Ulcerative Colitis Activity Research Articles

Efficacy and Safety of Tacrolimus or Infliximab Therapy in Children and Young Adults With Acute Severe Colitis.

One-third of children and young adults admitted for management of acute severe colitis (ASC) fail intravenous corticosteroids. Infliximab (IFX) or tacrolimus (TAC) is often used to prevent urgent colectomy in these patients. However, no prior studies have reviewed the outcome of pediatric patients with ASC who were treated with either IFX or TAC. We retrospectively identified 170 pediatric patients with ASC admitted to our institution who did not respond to intravenous corticosteroids and were subsequently treated with either IFX or TAC. We compared 6-month colectomy rates, time to colectomy, improvement in disease activity indices, and adverse effects. The mean age of patients in the IFX (n = 84) and TAC (n = 86) groups were 14 and 13.8 years, respectively. The median study follow-up time was 23 months. The rate of colectomy 6 months from rescue therapy was similar whether patients received IFX or TAC (22.6% vs 26.7%, respectively, P = 0.53). The mean decline in Pediatric Ulcerative Colitis Activity Index scores from admission to discharge in those treated with IFX (31.9) or TAC (29.8) was similar (P = 0.63). Three patients treated with IFX experienced infusion reactions. Six patients treated with TAC experienced changes in renal function or electrolytes, and 4 patients reported neurologic symptoms. There were no significant differences in the likelihood of colectomy 6 months after initiating IFX or TAC rescue therapy. Efficacy of both agents was comparable. The types of adverse effects differed by therapy. These data support the use of either TAC or IFX in children with ASC refractory to intravenous corticosteroids.

Relation of Antioxidant Native Thiol Level with Inflammatory Markers and Disease Activity Index in Pediatric Ulcerative Colitis

Objective: Pediatric ulcerative colitis (PUC) is an inflammatory disease. PUC pathogenesis is associated with an imbalance between reactive oxygen species and antioxidant activity which creates oxidative stress. Native thiol (NT) level is antioxidant capacity which is practical and repeatable marker of inflammation and antioxidan level. We aimed to analyse the relation of NT level with inflammatory markers and pediatric ulcerative colitis activity index (PUCAI). Material and Methods: Thirty-eight PUC patients (SG) and 33 control group (CG) participants were included in the study. PUC patients grouped as in remission, mild, moderate and severe activity according to disease activity according to PUCAI. NT, hemoglobin (Hb), white blood cell (WBC), platelet (PLT), mean platelet volume (MPV), albumin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin 6 (IL-6) levels of all participants were measured at the time they were enrolled in the study and recorded. Results: Mean age and gender ratio of groups were similar (p>0.050). NT level of SG statistically high compared to CG (p=0.001). Hb, PLT, MPV, CRP, ESR, IL-6 levels of SG were statistically different than CG (p=0.045, p=0.026, p=0.001, p=0.001, p=0.001, p=0.001). NT level of SG was positively correlated with Hb, MPV, albumin (p=0.001, for all). NT level of SG was negatively correlated with PLT, CRP, ESR, IL-6 and PUCAI (p=0.001). Conclusion: NT level of PUC is significantly lower than CG. NT level of SG was positively correlated with albumin which is a good prognostic factor in PUC patients. NT may be repeatable, noninvasive candidate serum biomarker for PUC management.

Crohn’s disease proteolytic microbiota enhances inflammation through PAR2 pathway in gnotobiotic mice

ABSTRACT Emerging evidence implicates microbial proteolytic activity in ulcerative colitis (UC), but whether it also plays a role in Crohn’s disease (CD) remains unclear. We investigated the effects of colonizing adult and neonatal germ-free C57BL/6 mice with CD microbiota, selected based on high (CD-HPA) or low fecal proteolytic activity (CD-LPA), or microbiota from healthy controls with LPA (HC-LPA) or HPA (HC-HPA). We then investigated colitogenic mechanisms in gnotobiotic C57BL/6, and in mice with impaired Nucleotide-binding Oligomerization Domain-2 (NOD2) and Protease-Activated Receptor 2 (PAR2) cleavage resistant mice (Nod2 −/−; R38E-PAR2 respectively). At sacrifice, total fecal proteolytic, elastolytic, and mucolytic activity were analyzed. Microbial community and predicted function were assessed by 16S rRNA gene sequencing and PICRUSt2. Immune function and colonic injury were investigated by inflammatory gene expression (NanoString) and histology. Colonization with HC-LPA or CD-LPA lowered baseline fecal proteolytic activity in germ-free mice, which was paralleled by lower acute inflammatory cell infiltrate. CD-HPA further increased proteolytic activity compared with germ-free mice. CD-HPA mice had lower alpha diversity, distinct microbial profiles and higher fecal proteolytic activity compared with CD-LPA. C57BL/6 and Nod2 −/− mice, but not R38E-PAR2, colonized with CD-HPA had higher colitis severity than those colonized with CD-LPA. Our results indicate that CD proteolytic microbiota is proinflammatory, increasing colitis severity through a PAR2 pathway.

Therapeutic effect of ursodeoxycholic acid-berberine supramolecular nanoparticles on ulcerative colitis based on supramolecular system induced by weak bond

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.

Early Intestinal Ultrasound Predicts Long-Term Endoscopic Response to Biologics in Ulcerative Colitis.

The Milan ultrasound criteria [MUC] is a validated score to assess endoscopic activity in ulcerative colitis [UC]. MUC > 6.2 detects Mayo endoscopic score [MES] > 1. In this study we evaluated the predictive value of MUC for biologic treatment response, using colonoscopy [CS] as a reference standard. Consecutive UC patients starting biologic therapy were included, and underwent CS, IUS, clinical assessment and faecal calprotectin [FC] measurement at baseline and within 1 year. In addition, IUS, clinical and FC assessments were performed at week 12. The primary objective was to evaluate whether ultrasound improvement [MUC ≤ 6.2] at week 12 predicted endoscopic improvement at reassessment [MES ≤ 1]. Endoscopic remission was defined as MES = 0. Forty-nine patients were included [59% under infliximab, 29% under vedolizumab, 8% under adalimumab, 4% under ustekinumab]. MUC ≤ 6.2 at week 12 was the only independent predictor for MES ≤ 1 and MES = 0 at reassessment (odds ratio [OR] 5.80, p = 0.010; OR 10.41, p = 0.041; respectively). MUC ≤ 6.2 at week 12 showed a negative predictive value of 96% for detecting MES = 0. A ≥2 reduction of the MUC predicted MES = 0 (area under the curve [AUC] 0.816). MUC ≤ 4.3 was the most accurate cut-off value for MES = 0 [AUC 0.876]. Guyatt's responsiveness ratio for the MUC was 1.73 [>0.8]. MUC ≤ 6.2 at week 12 predicts long-term endoscopic response. MUC is accurate in monitoring treatment response and may be used in both clinical trials and routine practice.

Novel mRNA Signature for Anti-TNF-α Therapy Primary Response in Patients With Ulcerative Colitis.

Ulcerative colitis (UC), an idiopathic, chronic inflammatory disorder of the colonic mucosa, is commonly treated with antitumor necrosis factor α (anti-TNF-α) agents. However, only approximately two-thirds have an initial response to these therapies. We integrated gene expression profiling from 3 independent data sets of 79 UC patients before they began anti-TNF-α therapy and calculated the differentially expressed genes between patient response and nonresponse to anti-TNF-α therapy and developed a de novo response-associated transcription signature score (logOR_Score) to demonstrate the predictive capability of anti-TNF-α therapy for therapeutic efficacy. Furthermore, we performed association analysis of the logOR_Score and clinical features, such as disease activity and immune microenvironment. A total of 2522 responsive and 1824 nonresponsive genes were identified from the integrated data set. Responsive genes were significantly enriched in metabolism-related pathways, whereas nonresponsive ones were associated with immune response-related pathways. The logOR_Score enabled the accurate prediction of the therapeutic efficacy of anti-TNF-α in 4 independent patient cohorts and outperformed the predictions made based on 6 transcriptome-based signatures. In terms of clinical features, the logOR_Score correlated highly with the activity of UC. From an immune microenvironment perspective, logOR_Scores of CD8+IL-17+ T cells, follicular B cells, and innate lymphoid cells significantly decreased in inflamed UC tissue. The de novo response-associated transcription signature may provide novel insights into the personalized treatment of patients with UC. Comprehensive analyses of the response-related subtypes and the association between logOR_Score and clinical features and immune microenvironment may provide insights into the underlying UC pathogenesis.

Fecal microbiota transplantation for recurrent Clostridioides difficile infection in patients with concurrent ulcerative colitis

AimsClostridioides difficile infection (CDI) is a major challenge for healthcare systems. Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease, is a risk factor for primary and recurrent CDI (rCDI). Moreover, CDI itself often worsens the clinical picture of IBD, increasing the risk of complications. Fecal microbiota transplantation (FMT) is a highly effective treatment for rCDI, but data from patients with IBD and CDI are limited and often referred to mixed cohorts. We aimed to report outcomes from a cohort of patients with UC treated with FMT for rCDI superinfection. Methods and resultsIn a retrospective, single-centre cohort study we evaluated characteristics and outcomes of patients with UC who received FMT for rCDI. The primary outcome was negative C. difficile toxin 8 weeks after FMT. Thirty-five patients were included in the analysis. Sixteen patients were cured after single FMT, while 19 patients received repeat FMT. Overall, FMT cured rCDI in 32 patients (91%), and repeat FMT was significantly associated with sustained cure of CDI compared with single FMT (84% vs 50%, p = 0.018). Twenty-four patients (69%) experienced remission or an amelioration of UC activity. Serious adverse events were not observed. ConclusionsIn our cohort of patients with UC, FMT was highly effective in curing rCDI without severe adverse events and repeat FMT was significantly associated with CDI cure. Most patients also experienced remission or amelioration of UC activity after FMT. Our findings suggest that a sequential FMT protocol may be used routinely in patients with UC and rCDI.

Maladies inflammatoires chroniques intestinales : scores et optimisation des comptes rendus anatomopathologiques

The two main forms of inflammatory bowel disease (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). Both diseases have inflammatory flare-ups that alternate with periods of remission. The pathologist may examine biopsies of the digestive tract from IBD patients in different contexts: at the time of the initial diagnosis, in the event of a disease flare-up in order to differentiate a flare of the disease from another cause, particularly an infectious one, and during the long term follow-up of the disease in order to detect the occurrence of dysplastic lesions. Pathologists are increasingly involved in the evaluation of inflammatory activity during the follow-up of IBD patients. The therapeutic management of IBD has evolved significantly and the emergence of new treatments allows a global approach targeting endoscopic mucosal healing. However, mucosal healing is not always correlated with histological healing. Numerous studies have shown the value of histological evaluation during follow-up. A higher score for histological activity in ulcerative colitis predicts a higher likelihood of neoplasia. Histological activity is a better predictor than endoscopic inflammation of the risk. In UC, histological remission may be a long-term therapeutic goal but its role in CD remains unclear. Different scores have been developed to quantify the inflammatory activity of IBD patients and the response to treatment. The aim of this review is to present the main activity scores used in the follow-up of IBD, their interest, their evaluation and their limitations.

Association between Food Specific IgG Antibodies with Clinical Activity of Disease in Patients with Inflammatory Bowel Disease: A Cross-Sectional Study

Background: Inflammatory bowel disease (IBD) is an autoimmune disease that is influenced by food, an important factor in accelerating its clinical disease activity because of intestinal inflammation trough formation of antigen-antibody complex. Food-specific IgG examination can identify the types of person foods consumes that are maybe responsible for disease activity. It is useful in treating IBD without risking malnourishment as it is tailored to the individual immune profile.Method: This is a cross-sectional study involving 113 patients diagnosed with IBD by colonoscopy. Examination of serum IgG specific for 220 types of foods was performed using ELISA and immuno-array techniques. Disease clinical activity was assessed using the Mayo index and Crohn's disease activity index.Results: The highest proportion of dietary IgG in Crohn's disease was peas (100%), barley (97.9%), eggs (95.9%), milk (81.6%), and corn (75.5%); while in ulcerative colitis it was barley (98.4%), peas (96.8%), egg whites (92.2%), corn (82.8%), and prunes (78.1%). In ulcerative colitis, there was a weak negative correlation between cashew nuts IgG (r = -0.347; p = 0.041) and chickpeas IgG (r = -0.473; p = 0.017) with clinical disease activity; while in Crohn's disease, a weak positive correlation with disease activity was seen in barley (r = 0.261; p = 0.042).Conclusion: There was a weak negative correlation between cashew and chickpea-specific IgG antibodies with clinical activity of ulcerative colitis, and a weak positive correlation between barley-specific IgG antibodies and Crohn's disease clinical activity.

Serum Osteoprotegerin (OPG) as a Potential Biomarker for Disease Activity in Ulcerative Colitis

Serum Osteoprotegerin (OPG) as a Potential Biomarker for Disease Activity in Ulcerative Colitis

384 Alterations in the fungal microbiome in ulcerative colitis

OBJECTIVES/GOALS: Although gut fungi have been implicated in the immunopathogenesis of inflammatory bowel disease, the fungal microbiome has not been deeply explored across endo-histologic activity and treatment-exposure in ulcerative colitis. METHODS/STUDY POPULATION: Our retrospective cohort was derived from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease. We evaluated the fungal composition of fecal samples from 98 ulcerative colitis patients across endoscopic activity (n=43), endo-histologic activity (n=41), and biologic-exposure (n=98). Across all subgroups, we assessed fungal diversity and differential abundance of specific taxonomic groups. RESULTS/ANTICIPATED RESULTS: We identified 504 unique fungal amplicon sequence variants across the cohort of 98 patients, dominated by phylum Ascomycota. Compared to endoscopic remission, patients with endoscopic activity had an increased global fungus load (p DISCUSSION/SIGNIFICANCE: Endoscopic inflammation in ulcerative colitis is associated with altered fungal diversity driven by expansion of Saccharomyces and Candida compared to remission. The role of these fungal taxa as potential biomarkers and targets for personalized approaches to therapeutics in ulcerative colitis should be evaluated.

A comparison of the Child Health Utility 9D and the Health Utilities Index for estimating health utilities in pediatric inflammatory bowel disease

PurposeHealth utilities are challenging to ascertain in children and have not been studied in pediatric Crohn’s disease (CD) and ulcerative colitis (UC). The objective was to assess discriminative validity by comparing utilities elicited using the Child Health Utility-9 Dimension (CHU9D) to the Health Utilities Index (HUI) across multiple disease activity scales in pediatric UC and CD.MethodsPreference-based instruments were administered to 188 children with CD and 83 children with UC aged 6 to 18 years. Utilities were calculated using CHU9D adult and youth tariffs, and HUI2 and HUI3 algorithms in children with inactive (quiescent) and active (mild, moderate, and severe) disease. Differences between instruments, tariff sets and disease activity categories and were tested statistically.ResultsIn CD and UC, all instruments detected significantly higher utilities for inactive compared to active disease (p < 0.05). Mean utilities for quiescent disease ranged from 0.810 (SD 0.169) to 0.916 (SD 0.121) in CD and from 0.766 (SD 0.208) to 0.871 (SD 0.186) in UC across instruments. Active disease mean utilities ranged from 0.694 (SD 0.212) to 0.837 (SD 0.168) in CD and from 0.654 (SD 0.226) to 0.800 (SD 0.128) in UC.ConclusionCHU9D and HUI discriminated between levels of disease activity in CD and UC regardless of the clinical scale used, with the CHU9D youth tariff most often displaying the lowest utilities for worse health states. Distinct utilities for different IBD disease activity states can be used in health state transition models evaluating the cost-effectiveness of treatments for pediatric CD and UC.

QUANTITATIVE AND EXPLAINABLE ARTIFICIAL INTELLIGENCE (AI)-POWERED APPROACHES TO PREDICT ULCERATIVE COLITIS DISEASE ACTIVITY FROM HEMATOXYLIN AND EOSIN (H&E)-STAINED WHOLE SLIDE IMAGES (WSI)

Microscopic inflammation has been shown to be an important indicator of disease activity in ulcerative colitis (UC). However, manual histologic scoring is semi-quantitative and subject to interobserver variation, and AI-based solutions often lack interpretability. Here we report two distinct quantitative approaches to predict disease activity scores and histological remission using AI-powered digital pathology. Both the random forest classifier (RFC) and graph neural network (GNN) further provide explainability and biological insight by identifying histological features informing model predictions.

REAL-WORLD USTEKINUMAB PERSISTENCE IN PATIENTS WITH ULCERATIVE COLITIS ATTAINING THE MAINTENANCE PHASE

Sustained use of biologics and small molecule/advanced therapy has proven to be effective for controlling disease activity in ulcerative colitis (UC). The anti-interleukin agent ustekinumab was recently approved for UC in 2019. This study aimed to describe real-world ustekinumab persistence among patients with UC attaining the maintenance phase.

METHODS TO DERIVE A MODIFIED MAYO SCORE FROM ELECTRONIC HEALTH RECORDS DATA

The modified Mayo Score (MMS), which consists of stool frequency, rectal bleeding, and endoscopic subscores, is the most commonly used method for measuring disease activity in Ulcerative Colitis (UC) patients. It is a standard outcome measure in clinical trials, and is recommended as a clinical trial endpoint by the US Food and Drug Administration. Each component has a score from 0-3; the total MMS ranges from 0 to 9. MMS is infrequently recorded in routine care, in part because it requires an endoscopic assessment. Real world data, including electronic health record (EHR) databases, are useful for studying longitudinal disease and treatment outcomes, but most EHR databases do not include Mayo scores. Building off the methods described by Rudrapatna et al., 2021, we calculated a derived MMS using data elements available in EHRs.

Thiols as a marker of inflammatory bowel disease activity: a systematic review

BackgroundEvidence indicates that inflammation in Inflammatory Bowel Disease (IBD) is associated with increased systemic levels of reactive oxygen species. Systemic oxidative stress has been associated with reduced levels of plasma thiols. Less invasive tests capable of reflecting and predicting IBD activity are increasingly sought after. We sought to systematically review the evidence inherent in serum thiol levels as a marker of Crohn's Disease and Ulcerative Colitis activity (PROSPERO: CRD42021255521).MethodsThe highest quality documents for systematic reviews standards were used as reference. Articles were searched on Medline via PubMed, VHL, LILACS, WOS, EMBASE, SCOPUS, COCHRANE, CINAHL, OVID, CTGOV, WHO/ICTRP, OPENGREY, BDTD and CAPES, between August, 03 and September, 03 on 2021. Descriptors were defined according to the Medical Subject Heading. Of the 11 articles selected for full reading, 8 were included in the review. It was not possible to perform a pooled analysis of the studies, as there were no combinable studies between subjects with active IBD and controls/inactive disease.ResultsFindings from the individual studies included in this review suggest an association between disease activity and systemic oxidation, as measured by serum thiol levels, however, there are limitations that preclude weighting the study results in a meta-analysis.ConclusionsWe recommend conducting better-designed and controlled studies, that include individuals of both phenotypes and at different stages of IBD, involving a larger number of participants, using the standardization of the technique for measuring serum thiols, to confirm whether thiols can be a good parameter for monitoring the clinical course of these intestinal diseases and the degree of clinical applicability.

Composite Assessment Using Intestinal Ultrasound and Calprotectin Is Accurate in Predicting Histological Activity in Ulcerative Colitis: A Cohort Study.

Beyond endoscopic remission, histological remission in ulcerative colitis (UC) is predictive of clinical outcomes. Intestinal ultrasound (IUS) may offer a noninvasive surrogate marker for histological activity; however, there are limited data correlating validated ultrasound and histological indices. Our aim was to determine the correlation of IUS activity in UC with a validated histological activity index. Twenty-nine prospective, paired, same-day IUS/endoscopy/histology/fecal calprotectin (FC) cases were included. Intestinal ultrasound activity was determined using the Milan Ultrasound Criteria, histological activity using the Nancy Histological Index, endoscopic activity using Mayo endoscopic subscore and Ulcerative Colitis Endoscopic Index of Severity, and clinical activity using the Simple Clinical Colitis Activity Score. Histological activity demonstrated a significant linear association with overall IUS activity (coefficient 0.14; 95% CI, 0.03-0.25; P = .011). Intestinal ultrasound activity was also significantly associated with endoscopic activity (0.32; 95% CI, 0.14-0.49; P < 0.001), total Mayo score (0.31; 95% CI, 0.02-0.60; P = .036) but not FC (0.10; 95% CI, -0.01 to 0.21; P = .064) or clinical disease activity (0.04; 95% CI, -0.21 to 0.28; P = .768). A composite of IUS and FC showed the greatest association (1.31; 95% CI, 0.43-2.18; P = .003) and accurately predicted histological activity in 88% of cases (P = .007), with sensitivity of 88%, specificity 80%, positive predictive value 95%, and negative predictive value 57%. Intestinal ultrasound is an accurate noninvasive marker of histological disease activity in UC, the accuracy of which is further enhanced when used in composite with FC. This can reduce the need for colonoscopy in routine care by supporting accurate point-of-care decision-making in patients with UC.

Clinical outcome of ulcerative colitis with severe onset in children: a multicenter prospective cohort study.

As best practices for treating children with severe-onset ulcerative colitis remain controversial in the era of biologic agents, we prospectively investigated treatments and outcomes in a multicenter cohort. Using a Web-based data registry maintained in Japan between October 2012 and March 2020, we compared management and treatment outcomes in an S1 group defined by a Pediatric Ulcerative Colitis Activity Index of 65 or more points at diagnosis with those in an S0 group defined by an index value below 65. Three hundred one children with ulcerative colitis treated at 21 institutions were included, with follow-up for 3.6 ± 1.9years. Among them, 75 (25.0%) were in S1; their age at diagnosis was 12.3 ± 2.9years, and 93% had pancolitis. Colectomy free rates in S1 were 89% after 1year, 79% after 2, and 74% after 5, significantly lower than for S0 (P = 0.0003). Calcineurin inhibitors and biologic agents, respectively, were given to 53% and 56% of S1 patients, significantly more than for S0 patients (P < 0.0001). Among S1 patients treated with calcineurin inhibitors when steroids failed, 23% required neither biologic agents nor colectomy, similarly to the S0 group (P = 0.46). Children with severe ulcerative colitis are likely to require powerful agents such as calcineurin inhibitors and biologic agents; sometimes colectomy ultimately proves necessary. Need for biologic agents in steroid-resistant patients might be reduced to an extent by interposing a therapeutic trial of CI rather than turning to biologic agents or colectomy immediately.

A3 CROHN’S DISEASE PROTEOLYTIC MICROBIOTA ENHANCES INFLAMMATION THROUGH PAR2 PATHWAY IN GNOTOBIOTIC MICE

Abstract Background An imbalance in host proteases has been implicated in inflammatory bowel disease (IBD). Recent evidence implicates microbial proteolytic activity (PA) in ulcerative colitis but whether it also plays a role in Crohn’s disease (CD) remains unclear. Purpose We therefore investigated the colitogenic potential and underlying pathways of proteolytic CD microbiota. Method Adult germ-free (GF) C57BL/6 mice were colonized with CD microbiota selected based on high (CD-HPA) or low fecal proteolytic activity (CD-LPA), and from healthy controls with LPA (HC-LPA), after which total fecal proteolytic, elastolytic and mucolytic activity were analyzed in the mice. Microbial community was assessed by 16S rRNA gene sequencing. Immune function and colonic injury were investigated by inflammatory gene expression (NanoString) and histology. Colitis severity and underlying pathways were investigated in C57BL/6, Nucleotide-binding Oligomerization Domain-2 knock-out (Nod2-/-), and Protease-Activated Receptor 2 (PAR2) cleavage resistant mice (R38E-PAR2) subjected to 2% dextran sodium sulfate in drinking water for 5 days followed by 2 days on water. Result(s) Colonization with HC-LPA or CD-LPA lowered baseline fecal proteolytic activity compared with GF mice, which was paralleled by lower acute inflammatory cell infiltrate. CD-HPA further increased proteolytic activity compared with GF mice. Fecal supernatants from CD-LPA or HC-LPA colonized mice had lower in vitro PAR2 cleavage compared to supernatants from GF and CD-HPA colonized mice. Several genes, such as Map kinases, Rhoa, Myd88, and Tollip, were increased in GF mice compared to colonized mice. 18 genes related to inflammation and barrier function (e.g., Mapk2k6, Tnf, Claudin1) were differentially expressed between CD-LPA and CD-HPA. CD-HPA mice had lower alpha diversity, distinct microbial profiles, and higher fecal proteolytic activity compared with CD-LPA. Abundance of several beneficial species (e.g., Akkermansia muciniphilia) was decreased while other taxa were increased (e.g., Hungattella hathewayi) in CD-HPA compared to CD-LPA. H. hathewayi as well as the serine protease K04772 were transcriptionally increased in fecal samples from CD-HPA colonized mice. C57BL/6 and Nod2-/- mice, but not R38E-PAR2 mice, colonized with CD-HPA developed earlier and more severe colitis compared with mice colonized with CD-LPA. Conclusion(s) CD proteolytic microbiota is proinflammatory through a PAR2 pathway. H. hathewayi correlates with the proinflammatory phenotype through the serine protease K04772 in this model. The results support a role of microbial PA in CD, which could constitute a biomarker for identifying patients who would benefit from anti-proteolytic therapies. Disclosure of Interest None Declared

The urotensin-II receptor: A marker for staging and steroid outcome prediction in ulcerative colitis.

Urotensin-II receptor- (UTR) related pathway exerts a key-role in promoting inflammation. The aim was to assess the relationship between UTR expression and clinical, endoscopic and biochemical severity of ulcerative colitis (UC), exploring its predictivity of intravenous (iv) steroid administration therapeutic outcome. One-hundred patients with first diagnosis of UC and 44 healthy subjects were enrolled. UTR expression was assessed by qPCR, Western Blot (WB) and immunohistochemistry (IHC). Clinical, endoscopic and histological activity of UC were evaluated by using Truelove and Witts (T&W) severity index, Mayo Endoscopic Score (MES), and Truelove and Richards Index (TRI). The partial and full Mayo scores (PMS and FMS) were assessed to stage the disease. The UTR expression, resulted higher in the lesioned mucosa of UC patients in comparison to healthy subjects (p < .0001 all). Direct relationship between UTR (mRNA and protein) expression and disease severity assessment (T&W, PMS, MES and TRI) was highlighted (p < .0001 all). UTR expression resulted also higher in the 72 patients requiring iv steroids administration compared to those who underwent alternative medications, (p < .0001). The 32 steroid-non-responders showed an increased UTR expression (WB, IHC and qPCR from lesioned mucosa), compared to 40 steroid-responders (p: .0002, .0001, p < .0001 respectively). The predictive role of UTR expression (p < .05) on the negative iv steroids administration therapeutic outcome was highlighted and ROC curves identified the thresholds expressing the better predictive performance. UTR represents a promising inflammatory marker related to clinical, endoscopic, and histological disease activity as well as a predictive marker of steroid administration therapeutic outcome in the UC context.