Inflammation In Ulcerative Colitis Research Articles

Proportion of inflammatory bowel diseases patients withsuboptimal disease control in daily clinical practice-Real-world evidence from the inflammatory bowel diseases-podcast study.

Crohn's disease and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by a progressive nature of the disease resulting in subsequent intestinal damage, limited efficacy of current treatments and suboptimal disease management and a significant burden for patients. The IBD-PODCAST study aims to estimate the proportion of Crohn's disease and UC patients with suboptimal disease control (SDC) in a real-world setting. A non-interventional and cross-sectional study was conducted across 103 sites in 10 countries (Austria, Belgium, Canada, Germany, Greece, Italy, Portugal, Spain, Turkey, and UK). Criteria for SDC were based on STRIDE-II criteria and adapted by an expert panel. 2185 patients (Crohn's disease: n=1,108, UC: n=1077) with a mean (SD) age of 44.0 (14.8) years and mean (SD) disease duration of 12.4 (9.2) years were included (52.2% male). Ileal involvement was present in 39.1% of Crohn's disease patients, 35.3% of UC patients had extensive colitis. 77.3% of Crohn's disease and 65.3% of UC patients were on targeted immunomodulators and, according to STRIDE-II-based treatment phases, 85.6% of Crohn's disease and 85.4% of UC patients were assigned to the long-term treatment phase. SDC was detected in 52.2% of Crohn's disease and 44.3% of UC patients predominantly due to impaired quality of life (QoL), clinically significant extraintestinal manifestations, steroid overuse, signs of active inflammation in UC and Crohn's disease, and active fistulas in Crohn's disease. More than one criterion was seen in 37% of patients with SDC. Opportunities for on-label treatment optimization were observed in 49% of Crohn's disease and 61% of UC patients on advanced therapy. The high percentage of SDC in this global, real-world cohort suggests a large disease burden and high unmet medical need in IBD patients. Future analysis should focus on monitoring and responding to SDC in this cohort and on patients' QoL.

Amelioration of Dextran Sodium Sulfate-Induced Colitis in Mice through Oral Administration of Palmitoylethanolamide.

Inflammatory bowel disease (IBD) is a group of chronic disorders characterized by pain, ulceration, and the inflammation of the gastrointestinal tract (GIT) and categorized into two major subtypes: ulcerative colitis (UC) and Crohn's disease. The inflammation in UC is typically restricted to the mucosal surface, beginning in the rectum and extending through the entire colon. UC patients typically show increased levels of pro-inflammatory cytokines, leading to intestinal epithelial apoptosis and mucosal inflammation, which impair barrier integrity. Chronic inflammation is associated with the rapid recruitment and inappropriate retention of leukocytes at the site of inflammation, further amplifying the inflammation. While UC can be managed using a number of treatments, these drugs are expensive and cause unwanted side effects. Therefore, a safe and effective treatment for UC patients is needed. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide and an analog of the endocannabinoid anandamine. PEA administration has been found to normalize intestinal GIT motility and reduce injury in rodents and humans. In the current study, we examined the efficacy of PEA encapsulated in phytosomes following oral administration in experimental ulcerative colitis. Here, we showed that PEA at a human-equivalent dose of 123 mg/kg (OD or BID) attenuated DSS-induced experimental colitis as represented by the reduction in clinical signs of colitis, reduction in gross mucosal injury, and suppression of leukocyte recruitment at inflamed venules. These findings add to the growing body of data demonstrating the beneficial effects of PEA to control the acute phase of intestinal inflammation occurring during UC.

Beneficial Effects of Oxymatrine from Sophora flavescens on Alleviating by Improving Inflammation and Ferroptosis

Ethnopharmacological relevanceSophora flavescens is often used in traditional Chinese medicine for skin issues, diarrhea, and vaginal itching (Plant names have been checked with http://www.the plant list.org on Feb 22th, 2024). Oxymatrine (OY), a major bioactive compound from Sophora flavescens, is commonly used in China to treat ulcerative colitis, but its mechanisms are still unclear. Aim of the studyRecent studies have found that the crosstalk between ferroptosis and inflammation is an important mechanism in the pathogenesis of UC. The aim of this study was to investigate the potential underlying mechanisms of OY treatment on DSS-induced ulcerative colitis, specifically focusing on the processes of ferroptosis and inflammation. Materials and methodsBioinformatics methods were used to identify key targets of OY for ferroptosis and inflammation in ulcerative colitis, based on GEO data and FerrDb database. Then, 4% DSS solution was used to induce UC model. OY's impact on morphological changes was assessed using colon views, Hematoxylin and eosin (HE) staining, and transmission electron microscopy (TEM). Ferroptosis phenotype index and inflammations factors were detected by ELISA or chem-bio detection kitsThe screen out hub related genes about ferroptosis and inflammation were verified by RT-PCR, immunohistochemistry (IHC), immunofluorescence (IF), and western blotting (WB) respectively. ResultsBioinformatics results show that there are 16 key target genes involved in ferroptosis and inflammation interaction of OY treatment for UC, such as IL6, NOS2, IDO1, SOCS1, and DUOX. The results of animal experiments show that OY could depress inflammatory factors (IL-1β, IL-6, TNF-α, HMGB1, and NLRP3) and reduce iron deposition (Fe2+, GSH, and ferritin). Additionally, OY suppressed the hub genes or proteins expression involved in ferroptosis and inflammation, including IL-1β, IL-6, NOS2, HIF1A, IDO1, TIMP1, and DUOX2. ConclusionThis present study combines bioinformatics, molecular biology, and animal experimental research evidently demonstrated that OY attenuates UC by improving ferroptosis and inflammation, mainly target to the expression of IL-1β, IL-6, NOS2, HIF1A, IDO1, TIMP1, and DUOX2.

Comparison of diagnostic accuracy between linked color imaging and autofluorescence imaging in patients with ulcerative colitis: A prospective observational study.

Image enhancement endoscopy techniques, such as linked color imaging (LCI) and autofluorescence imaging (AFI), have shown promise in diagnosing mucosal inflammation in ulcerative colitis (UC). However, no studies have directly compared the diagnostic efficacy of LCI and AFI. This prospective observational study aimed to compare their diagnostic accuracy for histological healing in UC. This study included 81 UC patients, resulting in a total of 204 endoscopic images captured using LCI and AFI, respectively. Spearman's rank correlation coefficients assessed the correlation between LCI and AFI coloration and Geboes histopathology score (GHS). Six endoscopists, who were blinded to clinicopathological features, evaluated these images, and subsequently, the diagnostic accuracy was evaluated. Spearman's rank correlation coefficients between LCI index, AFI index (reverse gamma value), and GHS were 0.324 and -0.428, respectively (P<0.001), indicating a significant correlation between LCI and AFI coloration and histological healing. In LCI and AFI classifications, mean values for diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 76.3±2.2 versus 77.8±2.7, 91.8±4.0 versus 83.2±7.6, 53.4±10.0 versus 70.0±5.3, 74.0±3.5 versus 80.0±1.6, and 82.9±5.2 versus 75.5±7.5, respectively. No significant difference in diagnostic accuracy existed between LCI and AFI classifications. However, LCI displayed higher sensitivity than AFI while AFI showed higher specificity compared with LCI (P<0.05). LCI and AFI offer comparable diagnostic accuracy for histological healing. Clinically, it is necessary to recognize diagnostic features characterized by higher sensitivity in LCI and greater specificity in AFI.

Level of interleukin 17 in inflammatory bowel disease and its relation with disease activity

BackgroundInflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the gastrointestinal tract (GIT).It results in progressive intestinal epithelium structural and functional damage that necessitates lifetime medication.Thereis imbalance in the production of T helper 1 (Th1), Th2 and Th17 cytokines. This plays a crucial role in the chronic inflammatory process and the defective immune response to pathogenic agents; thus promoting the recurrence of the disease.Our aim of this study was to detect serum IL-17 levels in IBD patients and its relation with disease activity.MethodsThis was a single center case control study, conducted at hepatology and gastroenterology unit, Mansoura specialized Medical Hospital, Egypt.Patients who were included were aged 18–65 years, diagnosed either Ulcerative Colitis (UC)or Crohn’s Disease (CD) based on previous colonoscopy.IBD activity was measured for UC using the MAYO score and CD using the CD activity index (CDAI). Fifty five patients were UC, 24 patients were CD, 21 patients were control.Patients who were excluded were under 15 years old, with history of GIT malignancy, or any serious comorbidities. Study protocol was approved by Institution Research Board (IRB) of Mansoura Medical College.All patients were subjected to full history taking, routine physical examination, colonoscopy and laboratory investigations including serum IL-17 levels by ELISA besides CBC, CRP, ESR and fecal calprotectin.ResultsSerum IL-17 level was increased significantly among UC; median (min-max) = 72(21–502)pg/ml, in CD 54.5(25–260) versus control 19 (14–35), P < 0.001.However, it was not correlated to the disease activity either Mayo score of UC or CDAI of CD.There was significant correlation to the extent of inflammation in UC affecting the colon (either proctosigmoiditis, left sided colitis or pan colitis), also to the type of CD (either inflammatory, stricturing or fistulizing) by P < 0.05.It was not correlated significantly with any of the IBD activity markers (CRP, ESR, or fecal calprotectin).Yet there was negative significant correlation with Hb level (r =-0.28, p = 0.005).There was not significant association between median serum level of IL-17 & duration of disease (P = 0.6).However, median IL-17 was higher among hospitalized cases than non-hospitalized (73 & 55, pg/ml respectively; p < 0.002). AUC was significantly differentiating between IBD and control group = 0.993 with the best-detected cut off point from curve 32 pg/ml yielding sensitivity of 97.5% and specificity of 95.2%.ConclusionSerum IL-17 increases in colonic inflammation significantly more than in control group, however its increase is not correlated to IBD activity.

Rab7-dependent regulation of goblet cell protein CLCA1 modulates gastrointestinal homeostasis

Inflammation in ulcerative colitis is typically restricted to the mucosal layer of distal gut. Disrupted mucus barrier, coupled with microbial dysbiosis, has been reported to occur prior to the onset of inflammation. Here, we show the involvement of vesicular trafficking protein Rab7 in regulating the colonic mucus system. We identified a lowered Rab7 expression in goblet cells of colon during human and murine colitis. In vivo Rab7 knocked down mice (Rab7KD) displayed a compromised mucus layer, increased microbial permeability, and depleted gut microbiota with enhanced susceptibility to dextran sodium-sulfate induced colitis. These abnormalities emerged owing to altered mucus composition, as revealed by mucus proteomics, with increased expression of mucin protease chloride channel accessory 1 (CLCA1). Mechanistically, Rab7 maintained optimal CLCA1 levels by controlling its lysosomal degradation, a process that was dysregulated during colitis. Overall, our work establishes a role for Rab7-dependent control of CLCA1 secretion required for maintaining mucosal homeostasis.

Rab7-dependent regulation of goblet cell protein CLCA1 modulates gastrointestinal homeostasis.

Inflammation in ulcerative colitis is typically restricted to the mucosal layer of distal gut. Disrupted mucus barrier, coupled with microbial dysbiosis, has been reported to occur prior to the onset of inflammation. Here, we show the involvement of vesicular trafficking protein Rab7 in regulating the colonic mucus system. We identified a lowered Rab7 expression in goblet cells of colon during human and murine colitis. In vivo Rab7 knocked down mice (Rab7KD) displayed a compromised mucus layer, increased microbial permeability, and depleted gut microbiota with enhanced susceptibility to dextran sodium-sulfate induced colitis. These abnormalities emerged owing to altered mucus composition, as revealed by mucus proteomics, with increased expression of mucin protease chloride channel accessory 1 (CLCA1). Mechanistically, Rab7 maintained optimal CLCA1 levels by controlling its lysosomal degradation, a process that was dysregulated during colitis. Overall, our work establishes a role for Rab7-dependent control of CLCA1 secretion required for maintaining mucosal homeostasis.

Simple and versatile in situ thermo-sensitive hydrogel for rectal administration of SZ-A to alleviate inflammation and repair mucosal barrier in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon and disrupted intestinal function. Ramulus mori (Sangzhi) alkaloids (SZ-A), derived from twigs of mulberry, were approved by the National Medical Products Administration in 2020 for treating type 2 diabetes mellitus. Accumulated evidence has confirmed that SZ-A also alleviates non-alcoholic fatty liver disease and ameliorates inflammation, indicating its potential to address inflammation in UC. However, the treatment of UC faces challenges due to low drug delivery efficiency and short retention time. To overcome these challenges, an injectable and adherent in-situ thermo-sensitive hydrogel containing SZ-A was developed for rectal drug delivery, utilizing the thermo-sensitive polymers Poloxamer 407 and 188. The thermo-sensitive hydrogel system was designed with a moderate gelation temperature of 32 ± 0.5 °C, a short gelation time of 64 s, a pH range of 7–10, high moisturizing capability exceeding 90%, and moderate mechanical strength of 4–5 s. In a rat model with UC, the in situ thermo-sensitive hydrogel significantly extended the retention time at the colonic site and enabled sustained release after rectal administration. Symptoms of UC were markedly reduced following rectal administration of SZ-A thermo-sensitive hydrogel. Furthermore, the release of inflammatory factors, such as interleukin-1β (IL-1β), IL-6, IL-18, tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1), significantly decreased in the SZ-A thermo-sensitive hydrogel group. The integrity of the colonic mucosal barrier was significantly enhanced following the application of SZ-A thermo-sensitive hydrogel. In conclusion, rectal administration of SZ-A in situ thermo-sensitive hydrogel effectively alleviated UC symptoms, inhibited the secretion of inflammatory factors, and promoted the repair of the colonic mucosal barrier. This approach holds promise as a potential treatment for UC.

Moxibustion alleviates intestinal inflammation in ulcerative colitis rats by modulating long non-coding RNA LOC108352929 and inhibiting Phf11 expression

Long noncoding RNA (lncRNAs) are involved in the pathogenesis of ulcerative colitis (UC). Moxibustion, a traditional Chinese medicine, can improve symptoms in patients with UC and reduce intestinal inflammation in rats with UC. However, it remains unclear whether the ameliorative effect of moxibustion on intestinal mucosal inflammation in UC is related to lncRNAs. Thirty-two rats were randomly assigned to four groups: normal control, UC, moxibustion (MOX), and sulfasalazine (SASP). The UC rat model was induced by administering 4% dextran sulfate sodium (DSS) in drinking water. Rats in the moxibustion group underwent bilateral Tianshu (ST25) moxibustion using the herbs-partition moxibustion method. Rats in the sulfasalazine group received SASP solution via gavage twice daily for seven consecutive days. Our results revealed that, compared with the UC group [2.00 (1.00, 2.50)], the DAI score [0.25 (0.00, 0.50)] was significantly lower in the MOX group (P < 0.05). Compared with the UC group [13.00 (11.25, 14.00)], the histopathological score [5.50 (4.00, 7.75)] was significantly lower in the MOX group (P < 0.05). In addition, the CMDI and macroscopic scores were decreased in the MOX group (P < 0.05). Moxibustion significantly decreased the protein expression of inflammatory factors TNF-α, IFN-γ, and IL-1β in the colonic tissues of UC rats (P <0.05), thereby suppressing the inflammatory response. Moreover, moxibustion exerted a regulatory influence on colon lncRNA and mRNA expression profiles, upregulating LOC108352929 and downregulating Phf11 in rats with UC (P <0.05). Moxibustion also led to a reduction in the expression and colocalization of Phf11 and NF-κB in the colons of UC rats. Moreover, knockdown of LOC108352929 in rat enteric glial cells demonstrated a significant upregulation of TNF-α mRNA expression (P <0.05). In summary, these data illustrate that moxibustion effectively ameliorates DSS-induced colonic injury and inflammation while exerting regulatory control over the lncRNA-mRNA co-expression network in UC rats. Collectively, the in vivo and in vitro studies suggested that LOC108352929-Phf11 may serve as a potential biological marker for moxibustion in the treatment of UC.

A181 EXPLORING THE ROLE OF KLEBSIELLA VARIICOLA AND KLEBSIELLA PNEUMONIAE IN PEDIATRIC ULCERATIVE COLITIS PATHOGENESIS

Abstract Background Recent studies indicated that Klebsiella (K) pneumoniae (isolated from the stool of IBD patients) and K. variicola (isolated from the mesenteric tissue of Crohn disease patients) have the potential to induce inflammation in epithelial and preadipocyte cells, exacerbating colitis in murine models. Aims We isolated these strains from pediatric ulcerative colitis (UC) patients' appendix (relevant to UC pathogenesis given the protective effects of appendectomy) and other non-inflamed colon sections. We hypothesized that these isolates are invasive and induce inflammation in UC. These strains have not been previously studied in UC. Methods K. variicola and K. pneumoniae were isolated from two pediatric UC patients' appendices and other non-inflamed colon sections and identified using 16S DNA Sanger sequencing. Virulence of the two strains was determined by infecting Caco2 cell lines and performing adhesion and invasion assays, quantifying biofilm formation, and assessing barrier functions using transepithelial electrical resistance (TEER) measurement. Importantly, we monitored the production of pro-inflammatory (e.g., IL-8, TNF-α) and anti-inflammatory (IL-10) cytokines using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Results K. variicola and K. pneumoniae exhibited high levels of biofilm formation compared to adherent-invasive Escherichia coli (AIEC), which are commonly isolated from IBD patients. Furthermore, the Klebsiella strains adhered to epithelial cells within 2-3 hours post infection. TEER experiments showed compromised barrier integrity after 6 hours and overnight infection. Except for K. pneumoniae isolated from the ascending colon, the tested strains exhibited a significant increase in IL-8 expression. Similarly, K. variicola from the peri-appendicular region demonstrated elevated TNF-α gene expression. Conclusions K. variicola and K. pneumoniae isolated from UC patients have the potential to form biofilms, disrupt barrier integrity, and trigger inflammatory responses. These findings unravel a potential role for pathogenic Klebsiella strains in driving UC pathogenesis. Importantly, these data shed light on the role of appendix-associated bacteria in the development of UC. Future work includes using comparative genomics to map the virulence determinants of these bacteria. Funding Agencies CIHRWomen and Children's Health Research Institute (WCHRI)

Explore on the Mechanism of miRNA-146a/TAB1 in the Regulation of Cellular Apoptosis and Inflammation in Ulcerative Colitis Based on NF-κB Pathway.

Ulcerative colitis (UC) is a chronic non-specific inflammatory disease of the rectum and colon with unknown etiology. A growing number of evidence suggest that the pathogenesis of UC is related to excessive apoptosis and production of inflammatory cytokines. However, the functions and molecular mechanisms associated with UC remain unclear. The in vivo and in vitro models of UC were established in this study. MiRNA or gene expression was measured by qRT-PCR assay. ELISA, CCK-8, TUNEL, and flow cytometry assays were applied for analyzing cellular functions. The interactions between miR-146a and TAB1 were verified by luciferase reporter and miRNA pull-down assays. MiR-146a was obviously increased in UC patients, DSS-induced colitis mice, and TNF-ɑ-induced YAMC cells, when compared to the corresponding controls. MiR- 146a knockdown inhibited the inflammatory response and apoptosis in DSS-induced colitis mice and TNF-ɑ-induced YAMC cells. Mechanistically, we found that TAB1 was the target of miR-146a and miR-146a knockdown suppressed the activation of NF-κB pathway in UC. More importantly, TAB1 could overturn the inhibitory effect of antagomiR-146a on cell apoptosis and inflammation in UC. MiR-146a knockdown inhibited cell apoptosis and inflammation via targeting TAB1 and suppressing NF-κB pathway, suggesting that miR-146a may be a new therapeutic target for UC treatment.

Ultra-Processed Food, Disease Activity, and Inflammation in Ulcerative Colitis: The Manitoba Living With IBD Study.

The purpose of this study was to investigate the relationship between ultra-processed food (UPF) consumption and (i) symptomatic disease and (ii) intestinal inflammation among adults with inflammatory bowel disease (IBD). We identified participants (Crohn's disease [CD] and ulcerative colitis [UC]) from the Manitoba Living with IBD study. Active disease was defined using the IBD Symptom Inventory (score >14 for CD; >13 for UC); fecal calprotectin was measured for intestinal inflammation (>250 μg/g). Diet data were collected using the Harvard Food Frequency Questionnaire. UPF consumption was determined by the NOVA classification system. Percentage of energy consumption from UPFs was calculated and divided into 3 tertiles (T1 = low; T3 = high). Multiple linear regression analysis was used for active disease and inflammation predicted by UPF consumption. Among 135 participants (65% with CD), mean number of episodes of active disease (14.2 vs 6.21) and active inflammation (1.6 vs 0.6) was significantly higher among participants with UC in T3 compared with T1 of UPF consumption ( P < 0.05). When adjusting for age, sex, disease type, and duration, number of episodes of active disease was lower in T1 compared with T3 (β = -7.11, P = 0.02); similarly, number of episodes of intestinal inflammation was lower in T1 (β = -0.95, P = 0.03). No significant differences were observed among participants with CD. UPF consumption may be a predictor of active symptomatic disease and inflammation among participants with UC. Reducing UPF consumption is a dietary strategy that can be suggested for minimizing symptoms and inflammation among people living with IBD.

P119 Single-cell RNA sequencing in Inflammatory Bowel Disease in patients with Primary Sclerosing Cholangitis: a distinct form of colitis

Abstract Background Primary sclerosing cholangitis (PSC) is an inflammatory disorder of the bile ducts, in which Inflammatory bowel disease (IBD) concomitantly occurs (PSC-IBD). Substantial differences in clinical presentation are observed between PSC-IBD and ulcerative colitis (UC). In this study we aim to find distinct pathomechanisms for PSC-IBD using single-cell RNA sequencing. Methods Forty-seven colonic samples of PSC-IBD (n=24), UC (n=18) and non-IBD subjects (n=5) were collected. Whole biopsies were dissociated into single cells using collagenase digestion. Library preparation was done with 10x Genomics and sequencing was performed on an MGI2000 sequencer. Then, differential abundance, differential expression, and cell-cell interaction analyses were performed. Stainings for DUOX2 and HLA-DR were performed on paraffin embedded colon mucosal slides. Results In total, 71,798 high quality cells identified 54 distinct cell types, including a new type of epithelial cells: DUOX2+ enterocytes. DUOX2+ enterocytes are almost exclusively present in diseased inflamed colon and can act as antigen presenting cells through the expression of MHC2 on its surface. A general shift in cell type composition upon inflammation was observed, comparable between PSC and UC samples. However, an increased abundance was seen for stem cells in non-inflamed (NI) PSC, and not in UC-NI, compared to healthy controls. Additionally, we found distinct gene expression patterns between PSC and UC inflammation: while activation of inflammatory monocytes was observed in PSC inflammation, several types of fibroblasts were activated upon UC inflammation. Conclusion We describe DUOX2+ enterocytes, which may play a role in both PSC and UC colitis through antigen presentation. Furthermore, we show that intestinal inflammation in PSC-IBD, as compared to UC, is characterized by distinct mucosal cell composition and cell-specific gene expression patterns. PSC colitis, and not UC colitis, is driven by activation of inflammatory monocytes, with antigen presentation through HLA-DRB1, and activation of CD4+ T cells. Additionally, an increased abundance of stem cells in PSC-NI could be related with the increased colorectal cancer risk in PSC-IBD.

P108 Response to vedolizumab in ulcerative colitis is associated with reduced neutrophil extracellular traps formation and IL-1β production: insights from NEUTROVED study

Abstract Background Vedolizumab (VDZ) is a humanized mAb against integrin α4β7. VDZ inhibits gut inflammation by impeding intestinal T-cell homing, however, recent data suggest that effects of α4β7 blocking extend beyond T-cells to alterations in innate immunity. Neutrophils are key components of innate immune response and inflammation in ulcerative colitis (UC). Studies have provided evidence linking neutrophils with UC pathogenesis, through autophagy induction and production of IL-1β-enriched neutrophil extracellular traps (NETs). NEUTROVED aimed to investigate the effects of VDZ treatment on neutrophils that may be associated with clinical and endoscopic response. Methods Patients with moderate-to-severe UC who received VDZ in standard medical care were evaluated in two timepoints, 24 hours before treatment initiation (T1) and at week 14 of treatment (T2). Clinical/endoscopic scores and common laboratory indexes were evaluated. In parallel, RNA-sequencing in peripheral neutrophils was performed, and markers of NETs in plasma and intestinal biopsies were assessed. Results In total 5 patients completed the study until today (Table 1). In T2, 4 patients demonstrated complete remission, and one patient had mild disease. No adverse events were recorded. RNA-sequencing analysis of paired samples revealed 248 significantly downregulated and 109 upregulated genes in peripheral neutrophils after VDZ treatment. Bioinformatics analysis using the GeneCodis4 web-based tool revealed that downregulated DEGs clustered mainly in immune-related pathways, including neutrophil degranulation, Toll-like receptor cascades, signaling by interleukins, NETs formation, and HIF-1 signaling pathway, while upregulated DEGs were involved in RNA metabolism-related processes, and the ribosome biogenesis pathway. A comparative analysis between these differentially expressed genes (DEGs) and our previous RNA-sequencing data of peripheral neutrophils isolated from active UC patients (n=24) highlighted a set of 168 DEGs as restored targets after VDZ therapy. Of note, several unique genes implicated in neutrophil activation, including IL-1 signaling components, were found significantly downregulated after VDZ therapy. In line with the abovementioned transcriptome alterations, markers of NETs and IL1β-bearing NETs in plasma and colonic tissue were significantly reduced, recapitalizing clinical and endoscopic response to VDZ. Conclusion Response to VDZ treatment in UC is related to anti-inflammatory actions on neutrophils characterized by reduced NETosis and IL-1β production through NETs. Further mechanistic studies investigating the possible effects of VDZ on innate immunity and neutrophil-mediated responses are warranted.

P138 Novel serum markers for predicting disease activity in ulcerative colitis: results from a retrospective case-control study

Abstract Background Commonly used serum or faecal markers, such as C-reactive protein (CRP) and feacal calprotectin have several limitations and do not always correlate well with the degree of mucosal inflammation in the intestine as established by endoscopy. The aim of the current study was to evaluate the utility of a panel of serum markers (Visfatin, serum amyloid, LRG1, MMP-1, MMP-2, TFF3, Lipocalin-2 (NGAL), IL-6, IL-4, IL-7, IL-17) in predicting mucosal inflammation in ulcerative colitis(UC) patients. Methods We conducted an unmatched case-control retrospective study. Patients were selected consecutively, based on their enrollement date, from a prospective IBD cohort. We selected two groups of UC patients, each of them with active disease at baseline and different outcomes during follow-up: mucosal healing and persistant disease activity, as resulted from clinical and endoscopic evaluation. Inflammatory burden was investigated using the C-reactive protein and endoscopic activity was reported using the Mayo endoscopic score. Quality of life was also evaluated at each visit using The Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Clinical disease activity was quantified using the partial Mayo score. Clinical remission was defined as a partial Mayo score &amp;lt; 2. Endoscopic activity was assessed using the Mayo endoscopic score[i] . Mucosal healing was defined as Mayo endoscopic score of 0. The selection of investigated biomarkers was based on the results of a systematic review previously published by the research team [i] State M, Negreanu L, Voiosu T, Voiosu A, Balanescu P, Mateescu RB. Surrogate markers of mucosal healing in inflammatory bowel disease: A systematic review. World J Gastroenterol. 2021 Apr 28;27(16):1828-1840. doi: 10.3748/wjg.v27.i16.1828. Results 84 serum samples from 42 patients were retrospectively analyzed (21 patients with mucosal healing and 21 patients with persistant activity during follow-up). Lipocalin proved to be a reliable marker for the noninvasive assessment of endoscopic activity, with 90% sensitivity and 95% specificity at a cut-off level of 0,421μg/ml (AUROC 0,677). The combination of lipocalin, age, gender and BMI (Figure 1) is a good predictor of persistant activity during follow-up (AUROC 0.87, 95% CI, 0.762-0.979). Conclusion Our findings provide support for the use of lipocalin as a surrogate marker for mucosal inflammation. The combination of lipocalin, age, gender and BMI might be useful for guiding treatment and monitoring decisions.

P1238 Exploring the Role of Klebsiella variicola and Klebsiella pneumoniae in Pediatric Ulcerative Colitis Pathogenesis

Abstract Background Recent studies indicated that Klebsiella (K) pneumoniae (isolated from the stool of IBD patients) and K. variicola (isolated from the mesenteric tissue of Crohn disease patients) have the potential to induce inflammation in epithelial and preadipocyte cells, exacerbating colitis in murine models. We isolated these strains from pediatric ulcerative colitis (UC) patients' appendix (relevant to UC pathogenesis given the protective effects of appendectomy) and other non-inflamed colon sections. We hypothesized that these isolates are invasive and induce inflammation in UC. These strains have not been previously studied in UC. Methods K. variicola and K. pneumoniae were isolated from two pediatric UC patients' appendices and other non-inflamed colon sections and identified using 16S DNA Sanger sequencing. Virulence of the two strains was determined by infecting Caco2 cell lines and performing adhesion and invasion assays, quantifying biofilm formation, and assessing barrier functions using transepithelial electrical resistance (TEER) measurement. Importantly, we monitored the production of pro-inflammatory (e.g., IL-8, TNF-α) and anti-inflammatory (IL-10) cytokines using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Results K. variicola and K. pneumoniae exhibited high levels of biofilm formation compared to adherent-invasive Escherichia coli (AIEC), which are commonly isolated from IBD patients. Furthermore, the Klebsiella strains adhered to epithelial cells within 2-3 hours post infection. TEER experiments showed compromised barrier integrity after 6 hours and overnight infection. Except for K. pneumoniae isolated from the ascending colon, the tested strains exhibited a significant increase in IL-8 expression. Similarly, K. variicola from the peri-appendicular region demonstrated elevated TNF-α gene expression. Conclusion K. variicola and K. pneumoniae isolated from UC patients have the potential to form biofilms, disrupt barrier integrity, and trigger inflammatory responses. These findings unravel a potential role for pathogenic Klebsiella strains in driving UC pathogenesis. Importantly, these data shed light on the role of appendix-associated bacteria in the development of UC. Future work includes using comparative genomics to map the virulence determinants of these bacteria.

Celecoxib alleviates the DSS-induced ulcerative colitis in mice by enhancing intestinal barrier function, inhibiting ferroptosis and suppressing apoptosis

Introduction Ulcerative colitis (UC) is an inflammatory intestine disease characterized by dysfunction of the intestinal mucosal barrier, ferroptosis, and apoptosis. Previous researches suggest that celecoxib, a nonsteroidal anti-inflammatory drug, holds promise in alleviating inflammation in UC. Therefore, this study aims to investigate the effects and mechanisms of celecoxib in UC. Methods To identify ferroptosis-related drugs and genes associated with UC, we utilized the Gene Expression Omnibus (GEO), FerrDb databases, and DGIdb database. Subsequently, we established a 2.5% DSS (Dextran sulfate sodium)-induced colitis model in mice and treated them with 10 mg/kg of celecoxib to validate the bioinformatics results. We evaluated histological pathologies, inflammatory response, intestinal barrier function, ferroptosis markers, and apoptosis regulators. Results Celecoxib treatment significantly ameliorated DSS-induced UC in mice, as evidenced by the body weight change curve, colon length change curve, disease activity index (DAI) score, and histological index score. Celecoxib treatment reduced the level of pro-inflammatory factors and promoted the expressions of intestinal tight junction proteins such as Claudin-1 and Occludin, thereby restoring the integrity of the intestinal mucosal barrier. Furthermore, celecoxib treatment reversed the ferroptosis characteristics in DSS-induced mice by increasing glutathione (GSH), decreasing malondialdehyde (MDA), and increasing the expression of GPX-4 and xCT. Additionally, apoptosis was induced in mice with UC, as evidenced by increased Caspase3, BAD, P53, BAX, Caspase9 and Aifm1 production, and decreased expression of BCL-XL and BCL2. Celecoxib treatment significantly reversed the apoptotic changes in DSS-induced mice. Conclusion Our findings suggest that celecoxib effectively treats DSS-induced UC in mice by inhibiting ferroptosis and apoptosis.

Clinical usefulness of hypoxia imaging colonoscopy for the objective measurement of ulcerative colitis disease activity

Background and AimsColonic mucosal hypoxia is associated with mucosal inflammation in ulcerative colitis (UC). We aimed to assess the clinical usefulness of hypoxia imaging colonoscopy for the assessment of clinical, endoscopic, and histologic disease activities of UC. MethodsThis was a retrospective cohort study comprised of 100 consecutive UC patients who underwent hypoxia imaging colonoscopy between September 2022 and September 2023 at the University of Tsukuba Hospital. We measured colonic tissue oxygen saturation (StO2) at the biopsy sites and compared StO2 values between different disease activities. We used receiver operating characteristic (ROC) analysis to calculate the area under the ROC curve (AUROC). ResultsWe identified a significant correlation between rectal StO2 and the Simple Clinical Colitis Activity Index, with moderate accuracy to predict bowel urgency at a 40.5% cutoff (AUROC 0.74, 95% CI 0.62-0.87). Our analysis of 490 images showed median StO2 values for Mayo endoscopic subscores (MES) 0, 1, 2, and 3 as 52% (IQR 48%-56%), 47% (IQR 43%-52%), 42% (IQR 38.8%-47%), and 39.5% (IQR 37.3%-41.8%), respectively. Differences for all pairs were significant. Median StO2 was 49% (IQR 44%-54%) for Geboes scores 0-2, significantly higher than histologically active disease (Geboes score ≥ 3). At a colonic StO2 cutoff of 45.5%, AUROCs for endoscopically and histologically active diseases were 0.79 (95% CI 0.74-0.84) and 0.72 (95% CI 0.66-0.77), respectively. ConclusionsStO2 obtained by hypoxia imaging colonoscopy is useful for assessing clinical, endoscopic, and histologic activities of UC, suggesting StO2 may be a novel and objective endoscopic measurement.

The anti-inflammatory effects of antidepressants on colitis.

Clomipramine (tricyclic antidepressant), Risperidone (a non-typical antidepressant), and Escitalopram (selective serotonin reuptake inhibitor antidepressant) might be good candidates for investigating the anti-colitis activity. The incidence of depression with ulcerative colitis in patients has led to the use of antidepressants in their treatment. In addition to the antidepressant effect of these drugs, anti-inflammatory effects have also been reported. In this study, 36 rats were used 2 ml of 3% acetic acid solution rectally to show the colitis. Then, Clomipramine (25 mg/kg), Escitalopram (10 mg/kg), Prednisolone (5 mg/kg), Risperidone (2 mg/kg), and normal saline as the control was administered orally for six days. The levels of Tumor Necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and myeloperoxidase (MPO) were measured by Enzyme-linked immune sorbent assay (ELISA), and changes in the tissue pathology were investigated. IL-6 level was significantly reduced after the administration of clomipramine and Prednisolone (p=0.025). Risperidone has significantly reduced MPO activity in colonic tissue (P=0.006). We did find no statistical decrease in MPO activity and TNF-α and IL-6 levels after consumption of Escitalopram (p>0.05). Clomipramine showed the best anti-inflammatory effect compared to Escitalopram and Risperidone. Therefore, clomipramine showed the best relieving effect on inflammation of ulcerative colitis in rats.

Validity of Systemic Inflammatory Markers as Predictors of Severity and Extent of Mucosal Inflammation in Ulcerative Colitis

Validity of Systemic Inflammatory Markers as Predictors of Severity and Extent of Mucosal Inflammation in Ulcerative Colitis