Crohn's Disease Cohort Research Articles

Gut bacterial type III secretion systems aggravate colitis in mice and serve as biomarkers of Crohn’s disease

Mesenteric adipose tissue (mAT) hyperplasia, known as creeping fat, is a pathologic characteristic of Crohn's disease (CD). In our previously reported cohort, we observed that Achromobacter pulmonis was the most abundant and prevalent bacteria cultivated from creeping fat. A whole genomic sequencing and identification of T3SS orthologs of mAT-derived A. pulmonis were used. A functional type III secretion system (T3SS) mediated the pathogenic potential of A. pulmonis invitro and in mouse colitis model. Furthermore, a T3SS Finder pipeline was introduced to evaluate gut bacterial T3SS orthologs in the feces of CD patients, ulcerative colitis and colorectal cancer patients. Here, we reveal that mAT-derived A. pulmonis possesses a functional T3SS, aggravates colitis in mice via T3SS, and exhibits T3SS-dependent cytotoxicity via a caspase-independent mechanism in macrophages and epithelial cells, which demonstrated the pathogenic potential of the T3SS-harboring A. pulmonis. Metagenomic analyses demonstrate an increased abundance of Achromobacter in the fecal of Crohn's disease patients compared to healthy controls. A comprehensive comparison of total microbial vT3SS abundance in various intestine diseases demonstrated that the specific enrichment of vT3SS genes was shown in fecal samples of CD, neither ulcerative colitis nor colorectal cancer patients, and ten T3SS gene-based biomarkers for CD were discovered and validated in a newly recruited CD cohort. Furthermore, treatment with exclusive enteral nutrition (EEN), an intervention that improves CD patient symptomatology, was found associated with a significant reduction in the prevalence of T3SS genes in fecal samples. These findings highlight the pathogenic significance of T3SSs in the context of CD and identify specific T3SS genes that could potentially function as biomarkers for diagnosing and monitoring the clinical status of CD patients. This work is supported by the National Key Research and Development Program of China (2020YFA0907800), the China Postdoctoral Science Foundation (2023M744089), the National Natural Science Foundation of China (32000096), the Shenzhen Science and Technology Programs (KQTD20200820145822023, RCIC20231211085944057, and ZDSYS20220606100803007), National Key Clinical Discipline, Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), Qingfeng Scientific Research Fund of the China Crohn's & Colitis Foundation (CCCF) (CCCF-QF-2022B71-1), and the Sixth Affiliated Hospital, Sun Yat-sen University Clinical Research 1010 Program 1010CG(2023)-08. These funding provided well support for this research work, which involved data collection, analysis, interpretation, patient recruitment and so on.

Crohn’s Patients and Healthy Infants Share Immunodominant B Cell Response to Commensal Flagellin Peptide Epitopes

Inflammatory bowel disease (IBD) is a chronic manifestation of dysregulated immune response to the gut microbiota in genetically predisposed hosts. Nearly half of patients with Crohn's disease (CD) develop selective serum immunoglobulin (Ig)G response to flagellin proteins expressed by bacteria in the Lachnospiraceae family. This study aimed to identify the binding epitopes of these IgG antibodies and assess their relevance in CD and in homeostasis. Sera from an adult CD cohort, a treatment-naïve pediatric CD cohort, and 3 independent non-IBD infant cohorts were analyzed using novel techniques including a flagellin peptide microarray and a flagellin peptide cytometric bead array. A dominant B cell peptide epitope in patients with CD was identified, located in the highly conserved "hinge region" between the D0 and D1 domains at the amino-terminus of Lachnospiraceae flagellins. Elevated serum IgG reactivity to the hinge peptide was strongly associated with incidence of CD and the development of disease complications in children with CD up to 5 years in advance. Notably, high levels of serum IgG to the hinge epitope were also found in most infants from 3 different geographic regions (Uganda, Sweden, and the United States) at 1 year of age, which decrements rapidly afterward. These findings identified a distinct subset of patients with CD, united by a shared reactivity to a dominant commensal bacterial flagellin epitope, that may represent failure of a homeostatic response to the gut microbiota beginning in infancy.

Microbial assimilatory sulfate reduction-mediated H2S: an overlooked role in Crohn’s disease development

BackgroundH2S imbalances in the intestinal tract trigger Crohn's disease (CD), a chronic inflammatory gastrointestinal disorder characterized by microbiota dysbiosis and barrier dysfunction. However, a comprehensive understanding of H2S generation in the gut, and the contributions of both microbiota and host to systemic H2S levels in CD, remain to be elucidated. This investigation aimed to enhance comprehension regarding the sulfidogenic potential of both the human host and the gut microbiota.ResultsOur analysis of a treatment-naive CD cohorts' fecal metagenomic and biopsy metatranscriptomic data revealed reduced expression of host endogenous H2S generation genes alongside increased abundance of microbial exogenous H2S production genes in correlation with CD. While prior studies focused on microbial H2S production via dissimilatory sulfite reductases, our metagenomic analysis suggests the assimilatory sulfate reduction (ASR) pathway is a more significant contributor in the human gut, given its high prevalence and abundance. Subsequently, we validated our hypothesis experimentally by generating ASR-deficient E. coli mutants ∆cysJ and ∆cysM through the deletion of sulfite reductase and L-cysteine synthase genes. This alteration significantly affected bacterial sulfidogenic capacity, colon epithelial cell viability, and colonic mucin sulfation, ultimately leading to colitis in murine model. Further study revealed that gut microbiota degrade sulfopolysaccharides and assimilate sulfate to produce H2S via the ASR pathway, highlighting the role of sulfopolysaccharides in colitis and cautioning against their use as food additives.ConclusionsOur study significantly advances understanding of microbial sulfur metabolism in the human gut, elucidating the complex interplay between diet, gut microbiota, and host sulfur metabolism. We highlight the microbial ASR pathway as an overlooked endogenous H2S producer and a potential therapeutic target for managing CD.Dka3P5uGJeBhH66pkNJcogVideo

The Natural History of Crohn's Disease Leading to Intestinal Failure: A Longitudinal Cohort Study from 1973 to 2018.

The natural history of Crohn's disease leading to intestinal failure is not well characterised. This study aims to describe the clinical course of Crohn's disease preceding intestinal failure and compare disease course and burden between Crohn's disease patients with and without intestinal failure. Patients with Crohn's disease complicated by intestinal failure from Rigshospitalet, Copenhagen (n=182) and a nationwide Danish Crohn's disease cohort without intestinal failure (n=22,845) were included. Using nationwide registries in Denmark, disease course was determined from hospitalisations, surgeries and outpatient medications, and disease burden was determined from employment and mortality data. The 10-year cumulative incidence of intestinal failure following Crohn's disease diagnosis declined from 2.7% prior to 1980 to 0.2% after 2000. Compared to Crohn's disease patients without intestinal failure, those with intestinal failure experienced significantly longer duration of severe disease (50 vs. 19 years per 100 patient-years, p<0.01), secondary to greater corticosteroid use (71% vs. 60%, p=0.02), inpatient contacts (98% vs. 55%, p<0.01), and abdominal surgeries (99% vs. 48%, p<0.01). However, exposure to biologics was not different between the two groups (20.4% vs. 21%, p=0.95), and duration on biologics was shorter in Crohn's disease patients with intestinal failure (2,068 vs. 4,126 days per 100 patient-years, p=0.02). Standard mortality ratio in Crohn's disease patients with intestinal failure was 3.66 [97.5% CI 2.79,4.72]. Patients with Crohn's disease complicated by intestinal failure experienced a more persistently severe preceding course of Crohn's disease but were not more likely to be treated with biological therapy.

Intestinal mRNA expression profiles associated with mucosal healing in ustekinumab-treated Crohn's disease patients: bioinformatics analysis and prospective cohort validation

BackgroundVariations exist in the response of patients with Crohn’s disease (CD) to ustekinumab (UST) treatment, but the underlying cause remains unknown. Our objective was to investigate the involvement of immune cells and identify potential biomarkers that could predict the response to interleukin (IL) 12/23 inhibitors in patients with CD.MethodsThe GSE207022 dataset, which consisted of 54 non-responders and 9 responders to UST in a CD cohort, was analyzed. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the most powerful hub genes. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performances of these genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to estimate the proportions of immune cell types. These significantly altered genes were subjected to cluster analysis into immune cell-related infiltration. To validate the reliability of the candidates, patients prescribed UST as a first-line biologic in a prospective cohort were included as an independent validation dataset.ResultsA total of 99 DEGs were identified in the integrated dataset. GO and KEGG analyses revealed significant enrichment of immune response pathways in patients with CD. Thirteen genes (SOCS3, CD55, KDM5D, IGFBP5, LCN2, SLC15A1, XPNPEP2, HLA-DQA2, HMGCS2, DDX3Y, ITGB2, CDKN2B and HLA-DQA1), which were primarily associated with the response versus nonresponse patients, were identified and included in the LASSO analysis. These genes accurately predicted treatment response, with an area under the curve (AUC) of 0.938. T helper cell type 1 (Th1) cell polarization was comparatively strong in nonresponse individuals. Positive connections were observed between Th1 cells and the LCN2 and KDM5D genes. Furthermore, we employed an independent validation dataset and early experimental verification to validate the LCN2 and KDM5D genes as effective predictive markers.ConclusionsTh1 cell polarization is an important cause of nonresponse to UST therapy in patients with CD. LCN2 and KDM5D can be used as predictive markers to effectively identify nonresponse patients.Trial registration: Trial registration number: NCT05542459; Date of registration: 2022-09-14; URL: https://www.clinicaltrials.gov.

FPR1, as a Potential Biomarker of Diagnosis and Infliximab Therapy Responses for Crohn's Disease, is Related to Disease Activity, Inflammation and Macrophage Polarization.

Crohn's disease (CD) represents a multifaceted inflammatory gastrointestinal condition, with a profound significance placed on unraveling its molecular pathways to enhance both diagnostic capabilities and therapeutic interventions. This study focused on identifying a robust macrophage-related signatures (MacroSig) for diagnosing CD, emphasizing the role of FPR1 in macrophage polarization and its implications in CD. Expression profiles from intestinal biopsies and macrophages of 1804 CD patients were retrieved from the Gene Expression Omnibus (GEO). Utilizing CIBERSORTx, differential expression analysis, and weighted correlation network analysis to to identify macrophage-related genes (MRGs). By unsupervised clustering, distinct clusters of CD were identified. Potential biomarkers were identified via using four machine learning algorithms, leading to the establishment of MacroSig which combines insights from 12 machine learning algorithms. Furthermore, the expression of FPR1 was verified in intestinal biopsies of CD patients and two murine experimental colitis models. Finally, we further explored the role of FPR1 in macrophage polarization through single-cell analysis as well as through the study of RAW264.7 cells and peritoneal macrophages. Two distinct clusters with differential levels of macrophage infiltration and inflammation were identified. The MacroSig, which included FPR1 and LILRB2, exhibited high diagnostic accuracy and outperformed existing biomarkers and signatures. Clinical analysis demonstrated a strong correlation of FPR1 with disease activity, endoscopic inflammation status, and response to infliximab treatment. The expression levels of FPR1 were validated in our CD cohort by immunohistochemistry and confirmed in two colitis mouse models. Single-cell analysis indicated that FPR1 is predominantly expressed in macrophages and monocytes. In vitro studies demonstrated that FPR1 was upregulated in M1 macrophages, and its activation promoted M1 polarization. We developed a promising diagnostic signature for CD, and targeting FPR1 to modulate macrophage polarization may represent a novel therapeutic strategy.

Concordant B and T Cell Heterogeneity Inferred from the Multiomic Landscape of Peripheral Blood Mononuclear Cells in a Crohn's Disease Cohort.

Crohn's disease is characterized by inflammation in the gastrointestinal tract due to a combination of genetic, immune, and environmental factors. Transcriptomic and epigenomic profiling of intestinal tissue of Crohn's disease patients have revealed valuable insights into pathology, however have not been conducted jointly on less invasive peripheral blood mononuclear cells (PBMCs). Furthermore, the heterogeneous responses to treatments among individuals with Crohn's disease imply hidden diversity of pathological mechanisms. We employed single nucleus multiomic analysis, integrating both snRNA-seq and snATAC-seq of PBMCs with a variety of open source bioinformatics applications. Our findings reveal a diverse range of transcriptional signatures among individuals, highlighting the heterogeneity in PBMC profiles. Nevertheless, striking concordance between three heterogeneous groups was observed across B cells and T cells. Differential gene regulatory mechanisms partially explain these profiles, notably including a signature involving TGFß signaling in two individuals with Crohn's disease. A mutation mapped to a transcription factor binding site within a differentially accessible peak associated with the expression of this pathway, with implications for a personalized approach to understanding disease pathology. This study highlights how multiomic analysis can reveal common regulatory mechanisms that underlie heterogeneity of PBMC profiles, one of which may be specific to inflammatory disease.

Crohn's Disease Phenotypes and Associations With Comorbidities, Surgery Risk, Medications and Nonmedication Approaches: The MAGIC in IMAGINE Study.

We aimed to establish a cohort of persons with Crohn's disease (CD) enrolled from 14 Canadian centers to describe the contemporary presentation of CD in Canada. All enrollees were at least 18 years old and underwent chart review for phenotype documentation by Montreal Classification at time of enrollment, comorbidities, inflammatory bowel disease (IBD) and other surgeries, and use IBD and other therapies. Of 2112 adults, 59% were female, and the mean age was 44.1 (+/-14.9SD) years. The phenotype distribution was B1 = 50.4%, B2 = 22.4%, B3 = 17.3%, and missing information = 9.9%. Perineal disease was present in 14.2%. Pertaining to disease location, 35.2% of patients had disease in L1, 16.8% in L2, 48% in L3, and 0.4% in L4. There was no difference in phenotype by gender, anxiety score, depression score. Disease duration was significantly different depending on disease behavior type (B1 = 12.2 ± 10.1; B2 = 19.4 ± 12.9; B3 = 18.9 ± 11.8, P < .0001). Isolated colonic disease was much less likely to be fibrostenotic or penetrating than inflammatory disease. Penetrating disease was more likely to be associated with ileocolonic location than other locations. Perineal disease was most commonly seen in persons with B3 disease behavior (24%) than other behaviors (11% B1; 20% B2 disease, P < .0001) and more likely to be seen in ileocolonic disease (L3;19%) vs L2 (17%) and L1 (11%; P < .0001). Surgery related to IBD occurred across each behavior types at the following rates: B1 = 23%, B2 = 64%, and B3 = 74%. Inflammatory bowel disease-related surgery rates by location of disease were L1 = 48%, L2 = 21%, and L3 = 51%. In exploring this large contemporary CD cohort we have determined that inflammatory disease is the main CD phenotype in Canada and that CD-related surgery remains very common.

Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease

Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD. Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. Most EIMs occurred more commonly in female subjects (overall EIM: P= 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P= 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P= 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P= 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P= 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P= 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P= 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P= 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management.

DOP05 Bowel damage and its correlation with the disability index in patients with recently diagnosed Crohn´s Disease

Abstract Background Crohn’s disease (CD) progression can lead to bowel damage (BD) and disability. However, the longitudinal characterization of BD and disability in early CD patients remains limited. Methods The Crohn´s Disease Cohort (CROCO) is a multicentre, European cohort study of newly diagnosed CD patients (&amp;lt;12 months following diagnosis) intended to prospectively characterize BD progression and disability. At one year following inclusion (Y1), BD progression was evaluated using the Lémann Index (LI). Magnetic resonance enterography was completed by all patients, with additional endoscopy and/or pelvic MRI based on disease location. Absence of BD was defined as a LI=0, and any presence of bowel damage was indicated by LI&amp;gt;0. Disability was assessed using the validated IBD-disability index (IBD-DI) encompassing various domains. We report the LI at Y1 and its association with significant disease features and with the IBD-DI. Results Among the 261 included patients, 135 have completed the Y1 visit, with 100 having their LI calculated [57% male, median age at diagnosis of 36 years old (IQR 26-48)]. Most patients (90%) had ileal or ileocolonic involvement, 68% had inflammatory phenotype, and 11% had perianal disease. At inclusion, 7% of patients had undergone surgery (5 intestinal and 2 perianal), and 53% had initiated biological therapy within the first year of disease, primarily anti-TNF in mono or combination therapy. Of those with stricturing (B2) or penetrating (B3) behaviour, 77% and 79%, respectively, were on anti-TNF therapy. Overall, 61% of the patients exhibited some degree of BD (LI&amp;gt;0), yet the median LI at Y1 was low [0.6 (IQR 0-2)]. Univariate analysis revealed an association between the presence of any bowel damage at Y1 and disease behaviour at inclusion (B2 OR 3.33, 95%CI 0.84-13.18 and B3 OR 8.5, 95%CI 1.82, 39.66; p&amp;lt;0.01). Additionally, there was a significant association with anti-TNF therapy (OR 2.88, 95%CI 1.24-6.66, p=0.012). In a multivariate logistic model, only older age at diagnosis appeared protective against any BD (Table 1). Among those evaluated for the LI, 84 completed the IBD-DI at Y1. The median IBD-DI was 17.3 (IQR 10.7-32.6) and 30% experienced moderate-to-severe disability (IBD-DI&amp;gt;35). No association was observed between LI and IBD-DI at Y1 (OR 1.09, 95%CI 0.39-3.04, p=0.86) and there were no differences in the median LI across disability categories (p=0.67) (Figure 1). Conclusion In a cohort of newly diagnosed CD patients, one-third exhibited no bowel damage as per the LI evaluation. For those presenting any degree of damage, the global LI remained low. No association was found with disability assessed by the IBD-DI. These data add to the growing concept that early disease represents a window of opportunity.

P1088 Real-world data on the treatment with Upadacitinib in a biological-experienced Crohn's disease cohort

Abstract Background Upadacitinib was approved for the treatment of Crohn's disease in June 2023. However, real-world data, especially in biological-experienced patients, is scarce. We aimed to determine the treatment efficacy and persistence of Upadacitinib in treatment-experienced Crohn's disease (CD) patients Methods All patients treated for Crohn's disease in the IBD outpatient clinic of the University Hospital Frankfurt from 06/23-11/23 were retrospectively analyzed. Data on clinical (Harvey-Bradshaw index (HBI)) and biochemical disease activity (fecal calprotectin FC), as well as patient history, were collected. Patients were followed up for at least 12 weeks. Results Twenty patients with CD were included. All patients had already received at least one biological agent before starting upadacitinib. Six patients reported extraintestinal manifestations, most commonly arthralgia. Five patients had stenosis of the terminal/neoterminal ileum, and one patient underwent surgery during Upadacitinib induction. Five patients had preexisting fistulae; four reported fistulae activity at treatment initiation. The median Harvey-Bradshaw Index was 11. We report an HBI reduction after induction (8.5). The median FC level at induction was 719 ug/g. After the induction, the median FC was 216 ug/g. Nineteen of the twenty patients completed the induction period of 12 weeks at the time of this interim analysis. All patients continued with 30mg of Upadacitinib post-induction. The most common adverse event was acne. No significant changes in the patients' lipid status were observed. Conclusion We report preliminary real-world data on the treatment with upadacitinib. In our interim analysis, Upadacitinib is an effective and safe treatment in biological-experienced CD patients.

P1100 A multivariate time-dependent proportional hazard model to predict development of intestinal failure from Crohn’s Disease

Abstract Background Intestinal Failure (IF) is a rare but severe complication of Crohn’s disease (CD). Advancement in therapy has not eliminated incident IF from CD (CDIF), and risk factors for developing IF from CD are not well characterised. The Copenhagen Intestinal Failure Database contains one of the largest, comprehensively described adult CDIF cohort1 from 1973 to 2018, which can be linked with a Danish nationwide CD cohort2 to explore healthcare utilisation patterns associated with developing IF from onset of CD. Methods CDIF patients from Copenhagen Intestinal Failure Database and a nationwide CD cohort without IF were followed from CD diagnosis until IF, death, or censoring on 31/12/2018. Hospital contacts, surgeries, medication use and employment status were extracted from multiple Danish population-based registries. Unplanned hospitalisation or emergency department attendance (inpatient-contact), CD-related abdominal surgery, and stopping work for 6 months or more (in working-age CD patients, excluding full-time study and parental leave) were considered time-dependent covariates and tested for significance (p&amp;lt;0.05) in univariate proportional hazard models. Significant covariates were then modelled together with additional non-time-dependent clinical and demographic variables in multivariate proportional hazard models. Backward variable selection was performed to derive a final predictive model. Results 175 CDIF and 22845 CD patients from whom data was available were followed for 2283.1 and 293536.5 patient-years, respectively. Univariate time-dependent proportional hazard models showed that every instance of unplanned IBD inpatient contact, CD-related abdominal surgery, and stopping work was significantly associated with increased hazard of developing IF, with a hazard ratio of 4.91 (95% CI 3.54-6.80, p&amp;lt;0.001), 29.79 (95% CI 9.70-91.48, p&amp;lt;0.001) and 1.61 (95% CI 1.15-2.26, p=0.005). In multivariate analysis, earlier decade of IBD onset, unplanned IBD inpatient contacts, length of stay of the inpatient contact, CD-related abdominal surgery, complicated surgery, number of previous admissions and surgeries and previous median-long term unemployment increased the rate of developing IF (Table), whereas age and comorbidity level at CD onset, non-IBD inpatient contacts, type of surgery, biologics use, and current employment status were not found to be significantly associated with IF development. Conclusion This is the first study to demonstrate significantly increased risks of developing IF from CD from increased healthcare utilisation patterns.

P1118 High Crohn’s Disease burden but disproportionally low use of biologics in Crohn’s Disease patients with Intestinal Failure: a longitudinal comparative study from 1973-2018

Abstract Background Patients with Crohn’s Disease (CD) complicated by Intestinal Failure (CDIF) are considered to be among those with the most severe form of CD. Their clinical course before IF onset has not been well characterised. We aimed to describe and compare CD-specific natural history, disease burden and treatment between CDIF patients and CD patients without IF over a 40-year period. Methods CDIF patients from Copenhagen Intestinal Failure Database (1973-2018) and a Danish nationwide CD cohort without IF (1977-2018) were followed from onset of CD until IF, death, or 31/12/2018. Hospital contacts, surgeries, prescription dispensation, employment and mortality data were extracted from multiple population-based registries. Groups were compared using logistic regression for proportions and Poisson regression for rates. Standard mortality ratio (SMR) was calculated against age, gender and year-matched Danish population references, and an adjusted mortality rate ratio between CDIF and CD patients was obtained from Cox models. Results 182 CDIF and 22845 CD patients were followed for 3035.7 and 293536.5 patient-years, respectively. At CD diagnosis, CDIF patients were younger (median age 24 years vs 35 years, p&amp;lt;0.0001), from earlier decades (71.5% vs 16.5% before 1991, p&amp;lt;0.0001), and had fewer comorbidities (6.9% vs 20.4%, p&amp;lt;0.0001). The 10-year cumulative incidence of IF declined from 2.7% in patients diagnosed with CD prior to 1980 to 0.2% in patients diagnosed after 2000, but the number of new CDIF patients has not declined over the decades (Table). A greater proportion CDIF patients received at least 1 course of steroids (70.8% versus 59.8%, p=0.02) and immunomodulators (59.3% vs 48.7%, p=0.03), had IBD-related hospital contacts (98.2% vs 55.2%, p&amp;lt;0.0001) and abdominal surgeries (94.9% vs 47.6%, p&amp;lt;0.0001), and stopped working for &amp;gt;6 months (65.8% vs 57.8% of working-age patients, p=0.05). However, in the biologics era (after 2000), CDIF patients were not treated with biologics more often (20.4% vs 21% had any biologics, p=ns). In those who were treated, CDIF patients had less cumulative time on biologics (3.9 years vs 11.2 years per 100 patient-years, p=0.001). CDIF and CD patients had a SMR of 3.7 (97.5% CI 2.79,4.72) and 1.7 (97.5% CI 1.61, 1.72), respectively. After adjusting for age, sex and co-morbidity, CDIF patients were at 3.42 times risk of dying compared to CD patients. Conclusion The incidence of CDIF has reduced in newly diagnosed CD patients, however the number of new CDIF patients has not yet declined due to increasing CD prevalence. Despite CDIF patients experiencing a significantly higher burden of CD before the onset of IF, they were not more likely to receive biologics. They also appear more refractory to biologics.

P1241 Distinct gut microbiota in Crohn's Disease between inflammatory B1 and stricturing B2 phenotype

Abstract Background The gut microbiome represents a promising avenue to elucidate distinct underlying pathophysiology in Crohn's disease (CD).Our aim was to evaluate the composition of the microbiota in Inflammatory B1 and Stricturing B2 Phenotype. Methods We performed 16S ribosomal RNA sequencing on stool samples of 108 patients (64 B1 and 44 B2) included in the Chinese CD cohort and 58 health controls without any inflammatory disorder, in order to explore the structural composition of gut microbiota in different phenotype of CD. Results Comparison of gut microbiota between patients with CD and healthy controls, α diversity and β diversity were statistically different. At the genus level, compared with the normal group, the abundance of Blautia, Bifidobacterium, Faecalibacterium, Collinsella, Coprococcus, Gemmiger, Prevotella, Dialister, Roseburia and Clostridium were decreased significantly in the CD group. In contrast, the abundance of Bacteroides, Ruminococcus, Streptococcus, Enterococcus, Dorea, Escherichia, Phascolarctobacterium, Veillonella and Eubacterium increased significantly. Compared with B1 phenotype, Streptococcus, Collinsella, Veillonella, Coprococcus and Gemmiger were significant decreased in B2 phenotype group. However, Ruminococcus, Dorea, Lactobacillus and Dialister were significant increased. Conclusion Comparison of gut microbiota between patients with CD and healthy controls, α diversity and β diversity were statistically different. At the genus level, compared with the normal group, the abundance of Blautia, Bifidobacterium, Faecalibacterium, Collinsella, Coprococcus, Gemmiger, Prevotella, Dialister, Roseburia and Clostridium were decreased significantly in the CD group. In contrast, the abundance of Bacteroides, Ruminococcus, Streptococcus, Enterococcus, Dorea, Escherichia, Phascolarctobacterium, Veillonella and Eubacterium increased significantly. Compared with B1 phenotype, Streptococcus, Collinsella, Veillonella, Coprococcus and Gemmiger were significant decreased in B2 phenotype group. However, Ruminococcus, Dorea, Lactobacillus and Dialister were significant increased.

P512 Early proactive therapeutic drug monitoring with ustekinumab therapy in paediatric Crohn's Disease

Abstract Background In the treatment of paediatric Crohn’s disease (CD), the youngest (lightest) children have historically been underdosed by standard weight-based dosing. Paediatric data on optimal dosing and drug levels are sparse. We aimed to examine real-world post-induction pharmacokinetic and effectiveness in a prospective multicentre paediatric CD cohort. Methods Luminal CD patients 2-17 years old in the Canadian Children IBD Network were eligible if they received UST IV and had a serum UST level measured proactively at week (wk) 8. Wk8 and subsequent UST levels were compared between children &amp;lt;40 and ≥40 kg (Mann-Whitney-U), dosed in accordance with an ongoing phase 3 paediatric trial. We calculated a “dose to exposure ratio” by dividing induction dose by wk8 level. Clinical remission was defined as wPCDAI &amp;lt;12.5 while still on UST. We used ROC curves to define optimal (Youden index) wk8 levels associated with wk16 remission and subsequent UST continuation. Continuous measures are reported as median (IQR). Results 44 children were eligible from April 2017-April 2023 (70% M; age 13.1 (10.8-15.5) y; disease duration 0.3 (0.08-1.3) y; weight 44.7 (30.4-55.0) kg, 12 &amp;lt;40kg; 75% bio-naïve; L1 18%, L2 23%, L3 52%; SES-CD at diagnosis 17 (11-21)). At UST start, wPCDAI was 27.5 (10-52.5) and albumin was similar between weight groups (p=0.3). Median follow-up was 10 (7-13) months. 68% received 260 mg IV loading dose, 16% 390 mg. All received 90 mg SC q8 weekly maintenance. Induction doses in mg/kg and mg/m2 were significantly higher in children &amp;lt;40 kg (Table 1). Despite this, wk8 levels were similar between weight groups, with the same pattern at other times. The dose (mg/kg) to exposure ratio was 1.45x higher in children &amp;lt;40kg, indicating they received more drug per unit increase in serum UST level relative to heavier children. Interval shortening to q4wk occurred in 7 prior to wk16, and in 16 (36%) by 6 months. By wk16, 56% of patients with available wPCDAI were in clinical remission and 60% at 1 year. Overall, 7 (16%) ceased UST. Wk8 UST levels were numerically higher in those who achieved wk16 clinical remission (7.4 (6.2-10.2) vs. 5.5 (2.6-7.1), p=0.094), and numerically lower in those who ceased UST (4.9 (2.6-6.9) vs. 7.3 (5.4-10.7), p=0.087). Based on ROC, the optimal wk8 UST level associated with wk16 clinical remission was 5.8 (AUC 0.68, sensitivity 78%, specificity 57%). The optimal level associated with UST continuation was 7.9 (AUC 0.73, sensitivity 43%, specificity 100%, Figure 1). Conclusion Paediatric CD patients weighing &amp;lt;40kg required higher UST doses to achieve comparable drug exposure to those ≥40kg. Positive clinical outcomes were associated with higher UST levels (with optimal cut-offs 6-8). Figure 1

P1187 Persistence of Advanced Therapies in Patients with Inflammatory Bowel Disease: Retrospective cohort study using large healthcare claims database in Japan

Abstract Background Inflammatory bowel disease (IBD) is a lifelong disease and strategically utilizing advanced therapies is essential. Few studies exist to inform the drug utilization of biologics or JAK inhibitors in Japan. The objective is to describe persistence of index and subsequently used biologics or JAK inhibitors in patients with Crohn’s disease (CD) or ulcerative colitis (UC) in Japan. Methods This retrospective cohort study used the Japan Medical Data Center database, which contains claims data from 14 million individuals in Japan. Patients who were diagnosed with CD or UC, and received advanced therapy, including biologics and JAK inhibitors, between January 1, 2010 and September 30, 2022 were included. Patients aged at least 15 years old were required to have no treatment with advanced therapies within 6-month prior to the initiation of index treatments of interest: adalimumab, infliximab, vedolizumab, golimumab, ustekinumab and tofacitinib for CD and UC in Japan. Persistence was defined as having continuous treatment with each therapy over a specified follow-up period (i.e., 6 months, 12 months, 18 months, or 24 months since the index date), without the presence of a pre-defined treatment gap, i.e., 1.5 times the number of days covered by the prior day’s supply. Results The numbers of eligible patients with CD and UC during the study period were 1,115 and 1,942, respectively. Among patients with CD, the distribution of index treatment for adalimumab, infliximab, ustekinumab and vedolizumab was 41.4%, 37.4%, 18.2%, and 3.0%, respectively. Among patients with UC, the distribution of index treatment for infliximab, adalimumab, vedolizumab, golimumab, tofacitinib and ustekinumab was 33.6%, 24.8%, 17.5%, 11.2%, 7.3% and 5.6%, respectively. For CD cohort, persistence of ustekinumab was numerically highest in all periods (94.7% at 6 months, 91.3% at 12 months, 88.2% at 18 months and 80.4% at 24 months), followed by infliximab (94.1%, 87.7%, 82.0% and 76.8%, respectively). For UC cohort, highest persistence was observed in ustekinumab through all periods (95.1% at 6 months, 84.0% at 12 months, 81.6% at 18 months and 75.0% at 24 months), followed by vedolizumab (82.0%, 69.7%, 64.2% and 59.4%, respectively). As subsequent treatments, persistence of ustekinumab and infliximab were comparable for CD while the highest persistence was observed for ustekinumab through all periods for UC. Conclusion Persistence of advanced IBD treatments available in Japan was investigated. As an index treatment, ustekinumab maintained high persistence through 2 years from the index date both in CD and UC. This data provides valuable information on the management of patients living in Japan with IBD under real-world setting.

American Gastroenterological Association-Proposed Fecal Calprotectin Cutoff of 50 ug/g is Associated With Endoscopic Recurrence in a Real-World Cohort of Patients With Crohn’s Disease Post-ileocolic Resection

Abstract Background Fecal calprotectin (FC) is a reliable predictor of active bowel inflammation in postoperative Crohn’s disease (CD), but cutoffs vary between studies. Recent guidelines recommend a cutoff of &amp;lt;50 ug/g to avoid routine endoscopy in patients at low pretest probability for CD recurrence. We evaluated the performance of this threshold in a real-world CD cohort after ileocolic resection (ICR). Methods In this retrospective study, patients with CD post-ICR between 2009 to 2020 with FC &amp;gt; 60 days but &amp;lt; 1 year of surgery were included from a multicenter database. Established risk factors and/or biologic prophylaxis (biologic within 90 days of surgery) defined pretest probability. Those without postoperative colonoscopy were excluded. Rates of endoscopic recurrence, defined as Rutgeerts score ≥ i2b at any time after surgery, were compared between FC &amp;lt; 50 versus ≥ 50 ug/g. Student’s t-test and Fisher’s exact test were utilized for statistical analysis. All postoperative FCs were matched to closest colonoscopy within 1 year to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results Thirty-seven patients categorized as either low-risk or high-risk and received biologic prophylaxis and had postoperative colonoscopy were included. Median time to first FC was 217 days (IQR 131–288). 15 (41%) patients had initial FC &amp;lt; 50 ug/g versus 22 (59%) ≥50 ug/g. Median time to first colonoscopy was 234 days (IQR 189–369). Compared to initial FC ≥ 50 ug/g, FC &amp;lt; 50ug/g experienced less endoscopic recurrence (0% vs. 36%, P = .005). Median time to first endoscopic recurrence in FC ≥ 50 ug/g was 145 days. There were 39 matched pairs of FC and colonoscopy. At an FC cutoff of 50 ug/g, calculated sensitivity was 90% and NPV was 93%, whereas specificity and PPV were 48% and 38%, respectively. Conclusions In this real-world cohort, FC &amp;lt; 50 ug/g is a useful cutoff to exclude endoscopic recurrence in a post-ICR CD population that is at low pretest probability of recurrence.

A blood-based transcriptomic signature stratifies severe Crohn’s disease and defines potentially targetable therapeutic pathways

IntroductionDespite advances in medical therapy, many patients with Crohn’s disease (CD) ultimately require surgery for disease management. Identifying the underlying molecular pathways for subgroup stratification is critical to the improvement of prognostics and therapeutics and to biomarker discovery.MethodsWe purified CD3+ T cells from the paired blood and mucosa samples of 100 CD and 17 non-inflammatory bowel disease (IBD) subjects requiring surgery. Longitudinal samples (n = 49) were collected 4–13 months postoperatively.ResultsTranscriptional profiling at the time of surgery revealed two CD patient subgroups: the CD-PBT subgroup, which was clustered tightly with non-IBD subjects, and the CD-PBmu(cosal) subgroup, which shifted from peripheral toward a mucosal-like expression profile. The CD-PBmu subgroup was characterized by differential gene expression, elevated genetic transcriptional risk score (TRS), and a distinct T-cell subset composition associated with perianal-penetrating/stricturing disease, post-surgical recurrence, and immunoreactivity to multiple microbial antigens. CD-PBmu subtyping was validated in a CD cohort in whom anti-TNF therapy had been unsuccessful. The CD-PBmu subgroup, in contrast to the CD-PBT subgroup, was distinguished by decreased pro-inflammatory cytokine/chemokine and adhesion molecule expression postoperatively. For clinical translation, we identified a CD-PBmu 42-gene classifier associated with a TRS signature, clinical severity markers, and underlying protein kinase signaling pathways to identify therapeutic targets.DiscussionThe CD-PBmu signature holds potential for future investigation to improve accuracy in identifying a subset of patients with severe CD who may benefit from early initiation of therapeutics to defined molecular pathways.

T Cell Repertoire Homogeneity and Blood-Gut Overlap in Patients With Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) causes a marked increase in the number of T cells in the intestinal mucosa. Debate exists about whether these excess cells arise from local clonal proliferation or recruitment from the periphery. CD8+ T cells were sorted from colon biopsy specimens and blood for T-cell receptor (TCR) β-chain sequencing. Biopsy specimens from inflamed or uninflamed colon from ulcerative colitis or Crohn's disease cohorts were compared with colon biopsy specimens from people without IBD, as well as with autologous blood α4β7+, α4β7- effector/memory, terminal effector/memory CD45RA+ T cell, and mucosal-associated invariant T-cell CD8 subpopulations. CD8 TCR diversity in mucosa and blood did not correlate with inflammation. Repertoire overlap between any 2 distinct locations of a given person's colon was consistently high, although often lower between inflamed and uninflamed sites. CD8 TCR repertoires overlapped between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4β7+ T cells. Inflamed tissue consistently overlapped more than uninflamed tissue with each blood subpopulation. CD8 T-cell clones are spread homogenously throughout the length of the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar TCR diversity in both argues against local clonal expansion being the main source of excess cytotoxic T cells in inflamed mucosa. Rather, the increased TCR overlap observed between blood and inflamed mucosa supports the significance of T-cell trafficking in IBD pathogenesis, particularly concerning α4β7+ T-cell populations.

Association between body fat composition and disease duration, clinical activity, and intravenous corticosteroid-induced response in inflammatory bowel disease

BackgroundBody fat composition is believed to be associated with the progression, medical response, and prognosis of inflammatory bowel disease (IBD). Hence, we conducted this study to explore if fat metrics were associated with the disease activity of severe IBD and the response to intravenous corticosteroids (IVCS).MethodsWe included 69 patients with ulcerative colitis (UC) and 72 patients with Crohn's disease (CD) who had previously received IVCS during hospitalization. We quantified individual fat distribution using abdominal computed tomography slices. The correlations between fat parameters and disease activity were available with Spearman correlation analysis. The prediction model was developed using independent risk factors derived from multivariable logistic regression analysis. Model discrimination was evaluated leveraging the receiver operating characteristic curve. 1000 bootstrap resamples internally validated the model's prediction performance.ResultsNotable differences in age, nutritional status, serum cytomegalovirus replication, stool condition, and extraintestinal involvement between UC and CD patients were observed. UC subjects who responded to IVCS had higher subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), and mesorectal adipose tissue index (MATI) than non-responders. IVCS-responding CD individuals had lower VATI and mesenteric fat index (MFI) than non-responders. CD patients with a prolonged disease duration had a decreased SATI and an elevated MFI. VATI and MATI were reduced as UC clinically progressed, while more prominent clinical activity in CD correlated with increased VATI, MATI, and MFI. A high SATI indicated that patients with UC were more prone to be IVCS responders. For patients with CD, levels of VATI and MFI were negatively associated with effective IVCS treatment. The established models showed a discriminative accuracy of 0.834 [95% confidence interval (CI) 0.740–0.928] in the UC cohort and 0.871 (95% CI 0.793–0.949) in the CD cohort. Repeated samples supported the reliability of the developed models (AUCUC = 0.836, 95% CI 0.735–0.919; AUCCD = 0.876, 95% CI 0.785–0.946).ConclusionHuman fat indexes represent novel imaging biomarkers for identifying IBD patients who respond to IVCS, thus building accelerated therapy regimens and avoiding the adverse effects of ineffective IVCS.