bluuebunny/crossref_metadata_2025_split huggingface dataset:
P148 COLONIC SPROUTY2 IS ELEVATED IN INFLAMMATORY BOWEL DISEASE PATIENTS
Authors: Appel Keren , Schumacher Michael , Frey Mark 
Published: January 2020

Abstract

Background
The intestinal epithelium plays a central role in protecting against the development of colitis, and is disrupted in inflammatory bowel disease (IBD). It serves as the physical barrier that, when breached, allows luminal contents (i.e. bacteria, antigens) to stimulate inflammatory responses. Sprouty2 (SPRY2) is an intracellular regulator of growth factor receptor signaling that is downregulated in a compensatory response to inflammatory stimuli in cell lines and a mouse model of colitis. Additionally, mice with intestine-specific Spry2 deletion are protected against colitis and have elevated tuft and goblet cell numbers, cell types thought to protect the intestinal epithelium. This may represent a feedback mechanism to reinforce the intestinal epithelium during the initial stages of injury. However, the regulation of SPRY2 in IBD patients is unknown. We hypothesized that SPRY2 expression might be dysregulated in patients with IBD.

Methods
SPRY2 levels were measured by quantitative PCR analysis of human colonic tissue from endoscopic biopsies and surgical resection specimens from pediatric IBD and non-IBD patients. Human colonoids (primary cultures of colonic epithelium) were grown from surgical resection specimens of non-IBD control patients. SPRY2 expression was measured via qPCR in response to treatment with TNF for 24 hrs.

Results
SPRY2 expression decreased by an average of 24.41% (p = 0.0002, n =4) in colonoids from non-IBD patients treated with tumor necrosis factor (TNF) 10 ng/mL and 18.13% (p = 0.0016) for 100 ng/mL. However, SPRY2 expression in endoscopic biopsies from IBD patients was 2.325 ± 0.9846 fold higher in ulcerative colitis (UC) patients (p= 0.0242, n =8) and 9.825 ± 2.800 fold higher in Crohn’s disease patients (p= 0.0014, n=6) compared to non-IBD controls (n=27). In surgical specimens, SPRY2 levels were 37.10 ± 21.96 (p= 0.0459) fold higher in IBD (n=6) vs. non-IBD (n=4) patients. Furthermore, data mining of Gene Expression Omnibus dataset GDS3268 (biopsies from UC patients) revealed a significant negative correlation between SPRY2 and the protective tuft cell markers DCLK1 and TRPM5.

Conclusion
Acute TNF signaling repressed SPRY2 expression in a human colonoid model. In contrast, SPRY2 levels appear to be increased in human IBD and negatively correlate with tuft cell markers. Together these data suggest that, while acute inflammation can downregulate SPRY2 to drive increased numbers of protective secretory cells, in chronic disease this response either does not occur or is lost. A failure to down-regulate SPRY2 in response to early mucosal damage may be a factor in the development of IBD.
P149 DECREASED COLONIC ACTIVIN RECEPTOR-LIKE KINASE 1 DISRUPTS EPITHELIAL BARRIER INTEGRITY AND IS ASSOCIATED WITH A POOR CLINICAL OUTCOME IN CROHN’S DISEASE
Authors: Toyonaga Takahiko , Keith Benjamin , Barrow Jasmine , Schaner Matthew , Wolber Elizabeth , Beasley Caroline , Huling Jeniffer , Wang Yuli , Allbritton Nancy , Furey Terrence , Sethupathy Praveen , Sheikh Shehzad 
Published: January 2020

Abstract

Background and Aims
Intestinal epithelial cell (IEC) barrier dysfunction is critical to the development of Crohn’s disease (CD). Mechanisms controlling colonocyte differentiation and barrier defects are understudied in CD. We recently reported increased expression of microRNA-31-5p (miR-31-5p) in colonic IECs of CD patients compared to non-IBD (NIBD) controls. In this study we identify and characterize the miR-31-5p target gene Activin Receptor-Like Kinase 1 (ALK1) as a key regulator of colonocyte maturation and IEC barrier integrity, specifically the functional impact of aberrant ALK1 signaling on colonocyte differentiation, barrier integrity, and clinical disease outcomes in CD.

Methods
MiR-31-5p target genes were identified in CD patients by integrative analysis of RNA- and small RNA-sequencing data from colonic mucosa and confirmed by quantitative RT-PCR (qPCR) in isolated colonic IECs. Functional characterization of ALK1 in colonic IECs was performed ex vivo using 2- or 3-dimensional cultured human primary colonic IECs. The impact of altered colonic ALK1 signaling for the risk of surgery and endoscopic relapse was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator among CD patients.

Results
Integrative analysis of RNA- and small RNA-sequencing and follow-up qPCR identified ALK1 as a candidate target of miR-31-5p in the colonic IECs of CD patients. A 3’-UTR reporter assay with site-directed mutagenesis confirmed the direct regulation of ALK1 expression by miR-31-5p in HEK293T cells. Increased activation of ALK1 restricted the proliferation of primary colonic IECs in an EdU proliferation assay and down-regulated the expression of stemness-related genes, such as LGR5 and ASCL2. Activated ALK1 signaling directed the fate of human colonic IEC differentiation toward colonocytes. Down-regulated ALK1 signaling was associated with increased stemness-related gene expression and decreased colonocyte-specific gene expression in the isolated colonic IECs of CD patients compared to non-IBD controls. Activation of ALK1 did not affect colonic IEC migration in a wound healing assay, but enhanced epithelial barrier integrity in a trans-epithelial electrical resistance (TEER)-based permeability assay. Lower colonic ALK1 expression was associated with higher risks of surgery and endoscopic relapse in CD patients.

Conclusion
Decreased colonic ALK1 signaling disrupts colonic IEC barrier integrity and is associated with a poor clinical outcome in CD patients.
P145 MECHANISMS OF ACTION FOR THE IBD-RISK GENE C1ORF106/INAVA
Authors: Luong Phi , Lencer Wayne , Chang Denis , Li Qian 
Published: January 2020

Abstract
C1ORF106, also named INAVA (Innate Immune Activator), was identified as a risk gene for the chronic inflammatory bowel diseases (IBD) by genome-wide association studies and targeted exome sequencing. INAVA is highly enriched in polarized simple epithelia, the cell type that lines the intestine and interfaces most directly with the outside world. We discover that INAVA provides a direct mechanistic link between mucosal barriers and inflammation. This is driven by INAVA’s signature Domain of Unknown Function DUF3338, which we newly defined as an enhancer of IL-1β-TRAF6 polyubiquitination cascades. Our work shows that DUF3338 stably binds the GTP-exchange factor cytohesin-2 (ARNO), in one case blocking the formation of INAVA stress puncta and its effect on ubiquitination, and in another case acting at lateral membranes where the INAVA-ARNO complex regulates cortical F-actin dynamics and epithelial barrier function. We thus rename the DUF3338 domain CUPID for Cytohesin Ubiquitin Protein Inducing Domain. We performed a high throughput small molecule screen to identify molecules that modulated INAVA function in cells. Compounds hits identified in the screen links INAVA’s role in barrier and stress response mechanisms involving actin dynamics and proteostasis.
15 LONGITUDINAL EVALUATION OF MUCOSAL DNA METHYLATION IN ULCERATIVE COLITIS SHOWS DISEASE-SPECIFIC CHANGES
Authors: Venkateswaran Suresh , Kilaru Varun , Somineni Hari , Matthews Jason , Hyams Jeffrey , Investigators Protect , Cutler David , Smith Alicia , Conneely Karen , Kugathasan Subra 
Published: January 2020

Abstract

Background
Although inflammatory bowel disease (IBD) is heritable, the heritability is still largely unexplained despite substantial progress through GWAS and WGS. However, recent advances in epigenetics (gene environmental interactions), including DNA methylation (DNAm) analysis, has identified new disease-specific mechanisms controlling gene expression. We recently showed that IBD-associated blood DNAm patterns strongly correlated with inflammation (CRP as surrogate marker) and reverted to patterns seen in healthy controls following treatment, regardless of whether or not the underlying IBD was in remission, suggesting blood DNAm is more representative of the systemic inflammatory status rather than disease status (Gastroenterology, 2019, 156 (8): 2254–2265). Thus, we aimed to study DNAm patterns in rectal biopsies hypothesizing that DNAm in rectal biopsies will reflect disease status rather than systemic inflammatory status alone.

Method
Genome-wide DNA methylation was measured using the Illumina MethylationEPIC array on rectal biopsy DNA samples of 85 non-inflammatory, non-IBD controls and 215 newly diagnosed ulcerative colitis (UC) patients prior to therapy, along with 49 one-year follow-up UC cases (PROTECT cohort) to identify disease specific methylation patterns. Epigenome wide association studies (EWAS) were performed with UC and CRP as the outcomes in linear models adjusted for age, gender, race and five genotype-based principal components.

Results
At diagnosis, 2446 disease-specific CpG sites in rectal tissue (FDR&lt;0.05) were identified. At baseline, the disease-associated DNAm signature in rectal tissue is distinct from our previous study from blood as only 15 CpGs were common between rectal tissue DNAm and blood DNAm. In contrast to what was observed in blood DNAm where the initial DNAm signature reverted back to control levels upon treatment, rectal tissue DNAm signatures remained persistent during follow-up (Figure 1). The majority of the disease-specific CpG sites identified in rectal biopsies showed a strong positive correlation with CRP. This evidence suggests that the treatment affects systemic measures of inflammation more strongly than disease tissues.

Conclusion
When studied longitudinally, the UC-specific DNA methylation patterns in rectal tissue are distinct from blood samples. In contrast to blood DNAm which normalizes after therapy during follow-up, rectal tissue DNAm changes persist after treatment in UC. This suggests the currently available therapies control the systemic inflammation effectively, but have less direct effect on the disease itself. Future therapies targeting disease-specific DNAm may be more effective in disease management and long-term remission.
10 THE ROLE OF DIETARY L-SERINE IN THE REGULATION OF INTESTINAL MUCUS BARRIER DURING INFLAMMATION
Authors: Sugihara Kohei , Kamada Nobuhiko 
Published: January 2020

Abstract

Background
Recent accumulating evidence suggests that amino acids have crucial roles in the maintenance of intestinal homeostasis. In inflammatory bowel disease (IBD), amino acid metabolism is changed in both host and the gut microbiota. Among amino acids, L-serine plays a central role in several metabolic processes that are essential for the growth and survival of both mammalian and bacterial cells. However, the role of L-serine in intestinal homeostasis and IBD remains incompletely understood. In this study, we investigated the effect of dietary L-serine on intestinal inflammation in a murine model of colitis.

Methods
Specific pathogen-free (SPF) mice were fed either a control diet (amino acid-based diet) or an L-serine-deficient diet (SDD). Colitis was induced by the treatment of dextran sodium sulfate (DSS). The gut microbiome was analyzed by 16S rRNA sequencing. We also evaluate the effect of dietary L-serine in germ-free mice and gnotobiotic mice that were colonized by a consortium of non-mucolytic bacterial strains or the consortium plus mucolytic bacterial strains.

Results
We found that the SDD exacerbated experimental colitis in SPF mice. However, the severity of colitis in SDD-fed mice was comparable to control diet-fed mice in germ-free condition, suggesting that the gut microbiota is required for exacerbation of colitis caused by the restriction of dietary L-serine. The gut microbiome analysis revealed that dietary L-serine restriction fosters the blooms of a mucus-degrading bacterium Akkermansia muciniphila and adherent-invasive Escherichia coli in the inflamed gut. Consistent with the expansion of mucolytic bacteria, SDD-fed mice showed a loss of the intestinal mucus layer. Dysfunction of the mucus barrier resulted in increased intestinal permeability, thereby leading to bacterial translocation to the intestinal mucosa, which subsequently increased the severity of colitis. The increased intestinal permeability and subsequent bacterial translocation were observed in SDD-fed gnotobiotic mice that colonized by mucolytic bacteria. In contrast, dietary L-serine restriction did not alter intestinal barrier integrity in gnotobiotic mice that colonized only by non-mucolytic bacteria.

Conclusion
Our results suggest that dietary L-serine regulates the integrity of the intestinal mucus barrier during inflammation by limiting the expansion of mucus degrading bacteria.
21 NATURAL HISTORY OF COLECTOMY AMONG HOSPITALIZED PATIENTS WITH ULCERATIVE COLITIS IN THE CONTEMPORARY ERA OF BIOLOGICS
Authors: Sedki Mai , Stram Douglas , Alam Asim , Shirazi Aida , Velayos Fernando 
Published: January 2020

Abstract

BACKGROUND
Despite reducing mortality, the use of intravenous (IV) corticosteroids has not significantly reduced inpatient colectomy rates among hospitalized patients with ulcerative colitis (UC). Whether the occurrence of colectomy, estimated at 20–30% in this population in the prebiologic era, remains elevated is unknown.

Methods
A retrospective cohort study was conducted among health plan members of an integrated health care delivery organization that serves approximately 4.0 million members in urban, suburban, and semi-rural regions throughout Northern California. The study population consisted of 524 health plan members age &gt;18 years of age with a 1) diagnosis of ulcerative colitis (ICD-9 code 556; ICD-10 code K51); 2) first hospitalization between 2009 and 2017 coded with ulcerative colitis as the primary cause for admission; 3) no prior hospitalizations for UC; 4) at least 1 year of continuous membership prior to the index hospitalization; 5) No dispensing of biologic therapy (infliximab, adalimumab, golimumab, vedolizumab) recorded prior to hospitalization; 6) No record of Clostridium difficile or cytomegalovirus infection during the hospitalization or 30 days prior. The primary outcome was the occurrence of colectomy during the index hospitalization and up to 12 months after hospitalization. Additional outcomes assessed were trends in colectomy over this time period and predictors for colectomy during the index hospitalization.

Results
A total of 5.3% of UC patients underwent colectomy during the index hospitalization (95%CI 3.3–7.3%) and 11.9% underwent colectomy within the first year after hospitalization (95% CI: 9.1–14.6%). Inpatient colectomy declined from 6.5% (95%CI: 2.5–10.6%) in 2009–2010 to 3.4% (95%CI: 3.3–7.3%) in 2015–2017. Colectomy in the first year after admission declined from 15.7% (95%CI 10.0–21.4%) in 2009–2011 to (10.1%; 95% CI: 5.4–14.7) in 2015–2017. A total of 16.3% of patients received infliximab in the hospital and 36.3% received within the first year of admission. In a multivariable model, the 2015–2017 cohort experienced a 64% reduction in inpatient colectomy compared to the 2009–2011 cohort (OR 0.36; 95%CI: 0.11–1.14, p=0.082) and a 54% reduction in colectomy in the first year (OR 0.46; 95%CI: 0.22–0.96, p=0.038). A prior study between 1998–2004 in this same population showed colectomy rates of 20% during the index hospitalization and 30% at 1 year.

Conclusion
Colectomy within the first year after hospital admission for UC has declined over time in the modern era of biologics with a magnitude of colectomy that is lower than the historical rate of 20–30%. Our data imply cause for optimism that the natural history of colectomy in acute severe UC may be different and modifiable in the modern biologic era compared to the past.
P006 AFTER-HOURS PATIENT PHONE CALLS TO GI FELLOWS WITHIN AN IBD MEDICAL HOME
Authors: Rodriguez Jennifer , Dueker Jeffrey , Proksell Siobhan , Szigethy Eva , Schwartz Marc , Myers Cassie , Click Benjamin , Regueiro Miguel 
Published: January 2020

Abstract

Objective
The Inflammatory Bowel Disease (IBD) Medical Home is a care delivery model that provides a comprehensive, patient-centered, coordinated care environment, previously shown to lead to an approximate 50% reduction in unplanned care. However, the frequency and nature of IBD medical home patient phone calls to gastroenterology (GI) fellows after-hours, and the contribution to unplanned care from these encounters, is unknown.

Methods
We included all patients that were seen in the IBD medical home between 7/1/2015 to 6/30/2016 (n = 293) and examined all phone call activity in the subsequent year: 7/1/2016 to 6/30/2017. After-hours phone calls were defined as documented calls that were routed to on-call GI fellows when the clinic is closed. The details of each after-hours encounter were reviewed, and were categorized by the reason for call, training year of the GI fellow, advice given to patient, and unplanned care outcomes. For comparison, we also tracked frequency of patient calls for symptoms during clinic hours. Demographic information, disease type, disease activity index, quality of life (QoL), and depression/anxiety scores documented most recently to the start of the observation period were included in the analysis. Comparisons were made using Chi-square, T-tests and non-parametric median tests.

Results
259 of 293 patients (86.7%) had any documented phone interaction. Only 36 patients (12.3%) placed a total of 63 after-hours phone calls to GI fellows, with calls for symptoms representing the majority (71.4%). Among calls for symptoms (n = 45), patients were advised by GI fellows to present to the emergency department (ED) 44.4% of the time. There was no significant difference in ED recommendations by fellow training level (p = 0.17). Of the 20 ED encounters advised by fellows, 9 (45%) did not result in admission; and 2 patients had new cross-sectional imaging. Of the 11 admissions, 10 also had new cross-sectional imaging, with generation of 10 inpatient IBD consults, as well as 1 surgery for seton placement. After-hours callers were more likely to have Crohn’s disease and higher GAD-7 scores, with trends towards lower SIBDQ scores and higher PHQ-9 scores, but similar disease activity index scores, number of clinic visits, and demographics, compared to patients who called with symptoms during clinic hours (Table 1).

Conclusions
Among patients established within an IBD medical home model, a small population of patients called after hours resulting in frequent recommendation to present to the ED from GI fellows, however it is unknown if these encounters meaningfully changed their IBD care. Higher psychosocial complexity may influence this care behavior. Further studies of triage processes and educational initiatives aimed at GI fellows may help minimize unplanned ED and inpatient care in this patient population.
P010 FIRST SURVEILLANCE COLONOSCOPY FOR INFLAMMATORY BOWEL DISEASE – ARE WE GETTING IT RIGHT FROM THE START?
Authors: Patel Rajan , Tapper Louis , Lyne Holly , Moledina Saadiq , Cama Rigers , Besherdas Kalpesh 
Published: January 2020

Abstract

Background
Surveillance for colorectal cancer (CRC) is necessary in patients with inflammatory bowel disease (IBD). Patients with ulcerative colitis (UC) have a similar CRC risk to those with Crohn’s colitis (CC). British Society of Gastroenterology (BSG) guidelines from 2010 outlined recommendations for screening including surveillance intervals and pancolonic dye spraying with targeted biopsies. We aimed to identify reasons why the first surveillance colonoscopy is not being performed as advised, including the role of poor bowel preparation and disease activity.

Methods
Retrospective study of all IBD colonoscopies over a 7 year period (2011–2018) across two sites at a tertiary London based hospital trust. 214 patients were identified and exclusion criterion was applied (not first surveillance/diagnosis prior to year 2000/PSC/inadequate data). 93 patients were included for analysis.

Results
26 (28.0%) surveillance colonoscopies were performed prior to 10 years of diagnosis (ie. before BSG guideline recommendation). 22 (23.7%) surveillance colonoscopies performed after the recommended interval. Dye spray was performed in only 2 patients (2%). Reasons cited for not dying were only given in 4 (4.3%) cases, and included poor bowel prep or active disease. No reason was given in 87 (93%) cases. Targeted biopsies were performed in 24 (25.8%) patients, with random biopsies in 56 (60.2%) patients.

Conclusion
The first IBD surveillance colonoscopy is only being performed at the correct time interval in approximately 50% of cases with over a quarter being performed too soon and almost a quarter being performed too late. Pan-colonic dye spray is used in only 2% and targeted biopsies are taken in only 1 in 4 patients. Poor bowel preparation and disease activity do not appear to be limiting factors in the use of dye spray. We conclude that appropriate initial colitis surveillance is not being performed in the majority despite published guidelines. Organisational factors such as sufficient time allocated to dye spray colonoscopy, along with endoscopist skill, may be contributing factors.
P011 HIGH TIME: INCREASED INQUIRY ABOUT MARIJUANA USE IN IBD PATIENTS IS NECESSARY
Authors: Baumgartner Scott , Rao Vinay , Khan Ali , Dave Jenny , Chawla Karan , Borum Marie 
Published: January 2020

Abstract

Background
Marijuana use in the United States continues to increase with recreational sales legal in 11 states and the District of Columbia and medicinal approval expanded to include over two thirds of states. It is estimated that cannabinoid products are used by 15–40% of individuals with inflammatory bowel disease (IBD). However, the efficacy and safety have not been well-established. It is important that providers are aware of the extent of marijuana use in IBD patients. There is limited information about the frequency that providers inquire about recreational and medicinal use of marijuana. This study evaluated the frequency that providers screen for cannabinoid product use in individuals with IBD.

Methods
A chart review of all IBD patients seen at a university GI clinic over a 5-year period was performed. A confidential database using Microsoft Excel of patient age, gender, race, IBD diagnosis and recreational drug use was created. Charts were specifically queried for documentation of recreational or medicinal marijuana / cannabinoid (CBD) product use. Statistical analysis was performed using Fisher’s exact test with significance set at p&lt;0.05. The study was approved by the institutional IRB.

Results
381 records were analyzed. 284 patients had UC, 95 CD, and 2 indeterminate colitis. There were 172 men and 209 women (mean age 44.1 years; range 20–82). 195 patients were white, 97 African American, 11 Asian, 38 other/unknown, and 40 declined. Providers screened for recreational drug use, including marijuana, in 182 patients (47.8%). Marijuana / CBD use (medicinal or recreational) was noted in 19 (4.9%) charts (4 for IBD symptoms, 3 recreational, 12 no reason documented; 2 had prescriptions). There was no significant difference in the rate of screening for drug or marijuana / CBD use based on gender (p=0.627), race (p=0.447), or IBD type (p=0.169).

Discussion
The efficacy and safety of marijuana use in IBD remains unestablished despite that up to 40% of patients endorse cannabinoid use. It is important that providers are aware of the frequency of marijuana / CBD use by IBD patients. Identification of self-prescribed use may prompt further evaluation and modification of medication regimen. This study revealed that providers inconsistently inquire specifically about marijuana / CBD use. The growing prevalence of recreational and medicinal marijuana use should prompt increased screening and appropriate incorporation of this information into optimizing care.

References