bluuebunny/crossref_metadata_2025 huggingface dataset:
COLLABORATIVE DEVELOPMENT OF CROHN’S DISEASE CLINICAL DATA STANDARDS BY STANDARDS DEVELOPMENT AND CROHN’S DISEASE EXPERTS TO FOSTER DATA REVIEW, SHARING, AND REUSE
Authors: Owen, Rebecca Baker John
Published: January 2021

Background

The ability to access expansive collections of well-curated biological, clinical, and behavioral data will propel scientific progress and enable the discoveries needed to improve treatments for human disease. Development and adoption of standards transform incompatible and disparate data into universal and illuminating information, facilitating discoveries that could have invaluable impact on Crohn’s disease clinical research. When standards are applied, data is collected, organized, and analyzed in a clear and consistent manner, allowing all researchers to leverage information from studies around the world.

Required by the United States Food and Drug Administration (FDA) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) and adopted by the world’s leading research organizations, CDISC standards enable the accessibility, interoperability, and reusability of data. CDISC standards addresses each step of the clinical research process to drive operational efficiencies within the organizations that use them, expedite the regulatory review process and reduce time to market.

Methods

With support from The Leona M. and Harry B. Helmsley Charitable Trust, CDISC formed a team of standards development and Crohn’s disease experts to follow our consensus-based, clinical data standards process, which consists of six stages:

Scoping – Identification of development topics

Concept Modeling – Deep dive understanding of topics

Standards Development – Development of standards content

Internal Review – Targeted review

Public Review – User community review

Publication – Freely available on the CDISC website

Results

The project Standards Development and Internal Review stages completed in September 2020, resulting in the following topics available for the Public Review stage.

- Questionnaires, Ratings and Scales (including standard symptom measures, patient/investigator reported outcomes, and socio-economic measures)

- Prior and Baseline, and On-Study Treatments (including response to prior treatment)

- Disease Staging (location and phenotypic descriptions of the disease)

- Endoscopy Assessments

- Cross-section Imaging Assessments (including CT, MRI and Ultrasound)

- Histopathology of Biopsy Samples

- Biomarkers of Interest for Crohn’s Disease

Conclusion

To make the greatest impact on Crohn’s disease research, widespread promotion of the availability of the standards for researchers to adopt and implement to their data is of highest importance. CDISC provides complementary education courses and implementation information to assist in this adoption. Widespread adoption of the standards will bring clarity to Crohn’s disease data and will enable the accessibility, interoperability, and reusability of data, driving operational efficiencies, expediting regulatory review, and reducing time to market.
CIGARETTE SMOKE INCREASES RISK FOR COLORECTAL NEOPLASIA IN INFLAMMATORY BOWEL DISEASE
Authors: Van Der Sloot Kimberley , Tiems Johan , Visschedijk Marijn , Festen Eleonora , van Dullemen Hendrik , Weersma Rinse , Kats-Ugurlu Gursah , Dijkstra Gerard
Published: January 2021

Objective

Patients with inflammatory bowel disease are at increased risk of colorectal neoplasia (CRN) due to mucosal inflammation. As current surveillance guidelines form a burden on patients and healthcare costs, stratification of high-risk patients is crucial. Cigarette smoke reduces inflammation in ulcerative colitis (UC) but not Crohn’s disease (CD) and forms a known risk factor for CRN in the general population. Due to this divergent association, the effect of smoking on CRN in IBD is unclear and subject of this study.

Design

In this retrospective cohort study, 1,386 IBD patients with previous biopsies analyzed and reported in the PALGA register, were screened for development of CRN. Clinical factors and cigarette smoke were evaluated. Patients were stratified for guideline-based risk of CRN. Cox-regression modeling was used to estimate the effect of cigarette smoke and its additive effect within the current risk stratification for prediction of CRN.

Results

151 (11.0%) patients developed CRN. Previously described risk factors, i.e. first-degree family member with CRN in CD (p-value=0.001), presence of post-inflammatory polyps in UC (p-value=0.004), were replicated. Former smoking increased risk of CRN in UC (HR1.72;1.04–2.84), whereas passive smoke exposure yielded no effect. For CD, active smoking (2.52; 1.14–5.58) and passive smoke exposure (1.88;1.10–3.21) significantly increased CRN risk. Addition of cigarette smoking to the current risk-stratification model significantly improved model fit for CD.

Conclusion

This study is the first to describe the important role of cigarette smoke in CRN development in IBD patients. Adding this risk factor improves the current risk stratification for CRN surveillance strategies.
MINIMAL INVASIVE MANAGEMENT OF PEDIATRIC CROHN’S ANORECTAL STRICTURE, LESS IS MORE
Authors: Rocourt Dorothy , Hoover Travis
Published: January 2021

Background

Anorectal stricture (ARS) is an uncommon but potentially disabling manifestation of perianal Crohn disease (CD) in pediatric patients. Various treatment options are available but there is little data regarding their efficacy, particularly in the pediatric population. We present three case reports of patients with symptomatic ARS treated with serial dilation and biologic therapy.

Methods

An institutional review board-approved retrospective review was performed using electronic health records. Three patients with ileocolonic CD and perianal involvement with symptomatic ARS were identified. All patients were treated with serial rectal dilations under general anesthesia using Hegar dilators.

Results

All patients are currently asymptomatic at follow-ups ranging from 1 to 3.5 years since the last dilation. Patient demographics and details of ARS management are presented in Table 1. All patients tolerated the procedures well and did not experience complications such as perforation, sepsis, or fecal incontinence. Rectal biopsy in each patient showed active inflammation, suggesting type 1 stricture according to the Hughes-Cardiff Classification (vs. type 2 fibrotic stricture). Patient 1 experienced 6 recurrences, each managed with an average of 2 dilations until disease control was established with ustekinumab (USK) and eventually vedolizumab (VDZ). She underwent ileocecal resection three years after the final dilation. Patient 2 underwent ileocecal resection immediately following the first series of dilations. He later experienced one stricture recurrence at 2 years, which was managed with one dilation and increased USK dosing frequency. Patient 3 received steroid suppositories prior to dilation and has been self-dilating at home. He has had no recurrences requiring operative dilation. Self-dilation was not feasible in patients 1 and 2.

Conclusion

Inflammatory anorectal stricture associated with perianal Crohn disease in pediatric patients can be managed successfully with dilation until disease control with biologic therapy. Recurrences of stricture can also be managed with dilation and modification of biologic therapy. If tolerated, self-dilation may reduce recurrence.

Background

Anorectal stricture (ARS) is an uncommon but potentially disabling manifestation of perianal Crohn disease (CD) in pediatric patients. Various treatment options are available but there is little data regarding their efficacy, particularly in the pediatric population. We present three case reports of patients with symptomatic ARS treated with serial dilation and biologic therapy.

Crohn’s rectal stricture pre and post dilation
SHAPE MEMORY POLYMER HYDROGEL FOAMS FOR FISTULA CLOSURE
Authors: Monroe Mary , Beaman Henry , Vakil Anand , Du Changling
Published: January 2021

Introduction

Crohn’s disease can lead to fistula formation between portions of the urinary, reproductive, and digestive systems. The abnormal connections caused by these tunneling sores cause severe pain, infections, and abscess formation. Currently, 83% of Crohn’s patients with fistula formation undergo surgical intervention to either drain or bypass the fistula openings, and ~23% of these patients ultimately require bowel resections.

To address this clinical need, we propose to synthesize a shape memory polymer (SMP) hydrogel foam system for fistula closure and healing. SMP foams are porous materials that can be heated and compressed into a low-profile geometry that is retained after cooling. This shape enables minimally invasive delivery (i.e. via catheter) to a fistula site. Once the foams are heated to body temperature, they expand back to their original shape to conform to the implantation site geometry. Here, we present a degradable SMP hydrogel foam with antimicrobial and antioxidant phenolic acids for potential use as a fistula closure scaffold.

Methods

Foams were synthesized with 3-arm and linear poly(ethylene glycol) (PEG), amylopectin/pullulan, and phenolic acids in combination with hexamethylene diisocyanate in the presence of surfactants, catalysts, and foam blowing agents to form a hydrophilic, chemically crosslinked foam. Resulting foams were characterized in terms of swelling ratios, pore sizes, glass transition temperatures, and shape recovery. Degradation profiles were characterized in glucoamylase. Antimicrobial efficacy against E. coli was measured by quantifying colony forming units of bacteria following exposure to SMP hydrogels. Antioxidant properties were assessed in the presence of hydrogen peroxide.

Results

SMP hydrogel swelling ratio, stiffness, shape memory properties are tuned by altering monomer ratios and lengths and foaming conditions. In preliminary degradation studies in glucoamylase, degradation rates are dependent upon starch content; increased degradation is observe with increase pullalan content, Figure 1. Phenolic acid-containing SMP foams exhibit antimicrobial efficacy against E. coli and antioxidant properties in hydrogen peroxide.

Conclusions

Current studies include full material characterization of the library of synthesized hydrogels and longer-term degradation analysis. This system can be further built upon in future studies to include a drug-delivery component. Overall, SMP hydrogel foams present a highly tunable platform material that can be modified with required functionalities to promote fistula closure.
DIFFERENTIAL MANIFESTATIONS OF INLAMMATORY BOWEL DISEASE (IBD) BASED ON RAGE AND IMMIGRATION STATUS
Authors: Crowe Brooks , Khalessi Ali , Xia Yuhe , Rubinfeld Gregory , Baylor Jessica , Radin Arielle , Liang Peter , Chen Lea Ann
Published: January 2021

Background

The increasing incidence of IBD globally presents an important opportunity to study intrinsic and environmental determinants of disease development. We examined how race and immigration status influence IBD manifestations, treatments, and outcomes in a diverse, tertiary-care public hospital that serves predominantly the uninsured and underinsured.

Methods

We conducted a single-center retrospective review of all IBD patients treated from 1997–2017. Using logistic regression modeling, we compared disease onset, treatment, and outcomes by race (White, Black, Hispanic, Asian) and immigration status (US-born vs. foreign-born). To assess for the potential confounder of race in analyses of US versus foreign-born subjects, we further evaluated differences in IBD characteristics among foreign-born patients in each of the four racial groups.

Results

A total of 577 patients were identified, of which 29.8% were White, 27.4% Hispanic, 21.7% Black, and 13.0% Asian. Of these patients, 260 had a confirmed country of birth, with 69.6% being foreign-born. The time between IBD diagnosis and last documented follow up was not statistically different between races, nor by foreign versus US-born status. Asian IBD patients were less likely than White IBD patients to be female (OR 0.38, 95% CI: 0.20, 0.69). Among ulcerative colitis (UC) patients, Asians were more likely than White patients to have isolated proctitis (OR 10.34, 95% CI: 1.58, 203.08). Black patients were less likely to be diagnosed with UC (OR 0.57, 95% CI: 0.36, 0.91) and more likely to undergo IBD-related intestinal resection (OR 2.49, 95% CI: 1.40, 4.50), though the opposite was true in foreign-born Black patients. Overall, foreign-born patients were more likely to be diagnosed with UC (OR 1.77, 95% CI: 1.04, 3.02). They were also less likely to be diagnosed before 16 years of age (OR 0.19, 95% CI: 0.08, 0.41), have undergone intestinal resections (OR 0.39, 95% CI: 0.19, 0.83), or have received biologics (OR 0.43, 95% CI: 0.25, 0.76). No single race accounted for the decreased use of biologics or intestinal resections among foreign-born patients.

Conclusions

IBD phenotype varies by race, although foreign-born patients of all races show evidence of later onset and milder disease. As our study was performed in a large single-center safety-net hospital, our study design minimized socioeconomic confounders. These findings may aid in disease prognostication and clinical management and furthermore may provide insight into intrinsic and environmental influences on IBD pathogenesis.
IDENTIFYING INADEQUATE RESPONSE AMONG ULCERATIVE COLITIS PATIENTS ON AN ADVANCED THERAPY IN A REAL-WORLD ADMINISTRATIVE CLAIMS DATABASE
Authors: Naegeli April , Hunter Theresa , Grabner Michael , Isenberg Keith , Shan Mingyang , Teng Chia-Chen
Published: January 2021

Objectives

The purpose of this analysis was to assess the frequency of inadequate response (IR) over 1 year from advanced therapy (AT) initiation among ulcerative colitis (UC) patients in the United States using a claims-based algorithm. Baseline factors associated with IR to an AT were also analyzed.

Methods

This was a retrospective cohort study using claims data from the HealthCore Integrated Research Database (HIRD®). Adult patients with UC who initiated an AT (TNFi: adalimumab, golimumab, infliximab; non-TNFi: vedolizumab; other agent: tofacitinib) from 7/1/2016 to 8/31/2018 and had continuous enrollment ≥6 months before and ≥12 months after index date (date of first AT claim) were included. The index AT was defined as the first AT prescribed during the study time period. The claims-based algorithm used in this study to identify IR was originally developed and validated in rheumatoid arthritis1, and was modified for UC patients. Patients were identified as having IR to their index AT if during the 12 months after index date they had one or more of the following: low adherence (defined as proportion of days covered (PDC)<80%), switched/added new AT, added a new conventional therapy, increased dose/frequency of AT, addition or dose increase of oral glucocorticoids, used a new pain medication, or had surgery for UC. Baseline patient characteristics were compared between responders and IRs using chi-square tests for categorical variables and t-tests for continuous variables. A multivariable logistic regression model was constructed to identify baseline characteristics associated with IR to the index AT.

Results

A total of 1,692 UC patients were included in this analysis. Mean age was 42 years, 52% were male, 78% initiated a TNFi, and 22% initiated a non-TNFi as their index AT (Table 1). Over the 1-year follow-up period, 63% of UC patients had an IR to their AT: 42% of patients had low adherence, 24% switched/added a new AT, 18% added a new conventional therapy, 13% had a dose/frequency increase of their index AT, 14% had an addition/dose increase of oral glucocorticoids, 8% used a new pain medication, and 2% had surgery.

Inadequate responders were more likely to be prescribed a TNFi (odds ratio (OR)=2.76; p<0.001), and have a higher baseline Quan-Charlson Comorbidity Index (OR=1.15; p=0.015); while patients with baseline use of azathioprine were more likely to be responders (OR=0.72; p=0.025) (Table 2).
UNDERSTANDING REAL-WORLD BIOLOGIC MAINTENANCE DOSING PATTERNS AMONG PEDIATRIC ULCERATIVE COLITIS AND CROHN’S DISEASE PATIENTS
Authors: Crandall Wallace , Colletti Richard , Komocsar Wendy , Liu Chunyan , Dotson Jennifer , Benkov Keith , Steiner Steven , Zhang Nanhua , Hunter Theresa
Published: January 2021

Objectives

To assess the initial and long-term maintenance dosing of biologic medications in pediatric UC and CD patients, using data in the ICN registry.

Methods

Pediatric patients (2–17 years) in the US who were diagnosed with UC or CD between June 1, 2013 and December 31, 2019, who, after enrollment in the ICN registry, initiated a biologic (adalimumab, infliximab, certolizumab, golimumab, ustekinumab, vedolizumab, and natalizumab) and were actively followed for at least 12 months after first maintenance dose were included in this study. Descriptive statistics of baseline patient demographics were summarized for the overall Inflammatory Bowel Disease (IBD) patient population and separately for UC and CD. Biologic maintenance dosage was calculated for UC and CD patients who had data for both dose and weight for each biologic at the baseline visit (first maintenance dose), 1-year and 3-year time points.

Results

A total of 1,887 pediatric IBD patients (UC=350; CD=1,537) were included in this study. Patients had a mean age at diagnosis of 12.9 years (UC=13.1; CD=12.9), 57.1% were male (UC=48.9%; CD=59.0%), and 80.6% were White (UC=79.8%; CD=80.8%) (Table 1). Infliximab (77.0%) was the most commonly prescribed biologic for UC, followed by adalimumab (12.4%), vedolizumab (10.1%), certolizumab (0.3%), and ustekinumab (0.3%). Similarly, infliximab (80.6%) was the most commonly prescribed biologic for CD, followed by adalimumab (16.5%), vedolizumab (1.6%), ustekinumab (1.2%), and certolizumab (0.1%) (Table 2).

At first maintenance dose, UC patients on infliximab were receiving a mean dose of 10.5mg/kg/8wk, patients on adalimumab (weight <40kg) were receiving a mean dose of 1.3mg/kg/2wk, patients on adalimumab (weight≥40kg) were receiving a mean dose of 0.8mg/kg/2wk, and patients on vedolizumab were receiving a mean dose of 6.9mg/kg/8wks. Mean dose of infliximab among UC patients increased from 10.5mg/kg/8wk at first maintenance dose to 11.8mg/kg/8wk at 1-year from first maintenance dose.

At the first maintenance dose, CD patients on infliximab were receiving a mean dose of 8.1mg/kg/8wk, patients on adalimumab (weight <40kg) were receiving a mean dose of 1.1mg/kg/2wk, patients on adalimumab (weight ≥40kg) were receiving a mean dose of 0.8mg/kg/2wk, patients receiving vedolizumab were receiving a mean dose of 10.5mg/kg/8wks. Mean dose of infliximab among CD patients increased from 8.1mg/kg/8wk at first maintenance dose to 9.6mg/kg/8wk at 1-year from first maintenance dose.

Conclusion

These results highlight the biologic maintenance dose changes among pediatric UC and CD patients. TNF inhibitors remain the most commonly used class of biologic, but the doses being used are double the standard dosing guidelines. There is little evidence of dose reduction over time among pediatric UC and CD patients in the ICN registry.
ADENOSINE A3 RECEPTOR INTERACTS WITH GASDERMIN D TO MODULATE INTESTINAL EPITHELIAL CELL PYROPTOSIS IN ULCERATIVE COLITIS
Authors: Xiao Peng , Lv Minmin , Chen Wenke , Tian Ting , Ren Tianhua
Published: January 2021

Background

Adenosine A3 receptor (A3AR) plays a role in intestinal inflammation, but little is known about its mechnisms in intestinal inflammation such as ulcerative colitis (UC). Pyroptosis, characterized by Gasdermin D (GSDMD) activation, is implicated in the pathogenesis of UC. We investigated the role of A3AR in GSDMD-mediated pyroptosis in UC and its underlying molecular mechanisms.

Methods

The expression of A3AR in colonic mucosa of patients with UC were examined. A3AR agonist was used to study the role of A3AR in ex vivo colonic explants of UC patients. In addition, human intestinal epithelial cells Caco-2 were used to further verify the effect of A3AR on pyroptosis induced by LPS+ATP. RT-qPCR and western blotting were used to detect the expression levels of pyroptosis-associated factors including NLRP3, caspase-1, gasdermin-D N-terminal domain (GSDMD-NT), IL-1β and IL-18 in colonic tissues and Caco-2 cells. Immunofluorescence was used to detect the protein expression in tissues and cells. Enzyme-linked immunosorbent assay was used to determine the levels of IL-1β and IL-18 in tissue and cell culture supernatants. Lactate dehydrogenase (LDH) release assay and propidium iodide (PI) staining were used to measure cell pyroptosis. Molecular interactions beween A3AR and GSDMD were investigated using Co-IP and GST pull-down assays.

Results

A3AR expression was significantly reduced in colonic mucosa of patients with active UC, and colonic epithelial cells were the main cell subpopulation with down-regulated A3AR expression. Pyroptosis-associated factors, including Caspase-1, NLRP3, and GSDMD-NT, were upregulated in UC colonic tissues. The expression of A3AR and GSDMD-NT was negatively correlated. A3AR agonist reduced the production of cytokines (IL-1β and IL-18) and attenuates the expression levels of NLRP3 and GSDMD-NT in the colonic tissues of patients with UC. Furthermore, A3AR overexpression alleviated pyroptosis with reduced LDH release, PI-stained cell number and decreased expressions of GSDMD-NT, NLRP3, caspase-1, IL-1β, and IL-18 in the LPS+ATP-stimulated Caco-2 cells, whereas the opposite occurred in cells treated with small interfeing RNA (siRNA) targeting A3AR. Knockdown of GSDMD in Caco-2 cells significantly blocked the effects of A3AR overexpression or down-regulation on pyroptosis, suggesting that A3AR acts through the GSDMD-mediated pyroptosis pathway. Co-IP and GST pull-down assays showed that A3AR interacted with GSDMD.

Conclusion

A3AR modulates intestinal inflammation in UC through GSDMD-mediated intestinal epithelial cell pyroptosis. We propose a novel mechanism by which A3AR-GSDMD interaction affects UC through pyroptosis, suggesting that A3AR is a potential target for the treatment of UC.
NOVEL GENETIC SUSCEPTIBILITY CANDIDATES IN GRANULOMATOUS AND NON-GRANULOMATOUS PEDIATRIC CROHN’S DISEASE
Authors: Hodgkins Allyson , Harris R Alan , Qian Justin , Kellermayer Richard
Published: January 2021

Background

Non-caseating granulomas are a hallmark histopathological finding of Crohn’s disease (CD). Studies have suggested that the presence of granulomas may indicate a more aggressive CD phenotype associated with a complicated clinical course, including stricturing and/or penetrating disease, need for biologic therapy, and need for surgery. As such, identification of genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis, which in turn may optimize treatments and guide novel therapeutics to combat CD complications. There is relatively sparse genetic information known about CD subtypes, especially GCD. The aim of this study was to determine the extent of genetic variation between pediatric CD patients with and without a pathognomonic sub-mucosal granuloma detected at the time of diagnosis.

Methods

Whole-exome next-generation sequencing (WES) was performed on peripheral blood derived DNA from patients with GCD and non-GCD (NGCD). PLINK analysis was used to identify single nucleotide polymorphisms (SNPs) that were overrepresented in comparisons between groups, and subgroup allele frequencies were also compared to publically available, large population-based genomic data in gnomAD. The potential deleteriousness of single nucleotide variants was determined by the CADD scoring tool.

Results

WES was completed for 17 patients with GCD and 19 with NGCD. There were no significant differences in baseline clinical characteristics, treatments, nor 1-year outcomes between the groups. Overlap analyses between PLINK- and gnomAD-generated SNPs revealed significant enrichment in those associated with HLA-DQA1, LILRA1, SAA2, PCDHB, HLA-B, NOD2, and IGH shared by GCD and NGCD groups. In the meantime, GCD-specific (top candidates linked with HLA-B and MUC4) and NGCD-specific (top candidates linked with HLA-B and ACOT9) SNPs were sparse.

Conclusions

We are the first to examine WES-based genetic variation between treatment-naïve pediatric CD patients purely separated by the presence of a sub-mucosal epithelioid granuloma. While there were very few SNPs consistently differentiating between GCD and NGCD patients in our cohort using two distinct methodologies, we were able to identify several novel SNPs that were significantly enriched in pediatric CD patients compared to the control human genome. Our findings will require subsequent confirmation in larger but similarly scrutinized cohorts of patients.
GPR120 MAINTAINS INTESTINAL HOMEOSTASIS THROUGH REGULATION OF CD4+ T CELL IL-10 PRODUCTION
Authors: Yang Wenjing , Yao Suxia , Dann Sara , Cong Yingzi
Published: January 2021

Irregular CD4+ effector T cell responses play an essential role in the intestinal inflammation, while IL-10 produced by effector T cells limits their pathogenesis to maintain the intestinal homeostasis. Dietary free fatty acids are actively involved in regulating immune responses, and mammalian G protein-coupled receptor (GPR) 120, a receptor for long-chain fatty acids, has been implicated in metabolic syndrome. However, the effect of GPR120 on intestinal homeostasis is still unknown. Here, we showed that deficiency of GPR120 resulted in more severe colitis in mice induced by dextran sodium sulfate (DSS) and Citrobacter Rodentium. Interestingly, CD4+ T cells expressed a high level of GPR120, and mice specifically lacking GPR120 in CD4+ T cells were more susceptible to DSS-induced colitis. Besides, GPR120-deficient CD45Rbhi CD4+ cells are more colitogenic in Rag-/- mice, in which IL-17 and IFNg producing CD4+ T cells were increased but IL-10 production by CD4+ T cells was reduced. Furthermore, CpdA, the GPR120 agonist, promoted CD4+ T effector cell production of IL-10 through upregulating Blimp1 and inducing glycolysis, which were regulated by mTOR pathway. Besides, docosahexaenoic acid, a dietary long-chain fatty acid, also upregulated the IL-10 production in CD4+ T cells. Additionally, GPR120 agonist-treated Th1 effector cells induced less severe colitis, whereas this protection was absent in Blimp1-deficient Th1 cells. Importantly, oral administration of CpdA protected mice against intestinal inflammation. Thus, our findings demonstrate the roles of dietary fatty acids receptor GPR120 in regulating intestinal CD4+ T cell production of IL-10 and intestinal homeostasis.
PHENOTYPIC ALTERATIONS OF MACROPHAGE CONTRIBUTES TO EXTRACELLULAR MATRIX DEPOSITION IN CULTURED MACROPHAGE RAW 264.7
Authors: Li Chao , Kuemmerle John
Published: January 2021

Macrophages are essential immune cells for the maintenance of tissue homeostasis in the intestinal mucosa barrier. They are also involved in dysregulated process of wound healing, particularly in the context of intestinal damage and tissue repair in inflammatory bowel diseases. Phenotypic plasticity of macrophages from classical M1 to alternative M2 is regulated by a variety of inflammatory cytokines including IFN-γ and IL-4. The IL-4-derived M2 can further differentiate into myofibroblasts. Activated alpha-smooth muscle actin (α-SMA) positive-myofibroblasts are central to the wound healing process and in patients with fibrostenotic Crohn’s disease. They contribute to fibrosis by excessive production of extracellular matrix (ECM) proteins. Despite rapid advances in our understanding of how macrophages help maintain intestinal homeostasis following inflammation, the role of macrophages during the development of intestinal fibrosis in patients with Crohn’s disease is poorly studied. We have previously reported that increased endoplasmic reticulum (ER) stress contributed to the development of TGF-β1-induced intestinal fibrosis. We recently observed that epigallocatechin-3-gallate (EGCG), blocked macrophage polarization from M1 to M2 in bone marrow-derived macrophages from TNBS colitis mice. Here we hypothesized that ER stress regulates the phenotypic change of macrophages and ECM deposition. This notion was examined in RAW 264.7 murine macrophage cells, which were labeled with markers of phenotype: M1-CD38, M2-CD163 after incubation with IFN-γ and IL-4, respectively. Macrophage to myofibroblast transition and evaluation of ECM production were further determined by using myofibroblast marker: α-SMA and ECM markers: collagen 1α1 and periostin. Cells were treated with EGCG to determine whether inhibition of ER stress would block macrophage-to-myofibroblast transition and ECM production. The CD38+M1 increased by 43±2.1% and α-SMA expression increased by 15±1.2% in IFN-γ-induced macrophages compared to untreated control. Correspondingly, collagen 1α1 and periostin also increased by 81± 4.3% and 75±3.7% respectively in CD38+M1. The CD163+M2 increased by 21±1.2% in macrophages treated with IL-4 compared to untreated control. Collagen 1α1 and periostin also increased by 45± 2.3% and 38±1.8% respectively in CD163+M2. ER stress marker, GRP78, increased by 15±0.8% in CD38+ M1 compared to the 5±0.3% increase in CD163+M2. Treatment with EGCG decreased GRP78 by 15±0.8%, collagen 1α1 by 60±3%, and periostin by 63.5±2.1% in CD38+M1 compared to the same markers that decreased by 3±0.2%, 25±1.3%, and 35±1.8% in CD163+M2, respectively. Together, our data suggest that macrophage polarization from M1 to M2 plays a role in macrophage-to-myofibroblast transition, ECM deposition, and increase in ER stress response, which can be blocked by Inhibition of ER stress with EGCG.
RISK FACTORS FOR OUTCOMES OF PATIENTS WITH HISTOLOGICALLY PROVEN CHECKPOINT-INHIBITOR COLITIS
Authors: Voth Elida , Saha Srishti , Raffals Laura , Pardi Darrell , Khanna Sahil
Published: January 2021

Background

Immune checkpoint inhibitor (ICPI)-mediated diarrhea and colitis is the leading cause of discontinuation of ICPI therapy in patients with malignancy. Existing literature on predictors of adverse outcomes is limited. We evaluated the association between risk factors, concomitant Clostridioides difficile infection (CDI), and abdominal CT scan findings of colitis on outcomes in patients with ICPI-related diarrhea and colitis.

Methods

A retrospective study was conducted for patients who received an ICPI for treatment of malignancy and developed diarrhea or colitis, with endoscopic findings consistent with ICPI colitis. Variables including smoking history, proton pump inhibitor (PPI) use, non-steroidal anti-inflammatory (NSAID) use, concomitant CDI, and abdominal CT scan findings were extracted. The Common Terminology Criteria for Adverse Events (CTCAE) criteria was used to determine diarrhea and colitis severity. We analyzed the effect on risk factors on outcomes including hospitalization rates, diarrhea and colitis severity, and mortality at 1 year. Statistical analysis comprised of descriptive statistics and univariate and multivariate logistic regression analyses.

Results

There were 33 patients with histologically proven ICPI-related colitis with median age 70 years (28–92). Seventeen patients (52%) had melanoma and 24 patients (73%) had metastatic disease (Table 1). There was no association between age, gender, smoking history, PPI use, NSAID use on rates of hospitalization, toxicity severity, or mortality related to ICPI-related diarrhea or colitis (p>0.05) on univariate analysis. CDI at diagnosis was associated with a higher grade of toxicity (p=0.04) and higher rate of mortality at 1-year follow-up (p=0.03) compared to patients with a negative GI pathogen panel; however, this effect was not seen on multivariate analysis controlling for age and cancer stage (p>0.05). In patients with metastatic malignancy, there were significant higher rates of hospitalization for ICPI-colitis compared to those without metastatic disease on multivariate analysis controlling for age (OR, 4.53 [95% CI, 1.11–35.99]). In patients with CT scan findings consistent with colitis, there was a significantly higher rate of hospitalization compared to patients without these imaging findings on multivariate analysis controlling for age and cancer stage (OR, 2.99 [95% CI, 1.22–6.64]).

Conclusions

Patients with metastatic malignancy or CT scan findings consistent with colitis had a significantly higher rate of hospitalization for ICPI colitis compared to patients with non-metastatic disease or without radiographic features of colitis. CDI at diagnosis was associated with mortality and higher grade of toxicity. Further investigation is needed to examine predictors of adverse outcomes with use of ICPI to reduce morbidity and mortality in this patient population.
A NEW BACTERIAL TRANSFER THERAPY FOR IBD: ENDOSCOPIC BIFIDOBACTERIUM AND XYLOGLUCAN ADMINISTRATION
Authors: Bozkurt Hüseyin
Published: January 2021

Ulcerative colitis (UC) pathogenesis includes the altered gut microbiota, environmental factors, and human immune and genetic predisposition. Recently, its association with reduced bifidobacteria quantity in the microbiota is reported.Xyloglucan, a plant based prebiotic oligosaccharide, causes increase in bifidobacteria quantity.

In this article we share the results of our UC cases treated by intracolonic single dose administration of Bifidobacterium animalis subsp. Lactis and xyloglucan combination. Intracolonic single dose administration of 200 billion CFUs of Bifidobacterium animalis subsp. lactis and 4 gr of xyloglucan combination was administrated to ten severe UC patients, who were either unresponsive or had inadequate response to treatment. All patients continued treatment after the procedure. Treatment responses were evaluated by colonoscopic, laboratory and clinical examination after 6 weeks. Intracolonic single dose administration of Bifidobacterium animalis subsp. lactis and xyloglucan was found effective in the mucosal healing and resolution of colonic symptoms in ulcerative colitis patients. Intracolonic administration of Bifidobacterium animalis subsp. lactis and xyloglucan in UC is a new single strain and strain specific prebiotic combination method. It is easy to apply and has no observable side effect. Its effectiveness on mucosal healing could be attributed to the enhancement of non-stimulatory status and biodiversity in colonic mucosa. Nonetheless, it is still necessary to develop diagnostic strategies to determine the patients to whom this method would be the most applicable.
COMMON FOOD ADDITIVES ACCELERATE ONSET OF INFLAMMATORY BOWEL DISEASE IN MICE BY ALTERING MICROBIOME COMPOSITION AND HOST-MICROBE INTERACTION
Authors: Zangara Megan , Sangwan Naseer , McDonald Christine
Published: January 2021

Multiple factors contribute to inflammatory bowel disease (IBD) pathogenesis, including diet. Although correlations exist between the introduction of processed foods and a rise in IBD prevalence, it is not understood what components of processed foods drive disease pathogenesis or how. Despite a FDA classification of Generally Regarded As Safe (GRAS), food additives significantly impact microbe communities and phenotypes. We hypothesized that common food additives, such as maltodextrin (MDX) and carboxymethyl cellulose (CMC), alter intestinal microbes and increase the onset and progression of IBD. We tested this hypothesis using the interleukin-10 deficient (IL10KO) mouse model of spontaneous colitis. To standardize disease onset, IL10KO mice were pre-conditioned with fecal material from nucleotide-binding oligomerization domain 2 deficient mice (NOD2KO) to promote intestinal inflammation. Pre-conditioned IL10KO mice were randomized to chow diets containing either 1% MDX, 1% CMC, or a control diet. MDX and CMC accelerated the onset of colitis compared to the control diet. This was accompanied by elevated fecal lipocalin-2 (p<0.05) and serum amyloid A (p<0.01), intestinal infiltration of CD3+ cells, and intestinal pathology consistent with chronic inflammation (p<0.05). Although both dietary additives promote disease in this model, the molecular mechanisms involved appear to be distinct. Intestinal mucus modulates interactions of the microbiome and the host. Strikingly, goblet cells in MDX fed mice had reduced mucin granule content (~50% of control diet) as assessed by Muc2 and Periodic Acid Schiff staining. This mucin depletion did not correlate with degree of disease activity, suggesting this deficiency is not a result of inflammation in MDX fed mice and was not observed in CMC fed mice or control diet mice. Food additives also altered the intestinal microbiome, with MDX fed mice demonstrating a significant decrease in microbiome alpha diversity (p<0.05, ANOVA), and both food additives resulting in a significant shift in beta diversity (R2=0.40, p=0.002, PERMANOVA) as compared to the control diet. Flagella expression by microbes was slightly elevated in CMC-fed mice, but not in MDX-fed mice, suggesting that these food additives have distinct actions on microbes. Magnitude of genus-level changes in microbial abundance correlated with disease severity as assessed by serum amyloid A levels. This data indicates that common food additives are not biologically inert substances, and may drive the progression of inflammatory bowel disease through additive-specific alterations of the microbiome and host-microbe interactions.
INFLAMMATORY BOWEL DISEASE CLASSIFICATION USING THE GUT MICROBIOME: A BENCHMARK OF MICROBIAL DATA ANALYSIS METHODS
Authors: Kubinski Ryszard , Djamen Jean , Zhanabaev Timur , Martin Ryan
Published: January 2021

The prevalence of inflammatory bowel disease (IBD) is increasing throughout the developed world. For the newly diagnosed, the time between the appearance of symptoms and diagnosis can take months, involving invasive procedures. There is an urgent need to develop a simple, low cost, accurate and non-invasive diagnostic test.

With decreasing costs of next-generation sequencing, many studies have compared IBD gut microbiomes to healthy controls, successfully identifying bacterial biomarkers for IBD. Unfortunately, a majority of these studies utilize machine learning and statistical methods on either single or low-sample size datasets. This results in the creation of disease classification models that have a high level of overfitting and therefore minimal clinical application to new patient cohorts. There are several data preprocessing methods available for data normalization and reduction of cohort specific signals (batch reduction) which can address this lack of cross-dataset performance. With an abundance of potential methods, there is a need to benchmark the performance and generalizability of various machine learning pipelines (combination of data preprocessing and model) for microbiome-based IBD diagnostic tools.

We used a collection of 12 IBD-associated North American microbiome datasets (~4000 samples) to benchmark several machine learning pipelines. Raw sequencing data was processed, collapsed at the OTU or Genus level and merged using QIIME2. Datasets were then normalized using either sum-scaling or log based methods and batch reduction was performed using either zero-centering or Empirical Bayes’ approaches. Performance of pipelines was evaluated using binary accuracy, AUC, F1 metric and MCC score. Generalizability of pipelines was evaluated using leave one out cross validation, where data from one study was left out of the training set and tested upon. The best performing and most generalizable pipeline included a Random Forest model paired with centered log ratio based normalization and batch reduction via an Empirical Bayes’ based approach. This combination, along with others, showed equivalent or higher performance to that of more complex models involving deep neural networks (DNNs). In addition to benchmarking our pipelines, we also explore their limitations, such as the tendency of zero-centered batch reduction to rely on balanced data as input or the tendency of Empirical Bayes’ based methods to introduce artificial signals into data, evidencing certain methods as poor tools for clinical use.

To our knowledge, this is the first comprehensive benchmark of data preprocessing and machine learning methods for microbiome-based disease classification of IBD. These findings will help improve the generalizability of machine learning models as we move towards non-invasive diagnostic and disease management tools for patients with IBD.
IMPROVING PATIENT PARTICIPATION IN LONGITUDINAL RESEARCH: AN INNOVATIVE PATIENT-LED PATIENT-ORIENTED QUALITATIVE RESEARCH PROJECT TO UNDERSTAND THE MOTIVATIONS AND BARRIERS TO GETTING AND STAYING INVOLVED IN THE IMAGINE SPOR STUDY
Authors: Zelinsky Sandra , Daley Kimberlee , Neary Emma , Mason Kate , Bellissimo Gail , DeNino Alysia , MacKean Gail , Fernandes Aida , Moayyedi Paul , Marshall Deborah
Published: January 2021

Background

The Inflammation, Microbiome, & Alimentation, Gastro-Intestinal & Neuropsychiatric Effects (IMAGINE) Strategy for Patient-Oriented Research (SPOR) Network is conducting a large longitudinal research study to investigate the interactions between inflammation, microbiome, diet, and mental health in patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). This study aims to recruit 2000 patients with Crohn’s disease, 2000 with ulcerative colitis, 2000 with IBS, and 2000 healthy controls. Each subject is assessed annually for 4 years and is asked to submit blood, urine, and stool samples, and complete online questionnaires on their health status. Given the ambitious recruitment target, a group of IMAGINE Patient Research Partners (PRPs) led a qualitative study to better understand the motivations and barriers of healthy controls to participating in this study to inform more effective recruitment and retention strategies.

Methods

This study has been co-led, co-designed, and executed by IMAGINE’s PRPs with support from academic researchers. PRPs were trained in qualitative research, co-designed the interview guide, and developed a semi-structured interview guide. Qualitative semi-structured interviews were conducted by 7 PRPs and were recorded electronically. All of the interviews were transcribed by a PRP, a trained medical transcriptionist. Five PRPs conducted data analysis and coded the interview content into common themes.

Results

A total of 27 interviews (13 male and 14 female) were conducted. Participants ranged from 20–75 years old. The top four themes of key motivators to study participation that emerged were Convenience, Experience, Communication, and Compensation. The interview participants identified Convenience as being low time commitment, the flexibility of scheduling, multiple recruitment locations, or using a courier for collecting samples. The Experience category reflects the desire to stay involved if their experience is relaxed, hassle-free, and fun, with emphasis on the study being well-organized. Participants stressed the importance of Communication such as reminders, annual updates, and newsletters. Compensation was important to some participants such as gift cards, parking reimbursement, or non-monetary items such as thank you cards and tokens of appreciation.

Conclusions

This study was co-created by PRPs who were actively involved throughout all stages of the project. The results from this patient-led study will help inform adaptations to recruitment and retention strategies for the national IMAGINE SPOR study.
“ADULTING” WITH IBD: A NOVEL, VIRTUAL INFLAMMATORY BOWEL DISEASE TRANSITION PROGRAM FOR TEENS AND CAREGIVERS
Authors: Stellway Jacklyn , Waschmann Malika , Lin Henry , Harris Michael
Published: January 2021

Introduction: Rates of newly diagnosed inflammatory bowel disease (IBD) in pediatric patients increased by 133% from 2007–2016. With the rise comes an increase in patients ultimately transitioning from pediatric to adult GI care. While pediatric care is family-centered and multi-disciplinary adult care is patient-centered with expectation for autonomy. However, less than 15% of patients are fully responsible for their IBD care by late adolescents. The transition period is marked by adverse health outcomes including decreased compliance and increased disease activity and hospitalization. Our data recognized up to 74% of IBD youth reported not having discussed transition at home or with their GI providers, and a desire to receive information in person. Without guidance from the GI team patients may not have adequate time to plan for successful transition.

Methods: A one-day 3.5-hour transition preparedness workshop was developed to address the demonstrated need in a pediatric GI clinic. Recruitment letters were distributed to 134 IBD youth ages 15–19. Eighteen consenting participants completed measures prior to and following the workshop (at 3 and 12 months). Assessment tools included previously validated self- and parent-reports: Patient Health Questionnaire-8, General Anxiety Disorder-7), Transition Readiness Assessment Questionnaire, IBD Self Efficacy Scale; and Helping for Health Inventory.

Results: While the workshop was designed for in person the pandemic required shift to virtual had strengths and potential drawbacks. Youth across 300 miles were able to attend, as well as IBD young adult peers sharing their personal transition experiences. It is hypothesized pre-workshop data will demonstrate low levels of transition readiness and IBD self-efficacy, with increases in 3- and 12-month post-workshop data. Transition readiness is also presumed to correlate with measures of IBD self-efficacy and miscarried helping by parents. We will present program effectiveness data with factors known to both facilitate and obstruct successful transition from pediatric to adult IBD care.

Conclusion: There remains a paucity of literature evaluating the efficacy of IBD transition programs. This research informs such programs by evaluating the efficacy of a one-day virtual workshop on skill development and knowledge. Assessment data and follow up after transition to adult care will provide important information to guide development of evidence-based transition planning for IBD patients.