bluuebunny/crossref_metadata_2025 huggingface dataset:
P025 Evaluation of endoplasmic reticulum stress in intestinal mucosa from patients with Crohn’s disease
Authors: Rodrigues B , Pascoal L B , Coope A , Ayrizono M L S , Camargo M G , Velloso L A , Fagundes J J , Leal R F
Published: January 2020

Background

The endoplasmic reticulum (ER) is responsible for the synthesis and processing of secretory and membrane proteins. In some cases, proteins cannot reach their final conformation and they remain unfolded in the ER lumen. The accumulation of unfolded proteins leads to a state of stress in the ER (ER stress) that is considered toxic to the cells. As a result, cells may respond by driving the proteins to degradation, pausing the transcription process, or even inducing apoptosis.1 ER stress has recently been linked to the exacerbation of the inflammatory process in the pathogenesis of Crohn’s disease (CD).2 Therefore, our aim was to evaluate the effect of a chemical inhibitor on the activation of ER stress pathways and its modulation of pro-inflammatory cytokines.

Methods

After approval of a local Ethics Committee, biopsies of intestinal mucosa were collected by colonoscopy from patients with CD (CD group) and from patients without inflammatory bowel diseases (control group). Explant culture was performed to evaluate the occurrence of ER stress and was treated with a chemical ER stress inhibitor. Non-parametric tests were performed for statistical analysis adopting p < 0.05 as significant value.

Results

Samples were collected from 10 patients with active CD (CDEIS ≥5) and six control patients. After cell culture, a significant difference was observed in the activation of the main ER stress pathway in the CD group when compared with control group. After treatment with a chemical inhibitor, there was significant decrease in the expression of genes responsible for the activation of ER stress. In addition, a decrease in the expression of inflammatory cytokines was observed after treatment.

Conclusion

The use of a chemical inhibitor has been shown to be effective in significantly decreasing the activation of ER stress and to modulate the inflammation in CD. The activation of the main ER stress pathways may contribute to the inflammatory process in CD, and its blockade suggests a potential new target in the treatment of CD.

References
P034 GB004, a novel gut-targeted prolyl hydroxylase inhibitor, induces HIF-1α target genes and is efficacious in mouse colitis
Authors: Taylor Meadows K , Kennedy M , Naiman Z , Sergeeva M , Paulson B , Opiteck G , Slee D , Carter L , Salter-Cid L
Published: January 2020

Background

GB004 is a small molecule prolyl hydroxylase inhibitor (PHDi) that stabilises hypoxia inducible factor (HIF-α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF-α stabilisation. GB004 is in clinical development for the treatment of ulcerative colitis.

Methods

Female wild-type C57BL/6 and immunodeficient B6.129S6-Rag2tm1FwaN12 ko/ko mice (Rag2) mice received either a single oral dose of GB004 or daily oral dosing for 7 days. Colitis was induced by administering 100 µg of anti-CD40 monoclonal antibody interperitoneally in Rag2 mice. GB004 oral dosing started on day 0 and continued once daily for 7 days. Body weight was measured daily. At termination, plasma was isolated for compound exposure and colons were excised, measured and weighed. Colon tissue was preserved in formalin for histology and 1 cm colon sections were snap-frozen for compound exposure and preserved with RNA for gene expression.

Results

A single oral administration or 7 days dosing of 10 mg/kg GB004 in healthy mice resulted in significantly higher exposure in the gastrointestinal tract (GI) (pylorus, duodenum, ileum and colon) than in plasma with colon to plasma ratio of ≥500. Target engagement in colon was demonstrated by induction of HIF-dependent genes (HIF1A), epithelial barrier genes (AKAP12, TFF3, NT5E) and anti-apoptotic genes (BNIP3). In colitis mice, GB004 plasma exposure was elevated compared with plasma concentrations in healthy mice, even so, GB004 exposure was still higher in the colon than plasma at a ratio of 90. Target engagement was demonstrated by an increase in NT5E, CLND1, BNIP3 and CA9 and a reduction in IL12B. In colitis mice, 1, 3 and 10 mg/kg GB004 demonstrated a dose-dependent reduction in colon inflammation and gland loss and 10 mg/kg GB004 showed a significant reduction in neutrophil score. Gene expression 4 h after the final GB004 dose demonstrated an increase in barrier genes AKAP12 and CLDN1 and a decrease in IL12B.

Conclusion

These studies demonstrate that oral GB004 has significantly higher exposure in the GI tract than in the plasma and induces HIF-1α-dependent genes in colon. In mouse colitis, GB004 has high colon exposure, induces target genes involved in barrier function and repair and demonstrates efficacy by reducing inflammation, gland loss and neutrophil inflammation. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, PK and PD both systemically and in colon (NCT03860896). Sponsored by GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.
P044 Milk derived exosomes has a therapeutic effect on experimental colitis
Authors: Golan-Gerstl R , Koroukhov N , Elbaum Shiff Y , Shilo I , Reif S
Published: January 2020

Background

Inflammatory bowel disease (IBD) is a complex disorder that results from a dysregulated immune response in the gut. Emerging therapy for IBD treatment is mainly focused on regulation of the immune response. Exosomes are nanovesicle packing different molecules such as miRNAs that transfer their cargo to recipient cells. We and others found that mammalian milk contain high concentration of exosomes (milk-derived exosomes, MDE) carrying beneficial miRNAs such as miRNA-148. Furthermore, MDE are taken up by different cell type such as intestinal epithelial cells, modify target gene expression, promote proliferation and differentiation of colon epithelial cells. The aim of this study is to explore the therapeutic effect of MDE on colitis.

Methods

We used gavage administration of MDE labelled with DiR dye to track their localisation patterns in vivo. The therapeutic effect of MDE on colitis was study in mice model of SDS induced colitis, colon length, histopathological scoring grade, cytokine expression, stool consistency and miRNA expression were analysed.

Results

Imaging of mouse that have receive labelled MDE revealed an accumulation of fluorescent signal in the intestine. Moreover, fluorescent signal in the intestine and liver is time dependent. MDE reduced the histopathological scoring grade from 5.83 ± 1.47 to 0.6 ± 0.6, p < 0.05. The length of the colon of MDE-treated animals was 7.9 ± 0.19 in comparison to 6.92 ± 0.3 p < 0.05 of the untreated. The weight loss as a result of the colitis was reverted in MDE-treated mice. Likewise, MDE treatment reduced IL-6, TNF-α and caveolin expression from 3.83 to 0.78, 1.59 to 0.86 and 3.52 to 1.1, respectively. Highly expressed miRNAs (miRNA-320, 375, Let-7a and 6073) were found to be more abundant in colon of MDE treatment mice compared with the untreated.

Conclusion

This study demonstrated that MDE have a therapeutic effect on colitis in vivo. Proving the effect of MDE on colitis will have implications for the potential of adding MDE as a therapeutic nutrient to be included in the formulas for IBD patients.
P045 Profiling of human circulating dendritic cells and monocytes subsets discriminates type and mucosal status in patients with inflammatory bowel disease
Authors: Ortega Moreno L , Fernández Tomé S , Chaparro M , Marin A , Mora Gutiérrez I , Santander C , Baldán M , Gisbert J , Bernardo D
Published: January 2020

Background

Intestinal dendritic cells (DCs) and macrophages govern the mechanisms of immune homeostasis having a role in inflammatory bowel disease (IBD) onset. However, the profile of their circulating precursors (DC and monocytes) in IBD has not been previously described in depth. Our aim was to characterise blood DC and monocyte subsets in healthy controls (HCs) and IBD patients in order to understand their potential implication in IBD pathogenesis.

Methods

18 HC and 64 IBD patients were recruited. IBD patients were categorised into Crohn’s disease (CD) and ulcerative colitis (UC), either endoscopically active (aCD and aUC) or quiescent (qCD and qUC), based on the SES-CD or the Mayo index endoscopic subscore. Blood circulating type 1 conventional DC (cDC1), type 2 conventional DC (cDC2), plasmacytoid DC (pDC), classical monocytes, non-classical monocytes and intermediate monocytes were identified by flow cytometry and characterised for the expression of 18 homing and activation markers (β7, CCR1, CCR2, CCR3, CCR5, CCR6, CCR7, CCR9, CCRL1, CD40, CD86, CD137L, CD274 (PD-L1), CLA, CXCR1, CXCR3, ICOSL and HLA-DR). Association between markers and the presence, type or activity of IBD was tested by logistic regression. Discriminant canonical analysis was also performed to classify the patients on their own endoscopy category.

Results

All groups (HC, aCD, qCD, aUC and qUC) were separated from the others based on the discriminant canonical analyses of the 18 markers applied over all DC and monocytes subsets (Figure 1). Specifically, CCRL1, CCR3 and CCR5 expression on cDC1, CCRL1 on non-classical monocytes and CCR9 and b7 on classical monocytes were highly associated to IBD. CCR3 displayed an odds ratio (OR) of 2.29 along with its 95% confidential interval (CI) between 1.11 and 4.75, showing a strong association with activity in CD; whereas the other markers displayed an inverse association with IBD. Hence, expression of CCRL1 on cDC1 and non-classical monocytes from aUC showed an OR (95% CI) of 0.23 (0.08–0.66) and 0.52 (0.28–0.95), respectively. In the case of qUC, CCR5 on cDC1 and β7 on classical monocytes displayed an OR (95% CI) of 0.10 (0.01–0.83) and 0.56 (0.34–0.90), respectively. CCR9 was inversely associated to qCD with an OR (95% CI) of 0.64 (0.46–0.89) in the classical monocytes subset. Indeed, the same markers (excluding β7) were also associated with IBD when all DC and monocyte subsets were considered at the same time.

Conclusion

Differences on the expression of migration markers CCR3, CCR5, CCR9, b7 and decoy receptor CCRL1 on circulating DC and monocyte subsets from IBD groups suggest the presence of constitutive migratory differences underlying IBD pathogenesis in CD or UC and its condition (inflamed or non-inflamed).
P048 Mucosal macrophages express elevated levels of HDAC9 in inflamed and uninflamed mucosa of Crohn’s disease, but not ulcerative colitis
Authors: Ghiboub M , de Bruyn J , Reedquist K , Radstake T , Wichers C , Wildenberg M , Broen J , D’Haens G , de Jonge W
Published: January 2020

Background

Histone deacetylases (HDACs) are a group of enzymes that control histone and non-histone deacetylation and influence inflammatory gene transcription. Certain members of the HDAC family control the function of macrophages and play an important role in immune response. In this study, we aimed to study the expression of HDACs in mucosal macrophages isolated from inflammatory bowel diseases (IBD) patients.

Methods

Both macroscopically inflamed and non-inflamed colon resection tissue were collected from 15 Crohn’s disease (CD) and nine ulcerative colitis (UC) patients operated on for therapy refractory disease. Of the CD patients, 53% had ileal and 47% ileocolonic disease. Of the UC patients, 44% had left-sided colitis and 56% pancolitis. Lamina propria was separated from the muscularis externa, and a targeted array for epigenetic enzymes was performed. To assess the relevance of HDAC9 gene expression in terms of protein level, immunofluorescence staining of HDAC9 protein was undertaken in tissue sections from inflamed and non-inflamed mucosa. CD68 was used as a pan-macrophage marker.

Results

From our array, expression of HDAC9 was significantly higher in the inflamed mucosa of CD patients compared with UC patients (p = 0.005). Gene expression of HDAC9 in non-inflamed mucosa from CD was elevated compared with non-inflamed mucosa from UC. In addition, in CD, HDAC9 mRNA level was increased in inflamed tissue in comparison to non-inflamed tissue (p = 0.046). In conjunction with the expression data, HDAC9 protein was found highly expressed in inflamed tissue. HDAC9 was predominantly localised in the cytoplasmic compartment of macrophages in non-inflamed tissue whilst HDAC9 localised to the nucleus of macrophages in inflamed tissue.

Conclusion

HDAC9 is member of class IIA HDAC superfamily that exerts pro-inflammatory properties. The inhibition of HDAC9 in experimental murine colitis clearly enhances regulatory T-cell function, suggesting a critical role for HDAC9 in breaching immune homeostasis (de Zoeten EF et al, 2009). We suggest here that HDAC9 can serve as an additional marker to distinguish CD from UC in tissue biopsies. Furthermore, we show for the first time that HDAC9 protein is expressed in mucosal macrophages of CD patients, indicating its potential in mediating macrophage inflammatory function in IBD. Further studies are currently being undertaken to elucidate the role of HDAC9 in CD pathogenesis.
P049 A new preclinical rationale for first-line therapy of ulcerative colitis
Authors: Thorlacius H , Bjoerk A , Nordle Ö , Hedlund G
Published: January 2020

Background

Ulcerative colitis (UC) is a chronic inflammatory condition with no known medical cure. 5-Aminosalicylic acid (5-ASA [mesalazine]) represents the cornerstone of first-line therapy for mild-to-moderate UC. Sulfasalazine (SASP) is the original agent in this class of drugs. Meta-analyses of patients with mild-to-moderately active UC comparing 5-ASA to placebo showed 5-ASA to be significantly superior to placebo. However, about two-thirds of patients treated with 5-ASA fail to enter clinical remission. It is therefore most important to identify strategies to accelerate and maximise the therapeutic effects of 5-ASA. Therapeutic intervention against NFκB activation is a useful strategy for treatment of UC. The 4-alkanoylaminobenzamide PM0503 inhibits the breakdown of the NFκB inhibitor IκBβ, and SASP/5-ASA inhibits the breakdown of IκBα. This elicited a hypothesis of a possible synergistic action and converging effect on NFκB signalling. In the present study, we investigated the effect of combining SASP/5-ASA with PM0503 in experimental colitis.

Methods

SASP and PM0503 alone or in combination were administered for 5 days to Balb/c mice with colitis triggered by 5% dextran sulphate sodium (DSS). Blood in the stool, stool consistency and body weight loss were evaluated daily on a 0–4 point scale. The disease activity index (DAI) was calculated by summarising the total score of these three parameters.

Results

Addition of 5% DSS in the drinking water for 5 days produced reproducible symptoms of colitis. PM0503 was shown to inhibit DSS induced colitis by reducing mean DAI at day 5 from 6.9 in controls to 1.7 (a 75% decrease). Mean DAI recorded with SASP treatment at optimal doses in the same series of experiments was 4.4 (a 36% decrease). Furthermore, and most important, lower doses of PM0503 acted synergistically with SASP in ameliorating DSS-induced disease severity. The combination of PM0503 and SASP using suboptimal doses having minimal beneficial effects as monotherapies, showed more than 50% disease inhibition at day 5. In addition, no toxicity was observed with PM0503 alone or in combination with SASP.

Conclusion

Our findings offer a preclinical rationale for simultaneous coadministration of PM0503 and a 5-ASA agent such as SASP or 5-ASA as first-line treatment for patients with UC.
P051 Quantifying inflammation and fibrosis through a surgical histopathological score can differentiate ileal Crohn’s disease phenotypes and predict postoperative progressive disease
Authors: Tavares de Sousa H , Gullo I , Castelli C , Dias C C , Magro F
Published: January 2020

Background

The quantification of fibrosis in Crohn’s disease (CD) still relies on surgical specimens’ pathology. We aimed to correlate quantification of inflammation and fibrosis of CD ileal resection specimens with postoperative progressive disease.

Methods

All patients (patients) having primary ileal resection for CD complications with a follow-up >3 years (n = 262) were considered. Unavailability of specimen excluded 72 patients and 22 for absence of the three study sections: (1) proximal ileal margin; (2) most affected area (B2: narrower calibre of stricture; B3: area with fistulas/deep ulcers); (3) inflamed area (inflamed bowel, no lesions as in 2). Of the 168 patients with the three studied phenotypes (B2 and B3 with stenosis (B3s) and without stenosis (B3o), we randomly excluded 65 B3s for overrepresentation. We analysed three sections per patient (3 × 103 patients = 309 sections), stained with haematoxylin and eosin and Masson’s trichrome. Chiorean et al. histopathological score grades inflammation 1–3 and fibrosis 0–2. We add a ‘0’ category to inflammation and observed adipose tissue and muscularisation in submucosa. Progressive disease was previously defined as one of eight post-operative outcomes (reoperation, hospitalisation, steroids, start or change of immunosupressives or biologics, new stricturing/penetrating/anal event). Statistics: Continuous variables were described by mean(standard deviation), median(interquartile range), minimum and maximum, and categorical variables by absolute(n) and relative(%) frequencies. Chi-square, Mann–Whitney and Kruskal–Wallis compared groups. Hypotheses were tested at 5% level of significance, using IBM SPSS Statistics for Mac, vs. 24.0.

Results

We assessed 103 patients (B2–29; B3o–20; B3s–54), 55% males, mean age at diagnosis 30(12) years, followed for a mean time of 10(4) years. Median time from surgery to reoperation was 8.0 (7.0, 12.0) years. B3 patients have significantly more inflammation than B2 patients [score 3: 78%vs.55% and 96%vs.76% in most affected (p = 0.027) and inflamed (p = 0.005) sections, respectively]. B3s patients had significantly more fibrosis than B3o [score 1 + 2: 90%vs.60% in most affected (p = 0.011) and 99%vs.85% in inflamed (p = 0.048) sections] and significantly more inflammation than B2 patients [score 3: 81%vs.55% in most affected (p = 0.020) and 94%vs.76% in inflamed (p = 0.019) sections]. B3s had higher total score than B3o and B2 [score 4–5: 78%vs.45%vs.52%, p = 0.019] and more new penetrating events (p = 0.043). Of the 25 patients changing biologic after surgery, 88% had inflammation at the margins [score 3: 55%vs.12%, p = 0.035].

Conclusion

B3s stood out as a distinctive phenotype, with significantly more fibrosis than B3o but significantly more inflammation than B2. It displayed the highest total score and was associated to progressive disease.
P057 IL-17 regulates expression of chemotactic chemokines in human colonic subepithelial myofibroblasts
Authors: Filidou E , Tarapatzi G , Boulkou M , Arvanitidis K , Vradelis S , Valatas V , Bamias G , Kolios G , Koutroubakis I , Drygiannakis I
Published: January 2020

Background

Crohn’s disease (CD) and ulcerative colitis (UC), the two main entities of inflammatory bowel disease (IBD), are characterised by chronic and relapsing/remitting inflammation of the gastrointestinal tract, and occasionally ultimately result in debilitating intestinal fibrosis. Apart from their key role in fibrosis, there is evidence that subepithelial myofibroblasts (SEMFs) participate in the IBD inflammatory cascade, as they express various pro-inflammatory cytokine receptors. We examined the effect of pro-inflammatory IL-17—the hallmark cytokine of T-lymphocytes differentiated to Th17—on the expression of lymphocyte-chemotactic chemokines in SEMFs.

Methods

SEMFs were isolated from endoscopically obtained colonic biopsies from healthy controls, set to culture and stimulated with 100 ng/ml IL-17 for 6 h. Total RNA was extracted and mRNA expression of CCL5, CXCL1 and CXCL11 was assessed with reverse transcription quantitative (RT-q) PCR. Changes in cytokine mRNA are provided as medians (IQR).

Results

Untreated SEMFs had a basal expression of chemokines of the CCL and CXCL family groups. So far, our study has shown that the IL-17 stimulation leads to a statistically significant upregulation of CCL and CXCL chemokines in SEMFs (p < 0.001). In detail, CCL5 was upregulated 5.7-fold (4.9–7.5), CXCL1 72.9-fold (63.1–90.7) and CXCL11 25.4-fold (17.3–37.3).

Conclusion

IL-17 induced the expression of chemotactic factors in SEMFs. Our results further support a potential role of SEMFs in the shaping of intestinal mucosal immunity by serving as immunological intermediates that respond to cytokines of adaptive immunity and amplify the recruitment of immune cells via chemokine production.
P069 CD73 promotes colitis-associated tumourigenesis in mice
Authors: Wu X , Liu X , Lan N , Zheng X , Chen Y , Cai Z , Lan P , Wu X
Published: January 2020

Background

Patients with inflammatory bowel disease (IBD) are at a higher risk of developing colitis-associated colorectal cancer. The aim of the present study was to investigate the role of CD73 in IBD-associated tumourigenesis.

Methods

A mouse model of colitis-associated tumourigenesis (CAT) induced by azoxymethane and dextran sulphate sodium (AOM/DSS) was successfully constructed. Model mice were injected with CD73 inhibitor or adenosine receptor agonist. Colon length, body weight loss and tumour formation were assessed macroscopically. Measurement of inflammatory cytokines and RNA sequencing on colon tissues were performed.

Results

Inhibition of CD73 by adenosine 5′-(α,β-methylene) diphosphate (APCP) suppressed the severity of CAT with attenuated weight loss, longer colons, lower tumour number and smaller tumour size when compared with the model group. On the other hand, activation of adenosine receptors using 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-β-d-ribofuranuronamide (NECA) exacerbated CAT. Histological assessment indicated that inhibition of CD73 reduced while activation of adenosine receptors exacerbated the histological damage of the colon compared with the model group. Increased expression of pro-inflammatory cytokines (tumour necrosis factor-α and interleukin-6) in colonic tissue was detected in the NECA group. According to the results of RNA sequencing, potential oncogenes such as ALOX15, Bcl2l15 and Nat8l were found to be downregulated in the APCP group and upregulated in the NECA group compared with the model group.

Conclusion

Therefore, inhibition of CD73 attenuated IBD-associated tumourigenesis, while activation of adenosine receptors exacerbated tumourigenesis in a C57BL/6J mouse model. This effect may be associated with the expression of pro-inflammatory cytokines and the regulation of ALOX15, Bcl2l15 and Nat8l.
P079 High-dimensional mass cytometry after local MSC treatment in patients with refractory proctitis shows an effect on the myeloid compartment: preliminary data
Authors: Ouboter L , Barnhoorn M C , Hawinkels L J A C , van Pel M , Zwaginga J J , Verspaget H W , Koning F , Pascutti M F , van der Meulen-de Jong A E
Published: January 2020

Background

Ulcerative proctitis (UP) causes a chronic rectal mucosal inflammation. A subset of patients does not respond to one or more medication options. Mesenchymal stromal cells (MSCs) show beneficial effects in animal models and patients with immune diseases. However, the effects of MSCs on the mucosal immune composition in patients with inflammatory bowel disease (IBD) are not unravelled yet.

Methods

Patients with UP (N = 7) were locally treated with allogeneic bone marrow-derived MSCs. A total of 20 × 106 MSCs was injected if the inflammation was restricted to 7 cm and 40 × 106 if inflammation exceeds 7 cm. Medication was stable in all patients from at least 2 weeks before treatment up to week 6 after treatment. Biopsies were taken from the affected and unaffected colon before (t = 0) and 6 weeks (t = 6) after treatment from the same locations and faecal calprotectin (FCP) was determined. Single-cell suspensions from the biopsies were stained with a 42 antibody panel and analysed with a mass cytometer to identify and characterise possible effects of MSCs on immune subsets. The generated dataset was analysed with Hierarchical SNE (HSNE) in the Cytosplore analysis and visualisation tool.

Results

FCP decreased significantly in four out of seven patients (419→191; 365→40; 1744→346; 3270→291), ‘responders’, while in three patients FCP increased, ‘non-responders’. Unbiased hierarchical clustering of the subsets showed no clear differences in the major immune lineages before and after treatment. In some patients; however, a prominent myeloid population was present in the affected colon, whereas the CD8+− and CD3−CD7+ populations in affected tissue were in general less frequent compared with unaffected tissue from the same patients. We then zoomed into every major lineage separately, and observed changes in the frequencies of two myeloid clusters in the affected tissue of ‘responders’ compared with the ‘non-responders’ (see figure, Cluster 1=CD11b+CD11c+CD66b+CD15intCD16+CD45RA−CD45RO+ cells, Cluster 2= CD11b+CD11c+CD66b+ CD15−CD16−CD69+CD45RA+CD45RO+ cells).

Conclusion

These preliminary data show differences between ‘responders’ and ‘non-responders’ in the myeloid compartment in the inflamed tissue after MSC therapy. Since CD11b+ and CD11c+ populations mediate the tolerogenic effect of MSC in mouse models, we will explore the regulatory potential of the observed populations in MSC-treated UP patients in future studies. The inclusion of patients in a second cohort (N = 7) is currently ongoing.
P082 Spicy food is a vital trigger for relapse in patient with inflammatory bowel disease
Authors: Chen Y , Ma C , Dang Y , Chen K , Shen S , Jiang M , Zeng Z , Zhang H
Published: January 2020

Background

The dietary is one of the environmental triggers for inflammatory bowel disease (IBD). We investigated which types of food can induce the relapse and worsen the symptoms in IBD patients through the epidemiologic study, and then explored the underlying mechanisms in an animal study.

Methods

A questionnaire assessing demographics, dietary habits and relapse-associated risk factors in patients has been administered to consecutive IBD patients who suffered one or more relapses at West China Hospital from September 2016 to November 2018. The mice with dextran sulphate sodium (DSS)-induced chronic colitis were orally administrated with top one type of risk food. The severity of mice colitis after administration was evaluated by disease activity index (DAI), histology, activity of myeloperoxidase (MPO) and the level of inflammatory cytokines. The infiltration of immune cells in lamia propria (LP) of mice was analysed by flow cytometry (FCM).

Results

A total of 306 patients participated in the survey, including 188 ulcerative colitis (UC) patients and 118 Crohn’s disease (CD) patients. Spicy food ranked first for the relapse in patients with IBD. In particular, 54.3% (n = 102) UC patients and 53.4% (n = 63) CD patients reported that the intake of spicy food could cause a relapse. Fifty per cent UC (n = 94) patients and 40.7% (n = 48) CD patients reported that the intake of spicy food could worsen their symptoms. In the animal study, the oral administration of capsaicin aggravated the chronic colitis in mice, along with the increased activity of MPO and the upregulated level of inflammatory cytokines. The pro-inflammatory effect of capsaicin was dose independent but time dependent. The antagonist for transient receptor potential vanilloid 1 (TRPV1), the receptor of capsaicin, could significantly suppress the capsaicin-induced deterioration of colitis. FCM revealed that capsaicin-administration led to the recruitment of multiple types of immune cells in mice LP and the recruitment of neutrophils was the most prominent.

Conclusion

The intake of spicy food can contribute to the relapse and deterioration of symptoms in IBD patients with UC and CD. In mice, the oral administration of capsaicin exacerbated DSS-induced colitis which was characterised by the recruitment of neutrophils, indicating the association between neutrophils and the relapse-triggering effect of capsaicin in colitis.
P101 Biomarkers of elastin degradation are associated with clinical and biochemically active disease in Crohn’s disease
Authors: Pehrsson M , Domislović V , Karsdal M A , Brinar M , Barisic A , Krznaric Z , Manon-Jensen T , Mortensen J H
Published: January 2020

Background

In Crohn’s disease (CD), the extensive and potentially transmural inflammation results in increased activity of both matrix metalloproteases (MMPs) and serine proteases, causing a higher degree of intestinal tissue remodelling. This increased proteolytic activity could potentially cause degradation and loss of function of mechanical and functional matrix proteins, such as elastin. Therefore, we sought to investigate the association between biomarkers of elastin degradation and the disease activity in CD patients.

Methods

Seventy-two CD patients and 29 healthy donors (HD) were included in the study. Disease activity was determined according to the Crohn’s disease activity index score (CDAI >150) and/or a faecal calprotectin (fCALP >250). Additionally, CD patients were endoscopically assessed according to the simple endoscopic score (SES) for CD. Different protease derived biomarkers of elastin degradation: protease-3 (ELP-3), MMP-7 (ELM-7) and cathepsin-G (EL-CG) was measured in serum by ELISA. One-way ANOVA (Kruskal–Wallis) was applied for the statistical analysis.

Results

The levels of ELP-3 was significantly elevated in active CD when compared with the HD (p < 0.001), and inactive CD (p < 0.01). Levels of EL-G were significantly elevated when comparing active CD and HD (p < 0.05), with the same result observed for the levels of EL-CG when comparing active CD and the HD (p < 0.05). Endoscopically, ELP-3 was shown significantly elevated in moderate–to-severe CD patients when compared with the HD (p < 0.01).

Conclusion

In this study, measurements of the elastin degradation markers were capable of differentiating between CD patients with either a clinically active or biochemically active disease, with the biomarker levels being significantly highest in the patients with an active disease. This was also the case when assessing endoscopic disease activity, where the protease-3-derived biomarker levels were highest in patients of moderate-to-severe disease activity. As such, the data provide indications of the beneficial use of these serum biomarkers as additional disease activity assessment tools for CD patients.
P112 Body composition and resting energy expenditure in IBD patients receiving biological therapy
Authors: Vranesic Bender D , Cengic L , Ljubas Kelecic D , Karas I , Grbin Hodžić A , Domislović V , Brinar M , Juričić M , Krznarić Ž
Published: January 2020

Background

As a feature of changing phenotype of IBD in the last decade, we observe increased rates of obesity and increased BMI values as well as changes in body composition. Special interest is the impact of biological therapy on body composition and prevalence of obesity in IBD patients, since the data on this topic are limited. The aim of this study was to determine body composition and resting energy expenditure of patients treated with biological therapy.

Methods

The study included 74 patients (39 male and 35 female) at the Clinical Hospital Center Zagreb (52 patients with Crohn’s disease and 22 with ulcerative colitis) treated with infliximab/adalimumab/ustekinumab/vedolizumab. Resting energy expenditure was measured by the indirect calorimetry (Cosmed Quark CPET) and compared with the predicted resting energy expenditure calculated using Harris-Benedict equation. Detailed medical and nutritional anamnesis was taken and we measured the following body composition parameters using TANITA body composition analyser, BC-420MA: body mass index (BMI), fat mass (FM), visceral fat rating (VFR), muscle mass (MM) and skeletal muscle mass index (SMI) was calculated.

Results

Increased BMI was observed in 32% of the patients, while 41% of the whole sample had an increased FM. The mean value of skeletal muscle index (SMI) was 9,061,15 kg m−2 and it revealed the presence of moderate sarcopenia in 32 patients (43%), of which 30 were men. Indirect calorimetry (IC) obtained the value of resting energy expenditure (REE), with the measured REE (1569,81240,95 kcal) on average significantly lower than predicted (1640,36255,28 kcal), t(73)=−3.023, p < 0.05. The results of this study revealed a significant prevalence of moderate sarcopenia in men, increased body mass and fat mass, and slightly lowered resting energy expenditure. There was no significant difference between body composition parameters and REE between different types of biological therapy.

Conclusion

The incidence of classical forms of malnutrition in this group of patients is significantly lower in comparison with standard therapy and previous experience. Most of the patients were well nourished and we observed trends toward overweight and sarcopenic obesity in some patients. A slight decrease in REE in the whole sample could be a reflection of impact of biological therapy on fat tissue and profound modulation of lipid metabolism as well as decreased muscle mass and physical activity level of the patients.
P115 Real-world experience of peri-operative treatments on surgical complications after Ileo-caecal resection in Crohn’s disease
Authors: Di Stefano S , Liefferinckx C , Cremer A , Amininejad L , Van Gossum A , Devière J , Van de Stadt J , Franchimont D , Buggenhout A
Published: January 2020

Background

The current recommendations remain vague as to whether biologics are safe or deleterious when surgery is contemplated in patients with Crohn’s disease (CD). Conflicting data do not enable to adopt a definitive position on the time to surgery. The aims of this study were to evaluate the impact of perioperative treatments on the rate of surgical complications and to report surgical recurrence rate of CD after ileo-caecal (IC) resection.

Methods

This was a retrospective monocentric cohort study of consecutive CD patients who underwent IC resection between 1996 and 2018. An ethical committee has been approved (P2019/376). The overall rate of surgical complications was evaluated within 30 days after surgery. The effect of pre- and postoperative treatments was assessed on overall morbidity, general and infectious complications, anastomotic leakage and risk factors. Statistical analyses were performed using SPSS.

Results

Demographic data of the 165 CD patients who underwent a primary IC resection are presented in Table 1.

The median age at time of the first IC resection was 35 years (IQR 24–44) while the median follow-up was 6.1 years (IQR 1–11). The overall rate of complications was 18% including 8.7% and 3.3% patients with infectious complications and anastomotic leakage, respectively. No risk factors have been found to be associated with surgical complications. In particular, immunosuppressants and biologics did not increase the risk of surgical complications. Twenty-four per cent of patients (n = 39/160) needed a second IC resection due to stenosis at the anastomosis site in 69.2% of cases (n = 27/39). Surgical recurrence was found to increase linearly over time with a second surgery after a median follow-up of 8 years (IQR 2–12). Anti-TNF used as post-operative treatment had a protective role on surgical recurrence in multivariable regression with odd ration (OR) of 0.15, p = 0.001 (Table 2).

Conclusion

Prevalence of complications after an IC resection in CD patients was of 18% in this retrospective monocentric cohort. No risk factors were found to be associated with surgical complications. Anti-TNF seems to have a protective role on surgical recurrence.
P127 Lemann Index for Assessment of Crohn’s disease association with the quality of life, endoscopic disease activity and magnetic resonance indices of activity
Authors: Straksyte V , Kiudelis G , Kupcinskas L , Zaboriene I
Published: January 2020

Background

Crohn’s disease (CD) is one of the subtypes of idiopathic inflammatory bowel disease and is characterised by continuing inflammation and progressive gut damage. Despite many scoring indices of CD, there is a lack of more global assessment tools for the evaluation of the total disease impact on the gut.

Methods

One hundred adult patients with proven CD underwent magnetic resonance enterocolonography (MR-EC), colonoscopy and clinical activity assessment. Patients’ quality of life was assessed by IBDQ. MR-EC was used to evaluate the Magnetic Resonance Index of Activity (MaRIA- global (G)), modified (m)MaRIA-G, Clermont-G and the Lemann Index (LI). The CD Endoscopic Index of Severity (CDEIS) was used to score the endoscopic activity of the disease.

Results

LI and IBDQ (r = −0.813, p < 0.01) showed a strong negative correlation. IBDQ also demonstrated a strong negative correlation with other MR-EC indices: MaRIA-G, mMaRIA-G and Clermont-G (r = −0.731, r = −0.749, r = −0.726, p = 0.01) respectively. Moreover, there was a moderate correlation between MaRIA-G and CDEIS, also MaRIA-G and LI, respectively (r = 0.698 and r = 0.658, p = 0.01). As well as MaRIA-G and LI, other MR-EC indices mMaRIA-G and Clermont-G showed good correlation with CDEIS (r = 0.580 and r = 0.585, p = 0.01).

Conclusion

A strong negative correlation between LI and the quality-of-life measured by IBDQ was determined. This correlation was less pronounced when using the MaRIA-G index; therefore, the LI could be more helpful in assessing more global characteristics of the disease, besides the inflammatory activity of the gut.
P128 Colorectal cancer surveillance with chromoendoscopy in inflammatory bowel disease: results from a real life experience
Authors: Rubín De Célix Vargas C , Chaparro M , Moreno J A , Santander C , Gisbert J P
Published: January 2020

Background

Patients with inflammatory bowel disease (IBD) are at increased risk for developing colorectal cancer (CRC). Recent practice guidelines suggest the use of chromoendoscopy with targeted biopsies to identify dysplastic lesions. The aim of this study was to know the dysplasia detection rate with chromoendoscopy in a real life cohort and to describe endoscopic characteristics of the lesions detected and their management.

Methods

Single-centre retrospective and observational study of all chromoendoscopies done between January 2016 and May 2019 in adult patients with left-sided/extensive ulcerative colitis or Crohn’s disease involving more than one-third of the colon. All polyp characteristics were collected (localisation, size, Paris and Kudo classifications) and their treatments received (endoscopic resection or surgery).

Results

One hundred and eighty-six chromoendoscopies on 160 patients were included. Of all chromoendoscopies, the dysplasia detection rate was 24% (23% of patients had dysplasia in any chromoendoscopy done during the period of the study). Ninety-two patients (57%) were men. Eighty-six (54%) had ulcerative colitis, 72 (45%) Crohn’s disease and 2 (1%) non-classifiable IBD. Twenty-five (15%) had family history of CRC. 118 (74%) received treatment with aminosalicylates, 67 (42%) with thiopurines and 42 (26%) with biologics. A total of 212 lesions were detected, 94% were located in areas of mucosa close to the segment affected by IBD. Most of them were located in the rectum (36%) and left colon (30%). More than half of the lesions were flat polyps (31% Paris 0-IIa, 25% Paris 0-IIb). The most frequent Kudo pit pattern was Kudo II (43%) and Kudo IIIs (33%). A total of 123 (58 %) lesions were non-neoplastic and 74 (35%) were neoplastic. Among these, 69 (93%) were low-grade dysplasia and five were high-grade dysplasia: 5/5 located in rectum, and one of them could not be suitable for endoscopic resection. Twelve lesions could not be retrieved. Only five patients (3%) required surgical treatment. In the univariate analysis, the presence of dysplasia was not related with age, sex, smoking, or type of IBD. Dysplastic lesions were more frequently localised distal to the splenic flexure (OR, 0.543; 95% CI, 0.30–0.99; p < 0.05) compared with non-dysplastic lesions; they were non-polypoid lesions: Paris 0-IIa, 0-IIb, 0-IIc (OR, 0.11; 95% CI, 0.02–0.59; p < 0.001). The polyp size was not a predictor of dysplasia.

Conclusion

This study reports a high dysplasia detection rate (24%) via targeted chromoendoscopic biopsies in a real life cohort. Endoscopic resection removed the lesions in most of the cases; only 3% of patients need surgery (partial colectomy). Our results underlines the importance of colorectal cancer surveillance in IBD patients.
P132 Performance of a severity score in risk stratification of patients with ulcerative colitis
Authors: Morão B , Frias Gomes C , Gouveia C , Costa Santos M P , Torres J
Published: January 2020

Background

Patient stratification according to the risk of developing complications is an essential step to define the best treatment approach in patients with ulcerative colitis (UC). Recently, Siegel et al (Gut 2017) published a score that aims to access the disease severity, considering disease activity (both clinical and endoscopic factors) and complications during the disease course, ranging from 0 to 100 values (higher values indicating worse disease severity). Our goal was to evaluate the capacity of this score calculated at the time of diagnosis (dx) to predict disease course during follow-up (FU): steroid use, therapy escalation to immunomodulators or biologics, hospitalisation and/or abdominal surgery.

Methods

Retrospective cohort study including incident cases of UC in our centre between December 2012 and December 2018. We calculated the score at the time of dx and at the end of FU and collected data about disease course.

Results

Eighty-five patients (57% men with a mean age of 43 ± 17 years) with newly diagnosed UC were included. Disease extension according to Montreal was E1 in 30/85 patients, E2 in 37/85 patients and E3 in 18/85 patients. Median FU time was 40 months. Median risk score at the time of dx was 30 (IQR 3–91) and it was higher in patients with younger age (36 vs. 26, p = 0.08) and extensive colitis (64 vs. 26, p < 0.001). During FU, 19/85 and 17/85 patients needed steroid use and therapy escalation, respectively. Proximal disease extension occurred in one patient. Hospital admission for acute exacerbation and/or colectomy was required in 6/85. The score at dx was higher in patients who underwent hospital admission or colectomy (score: 70 vs. 26, p = 0.002), or that needed steroid (score: 57 vs. 26, p < 0.001) or therapy escalation (score: 57 vs. 26, p < 0.001) during FU. In a survival analysis, the time for steroid use (plogrank < 0.001) or therapy escalation (plogrank < 0.001) was lower in patients with a higher score at dx (61 vs. 88 months and 56 vs. 86 months, respectively). The median score at the end of FU was 3 (IQR 0–66); a second colonoscopy was not available in three patients, who were not included in this analysis. There was a score reduction in 77/82 patients (39/82 had a score of 0). Only one patient had a similar score and 4/85 patients had a higher score. Patients with a significant score reduction during FU (below the median) were more frequently patients with no need for steroid use (p < 0.001) or therapy escalation (p = 0.002).

Conclusion

This severity score seems to be a promising tool for risk stratification and prognosis determination in patients with UC, and its utility should be validated in prospective studies.
P135 Disease-related worries and concerns in UK patients with ulcerative colitis: 2-year data from ICONIC
Authors: Bhala N , Hart A , Watts D , Lewis S , Ghosh S , van Haaren S , Hansell C , Ahmad T
Published: January 2020

Background

ICONIC is the largest ongoing, prospective, multi-country observational study assessing cumulative disease-associated burden in adults with ulcerative colitis (UC) under routine care. This local subanalysis evaluated patient worries and concerns up to 2 years in UK patients using the Rating Form of inflammatory bowel disease (IBD) Patient Concerns (RFIPC) questionnaire.

Methods

Adults with early UC (diagnosed ≤36 months) were enrolled irrespective of treatment regimen or disease severity. Patients completed RFIPC, a 25-item questionnaire comprising frequently reported worries/concerns of IBD patients, at each visit (6-month intervals). Responses are scored on a 10-cm visual analogue scale for each individual question from 0 (no concerns) to 10 (a great deal). The mean of all 25 items represents the total score (lower scores indicate less worries/concerns). In this analysis, data are reported for UK patients as observed using descriptive statistics at baseline (BL, visit 1 [V1]), 1 year (V3), and 2 years (V5). Patients were stratified by physician-assessed disease severity (mild, moderate, severe, in remission) at baseline.

Results

Sixty-three UK patients were included (37 [59%] female; mean ± SD age 43.4 ± 15.7 years; median [interquartile range] time since UC diagnosis 126 (59 to 260) days; physician-assessed UC severity: mild 18 [29%], moderate 18 [29%], severe 11 [17%], in remission 16 [25%]). Mean ± SD total RFIPC scores for all patients were 2.9 ± 2.3 (n = 63) at V1, 2.7 ± 2.5 (n = 40) at V3, and 2.2 ± 2.0 (n = 35) at V5. At BL, mean ± SD RFIPC total scores by physician-assessed disease severity at BL were: mild 3.2 (1.9); moderate 2.6 (2.6); severe 4.8 (2.4); in remission 1.8 (1.7). The changes from BL to 2 years, stratified by physician-assessed disease severity at BL, were: mild −1.2 (1.4); moderate −0.7 (1.7); severe −2.2 (2.7); in remission −0.2 (1.0). The disease-related-specific concerns with the highest mean total RFIPC scores (i.e. scores >4.0) for all patients at BL were ‘energy level’, ‘having an ostomy bag’ and ‘effects of medication’. Mean total RFIPC scores for these specific concerns decreased between V1 and V5 for all patients. Of 5 UK sites, all had established multi-disciplinary teams (MDTs) and four had a psychologist in situ.

Conclusion

Despite all UK centres having MDTs and most having a psychologist in situ, this subanalysis from ICONIC demonstrated a high burden of worries and concerns in early UC patients with more severe disease. These concerns were most notable at BL, and appeared to decrease over time. The greatest concerns were with the treatment and complications of the disease; this included concerns about energy levels, highlighting that fatigue remains an unmet need for UC patients.