bluuebunny/crossref_metadata_2025_split huggingface dataset:
P061 The molecular landscape of perianal fistula in Crohn’s disease: opportunities for new therapeutic approaches
Authors: Bislenghi G , Verstockt B , Sabino J , Caenepeel C , Verstockt S , Wolthuis A , Ferrante M , D’Hoore A , Vermeire S 
Published: January 2020

Abstract

Background
Perianal Crohn’s disease (CD) is a debilitating condition, often refractory to medical therapy and requiring repetitive surgical interventions. Nonetheless, its pathophysiology is very poorly understood. Hence, we molecularly characterised the fistula tract and compared it to the molecular landscape of its inner rectal orifice.

Methods
We collected paired surgical biopsies from the fistula tract and the inner rectal fistula orifice in 29 CD patients with draining perianal fistula, requiring surgical examination under anaesthesia. RNA was extracted and single-end RNA sequencing performed using Illumina HiSeq4000. Sequencing data were analysed through differential gene expression (DESeq2) and corrected for the presence of proctitis. A false discovery rate of 0.001 was considered significant. In addition, cellular deconvolution methods (CIBERSORT) were applied to study the cellular composition of the fistula tract.

Results
Differential gene expression revealed 2701 transcripts being differentially expressed (1727 up, 974 down in fistula) between the fistula tract and the paired rectal mucosa. The top upregulated gene, LBP (fold change [FC]=2858.8, p = 3.6E−13), highlights the potential contribution of the microbiome. LBP has a central role in the innate immune system by binding to bacterial lipopolysaccharides (LPS) and facilitating the affinity between LPS and CD14, with the subsequent release of various cytokines. Several extracellular matrix proteins could be identified within the top 25 of upregulated genes, including MMP13 (FC = 358.8, p = 1.3E−11), ADAM12 (FC = 175.6, p = 1.4E−12), COL1A1 (FC = 77.1, p = 2.7E−10) and COL5A3 (FC = 32.1, p = 1.7E−12), emphasising the intense tissue remodelling going on in the fistula tract. Despite correcting for the confounding effect of proctitis, the fistula tract expressed higher levels of IL6 (FC = 133.1, p = 3.7E−9), TNF(FC = 14.2, p = 4.8E−5), OSM (FC = 24.3, p = 8.9E−5), IL12p40 (FC = 10.0, p = 8.1E−3), integrin α 4 (FC = 4.5, p = 9.3E−3), integrin β 7(FC = 3.8, p = 4.1E−3) but not IL23p19 (FC = 1.2, p = 0.9). Top downregulated genes were linked to the intestinal epithelium, including KRT19 (FC = −489.1, p = 5.5E−17), KRT8 (FC = −324.0, p = 1.1E−16), CEACAM6 (FC=−515.1, p = 4.5E−16) and MUC2 (FC=−795.4, p = 3.0E−15). Cellular deconvolution identified CD4 memory resting T cells (18.5%), M0 macrophages (17%), M2 macrophages (15.2%), neutrophils (9.2%) and plasma cells (7.5%) as the most abundant cells within the fistula tract.

Conclusion
We molecularly characterised the fistula tract in perianal CD and identified clear biological differences in comparison to the luminal tract, highlighting the potential of new therapeutic targets and cell types driving this debilitating condition.
P065 Metabolic utilisation of propanediol by adherent-invasive E. coli regulates intestinal tissue immunity
Authors: Viladomiu M , Metz M , Lima S , Guo C J , Simpson K , Scherl E , Longman R 
Published: January 2020

Abstract

Background
Our lab has recently shown that adherent-invasive E. coli (AIEC), which is enriched in patients with Crohn’s disease, is sufficient to induce intestinal Th17 cell inflammation. Although AIEC lack pathogenic factors including type III secretion systems, virulence-associated metabolic enzymes, including propanediol dehydratase (PduC), enable AIEC to use fucose-derived propanediol as an alternate carbon source in the gut. We hypothesised that this propanediol utilisation pathway functionally modulates AIEC contribution to intestinal tissue immunity and inflammation.

Methods
We generated pduC-deficient (ΔpduC) and catalytically inactive pduC (pduC*) mutants of a patient-derived, AIEC isolate. Gnotobiotic and genetic mouse models were used to evaluate the cellular and metabolic contribution of pduC to mucosal Th17-cell inflammation.

Results
We found that pduC is enriched in the microbiome and within E. coli genomes in Crohn’s disease patients compared with healthy controls. Mono-colonisation of mice with pduC-deficient AIEC resulted in reduced, inflammatory Th17 cells and attenuated weight loss using a T-cell transfer colitis model. Using mouse models for inducible deletion of CX3CR1+mononuclear phagocytes (MNPs) or IL10-deficiency, we found that MNPs are required for AIEC-mediated induction of Th17 cells and that IL-10 is required to restrain pduC-dependent colitis. Using a catalytically inactive mutant in mono-colonised mice, we determined that PduC metabolic activity was required for this immune phenotype. Cell-free supernatants from WT AIEC (but not pduC-deficient AIEC) promoted ex vivo Th17 cell polarisation and LC-MS of these supernatants defined PduC-dependent metabolites capable of promoting Th17 polarisation.

Conclusion
These data reveal a link between AIEC microbial metabolism and inflammatory Th17 cells with the potential to serve as a therapeutic target for tissue inflammation in the treatment of Crohn’s disease.
P078 Efficiency of evaluating the expression of Toll-like receptors 2, 4, 6 and proteins proteomic profiling as integral indicators for predicting the risk of early relapse of ulcerative colitis
Authors: Tarasova G , Volkov A , Iakovlev A , Ghazudin T , Shcherbakova I 
Published: January 2020

Abstract

Background
Success was made in the study of TLR in congenital and adaptive immunity, which determined a new look at immune processes at ulcerative colitis (UC). Modern achievements of proteomic methods of analysis research allow to define molecular characteristics of the inflammation in colon mucosa of patients with UC.

Methods
The study included 86 patients with UC, an average age of 39.0 ± 1.4 years. Groups: 1–15 (17.4%) patients with distal form of UC, 2–42 (48%) left-sided form, 3–29 (33.7%) patients with total UC. The expression of TLR on peripheral blood monocytes was determined in the immunofluorescence test. Two-colour analysis was performed on a flow-through laser cytofluorimeter (Cytomics FC500, Beckman Coulte). The percentage of monocytes (CD14 + cells) carrying TLR2, TLR4, TLR6 on their surface was assessed. The separation of proteins of colon mucosa was based on technologies of IEF, SDS–PAGE, 2DPAGE (Bruker, USA). The getting of mass spectrogram was determined by matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-TOF-MS/MS, Ultraflex II, Bruker, USA). Statistical analysis was performed using the software Statistica 10.0 (Statsoft).

Results
The direct average relationship was established between the number of monocytes expressing CD14 + CD282 +, CD14 + CD284 +, CD14 + CD286 + and the area of inflammation (r = 0.49, r = 0.55, r = 0.42, p &lt; 0.05). The nonlinear regression equation was used. Calculation example: the risk of recurrence UC = exp (−26.1 + (0.4) × TLR 2)/(1 + exp (−26.1 + (0.4) × TLR 2)), χ2 = 130, 59, p &lt; 0.0001. Thus, when the number of monocytes expressing TLR2 is not more than 60%, the risk of recurrence of the UC is not more than 11%, with values above 70%, the probability of recurrence exceeds 80%. We identified potentially new molecular markers of the early relapse of ulcerative colitis: SMAD2 activates the transcription of TFG1β and leads to development of fibrosis in colon submucosa in patients with UC; significant decrease of the expression of PPARγ promotes the activation of STAT and AP-1 signalling pathways that promotes the increase of the synthesis of IL-2,6,8,12,TNFα, the activity of immune and inflammation processes in colon mucosa; the reduction of expression of β-defensin-1 in cells of colon mucosa are accompanied with increased expression of CCR6, that promotes the formation of inflammatory infiltrates in colonic submucosa in UC.

Conclusion
Expression of TLR 2,4,6 in blood monocytes (the risk of recurrence UC ratio) and new protein molecular markers of colon mucosa (SMAD2, PPARγ and apoС-III) can be used as a tool for prediction of early relapse UC.
P092 Pathogenic B-cell response in ulcerative colitis that associates with treatment resistance and disease complications
Authors: Uzzan M , Martin J , Keningsberg E , Castro-Dopico T , Huang R , Ungaro R , Cohen B , Rahman A , Rosenstein A , Gurunathan S , Dubinsky M , Clatworthy M , Suarez-Farinas M , Argmann C , Colombel J F , Mehandru S 
Published: January 2020

Abstract

Background
Among the adaptive immune cells, B cells, dominated by IgA producing plasma cells (PC), are critical for intestinal homeostasis. However, the B-cell response remains under studied in ulcerative colitis (UC).

Methods
Using single-cell RNA sequencing (scRNA seq), single-cell IgH sequencing (sc IgH seq), multiparameter flow cytometry (FC), mass cytometry (MC) and immunofluorescent microscopy (IF), we have comprehensively defined the landscape of intestinal and circulating B cells in patients with UC. A Cohort of 88 patients with active UC, 14 patients with quiescent UC and 43 healthy volunteers were recruited. Two validation cohorts comprising of 53 patients with active UC, 59 patients with quiescent UC and 65 healthy volunteers (Validation cohort 1) and 65 patients with active UC, 42 patients with quiescent UC and 36 healthy volunteers (Validation cohort 2) were also studied.

Results
scRNA seq and FC demonstrate a dramatic increase in proliferating (Ki67+) plasmablasts (PB) as well as IgG+ PC in the inflamed colon of UC patients. Additionally, a significant increase in short-lived (CD19+CD45+) PC was observed during colonic inflammation. scIgH seq further demonstrates a significant decrease in somatic hypermutations and the diversity of intestinal PC of patients with active UC. Genes associated with Fc-dependent macrophage signalling were enriched in areas of active disease and were associated with non-response to TNF therapy. In circulation, a significant increase in a4b7+ gut-homing PC was noted that related to disease extent, severity and complications (defined by treatment non-response, hospitalisations and surgery).

Conclusion
Active UC results in an immature, IgG-dominated PB/PC response in inflamed GI tissue and an increase in the frequency of gut-homing PC in circulation that relates to disease activity and complications and may be used to monitor disease course. These data provide novel insights into the pathogenesis of UC with major implications for existing and emerging therapeutic agents.
P097 Depletion of delta-like ligand 4 (Dll4) contributes to the alteration of secretory progenitor differentiation in SAMP1/YitFc mice with Crohn’s disease-like ileitis
Authors: Hong S N , Song J H , Seong G , Kong S M , Shin J B , Eun Ran K , Dong Kyung C , Young-Ho K 
Published: January 2020

Abstract

Background
When the intestinal epithelium would be exposed to harmful substances, mucosal damage can be occurred and followed by epithelial restoration with regenerative epithelium derived from intestinal stem cells (ISCs). Crohn’s disease (CD) is characterised by chronic mucosal damage and ulceration predominantly involved in the ileum. Thus, we hypothesised that epithelial regeneration in CD might be impaired due to the dysfunction of ileal ISCs or its niche.

Methods
SAMP1/YitFcsI (SAMP1) mice are recombinant-inbred mice that spontaneously develop ileitis resembling human CD. Alterations in the crypt-villus structure, epithelial differentiation, organoid formation ability, and niche signalling pathways in the ileum of 10- to 14-week-old SAMP1 mice were analysed and compared with age-matched AKR mice.

Results
In the ileum of SAMP1 mice, the depth of the crypts increased and the surface area of the villi decreased. While the number of ISCs in the ileal crypts did not differ between SAMP1 and AKR mice. The number of Paneth cells decreased and the number of transient amplifying cells increased. The organoid formation ability of the ileal crypts of SAMP1 mice decreased significantly compared with that of AKR mice. RNA-seq revealed a differential gene expression pattern of ileal crypts of SAMP1 mice compared with those of AKR mice. Among the ISCs and niche signalling, the expression of delta-like ligand 4 (Dll4) was significantly decreased and the expression of genes associated with Notch signalling tended to decrease in the ileal crypts of SAMP1 mice.

Conclusion
The characteristic ileitis in SAMP1 mice may be caused by impaired Dll4-Notch signalling.
P116 The occurrence of venous thromboembolisms in paediatric-onset IBD
Authors: Aardoom M , Kemos P , Ruemmele F M , van Ommen C H , Croft N M , de Ridder L 
Published: January 2020

Abstract

Background
Venous thromboembolisms (VTEs) are one of the severe adverse events that may occur in patients with paediatric-onset inflammatory bowel disease (IBD). Based on available literature VTE incidence in the general paediatric population ranges from 0.07 to 0.49 per 10,000 children. Several studies in adults suggest an increased risk of venous thromboembolism in adult IBD patients, but data in paediatric IBD patients is limited. Due to the rarity of these events, international studies are needed to gain information on risk factors for this complication and optimise guidelines. With this study, we aim to assess the incidence and characteristics of VTEs in children with IBD.

Methods
As part of an international prospective safety registry in the PIBD-SETQuality project, paediatric gastroenterologists reply monthly to an electronic survey to indicate whether they have seen one of 10 predetermined complications, including VTE, in an IBD patient &lt;19 years of age. When a VTE is reported, additional information on patient and disease characteristics and previous therapy strategies is collected. In addition, participating physicians annually report the number of new and current PIBD patients under their care, which combined with the reporting period, is the denominator data for this project.

Results
Since October 2016, 150 paediatric gastroenterologists from 26 different countries are participating in the safety registry. In total, 14 cases of VTE were reported for 28,793 patient-years of follow-up. This results in an observed incidence of 4.86 per 10,000 PIBD patients annually (95% CI 2.66–8.16), which is a 10-fold increase compared with the VTE incidence reported in the literature in the general paediatric population. Among cases with available additional information (n = 10) were five cases of intracranial thromboembolism, four upper or lower limbs VTE and one pulmonary embolism, which occurred mainly in children with ulcerative colitis (UC) or IBD unclassified (IBDU) (5/8). Seventy per cent of cases occurred during an exacerbation of IBD, but only 40% during hospitalisation. Physicians reported steroid therapy (n = 4), immobility (n = 1), surgery (n = 1) and the presence of a central venous catheter (n = 1) as risk factors.

Conclusion
This registry has the ability to collect rare but severe complications and patient-at-risk information in paediatric IBD. Our data suggest a 10-fold increase of the VTE incidence in the paediatric IBD population compared with the general paediatric population. Most VTEs were reported in UC/IBD-U patients and occurred during an exacerbation of IBD. Ongoing data collection will help to understand possible causes and gain insight in differences in management and outcomes of these complications per country or region.
P119 Brain function and fatigue in patients with inflammatory bowel disease
Authors: Thomann A , Schmitgen M , Kmuche D , Griebe M , Ebert M , Wolf R C , Reindl W 
Published: January 2020

Abstract

Background
Fatigue is common in patients with inflammatory bowel diseases (IBD). It occurs in up to 80% of patients with active disease, but also a considerable proportion of patients in remission, and significantly affects quality of life. The underlying mechanisms are still poorly understood, and it is still unclear which patients will suffer from fatigue even in luminally quiescent disease. Task-based brain functional studies have examined neural correlates of fatigueability and found changes in the orbitofrontal cortex (OFC), among other regions. To the best our knowledge, the relationship between brain function and fatigue in IBD has not been investigated. This study aimed to examine the association between fatigue and resting-state brain function in remitted IBD patients.

Methods
We obtained resting-state-functional MRI (rs-fMRI) data from 45 IBD patients in stable remission without current steroid or biological therapy and 17 healthy controls (HCs). Fatigue was assessed with Würzburger Erschöpfungsinventar Multiple Sklerose (WEIMuS). Preprocessing of rs-fMRI-data and calculation of amplitude of low frequency fluctuations (ALFF) was performed using the Data Processing Assistant for rs-fMRI. The resulting individual maps were analysed via second-level SPM multiple regression models in patients and HC to test for correlations between ALFF data and WEIMuS scores. Age, gender and mean framewise displacement were included as covariates of no interest and results were displayed at p &lt; 0.001 (peak level) with a threshold of spatial extent (k) according to the expected voxels per cluster estimated by SPM.

Results
Fatigue scores did not differ significantly between patients and controls (mean WEIMuS-scores 17.9 (SD 13.9) vs. 12.3 (SD 16.5), p = .17). Proportions of participants with fatigue scores above the cutoff (&gt;32P.) were nearly identical in patients and HC (8/45 vs. 3/17). In patients, fatigue scores correlated positively with ALFF in the right central operculum and negatively with ALFF in the left OFC and left cerebellum (all p &lt; .001, Figure 1). Fatigue and ALFF in the left cerebellum were also found to correlate in HC.

Conclusion
This study shows fatigue-associated changes in brain activity in several brain regions. The negative association between fatigue and ALFF in the left OFC of IBD patients was not seen in HC, indicating that reduced ALFF in the OFC may represent a neural correlate of IBD-related fatigue. The OFC is thought to be involved in decision-making, which is described to be impaired in many fatigued IBD patients. If the association between fatigue and brain function detected in our study is confirmed in longitudinal IBD studies, these regions could serve as biomarkers when targeting fatigue in IBD.
P141 Scoring endoscopy in pediatric inflammatory bowel disease: a way to improve quality
Authors: Norsa L , Ferrari A , Arrigo S , Bramuzzo M , Deganello Saccomani M , Di Nardo G , Illiceto M T , Miele E , Paci M , Romano C , Romeo E , Daperno M , oliva S 
Published: January 2020

Abstract

Background
The aim of mucosal healing (MH) as a therapeutic target in paediatric inflammatory bowel diseases (IBD) has emphasised the role of the endoscopy. There is a great variability in evaluating mucosal lesions among different operators, especially in paediatric patients. This multicentre prospective study aims to evaluate the interobserver agreement among paediatric endoscopists in using validated endoscopic scores of IBD in children.

Methods
Fifteen videos of follow-up ileocolonoscopies in children with IBD (8 ulcerative colitis –UC-, 7 Crohn’s disease –CD-) were selected from 3 different referral sites in Italy. Eleven paediatric endoscopists from different centres were asked to evaluate all videos as independent and blinded readers. The scoring systems used were ulcerative colitis Endoscopic Index of Severity (UCEIS) for UC and simple endoscopic score for Crohn’s disease (SES-CD) for CD. Kappa statistics and intraclass correlation coefficients were used to measure agreement. Furthermore, an experienced adult gastroenterologist evaluated the same videos and scores them. His results were compared with paediatric endoscopists’ findings.

Results
The median age of the participants was 40 (interquartile range: 6) with a median experience of 12 (14) years in centres with a median number of 140 (230) of paediatric IBDs. Intercluster correlation agreement was 0.298 (95% CI: 0.13–0.55) for UC and 0.266 (0.11–0.52) for CD. When a disease activity categorisation was adopted (remission, moderate, mild and severe) Fleiss’ kappa coefficient was 0.408 (0.29–0.53) for UC and 0.552 (0.43–0.73) for CD (Figure 1). When stratified for item vascular pattern of UC was the most reliable item IC: 0.624 (0.321–0.854). The comparison between paediatric and expert gastroenterologist’s scores is shown in Figure 2. In the multivariate analysis none of the reviewer characteristic affected the readers’ errors.

Conclusion
This pilot multicentre study shows that there is a low level of agreement among paediatric endoscopists in evaluating children with IBDs. Agreement improved after using a disease activity categorisation, with better results for CD. Regardless to experience, all readers showed a low-grade accordance with adult gastroenterologist. According to these findings, the use of scoring systems should be implemented for all paediatric endoscopists. Future specific training programs should be considered to pursue this goal.
P185 A comparison of early response parameters to inform a treat-to-target approach in ulcerative colitis
Authors: Dulai P , Feagan B , Sands B , Lasch K , Lirio R , Feng D 
Published: January 2020

Abstract

Background
We aimed to evaluate early markers of response after vedolizumab (VDZ) induction therapy for their prognostic value in determining the long-term risk of colectomy.

Methods
Post hoc analysis of VDZ-treated patients (n = 588) enrolled in the GEMINI 1 and long-term safety (LTS) clinical trial programs. Rates of colectomy during the 7-year follow-up period were compared according to treatment response status at week 6 (induction) for various definitions of Clinical remission [CR] (rectal bleeding sub-score [RBS] 0 + stool frequency sub-score [SFS] ≤1), Biomarker remission [BR] (faecal calprotectin [FC] ≤50, ≤100, ≤250), or endoscopic improvement [EI] (Mayo endoscopic sub-score [MES] ≤1) and endoscopic remission [ER] (MES 0). Time-to-event with log-rank and Cox proportional hazard analyses were used and presented as hazard ratios (HR) with 95% confidence intervals (CIs).

Results
The risk of colectomy was comparable between UC patients achieving week 6 CR vs. those with persistent symptoms (HR 0.74, 95% CI 0.37–1.48, p = 0.39). The risk of colectomy trended lower in patients achieving week 6 EI (HR 0.55, 95% CI 0.28–1.10, p = 0.08), but was comparable between those achieving an MES of 1 vs. 0 (HR 1.45, 95% CI 0.39–5.48, p = 0.58). The risk of colectomy was significantly lower in patients achieving week 6 BR using an FC cut-off of 250 (HR 0.30, 95% CI 0.13–0.68, p = 0.002) and 100 (HR 0.18, 95% CI 0.04–0.73, p = 0.007) but not with a cut-off of 50 (HR 0.34, 95% CI 0.08–1.41, p = 0.12). The proportion of patients requiring colectomy over a 7-year period was lower among those achieving week 6 BR (FC 250, 3.3%; FC 100, 1.8%) compared with patients who achieved week 6 EI (5.6%), although over one-third of patients who achieved week 6 BR had moderate–severe endoscopic activity (MES 2–3) at week 6.

Conclusion
FC as an early biomarker of response at week 6 may aid in identifying patients who remain at low risk of future colectomy, despite having persistent symptomatic or endoscopic activity. These findings may be limited by overall low rates of colectomy in GEMINI LTS, but can inform considerations for early treat to target approaches.