bluuebunny/crossref_metadata_2025_split huggingface dataset:
OP10 IgA coating of intestinal microbiota is associated with inflammatory bowel disease in twin pairs discordant for inflammatory bowel disease
Authors: Brand E , Laenen Y , van Wijk F , de Zoete M , Oldenburg B 
Published: January 2020

Abstract

Background
The pathogenesis of inflammatory bowel disease (IBD) is thought to result from an interplay between microbiota, the immune system and the environment in genetically susceptible hosts. Immunoglobulin A (IgA) produced by the immune system can be specifically directed against bacteria. The IgA-coating pattern of intestinal bacteria thus reflects interactions between the immune system and specific bacteria. Studying IBD in twins, concordant and discordant for IBD, reduces the impact of genetic predisposition and childhood exposures and therefore offers the unique opportunity to focus on other factors such as intestinal microbiota composition and immune-interactions in IBD.

Methods
Faecal samples from twin pairs discordant for Crohn’s disease (CD) or ulcerative colitis (UC) were collected. Employing fluorescence-activated cell sorting, IgA+ and IgA− bacteria from the intestinal microbiota were sorted. Subsequently, (1) the total, (2) IgA+ and (3) IgA− microbial composition was determined by 16S rRNA sequencing (IgA-SEQ). We estimated the relative IgA coating per bacterial species by dividing the abundance of that species in the IgA+ fraction over the abundance in the IgA- fraction, representing the IgA coating index. Linear discriminant analyses were performed with LefSE.

Results
We included 31 twin pairs (62 individuals) discordant for IBD (CD: 15, UC: 16). 15/32 twin pairs were monozygotic, 43/62 of participants were female, the median age was 47 years (interquartile range: 34–58.5). Of 31 participants with IBD, 7 had signs of active inflammation based on endoscopy, Harvey–Bradshaw index or short clinical colitis activity index. Differences (log-linear discriminant analysis score &gt;3) in the microbial composition of IgA-coated bacteria were observed between CD patients and their twin-siblings not affected by IBD: Dorea formicigenerans (increased in IgA coating), Parabacteroides sp., Christensenellaceae sp., Clostridium sp. and Mollicutes RF39 sp. (decreased in IgA coating). In ulcerative colitis patients, an increase in IgA-coating was observed for Ruminococcus gnavus and Dorea formicigenerans, while Turicibacter sp., Barnesiellaceae sp. and an unclassified Clostridiales sp. were decreased in IgA-coating compared with their twin-siblings not affected by IBD.

Conclusion
In twins affected by IBD, the pattern of IgA-coated bacteria differs between IBD and non-IBD affected individuals. These data on immune-bacteria interactions could serve as a starting point for the elucidation of the immune-responses triggered by specific bacteria in IBD.
OP13 Glyco-fingerprint as a relevant risk factor on colitis-associated cancer
Authors: Dias A , Gomes E , Silva M , Fernandes Â , Garrido M , Marcos-Pinto R , Lago P , Pinho S 
Published: January 2020

Abstract

Background
Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract being considered a serious risk factor for the development of colitis-associated cancer (CAC). However, the molecular mechanisms underlying CAC progression are still elusive. We previously showed that decreased expression of MGAT5 glycogene on intestinal T lymphocytes from UC patients was associated with a hyperimmune response and with disease severity (Dias, AM et al. HMG,2014; Dias, AM et al. PNAS, 2018). On the other hand, we also demonstrated that the aberrant expression of MGAT5 glycogene in gastrointestinal cancer cells was associated with tumour invasiveness and progression (Carvalho S et al., Oncogene 2015). However, whether this differential expression of glycans in colitis and cancer contexts mediated by MGAT5 glycogene constitutes a new mechanism in CAC remains completely unknown.

Methods
A well-characterised cohort of paraffin samples from CAC patients at different stages of carcinogenesis (colitis; dysplasia and colon cancer) were evaluated by immunohistochemistry, using specific lectins to evaluate the N-glycosylation profile either in stroma or in epithelial cells. Furthermore, in vivo studies (using Azoxymethane (AOM)/dextran sodium sulphate (DSS) to induce CAC) were conducted in MGAT5 wild-type and null mice. The combined glycoimmune profile of colonic cells was analysed by flow cytometry. Analysis of RNAseq data from colitis-associated cancer mice model (the AOM/DSS mouse model) was performed to decipher the glyco-fingerprint in colonic cells during colitis; low- and high-grade dysplasia and adenocarcinoma.

Results
Our cross-sectional study revealed a distinct glycoprofile in stroma, characterised by a decreased expression of branched N-glycans in colitis followed by increased expression in dysplasia and colon carcinoma stages corroborated by the RNASeq analysis on the colon of AOM/DSS mouse model. Additionally, colonic T cells isolated from both AOM/DSS MGAT5 WT and KO mice presented a distinct glycoprofile along CAC development.

Conclusion
Our preliminary results both from human and mice samples demonstrate a distinct glycoimmuno profile along the colitis-associated carcinoma cascade, which potentially represents a biomarker to early identify risk UC patients.
OP15 Multi-omic data integration with network analysis reveals underlying molecular mechanisms driving Crohn’s disease heterogeneity
Authors: Sudhakar P , Verstockt B , Cremer J , Verstockt S , Korcsmaros T , Ferrante M , Vermeire S 
Published: January 2020

Abstract

Background
Crohn’s disease (CD) is a heterogeneous disease characterised by clinical phenotypes including differences in disease behaviour, disease location and extraintestinal manifestations. However, the molecular mechanisms which orchestrate CD heterogeneity are relatively unexplored. We tried to infer such mechanisms by integrating two -omic datasets (genomics and blood proteomics) generated from CD patients.

Methods
576 unique proteins were measured from blood isolated from CD patients (n = 98) using seven different Olink® panels. All patients were also genotyped using Immunochip. We integrated the above two datasets using an unsupervised data integration algorithm called Multi-Omics Factor Analysis (MOFA). MOFA identifies Latent Factors (LFs) which are hidden representative variables which capture the sources of variation in the provided -omic datasets. LFs capturing less than 2% of the variance were discarded. By using a regression model, we identified explanatory LFs which associate with clinical phenotypes. Proteins and mutations were ranked according to the scores assigned by the corresponding explanatory LF. Potential effects of mutations were inferred by analysing their impacts on coding and non-coding functions. Local network motifs which capture the direct and indirect effects of mutations on protein expression were identified by using the Cytoscape tool ISMAGS. Protein–protein and transcriptional regulatory relationships retrieved from the OmniPath and DoRothEA databases, respectively, were combined to compile the interaction networks used by ISMAGS.

Results
From the MOFA analysis, we identified five LFs associated with at least one clinical phenotype. Clustering patients along the explanatory LFs achieved meaningful separation of clinical phenotypes such as perianal penetrating disease. The top-ranking proteins associated with perianal-disease included those involved in inflammatory pathways, autophagy or already known to be involved in CD such as IL-8, Rho-GTPase activators, MIF, Caspase 8, TRIM5 and SNAP29. The networks corresponding to the top ranking proteins associated with the perianal phenotype could be broken down into 102 local network motifs. These local motifs pointed out control mechanisms by which a total of 7 mutations mapped to transcription factors (SMAD3, BACH2) and post-translational regulators (such as IFNGR2, IL10, IL2RA, SLC2A4RG and ZMIZ1) could potentially regulate perianal disease‘s pathophysiology and could, therefore, be considered novel drug targets.

Conclusion
By using integrated signature profiles generated from multiple -omic datasets, we identified molecular mechanisms which could potentially describe CD phenotypes such as the occurrence of perianal disease.
OP19 Perinatal factors do not affect paediatric inflammatory bowel disease risk: A Scottish Nationwide Cohort study using administrative health data 1981–2017
Authors: Burgess C , Schnier C , Chalmers I , Russell R K , Hansen R , Henderson P , Wood R , Wilson D C 
Published: January 2020

Abstract

Background
The incidence of paediatric-onset inflammatory bowel disease (PIBD) continues to rise, with genetic-environmental interactions expected to play a vital role. Given gestation and infancy are sensitive periods for environmental change, we aimed to determine whether a mode of delivery, gestational age or type of infant feeding contribute to the development of PIBD in a nationwide cohort of high-risk Scottish children using administrative health data research methodology.

Methods
All children born in Scotland 1981–2017 were identified within the Scottish Morbidity Record maternity inpatient dataset (SMR02). Data linkage was applied to determine mode of delivery, gestational age and type of infant feeding, with PIBD cases defined as any inpatient International Classification of Diseases (ICD) coding for Crohn’s disease (CD; 555/K50), ulcerative colitis (UC; 556/K51) or inflammatory bowel disease unclassified (IBDU; 558.9/K52.3) until age 16. Validation was performed within an entire Scottish health board (16% of the total population) via individual case-note verification. Hazard ratios (HRs) were calculated for each exposure using Cox proportional hazards models with the following potential confounding factors included as covariates: sex, maternal age, year of birth, postcode area and deprivation quintile. Dependent interactions were also explored between the three main exposures.

Results
A study population of 2 013 851 children were identified including 1721 PIBD cases. Individual validation was performed on all 298 (17%) PIBD-coded patients within NHS Lothian; 242/261 CD and UC cases were validated as true positive (positive predictive value 93%); all 37 IBDU cases were false positive with this ICD code excluded from all further analysis. Children delivered vaginally did not have an altered risk of developing PIBD compared with Caesarean section; adjusted HR 0.95 [95% CI 0.84–1.08] (p = 0.424). Children born prematurely did not have an altered risk of developing PIBD; 24–31 weeks gestation HR 0.97 [95% CI 0.56–1.68] (p = 0.922); 32–36 weeks gestation HR 0.96 (95% CI 0.76–1.20] (p = 0.699). Children not exclusively breast feeding at 6 weeks of age did not have an altered risk of developing PIBD; formula feeding HR 0.97 [95% CI 0.81–1.15] (p = 0.705); other/unknown feeding type HR 0.90 [95% CI 0.74–1.08] (p = 0.259). No two-way interactions were significant and none of the three exposures was significantly related to CD or UC in PIBD subtype analysis.

Conclusion
This robust, validated population-based study of over 2 million Scottish births utilising administrative health data confidently demonstrates no association between mode of delivery, gestational age, type of feeding and the development of PIBD.
OP25 Biologics before surgery for IBD: Are they associated with post-operative infectious outcomes? Results from the national surgical quality improvement programme inflammatory bowel disease collaborative
Authors: Holubar S , Jai X , Hull T , Hyman N , Ramamoorthy S , Einsenstein S 
Published: January 2020

Abstract

Background
We aimed to utilise the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Inflammatory Bowel Disease (IBD) Collaborative, which includes disease-specific variables, to assess the association between preoperative biologic exposure and post-operative infectious complications in the largest cohort reported to date.

Methods
Were obtained from ten IBD centres from 2017 - 2018. Univariate and multivariate analyses were performed, with any biologic use within 60-days of surgery as the primary predictor, adjusting for diagnosis, chronic steroid use, immunomodulator (IMM) use, ostomy construction, anaemia, malnutrition, operative length, emergency surgery, and other variables with p &lt; 0.05 from the univariate analysis. The primary endpoint was any (composite) infectious complication, and the secondary endpoint was any (composite) surgical site infection.

Results
A total of 1,562 patients were included, of which 832 (53%) were not exposed to biologics, and 730 (47%) were exposed to biologics before surgery. The biologics group had more preoperative weight loss, lower albumin, more systemic sepsis, more IMM and steroid use, and more had Crohn’s disease (all p &lt; 0.001). The biologics group were also more likely to receive a new ostomy and to have a colectomy (vs. proctectomy or small bowel procedure), and fewer had elective surgery (all p &lt; 0.001). On univariate analysis (Table 1), compared with no biologic exposure, biologic exposure was not associated with any infectious complications, any surgical site infections, anastomotic leak after colectomy, or other post-operative outcomes, but was associated with increased rate of anastomotic leak after proctectomy (n = 423), 6.7% vs. 1.9%, p = 0.02. With respect to the primary and secondary outcomes, the results of the multivariate analyses are shown in Table 2. Biologics were shown not to be associated with any infectious complication (OR 0.88, 95% CI 0.54 – 1.42) or any surgical site infection (OR 0.77, 95% CI 0.46 – 1.28), while Crohn’s disease was associated with any infectious complications (OR 2.11 95% CI 1.12 – 4, p = 0.02).

Conclusion
In the largest retrospective cohort to date, we found that biologics exposure within 60 days of surgery for IBD, using a well-validated methodology and after vigorous adjustment for disease- and surgery-specific covariates, was not associated with post-operative infectious or surgical site infectious complications.
OP35 Treatment outcomes of inflammatory bowel disease in the biological era—a nationwide retrospective cohort study in three Nordic countries: Results from the TRINordic study
Authors: Zhao M , Lördal M , Langholz E , Knudsen T , Voutilainen M , Høivik M L , Moum B , Saebo B , Haiko P , Malmgren C , Coskun M , Melberg H O , Burisch J 
Published: January 2020

Abstract

Background
Biological therapy has been suggested to decrease surgery and hospitalisation risk in patients diagnosed with inflammatory bowel disease (IBD). During 2010 to 2016, the use of biologics in Denmark (DEN), Sweden (SWE) and Norway (NOR) increased dramatically and the time to first biologic treatment declined.1 However, the impact of increasing use of biologics on disease outcomes remains to be shown in real-life practice. In this nationwide study in three Nordic countries, we aimed to investigate trends in surgery and hospitalisation rates in IBD patients in the biological era.1 Høivik ML et al. Time to first treatment with biologic agents for Ulcerative Colitis and Crohn’s Disease across four Nordic countries: Results from the TRINordic study, Submitted to ECCO 2020.

Methods
A total number of 67 758 IBD patients (42 894 patients with ulcerative colitis (UC) and 24 864 Crohn’s disease (CD) diagnosed during the period from 2010 to 2017 in DEN, NOR and SWE were included using the National Patient Registries. Patients were required to have 1-year follow-up; results are limited to patients diagnosed between 2010 and 2016, inclusive. Using the unique personal identification number, individual-level information on surgery, hospitalisation and drug treatment were extracted from the National Patient Registries and the National Prescription Registries. Disease outcomes within two years after diagnosis were compared across annual cohorts.

Results
During 2010 to 2016, 2-year surgery rates in CD patients showed a non-significant decline from 11.9% in 2011 to 9.5% in 2016 in SWE while remaining stable in NOR and DEN (Figure 1). No temporal pattern in surgery risk was observed for UC. The proportion of CD patients being hospitalised within two years from diagnosis declined in SWE and NOR from 52.3% and 51.0% in 2011 to 47.3% and 38.5% in 2015 (p &lt; 0.001), respectively, while hospitalisation in UC remained stable. In contrast, 2-year hospitalisation rates in DEN increased in CD from 27.0% in 2011 to 31.5% in 2016 (p = 0.045) and similarly in UC from 20.4 to 35.0% (p &lt; 0.001), respectively (Figure 2).

Conclusion
No clear pattern was seen in two-year surgery and hospitalisation rates in IBD patients during 2010 to 2017 despite a concurrent increase in biological use in all countries. However, differences in treatment practices across countries might influence these findings. The impact of increased biological use on long-term outcomes in IBD remains to be shown.
OP36 Investigating the role of bioactives produced by gut bacteria to modulate immune response in inflammatory bowel disease
Authors: Giri R , Shamsunnahar K , Salim A , Capon R , Morrison M , O Cuiv P , Begun J 
Published: January 2020

Abstract

Background
inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract. Although the pathogenesis of IBD is not fully understood, it is believed to result from the interaction between various genetic and environmental factors, including the microbiome, resulting in inappropriate gut inflammation. Under homeostatic conditions, the gut immune system exists in a tolerogenic state with the microbiota. However, microbial dysbiosis and an imbalance of pro- and anti-inflammatory cytokines in the gut characterise IBD and recently faecal microbiota transplantation studies have demonstrated that manipulation of the microbiome can induce remission. In this study, the ability of bioactives produced from single species of anaerobic gut bacteria cultured from healthy human faecal samples to modulate NF-kB activity was investigated, their biochemical properties were assessed and their ability to alleviate colitis was also investigated.

Methods
The NF-κB suppressive effects of culture supernatants (CSs) from 23 different isolates were tested on colonic epithelial cell lines. Suppressive CSs were also tested on human-derived colonic organoids from IBD patients and healthy controls and IL-8 expression was measured. Furthermore, CS from AHG0001 strain was also tested in spontaneous colitis model Winnie in vivo. The supernatant was further characterised by extraction in multiple solvents and fractionated through reversed-phase analytic HPLC column to test for suppressive fractions and further investigate their chemical characteristics.

Results
LS174T and Caco-2 reporter cells stimulated with TNFα and IL-1β respectively, resulted in NF-κB activation. Of the 23 isolates screened, CS from five isolates significantly suppressed NF-κB activation. The selected CSs also suppressed IL-8 secretion in PBMCs and gut organoids from both UC and CD patients, as well as healthy controls, with notable individual variation. Rectal gavage of CS from AHG0001 also reduced disease activity, improved histologic inflammation and reduced the pro-inflammatory gene expression in Winnie mice. Furthermore, a potent small molecule (IC50 = 3 nM) produced by AHG0001 was also identified through bioassay-guided solvent extractions and filtrations, followed by UPLC-QTOF and comparative metabolomics.

Conclusion
Our anaerobic culturing and NF-κB reporter assay system allows for the rapid identification of bacteria producing immunomodulatory bioactives, which could lead to the future development of novel therapeutics. Our in vivo and ex vivo testing utilising spontaneous colitis model and patient-derived organoids demonstrates the potential of precision medicine-based approaches for bacterial based therapeutics.
DOP02 The dose-dependent effect of enteral nutrition on faecal microbial metabolites of healthy volunteers
Authors: Svolos V , Gkikas K , Rizou V , Christina E , Kapranos P , Kleingunnewiek J , Seenan J P , Macdonald J , Gaya D R , Hansen R , Russell R K , Gerasimidis K 
Published: January 2020

Abstract

Background
Treatment with exclusive enteral nutrition (EEN) offers a nutritional therapy paradigm in Crohn’s disease, with the extensive modulation of gut microbiome being its proposed mechanism of action (1). Recent studies propose variable clinical efficacy for 85% EN (Cheat EN/CEN), 50% EN (Partial EN/PEN) and 20% EN (maintenance EN/MEN), and a dose-dependent effect of EN use in CD (2–5). Therefore, this study aims to investigate the dose-dependent effect of 100%, 85%, 50%, and 20% EN on faecal microbial metabolites; and to investigate if this effect can be used as a compliance marker for EEN.

Methods
Healthy adults followed EEN, CEN, PEN or MEN diet for 7 days. Fresh faecal samples were collected before and after each dietary intervention Dietary assessment was performed throughout the intervention using estimated weight food diaries. Faecal pH, water content, Bristol Stool Chart Score, short-chain fatty acids and hydrogen sulphide were measured.

Results
A total of 122 faecal samples were collected from 61 subjects. The Mean(SEM) EN intake for the four groups was EEN: 100(0), CEN: 85.6(0.5), PEN: 50.1(0.4), MEN: 19.9(0.2) % of total energy intake. The baseline levels of all faecal sample measures were no different between the four groups. Faecal water content, propionic acid and Bristol Stool Chart Score significantly decreased only during EEN (all p≤0.03). Faecal pH significantly increased during EEN, CEN and PEN (all p &lt; 0.001), but not during MEN (p = 0.728). Faecal pH post-intervention was highest for EEN, followed by CEN and PEN [Mean(SEM), EEN: 8.2(0.1); CEN: 7.8(0.2); PEN: 7.3(0.1), all pairwise p ≤ 0.002]. The faecal concentration of hydrogen sulphide, acetic and butyric acid significantly decreased following both EEN and CEN groups (all p ≤ 0.009). The concentration of acetic acid post-EEN was significantly lower than the concentration post CEN [Mean(SEM), EEN: 173(10); CEN: 261(24) μmol/g, p = 0.001]. Hydrogen sulphide and butyric acid concentrations post EEN and post CEN were unchanged (p = 0.337, p = 0.141).

Conclusion
EEN extensively modulates faecal microbial metabolites and CEN induces similar effects. PEN induces variable effects and further analysis should investigate if variation in responses reflects differences in the non-EN food intake of the participants (50%). MEN had no effect on faecal microbial metabolites. Further analysis including high-throughput deep sequencing techniques will provide additional information about the dose-dependent effect of EN regimen on gut microbiome composition.
References
1. Quince et al., Am J Gastroenterol, 110:1718–1729.
2. Logan et al., Aliment Pharmacol Ther, 2019;50:664–674.
3. Gupta et al., IBD, 2013;19:1374–1378.
4. Duncan et al., BMC Gastroenterol, 2014;14:50.
5. Lee et al., IBD, 2015;21:1786–1793.