bluuebunny/crossref_metadata_2025 huggingface dataset:
P047 Deconditioning in quiescent Crohn’s Disease patients with heightened fatigue perception
Authors: McGing J J , Nicholas R , Serres S , Gupta A , Radford S J , Bradley C , Bawden S , Francis S T , Greenhaff P L , Moran G
Published: January 2024

Background

Heightened fatigue perception and premature exercise fatigue are common in inflammatory bowel disease (IBD). Physical deconditioning is greater in patients with increased fatigue perception relative to patients with a lower perception of fatigue, implicating deconditioning as an aetiological factor.

This study used physiology and multiparametric Magnetic Resonance Imaging and Spectroscopy (MRI/MRS) during exercise to comprehensively phenotype quiescent IBD fatigue.

Methods

Participant body mass and regional body composition was assessed by DEXA, and tknee extensor strength and fatiguability using isokinetic dynamometry (Cybex, USA). A supine CPET was performed using an MR-compatible Ergometer (Cardiostepper, Ergospect) to standardize relative exercise intensity for in-bore 1H MRI measures. 1H MRI data were collected on a Philips 3T Ingenia wide bore scanner using a Philips Head/Neck coil and in-built posterior coil. Across rest, steady-state exercise (50% VO2 peak) and recovery, Phase Contrast-MRI was used to compute cardiac output and cerebral blood flow (CBF), and T2 Relaxation under spin tagging (TRUST-MRI) to measure brain oxygen extraction fraction (OEF).

31P MRS data was collected on a 3T Philips Achieva using a 14cm 31P coil over the medial gastrocnemius. Ischaemic plantar flexion exercise was performed at 50% maximum voluntary contraction (MVC) using an MR-compatible ergometer (Trispect, Ergospect) during non-localized pulse-acquire 31P-MRS. 31P spectra were analysed using the AMARES function in jMRUI Beta 6.0. In vivo muscle mitochondrial flux during post-exercise PCr recovery (VPCr = kPCr * ΔPCr) where ΔPCr is PCrendrecovery –PCrendex) was quantified after reinstating limb blood flow and fitting PCr recovery to a mono-exponential function in GraphPad prism (PCr(t) = PCrinitial+(PCrend – PCrinitial)(1-exp(-k.t) where t is time from start of non-ischaemic recovery).

Results

16 quiescent CD patients and 12 age and BMI matched HV’s completed the study. General fatigue score was greater in CD relative to HV (P = 0.001, Table 1). Body composition, isometric strength, fatigue development were not different between groups (Table 1). CBF response to steady-state exercise was less in CD (P = 0.003) alongside the maintenance of cardiac output and brain OEF in HV (Figure 1). VPCr following ischemic plantar flexion exercise was less in CD than HV (P = 0.02, Figure 1) (Figure 1).

Conclusion

Greater fatigue perception in CD was accompanied by lower CBF on exercise and blunted post-exercise PCr resynthesis, but no differences in body composition, strength and fatiguability relative to HV. These finding point to greater deconditioning in CD, corroborated by their lower daily step count relative to HV.
P055 GPR43 and GPR84 play a crucial role in supporting perianal fistula formation and disease progression in Crohn’s Disease
Authors: Rubbino F , Di Cristofaro A , Wozny M , Rizzo G , Pineda Chavez S E , Converso G , Heijink M , Giera M , Maroli A , Bezzio C , Loy L , Carvello M , Spinelli A , Laghi L , Repici A , Armuzzi A , Vetrano S
Published: January 2024

Background

Fistula complication represents one of the most disabling manifestations of Crohn’s Disease and a risk factor for more aggressive disease progression and mucinous adenocarcinoma . However, molecular mechanisms behind this transformation are completely unknown. Growing evidence supported epithelial-to-mesenchymal transition (EMT) as a critical process to replace impaired intestinal fibroblasts in repairing mucosal membrane damage. However, EMT drivers during fistula formation and progression are still not completely known. Here, we investigated whether G-protein coupled receptors serve as new drivers of EMT and fistula disease progression.

Methods

Surgical specimens (N=9) collected from perianal fistula and non-involved areas of CD patients were analyzed by bulk RNA-sequencing and Lipidomics analysis. Gene set enrichment analysis (GSEA) was used to detect the levels of differentially expressed pathways. GPR43 and GPR84 analysis was performed on perianal fistula; adenocarcinoma; and mucinous adenocarcinoma-associated (MA) CD fistula FFPE tissue section. Caco-2 cell line was stimulated for 24 h with agonists and antagonists of GPRs. Genes associated to EMT were evaluated by RT-PCR and WB.

Results

Gene sets related to the signatures of epithelial-to-mesenchymal transition, G-protein coupled receptors (GPRs), immune response, lipid oxidation were significantly enriched in the fistula compared to non-involved tissue. Among differentially GPRs expressed genes FFAR2 encoding for GPR43, sensor for Small Chain Fatty Acids (SCFAs), and GPR84 sensor for Medium Chain Fatty Acids (MCFAs), predominantly expressed in immune cells, reported to be upregulated in the context of acute inflammation. Upregulation of GPRs expression correlated positively with enzymes associated to lipid oxidation gen set including PLA2G2D, ALOX5, NR4A3, PLA2G7, ACOXL and negatively with their lipids substrates. Caco2 cells stimulated with SCFAs and MCFAs upregulated not only the expression of GPR43 and GPR84, but also of EMT-transcription factor Twist1 and PLA2G2D, all effects reverted in the presence of their antagonists. An increase expression of GPR43 and GPR84 in association with Twist1 was found in MA-CD tissue section.

Conclusion

Our results highlighted GPR43 and GPR84 as new potential factors of fistula formation that support the EMT process through increased fatty acid oxidation, which in turn fuels the activation of GPRs. However, the increase expression of both receptors in the fistula oncogenic disease progression suggests that strategies regulating lipid metabolism or targeting GPRs could pave the way for novel therapeutic approaches to prevent fistula complication in CD patients.
P088 Single-cell transcriptomic analysis identifies early immune disturbances in preclinical Crohn's disease
Authors: Kioroglou D , Egia-Mendikute L , Palazon A , Barreiro-de Acosta M , Rodríguez-Lago I , Martinez Marigorta U
Published: January 2024

Background

Despite the increasing incidence of Crohn’s disease (CD), its early immune disturbances have not been described yet. The preclinical period provides an opportunity to gain insight into the initial processes involved in the pathogenesis of the disease. The main aim of our study was to describe how the subclinical inflammatory process is modifying the individual’s immunologic environment while the patient is still on preclinical period.

Methods

We analysed scRNASeq data from peripheral blood mononuclear cells (PBMC) of patients with incidentally-diagnosed CD according to ECCO criteria during the colorectal cancer screening programme, after histologic confirmation. Their gene expression profile was compared to healthy individuals acquired from publicly available datasets. The analytical pipeline included merging of the datasets followed by batch correction concerning integration from different studies, quality control and filtering, and finally cell-type annotation and differential gene expression analysis.

Results

Two patients with CD (mean age 53,5 years) and 2 healthy controls were included. We observed distinct transcriptomic profile in preclinical patients compared to controls, with small intragroup differences. The cell-type annotation identified B cells (B), CD4+ and CD8+ T-cells (CD4T, CD8T), dendritic cells (DC), monocytes (Mono) and natural killer cells (NK). The analytical pipeline included 17,021 cells (B:3,274, CD4T:5,798, CD8T:3,476, DC:315, 2, Mono:928, NK:3,230) and 3000 quantified genes. Considering each cell type individually, we identified 49 differentially expressed genes (DEG) between CD patients and controls (B:39, CD4T:37, CD8T:41, DC:42, Mono:37, NK:37), from which 30 were DEGs in all cell types.

Building on the list of 49 detected DEGs, we report three insights into the preclinical period of the disease. First, pathway analysis revealed significant enrichment of the pathway that is related to immunoregulatory interactions between lymphoid and non-lymphoid cells, and functional annotation analysis identified gene products that are related to immunological defense. Second, we identified significant transcriptomic alterations in genes that have previously been related to the symptomatic phase of IBD, or reported as potential biomarkers. Third, after performing principal component analysis we observed greater separation between the patients groups in the CD8T cells compared to the other cell-types.

Conclusion

This study reveals the initial transcriptomic profiles and the main pathways that precede the onset of symptomatic inflammatory bowel disease. Our findings may help in identifying potential targets for early disease intervention.
P103 Natural compounds in Ulcerative Colitis and Irritable Bowel Syndrome: Insights from immune-metabolic profiles
Authors: McShane C , O'Connell F , Pigott M , Obaidi I , Sheridan H , Kevans D , O'Sullivan J
Published: January 2024

Background

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) represent chronic and occasionally disabling conditions, necessitating innovative treatment strategies. Covering 14% of Ireland's landscape, bogland ecosystems house unique plant biodiversity, yielding biologically active secondary metabolites. Informed by traditional medicinal knowledge and in vitro screening for immunomodulatory potential, three plant extracts (NTP0226A, NTP0127B, NTP0206EA) were selected for exploration of their potential to treat IBD and IBS within the "Unlocking Nature’s Pharmacy from Bogland Species" project.

Methods

Patients undergoing colonoscopy were prospectively recruited in three cohorts: healthy controls, IBS, and ulcerative colitis (UC). Recto-sigmoid biopsies were collected and cultured for 24 h with treatments (Infliximab, NTP0226A, NTP0127B, NTP0206EA). Colonic tissue explants underwent real-time energy metabolism profiling and quantification of 10 inflammatory mediators using Seahorse Xfe24 analyser and multiplex ELISA, respectively. P values <0.05 were considered significant in analyses.

Results

Twenty-seven patients were recruited (6 healthy controls, 6 IBS, and 15 UC). UC patient explants exhibited elevated glycolytic metabolism and increased IL-4, IL-6, and IL-12p70 secretion compared to non-UC patients. No differences were observed between healthy controls and IBS patients. Linear regression did not show correlation between age and mitochondrial bioenergetics. There was no change in metabolism profiles of any cohort following treatment with Infliximab or the 3 novel extracts. In the UC tissue, treatment with Infliximab reduced IL-12p70 secretion (p=0.0098), this reduction was not seen in the other 2 cohorts. NTP0206EA reduced IL-10 secretion in the UC cohort (p=0.0255). In the IBS cohort; NTP0127B reduced IL-10 secretion (p=0.0048) and NTP0226A reduced IL-4 (p=0.004) and IL-6 (p=0.0219) secretion. Principal component analysis demonstrated reduced separation between the immune-metabolic profiles of UC patients and healthy controls following treatment with NTP0226A (Figure 1).

Conclusion

Using an explant model, we have shown that UC patients have a distinct immune-metabolic profile modifiable by a standard IBD therapy and novel plant extracts. Blockade of IL-6 trans-signalling has recently shown promise as an effective treatment target in IBD. Our natural extract NTP0226A reduced IL-6 secretion in IBS patients and is a promising candidate for therapeutic exploration. These findings contribute to our understanding of the complex interplay in the colonic microenvironment and highlight potential avenues for novel therapeutic interventions.
P121 Characterisation of the miRNAome in Crohn’s Disease patients reveals transcriptomic changes associated with tissue composition and drug treatment
Authors: Cervera Seco L M , Baldán-Martín M , Fernández-Tomé S , Ortega Moreno L , Aransay A M , Chaparro M , Gisbert J P , Marigorta U M
Published: January 2024

Background

Gene regulation plays a major role in Crohn's Disease (CD) susceptibility and drug response. MicroRNA (miRNA)-mediated mechanisms tune gene expression at the post-transcriptional level. MiRNAs are 20-to-25-nt long non-coding RNAs that repress protein expression by direct inhibition or cleavage of the targets. Evaluating the miRNAome is emerging as a promising tool to clarify pathogenesis and identify promising biomarkers. We characterised the regulatory miRNAome across disease subtypes, gut tissue locations and infliximab treatment in CD.

Methods

We generated 120 transcriptomic profiles from terminal ileum and left colon biopsies from Hospital Universitario de la Princesa (Madrid). This cohort is composed of 10 patients with active endoscopy, 10 quiescent CD cases, and 10 controls (30 in total). In a balanced setting, half of the samples were incubated with infliximab for 18 hours at 37ºC and the rest with basal medium (Table 1).

We carried out an exploratory analysis to gain insights into the determinants of miRNAome variability, including variance partition analyses and linear mixed modelling to detect significantly altered miRNAs. We also harnessed results from several publications including GSE16879 dataset to perform a comparative study with infliximab response signatures.

Results

Tissue location is the primary determinant of miRNA expression variability. The Variance Partition model identified 30 top miRNAs whose variability is maximised across regions. However, patient-specific effects also play a relevant role. We also identified 96 differentially expressed miRNAs between terminal ileum and left colon, with an overrepresentation of molecules involved in stress and developmental pathways (Fig.1). Among these, we find miR200s and miR429, that are associated with suppression of epithelial-mesenchymal transition and are up-regulated in colon more than in ileum. Down-regulation of miR196 is also shown in terminal ileum.

Regarding the effects of infliximab treatment, we detected nine deregulated miRNAs which are associated with cellular response pathways. These include miR200s and miR192, which targets NOD2 and down-regulates NF-κB. Our results show an up-regulation of miR192 upon infliximab incubation (log2FC=2.37), which is associated with a reduction in TNFα expression and, consequently, with induced overexpression of miR192. We conclude that this miRNA is a potential target for therapy development.

Conclusion

In short, tissue location, and to a lesser extent disease subtype, are the main determinants of miRNAome in CD. A few treatment-responsive miRNAs like miR192 and miR200s are identified, in spite of detection challenges, emphasizing the need to improve our comprehension of the miRNA dynamics associated with drug response.
P136 Blood-based biomarkers of type III collagen remodeling as surrogate markers of endoscopic disease activity in patients with Ulcerative Colitis
Authors: Pehrsson M , Poulsen A , Alexdottir M S , Karsdal M A , Bay-Jensen A C , Seidelin J B , Mortensen J H
Published: January 2024

Background

The chronic inflammation of Ulcerative Colitis (UC) causes excessive extracellular matrix (ECM) remodeling, resulting in clinical complications. Currently, endoscopic evaluation remains the gold standard method for determining disease activity. However, due to its invasiveness and accompanying patient discomfort, novel methods are wanted. Focusing on type III collagen, a major component of the intestinal ECM, we sought to investigate three blood-based neoepitope biomarkers of type III collagen formation, degradation, and fibrosis resolution as surrogate markers of disease activity.

Methods

Fifty-one patients with UC were scored endoscopically at weeks 0 (W0) and 24 (W24), according to the total Mayo score (TMS) and the UC Endoscopic Index of Severity (UCEIS). Three biomarkers of type III collagen remodeling, PRO-C3 (formation), C3M (MMP-9 degradation), and CTX-III (fibrosis resolution), were measured in the sera of patients and evaluated against the disease activity scores. Patients were grouped based on their disease activity score, and the biomarkers were evaluated by one-way ANOVA, correcting for multiple comparisons using Tukey (parametric data) or Dunn’s test (nonparametric).

Results

Grouping patients according to the TMS at W0, patients with severe disease had elevated serum C3M compared to patients with mild or moderate disease (p<0.05 and <0.01) (Figure 1A). Based on the UCEIS, patients with a severe disease presented with reduced CTX-III than moderate disease activity (p<0.05) (Figure 1C). While not statistically significant, a numerical trend of elevated C3M levels with increasing endoscopic disease activity was observed at W24 (Figure 1B). No statistically significant results were achieved evaluating C3M according to the UCEIS score, CTX-III according to the TMS or PRO-C3 according to the TMS and UCEIS score (Data not shown).

Conclusion

The serum levels of C3M were elevated in patients with UC at W0 when scoring their endoscopic disease activity using the TMS. At W24, a similar trend of elevated C3M with increasing disease activity could be observed. Using the UCEIS score, the CTX-III biomarker reflecting type III collagen resolution was reduced in patients with severe endoscopic disease. The data suggest an elevation of MMP-9 catalyzed type III collagen degradation with disease severity and reduced type III collagen resolution. The PRO-C3 biomarker provided no statistical value in the current study.
P138 Novel serum markers for predicting disease activity in ulcerative colitis: results from a retrospective case-control study
Authors: State R M , Popp C , Balanescu P , Voiosu A , Coman A , Bengus A , Negreanu L , Mateescu R B , Voiosu T
Published: January 2024

Background

Commonly used serum or faecal markers, such as C-reactive protein (CRP) and feacal calprotectin have several limitations and do not always correlate well with the degree of mucosal inflammation in the intestine as established by endoscopy. The aim of the current study was to evaluate the utility of a panel of serum markers (Visfatin, serum amyloid, LRG1, MMP-1, MMP-2, TFF3, Lipocalin-2 (NGAL), IL-6, IL-4, IL-7, IL-17) in predicting mucosal inflammation in ulcerative colitis(UC) patients.

Methods

We conducted an unmatched case-control retrospective study. Patients were selected consecutively, based on their enrollement date, from a prospective IBD cohort. We selected two groups of UC patients, each of them with active disease at baseline and different outcomes during follow-up: mucosal healing and persistant disease activity, as resulted from clinical and endoscopic evaluation. Inflammatory burden was investigated using the C-reactive protein and endoscopic activity was reported using the Mayo endoscopic score. Quality of life was also evaluated at each visit using The Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Clinical disease activity was quantified using the partial Mayo score. Clinical remission was defined as a partial Mayo score < 2. Endoscopic activity was assessed using the Mayo endoscopic score[i] . Mucosal healing was defined as Mayo endoscopic score of 0. The selection of investigated biomarkers was based on the results of a systematic review previously published by the research team [i] State M, Negreanu L, Voiosu T, Voiosu A, Balanescu P, Mateescu RB. Surrogate markers of mucosal healing in inflammatory bowel disease: A systematic review. World J Gastroenterol. 2021 Apr 28;27(16):1828-1840. doi: 10.3748/wjg.v27.i16.1828.

Results

84 serum samples from 42 patients were retrospectively analyzed (21 patients with mucosal healing and 21 patients with persistant activity during follow-up). Lipocalin proved to be a reliable marker for the noninvasive assessment of endoscopic activity, with 90% sensitivity and 95% specificity at a cut-off level of 0,421μg/ml (AUROC 0,677). The combination of lipocalin, age, gender and BMI (Figure 1) is a good predictor of persistant activity during follow-up (AUROC 0.87, 95% CI, 0.762-0.979).

Conclusion

Our findings provide support for the use of lipocalin as a surrogate marker for mucosal inflammation. The combination of lipocalin, age, gender and BMI might be useful for guiding treatment and monitoring decisions.
P148 Longitudinal single-cell data informs deterministic modelling of inflammatory bowel disease
Authors: Kilian C , Ulrich H , Zouboulis V , Sprezyna P , Büttner M , Biton M , Villablanca E J , Huber S , Adlung L
Published: January 2024

Background

Crucial contributions to our understanding of the inflammatory process in inflammatory bowel disease (IBD) have been made using single cell level approaches. Extracting mechanistic details of cell and gene dynamics would be critical to understanding the mechanisms mediating mucosal healing and predicting response to specific therapies. However, this remains challenging. Therefore, our aim was to use ordinary differential equations (ODEs) for mathematical modelling of cell abundance and prediction of biological processes in IBD.

Methods

We used mathematical modelling of published longitudinal single-cell mRNA sequencing (scRNA-seq) data from DSS colitis in mice to simulate cellular dynamics during IBD. We validated our predictions using pseudo-bulk gene expression analysis and flow cytometry. We also analysed a published microarray dataset from colonic biopsies of 51 IBD patients prior to infliximab treatment.

Results

Based on the scRNA-seq data, we used our mathematical model to predict the immune dynamics of a different mouse colitis protocol. We validated these predictions experimentally using flow cytometry and found good agreement between model simulation and experimental data (predicted vs. observed, Pearson's rho=0.92). We found that the estimated turnover rates predicted the protein level of the proliferation marker KI-67 (rho=0.88) in DSS colitis. Finally, we wanted to investigate whether our mathematical model reflected processes in human IBD. We reasoned that genes correlated with epithelial cell dynamics might be indicative of mucosal healing after DSS retrieval. We found more highly correlated genes when using simulated epithelial abundance compared to experimentally measured epithelial abundance. Many genes associated with tight junctions (Cldn8, Cftr, Crb3, Jam2) were among the highly positively correlated genes and genes associated with inflammation (Il1b, Jak2, Il10ra) were among the negatively correlated genes with epithelial cell abundance. We then looked for differentially expressed (DE) genes in pre-treatment colon biopsies between responders and non-responders to infliximab. We found a significant overlap of 25 positively correlated genes with upregulated DE genes in responders, i.e. associated with tight junctions, and 73 negatively correlated genes with upregulated genes in non-responders, i.e. associated with inflammatory pathways.

Conclusion

We demonstrate that mathematical modelling of colonic cell dynamics provides insight into IBD progression and treatment response. Furthermore, our results suggest that pre-treatment barrier integrity may predict and influence response to infliximab treatment.
P176 TYK2 inhibition attenuates the stimulation of sensory neurons with hyper-IL-6
Authors: Pritchard T , Meng M , Higham J , Bulmer D
Published: January 2024

Background

Abdominal pain and diarrhoea are a cause of significant morbidity for people with colitis. Recent single cell RNA sequencing of sensory neurons innervating the gut highlights a likely role for sensory nerves in the pathophysiology of these symptoms based on the marked expression of cytokine receptors from the IL-6 receptor family in gut projecting sensory neurons. In keeping with the reported downstream signalling pathway for these receptors marked co-expression of TYK2 transcripts were also found along with IL-6 signal transducer (GP130) in colonic nociceptors characterised by expression of the capsaicin receptor TRPV1. These observations suggest that TYK2 inhibitors may ameliorate symptoms of pain and diarrhoea in people with colitis by preventing neurogenically mediated gut contractility and nociceptor activation.

Methods

TYK2 mediated sensory neuron activation: changes in the intracellular [Ca2+]i within thoracolumbar (T12-L5 spinal segments) dorsal root ganglia sensory neurons were examined in cells cultured overnight and loaded with Fluo-4-AM (30min) prior to imaging. Responses were measured to the hyper-IL-6 fusion protein of the soluble IL-6 receptor and IL-6, which transactivates the GP130 receptor subunit to mimic IL-6 family receptor signalling following pre-treatment with vehicle, the TYK2 inhibitor Deucravacitinib (100nM) or the pan-JAK inhibitor Pyridone-6 (2 μM). Afterwards cells were exposed to capsaicin (1 µM) followed by 50 mM KCl, to confirm the presence of nociceptors and neurons respectively by positive response.

All experiments were performed using tissue from male C57/B6 mice euthanised by rising concentration of CO2followed by exsanguination in accordance with Schedule 1 of the UK Animals Scientific Procedures act (1986).

Results

Application of hyper-IL-6 produced a robust increase in [Ca2+]i levels in DRG sensory neurons which was significantly attenuated by pre-treatment with the TYK2 specific inhibitor Deucravacitinib (p<0.01) or the pan JAK inhibitor Pyridone-6 (p = <0.05).

Conclusion

Findings demonstrate that inhibition of TYK2 inhibitor prevents sensory neuron activation in response to IL-6 trans-signalling. This data suggests that TYK2 inhibitors may have utility for the treatment of abdominal pain in people with colitis.
P198 Systematic review to highlight practices and programmes for transition for adolescents with Inflammatory bowel disease
Authors: Chan P , McNamara J , Vernon-Roberts A , Havrlant R , Christensen B , Giles E , Williams A J
Published: January 2024

Background

Adolescents with inflammatory bowel disease (IBD) will eventually transition from the family-centric paediatric healthcare team to the adult service. This process happens at an appropriate age or level of development and depends on a number of factors such as transition readiness, disease specific factors, and local policies and practice. This transition period is challenging for patients, families and healthcare providers. The use of structured transition programmes is increasingly incorporated into standards of care, yet the optimal format is not yet fully delineated, and practices vary considerably. The aim of this study was to carry out a systematic review of structured transition programmes and their components to assess impact on disease-specific and transition-related outcomes.

Methods

A literature review was carried out in four main databases (PubMed, CINAHL, CENTRAL, EMBASE) and relevant publications from the year range 1970-2023 reviewed. Inclusion criteria: reporting on adolescent IBD patients and investigating structured transition programmes/interventions. Exclusion criteria: not reporting outcomes relating to transition readiness/skills or disease related outcomes. Two investigators reviewed the articles, extracted data, and two assessed bias.

Results

There were 3432 articles identified from initial searches, and 38 included in the final review. Twenty-six studies reported the use of structured transition programmes, and 12 investigated discrete interventions. The key outcomes studies included knowledge, self-efficacy, adherence, clinic attendance and transition readiness. These outcomes consistently improved with the use of structured transition programmes. Those adolescents with IBD transitioning with no structured programme experienced a 3.5-fold increase in IBD related surgical rates, and 2-fold increase in hospital admission rates. Structured transition programmes were shown to significantly improve transition readiness assessment scores. Transitional care programmes consistently improved the following outcomes; relapse/admission rates, corticosteroid use, quality of life, and surgery. The bias assessment showed between-study heterogeneity, low quality of evidence, and high risk of bias.

Conclusion

Transition outcomes for adolescents with IBD were consistently improved with the use of structured transition programmes. This literature review highlights the considerable variation in delivery of transition care, and the need for optimization of strategies. There is no current standardized model for adolescent IBD patients in Australasia, and this review will guide development of regional IBD transitional care consensus statements.
P202 Streamlining primary and secondary care pathways reduces the time-to-specialist IBD care: the emergence of FIT and the relative decline of calprotectin testing in primary care
Authors: Smith R , Cairnes V , Bishara M , Djouider Y , Chee D , Roberts C , Kennedy N , Ahmad T , Goodhand J
Published: January 2024

Background

Streamlining primary and secondary care pathways reduces the time-to-specialist IBD care. Prior to the COVID-19 pandemic, using an algorithm that screens endoscopy reports for probable IBD, we halved the time to IBD specialist review and treatment. Previous studies report that faecal immunochemical testing (FIT) could be used like calprotectin to test for suspected IBD.

We sought to define the changing use of calprotectin and FIT prior to the diagnosis of IBD, and to determine whether their use influenced the time to secondary care treatment.

Methods

We conducted a retrospective observational cohort study of the time from endoscopic diagnosis of IBD to initiation of treatment. Demographics, stool testing, referral route, disease type, clinical review and treatment data were recorded from our electronic patient record.

We sought factors associated with a delay in treatment defined as the upper quartile of time-to-treatment using logistic regression.

Results

Between 01/07/16 and 01/09/23 there were 805 new diagnoses of IBD (503 UC, 225 Crohn’s disease and 77 IBD-U). Monthly diagnosis rates were stable across the pandemic, except for March 2020 due to endoscopy unit closure. The median time from endoscopy to specialist review was 19.0 days (IQR7.0-44.0) and time to outpatient treatment 5.0 days (IQR 0.0-29.0 days).

Overall, the use of pre-IBD diagnosis stool biomarkers has increased over time, but since 2020 there has been a progressive rise in FIT, and a decrease in calprotectin, testing (Fig 1). By 2023, people with a new diagnosis of IBD were more likely to have FIT than calprotectin testing. Whilst stool biomarker testing did not influence the time-to-IBD treatment, FIT testing was associated with a reduced delay from primary referral to endoscopy (OR 0.17 p=0.023).

Factors associated with a delay in treatment were a diagnosis of Crohn’s disease versus UC/IBDU, having your index endoscopy undertake by a colorectal surgeon and being managed on a non-emergency pathway. IBD nurse contact prior to medical clinic review was associated with a significant reduction in delay to treatment (OR 0.55 p=0.003)

Conclusion

In the Southwest of the UK, pre-IBD diagnosis FIT, is now more common than pre-IBD diagnosis calprotectin testing. Factors linked to a delay in treatment were being diagnosed with Crohn’s disease versus UC/IBDU, having your index endoscopy undertaken by a colorectal surgeon and not specialist nurse or gastroenterologist and being managed on a non-emergency pathway. Further studies are needed to understand the influence of FIT versus calprotectin testing in the primary care diagnosis of IBD.
P224 JAK-STAT-Driven Tryptophan Degradation Fuels Mucosal Inflammation through QPRT Suppression-Induced Quinolinic Acid Overflow
Authors: Welz L , Kim N M , Harris D , Alsaadi A , Oumari M , Credidio G , Taubenheim J , Tran F , Sievers L K , Volk V , Koncina E , Verstockt B , Kaleta C , Letellier E , Feuerhake F , McReynolds M , Rosenstiel P , Schreiber S , Aden K
Published: January 2024

Background

Inflammatory bowel disease is characterized by disturbed metabolism, including disrupted tryptophan (TRP) metabolism along the kynurenine pathway (KP). However, the molecular mechanism how this fuels inflammation is not understood. Here, we unravel rewiring of TRP metabolism in IBD by combining murine DSS colitis with multi-omics of longitudinal IBD cohorts.

Methods

Serum metabolites were associated with CRP, e/pMayo, SESCD and CDAI (n=83 UC, n=51 CD). Mucosal IDO1 and QPRT expression (both KP enzymes; indoleamine2,3-dioxygenase1, quinolinate phosphoribosyltransferase; n=273 UC) was correlated with Nancy index and eMayo. Murine enterocytes were treated with Qprt siRNA, LPS or IFNγ and cytokines measured by RT-qPCR. Tissue and serum of DSS colitis (C57BL/6, 2.5%, 5 days) and human PBMC or colon organoids (hOG) treated with IFNγ or Tofacitinib (Tofa) were analysed by LC-MS. Blood and biopsies for metabolomics and transcriptomics were obtained over 14 weeks from IBD patients (n=62) first introduced to biologics. Mucosal IDO1/QPRT expression was assessed at week 0, 8 and 16 in Tofa-treated UC (n=15).

Results

In longitudinal IBD therapy intervention cohorts, restoration of serum TRP metabolism was associated with 12-month disease control. Quinolinic acid (QUIN) levels relative to other TRP derivatives positively correlated with several disease activity metrics. Increased mucosal IDO1 and decreased QPRT expression upon proceeding disease severity suggested unbalanced QUIN levels as a joint result of augmented TRP turnover by IDO1 and blocked QUIN conversion by QPRT in active disease. In-vitro, QUIN overflow exaggerated pro-inflammatory cytokine responses. Accumulation of colonic QUIN was reproduced in DSS colitis and resulted in NAD+ (nicotinamide adenine dinucleotide) exhaustion, suggesting a local KP roadblock due to QPRT suppression. Integrated metabolomics and transcriptomics of IBD blood and biopsies confirmed TRP hyper-degradation at the inflammation site and revealed common JAK/STAT pathway upregulation in blood and mucosa. As IDO1 exerts the KP via JAK/STAT, IFNγ-induced KP-activation was rescued by JAK inhibition (JAKi) in human PBMC and hOG. Ultimately, we found mucosal QPRT and IDO1 expression to be significantly associated with therapy response to Tofa in UC, suggesting their baseline expression as an a priori predictor of JAKi therapy response.

Conclusion

TRP wasting in IBD appears to fuel mucosal inflammation due to QPRT suppression and subsequent QUIN overflow. Whether this mechanism is unique to IBD remains to be shown. Obvious future applications may include diagnostic patient classification and targeting therapeutic interventions in the TRP pathway.
P226 Disability in Crohn’s Disease Patients at diagnosis: Findings from the CROCO (Crohn´s Disease Cohort) study
Authors: Revés J , Roager Madsen G , Burisch J , Wong C , Arebi N , Bonnet-Dodel M , Buisson A , Gatt K , Ellul P , Vieujean S , Ordas I , Duricova D , Rodríguez-Lago I , Sebastian S , Mocanu I , Kaimakliotis I , Goldis A , Hernandez V , Nachury M , Fumery M , Alloca M , Pedersen N , Barberio B , Guedes A , Ribeiro R , Ungaro R , Mary J Y , Bigot N , Lambert J , Colombel J F , Torres J
Published: January 2024

Background

Crohn’s disease (CD) can lead to progressive bowel damage and disability. Disability has been proposed by the SPIRIT-IOIBD consensus as an endpoint in disease-modification trials. Despite this, there is scarce data on disability at CD diagnosis.

Methods

The Crohn´s Disease Cohort (CROCO) is an ongoing prospective cohort study with newly diagnosed CD patients (within 12 months of diagnosis) aiming to assess the evolution of bowel damage and disability over time. Disability evaluation was conducted via the validated IBD-Disability Index (IBD-DI), which encompasses 14 questions ranging from 0-100 intended to measure overall health, sleep and energy, affect, body image, pain, defecation, interpersonal activities, and work and education.1 This study explored disability scores (DS) and their association with disease features and activity at diagnosis in patients with newly diagnosed CD. The IBD-DI was categorized as previously reported in no disability (scores 0-20), mild disability (scores 21-35), and moderate-severe disability (scores 36-100).2

Results

From a cohort of 261 patients [58% male, median age at diagnosis of 35yo (IQR 25-49)], 224 completed the IBD-DI at inclusion. Median time from inclusion to baseline visit was 4 months (IQR 1.7-7.8). Most patients presented with ileal or ileocolonic disease location (87%) and an inflammatory phenotype (69%); 16% had perianal disease and 27% had extraintestinal manifestations. At inclusion, 21% had been hospitalised, and 10% had a CD-related surgery. Treatments included steroids (56%), immunosuppressants (34%), and anti-TNF therapy (40%). The median DS at inclusion was 22.2 (IQR 10.4-37.9), with 48% exhibiting no disability and 30% displaying moderate-severe disability (Figure 1). Moderate-severe disability at baseline visit was associated with female gender (OR 3.65, 95%CI 2.01-6.62, p<0.001), stricturing behaviour (OR 2.34, 95%CI 1.1-4.98), Harvey-Bradshaw Index (OR 1.36, 95%CI 1.23-1.5, p<0.001), extraintestinal manifestations (OR 2.61, 95%CI 1.41-4.84, p<0.002), and steroid use (OR 1.89, 95%CI 1.04-3.45, p=0.034). No significant associations were found with age, smoking, or biomarkers (Table 1).

Conclusion

One-third of newly diagnosed CD patients have moderate-severe disability. Disability was associated with female gender, disease phenotype, clinical severity, extraintestinal manifestations, and steroid usage. Disability is an important feature of newly diagnosed CD and may characterize a unique group of patients at diagnosis.

References

1 - PMID: 26646934

2 - PMID: 27516406
P272 Healing of Perineal Wounds after Proctectomy for Crohn's Disease: A Systematic Review and Meta-Analysis
Authors: Alipouriani A , Erozkan K , Schabl L , Holubar S
Published: January 2024

Background

Non-healing perineal wounds are common in patients undergoing proctectomy for Crohn’s disease. We systematically reviewed the literature and performed a meta-analysis to estimate the pooled proportion of perineal wound healing after proctectomy for Crohn’s disease.

Methods

A comprehensive literature search was conducted in PubMed, Embase, and Scopus databases to identify relevant studies reporting perineal wound healing after proctectomy in patients with Crohn’s disease from 2010 to 2023. Articles were screened and those reporting perineal wound healing rates after proctectomy were included. Data on the study characteristics and proportion of healed wounds were extracted. Random effects meta-analysis was performed to estimate the pooled proportion and 95% confidence intervals using the ‘meta’ package in R. Heterogeneity was assessed using the I2 statistic.

Results

The literature search yielded 501 articles, of which 252 articles remained after removing duplicates. After screening the titles and abstracts, four retrospective cohort studies involving 332 patients with Crohn’s who underwent proctectomy were included in the meta-analysis. Across the four studies, the pooled proportion of completely healed perineal wounds at 6 months was 65% (95% CI 52%-80%) and at 12 months was 70% (95% CI 60%-83%). Significant heterogeneity was found between studies (I2=86% at 6 months). Only one study examined the predictors of impaired healing after proctectomy. Factors such as age, sex, BMI, smoking, steroid use, presence of high fistula-in-ano, and surgical technique were not significantly associated with impaired healing in univariate and multivariate analyses in this study. However, preoperative perineal sepsis was independently associated with impaired healing in the univariate and multivariate analyses in this study (p = 0.001). Study 4 included both Crohn's disease (n=54) and ulcerative colitis (n=20) patients who underwent proctectomy and reported fewer overall perineal complications in patients with UC than in those with Crohn’s disease (15% vs. 46.3%, p=0.01).

Conclusion

This meta-analysis revealed complete perineal healing in 70% of patients with Crohn's 12 months after proctectomy. Significant heterogeneity was observed between the studies. This review highlights the gaps in the best practices for optimizing perineal wound healing after proctectomy. These findings suggest the need to study techniques, such as vacuum-assisted closure and flap reconstruction. Further research is needed to identify modifiable factors to increase healing rates and develop evidence-based protocols for surgical approach, wound closure, and postoperative care in Crohn's disease patients.
P278 Radiation exposure in patients with inflammatory bowel disease
Authors: Jorissen T , Fierens L , Bosmans H , Verstockt B , Sabino J , Vermeire S , Vanbeckevoort D , Ferrante M
Published: January 2024

Background

Radiological imaging plays an important role in diagnosis and follow-up of patients with IBD. Due to the progressive character of the disease, repeated imaging may be necessary. A cumulative effective dose (CED), meaning the total diagnostic radiation received, of 75 mSv is often described as the risk level one needs to try not to exceed. However, data on cumulative exposure are limited in IBD. In this retrospective study, we analysed the cumulative radiation exposure of patients with IBD in a Belgian tertiary referral centre.

Methods

Electronic health records (EHRs) from all IBD patients followed at the tertiary referral centre between January 1st 1990 and December 31st 2021 were searched for examinations with radiation exposure and received doses in house or in any of 27 collaborating Nexuz hospitals working with the same EHR. Both the annual effective dose (AED) and CED were calculated. A sub-analysis of patients diagnosed after January 1st 2007 was performed, as detailed radiation doses were maintained prospectively from that date onwards.

Results

In total, 3429 IBD patients were included. The median (IQR) AED was 0.39 (0.01-1.66) mSv/year, and was higher in patients with CD than in patients with UC [0.58 (0.01-1.81) vs. 0.17 (0.01- 1.24) mSv/year, p=0.028]. During the first 20 years after diagnosis, the received CED were found higher in patients with CD than UC (Figure, p<0.01). In 5.5% of patients, a CED ≥75 mSv was reached after a median (IQR) of 24 (13-34) years of follow-up. Sub-analysis of 1633 patients diagnosed after January 1st 2007 showed a median (IQR) AED of 0.44 (0.01- 2.12) mSv/year, again higher in patients with CD than in patients with UC [0.82 (0.02-2.38) mSv/year vs. 0.12 (0.01-1.47) mSv/year respectively, p=0.040]. Here, 3.3% patients reached a CED ≥75 mSv during a median (IQR) of 9 (6-12) years of follow-up. Most common reasons for high radiation exposure were comorbidities like malignancy and postoperative complications. Chart review by an IBD expert showed that the indication for most of these examinations was appropriate and that no alternative examination was available in a timely manner.

Conclusion

Up to 5.5% of patients with IBD were exposed to a CED of ≥75 mSv. Although most decisions to perform imaging with radiation exposure were appropriate, vigilance for unconsidered and excessive imaging should be maintained.
P282 High Correlation Between Fecal Immunochemical Test and Fecal Calprotectin for the Evaluation of Activity in Inflammatory Bowel Disease
Authors: Yamamoto-Furusho J K , Torres-Diaz J A
Published: January 2024

Background

Fecal calprotectin (FC) is one of the most widely used biomarkers in IBD. The evidence suggest it has a good correlation with clinical disease activity, endoscopic and histological indices, thereby it can be used as treatment target. However, the availability and cost of the FC, makes it unattainable in some regions. We aimed to assess the correlation of noninvasive Fecal Immunochemical Test (FIT) and FC for activity prediction in IBD.

Methods

Consecutive outpatients with Crohn’s disease or ulcerative colitis were clinically evaluated and stool samples for FIT and FC were collected. The Mayo endoscopic sub-score and SES-CD were used to define endoscopic activity. Spearman’s rank correlations were used to evaluate the association between FIT and FCP. Receiver operator characteristic (ROC) curves were constructed to calculate the accuracy of FIT and calprotectin in discriminating patients with endoscopic inflammation.

Results

Two hundred and six patients (148 ulcerative colitis and 58 Crohn’s disease) were enrolled. There was a good correlation between FIT and FC (Spearman rank correlation coefficient rs = 0.71, P < 0.01). For calprotectin, a cutoff value of 250 mg/g predicted endoscopic inflammation with 75% sensitivity, 90% specificity, 97% positive predictive value, 50% negative predictive value, and an area under the curve of 0.861. For FIT, a cutoff value of 20 mg/g indicated endoscopic inflammation with 62.5% sensitivity, 90% specificity, 96% positive predictive value, 60% negative predictive value, and an area under the curve of 0.82.

Conclusion

Fecal Immunochemical Test has a good correlation with fecal calprotectin and can identify patients with IBD with endoscopic activity with a predictive accuracy similar to fecal calprotectin.
P286 Variation of outcomes in inflammatory bowel disease at ten Australasian centres - Crohn's Colitis Cure (CCC) Data Insights Program
Authors: Mcnamara J , Wilson W , Pipicella J , Ghaly S , Gearry R , Begun J , Ng W , Lynch K , Lawrance I , Schultz M , Walker G , Radford-Smith G , Andrews J M , Connor S J
Published: January 2024

Background

Inflammatory bowel disease (IBD) is a global health issue with Australia having amongst the highest prevalence rates worldwide. Our study examined the quality, safety and equity of care amongst ten Australasian centres using Crohn’s Colitis Care electronic management record. The aim was to describe current care delivery at each centre for a range of performance indicators to provide a baseline from which to engage in a regional care quality benchmarking initiative

Methods

Deidentified data prospectively entered by clinicians during routine clinical practice throughout 2022 were retrospectively analysed. Only centres with >100 eligible people with IBD and an assessment during the trial period were included. Sites from Australia and New Zealand were a mixture of public and private IBD referral centres

Results

The cohort included 7172 people with IBD from 10 centres; 58.6% with Crohn’s disease (CD), 39.1% ulcerative colitis (UC) and 2.3% IBD-unclassified (IBDU). Mean age was 44.3 (SD +/- 18.0) with an even gender balance (50.7% female). The number of people with IBD per centre ranged from 201 to 2151 (median 566).

In the total cohort, 38.3% were currently on advanced IBD therapy (biologics or new small molecules), with centre variation from 30.8% to 43.5% (p<0.001). Of those on advanced therapy, 42% were on dose escalated therapy which varied between centres substantially from 18% to 64%. Current steroid use ranged from 0.3% to 6.1% (median 1.6%; p<0.001). Documented IBD surgical rates varied from 0.1% to 7.2% (median 2.0; p<0.001). IBD admission rates ranged from 0.1% to 13.6% (median 1.2; p<0.001) while current smokers comprised 1.7% to 12.5% (p<0.001) of the cohort with a mean of 6.0% across all ten centres. A total of 3,379 faecal calprotectin’s (FCP) with an overall remission rate (< 250μg/g) of 71% varying from 63.4% to 83.1% (median 69.1; p=0.001); 2,616 lower endoscopies were performed with an observed remission rate of 56%; this varied between sites from 0% to 69%.

Recorded Influenza vaccination rates varied from 6.3% to 54.4% (median 19.8) and Covid vaccination rates from 14% to 78.5% (median 43.4). Skin care check completion rates ranged from 16.3% to 32.3% (median 22.9). The centre with the highest documented healthcare maintenance completion rate across all three domains was private.

Conclusion

Despite advances in treatment and much literature addressing care guidelines and targets, significant disparity in care documentation and outcomes remains for people with IBD in routine care. CCCare as an IBD-specific EMR supports easy, serial examination of these measures at scale and is therefore a useful tool to measure and drive efforts to improve these deficiencies and reduce unwarranted care variation