bluuebunny/crossref_metadata_2025_split huggingface dataset:
P064 3-oxo-C12:2, a Quorum Sensing molecule from the gut, exerts anti-inflammatory effects through a bitter taste receptor
Authors: Coquant G , Aguanno D , Peyrottes A , Brot L , Belloir C , Briand L , Grill J P , Thenet S , De Sordi L , Seksik P 
Published: May 2021

Abstract

Background
Acyl-Homoserine Lactones (AHLs) are Quorum Sensing molecules involved in the communication network of bacteria and can also have an impact on the host’s cells. We recently showed, in the gut ecosystems, the presence AHLs and among them we identified one that has never been described: 3-oxo-C12:2. This molecule was decreased in Inflammatory Bowel Disease (IBD) patients, especially during flare, and its presence was correlated to normobiosis. Interestingly, 3-oxo-C12:2 is structurally close to an AHL well described and synthesized by P. aeruginosa, 3-oxo-C12. We intent to describe 3-oxo-C12:2 effects on gut inflammation and to identified which signalling pathways are involved. Given its analogous structure to 3-oxo-C12, we hypothesized that 3-oxo-C12:2 can interact with the same cellular partners, in particular a bitter taste receptor (BTR), called T2R138, which is a GPCR expressed by immune and epithelial gut cells.

Methods
To test our hypothesis, we used murine macrophages cell line RAW264.7, stimulated by interferon-ɣ (IFN-g, 20U/mL) and lipopolysaccharide (LPS, 10ng/mL). We performed a transcriptome analysis using RNAseq to identify inflammatory pathways involved in the effects. Inflammatory response was monitored by measuring cytokine secretion TFNα via ELISA. Probenecid, a known allosteric inhibitor for T2R138, was used to study T2R138 role in AHL signalling. BTR screening assay was performed to extend search for 3-oxo-C12:2 receptors. Cytotoxicity was measured via Lactate Dehydrogenase release.

Results
After LPS/IFN-γ activation, we observed a decrease of secreted TNFα when cells are exposed to 3-oxo-C12:2, in a dose dependent manner: 15μM (-30%, p&lt;0.05), 25μM (-50%, p&lt;0.001) et 50μM (-65%, p&lt;0.0001), no change were observed in steady state. Itreflects an anti-inflammatory effect, without increasing cytotoxicity. To identify mechanisms behind those effects, we analysed the transcriptome of RAW264.7 cells exposed to AHL. JAK-STAT and NF-κB pathways were differentially down-regulated in presence of 3-oxo-C12:2. In addition, the anti-inflammatory effects were lost in presence of Probenecid, a T2R138 inhibitor. In a BTR screening assay, we confirmed that 3-oxo-C12:2 activates T2R38, but also five other BTR (T2R13, T2R8, T2R14, T2R1, T2R10).

Conclusion
3-oxo-C12:2 exerts a dose dependent anti-inflammatory effect on murine immune cells. This response is partly mediated by the bitter taste receptor T2R138. This receptor is a potential target of our AHL of interest and we are currently studying the inflammatory pathways involved behind those effects. Studying the signalling between the receptor and the anti-inflammatory response would allow us to better understand the inter-kingdom dialogue between microbiota involving AHL in IBD.
P073 An increased autophagy and decreased apoptosis is detected in intestinal fibroblasts from Crohn’s Disease patients
Authors: Gisbert-Ferrandiz L , Queralt M , Cosín-Roger J , Coll S , Bauset C , Ortiz-Masia D , Llau J , Navarro-Vicente F , Calatayud S , Barrachina M D 
Published: May 2021

Abstract

Background
Fibrosis is a complication commonly present in Crohn’s disease (CD) patients with a structuring (B2) or penetrating (B3) phenotype, with no effective treatment. This process is characterized by a disequilibrium between the production and degradation of the extracellular matrix (ECM), mainly regulated by myofibroblasts. We aim to analyse here, the expression of markers of autophagy, apoptosis and proliferation in intestinal fibroblasts from CD patients.

Methods
Fibroblasts were isolated from the damaged intestinal mucosa of CD patients with a penetrating and stenotic behaviour. Control cells were obtained from the non-damaged intestine of patients with colorectal cancer. Protein levels of markers of autophagy and apoptosis were determined by Western Blot in isolated fibroblasts. The proliferation marker Ki67 was analysed by immunohistochemistry (IHC) in 5 µm slides of intestinal tissue from control or CD patients. Statistical significance was measured by t-test.

Results
In fibroblasts from CD patients, we detected a significant decrease in the ratio phospho-mTOR / mTOR (Fig. A) in parallel with a non-significant increment in the LC3 II / LC3 I protein ratio (174% ± 46.5), and a decrease in p62 protein levels (84.8% ± 5.5). When compared between CD behaviours, a significant decreased in the phospho-mTOR / mTOR protein ratio was detected in fibroblasts from B2- compared to that obtained in cells from B3-CD patients (Fig. B). The analysis of the expression of an apoptosis marker, Caspase 3, revealed a decreased of cleaved caspase 3 protein levels in CD fibroblasts compared to levels detected in control cells (Fig C). Finally, we observed in the lamina propria of the intestine from CD patients an increased number of Ki67 positive cells, compared to that detected in control tissue.

Conclusion
Our data show an increased autophagy and decreased apoptosis in isolated intestinal fibroblasts from CD patients; the high number of cells proliferating in the lamina propria of the intestinal tissue of these patients, strongly suggests a higher viability of these cells in the fibrotic context.
P082 Assessment of anti-inflammatory effect of high acetate administration in UC patient-derived epithelial monolayer cultures
Authors: Deleu S , Arnauts K , Machiels K , Huys G R B , Thevelein J , Raes J , Vermeire S 
Published: May 2021

Abstract

Background
Human organoid-based intestinal monolayer cultures provide an interesting tool to preclinically assess new therapeutic properties in inflammatory bowel disease (IBD). Recently, short-chain fatty acids (SCFA) such as acetate and butyrate have gained interest for their potential beneficial effects in IBD therapy. Most studies have focused on butyrate, given its beneficial effects on gut microbiome composition, intestinal barrier function and the immune system1. Effects of acetate are less well known, despite its lower toxicity to epithelial cells and its potential to support growth of butyrate-producing bacteria by metabolic cross-feeding2. In fact, a recent report suggested that the probiotic potential of Saccharomyces cerevisiae var. boulardii might be related to its high acetic acid production3. We here studied the effect of acetate on organoid-derived epithelial monolayer cultures from ulcerative colitis (UC) patients.

Methods
Colonic biopsies were obtained from non-inflamed regions in 3 patients with UC. Crypts were isolated, cultured and expanded as 3D-organoids. These organoids were then dissociated and transferred to transwell inserts as monolayer cultures. Upon confluency of the monolayer, evaluated by Transepithelial electrical resistance (TEER), cells were basolaterally stimulated with control medium (CTRL) or an inflammatory mix (INFL) containing 100 ng/ml TNF-α, 20 ng/ml IL-1β and 1 µg/ml Flagellin (Fig. 1). After 24h, cells were apically stimulated with control medium or high acetate (HA) (100mM). TEER was measured at 0, 24 and 48h stimulation. After 48h, cells were subjected to RNA extraction followed by reverse transcriptase qPCR targeting a selection of key diagnostic marker genes. The apical and basolateral media were collected for cytokine determination by Mesoscale (Proinflammatory panel 1). Data were analyzed using GraphPad Prism 9 (D’Agostino & Pearson test for normality followed by a Friedman test).

Results
A protective effect (Fig. 2) of high acetate administration on TEER values (HA vs INFL: p=0˒017) was observed, together with a trend towards decrease in IL8 (p=0˒11), TNFA (INFL vs INFL+HA: p=0˒68) and CLDN2 (CTRL vs HA: p=0˒03). Moreover, this was confirmed by a decrease of most proinflammatory cytokines (Fig. 3) in the apical and basolateral media upon HA stimulation e.g., IFN-γ (INFL vs INFL+HA: p=0˒25) and IL 10 (CTRL vs HA: p=0˒11).

Conclusion
In this patient-derived human epithelial cell culture model, a protective effect of high acetate administration on TEER-values, gene expression and cytokine production was observed. Ongoing experiments are expanding the number of patients to 10.

References
P106 Cromoendoscopy versus second generation Narrow band Imaging for dysplasia detection in IBD. An interim analysis of a prospective randomized control trial
Authors: Martin Arranz E , Suarez Ferrer C , García Ramirez L , Sanchez Azofra M , Rueda García J L , Poza Cordón J , Martín Arranz M D 
Published: May 2021

Abstract

Background
Colonic neoplastic risk is increased in long-standing colitis. Chromoendoscopy (CE) is the recommended screening method. Narrow band imaging (NBI) is potentially a more convenient alternative. Few studies have explored the diagnostic yield of second generation NBI (Olympus 190 series) versus chromoendoscopy.

Methods
NBICromo (NCT04403997) is an ongoing prospective randomized controlled trial in which patients with clinical indication for CE (&gt;8 years of disease, left-side or extensive colitis, colonic Crohn′s disease with &gt;2 colonic segments affected or associated primary esclerosing cholangitis) are randomized on 1:1 ratio to CE with methylene blue 0,1% or NBI. All procedures are done with Olympus HQ190 endoscopes by endoscopists with experience in IBD. Biopsies are taken from all visible lesions. Primary objective is to compare the total number of neoplastic lesions detected in each group. Secondary objectives are to compare the procedure time, the number of biopsies taken,and the accuracy of optical characterization of the lesions. The study has been approved by the Hospital Ethics Committee and patient informed consents were obtained.
Estimated sample size for the study is 175 patients, and recruitment is currently ongoing. An interim analysis was conducted with the first 75 randomized patients to exclude futility due to slowed recruitment caused by covid-19 pandemic.

Results
75 patients were randomized, 34 to CE and 41 to NBI. 10 patients were excluded due to presence of inflammation or poor bowel preparation in the colonoscopy. 65 patients were analyzed per protocol, 31 in the CE arm and 34 in the NBI arm. Mean age was 57±13 years, 46.15% were male and 53.85% female. Mean disease duration was 17.1 ± 8.3 years. No significant differences were found between groups in basal characteristics.
123 lesions were detected. 77 with CE and 46 with NBI, of these 34 (27,6%) were neoplastic (14 neoplastic lesions were found in NBI group and 19 in CE group p=0.1. Neoplastic lesions were found in 13 patients in CE group (41,9%) and 7 patients with NBI (20,5%) p=0.06. Total withdrawal time (including staining and/or therapeutics) was significantly shorter in the NBI group (17.6 ±9.8 vs 30.5 ± 16.5 min p&lt;0.001). No differences were found in biopsies numbers (2.5 ± 2.5 CE vs 1.7 ±1.6 NBI p=0.16).
AE were 1 mild post resection bleeding and 1 mild fever, both in the CE group p=0.07.

Conclusion
In this interim analysis there are no significant differences in dysplasia detection between CE and NBI, although more sample size is needed. NBI could be a more convenient alternative to CE, with significant shorter and more simple procedures. The ongoing clinical trial will be completed.
P123 Type I collagen degradation fragments and type IV collagen formation/degradation ratio are serological biomarkers for stricturing (Montreal B2) Crohn’s disease
Authors: Bourgonje A R , Alexdottir M , Loveikyte R , Bay-Jensen A C , van Dullemen H M , Visschedijk M C , Festen E A M , Weersma R K , Karsdal M A , Faber K N , Mortensen J H , Dijkstra G 
Published: May 2021

Abstract

Background
Crohn’s disease (CD) is characterized by increased extracellular matrix (ECM) remodeling, which is a key pathophysiological mechanism underlying intestinal stricture formation and other fibrotic disease complications. Alterations in intestinal ECM turnover may be reflected by products of collagen formation and degradation that are released into the systemic circulation. In this study, we aimed to investigate associations between serological biomarkers of collagen turnover and disease behavior subtypes according to the Montreal classification in patients with CD.

Methods
Serological biomarkers of collagen formation (PRO-C3, PRO-C4) and matrix metalloproteinase (MMP)-mediated collagen degradation (reC1M, C3M, C4M, C4G, C6Ma3) were measured using neo-epitope solid-phase competitive enzyme-linked immunosorbent assay (ELISA) technology in 101 patients with CD (Montreal B1: n=47; B2: n=28; B3: n=26) who were characterized according to the Montreal classification. Logistic regression modelling and receiver operating characteristics (ROC) statistics were used to assess discriminative power.

Results
Specific fragments of MMP-2,9,13-mediated degradation of type I collagen (reC1M) were significantly reduced in patients with stricturing (Montreal B2) disease compared to other disease phenotypes (B1 and B3) (P&lt;0.001). Ratios of type IV collagen formation and degradation (PRO-C4/C4M) were significantly elevated in Montreal B2 patients (P&lt;0.001). No differences in remaining serological biomarkers were observed between the different Montreal subtypes. Both reC1M and PRO-C4/C4M ratios demonstrated high discriminative power to distinguish inflammatory CD (B1) from stricturing (B2) CD, also after adjustment for confounding factors (area under the curve [AUC] 0.85 and 0.84, respectively).

Conclusion
Elevated degradation of type I collagen and excessive (relative) formation of type IV collagen strongly associate with stricturing CD (Montreal B2) and accurately discriminate it from inflammatory CD (Montreal B1). Therefore, reC1M and PRO-C4/C4M ratios could serve as serological biomarkers for stricturing CD. Our results should be validated in additional prospective, larger patient cohorts to corroborate these findings.
P146 The Toronto IBD global endoscopic reporting (TIGER) score demonstrates significant correlation with fecal calprotectin, CRP and IBD Disk in Crohn’s disease patients
Authors: Zittan E , Steinhart A H , Aran H , Milgrom R , Koifman E , Gralnek I M , Zelber-Sagi S , Silverberg M S 
Published: May 2021

Abstract

Background
Commonly used endoscopic indices in IBD lack ability to provide overall disease burden and severity, generate low inter-observer agreement, and demonstrate incomplete validation of some scores. We developed an endoscopic reporting tool, the Toronto IBD Global Endoscopic Reporting (TIGER) score for Crohn’s disease (CD) and ulcerative colitis (UC) patients. The aim of our study was to compare the usability and validity of the TIGER score against fecal calprotectin (FC), C-reactive protein (CRP) and IBD DISK score in CD patients.

Methods
A cohort of 60 CD patients participated in the study. Blinded IBD experts reviewed and graded ileocolonoscopy videos. In the validation phase, the TIGER score was compared to: (1) the Simple endoscopic Score for Crohn’s disease (SES-CD) as a reference standard and: (2) inflammatory biomarkers FC and CRP and (3) IBD Disk score.

Results
Inter-observer reliability per segment between reviewers was excellent: Interclass Correlation Coefficient (ICC)=0.94; [95%CI: 0.92–0.96]. For categorized TIGER score, lowest overall agreement was 96.6% [95%CI: 93.5–98.6] and lowest kappa 0.91 [95%CI: 0.84–0.98], reflecting excellent agreement. Overall agreement per segment between SES-CD and TIGER was 91% [95%CI: 84–95] with kappa coefficient 0.77 [95%CI: 0.63–0.91]. Per subject analysis for CD yielded overall agreement of 80% [95%CI: 64–91] and kappa coefficient 0.44 [95%CI: 0.14–0.75]. There was a significant correlation between TIGER and CRP (r s = .689, p &lt; .0083), and TIGER and FC (r s = .687, p &lt; .0001). In addition, there was significant correlation between TIGER and IBD Disk (r s = .613, p &lt; .0001).

Conclusion
The TIGER score demonstrates significant correlation with FC, CRP and IBD disk score in Crohn’s disease patients and thus can be used as a reliable and simple endoscopic score for CD patients to capture overall endoscopic disease burden.
P167 Sexual dysfunction and associated factors in young patients with Crohn’s disease
Authors: Rodríguez A , Herreros B , Muñoz R , Sempere L , Bernal L , Hurtado A , Orts B , Zapater P , Moreno O , Gutiérrez A 
Published: May 2021

Abstract

Background
The prevalence of sexual dysfunction (SD) in general population has been estimated up to 30% in women and 5% in men, and 50% and 25% in IBD patients, respectively. We aimed to compare the rates of SD in young patients with Crohn’s disease (CD) with healthy controls (HC), as well as to identify SD associated factors in CD patients.

Methods
This was a cross-sectional, case-control, observational study, including CD out-patients, aged 18–40 years-old, and HC paired by gender and age. Sociodemographic and disease features were recorded. SD was measured by the Index of Female Sexual Function(IFSF) in women, and by International Index of Erectile Function(IIFE-15) in men. Psychological functioning was evaluated using the Hospital Anxiety and Depression Scale [HAD], and quality of life in IBD by SIBDQ-9. Differences between groups were statistically compared.

Results
A total of 122 subjects were included:73 men(48 CD, 25 HC) and 49 women(21 CD, 28 HC). Nineteen percent of CD women and 8.3% of men had active disease according to Harvey-Bradshaw Index. Nineteen percent of CD women and 6.3% of men were receiving steroids, 23.8% and 14.6% immunosuppressants, and 71.4% and 72.9% biologics, respectively. CD women had more sedentary lifestyle than HC(38.1% vs 3.6%, p=0.005). In women SD rates were 35% in CD vs 12% in HC(p &lt; 0.08). Mean IFSF values were lower in CD women(27 CD vs 30 HC, p=0.02), as well as in the desire item(3.5 CD vs 4.3 HC, p=0.005). SD in men did not show significant difference between groups. Mean IIFE values differed between CD and HC(53.6 vs 67.2, p=0.001), as well as erectile disfunction, orgasm and global satisfaction(p&lt; 0.05)(Table 1). Main factors associated with an abnormal SD in CD women were high fecal calprotectine, current use of steroids, lower SIBDQ score and higher depression score(p&lt;0.05). Although disease features or current treatments did not correlate to SD in CD men, both perianal disease and surgery were associated with lower values of orgasm domain (p&lt;0.05).

Conclusion
In our serie SD was numerically higher in CD patients compared to HS. SD in CD women, but not in men, was driven by disease activity, current steroid treatment and depression.
P241 Gastrointestinal ultrasound instead of magnetic resonance enterography: Large potential cost savings with limited clinical downsides
Authors: Luber R , Petri B , Griffin N , Irving P 
Published: May 2021

Abstract

Background
Gastrointestinal ultrasound (GIUS) is a non-invasive imaging modality capable of detecting intestinal inflammation & associated complications. It has comparable sensitivity & specificity to magnetic resonance enterography (MRE) in detecting ileocolonic disease, however it is less expensive (£24 vs £180) & can be performed at point of care.
We aimed to establish the proportion of MREs that could have been performed as GIUS at a tertiary inflammatory bowel disease (IBD) unit, the potential cost savings, & the predicted pathology miss-rates.

Methods
All MREs performed in January 2018 were retrospectively reviewed. Demographics, scan indication, IBD characteristics, surgical history, & gastrointestinal & non-gastrointestinal findings were collected. Indications deemed suitable for GIUS included: assessment of disease activity of known small bowel (SB) Crohn’s disease; first assessment for presence of SB disease in IBD; & investigation for SB disease in patients without a known diagnosis of IBD. Obesity, complicated surgical history (&gt;1 resection or strictureplasty involving different segments, or stoma), & known proximal SB disease were deemed unsuitable.

Results
105 MREs were performed in January 2018. 59 (56%) were deemed suitable for GIUS instead of MRE. Most common reasons for unsuitability included complex surgical history (n=17, 37%), obesity (n=14, 30%), non-appropriate indication (n=12, 26%) & known upper gastrointestinal disease (n=10, 22%).
Of suitable cases, 32/59 (54%) had active inflammation detected including 17 (53%) isolated ileal, 8 (25%) ileocolonic, & 6 (19%) isolated colonic. In one case performed as first assessment for SB disease, both ileal & jejunal disease were found, the latter likely to be missed with GIUS. No cases of isolated upper gastrointestinal inflammation were found. Regarding non-gastrointestinal findings in potential GIUS patients, there were two cases of pancreatic cysts necessitating further investigation with serial MRIs & endoscopic ultrasound, yielding a side branch intraductal papillary mucinous neoplasm & a benign serous cyst adenoma. One case of multiple high T2 skeletal lesions was deemed clinically insignificant following further investigations. No other significant extra-intestinal findings not expected to be seen on GIUS were identified.

Conclusion
Over 50% of MREs could have been performed as GIUS instead, with a potential annual cost saving of over £110,000. No instances of inflammation would have been missed based on distribution, although in one case the full extent of disease may not have been identified on GIUS. Incidental non-gastrointestinal findings resulted in multiple investigations but were of limited clinical significance.
P246 Development of a new Inflammatory Bowel Disease Patient Identifier shortens time to clinic review and initiation of treatment
Authors: Chee D , Hamilton B , Cairnes V , Lin S , Chanchlani N , Ahmad T , Goodhand J , Kennedy N 
Published: May 2021

Abstract

Background
Timely diagnosis of inflammatory bowel disease (IBD) is important because earlier use of biologic therapies leads to mucosal healing, a reduction in hospitalisations and surgeries and improvements in quality of life. In the United Kingdom, general practitioners refer patients with symptoms suggestive of IBD to colorectal surgeons, emergency department physicians, gastroenterologists or directly for a lower gastrointestinal endoscopy. Consequently, there is variation in the time from endoscopic diagnosis of IBD to specialist review. We created an electronic tool that screens all endoscopy reports for a new diagnosis of IBD. These cases are then reviewed in our weekly complex multidisciplinary team (MDT) meeting and new patients are allocated an IBD specialist. We sought to determine whether our new patient identifier reduced the time to clinical review by an IBD specialist and initiation of IBD treatment.

Methods
We designed a retrospective observational cohort study comparing time from endoscopic diagnosis of IBD to initiation of treatment and IBD specialist review. Outcomes were compared in the 18 months before and after the introduction, in January 2018, of our new IBD patient identifier. Demographic, endoscopic and treatment outcome data were recorded from our electronic patient record. Categorical and continuous variables were summarised as frequencies (%) and median [IQR] and compared with Fisher’s exact and Mann Whitney U tests respectively.

Results
Between the 1st January 2018 and 30th June 2019, 116 new patients diagnosed with IBD were identified and reviewed in our MDT meeting. In the preceding 18 months, 111 patients were diagnosed with IBD. There were no significant differences between groups according to sex, age, age at diagnosis, disease type, or phenotype according to the Montreal classification (Table 1). Both the median time from endoscopic diagnosis to treatment initiation (0 days [IQR 0 – 14.2] vs 14 days [IQR 0 – 31.6], p=0.007) and specialist clinic review (21 days [IQR 7 - 25] vs 48 days [IQR 34 – 63], p&lt;0.0001) were shorter following the introduction of the new IBD patient identifier screening tool (Figure 1).

Conclusion
Systematic electronic screening of endoscopic reports linked to MDT review reduces the time to first treatment and specialist review in newly diagnosed patients with IBD.