IBD Subjects Research Articles

VISUALIZING HETEROGENEOUS TRAJECTORIES OF SUBJECTS WITH SURGICAL RELAPSE IN INFLAMMATORY BOWEL DISEASE FROM UK BIOBANK GENERAL PRACTICE DATA

Abstract BACKGROUND AND AIMS The United Kingdom (UK) Biobank (UKBB) is a large-scale biomedical database and research resource, containing in-depth health information from half a million participants in UK that have been used for detailed analyses of IBD. Using the UKBB, we examined the lab findings and prescription medication use in IBD subjects to identify trajectory patterns of disease with respect to surgical relapse. METHODS Of the 363 subjects in the UKBB with an established IBD diagnosis (UC, CD, or both) and an initial GI surgery, 116 had a subsequent surgery within 5 years of initial surgery and had follow up lab values of urine and serum creatinine, plasma and serum C-reactive protein, urine and serum albumin, urine albumin-creatinine ratio, total white blood count, urine microalbumin, total white cell count, hemoglobin estimation, and erythrocyte sedimentation rate. Additionally, data for the 9 most used IBD prescription medications: budesonide, sulfasalazine, methotrexate, hydrocortisone, balsalazide, olsalazine, prednisolone, azathioprine, and mesalamine was analyzed as well. Hidden Markov Models (HMM) using these variables and open-source packages were incorporated to label observations of each subject-visit until the subsequent surgery. Interactive visualizations using DPVis open-source package were then applied to identify individual trajectories and explore clinical characteristics. RESULTS Five hidden states were observed from HMM. The five states observed are based on differing prescription medication usage for the treatment of IBD and were assigned a color to allow for comparison (Figure 1). The majority of patients fell within the states labeled “blue” (azathioprine, sulfasalazine, and prednisone) “red” (mesalamine only) or “purple” (azathioprine, balsalazide, and prednisolone). The visualizer showed that while some transitions among states were observed, most patients fell into one of three major trajectory patterns as a factor of time to surgical relapse and were largely segregated by state. Based on the trajectories, a comparison of subjects with prescription of mesalamine-only vs. any immunosuppressive medications (azathioprine + sulfasalazine + balsalazide) in combination with prednisolone showed a significant difference in time to surgical relapse (P < 0.005) (Figure 2), with a shorter time to surgical relapse identified in patients who took mesalamine only. CONCLUSIONS We identified three distinct trajectories leading up to surgical relapse. These trajectories show distinctive medication prescription patterns (5-ASA vs. Azathioprine with steroid use), as well as significantly different times to surgical relapse. Furthermore, heterogeneity is shown within each trajectory pattern in terms of progression time and warrant further investigation. Figure 1 Three Trajectories of time to surgical relapse generated from 5-State HMM using lab values and prescription medications. Note that a patient can traverse multiple states so the summation of the observed subjects of those states exceeds the cohort size (N=116). Figure 2 Kaplan-Meier curves for the UC/CD subgroup with surgical relapse considering events from the first documented lab values and/or planned prescription at most 2 years prior to the baseline surgery up to the subsequent 5 years.

P1112 Clinical features between familial versus sporadic inflammatory bowel disease: a retrospective single centre study

Abstract Background Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions of the gastrointestinal tract. The two main types of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Both conditions have a complex and multifactorial etiology, involving a combination of genetic, environmental, and immunological factors. If there is a family history of IBD, particularly in first-degree relatives (parents, siblings), there may be a higher risk for other family members to develop the disease. A retrospective cohort study was conducted between 2010 and 2022, to assess clinical features between familial versus sporadic inflammatory bowel disease Methods This observational monocentric retrospective study, includes 903 patients: 794 with IBD, with and without familiarity, referring to the Gastroenterology Service of the "Azienda Sanitaria Universitaria del Friuli Centrale". 10,6% of the patients have familiarity (54,2% with a first degree and 44,8% with a second degree relative). Table 1 provides data on patients and disease characteristics. Results The mean age of patients with familiarity for IBD was significantly lower compared to subjects without familiarity. Unexpectedly in our cohort familiarity in CD vs UC subjects were similar (respectively 10.7% vs 11.8%). A slight increase of women in the group with familiarity was detected although not statistically significant. EIMs occurred predominantly in the cohort with familiarity but the difference was not statistical significant. IBD subjects with familiarity need less surgery if compared with those with non familiarity (respectively 14,6% vs 18,2%), but the difference was no significant. Biological drugs have been used earlier and more frequently in patients with familiarity compared with those with not familiarity (29,3% vs 38,5%) although also in this case non significant. No differences on IBD phenotype have been noted between familial IBD vs sporadic IBD. Main data described in Table 2. Conclusion In this retrospective cohort study, family history of IBD was present in similar percentage between CD and UC. The only significant data in our cohort was the early age of onset of IBD in patients with familiarity. However IBD familiarity was associated with a trend of decreased risk of surgical procedures, increased use of biological medications and a trend for developing EIMs. While some data, for example the earlier and larger use of biologics could explain the less need of surgery in IBD patients, larger cohorts are essential to define the similarities and differences more robustly between familial and sporadic IBD.

P023 Serological markers of intestinal barrier function in patients with primary sclerosing cholangitis after liver transplantation

Abstract Background Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease associated with inflammatory bowel disease. Liver transplantation (LT) is the only curative treatment for most patients with PSC. Recurrence of PSC (rPSC) is a common long-term complication after liver transplantation in this patient group, affecting graft survival and overall patient survival. There are several lines of evidence indicating that dysregulation of the microbiome and gut barrier dysfunction are key etiologic factors in the pathogenesis of PSC. The aim of this study was to evaluate serological markers of intestinal barrier function in patients with PSC after LT and in control group, to determine potential biomarkers for rPSC. Methods This is a cross-sectional study of patients after LT for PSC at the Institute for Clinical and Experimental Medicine, Prague. The control group consists of patients who underwent liver transplantation for alcohol-related liver disease and/or hepatocellular carcinoma. The rPSC was assessed by MRCP and/or liver biopsy according to the Mayo criteria. IBD status was assessed by endoscopy, biopsy, and faecal calprotectin. We performed ELISA for Zonulin and Reg3a. The Kruskal-Wallis and Mann-Whitney test were used to evaluate the statistical differences. Results A total of 85 patients were included in the study after LT for PSC and 56 controls. rPSC was detected in 18 (21.18%) patients. IBD was diagnosed in 77 (90.5%) patients, of which 3 (3.9%) were categorised as Crohn’s disease. The remainder, 82 patients, were classified as ulcerative colitis, 41.9% with right-sided predominance and 24.3% with back-wash ileitis. The IBD treatment consisted of 5-ASA in 58 patients, azathioprine in 12 patients, vedolizumab in 5 patients, anti-TNFa in 1 patient and 9 patients were on 10 mg or more of prednisone or equivalent. MayoDAI was evaluated at the time of the visit with mean 1.74 (SD ±2.06). There was a significant difference in Reg3a levels between patients with IBD and control subjects (p<0.05, Figure 1.). No significant difference in Reg3a levels was found between rPSC patients and controls (p=0.3). Interestingly, Zonulin levels were significantly higher in the control group than in PSC patients with or without IBD (p<0.001). No significant difference in Reg3a and Zonulin was found between PSC and rPSC patients and between patients in remission and with active IBD. Conclusion Reg3a was associated with PSC-IBD in patients with PSC after LT, but its association with rPSC is unclear and should be investigated in a prospective setting. Zonulin reached higher levels in the control group.

P118 Fecal content from IBD patients disturbs epithelial functions in two model systems

Abstract Background Inflammatory Bowel Diseases (IBD) result from abnormal interactions between the immune system, epithelial barrier, and gut microbiota. However, understanding the abnormal interaction between aerobic epithelia and mainly anaerobic microbiota is complicated and is limited in part by the lack of human-relevant models. Methods We developed a model system that is based on whole human fecal samples and human-derived epithelia to study the interactions between the gut bacteria and the epithelia. To capture patient heterogeneity, we prioritized and pooled fecal material from 10 Crohn disease (CD), 10 ulcerative colitis (UC), and 10 healthy subjects. Prioritization of samples was based on our published gut microbial health index (PMID: 35197084), matching gender and age. Monolayered epithelial cells (Caco2 cells and patient-derived colonoids) were used for the co-culturing. Measurable outputs included cell viability, epithelial integrity, and secretion of CXCL1. Results Fecal samples were processed by separating the supernatant, heat-killing the bacteria, and rejoining the samples (Fig. 1A). 16S sequencing showed that bacterial composition and alpha diversity (Faith) were overall preserved after the heat-killing (Fig. 1B), as seen in the original samples. The gut microbial health index was higher among the control samples and pool, compared to the IBD samples (Fig. 1C), preserving the IBD pathogenic signals. Because previous studies indicated the enrichment of salivary bacteria in IBD feces, salivary samples were also processed for comparison. We confirmed that similar amounts of bacterial DNA (as a proxy of bacterial mass) were used for coculturing as indicated by qPCR of the 16S-V4 (Fig. 1D). Co-culturing the fecal and saliva pools with Caco-2 cells revealed a significant increase in CXCL1 proinflammatory chemokine secretion to the media in comparison to no-treatment (Fig. 2A). Moreover, the UC and CD pools significantly decreased epithelial integrity [transepithelial electrical resistance (TEER)], without affecting cellular viability (Fig. 2B-D). Finally, incubation of the fecal content with colon-derived organoids (from 2 controls and 1 UC) resulted in a substantial reduction of cell viability, which was more pronounced with fecal content derived from UC patients (Fig. 2E), and this effect was noted most with the UC fecal supernatants. Conclusion Using a novel co-culturing system, we demonstrated the effects of fecal contents from IBD and control subjects on CXCL1 secretion and epithelial integrity in Caco2 cells, and on colonoids viability. These models will be used to identify fecal factors and interventions relevant to IBD epithelial functions.

IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling

ObjectiveWe sought to investigate the role of interleukin (IL)-20 in IBD and experimental colitis.DesignExperimental colitis was induced in mice deficient in components of the IL-20 and signal transducer and activator...

Multiomic spatial analysis reveals a distinct mucosa-associated virome

ABSTRACT The human gut virome has been increasingly explored in recent years. However, nearly all virome-sequencing efforts rely solely on fecal samples and few studies leverage multiomic approaches to investigate phage–host relationships. Here, we combine metagenomics, metaviromics, and metatranscriptomics to study virome-bacteriome interactions at the colonic mucosal-luminal interface in a cohort of three individuals with inflammatory bowel disease; non-IBD controls were not included in this study. We show that the mucosal viral population is distinct from the stool virome and houses abundant crAss-like phages that are undetectable by fecal sampling. Through viral protein prediction and metatranscriptomic analysis, we explore viral gene transcription, prophage activation, and the relationship between the presence of integrase and temperate phages in IBD subjects. We also show the impact of deep sequencing on virus recovery and offer guidelines for selecting optimal sequencing depths in future metaviromic studies. Systems biology approaches such as those presented in this report will enhance our understanding of the human virome and its interactions with our microbiome and our health.

Inhibition of NLRP3 attenuates sodium dextran sulfate-induced inflammatory bowel disease through gut microbiota regulation

BackgroundInflammatory bowel disease (IBD) is a chronic, life-threatening inflammatory disease of gastrointestinal tissue characterized by inflammation of the gut. Recent studies have shown that gut microbiota is involved in the pathophysiology of IBD. However, it is unknown whether direct inhibition of NLR family pyrin domain containing 3 (NLRP3) inflammasome regulates IBD and alters gut microbiota. MethodsHere, the NLRP3 expression was evaluated in the colon of IBD subjects. Then, we investigated the effects of NLRP3 inhibition by MCC950 on the gut microbiota and IBD-like symptoms induced by dextran sulfate sodium (DSS). ResultsFirstly, NLRP3 and IL-1β levels were increased in patients with IBD as compared with healthy individuals. Then, the animal experiment showed that NLRP3 inhibition by MCC950 significantly attenuated IBD-like symptoms such as diarrhea and colonic inflammation in DSS-induced mice. In addition, NLRP3 inhibition inhibited NLRP3/ASC/caspase-1/IL-1β signaling pathway in the colon, which was over-activated by DSS. Furthermore, MCC950 increased the abundance of phylum Firmicutes, decreased the abundance of phylum Bacteroidetes, and increased the Firmicutes/Bacteroidetes ratio, indicating that the inhibition of NLRP3 inflammasome could regulate the abundance of intestinal flora. According to correlation analysis, NLRP3 might produce its functional role in the regulation of oxidation indicators by changing the gut microbiota composition, especially the phylum Bacteroidota, genus Lactobacillus and species Lactobacillus reuteri. ConclusionsThis study suggests that NLRP3 inflammasome inhibition attenuates IBD-like symptoms by regulating gut microbiota, and provides a basis for the clinical application of NLRP3 as a target for the treatment of IBD.

DOP13 Plasma metabolite fingerprint could discriminate inflammatory bowel disease patients from healthy subjects

Abstract Background Inflammatory bowel diseases (IBD, Crohn’s disease [CD], ulcerative colitis [UC]) are chronic immune-mediated systemic diseases with unknown aetiology. In the past few years, experimental studies revealed associations of human serum and plasma metabolites’ with IBD with a possible discriminative power between IBD and healthy subjects. Our study focused on the utility of plasma metabolome profiling as a diagnostic marker in patients with different phenotypes. Methods IBD patients were enrolled in a double-centre prospective cohort study. Large number of healthy subjects were included to reduce methodological bias. Blood samples were obtained at baseline and stored at –20°C and plasma metabolites were measured by high performance liquid chromatography coupled with tandem-mass spectrometry (HPLC-MS/MS). Logistic regression, minimum redundancy maximal relevance (mRMR), principal component analysis (PCA), and linear discriminant analysis (LDA) were used to calculate discriminative power. Results Plasma metabolome profile of 26 IBD (13 UC and 12 CD) patients and 168 HC participants were analyzed, and 388 metabolites were measured. 33 and 58% of CD patients and 31 and 39% of UC patients had clinical and endoscopic activity based on clinical (mean pMayo: 2.8±3.4, CDAI: 56±62) and endoscopic (mean PanMayo: 7.4±13.3 and SES-CD: 7.3±8.2) indices. Low plasma level of cysteine (CV=-0.36; p<0.01), triglycerides (CV=-0.19; p<0.01) and hexosylceramide (HexCer(d18:1/23:0); CV=-0.18; p<0.01), while high level of arginine (CV=0.3; p<0.24), hexosylceramide (HexCer(d18:2/23:0); CV=0.2; p=0.02), glutamate (CV=0.19; p<0.01) and lactate (CV=0.16; p=0.01) were significantly associated with IBD. According to mRMR analysis, cysteine (p<0.001), triglyceride (p<0.01), and HexCer(d16:1/22:0); (p<0.001) ranked highest in terms of feature importance (discriminative power). Based on the 16 metabolites considered to be of the highest discriminative power, the healthy and the IBD groups were well separated (PC1=18.2%, PC2=14.7%; Figure 1.). Conclusion Based on our results, plasma metabolite levels may help to discriminate IBD and healthy subjects. Integrative analysis of different biological samples may potentially predict IBD and could promote achieving personalized medicine. Further sample collections and analysis within this study can reveal discriminative metabolite fingerprints among IBD subtypes and correlations with activity as well.

REAL-TIME CONTINUOUS REPORTING OF IBD BIOMARKERS IN SWEAT

Abstract INTRODUCTION Calprotectin and C-reactive protein (CRP) are key biomarkers to assess a flare-up and inflammation in IBD patients. Flare-ups in IBD patients can create excruciating pain, discomfort, and occur in a random way. Therefore, continuous monitoring of these biomarkers in real-time can aid in providing active feedback and decision support on the health state for better IBD patient management. This work demonstrates a novel way of empowering IBD patients with actionable data through capturing temporal profiles of IBD markers (Calprotectin and CRP) from sweat for patient-driven outcomes. MATERIALS AND METHODS 10 healthy and one IBD subject were recruited in compliance with an approved IRB at UT Dallas. The levels of Calprotectin were quantified using the SWEATSENSER and ELISA. The basal levels of Calprotectin were compared between healthy and IBD cohort. Further, the wearable SWEATSENSER was used to measure CRP and Calprotectin continuously for a minimum of 6 hours. The levels of the study biomarkers were compared between healthy and IBD subjects to determine the statistical significance in differentiating between both the cohorts. RESULTS CRP levels between healthy and IBD subjects were measured through continuous monitoring using the SWEATSENSER for up to 24 hours over multiple days. Figure 1A shows a comparison between healthy (n=108 data points) and IBD (n=43 data points) CRP levels in sweat and a statistically significant difference between(p<0.05) was achieved. The levels were computed as a time-average of every 2 hours. Further, healthy calprotectin levels ranged 379 ng/mL while, the basal levels in IBD subject were reported to be 620 ng/mL as demonstrated in Figure 1B. The basal levels of calprotectin were significantly different between healthy and IBD subjects confirming the first proof-of-feasibility of real-time monitoring of IBD markers from sweat in detecting elevated IBD levels and an impending flare-up. CONCLUSION The SWEATSENSER device can differentiate the marker levels between healthy and IBD subjects. The developed device can be useful in better management of IBD patients by monitoring biomarker levels in real-time to report an impending flare-up. Further, the feasibility of real-time monitoring of CRP and Calprotectin using SWEATSENSER enables actionable data to patients during transition from remission to relapse of the disease. This is the first in-human demonstration of a wearable technology for tracking and stratification between healthy and IBD subjects.

P566 Humoral immune response to mRNA COVID-19 vaccine in Puerto Ricans with IBD does not differ between class of biologics

BackgroundThe COVID-19 vaccine trials did not include subjects with IBD or immunosuppression, limiting the effectiveness data of the vaccine in this population. The impact of biologics with different mechanisms of action on antibody concentrations and neutralizing capacity produced by the vaccine may alter prevention strategies. We aim to describe a comparison of the humoral response to COVID-19 vaccine in patients with IBD on biologics between different therapies and a control group.MethodsPatients ≥21 years of age with Crohn’s disease (CD) and ulcerative colitis (UC) on biologic therapy were recruited. Blood samples were collected at 14 ± 2 days (Cohort 1) and 60 ±7 days (Cohort 2) after receiving a 2nd dose of mRNA COVID-19 vaccine [BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna). Anti-spike protein receptor binding domain IgG levels and neutralizing capability using SARS-CoV-2 surrogate virus neutralization test (sVNT%) were measured. A result >30% is positive for effective viral inhibition. Results were stratified by mechanism of action of the drug and compared with a healthy control group. Comparisons were evaluated by Kruskal-Walls test and Dunns Pairwise/Bonferroni. The study is approved by the MSC IRB.Results32 subjects exposed to biological therapy divided into 2 cohorts (14-days, n=19/60-days, n=13) and 18 samples of healthy controls (14-days, n=12/60-days, n=6) are reported. Of the IBD subjects, 81% (26/32) had CD, 56% were males (18/32) and mean age was 39. All subjects were receiving biological monotherapy, one subject was also on azathioprine. All groups developed detectable antibody levels and >60% neutralizing antibody detection after 14 and 60 days of the second vaccine dose. IgG levels at 14 days (p<0.001) and sVNT% at 14- and 60-days post second vaccine dose (p=0.007, 0.024) were significantly different between subjects vs. controls. When stratified by mechanism of action, there was a significant difference between each biologic vs. control (p<0.001), but no difference between biologic classes. Initial analysis for the sVNT% at 14 days showed statistical significance (p=0.046). Post-hoc analysis showed no statistical significance in the individual comparisons. No significant differences were found between each therapy vs. control for IgG levels nor sVNT% at 60-days (p=0.257, 0.113). ConclusionOur study shows that IBD patients on biological therapy who receive a COVID-19 vaccine develop a lower but effective humoral response up to 60 days after the second dose when compared to healthy individuals. No difference was found between class of biologics. A larger sample is needed.

P183 Risk of eating disorders in italian children and adolescents with Inflammatory Bowel Disease: results of a multicenter nationwide study

Abstract Background The prevalence and risk of Eating Disorders (ED) in IBD, despite the potential overlap of these two conditions, have been rarely reported. ED diagnosis should be considered in patients with IBD and multidisciplinary approach would be recommended in these complex cases to provide an adequate therapeutic intervention. Screening tools to evaluate eating attitudes and behaviours in patients with IBD could be used in daily practice, as for example the Eating Attitude Test – 26 Methods Children and adolescents (8–18 years) with IBD and age and gender matched healthy controls were prospectively enrolled in 5 italian pediatric IBD units between June 2019 and August 2020. Subjects with an existing diagnosis of ED were excluded. The risk of ED was assessed using a 26 points Likert scale screening tool (CH-EAT-26 and EAT-26 for children &amp;lt; and &amp;gt; 14 years respectively), with a total score of 20 or above indicating a risk for ED. Correlations between clinical and disease’s parameters and the CH-EAT-26/EAT-26 score were calculated Results 110 patients with IBD and 110 age and matched healthy controls were screened with the CH-EAT26/EAT-26 questionnaire. The total EAT26 scores and the prevalence of an at-risk score (score&amp;gt;20) did not differ in IBD subjects compared to controls. IBD patients were more frequently on an exclusion diet with lactose free-diet being the most common regimen. Furthermore, 8.1% of IBD children was on a partial enteral nutrition (PEN). In IBD subjects elevated scores on the Ch-EAT26/EAT-26 were associated with being younger (r=-0,2226, p=0.002), following an exclusion diet (r=0.25, p=0.009) and a partial enteral nutrition (PEN: r=0,2507, p=0.009). Type, duration and activity of disease, gender, weight, height and BMI z-scores were not significantly correlated to the CHEAT26/EAT-26 score. Being on a PEN and following an exclusion diet were the only independents factors influencing the EAT26 score at the multiple regression analysis (p= 0,004; p= 0,034; R2 = 0,25) Conclusion Our results indicate that 5.45% of IBD children have a behavior at risk for developing an ED, a percentage that is not statistically different compared to healthy controls. A particular follow-up should be reserved to patients on restricted diets and on partial enteral nutrition, that can develop maladaptive attitudes toward eating. The development of a disease specific tool or a validation of pre-existing questionnaires would help to identify a robust screening instrument and ultimately to correctly classify the risk of patients. Once the risk is correctly assessed it is mandatory to address the patient to a specific multidisciplinary follow-up.

P502 Dietary habits and nutritional status in children and adolescents with Inflammatory Bowel Disease: an italian multicenter case-control study (NUTRIBD study)

Abstract Background Nutrition is involved in several aspects of pediatric IBD, ranging from disease etiology to induction and maintenance of disease. Presence of nutritional deficiencies can influence clinical outcomes and affect the immune system, growth and sexual maturation in children. Few studies assessed the dietary intake of IBD’s pediatric patients and investigated whether their dietary intakes meet the recommended daily allowances (RDA). Methods Children and adolescents with a diagnosis of IBD (&amp;gt; 1 year) and healthy controls (age and gender matched) were prospectively enrolled in 5 pediatric Italian IBD units. Daily dietary intake in the previous 6 months was assessed using a Food Frequency Questionnaire (FFQ). Energy intake (EI) and macro and micronutrients intakes were compared to the national RDA (LARN) and EI to the predicted total energy expenditure (TEE) based on the Schofield equation. Adherence to the Mediterranean diet was measured through the KIDMED score. Clinical and auxological data were recorded Results 110 IBD subjects and 110 controls (median age±SD: 14,6 ±2,2 and 13,8±2,8 years, p= 0,45) were enrolled. Weight and height z-scores were significantly lower in IBD compared to controls (p= 0,0005 and p=0,036).Weight, height and BMI z-score did not differ between CD and UC. EI (Kcal/day), the EI/RDA ratio (%) and the EI/TEE ratio (%) were significantly lower in IBD compared to the controls (1893 vs 2068 kcal/day, p= 0,009; 71,5% vs 84,7%, p&amp;lt; 0,0001; 79,8% vs 90,8%, p=0,007). When distributing patients by clinical disease activity, the TEE was lower in patients with active disease compared to patients in remission (1850 vs 1915; p=0,039). A significant correlation was not found between age, gender, type of disease, disease activity, and EI/RDA % and EI/TEE %. Total protein and fat intake were lower in children with IBD compared to controls. Conversely the total carbohydrate intake did not differ between IBD patients and controls (median 289,8 vs 311,7 gr/day, p= 0,077) while the percentage of carbohydrate to EI was higher (CHO % : 61 vs 58; p=0,012). Total charbohydrates intake was significantly lower in patients with active disease compared to patients in remission (265.7 vs 294.3 gr/day; p=0,002). IBD patients reported a lower intake of the main dietary micronutrients compared to controls. A poor adherence to the Mediterranean diet was more frequent in IBD children (37.2% vs 22.7%, p= 0,013). Conclusion The diet of Italian children and adolescents with IBD differs substantially from the general pediatric population and frequently does not meet the RDA. Our data suggest the need of an accurate evaluation of the dietary intake and nutritional status in order to prevent nutritional deficiencies and promote health.

DOP19 Urinary metabolome in newly diagnosed treatment-naïve Crohn’s Disease patients: Results from the IBDomics study

Abstract Background The urinary metabolome of patients with Crohn’s disease (CD) differs significantly from healthy subjects and, among other features, reflects the specific gut dysbiosis affecting these patients. However, most of the studies included established and treated CD patients. Our aim was to characterize the urinary metabolome of onset and treatment-naïve CD patients and to identify the metabolic profile related to the different CD clinical classifications. Methods Patients newly diagnosed with CD (n=131) were prospectively included. Control healthy subjects (HC, n=338) were recruited among the general population and matched for sex, age and BMI to the IBD subjects. Fasting urine was obtained before starting any treatment. Metabolomic analysis was performed by proton nuclear magnetic resonance (1H NMR). We performed a comparative assessment of the urinary metabolome profile using a linear regression model for each metabolite, including sex, age, BMI, and smoking habit as covariates to control for confounding. The different subgroup comparisons within CD were made as follows: (1) CD; (2) CD location (Montreal Classification): L1 (ileal) + L4 (ileal and upper-intestinal), L2 (colonic) and L3 (ileocolonic); (3) endoscopic CD activity: 0, 1, 2 and 3; and (4) CD phenotype: B1 (inflammatory), B2 (stricturing) and B3 (penetrating), versus HC. In addition, data analysis was carried out using partial least squares-discriminate analysis (PLS-DA) to determine class membership based on distinct metabolomic profile. Results The primary characteristics of the CD patients and HC are shown in Table 1. Several metabolites were identified to be differently abundant in each group (Table 2). These metabolites are involved in relevant processes related to energy and aminoacids metabolism, and also include gut-derived metabolites. The PLS-DA model separated patients within the different clinical subgroups (Figures 1–4). Figures 1–4(b) show the main metabolites involved in each group separation. Many of these metabolites are in accordance with the differential metabolites obtained using the univariate analysis (Table 2), showing the potential of this approach to group CD patients and to identify potential biomarkers. Conclusion Analysis of urinary metabolites can help to understand the etiopathological mechanisms in CD. It has the potential to provide a non-invasive means of diagnosing CD, and can differentiate between CD clinical expressions.

Risk mitigation in Crohn's disease and ulcerative colitis: Session four summary.

In corporate industry, risk can be a creator of value and can play a unique role in driving business performance, and so strategies for corporate risk management must be developed to help guide the business as it decides which risks to take. Risk management, then, is the identification, assessment and prioritization of risks or uncertainties in business. Any strategies for corporate risk management must be backed up by a risk management analysis and a plan for controlling or mitigating those risks. Rules-based modeling can mitigate many medical risks. Available clinical data have translated into best-practice consensus guidelines in the management of IBD. Where possible, consensus needs to be appropriate for local resources and regulatory authorities. They should be developed by national organizations and societies by a group of cross-discipline healthcare providers. In acute severe ulcerative colitis, risk may be measured as death or colectomy. The Australian IBD Consensus Working Group developed consensus statements on the management of acute severe ulcerative colitis that can be easily found by online search terms “GESA acute severe ulcerative colitis.”5 The document shows the level of evidence and provides grades for each statement. Further, the consensus statement guides readers in the identification of the presenting condition, highlights relevant investigations required, and provides advice on areas such as the need for unprepared sigmoidoscopy and treatment pathways. Corticosteroids are the mainstays of induction therapy in IBD. Risks of complications accumulate with extended use, but underutilization of corticosteroids may be associated with failure to induce clinical remission and ongoing poor quality of life. Chronic use of corticosteroids is an immediate trigger for treatment escalation. This is most relevant in the older patients, a group where overutilization of systemic immunosuppression is discouraged. In older patients and those with significant comorbidities, a survey of gastroenterologists showed that vedolizumab was more frequently prescribed than immunomodulators and anti-tumor necrosis factor (TNF) biological agents in this patient population (TNF P < 0.0001).6 Another cohort study of 255 patients with IBD from the Sydney IBD Cohort showed that patient age was not a barrier to the introduction of immunomodulators, but the presence of comorbidities was.7 In that study, the benefit of commencing immunomodulators early was seen in both young- and elderly-onset Crohn's disease with a significant reduction in abdominal and perianal surgery (HR: 0.177, 95% CI: 0.089–0.351).8 Overseas travel, although reduced since the SARS-CoV2 (COVID-19) pandemic, is a frequently encountered topic of discussion during consultations. Patients with IBD treated with systemic immunosuppressive drugs are at risk of opportunistic infections when travelling overseas, but many of these risks can be mitigated through preventative and surveillance strategies.7 Vaccination and risk avoidance strategies are required in high-risk areas of the Asia-Pacific, and screening for latent tuberculosis can be recommended following return from high tuberculosis-prevalence regions. A survey of 305 gastroenterologists from 23 countries identified only half of all respondents discussed travel-related issues with patients, and there was great variability in the advice given.9 Another international survey of 2491 IBD subjects found that over a third of all patients did not seek medical advice prior to overseas travel indicating pre-emptive discussions on travel to be appropriate.10 A discussion of risk is complex and sometimes not possible due to the many competing topics that need to be covered. The above examples are merely some of the areas where risk mitigation is possible. This summary aims to remind readers of the need to consider risks encountered, but this includes the risk of undertreating patients and not just risks of treatments. Risks are also dynamic and change with patients' growing age, disease condition, changes in life circumstances, and the acquisition of other comorbidities. The dynamic nature means the need for constant evaluation of risks over other competing health conditions that the patient faces. Prof Rupert Leong served on the advisory boards of AbbVie, Aspen, BMS, Celgene, Chiesi, Ferring, Glutagen, Hospira, Janssen, MSD, Novartis, Pfizer, Takeda and has received research grants from NHMRC, Endochoice, Shire, Janssen, Takeda, Gastroenterological Society of Australia, Gutsy Group Funded through an unrestricted educational grant from Takeda Pharmaceuticals Pty Ltd.

Knowledge and Attitudes Towards Pregnancy in Females with Inflammatory Bowel Disease: An International, Multi-centre Study.

Poor knowledge of inflammatory bowel disease [IBD] in pregnancy underlies unwarranted voluntary childlessness [VC], and risks poorer obstetric outcomes and adverse fetal outcomes. IBD is increasing worldwide but education on IBD issues might be heterogeneous based on cultural differences and variations in models of care. Consecutive female IBD subjects aged 18-45 years were prospectively recruited from two dedicated IBD-pregnancy clinics, two multidisciplinary IBD clinics and nine general gastroenterology clinics. Subjects completed the validated CCPKnow [score 0-17] with questions on demographics, medical history and pregnancy knowledge. The primary outcome was knowledge per clinic-type and per geographical region. Surveys were completed by 717 subjects from 13 hospitals across ten countries. Dedicated IBD-pregnancy clinics had the highest knowledge, followed by multidisciplinary IBD clinics then general IBD clinics (median CCPKnow 10.0 [IQR: 8.0-11.0], 8.0 [IQR: 5.0-10.5] and 4.0 [IQR:2.0-6.0]; p < 0.001). Median CCPKnow scores in Western, Asian and Middle Eastern clinics were 9.0, 5.0 and 3.0 respectively [p < 0.001]. Dedicated IBD-pregnancy clinics, IBD support organization membership, childbearing after IBD diagnosis and employment independently predicted greater knowledge. Patient perception of disease severity [r = -0.18, p < 0.01] and consideration of VC [r = -0.89, p = 0.031] negatively correlated with CCPKnow score. The overall VC rate was 15.0% [95% CI: 12.2-18.2]. VC subjects had significantly lower pregnancy-specific IBD knowledge than non-VC subjects (median CCPKnow 4.0 [IQR: 2.0-6.0] and 6.0 [IQR: 3.0-9.0] respectively; p < 0.001). Pregnancy-specific IBD knowledge and dedicated IBD-pregnancy clinic attendance were significant negative predictors of VC. In this large international study we identified predictors of pregnancy-specific IBD knowledge. Dedicated IBD-pregnancy clinics had the greatest IBD-related pregnancy knowledge and lowest VC rates, reflecting the benefits of pre-conception counselling.

A246 POPULATION WIDE STUDY OF THE EPIDEMIOLOGY AND OUTCOMES OF ANTI-TNF DOSE AUGMENTATION IN INFLAMMATORY BOWEL DISEASE

Abstract Background Inflammatory bowel disease (IBD) patients who experience loss of response to anti-tumor necrosis factor (anti-TNF) therapy are often treated with augmented doses of anti-TNF to recapture response. Despite this, factors associated with dose augmentation and treatment outcomes following dose augmentation remain largely undefined. Aims To examine the epidemiology of anti-TNF dose augmentation and determine the associated treatment outcomes among a province-wide cohort of anti-TNF treated IBD subjects. Methods The University of Manitoba Inflammatory Bowel Disease Epidemiological Database was used to identify patients receiving infliximab or adalimumab maintenance therapy for IBD in the Canadian province of Manitoba. Anti-TNF dose augmentation was defined as a ≥50% increase in anti-TNF dose or a shortening of dosing interval to ≤42 days for infliximab or ≤10 days for adalimumab. Anti-TNF failure was defined as corticosteroid use, IBD-related hospitalization, resective IBD surgery, or change in anti-TNF agent. Competing risks regression using a proportional subhazards model was used to determine the associations between dose augmentation, anti-TNF failure, anti-TNF discontinuation and a number of patient, disease, and treatment factors. Results 871 persons (624 Crohn’s disease (CD), 247 ulcerative colitis (UC)) using anti-TNF maintenance therapy were identified. Cumulative incidence of dose augmentation among continued users was 25.7% at 90 days, 52.3% at 1 year, and 72.8% at 5 years. Anti-TNF failure occurred in 261 of 575 dose augmented subjects, with corticosteroid use the most common failure-defining event. Failure of standard dose anti-TNF in the 90 days preceding dose augmentation was strongly associated with failure of dose augmentation (HR 2.98 (2.27–3.93); p&amp;lt;0.0001). Persons with CD were less likely to receive corticosteroids but more likely to switch anti-TNF agents than persons with UC. Conclusions Rates of adverse IBD outcomes remain high after dose augmentation, particularly when dose augmentation is undertaken shortly after (or in response to) one of these adverse events. Our data suggest that dose augmentation may not be as effective as uncontrolled observational studies have indicated. Funding Agencies None

P059 SIGNIFICANTLY INCREASED MUCOSAL EOSINOPHILS IN PATIENTS WITH POST-IBD IBS-D SYNDROME MAY HAVE A NEW AVENUE

Abstract Introduction Inflammatory bowel disease (IBD) patients in remission who present with irritable bowel syndrome with diarrhea (IBS-D) like symptoms pose a diagnostic and therapeutic dilemma that is called post-IBD IBS-D. This syndrome was first reported by Isgar et al. who documented IBS-type symptoms in 33% of their patients with chronic ulcerative colitis (CUC) in remission in 1983. In their meta-analysis of 13 studies incorporating 1,703 patients, Halpin and Ford in 2012 calculated a pooled prevalence of 35% for IBS symptoms among IBD subjects in remission. The post-IBD IBS-D syndrome represents a source of considerable stress, incurs morbidity and impairs quality of life of these patients. The etiology of this syndrome is unknown and may be multifactorial such as environmental, psychological, GI motility disarray, genetic components and possibly by gut microbiome. Methods We conducted a retrospective, single-center study of patients with history of IBD and IBS-D like symptoms. The demographic characteristics, type of IBD, colonoscopy, biopsy findings and empirical medical management outcome were analyzed. Results We have found significantly increased mucosal eosinophils (&amp;gt;50 HPF in both side of the colon examined) in our patients with post-IBD IBS-D syndrome. In this study, 15 CUC patients and 20 Crohn’s disease patients with this syndrome were investigated and showed no clinical, serological, mucosal or microscopic IBD activity. These patients had non-bloody diarrhea (5–20 x daily), lower abdominal cramps (%90), mild weight loss (4–6 lbs) and fecal incontinence (%25) who were placed on the GI-hypoallergenic diet and budesonide therapy. Sixty seven percent of these 35 patients with post-IBD IBS-D responded well clinically to this management. Increased mucosal eosinophils in these patients with post-IBD IBS-D may have eosinophilic colopathy that may be related to intestinal permeability disarray. The epithelium in these IBD patients who are in remission may have the production of pro-inflammatory cytokines by the eosinophils, especially IL-23 and IL-33. This interesting area investigation is in progress by our research faculty. Conclusion In summary, this is an exciting new finding that significantly increased mucosal eosinophils in our patients with post-IBD IBS-D syndrome may have a new avenue, eosinophilic colopathy. Interestingly, these patients have responded to the GI-hypoallergenic diet and budesonide therapy. Obviously, we need more patients in the near future with longer follow-up and we hope that the other investigators may confirm our findings.

P022 SHIFTING COST-DRIVERS OF HEALTH CARE EXPENDITURES IN INFLAMMATORY BOWEL DISEASE

Abstract Background Inflammatory bowel diseases (IBD) are costly, chronic illnesses. Key cost-drivers of IBD healthcare expenditures include pharmaceuticals and unplanned care, but evolving treatment approaches have shifted these factors. We aimed to assess changes in cost of care, determine shifts in IBD cost-drivers, and examine differences by socioeconomic and insurance status over time. Methods The Medical Expenditure Panel Survey (MEPS), a nationally representative database that collects data on healthcare utilization and expenditures from a nationally representative sample since 1998 was utilized. Adult subjects with IBD were identified by ICD-9 codes. In order to determine changes in per-patient costs or cost-drivers unique to IBD, a control population of rheumatoid arthritis (RA) subjects was generated and matched in 1:1 case to control. Total annual healthcare expenditures were obtained and categorized as outpatient, inpatient, emergency, or pharmacy related. Temporal cohorts from 1998 to 2015 were created to assess change over time. Per-patient expenditures were compared by disease state and temporal cohort using weighted generalized linear models. Results Total of 641 IBD subjects were identified and matched to 641 RA individuals. From 1998 to 2015, median total annual healthcare expenditures nearly doubled (adjusted estimate 2.20; 95% CI 1.6–3.0) and were 36% higher in IBD compared to RA. In IBD, pharmacy expenses increased 7% to become the largest cost driver (44% total expenditures). Concurrently, inpatient spending in IBD decreased by 40%. There were no significant differences in the rate of change of cost-drivers in IBD compared to RA. Conclusions Per-patient healthcare costs for chronic inflammatory conditions have nearly doubled over the last 20 years. Increases in pharmaceutical spending in IBD may be accompanied by reduction in inpatient care. Additional studies are need to explore patient, disease, system, and industry level cost mitigation strategies.

P842 Analysis of fungal microbiota dysbiosis in inflammatory bowel disease

Abstract Background Inflammatory bowel disease（IBD）is chronic relapsing and remitting disease of the gastrointestinal tract. Although the precise aetiology and pathogenesis of IBD remains elusive, epidemiological data conclusively point to be attributed to an aberrant immune response against environmental factors such as the gut microbiota in a genetically susceptible host. The bacterial microbiota plays a major role in human physiology and pathogenesis of IBD. The Fungi are often ignored in studies. Although the role of fungi has been suggested in pathogenesis of IBD, the available data are scarce. The aim of our study was to analyse and compare the faecal fungal microbiota in patients with IBD and healthy subjects (HS). Methods Our study evaluated fungal composition of the faecal microbiota of 66 patients with CD and 38 patients with UC diagnosed in West China Hospital and 39 HS by ITS2 sequencing. The Qiime pipeline was used to assess composition and diversity. Using LEfSe observed differential fungal composition between subjects. Results The faecal fungal microbiota was dominated by two phyla, basidiomycetes and ascomycetes in both IBD and HS. We observed that fungal microbiota was skewed in IBD, with an decreased basidiomycota/ascomycota ratio, a decreased proportion of Aspergillus and Saccharomyces and an increased proportion of Exophiala. Polythrincium, clonostachys, Candida compared with HS. Using LEfSe, we observed several differential fungal composition in different subject. Exophial a (p = 0.02), Agaricales (p = 0.02)species were overrepresented in UC, whereas Bulleribasidiaceae (p = 0.01), Ustilaginaceae (p = 0.007), Ustilaginales (p = 0. 007),Ustilaginomycetes (p = 0.007)species were overrepresented in HS. We then directly compared the fungal composition between subgroup of CD and UC, we observed Eurotiales（p = 0.007）, Aspergillus（p = 0.025), Thermoascus（p = 0.04）species were overrepresented in UC-remission. Ascomycota (p = 0.008) and Didymellaceae (p = 0.02)species were associated with CD-remission, whereas Saccharomyces (p = 0.03) and Xylariaceae (p = 0.006) species were associated with CD-flare. There was no significant difference in fungal Alpha diversity between IBD and HS. Beta diversity analysis showed that one subgroup of IBD samples segregated from HS whereas another subgroup overlapped with HS. Conclusion There was no significant change in fungal diversity in IBD. However, we observed fungal composition was skewed with decreased basidiomycota/ascomycota ratio on phyla level, particularly in IBD-flare group. The fungal composition was dominated by Aspergillus and Saccharomyces in HS, while the proportion of Exophiala, Polythrincium, Clonostachys, Candida was increased in IBD on genus level.

Shifting Cost-drivers of Health Care Expenditures in Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD) are costly, chronic illnesses. Key cost-drivers of IBD health care expenditures include pharmaceuticals and unplanned care, but evolving treatment approaches have shifted these factors. We aimed to assess changes in cost of care, determine shifts in IBD cost-drivers, and examine differences by socioeconomic and insurance status over time. The Medical Expenditure Panel Survey (MEPS), a nationally representative database that collects data on health care utilization and expenditures from a nationally representative sample since 1998, was utilized. Adult subjects with IBD were identified by ICD-9 codes. To determine changes in per-patient costs or cost-drivers unique to IBD, a control population of rheumatoid arthritis (RA) subjects was generated and matched in 1:1 case to control. Total annual health care expenditures were obtained and categorized as outpatient, inpatient, emergency, or pharmacy related. Temporal cohorts from 1998 to 2015 were created to assess change over time. Per-patient expenditures were compared by disease state and temporal cohort using weighted generalized linear models. A total of 641 IBD subjects were identified and matched to 641 RA individuals. From 1998 to 2015, median total annual health care expenditures nearly doubled (adjusted estimate 2.20; 95% CI, 1.6-3.0) and were 36% higher in IBD compared with RA. In IBD, pharmacy expenses increased 7% to become the largest cost-driver (44% total expenditures). Concurrently, inpatient spending in IBD decreased by 40%. There were no significant differences in the rate of change of cost-drivers in IBD compared with RA. Per-patient health care costs for chronic inflammatory conditions have nearly doubled over the last 20 years. Increases in pharmaceutical spending in IBD may be accompanied by reduction in inpatient care. Additional studies are needed to explore patient-, disease-, system-, and industry-level cost mitigation strategies.