188 results on '"Simon Keely"'
Search Results
52. Su1119: STRAIN-LEVEL FUNCTIONAL AND PHENOTYPIC RESOLUTION OF THE DUODENAL MUCOSA-ASSOCIATED MICROBIOTA IN FUNCTIONAL DYSPEPSIA AND HEALTHY CONTROL SUBJECTS VIA A NOVEL EX VIVO COMBINATION OF MICROBE CULTURE AND METAGENOMIC SEQUENCING
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Lauren F. Schooth, Ahmed Sid Ahmed, Seungha Kang, Ayesha Shah, Thomas Fairlie, Jing Jie Teh, Yenkai Lim, Emily C. Hoedt, Nicholas J. Talley, Simon Keely, Gerald J. Holtmann, and Mark Morrison
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Hepatology ,Gastroenterology - Published
- 2022
53. Sa1647: THE MUCOSAL ASSOCIATED MICROBIOTA AS BIOMARKERS OF RISK FOR ANASTOMOTIC LEAK ASSOCIATED WITH COLORECTAL CANCER SURGERY
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Emily C. Hoedt, Samwel Makanyengo, Georgia Carroll, Bree Stephensen, Katie L. Togher, Mark Morrison, Veral Vishnoi, Nicholas J. Talley, Simon Keely, and Peter Pockney
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Hepatology ,Gastroenterology - Published
- 2022
54. Tu1058: DUODENAL EOSINOPHILS AND MAST CELLS IN FUNCTIONAL DYSPEPSIA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF CASECONTROL STUDIES
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Ayesha Shah, Thomas Fairlie, Georgia Brown, Michael P. Jones, Guy D. Eslick, Kerith Duncanson, Nikhil Thaparl, Simon Keely, Natasha A. Koloski, Mohit Shahi, Marjorie M. Walker, Nicholas J. Talley, and Gerald J. Holtmann
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Hepatology ,Gastroenterology - Published
- 2022
55. 334: FUNCTIONAL DYSPEPSIA PATIENTS HAVE IGG ANTIBODIES AGAINST A NOVEL ISOLATE OF STREPTOCOCCUS SALIVARIUS
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Grace L. Burns, Emily C. Hoedt, M Fairuz Jamaluddin, Erin R. Shanahan, Yenkai Lim, Jing Jie Teh, Jessica K. Bruce, Juhura Almazi, Ameha S. Woldu, Matthew D. Dun, Pradeep Tanwar, Michael D. Potter, Kyra Minahan, Jay C. Horvat, Paul S. Foster, Gerald Holtmann, Martin Veysey, Marjorie M. Walker, Mark Morrison, Nicholas J. Talley, and Simon Keely
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Hepatology ,Gastroenterology - Published
- 2022
56. Evidence for Local and Systemic Immune Activation in Functional Dyspepsia and the Irritable Bowel Syndrome: A Systematic Review
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Paul S. Foster, Jay C. Horvat, Grace Burns, Georgia M. Carroll, Nicholas J. Talley, Marjorie M. Walker, Simon Keely, and Andrea Mathe
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medicine.medical_specialty ,Colon ,Duodenum ,Gastrointestinal Diseases ,T-Lymphocytes ,Lymphocyte Activation ,Gastroenterology ,Irritable Bowel Syndrome ,03 medical and health sciences ,Th2 Cells ,0302 clinical medicine ,Gastro ,Internal medicine ,Eosinophilia ,Humans ,Medicine ,Lymphocyte Count ,Mast Cells ,Dyspepsia ,Irritable bowel syndrome ,B-Lymphocytes ,Hepatology ,business.industry ,digestive, oral, and skin physiology ,Increased mast cells ,medicine.disease ,digestive system diseases ,030220 oncology & carcinogenesis ,Th17 Cells ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,Immune activation - Abstract
Subtle histopathologic features such as eosinophilia and increased mast cells have been observed in functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and the irritable bowel syndrome (IBS). The mechanisms that drive recruitment of these cells to the gastrointestinal tract remain unexplained, largely due to the heterogeneity in phenotypes among patients diagnosed with such conditions. We aimed to systematically review the literature and collate the evidence for immune activation in FD and IBS, and where possible, detail the nature of activation.Seven literature databases were searched using the keywords: 'functional gastrointestinal disorder', FGID, 'functional dyspepsia', 'non-ulcer dyspepsia', 'idiopathic dyspepsia', 'irritable bowel syndrome', IBS and 'immun*'.Fifty-one papers reporting discordant immune features met the selection criteria for this review. Changes in lymphocyte populations, including B and T lymphocyte numbers and activation status were reported in IBS and FD, in conjunction with duodenal eosinophilia in FD and increased colonic mast cells in IBS. Increases in circulating α4+β7+ gut-homing T cells appear to be linked to the pathophysiology of both FD and IBS. Studies in the area are complicated by poor phenotyping of patients into subgroups and the subtle nature of the immune activity involved in FD and IBS.Alterations in proportions of gut-homing T lymphocytes in both FD and IBS indicate that a loss of mucosal homeostasis may drive the symptoms of FD and IBS. There is indirect evidence that Th17 responses may play a role in FGIDs, however the evidence for a Th2 immune phenotype in FD and IBS is limited. Although immune involvement is evident, large, well-characterised patient cohorts are required to elucidate the immune mechanisms driving the development of FGIDs.
- Published
- 2018
57. Pharmacological HIF-1 stabilization promotes intestinal epithelial healing through regulation of α-integrin expression and function
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Gang Liu, Kyra Minahan, Jay C. Horvat, Bridie J. Goggins, Wai S. Soh, Simonne Sherwin, Simon Keely, Marjorie M. Walker, Jennifer Pryor, Andrea Mathe, Jessica Bruce, and Darryl A. Knight
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Physiology ,Colon ,Integrin ,Integrin alpha2 ,Integrin alpha6 ,Cell Movement ,Physiology (medical) ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Intestinal Mucosa ,Cell Proliferation ,Mice, Inbred BALB C ,Wound Healing ,Hepatology ,biology ,Gastroenterology & Hepatology ,Chemistry ,Protein Stability ,Gastroenterology ,Prolyl-Hydroxylase Inhibitors ,Colitis ,Hypoxia-Inducible Factor 1, alpha Subunit ,Epithelium ,Cell biology ,Disease Models, Animal ,medicine.anatomical_structure ,0606 Physiology, 1116 Medical Physiology ,Integrin expression ,Trinitrobenzenesulfonic Acid ,Epithelial restitution ,biology.protein ,Female ,Wound healing ,Integrin alpha Chains ,Function (biology) ,Signal Transduction - Abstract
Intestinal epithelia are critical for maintaining gastrointestinal homeostasis. Epithelial barrier injury, causing inflammation and vascular damage, results in inflammatory hypoxia, and thus, healing occurs in an oxygen-restricted environment. The transcription factor hypoxia-inducible factor (HIF)-1 regulates genes important for cell survival and repair, including the cell adhesion protein β1-integrin. Integrins function as αβ-dimers, and α-integrin-matrix binding is critical for cell migration. We hypothesized that HIF-1 stabilization accelerates epithelial migration through integrin-dependent pathways. We aimed to examine functional and posttranslational activity of α-integrins during HIF-1-mediated intestinal epithelial healing. Wound healing was assessed in T84 monolayers over 24 h with/without prolyl-hydroxylase inhibitor (PHDi) (GB-004), which stabilizes HIF-1. Gene and protein expression were measured by RT-PCR and immunoblot, and α-integrin localization was assessed by immunofluorescence. α-integrin function was assessed by antibody-mediated blockade, and integrin α6 regulation was determined by HIF-1α chromatin immunoprecipitation. Models of mucosal wounding and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis were used to examine integrin expression and localization in vivo. PHDi treatment accelerated wound closure and migration within 12 h, associated with increased integrin α2 and α6 protein, but not α3. Functional blockade of integrins α2 and α6 inhibited PHDi-mediated accelerated wound closure. HIF-1 bound directly to the integrin α6 promoter. PHDi treatment accelerated mucosal healing, which was associated with increased α6 immunohistochemical staining in wound-associated epithelium and wound-adjacent tissue. PHDi treatment increased α6 protein levels in colonocytes of TNBS mice and induced α6 staining in regenerating crypts and reepithelialized inflammatory lesions. Together, these data demonstrate a role for HIF-1 in regulating both integrin α2 and α6 responses during intestinal epithelial healing.NEW & NOTEWORTHY HIF-1 plays an important role in epithelial restitution, selectively inducing integrins α6 and α2 to promote migration and proliferation, respectively. HIF-stabilizing prolyl-hydroxylase inhibitors accelerate intestinal mucosal healing by inducing epithelial integrin expression.
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- 2021
58. Mechanisms of Food-Induced Symptom Induction and Dietary Management in Functional Dyspepsia
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Nicholas J. Talley, Grace Burns, Simon Keely, Jennifer Pryor, and Kerith Duncanson
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Dietary assessment ,lcsh:TX341-641 ,Review ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Upper gastrointestinal ,Humans ,030212 general & internal medicine ,Dyspepsia ,Irritable bowel syndrome ,Nutrition and Dietetics ,business.industry ,Gastrointestinal microbiota ,digestive, oral, and skin physiology ,Dietary management ,medicine.disease ,functional dyspepsia ,Diet ,Symptom profiles ,Natural food ,gastrointestinal symptoms ,Food ,030211 gastroenterology & hepatology ,Narrative review ,dietary management ,business ,lcsh:Nutrition. Foods and food supply ,Food Science ,Diet Therapy - Abstract
Functional dyspepsia (FD) is a common disorder of gut-brain interaction, characterised by upper gastrointestinal symptom profiles that differentiate FD from the irritable bowel syndrome (IBS), although the two conditions often co-exist. Despite food and eating being implicated in FD symptom induction, evidence-based guidance for dietetic management of FD is limited. The aim of this narrative review is to collate the possible mechanisms for eating-induced and food-related symptoms of FD for stratification of dietetic management. Specific carbohydrates, proteins and fats, or foods high in these macronutrients have all been reported as influencing FD symptom induction, with removal of ‘trigger’ foods or nutrients shown to alleviate symptoms. Food additives and natural food chemicals have also been implicated, but there is a lack of convincing evidence. Emerging evidence suggests the gastrointestinal microbiota is the primary interface between food and symptom induction in FD, and is therefore a research direction that warrants substantial attention. Objective markers of FD, along with more sensitive and specific dietary assessment tools will contribute to progressing towards evidence-based dietetic management of FD.
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- 2021
59. Genetic Variation in the Bitter Receptors Responsible for Epicatechin Detection Are Associated with BMI in an Elderly Cohort
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Christopher J. Scarlett, Mark Lucock, Emma L. Beckett, Martin Veysey, Simon Keely, and Alexandria Turner
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0301 basic medicine ,Male ,medicine.medical_specialty ,Taste ,obesity ,Aging ,Genotype ,030209 endocrinology & metabolism ,lcsh:TX341-641 ,Overweight ,Polymorphism, Single Nucleotide ,Article ,Catechin ,Body Mass Index ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,BMI ,Eating ,0302 clinical medicine ,Internal medicine ,medicine ,phenol ,Humans ,Receptor ,Aged ,030109 nutrition & dietetics ,Nutrition and Dietetics ,business.industry ,Australia ,Genetic Variation ,epicatechin ,medicine.disease ,Obesity ,bitter ,Minor allele frequency ,Endocrinology ,Cross-Sectional Studies ,Cohort ,taste genetics ,taste receptors ,Female ,medicine.symptom ,business ,Body mass index ,lcsh:Nutrition. Foods and food supply ,Food Science - Abstract
Globally, more than one-third of adults are overweight. Overweight and obesity are complex and multifaceted conditions, associated with an increased risk of chronic illness and early mortality. While there are known risk factors, these alone do not fully explain the varying outcomes between individuals. Recently, taste receptors have been proposed to have a role in the risk for obesity. These receptors are expressed throughout the gastrointestinal tract. In this system, they may be involved in modulating dietary intake and metabolic processes. The taste 2 family of receptors (T2Rs) detects bitter compounds. Receptors T2R4 and T2R5 detect (-)-epicatechin (epicatechin), an antioxidant polyphenol, which may have protective effects against obesity. However, the potential role for taste receptors in this association has not been explored. This study assessed whether polymorphisms in TAS2R4 (rs2233998 and rs2234001) and TAS2R5 (rs2227264) were associated with body mass index (BMI). Genotyping (Taqman qPCR assays) was performed on DNA extracted from blood samples (n = 563) from an elderly cohort. Homozygosity for the minor allele of all polymorphisms was significantly associated with a lower BMI in males. The TAS2R4-rs2233998 CC genotype, the TAS2R4-rs2234001 CC genotype and the TAS2R5-rs2227264 TT genotype were associated with lower BMI (2.1, 2.1 and 2.2 units, p = 0.002, 0.003 and 0.001, respectively). Epicatechin intake was not associated with BMI and genotype was not associated with epicatechin intake. This suggests that the association between TAS2R genotype and elevated BMI risk occurs through altered extra-oral responses and not directly via altered epicatechin intake.
- Published
- 2021
60. γδ Intraepithelial Lymphocytes Facilitate Pathological Epithelial Cell Shedding Via CD103-Mediated Granzyme Release
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Simon Keely, Karen L. Edelblum, Alastair J.M. Watson, Grace Burns, Thomas J. Kelly, Edward M. Bonder, Inga Sandrock, Jonathan Agos, Immo Prinz, Prema M. Nair, David J. Granville, Matthew R. Zeglinski, Mudar Zand Irani, Madeleine D. Hu, Natasha B. Golovchenko, Wai Sinn Soh, and Alexander Lemenze
- Subjects
Lipopolysaccharides ,Male ,Intravital Microscopy ,Apoptosis ,Granzymes ,Mice ,0302 clinical medicine ,Crohn Disease ,Intestinal Mucosa ,Intraepithelial Lymphocytes ,Mice, Knockout ,0303 health sciences ,biology ,Caspase 3 ,Gastroenterology ,Receptors, Antigen, T-Cell, gamma-delta ,hemic and immune systems ,Middle Aged ,Cadherins ,3. Good health ,Jejunum ,medicine.anatomical_structure ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Female ,Tumor necrosis factor alpha ,Integrin alpha Chains ,Intravital microscopy ,Adult ,Adolescent ,Duodenum ,T cell ,chemical and pharmacologic phenomena ,Article ,GZMB ,Young Adult ,03 medical and health sciences ,Antigens, CD ,Ileum ,medicine ,Animals ,Humans ,030304 developmental biology ,Hepatology ,Tumor Necrosis Factor-alpha ,T-cell receptor ,Enterocytes ,Granzyme ,Perforin ,Immunology ,biology.protein ,Intraepithelial lymphocyte - Abstract
Background & Aims: Excessive shedding of apoptotic enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. Based on their cytolytic capacity and surveillance behavior, we investigated whether intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) are actively involved in the shedding of enterocytes into the lumen. Methods: Intravital microscopy was performed on GFP γδ T cell reporter mice treated with intraperitoneal lipopolysaccharide (10 mg/kg) for 90 minutes to induce tumor necrosis factor–mediated apoptosis. Cell shedding in various knockout or transgenic mice in the presence or absence of blocking antibody was quantified by immunostaining for ZO-1 funnels and cleaved caspase-3 (CC3). Granzyme A and granzyme B release from ex vivo–stimulated γδ IELs was quantified by enzyme-linked immunosorbent assay. Immunostaining for γδ T cell receptor and CC3 was performed on duodenal and ileal biopsies from controls and patients with Crohn's disease. Results: Intravital microscopy of lipopolysaccharide-treated mice revealed that γδ IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cadherin, and CD103 knockout or blockade significantly reduced lipopolysaccharide-induced shedding. Furthermore, we found that granzymes A and B, but not perforin, are required for cell shedding. These extracellular granzymes are released by γδ IELs both constitutively and after CD103/E-cadherin ligation. Moreover, we found that the frequency of γδ IEL localization to CC3-positive enterocytes is increased in Crohn's disease biopsies compared with healthy controls. Conclusions: Our results uncover a previously unrecognized role for γδ IELs in facilitating tumor necrosis factor–mediated shedding of apoptotic enterocytes via CD103-mediated extracellular granzyme release.
- Published
- 2022
61. Letter: budesonide for functional dyspepsia with duodenal eosinophilia—randomised, double‐blind, placebo‐controlled parallel‐group trial
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Grace Burns, Michael P. Jones, Raquel Cameron, Tom Fairlie, Nicholas J. Talley, T Hansen, Gerald Holtmann, Simon Keely, Natasha A. Koloski, Alok K. Shah, G Harris, and Marjorie M. Walker
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Budesonide ,Group trial ,medicine.medical_specialty ,Hepatology ,business.industry ,Gastroenterology ,MEDLINE ,Placebo ,Double blind ,Double-Blind Method ,Internal medicine ,Eosinophilia ,Gastroesophageal Reflux ,medicine ,Humans ,Pharmacology (medical) ,Dyspepsia ,medicine.symptom ,business ,medicine.drug - Published
- 2021
62. T-helper 22 cells develop as a distinct lineage from Th17 cells during bacterial infection and phenotypic stability is regulated by T-bet
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Jessica L, Barnes, Maximilian W, Plank, Kelly, Asquith, Steven, Maltby, Lorena R, Sabino, Gerard E, Kaiko, Alyssa, Lochrin, Jay C, Horvat, Jemma R, Mayall, Richard Y, Kim, Philip M, Hansbro, Simon, Keely, Gabrielle T, Belz, Hock L, Tay, and Paul S, Foster
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Mice, Knockout ,Interleukins ,Interleukin-17 ,Cell Differentiation ,Mice, Transgenic ,Bacterial Infections ,Immunophenotyping ,Disease Models, Animal ,Mice ,Gene Expression Regulation ,T-Lymphocyte Subsets ,Host-Pathogen Interactions ,Animals ,Th17 Cells ,Disease Susceptibility ,T-Box Domain Proteins - Abstract
CD4
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- 2020
63. Intense Sweeteners, Taste Receptors and the Gut Microbiome: A Metabolic Health Perspective
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Christopher J. Scarlett, Mark Lucock, Simon Keely, Martin Veysey, Emma L. Beckett, and Alexandria Turner
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Taste ,obesity ,sweetener ,030309 nutrition & dietetics ,Health, Toxicology and Mutagenesis ,Receptor expression ,media_common.quotation_subject ,lcsh:Medicine ,gut microbiome ,030209 endocrinology & metabolism ,Review ,Gut flora ,Bioinformatics ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,0302 clinical medicine ,Taste receptor ,taste receptor ,Glucose homeostasis ,Humans ,Receptor ,media_common ,0303 health sciences ,biology ,Gastrointestinal Microbiome ,lcsh:R ,Public Health, Environmental and Occupational Health ,Appetite ,biology.organism_classification ,Sweetening Agents ,non-nutritive sweetener ,metabolism ,gut hormone - Abstract
Intense sweeteners (IS) are often marketed as a healthier alternative to sugars, with the potential to aid in combating the worldwide rise of diabetes and obesity. However, their use has been counterintuitively associated with impaired glucose homeostasis, weight gain and altered gut microbiota. The nature of these associations, and the mechanisms responsible, are yet to be fully elucidated. Differences in their interaction with taste receptors may be a potential explanatory factor. Like sugars, IS stimulate sweet taste receptors, but due to their diverse structures, some are also able to stimulate bitter taste receptors. These receptors are expressed in the oral cavity and extra-orally, including throughout the gastrointestinal tract. They are involved in the modulation of appetite, glucose homeostasis and gut motility. Therefore, taste genotypes resulting in functional receptor changes and altered receptor expression levels may be associated with metabolic conditions. IS and taste receptors may both interact with the gastrointestinal microbiome, and their interactions may potentially explain the relationship between IS use, obesity and metabolic outcomes. While these elements are often studied in isolation, the potential interactions remain unexplored. Here, the current evidence of the relationship between IS use, obesity and metabolic outcomes is presented, and the potential roles for interactions with taste receptors and the gastrointestinal microbiota in modulating these relationships are explored.
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- 2020
64. Duodenal inflammation: an emerging target for functional dyspepsia?
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Marjorie M. Walker, Matthias Ceulemans, Lucas Wauters, Simon Keely, Tim Vanuytsel, Grace Burns, and Nicholas J. Talley
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0301 basic medicine ,medicine.drug_class ,Clinical Biochemistry ,Antibiotics ,Anti-Inflammatory Agents ,Proton-pump inhibitor ,Inflammation ,Bioinformatics ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Gastrointestinal Agents ,Drug Discovery ,medicine ,Animals ,Humans ,Microbiome ,Molecular Targeted Therapy ,Dyspepsia ,Pharmacology ,Duodenitis ,business.industry ,Therapeutic effect ,medicine.disease ,Pathophysiology ,Abdominal Pain ,030104 developmental biology ,030220 oncology & carcinogenesis ,Molecular Medicine ,medicine.symptom ,business ,Dysbiosis - Abstract
Introduction: Functional dyspepsia (FD) is one of the most common functional gastrointestinal disorders and is classified into postprandial distress and epigastric pain syndrome. Despite the recognition of duodenal inflammation as a potential trigger of symptoms, only limited anti-inflammatory therapies exist.Areas covered: This narrative review summarizes the recent advances in the pathophysiology and treatment of FD; it identifies potential therapeutic targets and gaps in the field. An electronic literature search was conducted in Pubmed up to 31st of December 2019.Expert opinion: There is compelling evidence for the role of duodenal inflammation and the eosinophil-mast cell axis in the pathogenesis of dyspeptic symptoms. Traditional prokinetic drugs and neuromodulators target gastric dysmotility and visceral hypersensitivity but are hampered by limited efficacy and side effects. Independent of acid suppression, the anti-inflammatory action of proton pump inhibitors, which remain the first-line therapy in FD, may also explain their therapeutic effect. Other existing and newly established anti-inflammatory drugs should be investigated while trials including probiotics and selective antibiotics should examine the host microbiome and immune activation. Targeted treatments for potential causes of duodenal pathology, such as impaired permeability and dysbiosis, are likely to emerge in the future.
- Published
- 2020
65. Duodenal bile acids as determinants of intestinal mucosal homeostasis and disease
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Nicholas J. Talley and Simon Keely
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medicine.medical_specialty ,Bile acid ,Endocrine and Autonomic Systems ,Physiology ,medicine.drug_class ,business.industry ,Duodenum ,Stomach ,Gastroenterology ,Bile Acids and Salts ,Immune system ,Endocrinology ,medicine.anatomical_structure ,Intestinal mucosa ,Internal medicine ,medicine ,Animals ,Homeostasis ,Humans ,Microbiome ,Dyspepsia ,business ,Barrier function - Abstract
The duodenal epithelium plays a pivotal role in the uptake and transport of dietary nutrients while simultaneously acting as physical and biochemical barrier to protect against harmful bacteria and antigens. In the case of functional dyspepsia (FD), the duodenum is of particular interest, due to observed local immune involvement and the proximity to the stomach and exposure to acidopeptic secretions. Recent observations in FD pathophysiology, including those reported by Beeckmans et al in this issue of the journal, have identified a loss of barrier function in the duodenal epithelium, an altered duodenal microbiome and alterations in intestinal bile acid pools. Because FD symptoms coincide with food intake and, thus, secretion of bile acids, these findings may indicate loss or imbalance of bile-acid-microbiota-epithelial homeostasis as a process driving FD. Here, we review the evidence linking these observations to FD symptoms.
- Published
- 2020
66. Duodenal bacterial load as determined by quantitative polymerase chain reaction in asymptomatic controls, functional gastrointestinal disorders and inflammatory bowel disease
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Bradley J. Kendall, Natasha A. Koloski, Erin R. Shanahan, Marjorie M. Walker, Michael P. Jones, Ayesha Shah, Graeme A. Macdonald, Mark Morrison, Simon Keely, Nicholas J. Talley, and Gerald Holtmann
- Subjects
Adult ,Male ,medicine.medical_specialty ,Duodenum ,Gastrointestinal Diseases ,Biopsy ,Asymptomatic ,Gastroenterology ,Inflammatory bowel disease ,Polymerase Chain Reaction ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,RNA, Ribosomal, 16S ,Small intestinal bacterial overgrowth ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Aged ,Breath test ,Hepatology ,medicine.diagnostic_test ,Bacteria ,business.industry ,Middle Aged ,medicine.disease ,Inflammatory Bowel Diseases ,Ulcerative colitis ,Bacterial Load ,Real-time polymerase chain reaction ,Glucose ,Breath Tests ,Gastric acid ,030211 gastroenterology & hepatology ,Female ,medicine.symptom ,business - Abstract
Background: Small intestinal bacterial overgrowth may play a role in gastrointestinal and non-gastrointestinal diseases. Aims: To use quantitative polymerase chain reaction (qPCR) to determine and compare bacterial loads of duodenal biopsies in asymptomatic controls, and patients with functional gastrointestinal disorders (FGIDs) and inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD). To define effects of gastric acid inhibition on bacterial load, explore links of bacterial load and gastrointestinal symptoms in response to a standardised nutrient challenge and compare bacterial load with glucose breath test results. Methods: In 237 patients (63 controls, 84 FGID and 90 IBD), we collected mucosal samples under aseptic conditions during endoscopy extracted and total DNA. Bacterial load metric was calculated utilising qPCR measurements of the bacterial 16S rRNA gene, normalised to human beta-actin expression. Standard glucose breath test and nutrient challenge test were performed. Results: The duodenal microbial load was higher in patients with FGID (0.22 ± 0.03) than controls (0.07 ± 0.05; P = 0.007) and patients with UC (0.01 ± 0.05) or CD (0.02 ± 0.09), (P = 0.0001). While patients treated with proton pump inhibitors (PPI) had significantly higher bacterial loads than non-users (P < 0.05), this did not explain differences between patient groups and controls. Bacterial load was significantly (r = 0.21, P < 0.016) associated with the symptom response to standardised nutrient challenge test. Methane, but not hydrogen values on glucose breath test were associated with bacterial load measured utilising qPCR. Conclusions: Utilising qPCR, a diagnosis of FGID and treatment with PPI were independently associated with increased bacterial loads. Increased bacterial loads are associated with an augmented symptom response to a standardised nutrient challenge.
- Published
- 2020
67. Prevalence and Characteristics of Gastrointestinal Symptoms in SARS-CoV-2 Infection: Systematic Review and Meta-Analysis
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Simon Keely, Grace L. Burns, Kening Fan, Wai S. Soh, Georgia Brown, Marjorie M. Walker, Michael Jones, and Nicholas J. Talley
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2019-20 coronavirus outbreak ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Nausea ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,fungi ,body regions ,Internal medicine ,Meta-analysis ,Vomiting ,medicine ,medicine.symptom ,skin and connective tissue diseases ,business - Abstract
Background: Gastrointestinal (GI) manifestations of SARS-CoV-2, designated COVID-19, have been reported, including diarrhoea, nausea, vomiting and abdominal pai
- Published
- 2020
68. Interactions between taste receptors and the gastrointestinal microbiome in inflammatory bowel disease
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Mark Lucock, Christopher J. Scarlett, Emma L. Beckett, Alexandria Turner, Martin Veysey, Simon Keely, and Eileen Chijoff
- Subjects
0301 basic medicine ,Gastrointestinal tract ,Nutrition and Dietetics ,business.industry ,Endocrinology, Diabetes and Metabolism ,Receptor expression ,Gastrointestinal Microbiome ,lcsh:TX341-641 ,medicine.disease ,Inflammatory bowel disease ,lcsh:Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Taste receptor ,Immunology ,medicine ,030211 gastroenterology & hepatology ,lcsh:QD415-436 ,Gastrointestinal function ,business ,Receptor ,Dysbiosis ,lcsh:Nutrition. Foods and food supply ,Food Science - Abstract
Incidence rates of inflammatory bowel disease (IBD) are increasing worldwide. This correlates with increased consumption of red meats, alcohol, refined sugars, oils and animal fats, typical of a “Western” diet. Poor dietary habits are the most ubiquitous environmental factor implicated in IBD, along with gastrointestinal dysbiosis. Taste genetics and oral receptor expression levels determine dietary preferences and therefore, nutritional intake. Taste receptors (TRs) are also expressed throughout the gastrointestinal tract, where they are involved in modulating metabolic processes and gastrointestinal function. Importantly, these receptors are known to be involved in the modulation of inflammatory processes in the respiratory tract. In this system, TRs detect and respond to bacteria and bacterial signalling molecules and initiate protective responses. We propose that TRs play a similar role in the gastrointestinal tract, thereby modulating risk for IBD. TRs may indirectly affect risk for IBD by altering dietary intake, and therefore microbial composition and function. Alternatively, TRs may directly detect and respond to gastrointestinal bacterial components. Overall, there is evidence to suggest an emerging role for TRs in the aetiology of IBD. Furthermore, targeting these receptors via dietary modulation may have therapeutic potential. Keywords: Taste receptors, Nutrition, Microbiome, Inflammatory bowel disease, Diet
- Published
- 2019
69. Reduced deoxyribonuclease enzyme activity in response to high postinjury mitochondrial DNA concentration provides a therapeutic target for Systemic Inflammatory Response Syndrome
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Simon Keely, Daniel J. McIlroy, Philip M. Hansbro, Zsolt J. Balogh, Natalie Lott, Doug W. Smith, and Kyra Minahan
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Multiple Organ Failure ,Critical Care and Intensive Care Medicine ,DNA, Mitochondrial ,Gastroenterology ,03 medical and health sciences ,Injury Severity Score ,0302 clinical medicine ,Interquartile range ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Deoxyribonucleases ,business.industry ,030208 emergency & critical care medicine ,Deoxyribonuclease ,Perioperative ,Middle Aged ,medicine.disease ,Deoxyribonuclease activity ,Emergency & Critical Care Medicine ,Systemic Inflammatory Response Syndrome ,Systemic inflammatory response syndrome ,030104 developmental biology ,Real-time polymerase chain reaction ,Case-Control Studies ,Female ,Surgery ,business ,Cell-Free Nucleic Acids - Abstract
© 2018 Wolters Kluwer Health, Inc. All rights reserved. BACKGROUND Cell-free mitochondrial DNA (mtDNA) is proinflammatory and has been detected in high concentrations in trauma patients' plasma. Deoxyribonuclease (DNAse) is the free plasma enzyme responsible for the digestion of extracellular DNA. The relationship between mtDNA and DNAse after major trauma is unknown. We hypothesized that DNAse activity would be elevated after injury and trauma surgery and would be associated with high concentrations of extracellular DNA. METHODS Two-year prospective study was performed on 103 consecutive trauma patients (male, 81%; age, 38 years [interquartile range, 30-59 years]; injury severity score, 18 [interquartile range, 12-26 years]) who underwent standardized major orthopedic trauma surgical interventions. Blood was collected at five perioperative time points (preoperative, postoperative, 7 hours, 24 hours, and 3 days postoperatively). Healthy control subjects (n = 20) were also sampled. Cell-free mtDNA and nuclear DNA (nDNA) were measured using quantitative polymerase chain reaction. Deoxyribonuclease was also assayed in the same plasma samples. RESULTS Increased levels of mtDNA (from preoperative 163 ± 86 ng/mL to 3 days 282 ± 201 ng/mL, p < 0.0001) and nDNA (from preoperative 28 ± 20 ng/mL to 3 days 37 ± 27 ng/mL, p < 0.05) were present in trauma patients at all perioperative time points compared with healthy controls (mtDNA: 4 ± 2 ng/mL; nDNA: 10 ± 5 ng/mL). Deoxyribonuclease activity was lower in the trauma cohort (from preoperative 0.06 ± 0.04U/mL to 3 days 0.08 ± 0.04U/mL, p < 0.0001) compared with healthy controls (DNAse: 0.17 ± 0.03U/mL). There was no correlation between DNAse and perioperative DNA concentrations. Elevated mtDNA (but not nDNA) correlated with the development of systemic inflammatory response syndrome (SIRS) (p = 0.026) but not multiple organ failure. CONCLUSIONS The significant perioperative elevation in plasma-free mtDNA concentration is associated with the development of SIRS. The fact that increased cell-free DNA concentrations present with significantly lower than healthy control DNAse activity suggests a potential therapeutic opportunity with DNAse administration to modulate postinjury severe SIRS. LEVEL OF EVIDENCE Prognostic/Epidemiological, level II.
- Published
- 2018
70. What’s in a name? ‘Non-coeliac gluten or wheat sensitivity’: controversies and mechanisms related to wheat and gluten causing gastrointestinal symptoms or disease
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Michael D. Potter, Simon Keely, Marjorie M. Walker, and Nicholas J. Talley
- Subjects
Glutens ,Population ,Wheat Hypersensitivity ,Disease ,Inflammatory bowel disease ,Coeliac disease ,Irritable Bowel Syndrome ,03 medical and health sciences ,Global population ,0302 clinical medicine ,Terminology as Topic ,medicine ,Humans ,Enteropathy ,030212 general & internal medicine ,Dyspepsia ,education ,Irritable bowel syndrome ,chemistry.chemical_classification ,education.field_of_study ,business.industry ,Gastroenterology ,nutritional and metabolic diseases ,Eosinophilic Esophagitis ,Inflammatory Bowel Diseases ,medicine.disease ,Gluten ,digestive system diseases ,chemistry ,Immunology ,Dysbiosis ,030211 gastroenterology & hepatology ,business - Abstract
The global population has more than doubled over the past 40 years, supported by the ‘green revolution’ in agriculture producing high-yield grain varieties, including wheat, that are central to the modern diet.1 Wheat covers more than 200 million hectares of land,2 is the third most produced cereal behind rice and maize,3 and is responsible for one-fifth of the world’s calorific input.2 Wheat contains gluten proteins, predominantly made of equal parts of glutenins and gliadins, which are resistant to digestion, and their partially digested epitopes are immunogenic and central to the process that leads to coeliac disease,3 4 an autoimmune condition characterised by an aberrant immune response to ingested gluten in genetically susceptible individuals, which results in small bowel inflammation, enteropathy and potential malabsorption.5 The prevalence of coeliac disease in the past 50 years has risen to approximately 0.7%–2%, a phenomenon attributed to increased awareness and detection, as well as a true increase in prevalence.6 7 The sole and current only curative treatment, a lifelong gluten-free diet, considered central to the management of coeliac disease has also seen increasing popularity in the general population; there is a widespread underlying belief that a gluten-free diet may be ‘healthier’, despite a lack of evidence to support this notion and even evidence that it may be harmful to the non-coeliac population.8 This has seen the gluten-free food industry boom to an estimated US$6 billion per year industry.5 Gluten, or more generally wheat, has also been associated with other GI disease. In the absence of coeliac disease and under the guise of the increasingly fashionable but controversial label ‘non-coeliac gluten/wheat sensitivity’ (NCG/WS), gluten has been popularised in the press as a potential cause of almost all possible conceivable physiological complaints, ranging from GI to neurological, dermatological, psychological and musculoskeletal …
- Published
- 2018
71. IL-6 Drives Neutrophil-Mediated Pulmonary Inflammation Associated with Bacteremia in Murine Models of Colitis
- Author
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Hock L. Tay, Paul S. Foster, Jay C. Horvat, Bridie J. Goggins, Steven Maltby, Philip M. Hansbro, Ellen Marks, Marjorie M. Walker, Sean W. Mateer, Michael Fricker, Kyra Minahan, Andrea Mathe, Grace Burns, Jessica Bruce, Richard Kim, Robert C. Callister, Gang Liu, and Simon Keely
- Subjects
0301 basic medicine ,Chronic bronchitis ,Neutrophils ,Bacteremia ,Systemic inflammation ,Inflammatory bowel disease ,Pathology and Forensic Medicine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Pathology ,Animals ,Medicine ,Colitis ,Interleukin 6 ,Mice, Inbred BALB C ,Bronchiectasis ,biology ,Interleukin-6 ,business.industry ,Dextran Sulfate ,Pneumonia ,medicine.disease ,Neutrophilia ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Immunology ,biology.protein ,Female ,030211 gastroenterology & hepatology ,medicine.symptom ,business - Abstract
© 2018 American Society for Investigative Pathology Inflammatory bowel disease (IBD) is associated with several immune-mediated extraintestinal manifestations. More than half of all IBD patients have some form of respiratory pathology, most commonly neutrophil-mediated diseases, such as bronchiectasis and chronic bronchitis. Using murine models of colitis, we aimed to identify the immune mechanisms driving pulmonary manifestations of IBD. We found increased neutrophil numbers in lung tissue associated with the pulmonary vasculature in both trinitrobenzenesulfonic acid– and dextran sulfate sodium–induced models of colitis. Analysis of systemic inflammation identified that neutrophilia was associated with bacteremia and pyrexia in animal models of colitis. We further identified IL-6 as a systemic mediator of neutrophil recruitment from the bone marrow of dextran sulfate sodium animals. Functional inhibition of IL-6 led to reduced systemic and pulmonary neutrophilia, but it did not attenuate established colitis pathology. These data suggest that systemic bacteremia and pyrexia drive IL-6 secretion, which is a critical driver for pulmonary manifestation of IBD. Targeting IL-6 may reduce neutrophil-associated extraintestinal manifestations in IBD patients.
- Published
- 2018
72. The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing
- Author
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Stephen J. Keely, Bridie J. Goggins, Simon Keely, Magdalena S. Mroz, and Natalia Lajczak
- Subjects
0301 basic medicine ,Transcription, Genetic ,Colon ,Physiology ,medicine.drug_class ,Cystic Fibrosis Transmembrane Conductance Regulator ,Receptors, Cytoplasmic and Nuclear ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,Physiology (medical) ,medicine ,Animals ,Humans ,Intestinal Mucosa ,Promoter Regions, Genetic ,Cell Proliferation ,Wound Healing ,Hepatology ,Bile acid ,Ursodeoxycholic Acid ,Deoxycholic acid ,Gastroenterology ,G protein-coupled bile acid receptor ,Epithelium ,Ursodeoxycholic acid ,3. Good health ,Mice, Inbred C57BL ,HEK293 Cells ,Retinoid X Receptors ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Female ,030211 gastroenterology & hepatology ,Farnesoid X receptor ,Wound healing ,Deoxycholic Acid ,Signal Transduction ,medicine.drug - Abstract
The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial restitution. Wound healing in T84cell monolayers grown on transparent, permeable supports was assessed over 48 h with or without bile acids. Cell migration was measured in Boyden chambers. mRNA and protein expression were measured by RT-PCR and Western blotting. DCA (50–150 µM) significantly inhibited wound closure in cultured epithelial monolayers and attenuated cell migration in Boyden chamber assays. DCA also induced nuclear accumulation of the farnesoid X receptor (FXR), whereas an FXR agonist, GW4064 (10 µM), inhibited wound closure. Both DCA and GW4064 attenuated the expression of CFTR Cl−channels, whereas inhibition of CFTR activity with either CFTR-inh-172 (10 µM) or GlyH-101 (25 µM) also prevented wound healing. Promoter/reporter assays revealed that FXR-induced downregulation of CFTR is mediated at the transcriptional level. In contrast, UDCA (50–150 µM) enhanced wound healing in vitro and prevented the effects of DCA. Finally, DCA inhibited and UDCA promoted mucosal healing in an in vivo mouse model. In conclusion, these studies suggest bile acids are important regulators of epithelial wound healing and are therefore good targets for development of new drugs to modulate intestinal barrier function in disease treatment.NEW & NOTEWORTHY The secondary bile acid, deoxycholic acid, inhibits colonic epithelial wound healing, an effect which appears to be mediated by activation of the nuclear bile acid receptor, FXR, with subsequent downregulation of CFTR expression and activity. In contrast, ursodeoxycholic acid promotes wound healing, suggesting it may provide an alternative approach to prevent the losses of barrier function that are associated with mucosal inflammation in IBD patients.
- Published
- 2018
73. A Rodent Model of Anxiety: The Effect of Perinatal Immune Challenges on Gastrointestinal Inflammation and Integrity
- Author
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Jessica Bruce, Pedro Garcia-Sobrinho, Lauren Harms, Sharon L. Hollins, Rafael Barreto, Simon Keely, Luke Brock, Marjorie M. Walker, Deborah M. Hodgson, Phillip W. Dickson, and Ariel Dunn
- Subjects
Male ,0301 basic medicine ,Offspring ,Immunology ,Gut–brain axis ,Inflammation ,Anxiety ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Immune system ,Neurochemical ,Pregnancy ,medicine ,Animals ,Rats, Wistar ,Maze Learning ,Tight junction ,Endocrine and Autonomic Systems ,business.industry ,Rats ,Gastrointestinal Tract ,Disease Models, Animal ,Poly I-C ,030104 developmental biology ,Neurology ,Prenatal Exposure Delayed Effects ,Gestation ,Female ,Inflammation Mediators ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Objectives: Gastrointestinal (GI) inflammation and GI integrity deficits are common comorbidities of neuropsychiatric disorders. Ongoing research suggests that these aberrations may be contributing to heightened immune signals that have the potential to disrupt neuronal homeostasis and exacerbate behavioural deficits. The current study aimed to determine whether the well-characterized animal model of neuropsychopathology, the maternal immune activation (MIA) model, produced GI inflammation and integrity disruptions in association with anxiety-like behaviour. Methods: Pregnant Wistar rats were exposed to the viral mimetic polyriboinosinic:polyribocytidilic acid (polyI:C) on gestational days (GD) 10 and 19. Evidence of ANS activation, GI inflammation, and GI barrier integrity was assessed in both neonatal (postnatal day, P7) and adult (P84) offspring. Anxiety-like behaviour was assessed at P100. Results: Neonatal MIA offspring exhibited an altered intestinal inflammatory profile and evidence of an increase in lymphoid aggregates. MIA neonates also displayed disruptions to GI barrier tight junction protein mRNA. In addition, adult MIA offspring exhibited an increase in anxiety-like behaviours. Conclusion: These results indicate that the MIA rat model, which is well documented to produce behavioural, neurochemical, and neuroanatomical abnormalities, also produces GI inflammation and integrity disruptions. We suggest that this model may be a useful tool to elucidate biological pathways associated with neuropsychiatric disorders.
- Published
- 2018
74. In the ZOne: How Impedance Facilitates Progress in Functional Dyspepsia Research
- Author
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Nicholas J. Talley and Simon Keely
- Subjects
medicine.medical_specialty ,Duodenum ,Physiology ,business.industry ,Gastroenterology ,MEDLINE ,Hepatology ,medicine.anatomical_structure ,Transplant surgery ,Gastritis ,Internal medicine ,Electric Impedance ,Gastroesophageal Reflux ,medicine ,Humans ,Dyspepsia ,medicine.symptom ,business - Published
- 2019
75. 463 ALLERGIC-LIKE EFFECTOR MEMORY T HELPER (TH) 2 AND AUTOIMMUNE-LIKE TH17.1 CELL POPULATIONS ARE INCREASED IN THE DUODENUM OF PATIENTS WITH FUNCTIONAL DYSPEPSIA
- Author
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Grace Burns, Jessica Bruce, Marjorie M. Walker, Martin Veysey, Kyra Minahan, Raquel Cameron, Bridie J. Goggins, Simon Keely, Michael D. Potter, Andrea Mathe, Nick Powell, Jay C. Horvat, Paul S. Foster, Nicholas J. Talley, Prema M. Nair, Gerald Holtmann, and Crystal Naudin
- Subjects
medicine.anatomical_structure ,Hepatology ,Effector ,business.industry ,Cell ,Immunology ,Gastroenterology ,medicine ,Duodenum ,business - Published
- 2021
76. 468 PHARMACOLOGICAL HIF-1 STABILIZATION PROMOTES INTESTINAL EPITHELIAL HEALING THROUGH REGULATION OF α-INTEGRIN EXPRESSION AND FUNCTION
- Author
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Simon Keely, Nicholas J. Talley, Kyra Minahan, Simonne Sherwin, Gang Liu, Bridie J. Goggins, Marjorie M. Walker, Wai S. Soh, Jay C. Horvat, Darryl A. Knight, Jessica Bruce, Jennifer Pryor, and Andrea Mathe
- Subjects
Hepatology ,Integrin expression ,Chemistry ,Gastroenterology ,Function (biology) ,Cell biology - Published
- 2021
77. Fr561 COLONIC SPIROCHETES AND GASTROINTESTINAL PATHOLOGY AND SYMPTOMS: A META-ANALYSIS OF CASE-CONTROL STUDIES
- Author
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Nicholas J. Talley, Simon Keely, Guy D. Eslick, Kening Fan, Prema M. Nair, and Grace Burns
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Meta-analysis ,Internal medicine ,Gastroenterology ,Case-control study ,Medicine ,Gastrointestinal pathology ,business - Published
- 2021
78. Fr237 MUCOSAL EFFECTOR T HELPER 17 RESPONSES TO GLUTEN STIMULATION ARE ASSOCIATED WITH GENE EXPRESSION OF TRAV26-2, A GLIADIN-BIASED T CELL RECEPTOR VARIANT IN PATIENTS WITH FUNCTIONAL DYSPEPSIA
- Author
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Kerith Duncanson, Jay C. Horvat, Jessica Bruce, Grace Burns, Nicholas J. Talley, Jessica L. Barnes, Gerald Holtmann, Simon Keely, Michael D. Potter, Kyra Minahan, Andrea Mathe, Martin Veysey, Nick Powell, Annalisa Cuskelly, Marjorie M. Walker, and Paul S. Foster
- Subjects
chemistry.chemical_classification ,Hepatology ,Effector ,T-cell receptor ,Gastroenterology ,Stimulation ,Biology ,Gluten ,chemistry ,Immunology ,Gene expression ,biology.protein ,In patient ,Gliadin - Published
- 2021
79. Altered intrinsic and synaptic properties of lumbosacral dorsal horn neurons in a mouse model of colitis
- Author
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Brett A. Graham, Alan M. Brichta, Marjorie M. Walker, Simon Keely, Robert J. Callister, and Kristen E. Farrell
- Subjects
Male ,0301 basic medicine ,Sacrum ,Patch-Clamp Techniques ,Colon ,Action Potentials ,Stimulation ,macromolecular substances ,Inhibitory postsynaptic potential ,03 medical and health sciences ,0302 clinical medicine ,Physical Stimulation ,Spinal Cord Dorsal Horn ,medicine ,Animals ,Colitis ,Posterior Horn Cell ,Skin ,Lumbar Vertebrae ,business.industry ,General Neuroscience ,Rectum ,Excitatory Postsynaptic Potentials ,Visceral pain ,Visceral Pain ,Spinal cord ,medicine.disease ,Mice, Inbred C57BL ,Posterior Horn Cells ,Disease Models, Animal ,Electrophysiology ,030104 developmental biology ,medicine.anatomical_structure ,Trinitrobenzenesulfonic Acid ,Acute Disease ,medicine.symptom ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Visceral pain in inflammatory and functional gastrointestinal conditions is a major clinical problem. The exact mechanisms underlying the development of pain, during and after visceral inflammation are unknown. However, clinical and pre-clinical evidence suggests plasticity within the spinal cord dorsal horn is a contributing factor. Here we use an in vivo preparation and patch-clamp electrophysiology to test whether the synaptic and intrinsic properties of superficial dorsal horn (SDH) neurons are altered 5days after the induction of mild colitis in adult male mice (i.e. during acute inflammation of the colon). Whole-cell recordings were made from lumbosacral (L6-S1) superficial dorsal horn neurons (SDH), in animals under isoflurane anesthesia. Noxious colorectal distension (CRD) was used to identify SDH neurons with colonic inputs, while stimulation of the hind paw and tail was employed to assess convergent cutaneous input. Following inflammation, a significantly increased proportion of SDH neurons received both colonic and cutaneous inputs, compared to neurons in naïve animals. In addition, the nature and magnitude of responses to CRD and cutaneous stimulation differed in inflamed animals, as was spontaneous excitatory synaptic drive. Conversely, several measures of intrinsic excitability were altered in a manner that would decrease SDH network excitability following colitis. We propose that during inflammation, sensitization of colonic afferents results in increased signaling to the SDH. This is accompanied by plasticity in SDH neurons whereby their intrinsic properties are changed to compensate for altered afferent activity.
- Published
- 2017
80. The Alignment of Dietary Intake and Symptom-Reporting Capture Periods in Studies Assessing Associations between Food and Functional Gastrointestinal Disorder Symptoms: A Systematic Review
- Author
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Tracy Burrows, Kerith Duncanson, Marjorie M. Walker, Gayatri Das, Simon Keely, Michael D. Potter, and Nicholas J. Talley
- Subjects
medicine.medical_specialty ,Dietary assessment ,Gastrointestinal Diseases ,Symptom reporting ,lcsh:TX341-641 ,Review ,03 medical and health sciences ,0302 clinical medicine ,Functional gastrointestinal disorder ,systematic review ,Internal medicine ,Humans ,Medicine ,Ingestion ,Irritable bowel syndrome ,irritable bowel syndrome ,Nutrition and Dietetics ,business.industry ,Dietary intake ,dietary assessment ,Feeding Behavior ,functional gastrointestinal disorder ,medicine.disease ,functional dyspepsia ,Diet ,Food ,030220 oncology & carcinogenesis ,030211 gastroenterology & hepatology ,business ,lcsh:Nutrition. Foods and food supply ,Food Science ,Systematic search - Abstract
Food ingestion is heavily implicated in inducing symptoms of irritable bowel syndrome (IBS) and functional dyspepsia (FD), which affect over one-third of adults in developed countries. The primary aim of this paper was to assess the alignment of dietary assessment and symptom-reporting capture periods in diet-related studies on IBS or FD in adults. Secondary aims were to compare the degree of alignment, validity of symptom-reporting tools and reported significant associations between food ingestion and symptoms. A five-database systematic literature search resulted in 40 included studies, from which data were extracted and collated. The food/diet and symptom capture periods matched exactly in 60% (n = 24/40) of studies, overlapped in 30% (n = 12/40) of studies and were not aligned in 10% (n = 4/40) of studies. Only 30% (n = 12/40) of studies that reported a significant association between food and global gastrointestinal symptoms used a validated symptom-reporting tool. Of the thirty (75%) studies that reported at least one significant association between individual gastrointestinal symptoms and dietary intake, only four (13%) used a validated symptom tool. Guidelines to ensure that validated symptom-reporting tools are matched with fit-for-purpose dietary assessment methods are needed to minimise discrepancies in the alignment of food and symptom tools, in order to progress functional gastrointestinal disorder research.
- Published
- 2019
81. Systematic Review on the Influence of Tissue Oxygenation on Gut Microbiota and Anastomotic Healing
- Author
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Georgia M. Carroll, Bridie J. Goggins, Peter Pockney, Samwel Makanyengo, Stephen R. Smith, and Simon Keely
- Subjects
medicine.medical_specialty ,Context (language use) ,Anastomotic Leak ,Gut flora ,Anastomosis ,Hyperoxia ,Gastroenterology ,Hypercapnia ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Animals ,Humans ,Microbiome ,Intestinal Mucosa ,Hypoxia ,Wound Healing ,biology ,business.industry ,Anastomosis, Surgical ,Hypoxia (medical) ,biology.organism_classification ,Oxygen tension ,Gastrointestinal Microbiome ,Oxygen ,Disease Models, Animal ,030220 oncology & carcinogenesis ,030211 gastroenterology & hepatology ,Surgery ,medicine.symptom ,business - Abstract
Background Anastomotic leak rates have not improved over several decades despite improvements in surgical techniques and patient care. The gut microbiome has been implicated in the development of leaks. The exact mechanisms by which tissue oxygenation affects gut microbial composition and anastomotic healing physiology are unclear. Also, commonly used carbon dioxide (CO2) is a known vasodilator that improves tissue oxygen tension. We performed a systematic review to determine the influence of hyperoxia, hypoxia, and hypercapnia on the gut microbiome and anastomotic healing. Methods A literature search was performed in MEDLINE, EMBASE, and COCHRANE to identify studies investigating the effects of hyperoxia, hypoxia, and hypercapnia on anastomotic healing and gut microbiota published between 1998 and 2018. Two reviewers screened the articles for eligibility and quality. Fifty-three articles underwent full text review, and a narrative synthesis was undertaken. Results Hyperoxia is associated with better anastomotic healing, increased gastrointestinal oxygen tension, and may reduce gut anaerobes. Hypoxia is associated with poor healing and increased gut anaerobes. However, it is unclear if hypoxia is the most important predictor of anastomotic leaks. Low pressure CO2 pneumoperitoneum and mild systemic hypercapnia are both associated with increased gastrointestinal oxygen tension and may improve anastomotic healing. We found no studies which investigated the effect of hypercapnia on gut microbiota in the context of anastomotic healing. Conclusions Tissue oxygenation influences gut anastomotic healing, but little evidence exists to demonstrate the influence on the gut microbiome in the context of healing. Further studies are needed to determine if anastomotic microbiome changes with altered tissue oxygenation and if this affects healing and leak rates. If confirmed, altering tissue oxygenation through hyperoxia or hypercapnia could be feasible means of altering the microbiome such that anastomotic leak rates reduce.
- Published
- 2019
82. Effects of Antibiotic Therapy in Primary Sclerosing Cholangitis with and without Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis
- Author
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Nicholas J. Talley, Peter Lewindon, Katherine A. Stuart, Neal Martin, Gerald Holtmann, Michael P. Jones, Marjorie M. Walker, Ayesha Shah, Mark Morrison, Darrel Crawford, Graeme A. Macdonald, Daniel Burger, Simon Keely, and Caroline Tallis
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.drug_class ,Antibiotics ,Cholangitis, Sclerosing ,Inflammatory bowel disease ,Gastroenterology ,Primary sclerosing cholangitis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Adverse effect ,Crohn's disease ,Framingham Risk Score ,Hepatology ,business.industry ,Bilirubin ,medicine.disease ,Alkaline Phosphatase ,Inflammatory Bowel Diseases ,Ulcerative colitis ,Anti-Bacterial Agents ,030104 developmental biology ,Vancomycin ,030211 gastroenterology & hepatology ,business ,medicine.drug - Abstract
The authors conducted a systematic review and meta-analysis to assess the effect of antibiotic therapy in primary sclerosing cholangitis (PSC). Effect of antibiotic therapy on Mayo PSC Risk Score (MRS), serum alkaline phosphatase (ALP), total serum bilirubin (TSB), and adverse events (AEs) rates were calculated and expressed as standardized difference of means or proportions. Five studies including 124 PSC patients who received antibiotics were included. Overall, antibiotic treatment was associated with a statistically significant reduction in ALP, MRS, and TSB by 33.2, 36.1, and 28.8%, respectively. ALP reduction was greatest for vancomycin (65.6%, p
- Published
- 2019
83. Platelet activating factor receptor acts to limit colitis-induced liver inflammation
- Author
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Marie J. Parsons, Geoffrey W. McCaughan, Prema M. Nair, Brett Nixon, Rachel Neal, Samwel Makanyengo, David A. Skerrett-Byrne, Jinbiao Chen, Phil M. Hansbro, Andrea Mathe, Hock L. Tay, Sean P. Colgan, Gerald Holtmann, Alan W. Baird, Simon Keely, Wai S. Soh, Bridie J. Goggins, Kyra Minahan, Kening Fan, and Gang Liu
- Subjects
0301 basic medicine ,Male ,Colon ,Inflammasomes ,Kupffer Cells ,Interleukin-1beta ,Inflammation ,Platelet Membrane Glycoproteins ,Biochemistry ,Inflammatory bowel disease ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,Mice ,0302 clinical medicine ,NLR Family, Pyrin Domain-Containing 3 Protein ,Genetics ,medicine ,Animals ,Humans ,Colitis ,Receptor ,Molecular Biology ,Cells, Cultured ,biology ,Sirtuin 1 ,business.industry ,Caspase 1 ,Dextran Sulfate ,Interleukin ,Inflammasome ,medicine.disease ,Inflammatory Bowel Diseases ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,030104 developmental biology ,Liver ,biology.protein ,Cancer research ,Hepatocytes ,Platelet-activating factor receptor ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Biotechnology ,medicine.drug - Abstract
Liver inflammation is a common extraintestinal manifestation in inflammatory bowel disease (IBD), yet, the mechanisms driving gut-liver axis inflammation remain poorly understood. IBD leads to a breakdown in the integrity of the intestinal barrier causing an increase in portal and systemic gut-derived antigens, which challenge the liver. Here, we examined the role of platelet activating factor receptor (PAFR) in colitis-associated liver damage using dextran sulfate sodium (DSS) and anti-CD40-induced colitis models. Both DSS and anti-CD40 models exhibited liver inflammation associated with colitis. Colitis reduced global PAFR protein expression in mouse livers causing an exclusive re-localization of PAFR to the portal triad. The global decrease in liver PAFR was associated with increased sirtuin 1 while relocalized PAFR expression was limited to Kupffer cells (KCs) and co-localized with toll-like receptor 4. DSS activated the NLRP3-inflammasome and increased interleukin (IL)-1β in the liver. Antagonism of PAFR amplified the inflammasome response by increasing NLRP3, caspase-1, and IL-1β protein levels in the liver. LPS also increased NLRP3 response in human hepatocytes, however, overexpression of PAFR restored the levels of NLPR3 and caspase-1 proteins. Interestingly, KCs depletion also increased IL-1β protein in mouse liver after DSS challenge. These data suggest a protective role for PAFR-expressing KCs during colitis and that regulation of PAFR is important for gut-liver axis homeostasis.
- Published
- 2019
84. Isolation and In Vitro Culture of Human Gut Progenitor Cells
- Author
-
Jessica, Bruce, Gerard E, Kaiko, and Simon, Keely
- Subjects
Intestines ,Organoids ,Culture Media, Conditioned ,Stem Cells ,Cell Culture Techniques ,Humans ,Epithelial Cells ,Cell Proliferation - Abstract
The gastrointestinal epithelium is a highly regenerative organ, where each cell is replaced in a cycle of 4-6 days, depending on the mammalian species. This highly proliferative state is driven by gastrointestinal stem and progenitor cells, located at the base of crypts. These cells give rise to at least six types of differentiated epithelial cells, each with a distinct function in maintaining homeostasis between the intestinal interface and the luminal environment. The isolation and culture of these cells from mammalian gastrointestinal tissue is a novel technique, which allows for the generation and maintenance of an in vitro culture system for adult epithelial cells. There are two predominant methods for isolation and propagation of gastrointestinal epithelial cells, the first is the organoid system developed in 2009, and the second is a later version known as the L-WRN spheroid system. In this chapter, we describe the method to isolate and culture human gastrointestinal stem and progenitor cells and culture them as three-dimensional spheroids using L-WRN cell conditioned media.
- Published
- 2019
85. Follow up on atopy and the gastrointestinal tract - a review of a common association 2018
- Author
-
Marjorie M. Walker, Nicholas J. Talley, and Simon Keely
- Subjects
Gastrointestinal Diseases ,Atopy ,03 medical and health sciences ,0302 clinical medicine ,Food allergy ,Risk Factors ,medicine ,Hypersensitivity ,Animals ,Humans ,Genetic Predisposition to Disease ,Microbiome ,Sensitization ,Gastrointestinal tract ,Hepatology ,business.industry ,Effector ,fungi ,Gastroenterology ,food and beverages ,Gastrointestinal inflammation ,Allergens ,medicine.disease ,Prognosis ,Gastrointestinal Microbiome ,body regions ,Gastrointestinal Tract ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,030211 gastroenterology & hepatology ,business - Abstract
Primary atopic disorders can be classified as heritable genetic disorders presenting with deregulated pathogenic allergic effector responses irrespective of sensitization. In the last decade, there are parallel rises in the burden of atopic and gastrointestinal (GI) diseases. Areas covered: There is increasing recognition of an association between atopy and GI disease through immune dysregulation, the microbiome and shared genetic pathways. Since the first article on atopy and the GI tract in 2014 in this journal, many more studies have shed light on the shared pathways in these diseases, particularly in the field of eosinophilic GI disease, functional GI disorders, and inflammatory bowel disease. Expert opinion: Understanding the links with common mechanisms in atopy and GI diseases that may lead to better targeting of treatment through manipulation of immune mechanisms, the microbiome, genetics, food allergens and specific GI diseases such as inflammatory bowel disease, functional GI disorders.
- Published
- 2019
86. Microbiome-focused asthma management strategies
- Author
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Kamal Dua, Shastri, Malik Quasir Mahmood, Nicole G. Hansbro, Gregory M. Peterson, Philip M. Hansbro, Wai Chin Chong, Kurtis F. Budden, Rajaraman Eri, Rahul P. Patel, Shakti D. Shukla, and Simon Keely
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Disease ,Asthma management ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Health care ,medicine ,Animals ,Humans ,In patient ,Microbiome ,Intensive care medicine ,Lung ,Asthma ,Pharmacology ,Asthma therapy ,High prevalence ,business.industry ,Microbiota ,medicine.disease ,respiratory tract diseases ,Intestines ,030104 developmental biology ,business - Abstract
Asthma is a common, heterogeneous and serious disease with high prevalence globally. Poorly controlled, steroid-resistant asthma is particularly important as there are no effective therapies and it exerts substantial healthcare and societal burden. The role of microbiomes, particularly in chronic diseases has generated considerable interest in recent times. Existing evidence clearly demonstrates an association between asthma initiation and the microbiome, both respiratory and gastro-intestinal, although its' roles are poorly understood when assessing the asthma progression or heterogeneity (i.e. phenotypes/endotypes) across different geographical locations. Moreover, modulating microbiomes could be preventive and/or therapeutic in patients with asthma warrants urgent attention. Here, we review recent advances in assessing the role of microbiomes in asthma and present the challenges associated with the potential therapeutic utility of modifying microbiomes in management.
- Published
- 2019
87. Incidence and prevalence of self-reported non-coeliac wheat sensitivity and gluten avoidance in Australia
- Author
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Nicholas J Talley Ac, Michael D. Potter, Natasha A. Koloski, Marjorie M. Walker, Michael P. Jones, Simon Keely, and Gerald Holtmann
- Subjects
Adult ,Male ,medicine.medical_specialty ,Glutens ,Adult population ,Wheat Hypersensitivity ,Coeliac disease ,New onset ,Irritable Bowel Syndrome ,03 medical and health sciences ,Diet, Gluten-Free ,0302 clinical medicine ,Internal medicine ,medicine ,Prevalence ,Humans ,030212 general & internal medicine ,Longitudinal Studies ,Dyspepsia ,Irritable bowel syndrome ,Aged ,Response rate (survey) ,chemistry.chemical_classification ,business.industry ,Incidence (epidemiology) ,Incidence ,General Medicine ,Middle Aged ,medicine.disease ,Gluten ,Celiac Disease ,Logistic Models ,chemistry ,Female ,Abdominal symptoms ,Self Report ,New South Wales ,business - Abstract
Objectives: To determine the incidence of self-reported non-coeliac wheat sensitivity (SR-NCWS) and factors associated with its onset and resolution; to describe the prevalence of factors associated with gluten avoidance. Design: Longitudinal cohort study; analysis of responses to self-administered validated questionnaires (Digestive Health and Wellbeing surveys, 2015 and 2018). Setting, participants: Subset of an adult population sample randomly selected in 2015 from the electoral rolls for the Newcastle and Gosford regions of New South Wales. Main outcome measures: Prevalence of SR-NCWS (2015, 2018) and incidence and resolution of SR-NCWS, each by demographic and medical factors; prevalence of gluten avoidance and reasons for gluten avoidance (2018). Results: 1322 of 2185 eligible participants completed the 2018 survey (response rate, 60.5%). The prevalence of SR-NCWS was similar in 2015 (13.8%; 95% CI, 12.0–15.8%) and 2018 (13.9%; 95% CI, 12.1–15.9%); 69 of 1301 respondents (5.3%) reported developing new onset (incident) SR-NCWS between 2015 and 2018 (incidence, 1.8% per year). Incident SR-NCWS was significantly associated with a diagnosis of functional dyspepsia, and negatively associated with being male or older. Gluten avoidance was reported in 2018 by 24.2% of respondents (20.5% partial, 3.8% complete avoidance); general health was the most frequent reason for avoidance (168 of 316 avoiders, 53%). All 13 participants with coeliac disease, 56 of 138 with irritable bowel syndrome (41%), and 69 of 237 with functional dyspepsia (29%) avoided dietary gluten. Conclusions: The prevalence of SR-NCWS was similar in 2015 and 2018. Baseline (2015) and incident SR-NCWS (2018) were each associated with functional gastrointestinal disorders. The number of people avoiding dietary gluten exceeds that of people with coeliac disease or SR-NCWS, and general health considerations and abdominal symptoms are the most frequently reported reasons for avoidance.
- Published
- 2019
88. Does Surgery Generate Neutrophil Extracellular Traps that Influence Colorectal Cancer Progression? A Systematic Review
- Author
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Grace Burns, Simon Keely, Marjorie M. Walker, Andrea Mathe, Stephen R. Smith, Peter Pockney, Joel Petit, and Georgia M. Carroll
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,Cancer ,Perioperative ,Neutrophil extracellular traps ,Disease ,medicine.disease ,Systemic inflammation ,Metastasis ,Sepsis ,Internal medicine ,medicine ,medicine.symptom ,business - Abstract
Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Almost half of those that have a potentially curative resection go on to develop metastatic disease. A recognised risk for recurrence is perioperative systemic inflammation and sepsis. Neutrophil extracellular traps (NETs) have been implicated as promotors of tumour progression. We aimed to examine the evidence in the literature for an association between NETs and postoperative metastasis in CRC. Materials and Methods: Studies published between 2000 and December 2018 that examined the role of NETs in sepsis and inflammation in CRC and in relation to tumour-related outcomes were identified through a database search of Cochrane, CINAHL and MEDLINE.Quality and bias assessment was carried out by two reviewers. Results: Of 8,940 screened, Of the 30 studies included, 21 were observational, 5 in vivo experimental, 1 in vitro and 3 used a combination of these approaches. There is clear evidence from the literature that presence of a pre-operative systemic inflammatory response predicts cancer recurrence following potentially curative resection, but the evidence for association of sepsis and progression is lacking. Conclusions: There is robust experimental evidence in murine models showing that NETs are present in sepsis and are associated with cancer progression. Some human observational studies corroborate the prognostic significance of NETs in progression of CRC. Further human studies are needed to translate the experimental evidence and to definitively associate sepsis and NETs with poor colorectal cancer-specific outcomes.
- Published
- 2019
89. Isolation and In Vitro Culture of Human Gut Progenitor Cells
- Author
-
Jessica Bruce, Simon Keely, and Gerard E. Kaiko
- Subjects
0303 health sciences ,Cell ,Spheroid ,Biology ,Gastrointestinal epithelium ,In vitro ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,medicine ,Organoid ,Progenitor cell ,030217 neurology & neurosurgery ,Function (biology) ,Homeostasis ,030304 developmental biology - Abstract
The gastrointestinal epithelium is a highly regenerative organ, where each cell is replaced in a cycle of 4-6 days, depending on the mammalian species. This highly proliferative state is driven by gastrointestinal stem and progenitor cells, located at the base of crypts. These cells give rise to at least six types of differentiated epithelial cells, each with a distinct function in maintaining homeostasis between the intestinal interface and the luminal environment. The isolation and culture of these cells from mammalian gastrointestinal tissue is a novel technique, which allows for the generation and maintenance of an in vitro culture system for adult epithelial cells. There are two predominant methods for isolation and propagation of gastrointestinal epithelial cells, the first is the organoid system developed in 2009, and the second is a later version known as the L-WRN spheroid system. In this chapter, we describe the method to isolate and culture human gastrointestinal stem and progenitor cells and culture them as three-dimensional spheroids using L-WRN cell conditioned media.
- Published
- 2019
90. A Role for Primary Care Pharmacists in the Management of Inflammatory Bowel Disease? Lessons from Chronic Disease: A Systematic Review
- Author
-
Kerith Duncanson, Ayesha Shah, Marjorie M. Walker, Therese Kairuz, Simon Keely, Sharmila S Prasad, Nicholas J. Talley, and Gerald Holtmann
- Subjects
medicine.medical_specialty ,pharmacist ,Psychological intervention ,Pharmacist ,lcsh:RS1-441 ,Review ,Disease ,Type 2 diabetes ,Inflammatory bowel disease ,lcsh:Pharmacy and materia medica ,primary care ,03 medical and health sciences ,0302 clinical medicine ,Patient satisfaction ,Quality of life (healthcare) ,inflammatory bowel disease ,medicine ,Pharmacology (medical) ,030212 general & internal medicine ,General Pharmacology, Toxicology and Pharmaceutics ,intervention ,Asthma ,diabetes ,business.industry ,asthma ,medicine.disease ,Family medicine ,030211 gastroenterology & hepatology ,business ,chronic disease - Abstract
Background and aims: Chronic disease, particularly inflammatory bowel disease (IBD), requires a multifaceted approach to managing patients, but it is apparent that primary care pharmacists are being underutilized. To demonstrate the benefits of pharmacist interventions in primary care, a systematic review was conducted of interventions in asthma and type 2 diabetes where pharmacists have a defined role in chronic disease management. We also explored potential opportunities for primary care pharmacists to deliver tailored care to patients with inflammatory bowel disease. Methods: The search strategy retrieved original research articles from seven databases; eligible articles were assessed for inclusion. Quality appraisal was performed independently by two reviewers. Results: Thirty-seven included studies were grouped into four categories of interventions: education/counseling (43%), medication management (34%), monitoring/follow-up (17%), and screening/risk prevention (6%). Education plus counseling was reported as the main intervention delivered by pharmacists. Three measurable outcomes were identified: clinical, humanistic (e.g., quality of life), and economic. Clinical outcomes (63%) were reported more commonly than humanistic (26%) and economic (11%) outcomes. Pharmacist interventions led to statistically significant improvements in control of disease, severity, and medication adherence, as well as improvements in overall patient satisfaction, quality of life among patients with asthma and type 2 diabetes. Conclusion: As one of the most accessible sources of primary health care, pharmacists are well-placed to minimize the impact of chronic diseases on patients and communities. Evidence suggests there are opportunities for primary care pharmacists to play a more active role in the management of chronic diseases such as IBD.
- Published
- 2020
91. Genetics, Mucosal Inflammation and the Environment in Post-Infectious Chronic Gut Syndromes
- Author
-
Rodney J. Scott, Marjorie M. Walker, Nicholas J. Talley, and Simon Keely
- Subjects
0301 basic medicine ,Genetics ,business.industry ,digestive, oral, and skin physiology ,fungi ,Mucosal inflammation ,equipment and supplies ,complex mixtures ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immunology ,bacteria ,Medicine ,030211 gastroenterology & hepatology ,business - Abstract
Genetics, Mucosal Inflammation, and the Environment in Post-Infectious Chronic Gut Syndromes
- Published
- 2016
92. In vivo characterization of colorectal and cutaneous inputs to lumbosacral dorsal horn neurons in the mouse spinal cord
- Author
-
Robert J. Callister, Brett A. Graham, Michelle M. Rank, Alan M. Brichta, Simon Keely, and Kristen E. Farrell
- Subjects
Male ,0301 basic medicine ,Patch-Clamp Techniques ,Colon ,Population ,Action Potentials ,Stimulation ,Biophysical Phenomena ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Physical Stimulation ,medicine ,Animals ,Patch clamp ,education ,Posterior Horn Cell ,Skin ,Afferent Pathways ,education.field_of_study ,business.industry ,General Neuroscience ,Lumbosacral Region ,Excitatory Postsynaptic Potentials ,Spinal cord ,Electric Stimulation ,eye diseases ,Mice, Inbred C57BL ,Posterior Horn Cells ,030104 developmental biology ,Rheobase ,medicine.anatomical_structure ,Spinal Cord ,nervous system ,Excitatory postsynaptic potential ,business ,Neuroscience ,030217 neurology & neurosurgery ,Lumbosacral joint - Abstract
Chronic abdominal pain is a common symptom of inflammatory bowel disease and often persists in the absence of gut inflammation. Although the mechanisms responsible for ongoing pain are unknown, clinical and preclinical evidence suggests lumbosacral spinal cord dorsal horn neurons contribute to these symptoms. At present, we know little about the intrinsic and synaptic properties of this population of neurons in either normal or inflammed conditions. Therefore, we developed an in vivo preparation to make patch-clamp recordings from superficial dorsal horn (SDH) neurons receiving colonic inputs in naive male mice. Recordings were made in the lumbosacral spinal cord (L6-S1) under isoflurane anesthesia. Noxious colorectal distension (CRD) was used to determine whether SDH neurons received inputs from mechanical stimulation/distension of the colon. Responses to hind paw/tail cutaneous stimulation and intrinsic and synaptic properties were also assessed, as well as action potential discharge properties. Approximately 11% of lumbosacral SDH neurons in the cohort of neurons sampled responded to CRD and a majority of these responses were subthreshold. Most CRD-responsive neurons (80%) also responded to cutaneous stimuli, compared with
- Published
- 2016
93. Towards an integrated understanding of the therapeutic utility of exclusive enteral nutrition in the treatment of Crohn's disease
- Author
-
Jakob Begun, Simon Keely, Mark Morrison, Páraic Ó Cuív, and Peter Lewindon
- Subjects
0301 basic medicine ,Inflammation ,Disease ,Bioinformatics ,03 medical and health sciences ,Enteral Nutrition ,0302 clinical medicine ,Crohn Disease ,medicine ,Humans ,Food, Formulated ,Gastrointestinal tract ,Crohn's disease ,business.industry ,Incidence (epidemiology) ,Therapeutic effect ,Gastrointestinal Microbiome ,General Medicine ,medicine.disease ,Gastrointestinal Tract ,030104 developmental biology ,Parenteral nutrition ,Immunology ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,Food Science - Abstract
Crohn's disease (CD) is a chronic disease characterized by episodic and disabling inflammation of the gastrointestinal tract in genetically susceptible individuals. The incidence and prevalence of CD is rising rapidly across the world emphasising that disease risk is also influenced by environmental and lifestyle factors, as well as the microbial community resident in the gut. Childhood-onset CD is associated with an aggressive disease course that can adversely impact patient growth and development. There is no cure for CD however new onset and recurrent cases of paediatric CD are often responsive to exclusive enteral nutrition (EEN) treatment. EEN treatment involves the exclusive consumption of an elemental or polymeric formula for several weeks and it is well established as a primary intervention strategy. EEN treatments typically achieve remission rates of over 80% and importantly they are associated with a high rate of mucosal healing, far superior to steroids, which is prognostic of improved long-term health outcomes. Furthermore, they are safe, have few side effects, and improve nutritional status and linear growth. Surprisingly, despite the utility of EEN our understanding of the host-microbe-diet interactions that underpin clinical remission and mucosal healing are limited. Here, we review the current state of knowledge and propose that the induction of autophagy, in addition to modulation of the microbiota and coordinated effects on inflammation and epithelial cell biology, may be critical for the therapeutic effects associated with EEN. A better understanding of EEN treatment will provide new opportunities to restore gut homeostasis and prolong periods of remission, as well as provide new insights into the factors that trigger and perhaps prevent CD.
- Published
- 2016
94. Immune dysregulation in the functional gastrointestinal disorders
- Author
-
Nicholas J. Talley, Ellen Marks, Marjorie M. Walker, and Simon Keely
- Subjects
Gastrointestinal Diseases ,Clinical Biochemistry ,Disease ,medicine.disease_cause ,Biochemistry ,Irritable Bowel Syndrome ,Immune system ,Intestinal mucosa ,Hypersensitivity ,medicine ,Homeostasis ,Humans ,Microbiome ,Dyspepsia ,Intestinal Mucosa ,Irritable bowel syndrome ,business.industry ,General Medicine ,Immune dysregulation ,medicine.disease ,Phenotype ,Immune System Diseases ,Mucosal immunology ,Immunology ,Dysbiosis ,business - Abstract
Gastrointestinal conditions may be broadly classified into two: organic and functional disease, with functional disorders accounting for the majority of patients with chronic gastrointestinal symptoms. Functional gastrointestinal disorders (FGIDs) present with no obvious pathology or well-accepted biochemical mechanism and, as such, treatment strategies are limited and focus on symptoms rather than cure. Irritable bowel syndrome and functional dyspepsia are the most widely recognised FGIDs, and there is a growing body of evidence to suggest an underlying inflammatory phenotype in subsets with these conditions. Here, we discuss the current knowledge of immune involvement in FGIDs and the commonalities between the different manifestations of FGIDs and propose a new hypothesis, potentially defining an underlying immunopathological basis of these conditions.
- Published
- 2015
95. Wheat Sensitivity and Functional Dyspepsia: A Pilot, Double-Blind, Randomized, Placebo-Controlled Dietary Crossover Trial with Novel Challenge Protocol
- Author
-
Marjorie M. Walker, Michael P. Jones, Michael D. Potter, Simon Keely, Kerith Duncanson, and Nicholas J. Talley
- Subjects
Adult ,Male ,medicine.medical_specialty ,Glutens ,non coeliac wheat sensitivity ,lcsh:TX341-641 ,Pilot Projects ,Placebo ,Food Intolerance ,Gastroenterology ,Article ,Double blind ,Post-prandial ,Diet, Carbohydrate-Restricted ,Diet, Gluten-Free ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Elimination diet ,Internal medicine ,Humans ,Medicine ,Eosinophilia ,030212 general & internal medicine ,Dyspepsia ,Triticum ,FODMAPs ,chemistry.chemical_classification ,Cross-Over Studies ,Nutrition and Dietetics ,business.industry ,Middle Aged ,functional dyspepsia ,Gluten ,Crossover study ,digestive system diseases ,Fructans ,Treatment Outcome ,chemistry ,gluten ,Cohort ,Female ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,lcsh:Nutrition. Foods and food supply ,Food Science - Abstract
Introduction: Functional dyspepsia (FD), characterised by symptoms of epigastric pain or early satiety and post prandial distress, has been associated with duodenal eosinophilia, raising the possibility that it is driven by an environmental allergen. Non-coeliac gluten or wheat sensitivity (NCG/WS) has also been associated with both dyspeptic symptoms and duodenal eosinophilia, suggesting an overlap between these two conditions. The aim of this study was to evaluate the role of wheat (specifically gluten and fructans) in symptom reduction in participants with FD in a pilot randomized double-blind, placebo controlled, dietary crossover trial. Methods: Patients with Rome III criteria FD were recruited from a single tertiary centre in Newcastle, Australia. All were individually counselled on a diet low in both gluten and fermentable oligo-, di-, mono-saccharides, and polyols (FODMAPs) by a clinical dietitian, which was followed for four weeks (elimination diet phase). Those who had a >, 30% response to the run-in diet, as measured by the Nepean Dyspepsia Index, were then re-challenged with &lsquo, muesli&rsquo, bars containing either gluten, fructan, or placebo in randomised order. Those with symptoms which significantly reduced during the elimination diet, but reliably reappeared (a mean change in overall dyspeptic symptoms of >, 30%) with gluten or fructan re-challenge were deemed to have wheat induced FD. Results: Eleven participants were enrolled in the study (75% female, mean age 43 years). Of the initial cohort, nine participants completed the elimination diet phase of whom four qualified for the rechallenge phase. The gluten-free, low FODMAP diet led to an overall (albeit non-significant) improvement in symptoms of functional dyspepsia in the diet elimination phase (mean NDI symptom score 71.2 vs. 47.1, p = 0.087). A specific food trigger could not be reliably demonstrated. Conclusions: Although a gluten-free, low-FODMAP diet led to a modest overall reduction in symptoms in this cohort of FD patients, a specific trigger could not be identified. The modified Salerno criteria for NCG/WS identification trialled in this dietary rechallenge protocol was fit-for-purpose. However, larger trials are required to determine whether particular components of wheat induce symptoms in functional dyspepsia.
- Published
- 2020
96. Sa1983 SELF-REPORTED NON-CELIAC WHEAT SENSITIVITY IN PATIENTS WITH CHRONIC UNEXPLAINED (FUNCTIONAL) GASTROINTESTINAL SYMPTOMS: GUT FUNCTION, IMMUNE ACTIVATION AND DUODENAL MUCOSA ASSOCIATED MICROBIOME
- Author
-
Gerald Holtmann, Michael P. Jones, Nicholas J. Talley, Ayesha Shah, Simon Keely, Natasha A. Koloski, Anh Do, Seungha Kang, Marjorie M. Walker, Mark Morrison, and Erin R. Shanahan
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Gastroenterology ,Medicine ,Duodenal mucosa ,In patient ,Microbiome ,business ,Function (biology) ,Immune activation - Published
- 2020
97. Tu1765 FUNCTIONAL DYSPEPSIA AND NON-CELIAC WHEAT SENSITIVITY: RESULTS FROM A PILOT DOUBLE BLIND, PLACEBO CONTROLLED, DIETARY CROSSOVER TRIAL
- Author
-
Grace Burns, Nicholas J. Talley, Marjorie M. Walker, Kerith Duncanson, Michael D. Potter, and Simon Keely
- Subjects
Double blind ,medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Gastroenterology ,medicine ,Sensitivity (control systems) ,Placebo ,business ,Crossover study - Published
- 2020
98. Mo1582 IS THERE AN ASSOCIATION BETWEEN IMPROVEMENT OF GI SYMPTOMS IN PATIENTS WITH FUNCTIONAL GASTROINTESTINAL DISORDERS AND ALTERATIONS OF CIRCULATING GUT HOMING T CELLS AND PRO-INFLAMMATORY CYTOKINES IN RESPONSE TO A 12 WEEK MULTIDISCIPLINARY INTERVENTION?
- Author
-
Marjorie M. Walker, Natasha A. Koloski, Nicholas J. Talley, Michael P. Jones, Anh Do, Grace Burns, Nicola Bray, Gerald Holtmann, Che-yung Chao, Simon Keely, Jessica J. McMaster, and Tom Fairlie
- Subjects
Gi symptoms ,Hepatology ,business.industry ,Intervention (counseling) ,Immunology ,Gastroenterology ,Medicine ,In patient ,business ,Homing (hematopoietic) ,Proinflammatory cytokine - Published
- 2020
99. Hypoxia Inducible Factor (HIF)‐1 accelerates mucosal wound healing through regulation and trafficking of integrin‐α5β1
- Author
-
Jay C. Horvat, Simonne Sherwin, Bridie J. Goggins, Marjorie M. Walker, Simon Keely, Darryl A. Knight, Gang Liu, and Kyra Minahan
- Subjects
Integrin α5β1 ,Hypoxia-inducible factors ,business.industry ,Genetics ,Medicine ,business ,Wound healing ,Molecular Biology ,Biochemistry ,Biotechnology ,Cell biology - Published
- 2020
100. Population based study: atopy and autoimmune diseases are associated with functional dyspepsia and irritable bowel syndrome, independent of psychological distress
- Author
-
Marjorie M. Walker, Michael P. Jones, Alkesh V. Zala, Nicholas J. Talley, Martin Veysey, Gerald Holtmann, Simon Keely, and Natasha A. Koloski
- Subjects
Adult ,Male ,medicine.medical_specialty ,Allergy ,Psychological Distress ,Autoimmune Diseases ,Atopy ,Irritable Bowel Syndrome ,03 medical and health sciences ,0302 clinical medicine ,Food allergy ,Risk Factors ,Psoriasis ,Internal medicine ,Surveys and Questionnaires ,medicine ,Prevalence ,Animals ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Dyspepsia ,Irritable bowel syndrome ,Asthma ,Aged ,Hepatology ,business.industry ,Gastroenterology ,Australia ,Middle Aged ,medicine.disease ,Rheumatoid arthritis ,Population Surveillance ,Animal allergy ,030211 gastroenterology & hepatology ,Female ,business - Abstract
Background The pathogenesis of functional GI disorders (FGIDs) is uncertain. However, underlying immune activation and psychological distress has been documented in irritable bowel syndrome (IBS) and functional dyspepsia (FD). Epidemiological data from the UK suggest that FGIDs are linked to atopy and certain autoimmune diseases but this has not been confirmed. Aim To test if allergic or autoimmune diseases are independently associated with FGIDs, irrespective of psychological distress in a large population based study. Methods A total of 3542 people (mean age 57.9 years and 52.7% females) randomly selected from the Australian population, returned a mail survey (response rate = 43%). The survey asked about a physician diagnosis of autoimmune disease (scleroderma, psoriasis, rheumatoid arthritis and diabetes mellitus) or allergic conditions (asthma, food, pollen and/or animal allergy). The questionnaire assessed psychological distress and Rome III criteria for FD and IBS. Results Asthma, food, pollen and animal allergies, psoriasis and rheumatoid arthritis were univariately significantly associated with IBS and FD. Food allergy (OR = 1.66; 95% CI = 1.15-2.40, P = 0.007), psoriasis (OR = 1.81; 95% CI = 1.19-2.74, P = 0.006) and rheumatoid arthritis (OR = 1.68; 95% CI = 1.15-2.4, P = 0.007) were independent risk factors for IBS, controlling for age, gender and psychological distress. In FD, asthma (OR = 1.32; 95% CI = 1.04-1.68, P = 0.025) and food allergy (OR = 1.78; 95% CI = 1.28-2.49, P = 0.001) were independent predictors, controlling for age, sex and psychological distress. Conclusions There is evidence that both atopic and autoimmune diseases are risk factors for FGIDs, independent of psychological distress, differing in IBS and FD. This provides evidence that different peripheral pathways may be involved in the pathogenesis of certain FGIDs.
- Published
- 2018
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