bluuebunny/crossref_metadata_2025 huggingface dataset:
P070 TRENDS AND CHARACTERISTICS OF CLINICAL TRIALS PARTICIPATION IN THE IBD PARTNERS COHORT
Authors: Johnson Cole , Barnes Edward , Zhang Xian , Long Millie
Published: January 2020

Background and Aims

There are currently several recruitment challenges in randomized controlled trials (RCT) for inflammatory bowel disease (IBD) which prolong the drug approval process and affect the generalizability of study results. The purpose of this study is to characterize individuals who participate in IBD RCTs and identify factors which could influence future recruitment strategies.

Methods

We performed a cross-sectional study within the IBD Partners cohort comparing patients with current or prior participation in an interventional randomized controlled trial (RCT) of a medical therapy for IBD to those without any RCT participation. Bivariate statistics were used to compare RCT participation by IBD subtype and by other demographic and disease characteristics, and predictive modeling was used to identify factors predictive of RCT participation. We calculated the percent of the cohort that participated an in RCT during each calendar year from 2011–2018 and Clinicaltrials.gov was accessed to determine the number of active RCTs for IBD therapies per year during that same period.

Results

A total of 14,747 patients with IBD were included in the analysis and 1,116 (7.6%) reported RCT participation at any time. Demographic factors predictive of RCT participation (Table 1) included following at an academic institution (OR=1.8; 95%CI: 1.51–2.04) and age 36–75 (OR=1.6; 95%CI: 1.43–1.87). Patients with Crohn’s disease (CD) were more likely to participate than those with ulcerative colitis (UC) (OR=1.5; 95%CI: 1.35–1.77). Patients with more severe disease were more likely to participate, including those with prior IBD-related hospitalization (OR=2.6; 95%CI: 2.19–2.99), IBD-related surgery (OR=2.5; 95%CI: 2.24–2.87), biologic exposure (OR=3.2; 95%CI: 2.76–3.65), and “Poor” or worse quality of life (OR=1.7; 95%CI: 1.45–1.93). Steroid-free remission was associated with lower likelihood of RCT participation (OR=0.6; 95%CI: 0.53–0.70). While the number of active RCTs for IBD more than doubled between 2011 and 2018, RCT participation rates during that same time period decreased from 1.1% to 0.7% of the cohort (Figure 1).

Conclusions

RCT participation rates declined within this cohort between 2011–2018. Groups underrepresented in RCTs for IBD included younger patients, patients followed in community settings, and patients with more mild disease. The non-RCT group had mean sCDAI and SCCAI scores that did not meet remission thresholds, demonstrating populations in need of alternate therapies for whom clinical trials could be an option. Given anti-TNF exposure rates in this national cohort, studies should focus on anti-TNF failure populations. Investigators should make every effort to offer RCTs to all patients and network with community providers to increase awareness of RCTs.
P060 THE TREND OF DIAGNOSTIC COMPETENCY OF CROHN’S DISEASE IN THAI POPULATION FOR THE PAST TWO DECADES
Authors: Chaisidhivej Natapat , Aniwan Satimai , Pausawasdi Nonthalee , Limsrivilai Julajak
Published: January 2020

Background

Crohn’s disease (CD) is an uncommon disease in Thai population, leading to delay in diagnosis due to lacking of familiarity, which may increase disease complications. One of the most problematic issues is to differentiate CD from intestinal tuberculosis (ITB), and many scoring systems have been introduced since 2006. However, competency of diagnosis of CD in the latter period is still unknown in Thailand. Our aim is to compare this competency in the period of 2000–2006, 2007–2012, and 2013–2018.

Methods

Retrospective study collecting all patients, whom diagnosed with CD in two tertiary referral centers in Bangkok, was performed. We focused the competency of diagnosis of each period by using the following variables; duration of presenting symptoms, number of colonoscopy before diagnosis, receiving anti-TB medication before diagnosis, and having first surgery before and at diagnosis. Comparison in each parameter was done by statistical analysis.

Results

A total of 190 CD patients were identified. Characteristics of patients were shown in Table 1. The patients were classified into 3 groups by using time period of diagnosis, which included 27, 62, and 101 patients in the 2000–2006, 2007–2012, and 2013–2018 period groups, respectively. Mean age was 38.6, 46, and 47.7 respectively. Nearly 50% were male, and 80% had inflammatory phenotypes in all groups. The median duration of presenting symptoms was 15.8, 10.1, and 11.7 months in the 2000–2006, 2007–2012, and 2013–2018 period groups, respectively (p=0.67). The percentage of patients receiving anti-TB medication before diagnosis was 19.2%, 9.8%, and 10.2%, in each group respectively (p=0.31). The number of colonoscopy for 1, 2, and >2 times before diagnosis were 56.5%, 30.4%, and 13.1%; 55.7%, 24.6%, and 19.7%; and 41.7%, 38.5%, and 19.8% in each group, respectively (p=0.32). The percentage of patients undergoing first surgery before or at diagnosis were 33.3%, 21.0%, and 26.8%, respectively (p=0.80).

Conclusion

Competency in diagnosis of CD in Thailand has not changed in the past 2 decades. It is necessary to find effective methods helping physicians differentiate CD from other conditions to avoid the diagnosis delay, which may improve treatment outcomes.
P114 PERIANAL EXAMINATION AT TIME OF COLONOSCOPY - A MISSED OPPORTUNITY FOR IBD ASSESSMENT
Authors: Patel Rajan , Jameie-Oskooei Sina , Fromson Renate , Routledge Emma , Johnson Emma , Blad William , Wong Voishim
Published: January 2020

Introduction

The subtype of inflammatory bowel disease (IBD) is often not known at index colonoscopy and examining for perianal disease (PAD) can assist in establishing the diagnosis. PAD is common in Crohn’s disease (CD) but can also be seen in patients with ulcerative colitis (UC) in the form of fissures, abscesses and fistulae. Absence of perianal symptoms does not exclude PAD. Performing a routine perianal examination in a busy outpatient setting is not ideal and the endoscopy suite may be more appropriate. We hypothesise that perianal examinations are being omitted during IBD assessment colonoscopy.

Methods

Unisoft GI Reporting Tool was used to identify the last 70 consecutive CD and UC assessment colonoscopies performed over a 12 month period (August 2018 and July 2019) at a London-based district general hospital. Data was collected on demographics, known PAD, previous imaging and performance of perianal examination at colonoscopy.

Results

140 patients undergoing colonoscopy for IBD assessment were included in this study (70 CD, 70 UC).Median age 42 (IQR 32 – 55), Female 66 (47.1%).

15 (10.7%) had known perianal disease. Pelvic MRI had previously been performed in 20(14.3%). Perianal examination was performed in only 3 (2%) patients at the time of their last clinic consultation.

Although digital rectal examination (DRE) was performed in 132 (93.6%) of patients at the time of colonoscopy, only 9 (6.4%) had a perianal examination documented.

Conclusion

About 10% of patients in our cohort undergoing IBD assessment colonoscopy were known to have PAD but perianal examination was performed in only 2% of patients during clinic consultation and 6% during colonoscopy. Perianal examination at time of endoscopic assessment is an ideal setting to perform an intimate examination as you have an exposed, sedated and chaperoned patient. The omission of perianal examination at colonoscopy is a missed opportunity and improvement in this key element of disease assessment is required.
P131 NATIONAL TRENDS IN HOSPITALIZATION, SURGICAL RESECTION, AND COMORBIDITIES IN PEDIATRIC INFLAMMATORY BOWEL DISEASES
Authors: Ihekweazu Faith , Dongarwar Deepa , Salihu Hamisu , Kellermayer Richard
Published: January 2020

Background

Therapeutic options for pediatric inflammatory bowel disease (PIBD) have dramatically changed over the last decades with the widespread use of biologic medications. However, the overall impact of biologic therapy on PIBD outcomes (specifically hospitalizations, comorbidities, surgical rates, and postoperative complications) remains unclear. We aimed to fill this gap in the literature by using a large, validated, national database, to study the change in outcomes over the last decade. We hypothesized that morbidity in pediatric IBD has decreased over time with the increased use of biologic therapy.

Methods

The National Inpatient Sample (NIS) Database and ICD-9-CM codes were utilized to identify inpatient admissions with a primary or secondary diagnosis of pediatric Crohn’s disease (CD) or ulcerative colitis (UC) from 2002–2015. Trends in hospitalizations, comorbidities (including malnutrition and weight loss), surgical procedures, and post-operative complications were examined using joinpoint regression analysis.

Results

There were 119,282 admissions for PIBD during the study period. The annual incidence of hospitalization increased significantly over time for both CD (average annual percent change [AAPC] 6.0%, 95%confidence interval [CI] 4.7, 7.2) and UC (AAPC 7.2%, 95% CI 6.2, 8.1). The rate of intestinal resection decreased in CD patients (AAPC -6.4%, 95%CI, -8.7, -4.1) while postoperative complications remained unchanged. However, comorbidities increased significantly in CD patients (AAPC 6.8%, 95%CI, 4.6, 9.0). For pediatric UC patients, postoperative complications (AAPC 6.7%, 95%CI, 1.2, 12.4), and comorbidities (AAPC 10.2%, 95%CI, 8.8–11.6) increased significantly over time while intestinal resection rates remained stable.

Conclusions

Intestinal resection rate in pediatric CD has decreased over time, but not in pediatric UC. Annual incidence of hospitalization and comorbidities continue to increase in PIBD despite the increased availability and use of biologic medications. Our findings emphasize the critical need for prevention and novel therapeutic options for this vulnerable patient population.
P132 OUTCOMES AND REASONS FOR ADMISSION IN CROHN’S DISEASE. AN ANALYSIS OF NATIONWIDE INPATIENT SAMPLE 2016
Authors: Vohra Ishaan , Katiyar Vatsala , Sharma Sachit , Attar Bashar
Published: January 2020

Objective

Recent research suggests increasing nationwide admission for Crohn’s disease (CD), but the most common reasons for admission are not well known. We sought to enumerate the most common presentations of Crohn’s disease requiring admission in Nationwide Inpatient Sample (NIS) 2016 using ICD-10 codes.

Methods

We identified all adults aged greater than or equal to 18 years with a primary diagnosis of CD, using ICD 10 in Nationwide inpatient database. We analyzed inpatient demographics via chi-square. Inpatient mortality,Length of stay (LOS) and Total Charge (TOTCHG) was calculated using univariate and multivariable linear models.

Results

60,244 patients with CD required inpatient admission. Majority of patients were females (53%), white (69%), with private insurance (46%) admitted to large bed sized (53.3%) teaching hospitals (68%). The common reasons for admission in CD patients included bowel obstruction at 24.6% (14,850) of which 57.8% (8,590) presented with small bowel obstruction (SBO). 42.1% (6260) were admitted with both SBO and LBO. Other reasons for admission were GI bleeding (6.5%) and fistulizing CD (2.4%). The inpatient mortality was 0.5%. Age was an independent predictor of mortality in these patients. (aOR 1.08, 95% CI 1.04–1.12; p=0.000). Protein energy malnutrition (PEM) (aOR 2.45, p=0.348), patients requiring pressor support (aOR 4.2, p=1.06) and those with bowel obstruction (aOR 1.1.9 p=0.84) had higher odds of mortality on multivariate analysis model, but couldn’t reach statistical significance. The mean LOS was 4.9 days and patients admitted over weekend had a longer LOS (coeff 0.22, 95% CI 0.08–0.37, p=0.002) as compared to weekdays on multivariate linear regression. The total cost attributable to Crohn’s disease was 706$ million. Independent predictors of increased total charge were Large bed sized hospitals, African-American, protein energy malnutrition, patients requiring pressor support and bowel obstruction in multivariate linear analysis.

Conclusions

The common reasons for inpatient admission in patients with CD include bowel obstruction, GI bleeding and fistulizing CD. Age was an independent predictor of mortality. The economic burden was highest amongst African-Americans, malnourished, patients requiring pressor support and those with bowel obstruction.
P133 PRESCRIPTION OPIOID USE AMONG VETERANS WITH INFLAMMATORY BOWEL DISEASE
Authors: Love Bryan , Finney Christopher , Gaidos Jill
Published: January 2020

Background

Opioids are commonly prescribed to manage pain in patients with IBD despite increasing evidence of harm associated with chronic use. The aim of the current study was to describe trends in opioid use among veterans with IBD.

Methods

This was a retrospective cohort study derived from the Veterans Affairs (VA) Health Care System. A unique patient identifier facilitated longitudinal evaluation of electronic databases that include medical diagnoses, surgical procedures, pharmaceuticals, labs, vital status information, dates of treatment, and radiology findings. Veterans were labeled as having IBD if there were at least 2 outpatient or 1 inpatient health care encounters with an ICD-9/10 diagnostic code consistent with IBD from fiscal years 2002 to 2016. Veterans without a minimum of 2 years of follow-up or who had a cancer diagnosis within 1 year before or after IBD diagnosis were excluded. In order to standardize the quantity of opioid exposure, morphine milligram equivalents (MME) for each prescription was calculated using published conversion factors. Individual prescriptions with missing quantity or day’s supply and prescriptions exceeding 1000 MME/day were excluded. Opioid exposure during the first year following the initial diagnosis date was determined as the average MME/day for those with at least one opioid prescription. Annual opioid prescribing rates per 100 IBD patients were calculated. Comorbidities were assessed using a modified Charlson Comorbidity Index (CCI), excluding cancer from the calculation.

Results

During the study period, 65,817 veterans with IBD were identified. The majority were males (92.1%), Caucasian (78.2%), and had a mean age of 58.2 years. In total, 1,471,019 individual opioid prescriptions were evaluated. The quantity and rate of opioid prescriptions peaked in 2012, with 115,774 unique prescriptions and 698.5 opioid prescriptions per 100 IBD patients, respectively. Twenty-seven percent (n=17,844) of IBD patients had at least one opioid prescription within the initial year of diagnosis. Mean opioid exposure during the initial year of diagnosis averaged 33.2 MME/day, and 12.2% had mean opioid exposure greater than 50 MME/day. Opioid exposure peaked in 2005 at 37.4 MME/day and consistently declined to 29.3 MME/day in 2016.

Conclusion

There has been a significant decline in opioid prescriptions, prescribing rate, and mean opioid exposure since peaking in 2012. These trends are similar to those seen in the non-veteran US population.
P146 OXPHOS INDUCTION IN HEALING: A CRITICAL MISSING STEP IN INFLAMMATORY BOWEL DISEASE?
Authors: Kapur Neeraj , Bradford Emily , Thomas Justin , Perry Courtney , Barrett Terrence
Published: January 2020

Background

In Inflammatory Bowel Disease (IBD), mucosal healing represents a key outcome in clinical remission. Mitochondrial dysfunction is one of the major features of IBD, which is hallmarked by increased oxidative stress and impaired ATP production. However, partial wound healing continues even with repressed mitochondrial respiration in an inflammatory environment. In this study, we demonstrate that intestinal epithelial cells (IEC) responding to colitis produce a gene signature with downregulated mitochondrial expression associated with oxidative phosphorylation (OxPHOS) and upregulate epithelial-to-mesenchymal transition (EMT). These data were consistent with the notion that EMT induced in IEC is fueled by glycolysis (repressed OxPHOS). We also wish to determine if this OxPHOS repression is present in normal healing.

Methods

We are actively enrolling patients with Ulcerative Colitis (UC) and normal patients into a prospective study evaluating biopsy site healing. Biopsy samples from UC patients were collected in Allprotect® or PBS. Biopsy samples collected in PBS were processed for IEC isolation using enzymatic digestion followed by flow sorting of EpCAM+ cells. To investigate the healing process in colitis and normal patients, the sigmoid colon is tattooed at initial endoscopy and 10–12 biopsies are collected in Allprotect®. Patients are brought back a week later for a flexible sigmoidoscopy. The tattooed area is examined, and biopsies are obtained from the previous biopsy sites (“biopsy of the biopsy”) and collected in Allprotect®. RNA is extracted from Allprotect® preserved tissue or isolated IECs and analyzed with RT-PCR.

Results

Genes corresponding to subunits of NADH dehydrogenase (Ubiquinone) of complex I (ND1, ND2, ND3, ND4, ND5 and ND6) were consistently downregulated in ulcer sites of colitis patients as compared to “biopsy of the biopsy” sites near the tattoo in normal patients. As expected, samples from colitis patients exhibited significant upregulation of inflammatory markers (iNOS, NLRP3, CCL2, RANTES, TGF-b1, CCL20 and CXCL10) compared to “biopsy of the biopsy” sites in normal patients undergoing healing. Intriguingly, epithelial marker E-cadherin was noted to be decreased in samples obtained from colitis patients with concomitant increase in mesenchymal markers (Vimentin, Snail, Twist-1 and Zeb-1) compared to previously biopsied normal controls.

Discussion

Our data suggests that repressed OxPHOS observed in inflamed IEC from colitis patients may serves as an inducer of EMT governing delayed but partial healing in IBD. We found this to be in stark opposition to healing in normal patients, who exhibit enhanced OxPHOS associated with rapid healing. These important findings indicate OxPHOS metabolism may be an important target for therapeutic agents to improve healing in refractory colitis.
P147 PATIENT DERIVED INTESTINAL ORGANOIDS REPRESENT AN EPITHELIAL MODEL TO STUDY PEDIATRIC CROHNS DISEASE
Authors: Niklinska-Schirtz Barbara , Matthews Jason , Dodd Anne , Prince Jarod , Biliya Shweta , Venkateswaran Suresh , Kugathasan Subra
Published: January 2020

Background

Although therapeutics in Crohn’s disease (CD) have dramatically improved, current approaches targeting the immune system have limited success at a population level. Thus, there is a need for future therapeutics to target different pathways/cell types. Recently, patient derived stem cells have shown promise in helping to better understand the molecular basis of disease. We used patient derived organoids (PDOs), produced from both CD and healthy patients’ pinch biopsies, to determine the ability of PDOs to functionally represent the human intestinal epithelium, and to better understand the role of the epithelium in CD.

Methods

Mucosal biopsies from the terminal ileum were obtained from pediatric subjects (CD = 16, healthy controls = 13) by colonoscopy. We performed bulk RNA-seq on the freshly isolated ileal crypts (IC), and on the corresponding PDOs grown from the IC stem cells. The sequencing was performed on an Illumina HiSeq system in a single batch. The raw FastQ files were aligned with reference genome Hg38 using STAR package. Differential expression analysis was performed on the read counts using DEseq package. We compared the organoid gene expression to that of the IC for each patient, along with the differential analysis between groups.

Results

On average, 7.5M read counts were obtained for each IC and organoid sample. Of the 19,900 genes tested against Hg38, we found 15,554 genes expressed in either IC or organoids. Of those, 14,149 (91%) were expressed in both IC and organoids, 1,091 (7%) were expressed only in IC, and 314 (2%) expressed only in organoids. We compared PDOs from healthy controls to CD cases and the differentially expressed genes were identified using cutoff of log2FC > ±1.2 and statistically significant threshold p < 0.05. Compared to healthy controls, CCL5 and CXCL5 genes were up-regulated in CD, whereas PDGFB, IL-33 and ILDR2 genes were down-regulated.

Conclusion

We demonstrate that PDOs are 91% similar in gene expression to in vivo epithelium and thus are an excellent patient-specific in vitro epithelial model system. We have further used this model to show the CD specific transcriptional defects in the epithelium. Our data suggests that the epithelium is responsible, in part, in promoting neutrophil recruitment and inflammation through increases in CCL5 and CXCL5 expression, and changes in the Th1/Th2 profile through downregulation of IL-33 expression. Dysregulation of the cytoskeleton and barrier formation are both likely affected by down regulation of PDGFB and ILDR2, respectively, resulting in a negative effect on intestinal barrier function and restitution.
P138
SCGN DEFICIENCY RESULTS IN COLITIS SUSCEPTIBILITY
Authors: Sifuentes-Dominguez Luis , Li Haying , Llano Ernesto , Liu Zhe , Singla Amika , Patel Ashish , Kathania Mahesh , Khoury Areen , Norris Nicholas , Rios Jonathan , Starokadomskyy Petro , Park Jason , Gopal Purva , Liu Qi , Tan Shuai , Chan Lillienne , Ross Theodora , Harrison Steven , Venuprasad K , Baker Linda , Jia Da , Burstein Ezra
Published: January 2020

Inflammatory bowel disease (IBD) affects 1.5–3.0 million people in the United States. IBD is genetically determined and many common risk alleles have been identified. Yet, a large proportion of genetic predisposition remains unexplained. In this study we report the identification of an ultrarare missense variant (NM_006998.3:c.230G>A;p.Arg77His) in the SCGN gene causing Mendelian early-onset ulcerative colitis. SCGN encodes a calcium sensor that is exclusively expressed in neuroendocrine lineages, including enteroendocrine cells and gut neurons. SCGN interacts with the SNARE complex, which is required for vesicle fusion with the plasma membrane. We show that the SCGN mutation identified impacted the localization of the SNARE complex partner, SNAP25, leading to impaired hormone release. Finally, we show that mouse models of Scgn deficiency recapitulate impaired hormone release and susceptibility to DSS-induced colitis. Altogether, these studies demonstrate that functional deficiency in SCGN can result in intestinal inflammation and implicates the neuroendocrine cellular compartment in IBD.
P160 γδ T CELLS, IL-22, THE PROBIOTIC, LACTOBACILLUS DELBRUECKII, AND THE ROLE THEY PLAY IN ATTENUATION OF ALCOHOL INDUCED EXACERBATION OF DSS-COLITIS
Authors: Cannon Abigail , Shim Esther , Kuprys Paulius , Choudhry Mashkoor
Published: January 2020

Ulcerative colitis is characterized by cycles of active disease flare and inactive disease remission. During UC remission, IL-22 expression can be upregulated, acting as a hallmark of entrance into a UC remission period. Recently, we found that in our mouse model of binge alcohol consumption after DSS-induced colitis, alcohol increases severity of UC flare symptoms. In this study, we assessed whether alcohol influenced IL-22 expression and thereby perpetuates UC flare. Male C57BL/6 mice received 2% DSS or water ad libitum for 5 days. On day 5, DSS was removed to mimic entrance into remission. Additionally on day 5, DSS and Sham mice were subdivided into mice gavaged with ethanol (∼3g/kg) or with water on days 5, 6, and 7. Three hours after the last gavage on day 7, mice were humanely euthanized. Large intestine lamina propria (LP) cells were isolated. The percentage of total IL-22+ LP cells was significantly decreased (p<0.05) in DSS Ethanol compared to DSS Vehicle. No differences in IL-22+ T cells, Innate Lymphoid Cells Type 3, or neutrophils were observed. Examination of I γδ T cells revealed DSS Vehicle treated mice had a significantly increased percentage of IL-22+ γδ T cells, while DSS Ethanol treated mice were unable to mount this response. Therefore, we hypothesized that by re-establishing IL-22, through either rIL-22 or a probiotic, we could alleviate the alcohol-induced exacerbation of UC. Firstly, rIL-22 administration substantially restored weight loss of DSS Ethanol treated mice back to that of DSS Vehicle (∼12.5% back to ∼6% on day 7). Increased colonic shortening (p<0.001) and increased Enterobacteriaceae copy number were also attenuated following binge alcohol and colitis with IL-22 treatment. Knockout of STAT3 in IECs resulted in loss of IL-22 protection, demonstrating STAT3 is required for protection. Secondly, we utilized Lactobacillus delbrueckii, a common probiotic known to play a role in IL-22 release. Treatment with Lacto attenuated both weight loss and colon length in DSS Ethanol mice back to levels of DSS alone (p<0.01 and p<0.001, respectively). Additionally, Lacto treatment mitigated increases in Enterobacteriaceae copy number seen in DSS Ethanol mice and trended towards an increase in IL-22 in DSS Ethanol + Lacto mice. Levels of pSTAT3 were decreased in DSS Ethanol treated mice compared to DSS Vehicle, but administration of Lacto in DSS Ethanol mice increased levels of pSTAT3 back to that of the DSS Vehicle group. Treatment with Lacto supernatant alone was not sufficient to mitigate the exacerbation of UC following ethanol. Our findings suggest that both rIL-22 and Lactobacillus delbrueckii utilize the IL-22/pSTAT3 signaling pathway to attenuate alcohol-induced increases in ulcerative colitis symptoms. (R21AA022324, R21AA025806, T32AA013527, F30AA027442, F31AA025536)
P140 3D BIOENGINEERED TISSUE MODEL OF THE LARGE INTESTINE TO STUDY INFLAMMATORY BOWEL DISEASE
Authors: Roh Terrence , Chen Ying , Paul Harry , Guo Chengchen , Kaplan David
Published: January 2020

An in vitro model of intestine epithelium with an immune compartment was bioengineered to mimic immunologic responses seen in inflammatory bowel disease [1]. While aspects of intestinal immunity can be modeled in transwells and 2D culture systems, 3D tissue models improve physiological relevance by providing a 3D substrate which enable migration of macrophages towards the epithelium. An intestinal epithelium comprised of non-transformed human colon organoid cells and a subepithelial layer laden with monocyte-derived macrophages was bioengineered to mimic native intestinal mucosa cell organization using spongy silk scaffolds. Confluent epithelial monolayers with microvilli, a mucus layer, and infiltration of macrophages to the basal side of the epithelium were observed. Inflammation, induced by E. coli O111:B4 lipopolysaccharide and interferon γ resulted in morphology changes to the epithelium, resulting in ball-like structures, decreased epithelial coverage, and migration of macrophages to the epithelium. Analysis of cytokines present in the inflamed tissue model demonstrated significantly upregulated secretion of pro-inflammatory cytokines associated with active inflammatory bowel disease, including CXCL10, IL-1β, IL-6, MCP-2, and MIP-1β. The macrophage layer enhanced epithelial and biochemical responses to inflammatory stimuli, and this new tissue system may be useful to study and develop potential therapies for inflammatory bowel disease.

References: 6 Roh, T.T., et al., 3D bioengineered tissue model of the large intestine to study inflammatory bowel disease. Biomaterials, 2019: p. 119517.

7 In, J., et al., Enterohemorrhagic Escherichia coli reduce mucus and intermicrovillar bridges in human stem cell-derived colonoids. Cellular and molecular gastroenterology and hepatology, 2015. 2(1): p. 48–62.e3.

8 Chen, Y., et al., In vitro enteroid-derived three-dimensional tissue model of human small intestinal epithelium with innate immune responses. PLoS ONE, 2017. 12(11): p. e0187880.

Colonoid and macrophage cultivation scheme in the 3D bilayer system. (A) Human monocytes were isolated from whole blood and human colonoids from large intestine biopsies were cultured according to established protocols [2]. (B) Cell suspensions of colonoids were seeded on the film surface on the inner silk scaffold and monocyte-derived macrophages were seeded throughout the porous outer silk scaffold using established protocols [3]. (C) The model is cultured for 3 weeks total with 2 weeks in High WNT media and 1 week in differentiation media based on established protocol. Colonoids are present in the model throughout the 3 week culture time. 2 sets of macrophages are added with the first set added after the first week of culture and the second set replacing the first set after the second week.
P073 DIET AS A MICROBIOME-CENTERED THERAPY FOR IBD
Authors: Olednzki Barbara , Bucci Vanni , Cawley Caitlin , McCormick Beth , Ward Doyle , Maldonado-Contreras Ana
Published: January 2020

Your food is your best medicine. Nowhere else is this more real than for those suffering from inflammatory bowel disease (IBD). Thus, we developed the IBD-Anti-Inflammatory Diet (IBD-AID™) to relieve IBD symptoms while providing nutrient adequacy. The IBD-AID™ was designed to increase the diversity of bacteria that produce short-chain fatty acids (SCFAs) to modulate the local immune response. After 4 weeks on the IBD-AID™, patients have reported a reduction of symptoms and medication.

Our goal is to define diet-microbiome-inflammation interactions that promote health while consuming the IBD-AID™. We posit that IBD-AID™ favors SCFA-producing bacteria resulting in dampening of inflammation and assisting patient’s remission. We recruited 19 patients with mild to severe CD or UC, to determine diet-dependent changes in the microbiota that could support the hypothesis. The study design was a single-arm, prospective, pre-post intervention trial. After a ‘baseline’ period of 4 weeks, the dietary ‘Intervention’ phase started and continued for 8–10 weeks (Fig 1).

We performed metagenomic sequencing of 400+ fecal samples and analyzed 300+ food frequency questionnaires. Most (88.2%) patients achieved ≥50% diet compliance. The IBD-AID™ significantly promoted microbiota signatures that have been associated with colonic health. We found that increased intakes of prebiotics foods correlated with the abundance of SCFAs-producing members of the Bacteroides and Parabacteroides. Similarly, increase intakes of probiotics foods during intervention correlated with the abundance of Clostridium bolteae, a bacterium known to play a critical role in the induction of regulatory T cells. We found that vegetable and nuts intake -encouraged in IBD-AID™, correlated with the abundance of butyrate-producing Roseburia hominis, Eubacterium rectale, and Faecalibacterium prausnitzii. The increased abundance of those SCFAs-producing bacteria after the intervention was accompanied by declines in putative pathogenic strains, such as Escherichia sp., Alistipes sp., and Eggerthella sp. The majority (61.3%) of patients treated for at least 8 weeks, who achieved as minimum as 50% dietary compliance reported a dramatic decrease in disease severity.

To examine the role of those diet-dependent microbiome signatures in inflammation, we use P-glycoprotein (P-gp) expression as a biomarker. P-gp is an ABC transporter in epithelial cells implicated in the development and persistence of chronic intestinal inflammation in IBD. We found that fecal supernatants from IBD patients adopting the IBD-AID™ induced P-gp expression. Altogether, these results uncover a novel molecular mechanism of the diet-microbiome-immune interaction allowing us to customize dietary guidelines to emphasize foods with known effect on microbiome signatures associated with health.

Fig 1. Schematic representation of the study design and sampling schedule.
25 DONOR SELECTION OF FECAL MICROBIOTA TRANSPLANTATION IS IMPORTANT TO LONG-TERM MAINTENANCE OF ULCERATIVE COLITIS
Authors: Okahara Koki , Ishikawa Dai , Nomura Kei , Ito Shoko , Haga Keiichi , Takahashi Masahito , Shibuya Tomoyoshi , Nagahara Akihito
Published: January 2020

Background

Fecal microbiota transplantation (FMT) has been investigated as a potential treatment for various disease. However, the therapeutic mechanism is still unclear. We previously demonstrated that fresh-fecal microbiota transplantation following triple-antibiotic therapy [amoxicillin, fosfomycin, and metronidazole (AFM); A-FMT] for ulcerative colitis (UC) patients induced changes in the phylum Bacteroidetes, which constitutes a critical factor correlated with clinical responses. Here, we analyzed microbiota to examine the beneficial species, and observed long-term course (12 months) of the patients who treated with AFM and A-FMT. Moreover, we explore the concept of best donor for FMT success.

Methods

This prospective and non-randomized controlled study was conducted from July 2014 to March 2017 at Juntendo University Hospital. Eligible patients were at least 20 years of age, with a diagnosis of active UC which were required a Lichtiger’s clinical activity index (CAI) of 5 or more, or with an endoscopic Mayo score of 1 or more. Patients’ spouses or relatives in the family were selected as donors. AFM was administered to patients with UC for 2 weeks, and up to 2 days before fresh FMT. Clinical response was defined as a decrease of CAI of 3 points or more, and remission was defined as 3 points or less. Maintenance of efficacy was defined as no exacerbation of CAI and no intensification of treatments.

Results

Seventy-nine patients completed protocol (A-FMT; n = 47, mono-AFM; n = 32). At 4 weeks after treatment, clinical response and remission were observed in 31 and 19 patients (65.9%, 40.4%) in A-FMT, which higher than in mono-AFM respectively (56.2%, 18.7%). The maintenance rate of clinical responder was shown to be significantly higher in A-FMT than in AFM at 12 months after treatment (A-FMT vs mono-AFM, n = 13, 10; P = 0.046). Furthermore, in case that the age difference between donor and patient is more than 11 years, maintenance rate was significantly lower than 0–10 age difference in A-FMT (≧11 vs 0–10, n = 14, 16; P = 0.004). Siblings relationship has a significantly higher maintenance rate compared to parent–child relationship (Siblings vs parent-child; n = 7, 13; P = 0.009). An analysis of some cases in which the microbiota was followed for 24 months revealed a tendency that some bacterial species such as Bacteroides dorei and Bacteroides uniformis maintained their effects.

Conclusion

A-FMT exhibited reassuring clinical outcomes in terms of both short and long term. This is the first report of FMT to reveal importance of donor selection for long-term maintenance for UC.
P079 ISOLATION OF GASTROINTESTINAL PATHOGENS AFFECTS MEDICAL MANAGEMENT OF OUTPATIENTS WITH RELAPSE OF INFLAMMATORY BOWEL DISEASE
Authors: Hong Soonwook , Zaki Timothy , Main Michael , Hine Ashley , Chang Shannon , Hudesman David , Axelrad Jordan
Published: January 2020

Introduction

Evaluating for the presence of gastrointestinal infection is a critical component of the workup for relapse of inflammatory bowel disease (IBD). With the advent of stool multiplex gastrointestinal pathogen panels (GI PCR), infections are increasingly identified. Prior research has shown that detection of enteric infection significantly affects the management of IBD in the inpatient setting. We aimed to characterize the impact of enteric infection detection on the management of IBD therapy in outpatients with relapse of IBD.

Methods

In a cross-sectional study of IBD outpatients at an academic medical center presenting with acute gastrointestinal symptoms from September 2015 to April 2019 who received GI PCR testing, we recorded pathogens detected, demographic data, biomarkers of inflammation, presenting symptoms, IBD subtypes, and IBD therapy. Our primary outcome was dose escalation in IBD therapy, defined as the addition of a new therapeutic agent or an increase in the dose or frequency of an existing medication. Secondary outcomes included rates of endoscopy, abdominal imaging, and antibiotics in the 30-day period after the initial visit and rates of adverse outcomes, i.e. emergency room (ER) visits, hospitalizations, and abdominal surgeries in the 90-day period after the initial visit.

Results

We identified 134 IBD outpatients tested with GI PCR. A pathogen was identified in 35 (26%) patients, of whom 9 (27%) had an increase in their medication regimen; 2 (22%) were prescribed an additional mesalamine, 3 (33%) a biologic, and none glucocorticoids. In contrast, 49/99 (45%, p=0.03) patients without an infection had an increase in their medication regimen, with 3 (7%, p=0.49) prescribed mesalamines, 11 (24%, p=0.67) biologics, and 7 (16%, p=0.04) glucocorticoids (Table 1). No patient received immunomodulators. Patients with an infection received more antibiotics (49% vs. 12%, p<0.01). They were also more likely to present with vomiting (11% vs. 3%, p=0.06) and undergo less post-visit endoscopy (6% vs. 16%, p=0.13), but these differences were near significant. There were no significant differences in demographics, initial IBD medications on testing, presenting symptoms, lab markers, abdominal imaging, or adverse outcomes. The most commonly isolated organisms were Escherichia coli subtypes, with 22/35 (63%) patients having at least one species isolated on testing (Table 2).

Conclusion

Detection of an enteric infection in outpatients with relapse of IBD was associated with significantly fewer dose escalations in IBD therapy, including glucocorticoids, and increased exposure to antibiotics, and a marginal decrease in endoscopy. These changes in management were not associated with a difference in adverse outcomes.
2 EFFECTS OF AN IBD-ASSOCIATED MICROBIAL COMMUNITY STATE ON INTESTINAL INFLAMMATION IN HUMANIZED GNOTOBIOTIC MICE
Authors: Lagishetty Venu , Arias Nerea , Dong Tien , Hauer Meg , Katzka William , Dubinsky Marla , Braun Jonathan , Jacobs Jonathan
Published: January 2020

Background and Aims

We previously reported that 20% of unaffected first-degree relatives of pediatric IBD patients share the same microbial community structure (OTU-type) as IBD patients. This suggests that a preexisting dysbiosis can predispose to the development of IBD. The aims of this study were to establish that microbial community types identified in the family cohort could be reconstituted in gnotobiotic mice for further translational studies and to assess for any direct effects of this microbiota on intestinal inflammation.

Methods

Over 100 germ-free wild-type C57/BL6 mice were colonized for 4 weeks in the UCLA gnotobiotic facility with fecal microbiota from 30 human donors belonging to each of four groups from the pediatric family cohort: unaffected first-degree relatives with OTU-type 1, unaffected first-degree relatives with the IBD-associated OTU-type 2, Crohn’s disease (CD) with OTU-type 1, CD with OTU-type 2. Each group was represented by 8 human donors (n=3–4 mice/donor) with the exception of CD OTU-type 1 (only 5 donors available in the cohort). In addition, 35 eight week old germ-free IL-10-/- C57/BL6 mice were colonized for 12 weeks with fecal microbiota from 4 CD OTU-type 2 donors and 4 unaffected OTU-type 1 donors (n=4–5/donor). Luminal and mucosal microbial composition in the colon and small intestine was evaluated by 16S rRNA sequencing. Intestinal inflammation was assessed in the small intestine and colon by semiquantitative scoring of H&E stained sections.

Results

Donor-specific microbial composition was observed in the humanized gnotobiotic mice with clear separation between recipients of donor OTU-type 1 vs. OTU-type 2 stool. Parallel differences in differentially abundant microbes and microbial diversity were seen in these gnotobiotic mice as in the original human donors. No histologic evidence was found for colitis, enteritis, or fibrosis in wild-type colonized mice. However, fecal lipocalin was increased two-fold increase in recipients of OTU-type 2 microbiota from CD patients relative to the other three groups. CD humanized IL-10-/- mice exhibited lower microbial diversity and distinct microbial composition compared to non-IBD humanized IL-10-/- mice, mirroring differences in the human donors. Mice colonized with CD microbiota had increased histological disease severity in the colon and cecum (p=0.05) compared to mice colonized with non-IBD microbiota.

Conclusion

Our results demonstrate that human microbial community states identified in the pediatric IBD cohort could be reconstituted in gnotobiotic mice for translational studies. Moreover, CD-associated dysbiosis exacerbated colitis severity. These data support the concept that dysbiosis plays a direct role in promoting intestinal inflammation and provide an experimental framework for further mechanistic studies of IBD-associated microbial communities.
8 ROLE OF THE HOST IMMUNE RESPONSE TO ENTERIC PROKARYOTIC VIRUSES IN INFLAMMATORY BOWEL DISEASE
Authors: Angkeow Julia , Monaco Daniel , Handley Scott , Larman H B
Published: January 2020

Background

Gut microbiota comprise important environmental exposures that influence human immune systems and may alter the clinical course of inflammatory bowel disease (IBD). Little is known about the role of gut bacteriophages (viral components that infect prokaryotic bacteria) and their interactions with the host’s immune responses. We tested the hypotheses that (1) immune responses of individuals with IBD to phages differ from those without IBD and (2) immune responses to phages are associated with disease type (i.e. those with Crohn’s disease have different responses than those with ulcerative colitis).

Methods

We have constructed the first bacteriophage peptidome library (“phageome”), based on sequencing of environmental phages and large-scale metagenomic sequencing of virus-like particles isolated from stool samples from IBD patients and their non-IBD household contacts. Using Phage ImmunoPrecipitation Sequencing (PhIP-Seq) technology, we generated complete serum antibody binding profiles of 48 IBD patients (16 ulcerative colitis, 11 Crohn’s, and 11 indeterminate), 9 of their non-IBD household contacts, and an independent non-IBD cohort of 674 volunteers collected by the Vaccine Research Center (VRC) at the National Institutes of Health. Antibody binding profiles were compared among groups using nonparametric statistics.

Results

IBD patients as a group had lower antibody responses to specific phages compared to both non-IBD household contacts and the non-IBD VRC controls; this difference was significant and remained after control for unequal sample sizes [Figure 1]. Patients with Crohn’s disease compared to those with ulcerative colitis had similar antibody responses. Particularly for phages of the genera Phifelvirus, the immune responses of Crohn’s patients were significantly reduced compared to their non-IBD household contacts, while the immune responses of patients with ulcerative colitis did not significantly differ from non-IBD household contacts [Figure 2]. IBD disease type comparisons to the VRC controls yielded similar results.

Conclusion

PhIP-Seq with a phageome library can be used to study the relationship between immune responses and gut bacteriophages in IBD. Our results suggest that IBD patients may have lower antibody responses to specific phages compared to non-IBD individuals. Differential antibody reactivities in Crohn’s disease vs. ulcerative colitis compared to their household contacts and VRC controls suggest disease-specific response to the gut phageome that warrant further study.
P120 PRE-POUCH ILEITIS IS A RISK FACTOR FOR DEVELOPMENT OF CROHN’S DISEASE-LIKE COMPLICATIONS, NEED FOR BIOLOGIC THERAPY AND POUCH FAILURE
Authors: Shemtov Ron , Fleshner Phil , Syal Gaurav
Published: January 2020

Introduction

Pre-pouch ileitis or afferent limb inflammation is generally considered to be suggestive of de novo Crohn’s disease in patients with ileal pouch. However, the data on whether these patients progress to develop CD-like complications is limited. We aim to study the evolution of pre-pouch ileitis in this study.

Methods

All patients who underwent an IPAA surgery by an expert surgeon between 1990 and 2018 for diagnosis of ulcerative colitis (UC) or inflammatory bowel disease-unclassified (IBD-U) at our institution and later went to develop pre-pouch ileitis were included. Patient charts were reviewed were reviewed subsequent to the diagnosis of pre-pouch ileitis to assess development of CD-like complications (non-anastomotic strictures and fistulae developing >6 months after ileostomy closure) or requirement of J-pouch surgery or ileostomy. Pre-pouch ileitis was defined by presence of erosions or ulcers in the afferent limb.

Results

58 patients with J-pouch developed pre-pouch ileitis at a median of 21 months (range 1–216 months) from ileostomy closure. Baseline characteristics are shown in table 1.

Median follow up duration after the diagnosis of pre-pouch ileitis was 48 months (range 2–204 months). 54/58 (93%) patients had concomitant pouchitis with pre-pouch ileitis. 36/58 (62%) patients were initiated on biologic therapy during their follow up course and 3/58 (5%) were treated with an immunomodulator. 20/58 (35%) patients developed Crohn’s disease-like complications (10 developed non-anastomotic strictures and 10 developed perianal complications) at a median follow up of 17 months (range 2–85 months) from the diagnosis of pre-pouch ileitis. 5/58 (8.6%) needed endoscopic stricture dilation and 6/58 (10%) needed perianal surgery for fistula or abscess. Pouch failure occurred in 5/58 (9%) of patients (3 with pouch resection, 1 with pouch revision and 1 with permanent ileostomy), while 3/58 (5%) patients required temporary ileostomy.

Conclusions

Patients who develop pre-pouch ileitis are at high risk of developing CD-like complications (non-anastomotic strictures and perianal complications). The risk of pouch failure and requirement for endoscopic procedures or surgery in this cohort also appears to higher than traditionally reported in patients with pouchitis. Hence, pre-pouch ileitis should be considered suggestive of Crohn’s disease and treated aggressively.