bluuebunny/crossref_metadata_2025_split huggingface dataset:
P063 Expression of the coinhibitory receptor TIGIT on memory CD4+ T cells is induced by TCR ligation and retinoic acid co-stimulation and is elicited during microbial colonization of the intestine
Authors: Barendregt D , Joosse M E , van Berkel L A , van Schoonhoven A , Samsom J N 
Published: January 2022

Abstract

Background
The coinhibitory receptor T cell immunoglobulin and ITIM domain (TIGIT) is widely expressed by immune cells, including CD4+ T cells. Previously, we showed that circulating gut homing CD38+ (CD62LnegCD4+) effector T cells are enriched for TIGIT+ cells with an immunoregulatory phenotype. In newly diagnosed inflammatory bowel disease (IBD) patients, low frequencies of regulatory TIGIT+ cells in circulating gut homing CD38+CD62LnegCD4+ effector T cells associate with more severe disease. IBD is a chronic disease characterized by aberrant CD4+ T cell responses to intestinal microbiota. Together, this led us to hypothesize that TIGIT+CD4+ T cells regulate immune responses to intestinal bacteria thereby maintaining intestinal homeostasis.

Methods
We studied TIGIT expression in subpopulations of murine and human intestinal CD4+ T cells. In addition, we assessed the signals required for the induction of TIGIT expression in vitro using CD4+ T cells isolated from human healthy donor peripheral blood.

Results
TIGIT was expressed by more than 50% of memory, but not naïve, CD4+ T cells in the intestinal lamina propria of both mouse and human. Both Foxp3+ and Foxp3neg intestinal CD4+ T cells expressed TIGIT. Intestinal TIGIT expression depended on the presence of microbial antigens, as conventionalization of germ-free mice with specific-pathogen free (SPF) microbiota dramatically increased TIGIT expression in both small intestine and colon. T cell receptor (TCR) ligation mimicked by anti-CD3 stimulation was essential to induce TIGIT expression on CD4+ T cells isolated from human peripheral blood, but CD28 co-stimulation led to reduced TIGIT expression. TIGIT expression could only be induced on antigen-experienced CD4+ memory T cells, but not naïve CD4+ T cells. Using the calcium ionophore ionomycin and the calcineurin inhibitor tacrolimus, we demonstrated that the induction of TIGIT expression upon TCR ligation depended on downstream calcium-dependent signaling. We next assessed whether retinoic acid (RA), a metabolite produced by intestinal antigen-presenting cells (APCs), can further enhance TIGIT expression. RA plays an important role in mucosal immune responses, as it promotes the development of Foxp3+ regulatory T cells and induces the expression of the gut-homing markers CD38 and α4β7. We showed that co-stimulation with RA also significantly enhanced TCR-induced TIGIT expression, as it increased both the mean fluorescence intensity (MFI) and frequencies of TIGIT+ cells in CD4+ memory T cells.

Conclusion
In conclusion, these data argue that TCR ligation and retinoic acid production by intestinal APCs induces TIGIT expression on CD4+ memory T cells, which in turn may contribute to regulation of immune responses against microbial antigens.
P088 Metabolomic analysis reveals differences among UC and non-IBD human colonic resections: role of GPCRs
Authors: Bauset C , Carda-Diéguez M , Buetas E , Coll S , Lis-López L , Seco-Cervera M , Navarro F , Mira Á , Calatayud S , Barrachina M D , Cosín-Roger J 
Published: January 2022

Abstract

Background
Metabolomics is a recent technique that has bounced into Inflammatory Bowel Diseases (IBD) due to its capacity to elucidate specific metabolites involved in the pathology and changes in the metabolomic profile have been detected in urine, blood or feces from UC patients. G-protein coupled receptors (GPCRs) have been recently identified as promising pharmacological targets. We aim to characterize the metabolomic profile and metabolite-sensing GPCRs expression in colonic resections from UC patients.

Methods
Colonic resections from UC (n=18) and non-IBD (n=20) patients were obtained. Metabolomic analysis was performed using Nuclear Magnetic Resonance (NMR) to study polar metabolites and Gas-Chromatography or Liquid-Chromatography Mass-Spectrometry to study non-polar metabolites. Results are expressed as μg of metabolite per gram of tissue. Gene expression of GPCRs was analyzed by qPCR. Data were expressed as fold induction vs control (mean±SEM) and compared by a t-test. A p-value&lt;0.05 was considered statistically significant. Pearson correlation matrix were performed with R or mixOmics library in R.

Results
Metabolomic analysis revealed in colon of UC patients significant increased levels of propionic acid (7.7±1.1), undecanoic acid (0.3±0.02) decanoic acid (4.5±0.9), myristic acid (64.5±8.7), α-linoleic acid (23.1±4.0), aspartic acid (33.9±3.4), phenylalanine (8.8±1.6), glutamic acid, (136.3±10.8), b-hydroxybutyric (8.3±0.9) acid and lactic acid (297.5±34.7) vs non-IBD patients. Gene expression of GPR43 (22.7±9.5), GPR41 (4.7±1.7), GPR109a (19.1±5.3), GPR109b (13.6±4.6), GPR91 (13.2±5.7), GPR84 (6.7±2.0), GPR40 (6.6±1.8), GPR65 (3.0±0.5) and GPR68 (4.6±1.0) were significantly increased in UC patients compared with controls. In contrast, GPR120 (0.9±0.3), GPR119 (0.6±0.2) and GPR35 (0.5±0.1) were significantly reduced in UC patients. N-oleylethanolamide positively correlates with most of GPCRs, especially GPR68, GPR84 and GPR91 while acetic and succinic acids negatively correlate with GPR4 (Fig.1A). In UC patients, medium-chain fatty acids (FA) and most long-chain FA positively correlate with GPR84, GPR142, GPR43, GPR109a, GPR109b, GPR91 and GPR132 (Fig. 1C).

Fig1. Graphs show the correlations between data relative to mRNA expression of GPCRs (expressed as ΔCt) vs metabolites. (A) Data from controls and UC. (B) Only controls. (C) Only UC.

Conclusion
Increased levels of several metabolites and GPCRs are detected in the colon of UC patients and their correlations suggest potential candidates to be involved in UC pathophysiology.
P106 Macrophages as a source of NOTCH Ligands in Crohn’s disease: implications in fibrosis
Authors: Edo M M , Macias-Ceja D C , Bauset C , Lis L , Coll S , Seco-Cervera M , Cosin-Roger J , Calatayud S , Barrachina M D , Ortiz-Masiá D 
Published: January 2022

Abstract

Background
Fibrosis constitute the main complications associated to Crohn′s disease (CD). NOTCH signalling has been implicated in lung, kidney, liver and cardiac fibrosis. Macrophages contribute to fibrosis through the release of different mediators and the pattern of secretion may vary according to their microenvironment. The aim of the present study is to analyze the role of NOTCH ligands derived from macrophages in the complications of CD.

Methods
The aim of the present study is to analyze the role of NOTCH ligands derived from macrophages in the complications of CD. We have analyzed: the protein expression of NOTCH ligands and receptors in CD patients with fistulizing (B3) and stenting pattern (B2), the protein expression of NOTCH ligands in macrophages treated with the main cytokines present in CD patients (IFNγ-, IL10-, IL4, TNFα-U937 treated cells), the protein expression of HES1 and fibrosis markers in DLL4-HT29 and DLL3-HT29 treated cells. Results are expressed as fold induction (mean±SEM). Statistical analysis was performed with one-way ANOVA followed by Newman-Keuls test or t-tet.

Results
The expression of DLL4 and NOTCH4 were significantly higher in intestinal samples from B3 CD patients (3,2 ± 0,6 N=4* and 3,8 ± 0,6 N=8*, respectively) than in B2 patients (1,6 ± 0,2 N=4 and 1,7 ± 0,3 N=8, respectively) and controls (1,0 ± 0,1N=3 and 1,0 ± 0,1 N=8, respectively). IFNγ-U937 treated cells increased significantly the protein expression of DLL3 and DLL4 (1,6 ± 0,09 N=6* and 1,3 ± 0,1 N=7*, respectively) respect vehicle; IL4 increased significantly the expression of DLL4 (1,4 ± 0,1 N=7*) and TNFα increased significantly the expression of DLL3 (1,4 ± 0,1 N=5*), respect vehicle. DLL4-HT29 treated cells increased significantly fibrosis markers (VIMENTIN: 1,7 ± 0,1 N=3*; SNAIL: 2,2 ± 0,2 N=3*) and HES1 (1,4 ± 0,06 N=3*), respect vehicle (1,0 ± 0,07 N=6; 1,0 ± 0,05 N=6; and 1,0 ± 0,05 N=6, respectively). DLL3-HT29 treated cells only produced a reduction in the protein expression of ECADHERIN (0,4 ± 0,1 N=3*), respect vehicle (1,0 ± 0,09 N=6).

Conclusion
Macrophages may act as a source of NOTCH ligands who could act as fibrosis mediators in CD patients with a fistulizing (B3) behavior. The microenvironment rich in IFNγ could activate the fibrosis process in epithelial cells by favoring the expression of DLL4 and DLL3 in macrophages. DLL4 mainly activates transcription factors involved in mesenchymal epithelial transition in colonic epithelial cells (SNAIL), while DLL3 seems to have a more relevant role in cell-cell junction modification (ECADHERIN).
P111 Gut barrier markers in Inflammatory Bowel Disease
Authors: Nguyen A , Sparrow M P , Moore G , Gibson P R 
Published: January 2022

Abstract

Background
Blood monitoring for disease activity in inflammatory bowel disease (IBD) is largely limited to C-reactive protein (CRP), but this may be raised in other inflammatory conditions and normal in active disease. Aims were to: (a) compare plasma levels of putative gut barrier markers, lipoprotein polysaccharide-binding protein (LBP), soluble CD14 (sCD14), syndecan-1 and intestinal fatty acid-binding protein 2 (IFABP2) in patients with IBD with those in controls; (b) define association with inflammatory activity; (c) examine responsiveness to change after biologic induction therapy.

Methods
Plasma was prospectively collected from patients with IBD and matched healthy controls. IBD was considered active with faecal calprotectin (FCP) ≥150 μg/g and/or an intestinal ultrasound showing a Limberg score ≥2. Gut barrier markers were compared to FCP and CRP. In a subset of patients who commenced on biologic therapy, they were measured at baseline and at least 14 weeks later. Biomarker concentrations were described as medians and spearman correlation was used for comparison with traditional biomarkers.

Results
101 patients with IBD and 51 controls were matched in age (33 vs 34 years) and gender (males 54% vs 47%). Treatment for IBD included aminosalicylates (38%), immunomodulators (47%), biologics (58%) and steroids (20%). In Crohn’s disease (n=60), distribution was ileal (45%), ileocolonic (30%) and colonic (25%); 31 had active disease. In ulcerative colitis (n=41), distribution was pancolitis (63%), left-sided (29%) and proctitis (7%); 18 had active disease. Compared with controls, patients with IBD had higher levels for LBP (13.6 vs 10.1 μg/ml; p&lt;0.0001), sCD14 (1.3 vs 1.2 μg/ml; p&lt;0.001) and LBP:sCD14 ratio (11 vs 8.8; p=0.002), but lower levels for syndecan-1 (19.4 vs 30 ng/ml; p=0.006) and IFABP2 (1452 vs 1696 pg/ml; p=0.015).

Only LBP differentiated between active and inactive disease in Crohn’s disease (16.1 vs 13.5 μg/ml; p=0.045) and ulcerative colitis (16.7 vs 10 μg/ml; p=0.012). LBP, and not other markers, correlated with FCP in all patients with IBD (r=0.46; p&lt;0.001). LBP and sCD14 correlated with CRP (r=0.7 and r=0.46; p&lt;0.001). The best cut-off value for LBP in detecting active disease was &gt;15.9 μg/ml (AUC 0.71, sensitivity 57%, specificity 82%). In 18 patients who underwent biologic induction, LBP (17.1 to 13.8 μg/ml; p=0.094) and sCD14 (1.5 to 1.3 μg/ml; p=0.064) tended to fall.

Conclusion
Of putative barrier markers, only those associated with bacterial translocation (LBP, sCD14) were elevated in IBD with epithelial markers (syndecan-1, IFABP2) paradoxically reduced. Only LBP was associated with active disease though its responsiveness to therapy is uncertain and requires further prospective study.
P115 Implementation of a vaccination tool in the electronic patient health record significantly increases vaccination coverage
Authors: Fierens L , De Dycker E , Joly J , Vanhoutvin T , Verschueren P , De Haes P , Sabino J , Vermeire S , Ferrante M 
Published: January 2022

Abstract

Background
Patients with immune-mediated inflammatory diseases (IMID) are at higher risk for infectious diseases. Despite this increased risk and the available guidelines1, we reported a sub-optimal vaccination rate of 27.4% of IMID patients in 2018. In the meantime, a vaccination module was introduced in the electronic patient health record of our hospital to accurately document and monitor vaccination status of patients. The impact of this new module on vaccination coverage was re-evaluated in the same IMID patients in 2021.

Methods
Between Aug and Oct 2021, the vaccination status of 1448 (out of the original 1488) IMID patients (44.8% male, median age 53.6 years) was collected (798 patients with IBD, 612 with rheumatological, and 38 with dermatological inflammatory conditions) and compared to that of 2018. The vaccination status was obtained mainly through the patients’ electronic medical records. Missing data were added after contacting patients or their general practitioner.

Results
From 2018 to 2021, the overall vaccination coverage of all IMID patients significantly increased from 27.4% to 51.9% (p&lt;0.001, Figure 1).
The vaccination coverage in IBD patients increased significantly from 75.9% to 86.3% for influenza (p&lt;0.001), from 72.9% to 88.7% for pneumococci (p&lt;0.001), from 66.0% to 80.2% for hepatitis B (p&lt;0.001), from 79.9% to 85.7% for tetanus (p=0.041) and from 42.2% to 60.4% overall (p&lt;0.001) (Figure 1 and Table 1).
Similarly, the vaccination coverage significantly increased for rheumatology patients, namely from 69.3% to 78.3% for influenza (p&lt;0.001), from 34.5% to 85.0% for pneumococci (p&lt;0.001), from 32.8% to 36.5% for hepatitis B (p&lt;0.001) and from 7.8% to 32.6% overall (p&lt;0.001) (Figure 1 and Table 1).
For patients with dermatological inflammatory conditions, vaccination coverage significantly increased from 60.5% to 81.6% for pneumococci (p=0.031) and from 47.1% to 55.3% for hepatitis B (p=0.002) (Table 1).

Conclusion
The suboptimal vaccination rate measured in 2018 and the COVID-19 pandemic stressed the importance of vaccination recommendations to patients and healthcare professionals. We here show that the implementation of a vaccination tool integrated in the electronic medical record of patients is correlated with a significant increase in specific vaccination rates and also in the total amount of IMID patients that were fully vaccinated according to guidelines.

Reference
1. Rahier JF, Magro F, Abreu C, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8:443–468.
P129 Hepcidin and ferritin index can help to differentiate between different types of anaemia: an exploratory study
Authors: Bevers MD N , Adriaans G M C , Aliu A , Rezazadeh Ardabili A , Vreugdenhil A C E , de Almeida R , van Rheenen P F , Pierik M J 
Published: January 2022

Abstract

Background
Anaemia is frequent in patients with IBD. Iron deficiency anaemia [IDA] and anaemia of chronic disease [ACD] are the most common subtypes and warrant a different treatment approach.
The ESPGHAN/ NASHGAN position paper on Anaemia in Children with IBD describes cut-off values on ferritin, transferrin saturation [TSAT] and ferritin index (soluble transferrin receptor/log10(ferritin)) [sTfR-F], to distinguish between IDA and ACD. However, cut-off values for sTfR-F and hepcidin are based on adult data.
In this exploratory study we used a data driven approach to define different anaemia groups, using hepcidin and sTfR-F and studied differences between groups and their response to iron suppletion therapy. Insights contribute to a better description of ACD and IDA in a pediatric population.

Methods
Data from the multi-centre prospective POPEYE study (NTR4487) consisting of a paediatric IBD population was used. Subjects with anaemia (haemoglobin [Hb] &lt; 2 standard deviations [SD] below the mean of a healthy age reference group) with baseline ferritin, TSAT, hepcidin, sTfR-F and erythrocyte sedimentation rate [ESR] values were selected. Summary statistics of these biomarkers were generated for the data-driven groups and compared with existing characteristics for IDA and ACD groups. At baseline subjects received oral or intravenous iron repletion therapy, Hb was determined at baseline and 1 month after iron therapy. Kmeans was used, an unsupervised clustering algorithm using Euclidean distance, to divide data points into k clusters based on sTfR-F and hepcidin.

Results
Mean age was 13.6 (2.5 SD) years, and mean standardized Hb value -3.2 at baseline for 47 subjects. Data driven groupings using Kmeans (k=3) were based on baseline hepcidin and sTfR-F (figure 1).
Group 1 shows characteristics indicative for IDA, with mean ferritin &lt;15µg/l, TSAT &lt; 20% and sTfR-F &gt; 2. Group 2 shows signs suggestive for inflammation since ferritin, hepcidin and ESR were increased (mean ESR 28,5 mm/h [23,2 SD]); this group could be characterized as ACD. Group 3 could not be related to a specific anaemia type.
Mean standardized Hb increase 1 month after iron repletion for 37 patients, was 2,9 (SD 0,8), 0,8 (0,7 SD), 1,3 (1,1 SD), for group 1, 2 and 3 respectively.

Conclusion
Explorative data-driven analysis of a real-world data set showed that hepcidin and sTfR-F can be used to characterize groups that relate to ACD and IDA in a paediatric population. Children with high sTfR-F and low hepcidin possibly benefit more from iron repletion therapy (group 1), compared to when hepcidin is high (group 2). If validated in a larger patient population this determination could contribute to the development of diagnostic algorithms that support targeted therapy.
P136 Risk of polyps and colorectal cancer in patients with microscopic colitis: case-control study with long-term follow-up
Authors: Fajardo I , Zabana Y , Salas A , Aceituno M , Ruiz L , Esteve M , Fernández-Bañares F 
Published: January 2022

Abstract

Background
A previous study (Fernandez-Bañares et al, UEGJ 2016;4s: A434) showed that in microscopic colitis (MC) there is a low frequency of polyps and colorectal cancer (CRC) compared to the general population at medium risk, without observing differences with a group of chronic diarrhoea and normal colonic histology. The aim of the present study is to assess whether this low incidence of adenomas in patients with MC and chronic diarrhoea persists in the long term.

Methods
Patients with follow-up colonoscopies for control of colonic polyps or for diarrhoea recurrence after index colonoscopy were included in two groups: patients in the MC group (32/100 patients, Group A) and in the chronic diarrhoea group (68/200 patients, Group B). Colonic polyps were recorded, collecting adenomas, advanced adenomas (AA; high-grade dysplasia -HGD-, villous component and size &gt; 1cm) and CRC. A conditional logistic regression analysis was performed (COXREG: 1 case-2 controls, matched by age and sex).

Results
With a median follow-up of 9 years (IQR =7–12 years), 2 CRC were diagnosed in Group B (2/200). A total of 44 colonoscopies were performed in Group A and 105 in Group B, with no significant differences between groups (p=0.35). Recurrent diarrhoea was present in 25% of Group A and 38% of Group B (p=0.19). In these endoscopies, the total frequency of adenomas was: Group A 28% and Group B 56% (p=0.009). The frequency of AA was: Group A 12.5% and Group B 14.7% (p=1). The frequency of HGD/CRC was 0% in Group A and 5.8% in Group B (p=0.30). For adenomas, the COXREG OR was 0.2 (CI=0.05–0.75; p=0.017) and for AA (with CRC included) 0.8 (CI 0.26–2.9; p=0.8).

Conclusion
After long-term follow-up, patients with MC have a decreased frequency of adenomas and a trend to have less HGD/CRC compared with patients with chronic diarrhoea and normal colonic histology. These differences, therefore, are probably due to the MC itself and not to a protective effect of diarrhoea, as had been previously suggested. These results support the recommendation of not doing specific screening for CRC prevention in patients with MC.
P139 Body composition and Crohn’s disease behavior: Is adiposity the main game changer?
Authors: Morão B , Velho S , Agostinho L , Torres J , Cravo M 
Published: January 2022

Abstract

Background
Introduction: Visceral fat has been associated with unfavorable outcomes in Crohn’s disease (CD) patients. We investigated the association between body composition upon diagnosis and complicated phenotypes and time until surgery in patients with CD.

Methods
retrospective cohort study including patients with CD who had a computed tomography enterography (CT) or an entero magnetic resonance (MR) performed within 6 months of diagnosis. Skeletal muscle, visceral and subcutaneous adipose tissue cross-sectional areas were determined with CT or MR images at L3 vertebrae level, after being processed with Slice-o-Matic (Tomovison) and ABCS module (applicable only to CT scan images). Logistic regression was used to assess predictors of disease behaviourand time until abdominal urgery was modeled with proportional hazards Cox models.

Results
We included 63 patients: 33(52%) men with median age of 35 years. Disease location and behaviour according to Montreal classification was as follows: L1=28(44%), L2=13(21%), L3=18(28%), L1+L4=1(2%), L3+L4=3(5%); B1=39(62%), B2=11(17%), B3=13(21%); 20(32%) patients had perianal disease. At diagnosis, 17(27%) patients were treated with corticosteroids. Anti-TNF agents were started in 8(13%) patients, azathioprine in 23(36%), combination therapy in 15(24%); 17(27%) patients did not start any medical therapy. Visceral obesity was present in 12(19%) patients at diagnosis. Visceral obesity was associated with higher age of CD onset (median 60 vs 34 years, p=0.002) and complicated disease behaviour(B2/B3) at diagnosis (66.7% vs 31.7%, p=0.021), with an approximately 4 times higher risk of complicated behaviour(OR=4.37, 95%IC=1.19–18.44, p=0.03).After adjusting for age and perianal disease, total adipose tissue (visceral and subcutaneous fat) remained statistically significant and was associated with a 4% increase in the odds of complicated behaviourat diagnosis per 10 cm2of total adipose tissue (OR 1.004,95%CI 1.00–1.008, p=0.043). Median follow-up time was 3.35 years, during which 15 (24%) of patients underwent abdominal surgery. Visceral obesity was associated with a 5.10 times higher risk of abdominal surgery during follow-up (95%CI 1.52–17.09, p=0.008); after adjusting to disease behaviour, visceral obesity maintained a near significant association with a 2.90 times higher risk of surgery (95%CI 0.83–10.08, p=0.09).

Conclusion
In our cohort of patients with newly diagnosed CD, total fat upon diagnosis seems to be associated with B2 and B3 disease phenotypes. Furthermore, visceral obesity was associated with a 5.10 times higher risk of abdominal surgery during follow-up and with a shorter time until surgery.