bluuebunny/crossref_metadata_2025 huggingface dataset:
OP34 Whole blood profiling of T-cell-derived miRNA allows the development of prognostic models in inflammatory bowel disease
Authors: Kalla R , Adams A , White R , Clarke C , Ivens A , Ventham N , Kennedy N , McTaggart S ,   I. IBD Character Consortium, Ho G T , Buck A , Satsangi J
Published: January 2020

Background

There is an unmet need for blood-based biomarkers that help predict disease and its course at inception to allow tailoring of treatments, achieve early mucosal healing and improve clinical outcomes. In our study, we explore the clinical utility of miRNAs in Inflammatory bowel disease (IBD).

Methods

A 2-stage prospective multi-centre case–control study was performed. Small RNA sequencing was performed on a discovery cohort of immunomagnetically separated leucocytes (90 CD4+ and CD8+ T-lymphocytes and CD14+ monocytes) from 32 patients (9 CD, 14 UC, 8 healthy controls) to identify differentially expressed cell-specific miRNAs.Top miRNAs were then validated in whole blood in 294 treatment naïve newly diagnosed IBD and non-IBD patients (97 UC, 98 CD, 98 non-IBD) using RT-qPCR, recruited across 5 centres in UK and Europe. Phenotype and outcome data were collected and Cox proportional hazards were derived to assess the contribution of each miRNA to outcomes; defined as the need for 2 or more immunosuppressants and/or surgery after initial disease remission. RT-qPCR target miRNA relative quantification was calculated using 2−ΔΔCq method.

Results

Each leucocyte subset (30 CD4+ T cells, 28 CD8+ T cells and 32 CD14+ monocytes) was analysed between disease and controls, adjusting for age, gender and batch effects. A total of three miRNAs differentiated IBD from controls in CD4+ T cells including miR-1307-3p (FDR p = 0.01), miR-3615 (p = 0.02) and miR-4792 (p = 0.01); these signals being UC specific. In CD8 T cells, miR-200b-3p was the only differentially expressed miRNA and no CD14+ signals were seen.Three miRNAs were validated in whole blood in an independent multi-centre cohort of 294 patients using RT-qPCR. miR-1307-3p predicted IBD (1.55 fold change (fc),IQR: 1.00–1.87; p = 2.77 × 10–5),in particular UC (1.69 fc, IQR: 1.01–2.00; p = 1.56 × 10–6). Similarly, miR-3615 and miR-4792 were up-regulated in UC compared with controls (1.21fc, IQR:0.91–1.48; p = 8.26 × 10−4and 1.91 fc, IQR: 0.81–2.56; p = 9.21 × 10–3, respectively).There was no correlation with conventional inflammatory markers. Follow-up data were available on 195 IBD patients of which 80 patients required treatment escalation over a median time of 371 days (IQR: 140–711). miR-1307-3p was able to predict disease course in IBD (HR 1.98, IQR: 1.20–3.27; log-rank p = 1.80 × 10−3), in particular CD (HR 2.81; IQR: 1.11–3.53, p = 6.50 × 10–4). In UC, both miR-3615 (HR 3.34, CI: 1.43–7.78, p = 0.01) and miR-4792 (HR 3.96, CI: 1.65–9.52; p = 2.11 × 10–3) predicted treatment escalation.

Conclusion

We have identified unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These blood-based miRNAs are able to predict treatment escalation at disease inception and have the potential for clinical translation.
OP40 A core transferable microbiota in responders to faecal microbiota transplant for ulcerative colitis shape mucosal T-cell immunity
Authors: Gogokhia L , Lima S , Viladomiu M , Gerardin Y , Crawford C , Jacob V , Scherl E , Rosenthal M , Brown S E , Hambor J , LONGMAN R
Published: January 2020

Background

Biologic therapy has significantly improved treatment for UC, but nearly two-thirds of patients attenuate the response. Additional therapeutic modalities are therefore needed to address the underlying pathophysiology of UC. Faecal microbiota transplant (FMT) is an emerging therapy for the treatment of UC, but several randomised controlled trials have shown variable efficacy of FMT, and the microbial mechanisms responsible for clinical response are not well understood. Therefore, using samples from our pilot FMT study (Jacob, V, et al. Inflamm. Bowel Dis. 2017), we aim to identify the core transferable microbiota (CTM) in UC patients responsive to FMT therapy and to define the therapeutic mechanism of these strains in pre-clinical models.

Methods

IBD disease activity scores were used to define a clinical response. Metagenomic sequencing of a donor, recipient, and 4-week post-FMT faecal samples was performed to define the CTM. Strain-level transferability was defined using the StrainFinder algorithm. To define the transferable immune-reactive microbiota (TIM), IgA-seq was performed on a donor, recipient, and 4-week post-FMT faecal samples. TIM strains were isolated from faecal samples and gnotobiotic mouse models were used to evaluate their impact on mucosal immunity and mouse models of colitis.

Results

Here, we defined a CTM associated with clinical response to FMT for UC. Strain-level tracking of the CTM confirmed that clinical response correlated with strain transferability. In addition, we defined a core TIM by IgA-seq that correlated with clinical response. In humanised mouse models, these TIM were found to induce IgA in a T-cell independent manner. Colonisation of germ-free mice with a core TIM strain of Odoribacter induced IL-10-dependent, RORgt+/Foxp3+ iTreg cells and reduced the severity of transfer T-cell colitis in mono-colonised RAG−/− mice.

Conclusion

Our data highlight an immune-reactive, core transferable microbiota in responders to FMT for UC. Using pre-clinical mouse models of colitis, we define the mechanistic impact of these TIM in shaping mucosal immunity and guiding the response to UC. This work provides a framework for the rational selection of TIM for microbial-therapy in IBD.
DOP11 Normalisation of faecal calprotectin within 12 months of diagnosis is associated with a reduced risk of disease progression in Crohn’s disease
Authors: Plevris N , Fulforth J , Jenkinson P , Lyons M , Chuah C , Siakavellas S , Pattenden R , Arnott I , Jones G , Lees C
Published: January 2020

Background

Faecal calprotectin (FC) demonstrates an excellent correlation with endoscopic inflammation. In addition, a treatment-decision algorithm for Crohn’s disease (CD) incorporating FC outperforms and improves 12-month mucosal healing compared with a strategy based on symptoms alone. The aim of this study was to determine whether normalisation of FC (<250 μg/g) within 12-months of diagnosis is associated with a reduction in disease progression in CD.

Methods

This was a retrospective cohort study performed at a tertiary IBD centre. All incident cases of CD diagnosed between 2005 and 2017 were identified. Patients with an FC measurement of >250 μg/g at diagnosis who also had at least 1 follow-up FC measured within the first 12-months of diagnosis and >12 months of follow-up were included. The primary endpoint was a composite of progression in Montreal disease behaviour (B1 to B2/3 or B2 to B3 or new perianal disease), surgery or hospitalisation.

Results

A total of 375 patients were included with a median follow-up of 5.3 years (IQR 3.1–7.4). Normalisation of FC (<250 μg/g) within 12 months of diagnosis was confirmed in 43.5% (n = 163/375) of the cohort. On multivariable Cox-proportional hazards regression analysis, individuals who normalised their FC within 12 months of diagnosis had a significantly lower risk of composite disease progression (HR 0.351, 95% CI 0.235–0.523, p < 0.001) (Figure 1). Cumulative rates of composite disease progression were 7.8%, 21.4% and 29.9% in those that normalised their FC vs. 22.8%, 50.7% and 60.5% in those that did not at 2, 5 and 7 years after diagnosis, respectively. In addition, normalisation of FC was the only predictor that remained significant for all the separate progression end-points (progression in Montreal behaviour / new perianal disease: HR 0.250, 95% CI 0.122–0.512, p < 0.001; hospitalisation: HR 0.346, 95% CI 0.217–0.553, p < 0.001; surgery: HR 0.370. 95% CI 0.181–0.755, p = 0.006). The strongest predictor of whether an individual normalised their FC within 12 months was the commencement of a biologic within 3 months of diagnosis (OR 4.288, 95% CI 1.585–11.0601, p = 0.004).

Conclusion

Normalisation of FC by 12-months of diagnosis is associated with a reduced risk of disease progression in CD. Our data provide strong support for implementation of treat-to-target strategies earlier than previously tested in Crohn’s disease. The immediate implication for healthcare providers and patients is that by ensuring resolution of mucosal inflammation - measured by proxy with faecal calprotectin, and regardless of other variables - within 1 year of diagnosis has a dramatic effect on disease course.
DOP15 Transmural healing with vedolizumab in patients with active Crohn’s disease
Authors: Rimola J , Colombel J F , Bressler B , Adsul S , Siegelman J , Cole P E , Lindner D , Danese S
Published: January 2020

Background

VERSIFY, an open-label phase 3b study of vedolizumab (NCT02425111; EudraCT 2014-003509-13), demonstrated endoscopic mucosal healing in patients with Crohn’s disease (CD).1 An exploratory analysis of a subset of these patients who underwent magnetic resonance enterography (MREn) also demonstrated healing.1 Further exploratory analysis of MREn imaging features of transmurality in patients treated with vedolizumab is reported herein.

Methods

In VERSIFY, patients treated with intravenous vedolizumab (300 mg) on Day 1, Weeks 2 and 6, and then every 8 weeks for 26 or 52 weeks were imaged at screening, Week 26, and Week 52, with images assessed centrally.1 All patients with disease detectable by MREn at screening (≥1 ileocolonic segment with a segmental magnetic resonance index of activity [MaRIA] score ≥7) who completed 26 or 52 weeks of treatment and had evaluable segments at all MREn timepoints were included in this analysis. Ileocolonic segments with a MaRIA score ≥7 at baseline were evaluated for improvement of oedema and bowel wall thickness. Further exploratory assessment of mesenteric fluid and lymph nodes are ongoing.

Results

Week 26 analyses included 27 patients with a total of 83 ileocolonic segments; Week 52 analyses included 13 patients with a total of 38 segments. Week 26 and Week 52 patient populations had baseline mean (standard deviation [SD]) simplified endoscopic activity scores for CD (SES-CD) of 15.7 (7.7) and 16.5 (7.8) and Crohn’s disease activity index (CDAI) scores of 301 (61) and 297 (79), respectively. The proportion of segments with oedema or wall thickness >3 mm decreased from baseline to Week 26 and to Week 52 (Figure 1). All segments evaluated had wall thickness >3 mm at baseline. The proportion of patients with oedema or wall thickness >3 mm in ≥1 evaluated segment decreased from baseline to Week 26 and/or Week 52 (Figure 2). In the Week 26 population, 2/27 (7.4%) patients had no oedema with wall thickness <3 mm at Week 26 in segments that had MaRIA ≥7 at baseline. In the Week 52 population, 1/13 (7.7%) patients at Week 26 and 3/13 (23.1%) at Week 52 had no oedema with wall thickness <3 mm in segments that had MaRIA ≥7 at baseline.

Conclusion

Vedolizumab treatment of patients with CD reduced the number of ileocolonic segments with transmural inflammation (oedema, wall thickness >3 mm) as detected by MREn and the overall number of patients with transmural inflammation from baseline at treatment Weeks 26 and 52. This exploratory analysis contributes to the understanding of transmural disease processes in CD and the impact of vedolizumab on components of transmural inflammation in CD.

Reference
DOP17 Identification of biomarkers and mechanistic insight for upadacitinib in ulcerative colitis: Analysis of serum inflammatory mediators in the phase 2b U-ACHIEVE study
Authors: Vermeire S , Guay H , Verstockt B , Fann J , Cheng J , Hong F , Lee W J , Lacerda A , Zhou W , Danese S
Published: January 2020

Background

The U-ACHIEVE trial evaluated upadacitinib (UPA), an oral JAK1 selective inhibitor, in patients with moderately to severely active ulcerative colitis (UC). Patient-reported and endoscopic outcomes improved after UPA treatment. This analysis used pharmacodynamic profiling to link changes in serum biomarkers to changes in UC disease activity, and to assess the UPA mechanism of action in UC.

Methods

U-ACHIEVE (NCT02819635) was a randomised, double-blind, placebo (PBO)-controlled phase 2b clinical trial. Adults with an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, or biologic therapies were randomised to receive 7.5, 15, 30, or 45 mg UPA once daily or PBO for 8 weeks (weeks). Serum samples (baseline [BL], weeks 2, 4, and 8) were analysed by OLINK® inflammation panel (92 proteins) and by Singulex immunoassay for interleukin-1b (IL-1b), IL-17A, IL-17F, and IL-22. Protein-level changes were analysed by a mixed-effect model; BL protein level was adjusted as a covariate; treatment group, time point, and their interaction were included as fixed effects. Spearman rank-correlation coefficients were used to determine the relationship between changes of serum biomarker levels and improvements in adapted Mayo scores and endoscopic subscores. Multiplicity adjusted P values were calculated using 1000 runs of random permutations.

Results

Paired BL and week 8 serum samples were available from 114 patients (PBO, n = 17; UPA 7.5 mg, n = 21; UPA 15 mg, n = 21; UPA 30 mg, n = 29; UPA 45 mg, n = 26). UPA treatment reduced expression of pro-inflammatory mediators associated with immune cell migration, type I/II IFN responses, T-cell responses, macrophage and dendritic cell activity and increased expression of biomarkers associated with haematopoiesis, neuroprotection and mucosal repair in a dose-dependent manner. Improvements in adapted Mayo score, endoscopic subscore, and stool frequency correlated with increases in CX3CL1, DNER and FLt3L (p < 0.05 for all). Endoscopic improvements correlated with reductions in OSM, and improvements in fatigue correlated with increases in CCL25 and NT-3. There was a substantial overlap in biomarkers modulated by UPA in patients with UC and Crohn’s disease (Figure).

Conclusion

UPA modulated expression of serum pro-inflammatory mediators found in pathways associated with the pathogenesis of UC, including immune cell migration, type I/II IFN responses, T-cell responses, macrophage and dendritic cell activity, haematopoiesis, neuroprotection, and mucosal repair. Consistent correlations were observed between changes in biomarker expression and improvements in disease activity and symptoms of UC.
DOP19 Real-world healthcare resource utilisation among patients with inflammatory bowel disease administered vedolizumab for 6 months
Authors: Cohen B , Chang H , Jason Rogers J R , Garg S , Lawrence D , Fasihuddin F , Lissoos T , Atreja A
Published: January 2020

Background

Inflammatory bowel disease (IBD) is associated with high healthcare resource utilisation. Vedolizumab (VDZ) is a gut-selective monoclonal antibody that binds the α4β7 integrin and is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD). We investigated real-world healthcare resource utilisation for these patients in the 6 months after initiating VDZ treatment.

Methods

This retrospective, non-interventional, cohort study examined healthcare resource utilisation for adults with IBD treated with VDZ at Mt Sinai Medical Center (New York, NY) between June 1, 2014, and May 31, 2019. IBD-related healthcare resource utilisation (emergency room [ER] visits, hospitalisations, procedures, corticosteroids) and VDZ treatment patterns (induction, persistence, adherence) were assessed for 6 months after first VDZ infusion. Discontinuation was defined as a ≥90-day gap between infusions or stopping VDZ treatment <6 months after the first infusion. Patients who had ≥90-day gaps were not counted as discontinuing if they experienced clinical benefit that continued beyond the 6-month period.

Results

880 patients treated with VDZ were assessed. Mean age was 39.6 years; 51.6% of patients were female. 369 (41.9%) and 504 (57.3%) patients were diagnosed with CD and UC, respectively. 81.4% of patients received 3 VDZ induction doses by Day 98; 69.0% received 4 doses by Day 120. The rates of ER visits, hospitalisations and elective surgical or urgent hospitalisations and procedures among VDZ-treated patients were <1 per 100 pt–months. Steroids (oral or IV) were prescribed to 42.2% of patients during the 6-month period. In the 2 months after their last infusion, 81.6% of patients who received ≥3 VDZ doses were steroid-free. Timing of the last infusion was variable. Overall VDZ persistence was 68.0% (65.0% and 70.2% for CD and UC, respectively; Figure). Most patients (67.2%) had ≥80% of days covered in a 180-day period

Conclusion

At a tertiary IBD centre, VDZ was associated with low healthcare resource utilisation during the first 6 months of treatment. More than two-thirds of patients persisted with treatment, with most being steroid-free at last follow-up.
DOP25 Medication use and comorbidities among elderly when compared with younger patients with inflammatory bowel disease in the TARGET-IBD cohort
Authors: Barnes E , Hanson J , Regueiro M , Saha S , Sands B E , Rubin D , Dubinsky M , Siegel C , Gazis D , Crawford J , Long M
Published: January 2020

Background

When compared with younger patients, much less is known regarding inflammatory bowel disease (IBD)-related medications in the elderly (>65 years) patients. This analysis uses a large cohort of patients with IBD to describe the distribution of patient characteristics and patterns of medication use.

Methods

TARGET-IBD is a longitudinal cohort of patients with IBD receiving usual care at community and academic practices in the US. Patients with IBD enrolled between July 2017 and May 2019 were included in this analysis. The prevalence of medication use by drug class at the time of enrolment among patients with both ulcerative colitis (UC) and Crohn’s disease (CD) was estimated. Age was stratified into the following categories: <30, 30–49, 50–65 and >65 years. Proportions and means of patient characteristics were compared using tests of association. The odds of biologic use at enrolment was modelled as was the 95% CI by patient characteristics using logistics regression.

Results

681 patients with UC and 979 patients with CD were included in the analysis. At enrolment, mesalamine was the most common medication used among patients with CD >65 years (34%) and among patients with UC across all age categories (58%–77%, Table 1). The use of mesalamine generally increased with advancing age. Patients with CD >65 years were more than twice as likely to be users of mesalamine at enrolment than patients <30 years (p < 0.0001). Among patients with either disease type, anti-tumour necrosis factor α (anti-TNF) use decreased in patients >65 years compared with patients <30 years. Thiopurine use did not vary across age categories. Among patients >65 at enrolment, use of a 5-ASA derivative, anti-TNF, steroid, or thiopurine did not differ by established and newly diagnosed patients. There was no association between age, type of IBD, insurance, gender, race or cardiovascular disease and the odds of biologic use in patients >65 years (Figure 1).

Conclusion

Elderly patients with IBD, whether those with new diagnoses or individuals with the longstanding disease make up a substantial portion of the IBD population. Given that elderly patients demonstrate significant differences in medication use patterns compared with younger patients with IBD, studies of efficacy and adverse events specific to this population are warranted.
DOP34 Transplantation of human intestine into the mouse: A novel platform for study of inflammatory enterocutaneous fistulas
Authors: Bruckner R S , Nissim-Eliraz E , Marsiano N , Nir E , Shemesh H , Leutenegger M , Gottier C , Lang S , Spalinger M R , Leibl S , Rogler G , Yagel S , Scharl M , Shpigel N Y
Published: January 2020

Background

In Crohn’s disease patients, enteric and perianal fistulas represent a severe and medically challenging comorbidity that affects a broad number of patients. Enteric fistulas do not develop in animal models of colitis what prevents in vivo experiments so far. Based on our preliminary data, we proposed transplantation of the human foetal gut into mice as a novel platform for studying inflammatory enterocutaneous fistulas.

Methods

Human foetal gut segments were transplanted subcutaneously into mature SCID mice, where they grew and fully developed over the course of several months. We first analysed the resident immune cells and inflammatory response elicited by systemic lipopolysaccharide in normal, fully developed human gut xenografts. Thereafter, we used immunostaining to analyse fully developed xenografts that spontaneously developed entero-cutaneous fistulas.

Results

We found a broad number of resident human innate and adaptive immune cells in gut xenografts during steady-state and inflammation. The expression of human IL-8, IL-1β, IL-6, TNF-α, A20, and IkBα was significantly elevated in response to LPS, with no change in IL-10 gene expression. Approximately 17% [19/110] of fully developed subcutaneous human gut xenografts spontaneously developed enterocutaneous fistulas, revealing striking histopathological similarities with CD fistula specimens. Immunohistochemical analyses of fistulating xenografts revealed transmural lymphocytic enteritis associated with a massive expansion of resident human CD4+ lymphocytes and their migration into the intraepithelial compartment. Regionally, mucosal epithelial cells assumed spindle-shaped mesenchymal morphology and formed fistulous tracts towards chronic non-healing wounds in the host mouse skin overlying the transplants.

Conclusions

Inflammation and fistulas developed in human gut xenografts lacking IL-10 gene response. This novel model system will enable systematic studies of the inflamed and fistulating human gut in live animals.
DOP40 Does levels of concerns and expectations predict IBD disease status?
Authors: Pittet V
Published: January 2020

Background

Patient-reported disease perceptions may influence disease management thus health outcomes. Previous studies showed that concerns and expectations are numerous in IBD patients. Such perceptions may be indicative of overall well-being, thus of individual quality of life. We aimed at assessing if quality of life and its perceptions may predict clinical disease status in IBD patients.

Methods

We conducted a cross-sectional study on adult patients included in the Swiss IBD cohort study (SIBDCS). We sent patients a questionnaire on concerns and expectations, including a question on frequency and severity of their symptoms. We retrieved data on demographics, clinical parameters, treatments, and psychosomatics data from the SIBDCS databases. We built a binary outcome for disease status (clinical remission / active disease). Predictors associated with disease status were assessed through a series of classification models (K-nearest neighbours (KNN), decision trees, random forest and logistic regression). ROC curves were used to compare models predictive performance. We used a confusion matrix to visualise classification results.

Results

A total of 1102 patients were included in the study (54% CD, 54% women, mean age: 48 years, disease duration: 15.7 years). Among those patients, 623 were classified as being in clinical remission and 479 in active disease. We used 771 cases for training and constructing models, and the remaining 331 cases to test the respective models. The KNN model with selected variables showed the best prediction accuracy (precision/recall of 0.72/0.76 for remission and 0.67/0.65 for active disease), Figure 1 and Figure 2. Selected variables that contributed the most to the model performance were the following: age, hematocrit level, SF-36 overall mental and physical quality of life (QoL), IBD-specific QoL, coping based on distraction, disease and treatments concerns and expectations, and the absence of abdominal pain.

Conclusion

Prediction accuracy of the model was good to moderate. We found the variables that were important to predict our outcome were highly related to quality of life or perception of quality of life (concerns and expectations).
DOP49 Quantitative proteomics analysis of macrophages from Crohn’s disease patients and infected with adherent-invasive Escherichia coli
Authors: Douadi C , Vazeille E , Chambon C , Hébraud M , Dodel M , Pereira B , Coban D , Buisson A , Barnich N
Published: January 2020

Background

Crohn’s disease (CD) is a disabling inflammatory bowel disease. Currently, the available treatments only alleviate the symptoms. The anti-TNFα represent the most efficient therapeutic class, but its mechanisms are poorly known. Experimental data have highlighted the role of intestinal macrophages in the pathogenesis of CD. These macrophages present a defect in the control of CD-associated adherent-invasive E. coli (AIEC) replication, which is linked to altered autophagy. The main aim of this study was to compare the proteomic profile of macrophages from CD patients with and without anti-TNFα treatment, to those from ulcerative colitis (UC) patients or healthy subjects, both at the basal state and after AIEC infection.

Methods

Peripheral blood monocyte-derived macrophages (MDM) were obtained from 44 CD patients including 22 with and 22 without anti-TNFα treatment, 22 UC patients and 22 healthy subjects. MDM was infected or not with AIEC LF82 reference strain. The numbers of intracellular bacteria were determined at 1h and 6h post-infection, using gentamicin protection assay. The ‘bottom-up’ proteomic analysis of macrophages after 6h of AIEC LF82 infection or not, was assessed by a mass spectrometer, using the label-free quantification.

Results

AIEC survival was reduced within MDM from CD patients with anti-TNFα treatment compared with those from CD without TNFα treatment (p = 0.0235). The proteomic analysis identified 1359 proteins, of which, 71 were differentially expressed between MDM at the basal state and infected by AIEC LF82 whatever the origin, 30 proteins were specific in CD patients with anti-TNFα treatment and 16 in CD patients without anti-TNFα treatment (fold change >1.3). The bioinformatics analysis shows an impact of several pathways involved in cellular activation, immune process and lysosomal activity. Interestingly, CD macrophages expression levels of β3 integrin (ITGB3), glutathione peroxidase-1 (GPx-1) and peroxiredoxin 3 (PRDX3) are significantly correlated with AIEC survival at 6h post-infection and faecal calprotectin. The stratification of MDM from CD patients according to the level of faecal calprotectin highlighted that levels of calprotectin and α-L-Fucosidase 1 (FUCA-1) increased in a similar way, both at the basal state and after AIEC LF82 infection.

Conclusion

Our study highlighted that the anti-TNFα treatment limits bacteria replication and acts on macrophages function. For the first time, global proteomic analysis suggests that CD macrophages-AIEC interaction could be orchestrated by ITGB3, GPx-1, PRDX3 and FUCA-1. These proteins could represent potential therapeutic targets in CD patients that need to be further investigated.
DOP52 The phenotype of NOD-scid IL-2Rγnull mice reconstituted with peripheral blood mononuclear cells from patients with Crohn’s disease or ulcerative colitis reflects the respective disease
Authors: Unterweger A , Caesar J , Winkelmann P , Rüscher A , Seuß M , Breiteneicher S , Stallhofer J , Beigel F , Siebeck M , Gropp R
Published: January 2020

Background

Recently, we have developed a mouse model that relies on NOD-scid IL-2Rγnull (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMC) derived from patients with ulcerative colitis (UC, NSG-UC). In this model, symptoms of UC are induced by rectal challenge with ethanol. The objective of the study was to adapt this model to Crohn’s disease and to compare the phenotypes of the NSG-UC and NSG-CD mouse models.

Methods

NSG mice were reconstituted with PBMC from UC (n = 4) or CD (n = 3) patients. Mice were separated into two groups: unchallenged control and ethanol challenged mice. Readout were clinical-, colon and histological scores, analysis of frequencies of subgroups of human T cells, monocytes and B cells isolated from spleen and colon by flow cytometry, and the expression levels of the inflammatory markers TGFß, CRP, MCP-3, and IL-6 in the colon or serum by Luminex analysis.

Results

The pathological phenotype was markedly different in NSG-UC mice as compared with NSG-CD mice. Firstly, histological analysis revealed that NSG-UC mice exhibited more of a pro-inflammatory phenotype as indicated by a severe influx of inflammatory cells, oedema, crypt loss, crypt abscesses and epithelial hyperplasia. In contrast, NSG-CD mice displayed crypt loss and goblet cell atrophy and pronounced fibrosis indicating ongoing wound healing processes.

These observations were corroborated by frequencies of splenic and colonic leucocytes. Antigen experienced CD4+ T (CD45RO+) cells and switched B cells (CD19+ CD27+ IgD-) were significantly increased in NSG-UC mice, whereas significantly higher levels of experienced CD8+ T cells and M1 (CD64+), M2 (CD163+) CD14+ monocytes and unswitched B cells (CD19+ CD27+ IgD+) indicated a monocyte driven inflammation in NSG-CD mice.

This observation was also reflected in the colon of mice. Inflammation in UC was characterised by increased frequencies of neutrophils, activated CD4+ T cells (CD69+) and increased levels of CRP and MCP-3, whereas NSG-CD mice were signified by increased frequencies of M2 and M1 monocytes and of TGFß levels. In contrast to NSG-CD mice, NSG-UC mice also displayed higher serum levels of IL-6. Secondly, the impact of ethanol was more pronounced in the NSG-UC mice. In NSG-CD mice, the challenge did not evoke significant differences as compared with unchallenged control mice.

Conclusion

The comparison of pathological phenotypes of the NSG-UC and NSG-CD mouse models revealed differences, some of which reflect the respective human disease. The NSG-UC and NSG-CD mouse models may constitute powerful tools to get a better understanding of the different inflammatory processes in UC and CD.
DOP53 PTPN2 and TiO2 in the pathogenesis of inflammatory bowel disease
Authors: Conde J , Schwarzfischer M , Katkeviciute E , Häfliger J , Niechcial A , Brillant N , Atrott K , Bäbler K , Scharl M
Published: January 2020

Background

Inflammatory bowel disease (IBD) is caused by a complex interaction among genetic, immunological, bacterial and environmental factors. In this scenario, protein tyrosine phosphatase non-receptor type-2 (PTPN2) has been recognised as a risk factor for the development of IBD and functional studies revealed a major role for this protein in the development of experimental colitis through the regulation of the inflammasome, among other processes. In the same way, a potential relationship between diet components and IBD was suggested. In fact, it was reported that the food additive titanium dioxide (TiO2) was able to induce inflammasome activation in vitro and increase colitis severity in vivo. These observations led us to hypothesise a putative relationship between PTPN2 and TiO2 that could explain the effects of this microparticle in the pathogenesis of bowel inflammation.

Methods

DSS colitis model was performed in mice lacking PTPN2 in myeloid cells and their wild-type littermates, treated or not with titanium dioxide. After that, histology studies, flow cytometry, expression analysis, ELISA and barrier function experiments were performed. Also, bone marrow-derived macrophages (BMDMs) were used for in vitro studies.

Results

Titanium dioxide was able to exacerbate DSS-induced colitis, especially in mice lacking PTPN2 in myeloid cells. Flow cytometry analysis of the lamina propria revealed significant changes in different immune cell populations such as macrophages. In vitro experiments using BMDMs revealed that TiO2 induced the activation of the inflammasome. Also, this microparticle down-regulated the expression of the anti-inflammatory cytokine IL-10 and these effects were mainly mediated by JNK and ERK kinases.

Conclusions

The food additive titanium dioxide seems to play a negative role in colitis development by affecting the production of pro- and anti-inflammatory mediators in macrophages. This study reveals a new mechanism by which a certain component of the diet modulates intestinal inflammation.
N18 Facilitating involvement of patients from ethnic minority groups in research: experiences of offering patients a choice of interviewer
Authors: MUKHERJEE S , Beresford B
Published: January 2020

Background

Recruitment of inflammatory bowel disease (IBD) patients from an ethnic minority background to research is known to be very low. It has been suggested that interviewer characteristics may affect the willingness of individuals to take part in research, with some researchers advocating ethnicity and gender matching. A study on UK South Asian adults’ experiences of living with IBD provided an opportunity to explore these methodological issues further.

Methods

The study comprised qualitative interviews with adult patients with IBD identifying themselves as Indian/British Indian, Pakistani/British Pakistani, and Bangladeshi/British Bangladeshi. They were recruited from five clinics across England. Rather than presupposing what participants’ preferences might be, patients were offered a choice of interviewer in terms of the following characteristics: gender, shared experience (or not) of IBD, ethnicity and language (Bengali, Gujarati, Hindi, Mirpuri, Punjabi, Urdu). These interviewers were a particular type of ‘peer researcher’; distinctive in that they are a professional researchers and assumptions have not been made about the ‘peer’ characteristic which is most pertinent to study participants.

Results

Adopting this study design required strategic planning in terms of resources and research management. Recruitment to the study was good, with over 40% of those invited (n = 41) returning a response form indicating an interest in taking part. Some had no preference over who interviewed them (8 women, 6 men). Where a preference was expressed, gender was the most important factor. Almost all favoured a female rather than a male interviewer (12 vs. 1). The next most frequently requested option was for an interviewer with personal experience of IBD (n = 11). Very few prioritised the ethnicity of the interviewer. Of those that did, two also requested to be interviewed in a South Asian language. Involvement of ‘peer interviewers’ in the development of the interview guide led to the addition of research questions that would not otherwise have been included. In some interviews, shared experience (between interviewer and interviewee) increased the richness of data elicited which, on occasion, threatened ‘even-ess’ of emphasis across the dataset.

Conclusion

The study achieved an above average recruitment rate, the sampling frame was achieved, and rich data was generated. The research team intend to adopt a similar approach in future studies where it is anticipated recruitment to the study may be challenging and the topics for discussion are sensitive.
N20 The impact of inflammatory bowel disease-related fatigue on health-related quality of life: a qualitative semi-structured interview study
Authors: Radford S , Moran G W , Czuber-Dochan W
Published: January 2020

Background

Fatigue is a frequently reported symptom of inflammatory bowel disease (IBD), experienced by patients with active disease and in remission. Fatigue related to chronic conditions plays a significant negative role in Health-Related Quality of Life (HRQoL), but patients’ experience of this have not been researched in IBD. We aimed to explore experience of IBD fatigue and its impact on HRQoL in adults diagnosed with IBD.

Methods

Qualitative, semi-structured in-depth interviews were conducted with adults with IBD in remission, recruited from out-patient clinics in the UK. Eligibility and medical history were confirmed at recruitment. Interviews were audio-recorded and transcribed verbatim. Thematic analysis was employed to analyse the data using NVivo 12 software.

Results

Fourteen participants (eight female, average age 37.3 years old, range 21–64) were interviewed. All identified as ‘White British’, average length of living with IBD fatigue was 10.9 years (range 9 months–17 years). Twelve participants reported constant fatigue and two reported intermittent fatigue. There were three key themes reflecting patient experiences: (1) ‘The new normal’ established through attempts to adapt daily life and acceptance of IBD fatigue impact on daily life and HRQoL. HRQoL is negatively impacted by lack of feelings of fulfilment, not being able to continue on as before the onset of IBD fatigue and a negative perception of self in comparison to others without IBD fatigue; (2) ‘Energy as a resource’ describes participants attempts to better manage fatigue on a daily basis through planning and prioritising tasks, often prioritising employment or education over social or leisure activities; (3) ‘Keeping healthy’ encompasses participants beliefs that good nutrition, good general health and keeping active allow them to generate energy more easily allowing some situational control where they have little control over IBD symptoms, subsequently improving HRQoL. Participants reported a mix of physical activities that improved HRQoL; however, none reported a specific programme of exercise.

Conclusion

Adults with IBD fatigue try to establish a sense of ‘new’ normality, through maintaining the same or similar, level of activities related to employment or education. However, this is often at the expense of personal, social and leisure activities. The study also indicates that perceptions of conservation of energy through planning and prioritising tasks and high levels of social support were associated with better self-reported HRQoL. Further research is required to explore physical activity-based intervention in relation to IBD fatigue, with use of validated fatigue and HRQoL measures.
DOP62 Morbidity after primary ileocecal resection for Crohn’s disease in the years of biologics: Lesson learned over 631 patients exclusively treated in a tertiary centre
Authors: Rottoli M , Tanzanu M , Vago G , Belvedere A , Parlanti D , Pezzuto P , Bosi S , Caputo F , Rizzello F , Gionchetti P , Poggioli G
Published: January 2020

Background

Several risk factors for morbidity after surgery for Crohn’s disease of the terminal ileum have already been identified. However, the study population is rarely homogeneous, due to high-volume centres receiving patients treated in other hospitals with diverging medical protocols and different thresholds for surgical referral. A study including only patients undergoing homogeneous perioperative treatment in a single referral centre might reduce the selection bias. The aim of this study was to identify the risk factors for minor (Clavien-Dindo ≤2) and major (Clavien-Dindo ≥3) postoperative complications in patients who received medical treatment and surgery in a single centre.

Methods

Retrospective analysis of ileocecal resections for Crohn’s disease in biological era (2004–2019). Recurrence was excluded. Risk factors for minor and major complications were identified through univariate and multivariable logistic regression analyses. Variables were selected by univariate analysis with p < 0.2 criteria, then a stepwise selection with entry criteria p = 0.05 and stay criteria p = 0.1.

Results

Of 631 patients included (59.4% male, median age 37 years), 214 (34%) had previous surgery and 152 (24.1%) biologics. Laparoscopy was feasible in 35.9% of cases, 285 patients (45.1%) required surgery on other bowel sites due to multiple locations or fistulae. 281 (44.5%) patients presented with fistulizing disease.

Risk factors for 90-day minor complications (22.8%).

Risk factors for 90-day major complications (6.8%).

Conclusion

Risk of minor complications was higher in younger patients, especially after a longer medical treatment. Fistulating disease increases the risks only if the rectum and sigmoid colon are involved. Major complications seem to be related to specific patient’s comorbidities, rather than disease characteristics. Onset of hypertension and neuro-vascular disease, known adverse events of chronic steroid use, should not be underestimated in the preoperative assessment of patients. Poor nutritional status greatly increased the risk of minor and major complications; therefore, any effort should be made towards the nutritional optimisation of Crohn’s patients
N31 What factors affect quality of life and psychological well-being in patients with intestinal failure? A systematic review of quantitative studies
Authors: Roberts D , Liu Q , Czuber-Dochan W , Smith P , Norton C
Published: January 2020

Background

The most common cause of intestinal failure (IF) is Crohn’s disease (CD). The definition of IF is ‘the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth’. It is a result of the most severe phenotype of CD, where an individual can no longer obtain sufficient nutrients and fluids from their gut to sustain life without supplementation in the form of parenteral nutrition (PN) or intravenous fluids. Home PN (HPN) allows people to receive infusion at home and increases survival rates (65% after 6 years). Whilst HPN improves length of life, studies have demonstrated this treatment can severely negatively affect an individuals’ quality of life (QoL) and employment. The aim of this systematic review was to identify factors affecting QoL in people with IF.

Methods

A search of databases MEDLINE, PubMed, PsycINFO, Web of Science, Global Health, and Scopus was conducted in July 2019. Search terms included ‘Crohn’s disease’, ‘short bowel syndrome’, ‘intestinal failure’, ‘quality of life’, and ‘health-related quality of life’. Titles and abstracts were screened by one reviewer. Any uncertainties about inclusion of the papers were discussed with two reviewers. Full texts were screened by 3 reviewers. Quantitative studies that measured QoL as an outcome in people with IF were included.

Results

Nineteen studies including a total of 924 participants met the inclusion criteria. Six key themes of factors affecting QoL were identified: (1) Practicalities of IF and HPN, e.g. sleep disturbances from the noise of the pump; managing a high output stoma. (2) Impact of medical interventions, e.g. blood tests. (3) Social impact/physical activity/personal relationships, e.g. restricted ability to travel, socialise and eat with friends. (4) Personal and sexual impact, e.g. lack of sexual desire. (5) Impact of symptoms, e.g. fatigue. (6) Patient characteristics, e.g. age. Some studies also reported positive effects on health (such as more energy), improved symptoms and QoL with HPN, especially for those who had been very unwell previously.

Conclusion

People with IF often have poor QoL that is affected by many factors, from their symptoms to practical aspects of HPN. However, themes related to the ‘social’ and ‘personal’ impact of IF dominated in the literature. While there is considerable evidence on what affects QoL in people with IF, there appears to very little research on attempting to improve QoL in this patient group.
DOP64 Discovery of highly selective small-molecule oral inhibitors of integrin α4β7 for the treatment of inflammatory bowel diseases
Authors: WONG J , Bursavich M , Blanco N , Camblin A , Cappellucci L , Cohen R , Cui D , Krumpoch M , Zhong C , Hahn K , Lee D , Lippa B , Lin F Y , Lugovsky A , McShea M , Mostafavi S , Moy T , Sullivan A , Troast D , Wang L , Rogers B
Published: January 2020

Background

Integrins play a key role in facilitating immune cell trafficking throughout the body and represent an important receptor family for therapeutic intervention. In particular, the α4β7 integrin is a clinically validated target for the treatment of inflammatory bowel diseases (IBD), as exemplified by the humanised monoclonal antibody vedolizumab, which blocks the interactions between α4β7-expressing lymphocytes and its ligand MAdCAM-1. This blockade leads to the inhibition of these circulating lymphocytes from exiting the bloodstream and entering intestinal mucosal tissues resulting in a decrease in mucosal inflammation in patients. While oral inhibitors of the α4β7 integrin are advantageous over biologics, the efforts have been impeded by challenges to achieve desired selectivity and optimal DMPK properties. The aim of this study was to develop and characterise orally bioavailable small-molecule inhibitors of the α4β7 integrin and to determine their therapeutic potential.

Methods

Oral small-molecule inhibitors targeting the α4β7 integrin were discovered using Morphic Integrin Technology (MInT) platform. These small-molecule inhibitors were tested for potency and selectivity against a broad panel of integrin family members in multiple biochemical and cell-based functional assays in a ligand-competitive fashion. An acute PD assay with CFSE-labelled lymphocytes was developed to evaluate the activity of the small-molecule compounds in blocking lymphocyte trafficking to gut-associated lymphoid tissues in mice. The in vivo activity was also examined through changes in circulating α4β7+ CD4+ T memory cells in a relevant non-human primate model.

Results

Key drug candidate small molecules demonstrated over 1000-fold selectivity in vitro against a broad panel of integrin family members, including the α4β1 integrin. These compounds effectively blocked lymphocyte trafficking to mesenteric lymph nodes and Peyer’s patches in the gut in a dose-dependent manner, similar to an α4β7-specific antibody, in an acute gut-homing assay in mice. Additionally, these inhibitors also demonstrated effective occlusion of immune trafficking in a relevant non-human primate model. The lead compound has favourable DMPK properties, good oral bioavailability and is projected to have sufficient exposure in humans to effectively block α4β7-expressing immune cells in circulation.

Conclusion

Potent, selective, oral small-molecule inhibitors of α4β7 integrin have been discovered that demonstrate on-target, mechanistic efficacy in two animal models relevant to human IBD. It has the potential to be an effective and safe therapeutic in monotherapy as well as serving as a backbone for combination with other IBD drugs.
DOP66 A CEACAM5 small peptide restores the suppressive activity of CD8 + T cells in patients with Crohn’s disease
Authors: Roda G , Dunkin D , Correale C , Vetrano S , Merlino F , Marinelli L , Novellino E , Mayer L , Yeretssian G , Danese S
Published: January 2020

Background

Intestinal epithelial cells (IECs) play a pivotal role in controlling immune responses by activation of suppressive CD8+ T regulatory cells (Treg). In Crohn’s disease (CD) this response is impaired due to a defect in CEACAM5 expression on IECs. We previously identified a small region in CEACAM5 able to restore the impaired suppressive activity of CD8+ Treg cells in CD. Here, we tested the functionality of this small peptide in CD patients and evaluated its conformational structure to understand its interaction with T cells.

Methods

Suppression assays were done to assess the ability of peripheral blood (PB) CD8+ T cells isolated from healthy individuals and CD patients and stimulated with the small CEACAM5 peptide to suppress proliferation of activated CD4+ T cells. To understand the role of the Asparagine (N)71 residue present in the CEACAM5 small peptide, which has previously been shown to be pivotal for CD8+ T cell binding to CEACAM5, we tested a library of overlapping peptides in the same region as the small CEACAM5 peptide. Cytokine assays were performed to characterise CEACAM5 peptide-activated CD8+ T cells.

Results

CEACAM5 small peptide activated PB CD8+ T cells from CD patients significantly suppressed CD4+ T-cell proliferation. A new small peptide from the overlapping peptide library containing N71 induced the strongest suppression of proliferation. Peripheral CD8+ T cells produced increased interleukin (IL)-10 upon stimulation with the CEACAM5 peptide.

Conclusion

Our study offers a new approach for modulating the inflammatory state in CD by enhancing the suppressive function of CD8+ T cells using a CEACAM5 small peptide.