bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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&lt;0.05 and &lt;0.01) (Figure 1A). Based on the UCEIS, patients with a severe disease presented with reduced CTX-III than moderate disease activity (p&lt;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

Abstract

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 &lt; 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

Abstract

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

Abstract

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&lt;0.01) or the pan JAK inhibitor Pyridone-6 (p = &lt;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

Abstract

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

Abstract

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

Abstract

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.