bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP05 Target engagement and pharmacodynamic biomarker analysis following treatment with the oral gut-targeted HIF-1α stabilizer GB004 in a Phase 1b trial in Active Ulcerative Colitis
Authors: Sandborn W , Ding Z , Osterhout R , Feagan B , Danese S , Jucov A , Bhandari B R , Raghupathi K , Olson A , Van Biene C , Ford J , Aranda R , Levesque B G , Bruey J M 
Published: May 2021

Abstract

Background
Ulcerative colitis (UC) is characterized by the loss of epithelial barrier function and chronic mucosal inflammation. GB004 is an oral, gut-targeted, small molecule stabilizer of hypoxia inducible factor (HIF-1α) that promotes epithelial repair and function. A phase 1b study was conducted in patients with active UC where trends in clinical efficacy favoring GB004 were observed. Here we report the target engagement (TE) and pharmacodynamic (PD) biomarker analysis of colon biopsies and stool samples from the phase 1b study.

Methods
Subjects with active UC despite 5-ASA treatment were randomized 2:1 to GB004 120 mg solution or placebo (PBO) once daily for 28 days. Colon biopsies (sigmoid and rectum) and stool samples were collected at baseline and Day 28. HIF-1a and myeloperoxidase (MPO) immunohistochemistry was performed on formalin-fixed paraffin-embedded colon biopsies. Gene expression profiling (Affymetrix HTA 2.0) was performed on mRNA extracted from colon biopsies. Fecal calprotectin (FC) and secretory IgA (sIgA) were measured from stool samples. Results presented are overall means for baseline characteristics and differences in mean (HIF-1a, MPO) and median (FC, sIgA) percent change from baseline to Day 28 for GB004 vs PBO.

Results
Thirty-four subjects (age 45.4 years, Mayo score 7.5, sigmoid colon Mayo endoscopic subscore 2.2, sigmoid colon Robarts Histopathology Index 14.1) were randomized to a GB004 120 mg solution (n=23) or PBO (n=11) group. GB004 demonstrated evidence of TE, with an increase in the percent of HIF-1α positive cells (+11.4%) in sigmoid colon segment sections. Tissue and stool-based PD biomarkers of intestinal inflammation associated with lamina propria neutrophil infiltration and cytotoxicity measured by the MPO+ cell count per mm2 (-7.3%) and FC (-30.4%) levels decreased. Lastly, GB004 resulted in an increase in sIgA levels (+87.16%) and transcriptional changes consistent with enhanced epithelial integrity, such as increases in ITGA6 and TJP1.

Conclusion
In this phase 1b study, GB004, an oral gut-targeted HIF-1α stabilizer, demonstrated TE in the sigmoid colon and histologic, fecal biomarker, and transcriptional PD effects consistent with a reduction in inflammation and mucosal healing. These observations are consistent with the role of HIF-1α stabilization in improving barrier function in UC patients and support the trends in clinical effects observed, including histologic endpoints. A Phase 2 study of GB004 in patients with mild-to-moderate UC (SHIFT-UC, NCT04556383) is currently ongoing. Sponsored by GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.
DOP77 Effect of Inflammatory Bowel Disease and Related Medications on COVID-19 Incidence, Disease Severity, and Outcome -The Israeli Experience
Authors: Richter V , Bermont A , Cohen D L , Broide E , Shirin H 
Published: May 2021

Abstract

Background
The COVID-19 pandemic raised concerns among IBD patients fearing an increased risk of infection and poor outcomes. We aimed to evaluate the incidence of COVID-19 among IBD patients; its influence on disease severity and outcome; its relationship to medication use; and how the pandemic affected IBD management.

Methods
An anonymous questionnaire was posted online to members of the Israel Crohn’s Disease and Ulcerative Colitis Foundation (November 2020- January 2021). The questionnaire addressed the course of IBD disease and COVID-19 infection over the past year.

Results
2152 IBD patients completed the questionnaire. 104 (4.8%) had been infected with COVID-19, significantly lower than the “expected” infected cases among the Israeli population (p=0.033). The median age of participants was 39; 60.5% were female. Most patients (75.6%) had no comorbidities other than IBD.
No correlation was found between IBD type or disease severity and COVID-19 infection. Most IBD patients reported mild COVID-19 disease, regardless of the type of IBD medications. Multivariable logistic regression analysis revealed that younger age, elevated BMI, and diabetes were independent risk factors for COVID-19 infection. IBD treatment including 5-aminosalicylic acid, smoking, and hypertension were protective factors. 25.2% of COVID-19 patients discontinued their IBD treatment, compared to 8.5% of non-COVID-19 infected patients. IBD flares were significantly higher in those who discontinued treatment (p&lt;0.001).

Conclusion
IBD patients do not have an increased risk for COVID-19, regardless of IBD activity or treatment. Patients should be encouraged to continue effective IBD therapy, including biologics and steroids, to minimize active IBD.
N05 A Systematic Review of Self-Management Intervention Study for Patients with Inflammatory Bowel Disease
Authors: Iizawa M , Hirose L , Tairaka A , Maya N 
Published: May 2021

Abstract

Background
Patients with inflammatory bowel disease (IBD) have to deal with abdominal symptoms for a long time because the disease often develops at a young age, and radical treatment has not been established. To prevent worsening of symptoms associated with IBD and delay the progression of the disease, and lead a better daily life, patients must self-manage in their daily lives. At this moment, it is not clear which kinds of self-management are effective for IBD patients. Therefore, we conducted a systematic literature review (SLR) to clarify the present status and efficacy of self-management for IBD patients and find out the effective methods of self-management intervention.

Methods
The SLR was conducted in accordance with the methods recommended by the Cochrane Collaboration Handbook7, to reduce the risk of bias and errors. The searches were performed in Embase, Medline, and Cochrane databases. Additionally, the PsychInfo and the cumulative index of nursing and allied health literature (CINAHL) databases were searched, and relevant articles were included as other sources. Abstracts and full texts were screened to select relevant articles based on the inclusion criteria. A quality assessment was undertaken by using the Cochrane risk of bias tool checklist.

Results
Fifty studies met the inclusion criteria and were finally included in this review. In 31 studies, the overall population of IBD patients was included. Fourteen studies included only UC patients, 5 studies included only CD patients. Among 50 studies, 33 studies have statistically significant differences in the outcomes. We categorized the interventions and outcomes of all the studies based on Barlow’s study in 2002 and analyzed the efficacy of the intervention on the outcomes. The most common intervention was informational, subsequently management of psychological effects. The most common outcome was Inflammatory Bowel Disease Questionnaire (IBDQ). We found that psychological management and interventions related to problem-solving, goal setting, action plan, and coping skills had a positive effect on the body and psychology of IBD patients. There were six studies that investigated the effects of intervention by online medical care. Half of the online intervention showed an improvement in the use of medical services.

Conclusion
It is important for IBD patients and health care providers to work together to share the problem, followed by setting goals and decide on an action plan. To succeed in this process, multidisciplinary collaboration is necessary and continuous support by health care providers will be meaningful for IBD patients.
OP02 Ustekinumab versus adalimumab for induction and maintenance therapy in Moderate-to-Severe Crohn’s Disease: The SEAVUE study
Authors: Irving P M , Sands B E , Hoops T , Izanec J L , Gao L L , Gasink C , Greenspan A , Allez M , Danese S , Hanauer S B , Jairath V , Kuehbacher T , Lewis J D , Loftus E V , Mihaly E , Panaccione R , Scherl E , Shchukina O , Sandborn W J 
Published: May 2021

Abstract

Background
We studied the efficacy and safety of ustekinumab (UST) vs adalimumab (ADA) through 1 year in biologic-naïve patients (pts) with moderate-to-severe Crohn’s disease.

Methods
SEAVUE was a multicenter, randomized, blinded, parallel-group, active-controlled study in adults with CD Activity Index (CDAI) scores ≥220/≤450. Biologic-naïve pts failing/intolerant to conventional therapy with any size ulcer on baseline (BL) ileocolonoscopy were eligible. Pts were randomized 1:1 to UST (⁓6mg/kg IV at BL then 90mg SC every 8 weeks [Ws]) or ADA (160/80mg SC at BL/W2, then 40mg SC every 2 Ws) per US-approved regimens (no dose modifications). Primary endpoint was clinical remission at W52 (CDAI &lt;150). Major secondary endpoints were corticosteroid-free remission, clinical response (≥100-point CDAI decrease from BL), remission in pt-reported CDAI components (PRO-2 symptom remission: abdominal pain mean daily score ≤1 and stool frequency mean daily score ≤3), and endoscopic remission (SES-CD score ≤3/0 for pts with BL score=3) at W52 and clinical remission at W16.

Results
386 pts were randomized to UST or ADA. BL demographics and disease characteristics were balanced between groups and indicative of pts with early, moderate-to-severe CD (median CD duration, 2.58 years; CDAI, 289.5; SES-CD, 8.0). At W52, 65% of UST-treated and 61% of ADA-treated pts achieved clinical remission (Δ=4.0%; 95% CI, -5.5%, 13.5%; p=0.417). Major secondary endpoints, including endoscopic remission, were similar between groups (Table 1), as were remission rates at assessment points through W52. Some other secondary endpoints showed numerical (not statistical) differences between UST and ADA (Table 1). Key safety events are summarized in Table 2. Among UST-treated and ADA-treated pts, 34.0% and 40.5% had infections, 2.6% and 7.2% had serious adverse events (AEs) of worsening CD, and 6.3% and 11.3% had AEs that led to discontinuation (DC) of study drug, respectively. One ADA-treated pt had active pulmonary TB. Injection-site reactions associated with active treatment occurred in 1.0% of UST-treated and 10.3% of ADA-treated pts. Overall, 15.2% of UST-treated and 23.6% of ADA-treated pts DC before W52. Reasons for DC were primarily lack of efficacy (UST, 2.1% vs ADA, 5.1%), AEs (UST, 5.7% vs ADA, 10.7%), and withdrawal of consent (UST, 5.8% vs ADA, 5.1%). Time to treatment DC was longer with UST vs ADA (post hoc analysis).

Conclusion
Both UST and ADA were highly effective in this population of biologic-naïve pts. Rates of clinical remission at W52 were not statistically significantly different between treatment groups. DC rates were numerically lower for UST. Safety results were consistent with prior experience for both treatments.
OP13 Mucosal organoids capture Innate Lymphoid Cells (ILC) tissue-specific development and reveal that Inflammatory Bowel Disease-associated ILC modulate intestinal remodelling
Authors: Jowett G M , Read E , Norman M D , Arevalo P A , Vilà González M , Roberts L , Vallier L , Curtis M , Lord G , Gentleman E , Neves J F 
Published: May 2021

Abstract

Background
Innate Lymphoid Cells (ILC) develop from Common Lymphoid Precursors in the bone marrow, and ILC precursors (ILCP) migrate to mucosa where they mature, promote homeostasis, and provide a potent, antigen-non-specific sources of cytokines. Deciphering what local stimuli drive the final stages of ILCP maturation in these tissues remains a pressing question, as ILC frequencies can become dysregulated during chronic infection and inflammatory diseases. For example, Type-1 innate lymphoid cells (ILC1) are enriched in the mucosa of patients with active inflammatory bowel disease (IBD) and the impact of this accumulation remains elusive.

Methods
Here, we develop and use co-cultures of both murine and human iPSC-derived gut and lung organoids with ILCP and with mature ILC isolated from IBD patients’ intestinal biopsies.

Results
Harnessing these versatile models, we demonstrate that epithelial cells provide a complex niche capable of supporting the final maturation of all helper-like ILC1, ILC2, and ILC3. Notably, organoid identity was sufficient to robustly recapitulate tissue-specific ILC imprints and frequencies, even in the absence of microbial stimuli, other cell types, or cytokine supplementation.
In addition, we show that that ILC1 drive expansion of the epithelial stem cell crypt through p38γ phosphorylation, driving a potentially pathological proliferative feedback loop between β-catenin and Cd44v6. We harnessed this model to elucidate that this phenotype was unexpectedly regulated by ILC1-derived TGFβ1. We further show that human gut ILC1 also secrete TGFβ1, and drive CD44v6 expression in both HIO epithelium and mesenchyme. As TGFβ1 is a master regulator of fibrosis, the leading indicator for surgery in IBD, we next characterised the ability of ILC1 to regulate matrix remodelling using a functionalized, synthetic hydrogel system. We show that ILC1 drive both matrix stiffening and degradation, which we posit occurs through a balance of MMP9 degradation and TGFβ1-induced fibronectin deposition.

Conclusion
Taken together, our work provides unprecedented insight into in situ ILC maturation, which we show to be driven by epithelial signals, and into ILC function. We also report that intestinal ILC1 modulate epithelial and matrix remodelling, which may drive either wound healing in homeostasis, but may tip toward pathology when enriched in IBD.
Moreover, our work introduces a modular organoid platform, which provides exquisite control over both environmental stimuli and host genetics, making it a powerful tool for dissecting the interactions between complex mucosal tissues and rare cell subtypes in development and disease.
P001 Succinate, a gut microbiota-derived metabolite, modulates the inflammatory status of the creeping fat in Crohn’s disease
Authors: Serena C , Monfort-Ferre D , Bautista M , Menacho M , Martí M , Espin E , Vendrell J , Fernández-Veledo S 
Published: May 2021

Abstract

Background
Crohn’s disease [CD] is characterized by severe transmural inflammation with subsequent destruction of the intestinal barrier. Recent works suggest that bacterial infiltration across this leaky gut facilitates access to the mesenteric fat and the development of a subsequent inflammatory reaction in the surrounding adipose tissue named creeping fat [CF]. Dysbiosis in CD patients has been associated with an increase in succinate-producing bacteria and a decrease in succinate-consuming bacteria. In fact, elevated succinate levels have been found in the intestinal and faeces of CD patients. Succinate has been classically considered as a marker of hypoxia and tissue damage, assisting as a pro-inflammatory signal that triggers immune activation. However, recent observations support potential additional functions of succinate. We and others have shown that succinate plays a key role in fine-tuning of the inflammatory response, acting both as an alarmin and resolving molecule. Our hypothesis is that succinate, a microbiota-derived metabolite, is a new determinant of adipose tissue dysfunction in CD.

Methods
A well-characterized cohort was used to obtained mesenteric adipose tissue biopsies including a) 10 subjects with active CD that require surgery for their underlying pathology b) 10 subjects with inactive CD and c) 10 healthy controls undergoing surgery for non-acute process (herniorrhaphy, cholecystectomy for lithiasis, etc.). The groups were comparable in age, sex, and body mass index. We studied the effect of exogenous succinate in adipose tissue explants, adipose-stem cells (ASC), and adipose tissue macrophages (ATM) isolated from adipose tissue biopsies of CD patients with different clinical activity. Circulating succinate levels and inflammatory variables including hs-CRP and faecal calprotectin were also measured.

Results
We observed an increased expression of SUCNR1 in CF, including ASCs and ATMs, mainly in patients suffering from an active disease (figure 1A). Furthermore, succinate appears to elicit a different response in adipose tissue from CD patients, when activity status is considered. Thus, our results indicate that in an inflammatory local and systemic environment, such as occurs in CD active patients, succinate triggers a pro-inflammatory response in VAT depot, while when subjects are in a remission period, the response of VAT explants to succinate is similar to than the observed in healthy subjects, promoting an anti-inflammatory expression profile (Figure 1B). Interestingly, we found elevated circulating succinate levels in active CD patients but those decrease drastically in patients in remission of the disease (Figure 1C).

Conclusion
Succinate has a relevant role in adipose tissue dysfunction in CD.
P029 Activation of FXR restores expression of genes dysregulated in human IBD and suppresses TNFa and IL-6 signaling pathways in adoptive transfer colitis model
Authors: Liu X , Milik A , O’Connell R , White J , Wagner B 
Published: May 2021

Abstract

Background
Farnesoid X receptor (FXR) is a ligand-activated nuclear hormone receptor highly expressed in the gastrointestinal tract. We have shown that FXR agonists improve disease in multiple chronic IBD models (Adoptive transfer (AT) colitis, Mdr1a-/- colitis, and SAMP1/YitFc ileitis) with efficacy similar to anti-IL-12/23. To explore the mechanisms by which FXR agonists reduce colitis in these models and the relevance to human IBD, we identified the genes and pathways regulated by FXR in the AT colitis mice, and compared them with the gene expression profile in human IBD patients.

Methods
Colitis was induced by transplanting CD4+CD45RBhi T-cells to C.B-17 SCID mice. Mice were treated with vehicle (n=10), an FXR agonist (p.o. daily, n=10) or anti-IL-12p40 (i.p., weekly, n=5) in therapeutic mode (started 21 days post AT) for 4 weeks. Efficacy was assessed by colon histopathology of inflammation, erosion, gland loss and hyperplasia (0–5 each). RNAseq was performed on colon RNAs (n=5–7 samples/group). Genes differentially regulated by the FXR agonist were compared with published FXR ChIPSeq data (Thomas et al 2010 Hepatology) and a IBD patients’ gene expression dataset (GSE73661) to identify FXR target genes associated with human IBD. Gene set enrichment analysis (GSEA) was performed to identify enriched pathways.

Results
Direct FXR target genes were identified by comparing genes upregulated by the FXR agonist in the AT mice with FXR ChIPSeq data. Further comparison with GSE73661 identified FXR target genes relevant to human IBD. The majority of these genes are down-regulated in diseased mice and IBD patients compared to healthy controls. Importantly, in GSE73661 dataset, those genes were upregulated in patients that responded to therapy, while remained down-regulated in refractory patients. The function of those genes includes reducing inflammation, improving gut healing and transporter activities. Further pathway analysis by GSEA identified a number of inflammatory pathways significantly upregulated in AT mice and IBD patients, many of which show reduction with the FXR agonist treatment. Of note, TNFα/NF-κB and IL-6/STAT3 pathways, targeted by approved IBD therapies, were significantly elevated in AT mice but reduced by the FXR agonist or anti-IL-12/23.

Conclusion
Activation of FXR directly induces IBD-dysregulated genes that can suppress inflammation, promote gut healing and transporter functions. In addition, FXR activation reduced TNFα/NF-κB and IL-6/STAT3 pathways in AT colitis model. These findings support further development of novel FXR agonists as a potential oral therapy for IBD.
P034 Human primary 2D culture as a tool to explore JAK1 pathway inhibition in the intestinal epithelium using siRNA technology
Authors: Dotti I , Sulpice E , Nougarède A , Jary D , Clément F , Gidrol X , Navarro F , Salas A 
Published: May 2021

Abstract

Background
Oral inhibitors of JAK1 have become promising therapeutic agents for the treatment of inflammatory bowel diseases (IBD); however, concerns have been raised regarding their specificity and safety profiles. Currently, a local therapy based on specific JAK1 siRNA combined with lipid nanoparticle (LNP) technology is under investigation as a safer alternative to JAK inhibitors.The purpose of this study is to explore the inhibition of the JAK1 pathway in the intestinal epithelium mediated by siRNA/LNP technology, using human primary 2D culture.

Methods
Human primary 2D cultures were generated from colonic 3D organoids of non-IBD donors. The efficiency of JAK1 pathway inhibition was tested in IFN-y stimulated cultures using either filgotinib (a JAK1 inhibitor, used as a control) or the novel human JAK1 siRNA. JAK1 siRNA transfection was performed using Lipofectamine or LNPs. qPCR was performed on a panel of JAK1 target genes to evaluate the efficiency of JAK1 pathway inhibition.

Results
Incubation of the 2D culture with IFN-y induced the activation of the JAK1 pathway, as suggested by the significant up-regulation of JAK1-dependent genes (i.e., CXCL10, SOCS1, SOCS3 and PLA2G2A). The addition of filgotinib to the culture efficiently inhibited the JAK1 pathway by suppressing the expression of JAK1-target genes. JAK1 siRNA transfection using Lipofectamine reduced JAK1 mRNA expression by 50%, which was mirrored by the concomitant down-regulation (between 60 and 80%) of JAK1-dependent genes. Importantly, the silencing efficiency of the JAK1-dependent pathway by LNPs was comparable to that observed using Lipofectamine.

Conclusion
Organoid-derived 2D culture is a useful model for investigating the activation of the JAK1 pathway and its pharmacological inhibition in human intestinal epithelium. In particular, siRNA/LNP nanoplexes may be a promising technology for locally delivering highly specific siRNAs to the intestinal mucosa, which could pave the way for the development of more effective treatments for IBD patients.