bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP68 Natural history of isolated Crohn's Disease perianal fistula
Authors: Sangmo L , Quraishi B , Rajauria P , Colombel J F , Ungaro R , Wong S Y 
Published: January 2024

Abstract

Background
Approximately 20% of patients with Crohn’s disease (CD) have perianal fistulizing CD, which are most often complex PAF. Studies have shown that 4-5% of patients with CD present with PAF without luminal disease, termed isolated perianal CD (iPCD). Little is known about their natural history.

Methods
We performed a retrospective cohort study of patients seen within the Mount Sinai Health System (New York) with an ICD-10 diagnosis code for PAF between 7/22/2008 and 7/22/2022. Medical record review was conducted to identify patients with PAF, considered as possible iPCD, who did not have evidence of luminal disease and had &gt; 6 months of follow-up (Table 1). Demographics, comorbidities, imaging, endoscopy, surgeries, hospitalizations and medication data were collected. These patients were reviewed to determine progression to luminal disease, which was defined as any evidence of luminal ulcers, erosions, or strictures on endoscopy, histology, video capsule exam, or MRE. Descriptive and univariate analyses were performed. Complex PAF was defined by American Gastroenterological Association criteria. Complicated disease course was defined as a composite of any major CD-related surgery, PAF/IBD-related hospitalization or biologic use.

Results
Among 887 patients who presented with PAF, 62.2% (n=552) patients underwent luminal evaluation, of whom 80 patients (14.5%) were found to have no luminal disease and considered as having iPCD (Table 1). 57 of these 80 patients had &gt;6 months follow-up. Luminal disease developed in 13 patients (23%) with a mean time to diagnosis of 4.2 +/- 3.8 years after PAF presentation. Patients who developed luminal CD were more likely to be &lt;30 years old at PAF diagnosis (p=0.0225), had &gt;2 fistulas on imaging (p=0.002), and have concomitant autoimmune conditions (p=0.046) (Table 2). During the follow-up period, the patients who developed luminal CD
were more likely to receive biological therapy (77% vs 16%, p&lt;0.0001) or undergo CD/PAF-related hospitalization (62% vs 30%, p =0.0356) (Table 2). Overall, patients who developed luminal CD had a more complicated disease course (31% vs 2.3%, p=0.007) than those who did not.

Conclusion
Approximately 1 in 4 patients who presented with possible iPCD developed luminal CD at follow-up. Patients who developed luminal CD were more likely to be younger at diagnosis, had more fistula tracts, and had concomitant autoimmune conditions.
DOP85 An anti-fibrotic role for eosinophils in a DSS colitis RAG-/- and an in vitro co-culture model
Authors: Jacobs I , Deleu S , Cremer J , Dilissen E , De Hertogh G , Martens T , Vanden Berghe P , Vermeire S , Breynaert C , Vanuytsel T , Verstockt B 
Published: January 2024

Abstract

Background
In several disease areas, such as in the liver and lungs, a pro-fibrotic role for eosinophils has been suggested. However, information about the role of eosinophils in the development of intestinal fibrosis is scarce. We therefore aimed to assess the functional and mechanistic role of eosinophils in intestinal fibrosis and fibroblast activation.

Methods
Chronic DSS colitis (3 DSS cycles of 1 week DSS administration followed by 2 weeks of recovery (1.75% - 2.25% - 2.25%)) was introduced in 6-8-week-old C57BL/6 RAG-/- mice to induce intestinal fibrosis (Figure 1A). Mice were injected intraperitoneally with anti-CCR3 to deplete eosinophils (n=8) or with an isotype control (n=8). Intestinal fibrosis was assessed based on collagen deposition (hydroxyproline assay, Martius Scarlet Blue staining (MSB) and second harmonics generation (SHG)), while COL1A1 expression was assessed via RT-qPCR. Gene expression was performed using RT-qPCR and protein expression via the MSD platform. Secondly, circulating eosinophils were isolated from non-IBD controls (n=3) and co-cultured with fibroblasts, isolated from resection specimens obtained from the terminal ileum of Crohn’s disease patients undergoing right hemicolectomy (n=3). The effect of eosinophils on fibroblast activation was assessed through the expression of α-SMA via flow cytometry and immunocytochemistry. Lastly, fibroblasts were stimulated with 10ng/mL eosinophil cationic protein (ECP), a protein exclusively produced by eosinophils (n=3), in order to study whether this mediator could affect fibroblast activation.

Results
Anti-CCR3 mediated eosinophil depletion in the chronic DSS model resulted in increased fibrosis based on the hydroxyproline assay (p=0.06) (Figure 1B), MSB (p=0.0009) (Figure 1C) and COL1A1 expression (p=0.03) (Figure 1D). Similarly, we identified an increased collagen deposition in the eosinophil-depleted group based on the SHG (Figure 1E). Furthermore, an increase in the pro-fibrotic IL-1β and TGF-β3 on protein (p=0.03 and p=0.06) and gene level (p=0.04 and p=0.005) could be found in the eosinophil depleted mice. Co-culturing eosinophils with fibroblasts resulted in decreased α-SMA expression, indicative of a decrease in active fibroblasts. This could be observed via both flow cytometry (p=0.001) (Figure 1F) and immunocytochemistry (Figure 1G). Similarly, when fibroblasts were stimulated with ECP, a decrease in α-SMA was observed (p=0.04) (Figure 1H).

Conclusion
Depletion of eosinophils in a chronic DSS RAG-/- model resulted in more intestinal fibrosis. Similarly, in an in vitro setting, eosinophils, as well as ECP, decreased α-SMA expression in fibroblasts, suggesting that eosinophils may inactivate fibroblasts.
DOP86 FOod Additives on the Mucosal barrier study (FOAM): Effect of five emulsifiers on inflammation, intestinal permeability, and the microbiome: preliminary results
Authors: Wellens J , Vanderstappen J , Hoekx S , Vissers E , Luppens M , Raes J , Verstockt B , Ferrante M , Verbeke K , Matthys C , Vermeire S , Sabino J 
Published: January 2024

Abstract

Background
Common emulsifiers are associated with intestinal inflammation and are therefore excluded in new dietary therapeutic strategies in inflammatory bowel disease. Human data are scarce and involve a limited number of emulsifiers. We aimed to investigate the effect of five different emulsifiers on systemic and intestinal inflammation, intestinal permeability, and the gut microbiome.

Methods
We recruited 60 healthy volunteers to a 7-week double-blind placebo controlled randomized trial. After 1 week of recording their habitual diet (baseline), participants followed an emulsifier-free diet (EFD) for 6 weeks, starting at baseline. After 2 weeks, participants combined the EFD with 3 daily brownies that contained either 2.75 g carboxymethyl cellulose, 1.350 mg polysorbate-80, 380 mg carrageenan, 3.55 g soy lecithin, or 8.72 g native rice starch, or no additives (placebo) for a period of 4 weeks. Anthropometric measurements and bio samples were taken at baseline, week 2 and week 6. Blood samples were collected for routine tests, LPS-binding ELISAs, and serum proteomics using the Olink Target 96 Inflammation and Cardiometabolic panels. Stool samples were collected for analysis of the microbiota (16S rRNA sequencing), short chain fatty acids (Gas Chromatography – Mass Spectrometry (GC-MS)), and faecal calprotectin (FC) analysis. Urine samples were collected following the 2-hour lactulose mannitol ratio protocol to measure intestinal permeability (using GC-MS).

Results
Of the 60 healthy volunteers, 2 were excluded due to NSAID use. Median (IQR) age was 25.5 years (23.0-33.0), median BMI was 22.7 kg/m2 (21.2-25.6) and 19.0% were male. There was a median weight loss of 0.1 kg (p=7.6*10-4, paired Wilcoxon, unadjusted p-value). At week 6 and week 2, FC decreased significantly compared to baseline (p= 4.69*10-4, and p=2.81*10-4 respectively, paired Wilcoxon, unadjusted p-value, Table 1 and Figure 1A). No significant increase in FC was noted after consumption of any emulsifier during the trial. In the placebo arm, faecal acetic acid concentration was increased at week 2 (p=0.04). Compared to baseline, there was an increase in both acetic acid and propionic acid concentration (p=0.006 and p=0.04 respectively, paired Wilcoxon, unadjusted p-value, Figure 1B) in the same arm at week 6.

Conclusion
In this double-blind placebo controlled randomized trial faecal acetic and propionic acid increased in the placebo arm, but did not after consumption of any of the emulsifiers. FC did not increase after consumption of any emulsifier. Pending analysis will shed light on the effect of an EFD and distinct emulsifiers on the serum proteome, intestinal permeability and gut microbial changes.
P002 Regulation of miR-338-3p and miR-378a-3p in the intestinal mucosa of Crohn’s disease: Potential targets for modulating inflammation
Authors: Moon J M , Kim K U , Lim E , Hwang H W , Kim K , Seo J , Shin S Y , Min H , Choi C H 
Published: January 2024

Abstract

Background
A growing body of evidence suggests that epithelial cell-derived microRNAs are involved in the pathogenesis of inflammatory bowel disease (IBD). This immunological impairment leads to altered colonic epithelial permeability and the release of inflammatory cytokines, such as IL-33. In this prospective cohort study, we studied the expression of epithelial cell-derived microRNAs (miRNA) in Crohn’s disease (CD) patients compared to healthy controls. We also investigated their potential role in regulating inflammation in experimental IBD animal models.

Methods
We prospectively collected terminal ileum tissue samples via ileocolonoscopy from non-IBD healthy control (n=26), CD patients in remission (n=34) and active CD patients (n=42). CD remission was defined as clinical remission with a Crohn’s disease activity index score of less than 150 and the achievement of endoscopic mucosal healing. Both inflamed and non-inflamed lesions were sampled in the active CD patients. miRNA levels were measured by small-RNA sequencing and also validated via qRT-PCR. Diagnostic abilities of specific miRNAs found were evaluated by receiver operating characteristic (ROC) curve analysis. A signature of miRNAs was selected from RNA sequencing and qRT-PCR and single-strand mimics of these miRNAs were delivered in the 2.5% dextran sodium sulfate colitis model to determine the effect. Histologic grading and immunohistochemistry evaluation and flow cytometry analyses were performed.

Results
From the prospective study cohort of CD and non-IBD healthy control (mean follow-up period of 13.06 months), we found a distinct array of miRNAs between groups. Small-RNA sequencing of CD patients in remission and active state (both in inflamed and non-inflamed tissue) revealed distinct microRNA profiles. Through qRT-PCR validation, we found that the expression levels of miR-141-3p, miR-338-3p, miR-378a-3p, and miR-200b-3p were significantly decreased, while miR-125b-5p, miR-29b-3p and miR-155-5p were significantly increased in the inflamed tissue of active CD patients. ROC curve analysis of these miRNAs suggested that they have varying diagnostic activities related to both clinical disease activity and endoscopic inflammation status. In an IBD animal model, the delivery of miR-338-3p and miR-378-3p demonstrated an anti-inflammatory effect, as evidenced both histologically and in immunohistochemistry data, as well as in flow cytometry analyses. Consistent results were observed when these two miRNAs were combined.

Conclusion
We report miR-338-3p and miR-378a-3p as distinct features in mucosa of CD patients and these data support the promising future of use of these miRNAs as potential therapeutic targets for novel IBD therapies.
P007 Neutrophil function in lesional biopsies is a strong determinant of IBD severity and may relate to an altered functional state already present in circulating cells
Authors: Pascutti M F , Calado B , Nugteren S , Simons-Oosterhuis Y , Smits W K , Tuk B , Hulleman-van Haaften D H , Barendregt D M H , Heredia M , Klomberg R C W , de Ridder L , Samsom J N 
Published: January 2024

Abstract

Background
Neutrophils clear luminal bacteria from the intestinal lamina propria and have a protective role in Inflammatory Bowel Disease (IBD). However, their production of inflammatory cytokines, matrix metalloproteases and radical oxygen species causes irreversible tissue damage. Histological assessment of infiltrating neutrophils and indirect measurement of neutrophil-derived calprotectin in feces are used to assess disease severity in patients. Since IBD is a heterogeneous disease in terms of presentation, severity and course, we hypothesize that different patients have a different composition of their neutrophil compartment that leads to a different balance between protection and damage. We aim to study the variability in neutrophil phenotype and function and relate it to patient heterogeneity.

Methods
We analyzed endoscopic biopsies and peripheral blood samples from children diagnosed with IBD within the PIBD-SETQ cohort. Paired biopsies obtained at diagnosis were scored by a pathologist and analyzed by IHC and RNAseq. RNAseq was also performed on purified circulatory neutrophil at diagnosis and their phenotype was analyzed by whole-blood flow cytometry.

Results
At diagnosis, high numbers of infiltrating neutrophils in intestinal tissue differentiated IBD patients with high clinical disease activity, more severe endoscopic and histological disease and high plasma concentrations of IL-17. RNA sequencing of lesional intestinal biopsies revealed differential expression of genes linked to neutrophil degranulation and IL-17 signaling in the colon of IBD patients with high neutrophil infiltration. Moreover, these biopsies had high mRNA expression for Oncostatin M, a neutrophil product known to associate with therapy resistance.
To assess whether circulating neutrophils were altered in IBD before entering the intestinal tissue, we performed bulk RNAseq analysis of purified circulating neutrophils from non-IBD and CD patients. Neutrophils from CD patients had increased expression of genes related to granule formation and filling (MMP9, S100A8, S100A9) and pathogen sensing (TLR5, NLRC4) but not cytokine production (IL1B, OSM), relative to non-IBD patients. Expression of CD10 was decreased in circulating neutrophils from UC and CD patients while CD16 expression was lower in UC-derived neutrophils, suggesting these cells have a more immature state.

Conclusion
We have detected changes in the maturity of neutrophils in the circulation of some IBD patients that could have functional consequences in terms of bacterial clearance and tissue damage in the intestinal mucosa. Uncovering different functional profiles in neutrophils may help dissect patient heterogeneity and provide novel targets for therapy.
P041 Assessment of Serum Biomarkers associated with Vedolizumab Therapy Response in Inflammatory Bowel Disease
Authors: O'Connell J , Argue R , Dunne M , O'Connell F , Breslin N , Cullen G , Doherty G , Dunne C , Hartery K , Ismail M S , MacCarthy F , McDonagh P , McKiernan S , McNamara D , Mulcahy H , O'Connor A , Ryan B , Sheridan J , O'Sullivan J , Kevans D 
Published: January 2024

Abstract

Background
Vedolizumab (VDZ) is an anti α4β7-integrin inflammatory bowel disease (IBD) therapy postulated to reduce immune cell trafficking to the intestine. A significant proportion of patients fail to respond to VDZ. We aimed to assess the effect of VDZ on a panel serum inflammatory proteins (IPs) during induction therapy for IBD with the aim of identifying a serum biomarker of VDZ therapy response. We also aimed to gain further insights in VDZ mechanism of action by evaluating changes in serum IP concentrations during induction.

Methods
Patients commencing VDZ for IBD were prospectively recruited. All received standard VDZ induction. Baseline and week 6 serum concentrations of 54 IPs were measured by ELISA (Meso Scale Discovery, USA). Clinical outcomes were evaluated at weeks 14 and 30 of VDZ therapy. Corticosteroid-free remission (SFR) was defined as persistence of VDZ therapy, absence of corticosteroid therapy, a partial Mayo score ≤1 Ulcerative Colitis (UC) or HBI &lt;5 Crohn’s Disease (CD). The associations between baseline serum IP concentrations and VDZ therapy outcome at weeks 14 and 30 were evaluated. Changes in IP concentrations from week 0 to week 6 of VDZ therapy were assessed. P values &lt;0.05 following multiple test correction were considered significant in all analyses.

Results
Thirty-nine patients were included: 51% male, 51% UC, median [range]: age 52 [18.2-75.8] years; disease duration 13.4 [0.4–40.8] years; clinical Mayo subscore 4 [0–9]; and HBI 7 [1–20]. 28(72%) had received prior anti-TNF therapy. In univariate analysis, at higher baseline serum TNF-β concentration and lower IL-22, VEGF-C, and IL-7 concentrations were associated with week 14 SFR, p values p=0.003, 0.034, 0.042, and 0.045 respectively. Higher baseline serum IL-4, MDC and MCP-4 concentrations and lower baseline IL-10 concentration were associated with week 30 SFR, p=0.011, 0.026, 0.028 and 0.03 respectively. Significance was not maintained after correction for multiple testing. From baseline to week 6 post VDZ initiation, significant increases were observed in the concentration of six IPs: bFGF, eotaxin, eotaxin-3, MIP-1β, TARC and TNF-β, p=0.034, 0.0012, 0.0013, 0.043, 0.015 and 0.0077 respectively; and a significant decrease in one IP, IL-15, p=0.0004. The significant changes observed in IL-15, eotaxin, and eotaxin-3 concentrations from baseline to week 6 following VDZ initiation remained significant after multiple test correction.

Conclusion
No serum inflammatory protein was identified as a biomarker of SFR in patients receiving VDZ therapy for IBD. VDZ was observed to significantly affect serum IPs known to be involved in chemotaxis. Further study is required to identify biomarkers of VDZ therapy response.
P052 Mucosal IgG-like naive B-cell expansion and maturation contribute to ulcerative colitis pathogenesis
Authors: Fung I , Koelink P J , Li Yim A Y F , Mulders L G M , Admiraal I , Verseijden C , Verhoeff J , Patel A , Wildenberg M E , Luo Y , D’Haens G R , de Jonge W J 
Published: January 2024

Abstract

Background
A higher abundance of colonic naive B-cells and IgG plasma cells is implicated in the pathogenesis of ulcerative colitis (UC) during active inflammatory episodes. However, B-cell inhibition by targeting CD20 was found to be ineffective in achieving remission in UC patients indicating that the causal role of the B-cell expansion in UC is not well understood. In this study, we performed single cell RNA-sequencing (scRNA-seq) on mucosal tissue where we interrogated the B-cells in inflamed and non-inflamed UC colon biopsies. We subsequently explored the pathogenic role of B-cells in colitis mouse models.

Methods
We collected biopsies from the colon of 5 UC patients with active inflammation and 5 UC patients showing no inflamed mucosa. Three mucosal biopsies were collected from the same colon location for each patient and processed for scRNA-seq. We acquired usable transcriptomes of 21.475 cells. In a T-cell transfer colitis mice model, we evaluated the effects of the co-transfer of naive B-cells. Both CD4+ T and naive B-cells were transferred into SCID mice through intraperitoneal injection in ratios of 2:1, 1:1 and 1:2 (T:B ratio). The colitis course was followed for 35 days.

Results
Differential abundance analysis relative to all immune cells confirmed a higher abundance of naive B-cells (p= 0.03) and IgG plasma B-cells (p= 0.002) in inflamed relative to non-inflamed UC patient tissue, whereas no differences in abundance of transitional B-cells and memory B-cells were found. Pseudo-time analysis indicated a higher rate of maturation in the naive B-cells in inflamed tissue. This was evidenced by higher expression of IGHG1 (p= 0.025) and IGHG3 (p&lt; 0.001) in naive B-cells in inflamed tissue. In a T-cell transfer model, we co-transferred naive B-cells to the CD4+ T-cell pool into SCID mice in various ratios (2:1, 1:1 and 1:2 T to B-cells respectively) and T-cell only control. Significant increase in disease severity was observed in a 1:2 T:B ratio based on body weight loss, increase of colon density, mouse colitis histology index and histological changes by disrupted mucosa. This observation was associated to significant elevated IgG concentration in serum and colon and B-cell presence in colon through immunohistochemistry.

Conclusion
We observed significantly higher abundance of naive B-cells and IgG plasma cells in inflamed relative to non-inflamed UC colon tissue, where naive B-cells were shown to be more mature and IgG-like in inflamed condition. Notably, transferring increased ratio of naive B-cells resulted in elevated disease severity in a colitis model, demonstrating its pathogenic role. Our findings suggest that specific targeting of the IgG-like naive B-cell may be beneficial for UC patients.
P066 Serum amyloid A – A Novel Biomarker of Ulcerative Colitis Disease Activity
Authors: McShane C , O'Connell F , Corcoran R , Buckley C , Lynam-Lennon N , Kevans D , O'Sullivan J 
Published: January 2024

Abstract

Background
Despite recent advancements in the treatment of ulcerative colitis (UC), a substantial number of patients fail to achieve long-term remission. Persistent histological activity has been linked with poorer treatment outcomes. Histological remission is now an accepted treatment target; however there remains significant variability in the interpretation of UC histology. As such, there is a need for novel biomarker identification to aid assessment and ultimately predict disease relapse. Serum amyloid A (SAA) is an acute-phase protein, of which serum levels have shown promise as a biomarker in IBD1. This study aims to explore the utility of SAA levels in UC colonic tissue as a diagnostic biomarker for disease activity and progression.

Methods
Two cohorts were prospectively recruited, including healthy controls and UC patients. Sigmoid biopsies were collected and tissue explants generated. Tissue-conditioned media from these explants was collected and secreted SAA quantified using 54 V-plex ELISA. Demographic information, disease characteristics, endoscopic Mayo scores and disease progression were documented. Endoscopic remission was defined as a Mayo endoscopic sub-score ≤1. Disease progression was defined as the requirement for corticosteroid therapy, UC-related hospitalisation, UC-related surgery or the introduction of a new immunomodulatory agent in follow-up period. P values &lt;0.05 were considered significant in analyses.

Results
The two cohorts included 11 healthy controls and 16 UC patients (endoscopic remission n=6). Active UC patients demonstrated significantly higher SAA concentrations than healthy controls (p=0.0013) and those in endoscopic remission (p=0.02). There was no significant difference in SAA concentrations between healthy controls and UC patients in remission (p=NS). UC patients in the lowest SAA concentration quartile had a significantly longer time to disease progression (p=0.0462) (Figure 1).

Conclusion
Quantification of SAA secretion in IBD ex-plants has potential as a biomarker of UC activity and progression. Further investigation of SAA as a biomarker in IBD is warranted.

References
1. Chen R, Chen Q, Zheng J, Zeng Z, Chen M, Li L, et al. Serum amyloid protein A in inflammatory bowel disease: from bench to bedside. Cell Death Discov. 2023;9(1):154.