mucosal healing. For active CD cases, samples were taken from inflamed and non-inflamed regions. miRNA levels were quantified by small-RNA sequencing and validated by qRT-PCR. Based on these results, specific miRNAs were selected, and single-stranded mimics were administered in a 2.5% DSS-induced colitis model to evaluate their effects. Histological grading, immunohistochemistry, flow cytometry, and microbiome analysis using mouse fecal samples were performed. Results Small-RNA sequencing revealed distinct miRNA expression patterns in CD patients, both in remission and in active states (including inflamed and non-inflamed tissues), compared to healthy controls. qRT-PCR validation showed significantly reduced expression of miR-141-3p, miR-338-3p, miR-378a-3p, and miR-200b-3p, along with significantly increased levels of miR-125b-5p, miR-29b-3p, and miR-155-5p in inflamed tissue of active CD patients. Receiver operating characteristic curve indicated diagnostic potential for these miRNAs in relation to disease activity and endoscopic inflammation. In a DSS-induced colitis mouse model, miR-338-3p and miR-378a-3p showed anti-inflammatory effects, reducing body weight loss, colon inflammation, and immune cell markers. Target analyses identified MACC1 and IL-33 as key mRNA targets. Immunohistochemistry indicated an IL-33 pathway-dependent anti-inflammatory response via miR-378-3p, while miR-338-3p appeared to regulate gut inflammation by targeting MACC1 gene expression. In vitro analyses revealed that IL-33 activates MACC1, a process also reduced by miR-378a-3p treatment. Fecal microbiome analysis identified several bacterial species including Akkermansia muciniphilia and certain Bacteroides, associated with beneficial effects in the groups treated with both miRNA mimics. Conclusion This study identifies miR-338-3p and miR-378a-3p as modulators of inflammation in an IL-33-dependent manner in CD patients, underscoring their potential as promising targets for treatment of CD.

P0459 Plasma IgA as a biomarker and IL-21 as a potential therapeutic target in Inflammatory Bowel Disease

Abstract Background B cells and their secreted immunoglobulin A (IgA) play an increasingly recognised role in Inflammatory Bowel Disease (IBD) therapy. While plasma IgA levels have been shown to be elevated in IBD patients compared to healthy controls and decrease with biologic therapy1, its relationship with clinical parameters and therapeutic outcomes remains unclear. Cytokines such as interleukin-21 (IL-21), interleukin-6 (IL-6), and B-cell activating factor (BAFF) are known to regulate B-cell activity in IBD2, but their role in IgA secretion requires further investigation. This study aimed to explore these relationships and identify key cytokines regulating IgA secretion. Methods We enrolled 43 patients with IBD (31 ulcerative colitis (UC) and 12 with Crohn’s disease (CD)) between 2022 to 2024. Plasma levels of IgA, haemoglobin (Hb), haematocrit (HCT), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin, calcium, and ferritin were measured at baseline for all patients and at week 14 for patients receiving biological therapy (adalimumab or vedolizumab, n=16). Clinical response was defined as a Crohn’s Disease Activity Index (CDAI) <150 for CD patients or a ≥2-point reduction in the partial Mayo score for UC patients. Statistical analysis was performed using the Student’s t-test and linear regression. Additionally, the DAKIKI cell line was used to assess which cytokines influence IgA secretion. Results Plasma IgA levels significantly decreased at week 14 in most patients receiving biologic therapy (P = 0.0022) (Figure 1A), irrespective of clinical response. However, patients who did not achieve clinical response had significantly higher baseline IgA levels compared to those who did achieve (3057±217.2 vs 1880±214.1 μg/mL, P = 0.0032) (Figure 1B). In all patients, plasma IgA levels showed positive correlations with HCT and ESR, and a negative correlation with ferritin level. Notably, these correlations were stronger in CD patients, where IgA levels showed more significant associations with Hb (R² = 0.2754, P = 0.0369), ESR (R² = 0.3938, P = 0.0123), CRP (R² = 0.3003, P = 0.028), and CDAI (R² = 0.5739, P = 0.0017). In vitro, IL-21 and IL-6 both stimulated IgA secretion in DAKIKI cells, with IL-21 demonstrating greater potency (Figure 2). Conclusion Plasma IgA levels are correlated with disease activity and clinical parameters, particularly in patients with CD, and may serve as a useful biomarker for monitoring therapeutic response. Baseline IgA levels may predictive clinical response at week 14. Additionally, IL-21 appears to be a key cytokine driving IgA secretion, suggesting its potential as a therapeutic target in IBD management.

P0033 GPR84, which is increased in Ulcerative Colitis patients, regulates the cytokine secretion of macrophages

Abstract Background Inflammatory Bowel Disease (IBD) is a gastrointestinal disorder comprising Ulcerative Colitis (UC) and Crohn´s Disease (CD) characterized by an exacerbated and chronic immune response. Although GPR84 has emerged as a proinflammatory receptor in some pathologies such as atherosclerosis or reflux esophagitis, its role in IBD remains unclear. We aim to analyze the protein expression of GPR84 in IBD patients and its role in the cytokine secretion in macrophages. Methods Surgical resections from UC (n=5) and CD patients (n=5) were obtained. Healthy colon and ileum from colon-carcinoma patients (n=10) were used as controls. Protein expression of GPR84 and CD68 was analyzed by WesternBlot and immunohistochemistry. U937 monocytes were differentiated into macrophages with PMA (0,01μM) during 48 hours and treated with the GPR84 agonist decanoic acid (50-250μM) and a proinflammatory cocktail (0,1μM LPS + 20ng/mL IFNγ) during 24 hours. Some of them were treated with the GPR84 antagonist (10μM) or transiently silenced with a specific siRNA-GPR84. RNA was isolated and gene expression of pro- and anti-inflammatory cytokines was quantified by qPCR. Cytokine levels in supernatant were also quantified by Luminex. Data were expressed as fold induction vs control (mean±SEM) and compared by t-test. A p-value<0.05 was considered statistically significant. Results Protein levels of GPR84 were significantly increased in UC patients (150.3±11.75 vs 100.0±11.85), while no differences were observed in CD patients vs healthy ileums. Immunohistochemistry revealed a slight staining of this receptor in intestinal epithelial cells, whereas several cells of the lamina propria were strongly stained. Double immunohistochemistry confirmed that intestinal CD68 macrophages expressed GPR84 in both UC and CD patients. U937-derived macrophages treated with decanoic acid showed a significant increased expression of IL1b (2.68±0.86) and IL8 (2.44±0.48) vs vehicle-treated macrophages (0.998±0.23 and 1.05±0.17, respectively). In addition, IL1b levels in supernatant from macrophages treated with decanoic acid were significantly increased compared with the supernatant from vehicle-treated macrophages (4.50±1.05 vs 1.00±0.19). Moreover, the cotreatment with decanoic acid and GPR84 antagonist significantly reduced the expression of IL1b (0.99±0.29) vs vehicle-treated macrophages (1.94±0.26) and the transiently silencing of this receptor significantly reduced the expression of IL8 (0.89±0.25) vs siCtrl macrophages (4.02±1.59). Conclusion GPR84 is increased in UC patients and expressed in intestinal CD68+ macrophages. It regulates the expression of several cytokines pointing GPR84 as a promising pharmacological target for UC patients.

Formononetin ameliorates DSS-induced colitis by inhibiting the MAPK/PPAR-γ/NF-κB/ROS signaling pathways.

Formononetin (FMN) is a compound isolated from Astragalus membranaceus, that exhibits a range of pharmacological activities, including antitumor, anti-inflammatory, hypolipidemic, and antioxidant effects. Although preliminary study suggests that FMN have a therapeutic role in Inflammatory Bowel Disease (IBD), its specific mechanism of action requires further investigation. This study aimed to investigate the mechanism by which FMN treats DSS-induced colitis in mice. RAW264.7 and Bone marrow-derived macrophages (BMDMs) were treated with LPS to establish an inflammatory cell model. Biochemical parameters and morphological characteristics were assessed in the present or absent of FMN. 4 % solution of DSS was administered to C57BL/6 mice to induce IBD, which served as an animal model for investigating the pharmacodynamics of FMN. FMN significantly reduced colitis-associated injury, as evidenced by a decrease in the disease activity index (DAI), weight gain, and restoration of colon length. Furthermore, FMN inhibits protein expression of NLRP3 inflammasome, suppressed the nuclear translocation of NF-κB/p65, and prevented mitochondrial damage, this process results in a reduction in the accumulation of reactive oxygen species (ROS). Additionally, FMN inhibited the mitogen-activated protein kinase (MAPK) signaling pathway, upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) in the nucleus, and decreased the release of inflammatory factors, thereby exerting anti-inflammatory effects. By inhibiting mitochondrial damage, activating the MAPK/PPAR-γ/ROS signaling pathway, reducing the nuclear translocation of NF-κB, and suppressing the expression of NLRP3 inflammasome-associated proteins, FMN exerts anti-inflammatory effects.

P0132 ACSS2 inhibition alleviates inflammatory signaling and improves epithelial integrity in Inflammatory Bowel Disease in vitro models

Abstract Background Inflammatory bowel disease (IBD), encompassing Ulcerative Colitis (UC) and Crohn’s Disease (CD), is marked by chronic gastrointestinal inflammation stemming from genetic, environmental, immunological, and microbiota factors1. Acetyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) converts acetate into acetyl-CoA and is primarily cytosolic, but translocates to the nucleus under metabolic stress, where it regulates gene transcription and cellular processes2. Although the gastrointestinal microbiota influences acetate levels, the role of ACSS2 in colitis and intestinal inflammation remains poorly understood3. Methods To evaluate ACSS2's role in IBD, we employed in vitro IBD models using Caco-2 and HT-29 intestinal epithelial cell lines. ACSS2 activity was inhibited with an ACSS2 inhibitor, followed by inflammatory stimulation with 100 ng/ml Tumor Necrosis Factor-α (TNF-α) for 30 minutes or 1% Dextran Sodium Sulfate (DSS) for 6 hours. Protein expression levels were assessed via Western blot and immunohistochemistry (IHC) on paraffin-embedded samples from UC patients. The effects of ACSS2 inhibition on inflammatory signaling pathways and cell integrity were assessed using RT-qPCR, immunoblotting, and transepithelial electrical resistance (TEER) measurements. Results Treatment of Caco-2 and HT-29 cells with DSS or TNF-α induced upregulation of ACSS2 protein levels compared to controls. IHC analysis of 30 paired paraffin-embedded colon samples from UC patients revealed higher ACSS2 expression and nuclear localization in inflamed sections compared to non-inflamed regions. Inhibition of ACSS2 activity in stimulated Caco-2 and HT29 cells led to a significant decrease in the gene expression levels of pro-inflammatory cytokines such as Interleukin 8 (IL-8), IL-1β and TNF-α. Additionally, immunoblotting demonstrated reduced phosphorylation of p65 and ERK/MEK, indicating suppression of NF-κB and MAPK inflammatory signaling pathways. To assess the effect of ACSS2 inhibition on cell integrity, TEER assays revealed that ACSS2 inhibition preserved cell integrity in DSS-treated monolayers, accompanied by increased expression of tight junction proteins Occludin and ZO-1, suggesting improved epithelial integrity in the inflammatory context. Conclusion Our findings demonstrate a pro-inflammatory role for ACSS2 in IBD, mediated through its involvement in inflammatory signaling and epithelial integrity. These results highlight ACSS2 as a potential therapeutic target for IBD and warrant further investigations in more advanced models, including human-derived intestinal organoids and in vivo systems, to validate its role in disease pathogenesis and therapeutic potential.

DOP074 JAK inhibition to target fibroblasts and IBD-related fibrosis

Abstract Background Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD). Uncontrolled accumulation of extracellular matrix deposited by fibroblasts is thought to be the underlying cause of fibrogenesis. Janus kinases (JAK) inhibitors are a relatively novel therapeutic strategy in IBD which show a robust anti-inflammatory effect. We hypothesize that JAK-inhibitors might not only play a role in IBD by reducing inflammation, but also offer a therapeutic potential to treat intestinal fibrosis. In this study we explored the effects of JAK inhibition on intestinal fibroblasts in vitro and in vivo. Methods In vitro studies were performed with human CCD-18Co and primary colonic fibroblasts. Levels of activated JAKs and STATs were detected by western blot after cytokine stimulation and were inhibited using tofacitinib (10uM) or upadacitinib (10uM). For the T cell transfer colitis model, Rag-/- mice (n=5-12 mice/group) were used. After engraftment of donor T cells the severity of colitis was evaluated with the mouse endoscopy score (MEICS) and mice were treated with upadacitinib (20mg/kg, 4x/week intraperitoneal injection). Intestinal fibroblast subsets were analyzed using anti-CD90, anti-αSMA, anti-podoplanin, anti-FAP, anti-PDGFR-α and -β, by flow cytometry. Sirius red staining was performed to measure collagen deposition. Levels of activated JAKs and downstream STATs were detected by immunofluorescent staining. Results Re-analysis of our previously published single-cell RNA sequencing data from fibrostenotic tissue of Crohns disease patients identified that a pathogenic subset of activated pro-inflammatory FAP+ fibroblasts was driven by the activation of STAT3 [1]. Inflammatory cytokines activated the JAK-STAT pathway in human fibroblasts and both upadacitinib and tofacitinib strongly inhibited pJAK1, pJAK2, pSTAT1 and pSTAT3 in a concentration dependent manner. Mice treated with upadacitinib showed a significant lower MEICS compared to controls (2.4 vs 5.3, Figure 1). Interestingly, specific intestinal fibroblast subsets, e.g. CD90+PDGFR-β+ fibroblasts were less abundant upon JAK-inhibition. pSTAT3 expression in the colon seemed to change after JAK inhibition. Furthermore, upadacitinib was able to restore the amount and distribution of collagen in the colon. Conclusion Our study is the first to describe that the JAK-STAT pathway can be activated in intestinal fibroblasts and JAK-inhibitors including upadacitinib/ tofacitinib suppress this pathway in vitro. Furthermore, human data show activation of the JAK-STAT pathway in FAP+ fibroblasts and in mice, JAK inhibition has an effect on fibroblasts subsets and collagen deposition. This shows the potential of JAK-inhibitors to target more than immune cells.

P0164 Lauric Acid in Inflammatory Bowel Disease: Balancing Fibrosis Modulation and epithelial-mesenchymal transition Activation

Abstract Background Metabolomics has recently emerged as a valuable tool for understanding inflammatory bowel disease (IBD), revealing distinct metabolic profiles for ulcerative colitis (UC) and Crohn’s disease (CD). Lauric acid (LA), a medium-chain fatty acid with anti-inflammatory properties, has an unclear role in IBD, particularly within a fibrotic context. LA interacts with G protein-coupled receptor 84 (GPR84), which is notably elevated in UC1. Methods We evaluated the effects of LA (0, 50, 100, and 250 µM) on human intestinal fibroblasts (HSIF) and colonic epithelial cells (CoEpi) under basal and pro-fibrotic (TGFβ1 10 ng/ml) conditions. Fibrotic markers were analyzed using PCR (HSIF: COLA1A, COL3A1, COL4A1, ACTA2, FN1, TGFβ, GPR84; CoEpi: SNAI1/2, CDH1, COLA1A, FNCD4, VIM, GPR84) and Western blot (HSIF: GPR84). Data, expressed as fold induction (mean ± SEM) relative to 0 µM LA, were analyzed using either parametric or non-parametric ANOVA (Kruskal-Wallis) based on normality testing (*P < 0.05 vs. 0 nM LA, **P < 0.01 vs. 0 µM LA, #P < 0.05 vs. 0 µM LA + TGFβ1, ##P < 0.05 vs. 0 µM LA + TGFβ1). Results Under basal conditions, LA significantly reduced mRNA expression of collagen molecules [COL1A1 (250 µM: 0.2 ± 0.07**) and COL3A1 (50 µM: 0.4 ± 0.1**)] and αSMA [ACTA2 (100 µM: 0.1 ± 0.1**)] in HSIF cells. In pro-fibrotic conditions, LA maintained or enhanced its protective effect, often at lower doses [COL1A1 (50 µM: 1.1 ± 0.15##), COL3A1 (50 µM: 0.24 ± 0.1#), COL4A1 (250 µM: 0.6 ± 0.1#), ACTA2 (100 µM: 0.7 ± 0.4#)]. LA also increased GPR84 mRNA and protein expression under basal (250 µM: 1167 ± 646*) and pro-fibrotic (250 µM: 1048 ± 505##) conditions, with no changes in fibronectin or TGF expression in HSIF cells. In CoEpi cells, LA promoted epithelial-mesenchymal transition (EMT) under both conditions, shown by changes in mRNA for VIMENTIN (250 µM: 3.9 ± 0.6*; 250 µM + TGFβ1: 6.4 ± 1.5#), SNAI2 (250 µM: 3.4 ± 0.5*; 250 µM + TGFβ1: 3.9 ± 0.5##), E-CADHERIN (250 µM: 0.5 ± 0.08*; 250 µM + TGFβ1: 0.3 ± 0.07#), and FIBRONECTIN (250 µM: 2.6 ± 0.5*; 250 µM + TGFβ1: 4.4 ± 0.8##). GPR84 mRNA was significantly elevated by LA in basal (250 µM: 6.9 ± 1.5**) and pro-fibrotic (250 µM: 5.1 ± 1.0##) conditions. No changes were observed for COLA1A or SNAI1 expression in CoEpi cells. Conclusion LA exhibits a dual role in colonic epithelial and fibroblast cells, showing context-dependent effects that can offer therapeutic benefits or pose challenges. Its interaction with GPR84 underscores a complex regulatory function that requires further study. References Bauset C, Carda-Diéguez M, Cejudo-Garcés A, Buetas E, Seco-Cervera M, Macias-Ceja DC, Navarro-Vicente F, Esplugues JV, Calatayud S, Mira Á, Ortiz-Masiá D, Barrachina MD, Cosín-Roger J. A disturbed metabolite-GPCR axis is associated with microbial dysbiosis in IBD patients: Potential role of GPR109A in macrophages. Biochim Biophys Acta Mol Basis Dis. 2024 Dec;1870(8):167489. doi: 10.1016/j.bbadis.2024.167489. Epub 2024 Sep 2. PMID: 39233260.

P1204 Childhood EBV infection is protective against IBD, while adulthood EBV infection is not: a population-based cohort study

Abstract Background Emerging data indicate a role of Epstein Barr Virus (EBV) infection in immune-mediated diseases risk. However, its role in inflammatory bowel disease (IBD) risk remains to be elucidated. Methods We conducted a nationwide population-based cohort study leveraging cross-linked Danish registers consisting of individuals with a record of being tested for EBV between January 1, 2008 and August 31, 2020. We determined the impact of previous EBV infection, active IBV infection, and no EBV infection on IBD risk, based on EBV serological tests, using adjusted Cox proportional hazards regression analyses after adjusting for sex, type of test, year of test, and age at test. We also determined the impact of age at infection, categorized as early or late childhood or adulthood (0-12, 13-20, and ≥21 years, respectively). Results Of 20,386 individuals included in the study who were followed from the first EBV test for a median (IQR) of 3.93 (2.18-5.95) years, 250 developed IBD. In the overall analysis, there were null associations between prior or current EBV infection and IBD risk. In analyses stratified by age, EBV infection in early and late childhood were associated with a protective effect against IBD, although not statistically significant in the former group (aHR 0.81, 95% CI 0.40, 1.66 and 0.50, 95% CI 0.26, 0.95, respectively). This association was driven by an increase in the risk of Crohn’s disease (CD), but not ulcerative colitis (aHR 0.36, 95% CI 0.15, 0.87 and aHR 0.82, 95% CI 0.32, 2.11, respectively). Among adults, while EBV infection was not associated with IBD risk (aHR 2.17, 95% CI 0.71, 6.62), the effect estimate was in the opposite direction relative to that in childhood, suggesting a potentially increased risk. Conclusion In a nationwide cohort, childhood EBV infection was protective against CD. Adulthood EBV infection was not protective, and possibly associated with increased IBD risk, although this was not statistically significant. Validation studies will help elucidate further.

P0165 A highly miniaturized ingestible sensor for measuring gut health along the GI tract

Abstract Background The human gastrointestinal (GI) tract is challenging to examine due to its intricate structure and inaccessibility. Current diagnostic methods are either invasive, like endoscopy, or offer a limited view, such as faecal tests. Endoscopy capsules allow for a visual inspection of the whole GI tract but still require uncomfortable bowel preparation, including laxatives and dietary restrictions, and cannot provide biochemical analysis of the gut environment. Methods To enable non-invasive assessment of in vivo gut health, we developed a highly miniaturized, ultra-low-power ingestible sensor (the Gastrointestinal Smart Module, or GISMO) capable of measuring pH, temperature, and redox balance throughout the GI tract. Redox balance is crucial for maintaining intestinal barrier function and regulating interactions among the host, immune system, and gut microbiota. Imbalances in redox levels can lead to oxidative stress, characterized by an imbalance between oxidants and antioxidants, and are associated with adverse gut processes, such as inflammation1. Redox balance plays as such an important role in inflammatory bowel disease (IBD)2. The GISMO sensor was validated in both in vitro and in vivo pre-clinical models and subsequently tested in a first-in-human trial. Results In the first-in-human trial, the GISMO system demonstrated feasibility, safety, and ease of use, with 66 ingestible sensors administered to 15 healthy participants. Participants reported ease in swallowing the sensors and expressed willingness to ingest multiple capsules. No device-related adverse events occurred throughout the study. GISMO is the first device capable of measuring in vivo redox balance, providing high-resolution data every 20 seconds. The data revealed consistent profiles from an oxidative environment in the stomach to a strongly reducing environment in the colon. Conclusion We successfully developed, validated, and clinically tested miniaturized technology for assessing GI health in a simple, non-invasive manner. Our ingestible sensors are the first to measure in vivo redox balance along the human gut, requiring no uncomfortable bowel preparation, and enabling real-time monitoring. This innovative technology has the potential to enable easy localization and objective quantification of inflammation, revolutionizing the diagnosis and monitoring of IBD and other gastrointestinal diseases.

Advancing Inflammatory Bowel Disease Treatment by Targeting the Innate Immune System and Precision Drug Delivery.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, involves chronic inflammation of the gastrointestinal tract. Current immune-modulating therapies are insufficient for 30-50% of patients or cause significant side effects, emphasizing the need for new treatments. Targeting the innate immune system and enhancing drug delivery to inflamed gut regions are promising strategies. Neutrophils play a central role in IBD by releasing reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) -DNA-based structures with cytotoxic proteins-that contribute to mucosal damage and inflammation. Recent studies linking ROS production, DNA repair, and NET formation have identified NETs as potential therapeutic targets, with preclinical models showing positive outcomes from NET inhibition. Innovative oral drug delivery systems designed to target gut inflammation directly-without systemic absorption-could improve treatment precision and reduce side effects. Advanced formulations utilize properties such as particle size, surface modifications, and ROS-triggered release to selectively target the distal ileum and colon. A dual strategy that combines a deeper understanding of IBD pathophysiology to identify inflammation-related therapeutic targets with advanced drug delivery systems may offer significant promise. For instance, pairing NET inhibition with ROS-responsive nanocarriers could enhance treatment efficacy, though further research is needed. This synergistic approach has the potential to greatly improve outcomes for IBD patients.

Anti-CdtB and anti-vinculin antibodies to diagnose irritable bowel syndrome in inflammatory bowel disease patients

BackgroundDespite adequate treatment, a subgroup of patients with inflammatory bowel disease (IBD), including Crohn`s disease and ulcerative colitis, have persistent gastrointestinal symptoms that are not always related to mucosal damage. Recently, two autoantibodies, anti-CdtB and anti-vinculin, were validated as post-infectious IBS (PI-IBS) markers, however there is limited evidence of its diagnostic role in IBD population.MethodsPatients with more than 3 bowel movements/day and indication of colonoscopy were enrolled. Samples were collected at the time of colonoscopy for assessment of serum levels of anti-CdtB and anti-vinculin antibodies.ResultsA total of 160 subjects were included in 4 groups: active IBD (n = 44); quiescent IBD and chronic diarrhea IBD-IBS (n = 25); predominant-diarrhea IBS (n = 45) and controls (n = 46). The mean value of the optical density for anti-CdtB was 1.2 ± 0.65 in group 1, 1.27 ± 0.64 in group 2, 1.49 ± 0.47 in the group 3 and 1.6 ± 0.68 in group 4, p = 0.012. For anti-vinculin, optical densities were: 1.34 ± 0.78 in group 1, 1.46 ± 0.92 in group 2, 1.31 ± 0.79 in group 3 and 1.41 ± 0.86 for controls (p = 0.875). Using a cut-off of 1.56 for anti-CdtB, the positivity between groups was n = 10 (22.7%) in group 1, n = 9 (34.6%) in group 2, 19 (43.2%) in group 3, 21 (45.7%) in group 4 (p = 0.106). The positivity of anti-vinculin using a cut-off of 1.6 was n = 18 (40.9%) in group 1, n = 11 (42.3%), n = 15 (34.1%), n = 22 (47.8%) (p = 0.622).ConclusionsOur findings show that anti-CdtB and anti-vinculin could not identify IBD-IBS patients or discriminate IBS-D from healthy controls.

Vascular endothelial growth factor in inflammatory bowel disease: A systematic review and meta-analysis.

Vascular endothelial growth factor (VEGF) is linked to inflammation and angiogenesis, indicating a possible role in inflammatory bowel disease (IBD) and its main clinical manifestations, Crohn's disease (CD) and ulcerative colitis (UC). This systematic review and meta-analysis investigated studies assessing circulating VEGF concentrations in IBD patients and healthy controls, considering the effect of IBD type, sample type and geographical location. A systematic search identified 18 studies (28 group comparators) investigating 1741 IBD patients and 1291 controls. Data were extracted and analysed using standardized mean differences (SMD) with 95% confidence intervals (CI). VEGF concentrations were significantly higher in IBD patients (SMD = .71, 95% CI .38 to 1.04; p < .001). UC patients showed higher VEGF concentrations than CD patients. Serum samples indicated significant VEGF elevations, unlike plasma samples. Significant VEGF increases were observed in studies conducted in Western Europe and Asia, but not in Eastern Europe. No significant differences were found between active and inactive disease. VEGF concentrations are elevated in IBD patients, with variations by disease type, sample type and geography. However, VEGF is not a reliable marker of disease activity. Future research should standardize methods and explore regional influences to enhance VEGF's clinical utility as a biomarker of IBD.

Mendelian randomization reveals predictive, preventive, and personalized insights into inflammatory bowel disease: the role of gut microbiome and circulating inflammatory proteins.

A chronic illness with increasing global frequency, inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), profoundly affects patients' quality of life and healthcare systems. IBD pathogenesis consists of changes in gut microbiota, immune system dysregulation, and genetic predisposition. Although emerging data suggests that gut microbiota and circulating inflammatory proteins play critical roles in IBD, their utility as biomarkers for predictive, preventive, and personalized medicine (PPPM) remains incompletely understood. We hypothesized that specific gut microbiota and inflammatory proteins causally influence IBD risk and mediate pathways between gut microbiota and IBD development. We employed Mendelian randomization (MR) using genome-wide association studies (GWAS) to explore these causal relationships, including further analyses on UC and CD subtypes. We identified eight gut microbiota species linked to IBD, with four protective and four increasing risk. Nine inflammatory proteins were also associated, six increasing risk and three protective. MMP-10 and IL-10Rα mediated the effects of Clostridiaceae1 on IBD risk. For UC, five microbiota species were protective, five were risk factors, and two proteins increased risk while three were protective. IL-10Rα mediated the effects of Clostridiaceae1 on UC risk. For CD, eight microbiota species were protective, four increased risk, and nine proteins were implicated. However, no mediation pathways were supported by multivariable MR. This study highlights specific gut microbiota and inflammatory proteins that may serve as therapeutic targets for PPPM in IBD, UC, and CD. These findings offer new insights into IBD pathogenesis and suggest potential avenues for improved prevention, early detection, and personalized treatment strategies. The online version contains supplementary material available at 10.1007/s13167-024-00384-2.

A Novel Synbiotic Protects Against DSS-Induced Colitis in Mice via Anti-inflammatory and Microbiota-Balancing Properties.

Inflammatory bowel disease (IBD) is a chronic immune-inflammatory disease. Gut microbes, intestinal immunity, and gut barrier function play a critical role in IBD. Growing evidence suggests that synbiotic may offer therapeutic benefits for individuals with colitis, suggesting an alternative therapy against colitis. With this in mind, we creatively prepared a new synbiotic combination consisting of a probiotic strain (Limosilactobacillus reuteri) along with one prebiotic chitooligosaccharides (COS). The protective effects of the synbiotic on DSS-induced colitis and the underlying mechanisms were investigated. We demonstrated that the synbiotic ameliorated colitis in mice, as evidenced by a significant remission in body weight loss and colon shortening, and a decreased disease activity index (DAI). Notably, synbiotic reduced the intestinal inflammation and injury by synergistically decreasing inflammatory factors, inhibiting TLR4/Myd88/NF-κB/NLRP3 signaling, preventing macrophage infiltration, and enhancing the integrity of the intestinal barrier. Moreover, synbiotic selectively promoted the growth of beneficial bacteria (e.g., Akkermansia, Lactobacillus) but decreased the pathogenic bacteria (e.g., Helicobacter). BugBase's analysis supported its ameliorated role in reducing pathogenic bacteria. Collectively, our findings revealed the novel synbiotic had a potential to treat colitis, which was associated with its anti-inflammatory and microbiota-balancing properties. This study will contribute to the development of functional synbiotic products for IBD therapy and will provide valuable insights into their mechanisms.

Selenium, Immunity, and Inflammatory Bowel Disease.

Dietary intervention is a subject of growing interest in the management of inflammatory bowel disease (IBD), as new incident cases across the globe are rapidly rising, suggesting environmental factors as contributing elements. Dietary components and micronutrients have been associated with IBD pathogenesis or reductions in disease severity. Selenium, a diet-derived essential micronutrient that is important for proper immune system function, has received limited attention in the context of IBD. Selenium deficiency is a common finding in patients with IBD, but few clinical trials have been published to address the consequences of this deficiency. Here, we review the physiological and immunological roles of selenium and its putative role in IBD, and draw attention to knowledge gaps and unresolved issues, with the goal of stimulating more research on selenium in IBD.

Modulation of CB1 and CB2 receptors and endocannabinoid activity in inflammatory bowel diseases.

The endocannabinoid system (ECS) and nociceptin receptor (NOP) have been implicated in the pathology of inflammatory bowel diseases (IBD) mediating pain and alleviating inflammation. In this study we searched for the possible activation of ECS and NOP system and the correlation between CB1, CB2 and NOP receptors in IBD patients. Patients diagnosed with IBDs who underwent colonic surgical resection or biopsy at colonoscopy and control group (patients without diagnosis of IBD, which colonoscopy for the different medical indications) were recruited into the study. In surgical specimen the quantification of endocannabinoids was obtained by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry. In biopsy specimen, the expression of genes encoding CB1, CB2, and NOP receptors was determined with real-time RT-PCR. The relative expression of CB1 and CB2 receptors in human samples with IBD compared to the unrelated controls (HC) group was reduced compared to the controls, but no differences in relative expression of NOP receptor were detected. Statistical significance difference was reached only between the level of a relative expression of CB1 receptor in ulcerative colitis (UC) and HC groups (498 (57.45-1890) and 4946 (2098--12818) (P<0.05)). A statistically significant positive correlation between the relative expression of CB1 and NOP receptors (r=0.83, P<0.05) as well as CB2 and NOP receptors in Crohn's disease (CD) (r=0.87, P<0.05) was found. Several endocannabinoids were significantly (P<0.05) increased in tissue collected from UC and CD patients in comparison to controls. CB1 and CB2 but not NOP receptors were found to be downregulated in IBD. Correlation of CB1, CB2 and NOP expression may suggest their common roles and shared molecular pathways in CD. Upregulated level of several endocannabinoids may point out to their role in IBD. Their estimation may be possibly useful in IBD diagnostics.