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"Giles, Edward"
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Disease-specific loss of microbial cross-feeding interactions in the human gut
Many gut microorganisms critical to human health rely on nutrients produced by each other for survival; however, these cross-feeding interactions are still challenging to quantify and remain poorly characterized. Here, we introduce a Metabolite Exchange Score (MES) to quantify those interactions. Using metabolic models of prokaryotic metagenome-assembled genomes from over 1600 individuals, MES allows us to identify and rank metabolic interactions that are significantly affected by a loss of cross-feeding partners in 10 out of 11 diseases. When applied to a Crohn’s disease case-control study, our approach identifies a lack of species with the ability to consume hydrogen sulfide as the main distinguishing microbiome feature of disease. We propose that our conceptual framework will help prioritize in-depth analyses, experiments and clinical targets, and that targeting the restoration of microbial cross-feeding interactions is a promising mechanism-informed strategy to reconstruct a healthy gut ecosystem.
Gut microbes rely on nutrient exchange for survival, but these cross-feeding interactions remain poorly characterized. Here, Marcelino et al. present a metabolite-exchange scoring system derived from metagenome-scale metabolic models, designed to identify the potential microbial cross-feeding interactions most affected in human diseases.
Journal Article
The future of faecal transplants
Faecal microbiota transplant (FMT) is now accepted as an effective treatment for Clostridioides difficile infections. With the increasing number of FMT treatments and clinical trials for other indications there is an urgent need for standardized regulations to ensure patient safety and focused development of safer, rationally designed, microbiota-based medicines.
Journal Article
Systematic Review: Practices and Programs in Inflammatory Bowel Disease Transition Care
Adolescents with inflammatory bowel disease (IBD) transitioning to adult care is often deemed a challenging period for patients, their carers, and practitioners. The use of structured transition programs is increasingly incorporated into standards of care, yet the optimal format remains unknown. The aim of this study is to carry out a systematic review of structured transition programs and their components to assess the impact on disease-specific and transition-related outcomes.
A systematic review (PROSPERO ID: CRD42023380846) was performed across 4 databases (PubMed, CINAHL, CENTRAL, and EMBASE) and relevant publications up to March 2023 were reviewed. Studies evaluating either a structured transition program or targeted intervention which also measured a transition- and/or disease-related outcomes were included for evaluation in accordance with the PRISMA statement.
Three thousand four hundred and thirty-two articles were identified and 29 included in the final review. A structured transition program was reported in 21 studies and 8 investigated discrete transition-related interventions. The key transition-related outcomes included knowledge, self-efficacy, adherence, clinic attendance, and transition readiness which overall improved with the use of structured transition programs. Similarly, interventions consistently improved relapse/admission rates and corticosteroid use across most studies, although the benefit in hospitalization and surgical rates was less evident. Methodological limitations alongside heterogeneity in study design and outcome measures impacted on the quality of the evidence as assessed by the GRADE rating.
Transition- and medical-related outcomes for adolescents with IBD have been shown to benefit from structured transition programs but practices vary greatly between centers. There is no current standardized transition model for patients with IBD prompting further research to guide future development of guidelines and models of care.
Journal Article
Recognition of the antigen-presenting molecule MR1 by a Vδ3⁺ γδ T cell receptor
Unlike conventional αβ T cells, γδ T cells typically recognize non-peptide ligands independently of major histocompatibility complex (MHC) restriction. Accordingly, the γδ T cell receptor (TCR) can potentially recognize a wide array of ligands; however, few ligands have been described to date. While there is a growing appreciation of the molecular bases underpinning variable (V)δ1⁺ and Vδ2⁺ γδ TCR-mediated ligand recognition, the mode of Vδ3⁺ TCR ligand engagement is unknown. MHC class I–related protein, MR1, presents vitamin B metabolites to αβ T cells known as mucosal-associated invariant T cells, diverse MR1-restricted T cells, and a subset of human γδ T cells. Here, we identify Vδ1/2⁻ γδ T cells in the blood and duodenal biopsy specimens of children that showed metabolite-independent binding of MR1 tetramers. Characterization of one Vδ3Vγ8 TCR clone showed MR1 reactivity was independent of the presented antigen. Determination of two Vδ3Vγ8 TCR-MR1-antigen complex structures revealed a recognition mechanism by the Vδ3 TCR chain that mediated specific contacts to the side of the MR1 antigen-binding groove, representing a previously uncharacterized MR1 docking topology. The binding of the Vδ3⁺ TCR to MR1 did not involve contacts with the presented antigen, providing a basis for understanding its inherent MR1 autoreactivity. We provide molecular insight into antigen-independent recognition of MR1 by a Vδ3⁺ γδ TCR that strengthens an emerging paradigm of antibody-like ligand engagement by γδ TCRs.
Journal Article
Type 1 Interferon in the Human Intestine—A Co-ordinator of the Immune Response to the Microbiota
The human gut is in constant complex interaction with the external environment. Although much is understood about the composition and function of the microbiota, much remains to be learnt about the mechanisms by which these organisms interact with the immune system in health and disease. Type 1 interferon (T1IFN), a ubiquitous and pleiotropic family of cytokines, is a critical mediator of the response to viral, bacterial, and other antigens sampled in the intestine. Although inflammation is enhanced in mouse model of colitis when T1IFN signaling is lost, the action of T1IFN is context specific and can be pro- or anti-inflammatory. In humans, T1IFN has been used to treat inflammatory diseases, including multiple sclerosis and inflammatory bowel disease but intestinal inflammation can also develop after the administration of T1IFN. Recent findings indicate that “tonic” or “endogenous” T1IFN, induced by signals from the commensal microbiota, modulates the local signaling environment to prime the intestinal mucosal immune system to determine later responses to pathogens and commensal organisms. This review will summarize the complex immunological effects of T1IFN and recent the role of T1IFN as a mediator between the microbiota and the mucosal immune system, highlighting human data wherever possible. It will discuss what we can learn from clinical experiences with T1IFN and how the T1IFN pathway may be manipulated in the future to maintain mucosal homeostasis.
Journal Article
A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1
T cell receptors (TCRs) recognize antigens presented by major histocompatibility complex (MHC) and MHC class I–like molecules. We describe a diverse population of human γδ T cells isolated from peripheral blood and tissues that exhibit autoreactivity to the monomorphic MHC-related protein 1 (MR1). The crystal structure of a γδTCR–MR1–antigen complex starkly contrasts with all other TCR–MHC and TCR–MHC-I-like complex structures. Namely, the γδTCR binds underneath the MR1 antigen-binding cleft, where contacts are dominated by the MR1 α3 domain. A similar pattern of reactivity was observed for diverse MR1-restricted γδTCRs from multiple individuals. Accordingly, we simultaneously report MR1 as a ligand for human γδ T cells and redefine the parameters for TCR recognition.
Journal Article
Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease
Tumor-derived and bacterial phosphoantigens are recognized by unconventional lymphocytes that express a Vγ9Vδ2 T cell receptor (Vδ2 T cells) and mediate host protection against microbial infections and malignancies. Vδ2 T cells are absent in rodents but readily populate the human intestine, where their function is largely unknown. Here, we assessed Vδ2 T cell phenotype and function by flow cytometry in blood and intestinal tissue from Crohn's disease patients (CD patients) and healthy controls. Blood from CD patients included an increased percentage of gut-tropic integrin β7-expressing Vδ2 T cells, while \"Th1-committed\" CD27-expressing Vδ2 T cells were selectively depleted. A corresponding population of CD27+ Vδ2 T cells was present in mucosal biopsies from CD patients and produced elevated levels of TNFα compared with controls. In colonic mucosa from CD patients, Vδ2 T cell production of TNFα was reduced by pharmacological blockade of retinoic acid receptor-α (RARα) signaling, indicating that dietary vitamin metabolites can influence Vδ2 T cell function in inflamed intestine. Vδ2 T cells were ablated in blood and tissue from CD patients receiving azathioprine (AZA) therapy, and posttreatment Vδ2 T cell recovery correlated with time since drug withdrawal and inversely correlated with patient age. These results indicate that human Vδ2 T cells exert proinflammatory effects in CD that are modified by dietary vitamin metabolites and ablated by AZA therapy, which may help resolve intestinal inflammation but could increase malignancy risk by impairing systemic tumor surveillance.
Journal Article
Transitional care of adolescents with inflammatory bowel disease to adult services varies widely across Australia and New Zealand
Background and Aim Children and adolescents account for approximately 14% of inflammatory bowel disease (IBD) diagnoses. At an appropriate age and level of development adolescents with IBD have their care transferred from the pediatric to adult clinical team during a process termed “transition”. The study aim was to survey pediatric gastroenterologists throughout Australasia to identify commonality in the transition process to contribute to standardized guideline development. Methods A descriptive survey captured key variables: transition clinic format, process and infrastructure, transition assessments, and guidelines. The survey was distributed electronically to 59 Pediatric Gastroenterologists throughout Australasia in January 2023. Results Seventeen (29%) clinicians completed the survey: Australia 13 (76%). New Zealand 4 (24%). Thirteen (76%) respondents had access to a dedicated IBD transition clinic. Adolescents attended transition clinics 1–7 times, and the main processes transferred were: prescription provision, biologic appointments, and adult team contacts. Transition was first discussed age 13–15 years (53%), or 16–18 years (47%), with the main discussion topics including: continuing adherence (88%), smoking (59%), alcohol use (59%), recreational drug use (59%). Transition readiness assessments were done infrequently (24%). The minority (24%) used formal guidelines to inform the transition process, but 15 (88%) considered the development of a standardized Australasian guideline as beneficial/extremely beneficial. Conclusions This survey highlighted that transition care for adolescents with IBD is variable across Australasia. Australasian guideline development may optimize the transition process for adolescents with IBD and improve their longitudinal outcomes. A survey of Paediatric Gastroenterologists from across Australia and New Zealand showed that there is great variation between centres in the transition process followed for adolescents with IBD. This lack of standardised care may lead to poor outcomes following transition to adult healthcare services. Clinicians endorsed development of Transition Guidelines to address the current disparities.
Journal Article
Cryptogenic organising pneumonia: an unusual cause of pleuritic chest pain
A 76-year-old woman presented with a 2-hour history of pleuritic chest pain with no other associated symptoms. Blood investigations revealed raised inflammatory markers and an elevated white cell count. On chest radiograph, an airspace shadow indicative of a consolidation was prominent. This was followed by a CT scan of her thorax which showed a spiculated lesion in the right upper lobe, a lesion in the posterior segment of the left lower lobe and mildly enlarged right hilar lymph nodes. She was started on dual antibiotic therapy; however, the patient’s clinical status and inflammatory markers did not improve. A bronchoscopy was performed which excluded malignancy and atypical pathogens. CT-guided biopsy confirmed the presence of cryptogenic organising pneumonia. Prednisolone 50 mg daily was prescribed with quick resolution of symptoms.
Journal Article