Onset Inflammatory Bowel Disease Research Articles

OA09 Significant association between disease duration in axial spondyloarthritis and the occurrence of uveitis and inflammatory bowel disease, with no such association found for psoriasis

Abstract Background/Aims Axial spondyloarthritis is a chronic inflammatory condition primarily impacting the spine and sacroiliac joints. In addition to spinal inflammation and peripheral symptoms, it frequently presents with extra-musculoskeletal manifestations such as inflammatory bowel disease, psoriasis, and anterior uveitis, collectively adding to the overall disease burden. Although existing research has explored the heightened risk of ophthalmological manifestations with prolonged disease duration, there is a paucity of literature examining the association between disease duration in axial spondyloarthritis and the onset of inflammatory bowel disease and psoriasis. Aim: To investigate the relationship between axial spondyloarthritis disease duration and the development of extra-musculoskeletal manifestations. Methods This is a retrospective cohort study with data obtained from the Ankylosing Spondylitis Registry of Ireland (ASRI), which is a large cross-sectional, multicentre cohort study. Using both univariate and multivariate regression analyses, we examined the relationship between axial spondyloarthritis disease duration and extra musculoskeletal manifestations. In the multivariate analysis, several covariates including gender, body mass index, smoking, and HLA-B27 status were considered to account for their potential influence on the observed associations. Results Demographic details were available for 912 patients included at the time of analysis. The median disease duration in years for our cohort was 16. Table 1 presents relevant general characteristics of the ASRI cohort and the results of our regression analysis. Uveitis exhibited a highly significant association (P < 0.001) with AxSpA duration in both univariate and multivariate analyses, even after accounting for covariates. Inflammatory bowel disease also showed a significant association with AxSpA duration in both univariate and multivariate analyses (P < 0.003). In our analysis, psoriasis showed no significant relationship with AxSpA disease duration in both univariate (P = 0.298) and multivariate analyses (P1 = 0.249). Conclusion Our study, using a large data set, reveals distinct patterns of association between axial spondyloarthritis disease duration and inflammatory bowel disease and uveitis. Conversely, psoriasis demonstrates no significant link to disease duration when considering confounding factors. Clinically, these insights are crucial for tailored management strategies, emphasising the need for improved diagnostic time and multidisciplinary care to address the diverse manifestations of AxSpA and optimise patient outcomes. Disclosure B. Dinneen: None. M. Kenyon: None. F. O'Shea: None.

136 Hematopoietic stem cell transplantation for very early onset inflammatory bowel disease caused by IL10RA deficiency – preparation is the key to success

136 Hematopoietic stem cell transplantation for very early onset inflammatory bowel disease caused by IL10RA deficiency – preparation is the key to success

Alterations in Gut Microbiota as Early Biomarkers for Predicting Inflammatory Bowel Disease Onset and Progression: A Systematic Review.

Inflammatory bowel disease (IBD) is a chronic ailment impacting the digestive system, triggered by an unusual reaction of the immune system. It includes two types of diseases: ulcerative colitis and Crohn's disease. Nonetheless, the diagnosis and evaluation of disease progression in IBDare difficult due to the absence of distinct indicators. While conventional biomarkers from blood plasma and feces, such as C-reactive protein, fecal calprotectin, and S100A12, can be employed to gauge inflammation, they are not exclusive to IBD. There is a broad consensus that intestinal microorganisms significantly contribute to the onset of intestinal imbalance, a condition intimately linked with the cause and development of IBD. Numerous studies have indicated that the makeup of intestinal microorganisms varies between individuals with IBD and those who are healthy, particularly concerning the diversity of microbes and the proportional prevalence of certain bacteria.A total of1475 recordsunderwent examination. Following the eligibility assessment,17 reportswere considered. The final review encompassed12 studies, asfive articles were excluded due to insufficient details regarding cases, controls, and comparability. This article suggests that gut microbiota has potential biomarkers for the noninvasive evaluation of IBD activity. Recognizing the microbiome linked with disease activity paves the way for the development of a group of microbiota-derived indicators to evaluate the initiation and advancement of IBD. This article discusses whether changes in gut microbial compositioncan serve as early indicators of IBD onset and progression.

Increased Risk of Inflammatory Bowel Disease Among Patients With Nontyphoidal Salmonella Infections: A Population-Based Cohort Study.

Despite the known association between microorganisms and development of inflammatory bowel disease (IBD), the role of nontyphoidal Salmonella (NTS) in IBD is not adequately addressed. We aimed at elucidating the relationship between NTS infection and the risk of IBD. Based on the National Health Insurance Research Database in Taiwan, this retrospective cohort study enrolled patients with NTS infection (exposure group; n = 4651) and those without NTS infection (comparator group; n = 4651) who were propensity score matched (1:1) by demographic data, medications, comorbidities, and index date. All patients were followed until IBD onset, individual mortality, or December 31, 2018. Cox proportional hazards regression analysis was performed to determine the hazard ratios and 95% confidence intervals (CIs). Sensitivity analyses were used for cross-validation. The NTS group demonstrated an increased risk of IBD compared with the non-NTS groups (adjusted hazard ratio [aHR], 2.12; 95% CI, 1.62-2.78) with a higher risk of developing ulcerative colitis in the former (aHR, 2.27; 95% CI, 1.69-3.04). Nevertheless, the small sample size may contribute to lack of significant difference in Crohn's disease. Consistent findings were noted after excluding IBD diagnosed within 6 months of NTS infection (aHR, 2.28; 95% CI, 1.71-3.03), excluding those with enteritis/colitis before index date (aHR, 1.85; 95% CI, 1.28-2.68), excluding those using antibiotics for 1 month in the year before IBD onset (aHR, 1.81; 95% CI, 1.34-2.45), inverse probability of treatment weighting (aHR, 1.64; 95% CI, 1.31-2.04), and inclusion of individuals regardless of age (n = 10 431; aHR, 1.83; 95% CI, 1.53-2.19). Patients with NTS were associated with an increased risk of developing IBD, especially ulcerative colitis.

Children and Adolescents Diagnosed With Inflammatory Bowel Disease Are at Increased Risk of Developing Diseases With a Possible Autoimmune Pathogenesis.

The development of diseases with a possible autoimmune pathogenesis is common in adults with inflammatory bowel disease (IBD). In early onset IBD, it may differ but the evidence is sparse. We aimed to investigate the risk and time span from IBD diagnosis to outcomes with different associated disorders with possible autoimmune pathogenesis. A register-based study included all Danish patients with early onset of IBD (≤18 years) between 1980 and 2021 and 50 matched references without IBD for each case. We examined the risk of type 1 and type 2 diabetes, celiac disease, thyroid disease, rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis in Cox regression models. In total, 6822 patients with IBD were identified, and 337 728 matched references. The median age at the time of IBD diagnosis or index date for the matched references was 16 years (25-75 percentile: 13-18 years), and the median age at the time of an outcome or at the end of follow-up was 28.1 years (25-75 percentile: 21.5-37.0 years). According to the cumulative incidence plots psoriatic arthritis, and spondyloarthritis was diagnosed approximately 10 years after the IBD onset, and the remaining outcomes later. The adjusted hazard ratio after full follow-up was 4.72 (95% CI, 3.85-5.80) for psoriatic arthritis, 5.21 (95% CI, 4.17-6.50) for spondyloarthritis, 2.77 (95% CI, 1.92-4.00) for celiac disease, 2.15 (95% CI, 1.54-3.01) for rheumatoid arthritis, 1.69 (95% CI, 1.23-2.32) and 1.64 (95% CI, 1.21-2.21) for type 1 and type 2 diabetes, respectively. For thyroid disease, it was 1.16 (95% CI, 0.97-1.40). The risk estimates were significantly increased for all outcomes at the end of follow-up, except for thyroid disease, but according to the cumulative incidence plots, only psoriatic arthritis and spondyloarthritis occurred earlier in the IBD cohort than in the matched references.

Potential effects of nutrition-induced alteration of gut microbiota on inflammatory bowel disease: A review.

Inflammatory bowel disease (IBD), mainly comprising ulcerative colitis and Crohn's disease, is a group of gradually progressive diseases bringing significant mental anguish and imposes serious economic burdens. Interplay of genetic, environmental, and immunological factors have been implicated in its pathogenesis. Nutrients, as crucial environmental determinants, mainly encompassing carbohydrates, fats, proteins, and micronutrients, are closely related to the pathogenesis and development of IBD. Nutrition is essential for maintaining the dynamic balance of intestinal eco-environments to ensure intestinal barrier and immune homeostasis, while this balance can be disrupted easily by maladjusted nutrition. Research has firmly established that nutrition has the potential to shape the composition and function of gut microbiota to affect the disease course. Unhealthy diet and eating disorders lead to gut microbiota dysbiosis and further destroy the function of intestinal barrier such as the disruption of membrane integrity and increased permeability, thereby triggering intestinal inflammation. Notably, appropriate nutritional interventions, such as the Mediterranean diet, can positively modulate intestinal microecology, which may provide a promising strategy for future IBD prevention. In this review, we provide insights into the interplay between nutrition and gut microbiota and its effects on IBD and present some previously overlooked lines of evidence regarding the role of derived metabolites in IBD processes, such as trimethylamine N-oxide and imidazole propionate. Furthermore, we provide some insights into reducing the risk of onset and exacerbation of IBD by modifying nutrition and discuss several outstanding challenges and opportunities for future study.

Is the use of secukinumab after anti-TNF therapy greater than expected for the risk of developing inflammatory bowel disease?

ObjectiveIn this study, our objective was to present real-life data on the incidence of inflammatory bowel disease (IBD) among patients receiving secukinumab treatment. MethodsThe study consisted of 209 patients who had prior exposure to anti-tumor necrosis factor (TNF) or were biologically naive. Patients with a pre-existing history of IBD were excluded from the study. ResultsOf the 209 patients in the study, 176 (84.3%) had ankylosing spondylitis, while 33 (15.7%) had psoriatic arthritis. 112 (53.6%) patients had prior exposure to at least one anti-TNF treatment before initiating secukinumab. IBD developed in 10 (4.8%) of the 209 patients. The incidence of IBD among patients who initiated secukinumab as their first biologic agent was 1%. For patients who had previously received any anti-TNF treatment and subsequently transitioned to secukinumab, the incidence of IBD was 8% (p=0.018, odds ratio (OR): 8.38, 95% CI: 1.04–67.45). A mean of 3.67 months (±4.3) after anti-TNF use, whereas IBD symptoms developed in the biologically naive patient after 15 months. ConclusionOur study observed IBD incidence in 4.8% of patients using secukinumab. Patients who initiated secukinumab after previous anti-TNF treatment exhibited a significantly higher rate and risk of developing IBD. The onset of IBD occurred earlier in these patients (mean 3.67 months), whereas a single case of IBD showed a longer duration (15 months). Further studies with larger patient numbers are warranted to provide a more comprehensive understanding of our findings.

Impact of inflammatory bowel disease on the risk of acute coronary syndrome: A Swedish Nationwide Cohort Study.

There are conflicting data on the risk of acute coronary syndrome (ACS) in patients with inflammatory bowel disease (IBD). Only a few previous reports include patients diagnosed during the last decade. To assess and compare the risk of ACS between patients with IBD and the general population. In this cohort study, we used nationwide registers to identify patients diagnosed with IBD in Sweden 2003-2021. Every patient was matched by birth year, sex, calendar year and area of residence with up to 10 general population comparators. The primary outcome was incident ACS. We used semi-parametric Cox proportional hazard models to estimate hazard ratios (HRs). We identified 76,517 patients with IBD (Crohn's disease [CD], N = 22,732; ulcerative colitis [UC], N = 42,194 and IBD-unclassified, N = 11,591) and 757,141 comparators. During a median follow-up of 8 years, 2546 patients with IBD (37.5/10,000 person-years) were diagnosed with ACS compared with 19,598 (28.0/10,000 person-years) among comparators (HR 1.30; 95% confidence interval 1.24-1.35) after adjustments for confounding factors, and approximately one extra case of ACS in 100 IBD patients followed for 10 years. The highest HRs for ACS were in patients with elderly onset IBD (≥60 years) and among patients with CD or UC with extra-intestinal manifestations. No increased HRs were observed in patients diagnosed with IBD before the age of 40. In this contemporary cohort of patients with IBD, exposed to modern IBD care, there was an increased risk for ACS compared with individuals from the general population.

Brain imaging derived phenotypes: a biomarker for the onset of inflammatory bowel disease and a potential mediator of mental complications.

Inflammatory bowel disease (IBD), mainly categorized into Crohn's disease (CD) and ulcerative colitis (UC), is a chronic relapsing gastrointestinal disorder that significantly impairs patients' quality of life. IBD patients often experience comorbidities such as anxiety and depression, and the underlying mechanisms and treatment strategies remain areas of investigation. We conducted a Mendelian randomization(MR) analysis utilizing brain image derived phenotypes (IDP) from the UK Biobank database to investigate the causal relationships between IBD and alterations in brain structural morphology and connectivity of neural tracts. This study aimed to identify biological evidence linking IBD to psychiatric disorders such as anxiety and depression. Specifically, the volume of grey matter in the Left Frontal Orbital Cortex exhibited a negative association with the onset of Crohn's disease (odds ratio (OR) [95% confidence interval (CI)]: 0.315[0.180~0.551], adjusted P=0.001), while the volume of the superior frontal cortex in the right hemisphere showed a positive correlation with the development of Ulcerative colitis (OR [95% CI]: 2.285[1.793~2.911], adjusted P<0.001), and the volume of lateral occipital cortex in the left hemisphere demonstrated a positive relationship with Crohn's disease onset (OR [95% CI]: 1.709[1.671~1.747], adjusted P<0.001). In the context of reverse causality, the onset of UC or CD has led to alterations in imaging derived phenotypes associated with five disorders (anxiety, depression, schizophrenia, bipolar disorder, pain) and three functions (memory, emotion, language). Our study has demonstrated a causal relationship between IBD and IDPs. IDPs may serve as potential biomarkers for the progression of IBD and as predictive intermediaries for the development of neurological diseases in IBD patients.

The intestinal microbiome of inflammatory bowel disease across the pediatric age range

ABSTRACT Dysbiosis is associated with pediatric and adult-onset inflammatory bowel disease (IBD), but the role of dysbiosis and the microbiome in very early onset IBD (VEO-IBD) has not yet been described. Here, we aimed to demonstrate the impact of age and inflammation on microbial community structure using shotgun metagenomic sequencing in children with VEO-IBD, pediatric-onset IBD, and age-matched pediatric healthy controls (HC) observed longitudinally over the course of 8 weeks. We found disease-related differences in alpha and beta diversity between HC and children with IBD or VEO-IBD. Using a healthy microbial maturity index modeled from HC across the age range to characterize their gut microbiota, we found that children with pediatric-onset IBD and VEO-IBD had lower maturity than their age-matched HC groups, suggesting a disease effect on the microbial community. In addition, patients with pediatric IBD had significantly lower maturity than those with VEO-IBD, who had more heterogeneity at the youngest ages, highlighting differences in these two cohorts that were not captured in standard comparisons of alpha and beta diversity. These results demonstrate that young age and inflammation independently impact microbial community structure. However, the effect is not additive in the youngest patients, likely because of the heterogeneous and dynamic stool microbiome in this population.

Sustained Increase in Pediatric Inflammatory Bowel Disease Incidence Across the South West United Kingdom Over the Last 10 Years.

Pediatric inflammatory bowel disease (pIBD) incidence has increased over the last 25 years. We aim to report contemporaneous trends across the South West United Kingdom. Data were provided from centers covering the South West United Kingdom (Bristol, Oxford, Cardiff, Exeter, and Southampton), with a total area at-risk population (<18 years of age) of 2 947 534. Cases were retrieved from 2013 to 2022. Incident rates were reported per 100 000 at-risk population, with temporal trends analyzed through correlation. Subgroup analysis was undertaken for age groups (0-6, 6-11, and 12-17 years of age), sex, and disease subtype. Choropleth maps were created for local districts. In total, 2497 pIBD cases were diagnosed between 2013 and 2022, with a mean age of 12.6 years (38.7% female). Diagnosis numbers increased from 187 to 376, with corresponding incidence rates of 6.0 per 100 000 population per year (2013) to 12.4 per 100 000 population per year (2022) (b = 0.918, P < .01). Female rates increased from 5.1 per 100 000 population per year in 2013 to 11.0 per 100 000 population per year in 2022 (b = 0.865, P = .01). Male rates increased from 5.7 per 100 000 population per year to 14.4 per 100 000 population per year (b = 0.832, P = .03). Crohn's disease incidence increased from 3.1 per 100 000 population per year to 6.3 per 100 000 population per year (b = 0.897, P < .01). Ulcerative colitis increased from 2.3 per 100 000 population per year to 4.3 per 100 000 population per year (b = 0.813, P = .04). Inflammatory bowel disease unclassified also increased, from 0.6 per 100 000 population per year to 1.8 per 100 000 population per year (b = 0.851, P = .02). Statistically significant increases were seen in those ≥12 to 17 years of age, from 11.2 per 100 000 population per year to 24.6 per 100 000 population per year (b = 0.912, P < .01), and the 7- to 11-year-old age group, with incidence rising from 4.4 per 100 000 population per year to 7.6 per 100 000 population per year (b = 0.878, P = .01). There was no statistically significant increase in very early onset inflammatory bowel disease (≤6 years of age) (b = 0.417, P = .231). We demonstrate significant increases in pIBD incidence across a large geographical area including multiple referral centers. Increasing incidence has implications for service provision for services managing pIBD.

Evolving a Single Institution’s Approach to Very Early Onset Inflammatory Bowel Disease (VEO-IBD) through Literature Review and Collaborative Efforts

Evolving a Single Institution’s Approach to Very Early Onset Inflammatory Bowel Disease (VEO-IBD) through Literature Review and Collaborative Efforts

Humoral immune response and safety of SARS-CoV-2 vaccination in very early onset inflammatory bowel disease.

Children with very early onset inflammatory bowel disease (VEO-IBD) may respond differently to coronavirus disease 2019 (COVID-19) immunization compared to healthy children or other patients with IBD. We recruited children with VEO-IBD<6 years of age and younger following receipt of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Demographics, IBD characteristics, medication use, adverse events (AEs) and IBD exacerbations were collected. Blood draws (optional) were obtained for measurement of antireceptor binding domain (RBD) IgG antibodies following vaccination. Of 41 participants, none required emergency department visit or hospitalization due to AE, and only one experienced IBD exacerbation. Detectable antibody was present in 19/19 participants who provided blood sample; 6/7 participants (86%) had durable humoral response 12 months postvaccination. Children with VEO-IBD experience robust humoral immune response to COVID-19 immunization. Severe AEs were rare. These findings provide reassurance that children with VEO-IBD respond well and safely to SARS-CoV-2 vaccination.

A Versatile Intestine-on-Chip System for Deciphering the Immunopathogenesis of Inflammatory Bowel Disease.

The multifactorial nature of inflammatory bowel disease (IBD) necessitates reliable and practical experimental models to elucidate its etiology and pathogenesis. To model the intestinal microenvironment at the onset of IBD in vitro, it is important to incorporate relevant cellular and noncellular components before inducing stepwise pathogenic developments. A novel intestine-on-chip system for investigating multiple aspects of IBD's immunopathogenesis is presented. The system includes an array of tight and polarized barrier models formed from intestinal epithelial cells on an in-vivo-like subepithelial matrix within one week. The dynamic remodeling of the subepithelial matrix by cells or their secretome demonstrates the physiological relevance of the on-chip barrier models. The system design enables introduction of various immune cell types and inflammatory stimuli at specific locations in the same barrier model, which facilitates investigations of the distinct roles of each cell type in intestinal inflammation development. It is showed that inflammatory behavior manifests in an upregulated expression of inflammatory markers and cytokines (TNF-α). The neutralizing effect of the anti-inflammatory antibody Infliximab on levels of TNF-α and its inducible cytokines could be explicitly shown. Overall, an innovative approach to systematically developing a microphysiological system to comprehend immune-system-mediated disorders of IBD and to identify new therapeutic strategies is presented.

[Clinical features and genetic analysis of three patients with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome due to variants of FOXP3 gene].

To analyze the clinical characteristics of three patients with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Three patients with IPEX syndrome diagnosed at the Children's Hospital of Fudan University from January 24, 2013 to July 29, 2019 were selected as the study subjects. Their clinical features, laboratory investigations and results of genetic testing were summarized. Treatment and prognosis were also explored. All of the three children had developed the disorder during infancy. One child had initial features including diabetes and diabetic ketoacidosis, whilst the other two had initiated by diarrhea. All patients had gastrointestinal involvement, and one was diagnosed as very early onset inflammatory bowel disease by colonoscopy and biopsy. Two children also had endocrine glands involvement. One child had manifested type 1 diabetes and positivity for thyroglobulin and thyroid peroxidase antibodies, though his thyroid function had remained normal. Another one had hypothyroidism and was treated by levothyroxine. Genetic testing revealed that all children had harbored missense variants of the FOXP3 gene, including c.1222G>A (p.V408M), c.767T>C (p.M256T) and c.1021A>G (p.T341A). The clinical symptoms of one patient were alleviated following allogeneic hematopoietic stem cell transplantation. One patient was stable after treatment with infliximab plus insulin, and one child had died of refractory septic shock and multiple organ dysfunction syndrome at 3 months old. FOXP3 gene variant-associated IPEX syndrome may have very early onset and diverse clinical manifestations. For male patients with infantile onset chronic diarrhea, multiple endocrine or multiple system involvement, genetic testing is recommended, which may facilitate early diagnosis, treatment and genetic counseling.

CLINICAL OUTCOMES OF INFLAMMATORY BOWEL DISEASE AFTER ORTHOTOPIC HEART TRANSPLANT

Abstract BACKGROUND Limited data are available on outcomes of patients with pre-existing inflammatory bowel disease (IBD) who undergo orthotopic heart transplantation (OHT) or develop de novo IBD post-OHT. We aimed to assess the incidence and disease outcomes of pre-existing and de novo IBD in OHT patients while evaluating the effect of IBD on OHT outcomes. METHODS A retrospective review of records was performed from a tri-site tertiary care system between July 2000 and July 2022. A total of 83 OHT receipients were concomitantly diagnosed with colitis of infectious or inflammatory etiology. Only patients with a diagnosis of IBD were included. Sub-analyses of the outcomes and immunosuppressive regimens of OHT recepients were done relative to those with pre-existing or de novo IBD. RESULTS A total of 8 OHT patients with concomitant IBD were identified. The median patient age (IQR) was 54 (23) with OHT and IBD onset at 50 (21.2) and 32.5 (15.7), respectively. Six patients were diagnosed with ulcerative colitis (UC) and 2 were diagnosed with Crohn’s disease. Five of the patients were female. All patients developed IBD within 11.5 (8) years within OHT. Only 1 patient developed de novo IBD 15 years after the first OHT and 7 years prior to a second OHT. OHT immunosuppressive regimens included a combination of tacrolimus (TAC) and prednisone (n=2), TAC and mycophenolate mofetil (MMF) (n=2), TAC, MMF, and sirolimus (n=2), TAC and sirolimus (n=1), and MMF with sirolimus (n=1). Therapy for pre-existing IBD included maintenance of 5-aminosalicylic (5-ASA) (n=3), escalation to vedolizumab (VD) (n=2), and discontinuation of IBD therapy (5-ASA and azathioprine) (n=3). De novo IBD consistent with UC (15 years post-OHT) was managed with 5-ASA (n=1). Six patients (including de novo IBD case) maintained clinical and endoscopic remission of IBD with no flares post-OHT while 2 patients (1 UC and 1 CD) with active disease flares responded clinically and endoscopically to VD escalation from 5-ASA and azathioprine. Among two UC patients with ileal J-pouch pre-OHT, 1 developed refractory pouchitis requiring diverting ileostomy (while on TAC and prednisone) with no pouchitis in the other (maintained on TAC and MMF). Good graft tolerance limited to mild acute cellular rejection episodes was noted in 6 patients, while multiple or no rejection episodes were noted in the remaining two. None of the patients developed CMV or MMF-induced colitis. One patient died due to progressive functional decline unrelated to graft failure or IBD. DISCUSSION The clinical course and treatment of IBD preceding OHT or de novo (though rare) is not significantly worsened or altered post-OHT. The majority of patients achieve clinical and endoscopic remission while on heart transplant-related immunosuppression. Biologic therapy escalation to VD resulted in clinical remission with no effect on graft tolerance. Table 1 Clinical outcomes of OHT patients with concomitant IBD

UNIQUE MONOCYTE EXPRESSION SIGNATURE IN A STXBP2 MUTATION CAUSING INFANTILE ONSET VEO-IBD AND HLH

Abstract Mutations in syntaxin-binding-protein-2 (STXBP2) can result in NK cell dysfunction leading to a hyperinflammatory state including familial HLH and infantile onset inflammatory bowel disease (IBD). While the function of STXBP2 in NK cells and cytotoxic T cells has been well described, it is highly expressed in monocytes with unclear relevance. We report the case of an infant who presented with severe infantile onset diarrhea with an identified pathogenic mutation in STXBP2. We sought to utilize scRNA-Seq to study the impact of STXBP2 deficiency on monocyte transcription, with the goal of generating insight into the pathogenesis of disease. METHODS: Trio whole exome sequencing was performed. PBMCs were collected from the described patient (case), and two control groups: 3 patients with VEO-IBD, and 3 age matched healthy controls. Single cell RNA-Seq was performed using the 10x platform and data analysis was done using Seurat in R. RESULTS: A male infant presented at 1 week of age with diarrhea and metabolic acidosis. Endoscopic evaluation at 4 weeks of age showed histologic findings of colitis and marked epithelial cell changes, including cell rounding. WES identified a homozygous pathogenic mutation in STXBP2. Due to significant risk of HLH, he underwent evaluation for stem cell transplant. However, in the interim he developed severe HLH requiring ICU level care. He recovered following aggressive treatment and underwent HSCT at 4 months of age and retransplant for graft failure at 11 months of age. He is currently in endoscopic remission off therapy. We analyzed PBMCs from the case patient using single cell RNA-Seq, as compared to patients with VEO-IBD and age-matched controls. STXBP2 expression was most enriched in monocyte populations and reduced in the case patient compared to controls. 231 and 187 genes were differentially expressed in the case monocytes as compared to both controls. The case patient had a paucity of non-classical monocytes. Within the classical monocytes, differentially expressed genes showed enrichment of host defense, cytokine processes, and apoptotic processes. Within the intermediate monocytes, differentially expressed genes showed enrichment of chemotaxis pathways, antigen presentation and T cell activation processes. CONCLUSIONS: Mutations in STXBP2 are a life-threatening cause of fHLH and infantile onset IBD. We report a case of infantile onset IBD due to a homozygous mutation in STXBP2 with resolution of disease post HSCT. Transcriptional analysis of PBMCs from this patient reveals a paucity of non-classical monocytes in the peripheral blood, and differential regulation of genes implicated in host defenses, antigen presentation, chemotaxis and apoptosis. These results may suggest the role of monocyte function in pathogenesis of STXBP2 and in other forms of IBD.

BIOACTIVE INTERLEUKIN-1 DETECTED IN IBD PATIENT INTESTINAL BIOPSIES IS A HALLMARK OF ULCERS AND CORRELATES WITH TRANSCRIPTOMIC ASSESSMENTS, INCLUDING AN ULCER-ASSOCIATED GENE MODULE

Abstract BACKGROUND Interleukin (IL)-1 and its post-translationally modified and released forms, IL-1α and IL-1β, have been identified as key molecules to maintain mucosal homeostasis and to drive inflammatory bowel disease (IBD). Deep cellular phenotypic, transcriptional, and in vitro data highlight the importance of IL-1-associated cytokine networks and IL-1 producing cells in severe and anti-TNF non-responsive IBD. Nevertheless, little is known about the presence of bioactive IL-1 proteins within the cell-free gastrointestinal (GI) mucosal environment and associated function in severe IBD and ulceration. METHODS We established a highly sensitive functional assay (~500-fold greater than ELISA) to assess bioactive extracellular IL-1 protein from previously cryopreserved GI biopsies. We performed an ex vivo study in a cohort of Crohn’s disease (CD, n=23), ulcerative colitis (UC, n=18) and non-IBD (n=17) patients, with biopsies from paired inflamed and uninflamed intestinal regions per patient (primarily colon but also ileal). We assessed differential IL-1 bioactivity, including IL-1α vs IL-1β contributions, and performed RNA-seq of the matched cellular compartments of the samples. An ulcer-associated gene signature derived from RNA-seq analysis was evaluated in a single-cell RNA-seq cohort (n=42) of very early onset IBD including monogenic disorders. RESULTS The extent of bioactive intestinal mucosal IL-1α and IL-1β corresponded with disease and ulcer severity in both CD and UC. The most extreme signals were seen in select CD patients with deep ulceration. Bioactive IL-1α was the predominant contributor to total IL-1 signal in most patients although several with ulcers displayed an IL-1β-predominant signal. Matched RNA-seq analysis demonstrated enhanced IL-1 transcripts, correlating with IL-1 bioactivity, and a weighted gene co-expression network analysis (WGCNA) revealed a compelling ulcer-specific module enriched in IL-1 signaling genes and wound repair. We validated our findings in several published (e.g., RISK cohort of ileal CD) as well as unpublished independent adult and pediatric datasets from our group. Deconvolution of the ulcer-specific gene module and projection onto an unpublished single-cell RNA-seq cohort of very early onset IBD patients (including IBD-causative mutations such as IL-10R deficiency characterized by deep ulceration) implicated specific stromal and myeloid populations in ulcer biology. CONCLUSION Mucosal ulceration in IBD is associated with bioactive IL-1α and IL-1β proteins, and transcriptomic evaluation of the same correlates with bioactive signal. An ulcer-associated gene module, validated in other datasets, sheds light on IL-1 biology in intestinal epithelial repair. Results strongly suggest the IL-1 signaling pathway being an attractive and precision-based therapeutic target in subsets of IBD patients.

P071 Neonatal levels of inflammatory markers in individuals who later develop early onset Inflammatory Bowel Disease

Abstract Background The early life period is suggested to be important in development of Inflammatory Bowel Disease (IBD). Studies in babies from mothers with IBD observed increased faecal calprotectin and changes in the microbial compartments compared to babies from healthy mothers1,2, which suggests that changes in early life might be associated with later disease development. Prospective studies of IBD risk following early life changes at the molecular level are sparse. We aimed to investigate if individuals with early onset (EO) IBD had changes in systemic inflammatory markers shortly after birth. Methods We measured the concentration of 9 cytokines in a cohort of 464 neonatal dried blood spot samples stored at the Danish National Biobank from individuals who later developed EO IBD (median age of diagnosis 11 years), as well as matched controls. Individuals who developed IBD were identified through the use of the Danish National Patient Registry. Uni- and multivariate logistic regression with adjustment for birth year, sex, and gestational age was conducted to assess the association between 6 of the inflammatory markers with later disease development (INF-γ, TNF-α, IL-1β, IL-4, IL-6 and IL-17a). Further exploratory analyses were performed investigating risk of very early onset (VEO) IBD (onset from 0-5 years) in 88 cases and their matched controls. Results No significant association with EO IBD was observed for any of the cytokines in uni- and multivariate models when adjusting for multiple testing. In the exploratory analysis of VEO IBD, increased IL-4 was associated with significantly reduced risk of IBD (OR=0.992, p-value=0.023) and increased IL-17a was borderline-significantly associated with increased risk of IBD (OR=1.002, p-value=0.063) in a multivariate logistic model including all 6 cytokines. This association did not remain significant when adjusting for multiple testing, which may reflect limited power. Conclusion In our unique study of 464 dried blood spots from later IBD patients and controls, we could not find an association between measured cytokines and EO IBD. In contrast, patients with VEO IBD had decreased levels of IL-4 and increased levels of IL-17a. This sub-cohort was small, and significance disappeared after adjusting for multiple testing. Still, we find it important to report these findings, as they are novel and may inspire future studies into the aetiology of VEO IBD. 1. Kim, E. S. et al. Longitudinal Changes in Fecal Calprotectin Levels Among Pregnant Women With and Without Inflammatory Bowel Disease and Their Babies. Gastroenterology (2021) 2. Torres, J. et al. Infants born to mothers with IBD present with altered gut microbiome that transfers abnormalities of the adaptive immune system to germ-free mice. Gut (2020)

P1003 Dietary pattern can influence the level of fatigue in patients with Inflammatory Bowel Disease in remission

Abstract Background It is well known that dietary pattern can play an important role in the onset of inflammatory bowel diseases (IBD). In patients with established disease, they can influence the risk of relapse and the disease course. The aim of the study is to explore the impact of dietary patterns on health-related quality of life (HR-QoL), fatigue, anxiety and depression in patients with IBD in corticosteroid-free clinical remission. Methods A total of 96 consecutive patients diagnosed with IBD that were in corticosteroid-free remission for at least 12 weeks were enrolled in this observational, cross-sectional study. During an interview, patients were asked about their dietary patterns. Twelve categories of foods were identified, 6 of them being considered "healthy" (vegetables and fruits &amp;gt;4 portions/day, cereals &amp;gt;3 portions/day, seeds &amp;gt;4 portions/week, cheese &amp;gt;1 portion/day, yoghurt &amp;gt;1 portion/day, fish &amp;gt;2 portions/week) and the other 6 "unhealthy" (fatty red meat &amp;gt;1 portion/day, sweetened beverages &amp;gt;1L/day, cured meat &amp;gt;2 portions/day, fried food &amp;gt;1 portion/day, chips &amp;gt;1 portion/day, mayonnaise &amp;gt;1 portion/day) (see Figure 1). An "unhealthy" dietary pattern was considered if the proportion of "unhealthy" food categories from the total food categories consumed by the patient exceeded 50%. HR-QoL, fatigue, anxiety and depression were evaluated using the following self-administered questionnaires: IBDQ-32, FACIT-Fatigue and HADS. Results Out of the 96 patients included, 60 (62.5%) were men. The median patient age was 38 years (IQR 31.5 – 45.5). Sixty patients (62.5%) were diagnosed with CD, and 36 (37.5%) with UC. Most of the patients were treated with biologics (93.8%). An unhealthy dietary pattern was identified in 58 (60.4%) patients. Patients with an "unhealthy" dietary pattern experienced significantly more fatigue compared to patients with a "healthy" dietary pattern (mean FACIT-F score 40.3 vs. 44.4 points, p=0.02). Even though not statistically significant, patients with "unhealthy" dietary pattern had a trend towards a lower HR-QoL (mean IBDQ score 187.3 vs. 192.8, p=0.24). Anxiety and depression were less frequent among patients with "unhealthy" dietary pattern, but the differences were not statistically significant (anxiety: 24.1% vs. 31.6%, p=0.57; depression: 13.8% vs. 21.2%, p=0.51). Conclusion Patients with an "unhealthy" dietary pattern experience significantly higher levels of fatigue compared to patients that are eating "healthier" food. There is also a trend towards lower HR-QoL in this category of patients.