Publications by authors named "Jakob Begun"

53 Publications

IFNλ Therapy Prevents Severe Gastrointestinal Graft-versus-Host Disease.

Blood 2021 May 5. Epub 2021 May 5.

University of Washington, United States.

Immunopathology and intestinal stem cell (ISC) loss in the gastrointestinal (GI) tract is the prima-facie manifestation of graft-versus-host disease (GVHD) and is responsible for significant mortality after allogeneic bone marrow transplantation (BMT). Approaches to prevent GVHD to date focus on immune-suppression. Here we identify interferon-lambda (IFNl, IL-28/IL-29) as a key protector of GI GVHD immunopathology, notably within the intestinal stem cell (ISC) compartment. Ifnlr1-/- mice displayed exaggerated GI GVHD and mortality independent of Paneth cells and alterations to microbiome. Ifnlr1-/- intestinal organoid growth was significantly impaired and targeted Ifnlr1 deficiency demonstrated effects intrinsic to recipient Lgr5+ ISC and NK cells. PEGylated IL-29 (PEG-rIL-29) treatment of naïve mice enhanced Lgr5+ ISC numbers and organoid growth independent of both IL-22 and type-1 IFN and modulated proliferative and apoptosis gene sets in Lgr5+ ISC. PEG-rIL-29 treatment improved survival, reduced GVHD severity, and enhanced epithelial proliferation and ISC-derived organoid growth after BMT, The preservation of ISC numbers in response to PEG-rIL-29 after BMT occurred both in the presence and absence of IFNl,-signaling in recipient NK cells. IFNl is therefore an attractive and rapidly testable approach to prevent ISC loss and immunopathology during GVHD.
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http://dx.doi.org/10.1182/blood.2020006375DOI Listing
May 2021

So many therapies-So little data: How to choose? Session two summary.

Authors:
Jakob Begun

J Gastroenterol Hepatol 2021 Apr;36 Suppl 1:14-15

Mater Hospital Brisbane and the Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia.

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http://dx.doi.org/10.1111/jgh.15450DOI Listing
April 2021

Gut microbiota shape the inflammatory response in mice with an epithelial defect.

Gut Microbes 2021 Jan-Dec;13(1):1-18

Immunopathology Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Australia.

Intestinal epithelial cell endoplasmic reticulum (ER) stress has been implicated in intestinal inflammation. It remains unclear whether ER stress is an initiator of or a response to inflammation. mice, carrying a gene mutation resulting in intestinal goblet cell ER stress, develop spontaneous colitis with a depleted mucus barrier and increased bacterial translocation. This study aims to determine whether the microbiota was required for the development of colitis, and whether protein misfolding itself can initiate inflammation directly in absence of the microbiota. To assess the role of microbiota in driving colitis, and mice on the same background were rederived into the germ-free facility and housed in the Trexler-type soft-sided isolators. The colitis phenotype of these mice was assessed and compared to and mice housed within a specific pathogen-free facility. We found that colitis was substantially reduced but not abolished under germ-free conditions. Expression of inflammatory cytokine genes was reduced but several chemokines remained elevated in absence of microbiota. Concomitantly, ER stress was also diminished, although mucin misfolding persisted. RNA-Seq revealed that differentiated colon organoids have decreased expression of the negative regulators of the inflammatory response compared to . This data along with the increase in chemokine expression, suggests that the epithelial cells in the mice are more responsive to stimuli. Moreover, the data demonstrate that intestinal epithelial intrinsic protein misfolding can prime an inflammatory response without initiating the unfolded protein response in the absence of the microbiota. However, the microbiota is necessary for the amplification of colitis in mice. Genetic predisposition to mucin misfolding in secretory cells initiates mild inflammatory signals. However, the inflammatory signal sets a forward-feeding cycle establishing progressive inflammation in the presence of microbiota. Endoplasmic Reticulum: ER; Mucin-2: Muc-2; GF: Germ-Free; Inflammatory Bowel Disease: IBD.
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http://dx.doi.org/10.1080/19490976.2021.1887720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928202PMC
March 2021

Standardisation of intestinal ultrasound scoring in clinical trials for luminal Crohn's disease.

Aliment Pharmacol Ther 2021 04 28;53(8):873-886. Epub 2021 Feb 28.

Calgary, AB, Canada.

Background: Intestinal ultrasound (IUS) is a valuable tool for assessment of Crohn's disease (CD). However, there is no widely accepted luminal disease activity index.

Aims: To identify appropriate IUS protocols, indices, items, and scoring methods for measurement of luminal CD activity and integration of IUS in CD clinical trials.

Methods: An expert international panel of adult and paediatric gastroenterologists (n = 15) and radiologists (n = 3) rated the appropriateness of 120 statements derived from literature review and expert opinion (scale of 1-9) using modified RAND/UCLA methodology. Median panel scores of 1 to ≤3.5, >3.5 to <6.5 and ≥6.5 to 9 were considered inappropriate, uncertain and appropriate ratings respectively. The statement list and survey results were discussed prior to voting.

Results: A total of 91 statements were rated appropriate with agreement after two rounds of voting. Items considered appropriate measures of disease activity were bowel wall thickness (BWT), vascularity, stratification and mesenteric inflammatory fat. There was uncertainty if any of the existing IUS disease activity indices were appropriate for use in CD clinical trials. Appropriate trial applications for IUS included patient recruitment qualification when diseased segments cannot be adequately assessed by ileocolonoscopy and screening for exclusionary complications. At outcome assessment, remission endpoints including BWT and vascularity, with or without mesenteric inflammatory fat, were considered appropriate. Components of an ideal IUS disease activity index were identified based upon panel discussions.

Conclusions: The panel identified appropriate component items and applications of IUS for CD clinical trials. Empiric evidence, and development and validation of an IUS disease activity index are needed.
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http://dx.doi.org/10.1111/apt.16288DOI Listing
April 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Adhesion to E-selectin primes macrophages for activation through AKT and mTOR.

Immunol Cell Biol 2021 Feb 10. Epub 2021 Feb 10.

Mater Research Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD, Australia.

The endothelial adhesion protein E-selectin/CD62E is not required for leukocyte homing, unlike closely related family member P-selectin/CD62P. As transmigration through the endothelium is one of the first steps in generating a local immune response, we hypothesized that E-selectin may play additional roles in the early stages of immune activation. We found contact with E-selectin, but not P-selectin or vascular cell adhesion molecule 1 (CD106), induced phosphorylation of protein kinase B (AKT) and nuclear factor-κB in mouse bone marrow-derived macrophages (BMDMs) in vitro. This occurred within 15 min of E-selectin contact and was dependent on phosphatidylinositol-3 kinase activity. Binding to E-selectin activated downstream proteins including mammalian target of rapamycin, p70 ribosomal protein S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1. Functionally, adhesion to E-selectin induced upregulation of CD86 expression and CCL2 secretion. We next asked whether contact with E-selectin impacts further BMDM stimulation. We found enhanced secretion of both interleukin (IL)-10 and CCL2, but not tumor necrosis factor or IL-6 in response to lipopolysaccharide (LPS) stimulation after adhesion to E-selectin. Importantly, adhesion to E-selectin did not polarize BMDMs to one type of response but enhanced both arginase activity and nitric oxide production following IL-4 or LPS stimulation, respectively. In cultured human monocytes, adhesion to E-selectin similarly induced phosphorylation of AKT. Finally, when E-selectin was blocked in vivo in mice, thioglycollate-elicited macrophages showed reduced CD86 expression, validating our in vitro studies. Our results imply functions for E-selectin beyond homing and suggest that E-selectin plays an early role in priming and amplifying innate immune responses.
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http://dx.doi.org/10.1111/imcb.12447DOI Listing
February 2021

pH - Responsive colloidal carriers assembled from β-lactoglobulin and Epsilon poly-L-lysine for oral drug delivery.

J Colloid Interface Sci 2021 May 21;589:45-55. Epub 2020 Dec 21.

School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent St, Woolloongabba, QLD 4102, Australia. Electronic address:

Site specific oral delivery of many biopharmaceutical classification system (BCS) class II and IV drugs is challenging due to their poor solubility, low permeability and degradation in the gastrointestinal tract. Whilst colloidal carriers have been used to improve the bioavailability of such drugs, most nanocarriers based drug delivery systems suffer from multiple disadvantages, including low encapsulation efficiency (liposomes, polymeric nanoparticles), complex synthesis methods (silica, silicon-based materials) and poorly understood biodegradability (inorganic nanoparticles). Herein, a novel pH responsive nanocolloids were self-assembled using natural compounds such as bovine β-lactoglobulin (BLG) and succinylated β-lactoglobulin (succ. BLG) cross-linked with epsilon poly l-lysine (BCEP and BCP), and found to possess high loading capacity, high aqueous solubility and site-specific oral delivery of a poorly soluble nutraceutical (curcumin), improving its physicochemical properties and biological activity in-vitro and ex-vivo. Our optimized synthesis formed colloids of around 200 nm which were capable of encapsulating curcumin with ~100% encapsulation efficiency and ~10% w/w drug loading. By forming nanocomplexes of curcumin with BLG and succ. BLG, the aqueous solubility of curcumin was markedly increased by ~160-fold and ~86-fold, respectively. Encapsulation with BLG increased the solubility, whereas succ. BLG prevent release of encapsulated curcumin when subjected to gastric fluids as it is resistant to breakdown on exposure to pepsin at acidic pH. In conditions mimicking the small intestine, Succ. BLG was more soluble resulting in sustained release of the encapsulated drug at pH 7.4. Additionally, crosslinking succ. BLG with E-PLL significantly enhanced curcumin's permeability in an in-vitro Caco-2 cell monolayer model compared to curcumin solution (dissolved in 1% DMSO), or non-crosslinked BLG/succ. and BLG. In a mouse-derived intestinal epithelial 3D organoid culture stimulated with IL-1β, BLG-CUR and crosslinked BCEP nanoparticles reduced the production of inflammatory cytokines and chemokines such as Tnfα and Cxcl10 more than curcumin solution or suspension while these nanoparticles were non-toxic to organoids. Overall this work demonstrates the promise of nutraceutical-based hybrid self-assembled colloidal system to protect hydrophobic drugs from harsh gastrointestinal conditions and improve their solubility, dissolution, permeability and biological activity.
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http://dx.doi.org/10.1016/j.jcis.2020.12.054DOI Listing
May 2021

Crohn's Colitis Care (CCCare): bespoke cloud-based clinical management software for inflammatory bowel disease.

Scand J Gastroenterol 2020 Dec 8;55(12):1419-1426. Epub 2020 Nov 8.

Department of Gastroenterology, Royal Adelaide Hospital & University of Adelaide, Adelaide, Australia.

Background: Adherence to evidence-based management is variable in inflammatory bowel disease (IBD), which leads to worse patient outcomes and higher healthcare utilization. Solutions include electronic systems to enhance care, but these have often been limited by lack of clinician design input, poor usability, and low perceived value. A cloud-based IBD-specific clinical management software - 'Crohn's Colitis Care' (CCCare) was developed by Australia and New Zealand Inflammatory Bowel Disease Consortium clinicians and software developers to improve this.

Methods: CCCare captures patient-reported disease activity and medical assessment, medication monitoring, cancer screening, preventative health, and facilitates communication with the IBD team and referring doctor. De-identified longitudinal data are stored separately in a clinical quality registry for research. CCCare was tested for feasibility and usability in routine clinical settings at two large Australian hospitals. Users' experience was evaluated with System Usability Scale (SUS). Value to clinicians and patients was assessed by qualitative feedback. Security was assessed by penetration testing.

Results: Users ( = 13; doctors, nurses, patients) reported good usability and learnability (mean SUS score 75 (range 50-95), sub-scores were 77 (50-94) and 68 (38-100), respectively). Patients reported better communication with clinical team and greater ability to track disease. Clinicians highlighted structured management plans, medication adherence, and centralised data repository as positive features. Penetration testing was passed successfully.

Conclusions: Initial evaluation demonstrates CCCare is usable, secure, and valued in clinical use. It is designed to measure outcomes of clinical care, including efficacy, quality, cost, and complications for individuals, and to audit these at hospital and national level.
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http://dx.doi.org/10.1080/00365521.2020.1839960DOI Listing
December 2020

Switching Australian patients with moderate to severe inflammatory bowel disease from originator to biosimilar infliximab: a multicentre, parallel cohort study.

Med J Aust 2021 02 17;214(3):128-133. Epub 2020 Oct 17.

Fiona Stanley Hospital, Perth, WA.

Objective: To examine whether non-medical switching of patients with inflammatory bowel disease (IBD) from originator infliximab to a biosimilar (CT-P13, Inflectra) is safe and clinically non-inferior to continued treatment with originator infliximab.

Design: Prospective, open label, multicentre, parallel cohort, non-inferiority study in seven Australian hospitals over 48 weeks, May 2017 - October 2019.

Participants: Adults (18 years or older) with IBD receiving maintenance originator infliximab (Remicade) who had been in steroid-free clinical remission for at least 12 weeks.

Intervention: Managed program for switching patients in four hospitals from originator to biosimilar infliximab (CT-P13); patients in three other hospitals continued to receive originator infliximab (control).

Main Outcome Measures: Clinical disease worsening requiring infliximab dose escalation or change in therapy.

Results: The switch group included 204 patients, the control group 141 patients with IBD. Ten patients in the control group (7%) and 16 patients switched to CT-P13 (8%) experienced clinical deterioration; the adjusted risk difference (control v switch group) was -1.1 percentage points (95% CI, -6.1 to 8.2 percentage points), within our pre-specified non-inferiority margin of 15 percentage points. Serious adverse events leading to infliximab discontinuation were infrequent in both the switch (six, 3%) and control (six, 4%) groups.

Conclusion: Switching patients with IBD from originator to biosimilar infliximab is safe and non-inferior to continuing treatment with originator infliximab. Moreover, the introduction of biosimilar infliximab, by increasing market competition, has resulted in substantial cost savings for the Pharmaceutical Benefits Scheme.
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http://dx.doi.org/10.5694/mja2.50824DOI Listing
February 2021

Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure.

Aliment Pharmacol Ther 2020 11 27;52(10):1551-1562. Epub 2020 Sep 27.

Fitzroy, VIC, Australia.

Background: The impact of pregnancy on levels of biologic agents in patients with IBD is undefined and time to elimination in vedolizumab-exposed infants is unknown.

Aims: To determine the effect of pregnancy on infliximab, adalimumab and vedolizumab levels and to study infant vedolizumab clearance METHODS: In a prospective observational study, maternal drug levels were measured pre-conception, in each trimester, at delivery and postpartum. The association between drug levels and gestation in weeks was assessed using generalised estimating equation modelling. Infant vedolizumab levels were performed at birth (cord blood), 6 weeks and 3 months or until undetectable.

Results: We included 50 IBD patients (23 on infliximab, 15 on adalimumab and 12 on vedolizumab) with at least two intrapartum observations, plus 5 patients on vedolizumab with only mother and baby samples at delivery. Modelling showed no change in adalimumab levels, an increase in infliximab levels of 0.16 (95% CI 0.08-0.24) µg/L/week (P < 0.001) and a decrease of 0.18 (95% CI: -0.33 to -0.02) µg/L/week (P = 0.03) for vedolizumab. In 17 mother-baby pairs, median infant vedolizumab levels at birth were lower than maternal levels (P < 0.05) with an infant:maternal ratio of 0.7 (IQR 0.5-0.9). Vedolizumab was undetectable between 15 and 16 weeks of age in all 12 infants completing follow-up testing.

Conclusions: During pregnancy, adalimumab levels remain stable, while infliximab levels increase and vedolizumab levels decrease. However, the increments were small suggesting that intrapartum therapeutic drug monitoring and dose adjustment are not indicated. Unlike infliximab and adalimumab, infant vedolizumab levels are lower in cord blood than in mothers and appear to clear rapidly.
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http://dx.doi.org/10.1111/apt.16102DOI Listing
November 2020

Vedolizumab for ulcerative colitis: Real world outcomes from a multicenter observational cohort of Australia and Oxford.

World J Gastroenterol 2020 Aug;26(30):4428-4441

Centre for Inflammatory Bowel Diseases, St John of God Hospital, Subiaco 6008, Western Australia, Australia.

Background: Vedolizumab (VDZ), a humanised monoclonal antibody that selectively inhibits integrins is approved for use in adult moderate to severe ulcerative colitis (UC) patients.

Aim: To assess the efficacy and safety of VDZ in the real-world management of UC in a large multicenter cohort involving two countries and to identify predictors of achieving remission.

Methods: A retrospective review of Australian and Oxford, United Kingdom data for UC patients. Clinical response at 3 mo, endoscopic remission at 6 mo and clinical remission at 3, 6 and 12 mo were assessed. Cox regression models and Kaplan Meier curves were performed to assess the time to remission, time to failure and the covariates influencing them. Safety outcomes were recorded.

Results: Three hundred and three UC patients from 14 centres in Australia and United Kingdom, [60% = 182, anti-TNF naïve] were included. The clinical response was 79% at 3 mo with more Australian patients achieving clinical response compared to Oxford (83% 70% = 0.01). Clinical remission for all patients was 56%, 62% and 60% at 3, 6 and 12 mo respectively. Anti-TNF naive patients were more likely to achieve remission than exposed patients at all the time points (3 mo 66% 40% < 0.001, 6 mo 73% 46% < 0.001, 12 mo 66% 51% = 0.03). More Australian patients achieved endoscopic remission at 6 mo compared to Oxford (69% 43% = 0.01). On multi-variate analysis, anti-TNF naïve patients were 1.8 (95%CI: 1.3-2.3) times more likely to achieve remission than anti-TNF exposed ( < 0.001). 32 patients (11%) had colectomy by 12 mo.

Conclusion: VDZ was safe and effective with 60% of UC patients achieving clinical remission at 12 mo and prior anti-TNF exposure influenced this outcome.
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http://dx.doi.org/10.3748/wjg.v26.i30.4428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438197PMC
August 2020

The psychosocial burden of inflammatory bowel disease in adolescents and young adults.

Intern Med J 2020 Aug 25. Epub 2020 Aug 25.

Mater Young Adult Health Centre, Mater Health, Brisbane, Queensland, Australia.

Background And Aim: This study examined the psychosocial burden of inflammatory bowel disease (IBD) in young people aged 15-25 years attending a tertiary specialist health centre for adolescents and young adults in Brisbane.

Methods: Young people with IBD provided demographic information and psychosocial data via a cross-sectional self-report survey. Psychosocial data included the Kessler Psychological Distress Scale (K-10), Perceived Stress Scale (PSS-10), Brief Illness Perception Questionnaire (Brief IPQ), World Health Organisation Wellbeing Index (WHO-5), Pediatric Quality of Life Inventory (PedsQL), Short Quality of Life Questionnaire for IBD (SIBDQ), Multidimensional Scale of Perceived Social Support (MSPSS), Connor Davidson Resilience Scale 2 (CD-RISC2), and the Multidimensional Health Locus of Control Scale (MHLC).

Results: Surveys were collected from 51 young people with IBD and compared with surveys from 210 young people with juvenile rheumatic disease (n=31), phenylketonuria (n=21), cystic fibrosis (n=33), renal transplants (n=14), and craniomaxillofacial conditions (n=111). On the psychosocial domains, 41% of young people with IBD had poor wellbeing and 37% were at risk of depression. When assessed against the comparison group, young people with IBD reported higher depressive symptoms (p=0.04), worse illness perceptions (p<0.01), and lower internal locus of control (p<0.01).

Conclusion: Early recognition and treatment of depression and other psychosocial comorbidities within integrated pathways of care is crucial in adolescents and young adults with IBD and likely to improve the course of IBD and their overall health and wellbeing. Interventions aimed at enhancing self-efficacy and increasing public awareness are also likely to be helpful. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15034DOI Listing
August 2020

Practical management of inflammatory bowel disease patients during the COVID-19 pandemic: expert commentary from the Gastroenterological Society of Australia Inflammatory Bowel Disease faculty.

Intern Med J 2020 07;50(7):798-804

Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has emerged as a public health emergency and challenged healthcare systems globally. In a minority of patients, SARS-CoV-2 manifests with a severe acute respiratory illness and currently there is insufficient data regarding the virulence of COVID-19 in inflammatory bowel disease patients taking immunosuppressive therapy. This review aims to summarise the current literature and provide guidance on the management of inflammatory bowel disease patients in the context of the COVID-19 pandemic in the Australasian setting.
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http://dx.doi.org/10.1111/imj.14889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405147PMC
July 2020

Malnutrition and quality of life among adult inflammatory bowel disease patients.

JGH Open 2020 Jun 14;4(3):454-460. Epub 2019 Nov 14.

Mater Research Institute The University of Queensland Brisbane Queensland Australia.

Background And Aim: Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gut resulting in a significant risk for malnutrition. The reported prevalence of malnutrition in inflammatory disease patients varies from 5.7 to 82.8%. The aim of this study was to measure the prevalence of malnutrition and its association with quality of life (QOL) in a cohort of Australian IBD outpatients.

Methods: A total of 107 consecutive patients (68 Crohn's disease, 35 ulcerative colitis, 4 indeterminate colitis) were enrolled in this cross-sectional study. Demographic data were collected, and patients underwent a malnutrition assessment using the patient-generated subjective global assessment. The RAND 36-item health survey was used to measure QOL.

Results: Mild to moderate malnutrition was detected in 17 patients (16%). Malnourished patients were more likely to be underweight ( ≤ 0.01), have active disease ( ≤ 0.01), and have been admitted to hospital in the preceding 12 months ( ≤ 0.05). Malnourished patients had a significantly lower QOL in physical ( ≤ 0.01) and mental ( ≤ 0.01) health components. Patients with active or recently active disease had reduced QOL compared to patients in remission. Malnutrition factors predictive of poor physical health-related QOL were pain (odds ratio [OR] = 12.8, 95% confidence interval [CI] 2.0-80.4) and unintentional weight loss (OR = 3.1 per kg lost, 95% CI 1.2-7.9). The predictor of poor mental health-related QOL was early satiety (OR = 7.7, 95% CI 1.7-33.9).

Conclusions: The malnutrition prevalence for this population was 16%. Malnutrition was associated with being underweight, active disease, and increased number of hospital admissions. Disease activity and malnutrition were associated with poorer QOL.
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http://dx.doi.org/10.1002/jgh3.12278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273715PMC
June 2020

A Nucleotide Analog Prevents Colitis-Associated Cancer via Beta-Catenin Independently of Inflammation and Autophagy.

Cell Mol Gastroenterol Hepatol 2021 1;11(1):33-53. Epub 2020 Jun 1.

Inflammatory Bowel Diseases Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland; School of Clinical Medicine, Faculty of Medicine, University of Queensland. Electronic address:

Background & Aims: Chronic bowel inflammation increases the risk of colon cancer; colitis-associated cancer (CAC). Thiopurine treatments are associated with a reduction in dysplasia and CAC in inflammatory bowel disease (IBD). Abnormal Wnt/β-catenin signalling is characteristic of >90% of colorectal cancers. Immunosuppression by thiopurines is via Rac1 GTPase, which also affects Wnt/β-catenin signalling. Autophagy is implicated in colonic tumors, and topical delivery of the thiopurine thioguanine (TG) is known to alleviate colitis and augment autophagy. This study investigated the effects of TG in a murine model of CAC and potential mechanisms.

Methods: Colonic dysplasia was induced by exposure to azoxymethane (AOM) and dextran sodium sulfate (DSS) in wild-type (WT) mice and mice harboring intestinal epithelial cell-specific deletion of autophagy related 7 gene (Atg7). TG or vehicle was administered intrarectally, and the effect on tumor burden and β-catenin activity was assessed. The mechanisms of action of TG were investigated in vitro and in vivo.

Results: TG ameliorated DSS colitis in wild-type but not Atg7 mice, demonstrating that anti-inflammatory effects of locally delivered TG are autophagy-dependent. However, TG inhibited CAC in both wild-type and Atg7 mice. This was associated with decreased β-catenin activation/nuclear translocation demonstrating that TG's inhibition of tumorigenesis occurred independently of anti-inflammatory and pro-autophagic actions. These results were confirmed in cell lines, and the dependency on Rac1 GTPase was demonstrated by siRNA knockdown and overexpression of constitutively active Rac1.

Conclusions: Our findings provide evidence for a new mechanism that could be exploited to improve CAC chemoprophylactic approaches.
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http://dx.doi.org/10.1016/j.jcmgh.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593585PMC
June 2020

Aeromedical retrievals for gastrointestinal disorders in rural and remote Australia: the need for improved access to specialist advice.

Intern Med J 2020 05;50(5):619-623

Department of Gastroenterology and Hepatology, RAH and University of Adelaide, Adelaide, Australia.

The Royal Flying Doctor Service (RFDS) provides medical care to populations without access to traditional health-care services. From 2014 to 2018 the RFDS conducted 6007 (≈1201/year) aeromedical retrievals for gastrointestinal (GI) disorders. More detailed research is needed to determine specific GI disorders that contributed to this caseload, and in particular inform whether the establishment of a GI specialist service is justified.
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http://dx.doi.org/10.1111/imj.14822DOI Listing
May 2020

Monitoring Inflammatory Bowel Disease in Pregnancy Using Gastrointestinal Ultrasonography.

J Crohns Colitis 2020 Oct;14(10):1405-1412

Department of Gastroenterology, St Vincent's Hospital, Melbourne, VIC, Australia.

Background And Aims: Inflammatory bowel disease [IBD] affects women during their childbearing years. Gastrointestinal ultrasonography [GIUS] accurately identifies disease activity in non-pregnant patients with IBD. The utility of GIUS in pregnancy has not been established. We aimed to determine the feasibility and accuracy of GIUS in the assessment of IBD during pregnancy progression.

Methods: A multicentre observational study of women with IBD undergoing GIUS during pregnancy. Clinicians assessed the adequacy of bowel views and disease activity in four colonic segments and the terminal ileum. Location[s] in which views were impeded by the uterus were documented. GIUS disease activity [bowel wall thickness >3 mm] was compared with biochemical disease activity [faecal calprotectin >100 μg/g].

Results: Ninety patients and 127 GIUS examinations were included [median gestation 19 weeks, range 4-33]. Adequate colonic views were obtained in 116/127 [91%] scans. Adequate ileal views were obtained in 62/67 [93%] scans <20 weeks and 30/51 [59%] scans at 20-26 weeks. There was a positive correlation between bowel wall thickness and calprotectin [r = 0.26, p = 0.03]. GIUS delivered a specificity of 83%, sensitivity of 74%, and negative predictive value of 90% compared with calprotectin.

Conclusions: GIUS is a feasible and accurate modality for monitoring IBD in pregnancy. Adequate GIUS views of the colon and terminal ileum can be obtained in the majority of patients up to 20 weeks of gestation. Beyond 20 weeks, GIUS provides good views of the colon but the terminal ileum becomes difficult to assess.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa082DOI Listing
October 2020

Gastrointestinal ultrasound in inflammatory bowel disease care: Patient perceptions and impact on disease-related knowledge.

JGH Open 2020 Apr 9;4(2):267-272. Epub 2019 Oct 9.

IBD Service, Department of Gastroenterology The Queen Elizabeth Hospital Adelaide South Australia Australia.

Background And Aim: Objective monitoring of disease activity is integral to therapeutic decision-making in inflammatory bowel disease (IBD). Data are sparse on patients' perspectives of tools used to monitor disease activity in IBD. To evaluate patients' perspectives of gastrointestinal ultrasound (GIUS) performed during routine IBD clinical care, along with its impact on IBD-specific knowledge.

Methods: Patients with a formal diagnosis of IBD who underwent GIUS at two tertiary IBD services between March 2017 and January 2019 participated in this prospective study. Participants completed a questionnaire measuring the acceptability, tolerability, and usefulness of GIUS using a visual analogue scale (VAS) from 0 (disagree) to 10 (strongly agree). Comparative acceptability of IBD monitoring tools and the impact of GIUS on IBD-specific knowledge was measured.

Results: A total of 121 participants completed the questionnaire, with a mean age of 42 years (range 17-78), 54 (45%) males, and 79 (65%) Crohn's disease patients. In the overall population, GIUS was scored as highly acceptable for monitoring IBD (mean 9.20 ± 1.37) compared to colonoscopy (7.94 ± 2.30), stool sampling (8.17 ± 1.96), blood sampling (8.87 ± 1.62), and imaging (8.67 ± 1.60);  < 0.01 for each comparison. GIUS caused little patient discomfort (1.88 ± 1.83), and 98 (81%) participants ranked GIUS as their preferred IBD monitoring tool. GIUS also improved patients' overall IBD-specific knowledge (VAS IBD-specific knowledge 7.96 ± 1.92), including their understanding of the need for medical therapy and disease extent.

Conclusion: GIUS is a highly acceptable and well-tolerated tool for monitoring disease activity in IBD patients. GIUS is preferred by patients and enhances IBD-specific knowledge.
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http://dx.doi.org/10.1002/jgh3.12268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144798PMC
April 2020

Australian consensus statements for the regulation, production and use of faecal microbiota transplantation in clinical practice.

Gut 2020 05 11;69(5):801-810. Epub 2020 Feb 11.

The University of Sydney, Sydney, New South Wales, Australia

Objective: Faecal microbiota transplantation (FMT) has proved to be an extremely effective treatment for recurrent infection, and there is interest in its potential application in other gastrointestinal and systemic diseases. However, the recent death and episode of septicaemia following FMT highlights the need for further appraisal and guidelines on donor evaluation, production standards, treatment facilities and acceptable clinical indications.

Design: For these consensus statements, a 24-member multidisciplinary working group voted online and then convened in-person, using a modified Delphi approach to formulate and refine a series of recommendations based on best evidence and expert opinion. Invitations to participate were directed to Australian experts, with an international delegate assisting the development. The following issues regarding the use of FMT in clinical practice were addressed: donor selection and screening, clinical indications, requirements of FMT centres and future directions. Evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.

Results: Consensus was reached on 27 statements to provide guidance on best practice in FMT. These include: (1) minimum standards for donor screening with recommended clinical selection criteria, blood and stool testing; (2) accepted routes of administration; (3) clinical indications; (4) minimum standards for FMT production and requirements for treatment facilities acknowledging distinction between single-site centres (eg, hospital-based) and stool banks; and (5) recommendations on future research and product development.

Conclusions: These FMT consensus statements provide comprehensive recommendations around the production and use of FMT in clinical practice with relevance to clinicians, researchers and policy makers.
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http://dx.doi.org/10.1136/gutjnl-2019-320260DOI Listing
May 2020

Faecal calprotectin testing for identifying patients with organic gastrointestinal disease: systematic review and meta-analysis.

Med J Aust 2019 11 3;211(10):461-467. Epub 2019 Nov 3.

Mater Hospital Brisbane, Brisbane, QLD.

Objectives: To assess the clinical effectiveness of faecal calprotectin (FC) testing for distinguishing between organic gastrointestinal diseases (organic GID), such as inflammatory bowel disease (IBD), and functional gastrointestinal disorders (functional GIDs).

Study Design: Studies that assessed the accuracy of FC testing for differentiating between IBD or organic GID and functional GIDs were reviewed. Articles published in English during January 1998 - June 2018 that compared diagnostic FC testing in primary care and outpatient hospital settings with a reference test and employed the standard enzyme-linked immunosorbent FC assay method with a cut-off of 50 or 100 μg/g faeces were included. Study quality was assessed with QUADAS-2, an evidence-based quality assessment tool for diagnostic accuracy studies.

Data Sources: MEDLINE and EMBASE; reference lists of screened articles.

Data Synthesis: Eighteen relevant studies were identified. For distinguishing patients with organic GID (including IBD) from those with functional GIDs (16 studies), the estimated sensitivity of FC testing was 81% (95% CI, 74-86%), the specificity 81% (95% CI, 71-88%); area under the curve (AUC) was 0.87. For distinguishing IBD from functional GIDs (ten studies), sensitivity was 88% (95% CI, 80-93%), specificity 72% (95% CI, 59-82%), and AUC 0.89. Assuming a population prevalence of organic GID of 1%, the positive predictive value was 4.2%, the negative predictive value 100%. The difference in sensitivity and specificity between FC testing cut-offs of 50 μg/g and 100 μg/g faeces was not statistically significant (P = 0.77).

Conclusions: FC testing is clinically useful for distinguishing organic GID (including IBD) from functional GIDs, and its incorporation into clinical practice for evaluating patients with lower gastrointestinal symptoms could lead to fewer patients with functional GIDs undergoing colonoscopy, reducing costs for both patients and the health system.

Prospero Registration: CRD4201810507.
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http://dx.doi.org/10.5694/mja2.50384DOI Listing
November 2019

MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota.

Immunity 2019 11 18;51(5):885-898.e7. Epub 2019 Sep 18.

Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA. Electronic address:

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.
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http://dx.doi.org/10.1016/j.immuni.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959419PMC
November 2019

Distinct Tissue-Specific Roles for the Disease-Associated Autophagy Genes ATG16L2 and ATG16L1.

J Immunol 2019 10 26;203(7):1820-1829. Epub 2019 Aug 26.

Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;

The clear role of autophagy in human inflammatory diseases such as Crohn disease was first identified by genome-wide association studies and subsequently dissected in multiple mechanistic studies. ATG16L1 has been particularly well studied in knockout and hypomorph settings as well as models recapitulating the Crohn disease-associated T300A polymorphism. Interestingly, ATG16L1 has a single homolog, ATG16L2, which is independently implicated in diseases, including Crohn disease and systemic lupus erythematosus. However, the contribution of ATG16L2 to canonical autophagy pathways and other cellular functions is poorly understood. To better understand its role, we generated and analyzed the first, to our knowledge, ATG16L2 knockout mouse. Our results show that ATG16L1 and ATG16L2 contribute very distinctly to autophagy and cellular ontogeny in myeloid, lymphoid, and epithelial lineages. Dysregulation of any of these lineages could contribute to complex diseases like Crohn disease and systemic lupus erythematosus, highlighting the value of examining cell-specific effects. We also identify a novel genetic interaction between ATG16L2 and epithelial ATG16L1. These findings are discussed in the context of how these genes may contribute distinctly to human disease.
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http://dx.doi.org/10.4049/jimmunol.1800419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761021PMC
October 2019

MUC13 promotes the development of colitis-associated colorectal tumors via β-catenin activity.

Oncogene 2019 11 19;38(48):7294-7310. Epub 2019 Aug 19.

Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.

Many adenocarcinomas, including colorectal cancer (CRC), overexpress the MUC13 cell surface mucin, but the functional significance and mechanisms are unknown. Here, we report the roles of MUC13 in colonic tumorigenesis and tumor progression. High-MUC13 expression is associated with poor survival in two independent patient cohorts. In a comprehensive series of in vivo experiments, we identified a critical role for MUC13 in the development of this malignancy, by promoting survival and proliferation of tumor-initiating cells and driving an immunosuppressive environment that protects tumors from checkpoint inhibitor immunotherapy. In Muc13-deficient mice, fewer tumors are generated after exposure to carcinogens and inflammation, they have markedly reduced β-catenin signaling, have more tumor-infiltrating CD103 dendritic cells and CD8 T lymphocytes, fewer myeloid-derived suppressor cells, and are rendered sensitive to checkpoint inhibitor immunotherapy (anti-PD-L1). Mechanistically, we show that MUC13 protects β-catenin from degradation, by interacting with GSK-3β, which increases β-catenin nuclear translocation and promotes its signaling, thereby driving cancer initiation, progression, invasion, and immune suppression. Therefore, MUC13 is a potential marker of poor prognosis in colorectal cancer, and inhibiting MUC13 may be useful in the treatment of colitis-associated cancer and sensitizing tumors to immunotherapy.
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http://dx.doi.org/10.1038/s41388-019-0951-yDOI Listing
November 2019

Mindfulness-Based Cognitive Therapy Experiences in Youth With Inflammatory Bowel Disease and Depression: Protocol for a Mixed Methods Qualitative Study.

JMIR Res Protoc 2019 Jul 24;8(7):e14432. Epub 2019 Jul 24.

Mater Clinical School and Princess Alexandra Clinical School, School of Medicine, University of Queensland, South Brisbane, Australia.

Background: Mindfulness-based programs are increasingly used as a part of integrated treatment for inflammatory bowel disease (IBD). However, the majority of research has been quantitative with limited qualitative exploration of patients' experiences of mindfulness programs and no studies among adolescents and young adults with IBD. Furthermore, there has been a paucity of research exploring the role of common psychotherapy and group factors within mindfulness programs.

Objective: This study aims to explore the experiences of adolescents and young adults with IBD and depression who completed a mindfulness-based cognitive therapy (MBCT) group program, as well as the role of therapeutic alliance, group affiliation, and other common psychotherapy and group factors.

Methods: This mixed methods qualitative study, nested within a randomized controlled trial (RCT) of MBCT for adolescents and young adults with IBD, will obtain qualitative data from focus groups and open-ended survey questions. The study aims to conduct three to four focus groups with 6-8 participants in each group. It will employ data and investigator triangulation as well as thematic analysis of the qualitative data.

Results: The study was approved by the Mater Hospital Human Research Ethics Committee and recruitment commenced in May 2019; study completion is anticipated by early 2020.

Conclusions: The study will contribute to the assessment of acceptability and feasibility of the MBCT program for adolescents and young adults with IBD. It will also elucidate the role of previously unexplored common psychotherapy and group factors within mindfulness training and help inform the design of a future large-scale RCT of MBCT in this cohort.

Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617000876392; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373115.

International Registered Report Identifier (irrid): PRR1-10.2196/14432.
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http://dx.doi.org/10.2196/14432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685121PMC
July 2019

Interleukin-22: friend or foe?

Immunol Cell Biol 2019 04;97(4):355-357

Inflammatory Bowel Disease Group, Mater Research institute-The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.

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http://dx.doi.org/10.1111/imcb.12249DOI Listing
April 2019

Letter: vedolizumab drug concentrations in neonates following intrauterine exposure.

Aliment Pharmacol Ther 2018 12;48(11-12):1328-1330

St Vincent's Hospital, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/apt.15027DOI Listing
December 2018

Personalizing inflammatory bowel disease treatment symposium: Foreward.

Authors:
Jakob Begun

J Gastroenterol Hepatol 2018 Sep;33 Suppl 3

Mater Hospital Brisbane, and Mater Research Institute, University of Queensland, Brisbane, Australia.

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http://dx.doi.org/10.1111/jgh.14414DOI Listing
September 2018

Predictors in inflammatory bowel disease: Looking into the magic ball: Session one summary.

Authors:
Jakob Begun

J Gastroenterol Hepatol 2018 Sep;33 Suppl 3

Mater Hospital Brisbane, and Mater Research Institute, University of Queensland, Brisbane, Australia.

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http://dx.doi.org/10.1111/jgh.14415DOI Listing
September 2018

Positioning biologics-A case-based discussion: Ustekinumab.

Authors:
Jakob Begun

J Gastroenterol Hepatol 2018 Sep;33 Suppl 3:16-17

Mater Hospital Brisbane, and Mater Research Institute, University of Queensland, Brisbane, Australia.

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http://dx.doi.org/10.1111/jgh.14423DOI Listing
September 2018

Selectively targeting the gut in inflammatory bowel disease: Session four summary.

Authors:
Jakob Begun

J Gastroenterol Hepatol 2018 Sep;33 Suppl 3:25

Mater Hospital Brisbane, and Mater Research Institute, University of Queensland, Brisbane, Australia.

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http://dx.doi.org/10.1111/jgh.14430DOI Listing
September 2018