121 results found
Mullish BH, Forlano R, Abeles R, et al., 2019, Letter: role of mean platelet volume levels in prediction of major acute cardiovascular events in patients with non-alcoholic fatty liver disease – authors’ reply, Alimentary Pharmacology and Therapeutics, ISSN: 0269-2813
Allegretti JR, Mullish BH, Kelly C, et al., 2019, The evolution of the use of faecal microbiota transplantation and emerging therapeutic indications., Lancet, Vol: 394, Pages: 420-431
Developments in high-throughput microbial genomic sequencing and other systems biology techniques have given novel insight into the potential contribution of the gut microbiota to health and disease. As a result, an increasing number of diseases have been characterised by distinctive changes in the composition and functionality of the gut microbiota; however, whether such changes are cause, consequence, or incidental to the disease in question remains largely uncertain. Restoration of the gut microbiota to a premorbid state is a key novel therapeutic approach of interest, and faecal microbiota transplantation-the transfer of prescreened stool from healthy donors into the gastrointestinal tract of patients-is gaining increasing importance in both the clinical and research settings. At present, faecal microbiota transplantation is only recommended in the treatment of recurrent Clostridioides difficile infection, although a large number of trials are ongoing worldwide exploring other potential therapeutic indications.
Riaz Z, Wright M, Atkinson S, et al., 2019, Malignant and cirrhotic ascites demonstrate a similar microbiome profile, British Association for the Study of the Liver (BASL) Annual Meeting
Nathwani R, Mullish BH, Kockerling D, et al., 2019, A review of liver fibrosis and emerging therapies, European Medical Journal: Hepatology
With an increasing burden of liver cirrhosis, the most advanced stage of hepatic fibrosis, there is an emphasis to better understand the pathological processes and mechanisms to target specific treatments to reverse or cease fibrosis progression. Antiviral therapy for hepatitis B and C has effectively treated underlying causes of chronic liver disease and has induced fibrosis reversal in some however, this has not been targeted for the majority of aetiologies for cirrhosis including alcohol or non-alcoholic steatohepatitis. Fibrosis, characterized by the accumulation of extracellular matrix proteins, occurs due to chronic injury from toxic, infectious or metabolic causes. The primary event of fibrogenesis is increased matrix production and scar formation mediated by the hepatic stellate cell, the principal cell type involved. Experimental models using rodent and human cell lines of liver injury have assisted in better understanding fibrogenesis especially in recognising the role of procoagulant factors. This has led to interventional studies using anticoagulants in animal models with reversal of fibrosis as the primary endpoint. Though these trials have been encouraging, no antifibrotic therapies are currently licenced for human use. This literature review discusses current knowledge in the pathophysiology of hepatic fibrosis, including characteristics of the extracellular matrix, signalling pathways and hepatic stellate cells. We also review current types of experimental models used to induce fibrosis and up-to46 date anticoagulant therapies and agents targeting the hepatic stellate cell that have been trialled in animal and human studies with anti-fibrotic properties.
Forlano R, Mullish BH, Giannakeas N, et al., 2019, Impact of BMI and Ethnicity on histology as assessed by automated quantitation in liver biopsies of patients with NAFLD, EASL NAFLD summit 2019
Allegretti JR, Kassam Z, Mullish BH, et al., 2019, Effects of fecal microbiota transplantation with oral capsules in obese patients, Clinical Gastroenterology and Hepatology, ISSN: 1542-3565
Background & AimsStudies in mice have shown that the intestinal microbiota can contribute to obesity via the anorexigenic gut hormone glucagon-like peptide 1 (GLP1) and bile acids, which affect lipid metabolism. We performed a randomized, placebo-controlled pilot study of the effects of fecal microbiota transplantation (FMT) in obese, metabolically uncompromised patients.MethodsWe performed a double-blind study of 22 obese patients (body mass index [BMI] ≥ 35kg/m2) without a diagnosis of diabetes, non-alcoholic steatohepatitis, or metabolic syndrome. Participants were randomly assigned (1:1) to groups that received FMT by capsules (induction dose of 30 capsules at week 4 and maintenance dose of 12 capsules at week 8) or placebo capsules. FMT capsules were derived from a single, lean donor (BMI, 17.5 kg/m2). Patients were followed through week 26; the primary outcome was safety. Stool and serum samples were collected from patients at baseline and at weeks 1, 4, 6, 8 and 12 after administration of the first dose of FMT or placebo and analyzed by 16S RNA gene sequencing. Stool and serum samples were analyzed for metabolomics by liquid chromatography-mass spectrometry. Additional outcomes were change in area under the curve for GLP1 at week 12.ResultsWe observed no significant differences in adverse events between patients who received FMT vs placebo. There was no increase in the area under the curve of GLP1 in either group. Patients who received FMT had sustained shifts in microbiomes associated with obesity toward those of the donor (P<.001). Patients who received FMT had a sustained decrease in stool levels of taurocholic acid (P<.05), compared with baseline; bile acid profiles began to more closely resemble those of the donor. We did not observe significant changes in mean BMI at week 12 in either group.ConclusionsIn a placebo-controlled pilot study, we found that FMT capsules (derived from a lean donor) were safe but did not reduce BMI in obese metabol
Forlano R, Mullish BH, Nathwani R, et al., 2019, Non-alcoholic fatty liver disease and vascular disease, Current Vascular Pharmacology, ISSN: 1570-1611
Non-Alcoholic Fatty Liver Disease (NAFLD) represents an increasing cause of liver disease worldwide. However, notably, the primary cause of morbidity and mortality in patients with NAFLD is cardiovascular disease (CVD), with fibrosis stage being the strongest disease-specific predictor. It is globally-projected that NAFLD will become increasingly prevalent, especially among children and younger adults. As such, even within the next few years, NAFLD will contribute considerably to the overall CVD burden. In this review, we discuss the role of NAFLD as an emerging risk factor for CVD. In particular, this article aims to provide an overview of pathological drivers of vascular damage in patients with NAFLD. Moreover, the impact of NAFLD on the development, severity and the progression of subclinical and clinical CVD will be discussed. Finally, the review illustrates current and potential future perspectives for screening for CVD in this high-risk population.
Nathwani R, Mullish BH, Kockerling D, et al., 2019, Recurrent bacteraemia following variceal haemorrhage, Gut, ISSN: 0017-5749
Ghani R, Gan C, Mullish BH, et al., 2019, P13-2 Prevalence of recurrent Extended Spectrum Beta-Lactamase (ESBL) urinary tract infections (UTIs) in patients within a Urology service and introducing the concept of Faecal Microbiota Transplantation (FMT) as a treatment modality, British Association of Urological Surgeons Annual Scientific Meeting, Publisher: SAGE Publications, Pages: 83-85, ISSN: 2051-4158
Mullish BH, Kumar N, Goldin RD, et al., 2019, 27 Liver Biopsy, Evidence-based Gastroenterology and Hepatology, 4th Edition, Editors: McDonald, Feagan, Jalan, Kahrilas, Publisher: Wiley, ISBN: 978-1-119-21138-9
Allegretti JR, Kassam Z, Chiang AL, et al., 2019, 621 – Fecal Microbiota Transplantation for the Treatment of Obesity: A Randomized, Placebo-Controlled Pilot Trial, Gastroenterology, Vol: 156, Pages: S-129, ISSN: 0016-5085
McDonald JA, Perez JL, Mullish BH, et al., 2019, Mo1953 – Growth Inhibition of Clostridioides Difficile by Short and Medium Chain Fatty Acids, Gastroenterology, Vol: 156, Pages: S-898, ISSN: 0016-5085
Churchward MA, Michaud ER, Blanco JM, et al., 2019, Sa1924 – Effect of Short Chain Fatty Acids on Gut-Brain Axis Using a Microglial Cell Model, Gastroenterology, Vol: 156, Pages: S-455, ISSN: 0016-5085
Allegretti JR, Hurtado J, Carrellas M, et al., 2019, 7 – The Icon Study: Inflammatory Bowel Disease and Recurrent Clostridium Difficile Infection: Outcomes After Fecal Microbiota Transplantation, Gastroenterology, Vol: 156, ISSN: 0016-5085
McSweeney B, Allegretti JR, Fischer M, et al., 2019, In search of stool donors: a multicentre study of prior knowledge, perceptions, motivators and deterrents among potential donors for fecal microbiota transplantation, Gut Microbes, ISSN: 1949-0984
Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridioides difficile infection. Stool donors are essential, but difficult to recruit and retain. We aimed to identify factors influencing willingness to donate stool. This multi-center study with a 32-item questionnaire targeted young adults and health care workers via social media and university email lists in Edmonton and Kingston, Canada; London and Nottingham, England; and Indianapolis and Boston, USA. Items included baseline demographics and FMT knowledge and perception. Investigated motivators and deterrents included economic compensation, screening process, time commitment, and stool donation logistics. Logistic regression and linear regression models estimated associations of study variables with self-assessed willingness to donate stool. 802 respondents completed our questionnaire: 387 (48.3%) age 21-30 years, 573 (71.4%) female, 323 (40%) health care workers. Country of residence, age and occupation were not associated with willingness to donate stool. Factors increasing willingness to donate were: already a blood donor (OR 1.64), male, altruism, economic benefit, knowledge of how FMT can help patients (OR 1.32), and positive attitudes towards FMT (OR 1.39). Factors decreasing willingness to donate were: stool collection unpleasant (OR 0.92), screening process invasive (OR 0.92), higher stool donation frequency, negative social perception of stool, and logistics of collection/transporting feces. We conclude that 1) blood donors and males are more willing to consider stool donation; 2) altruism, economic compensation, and positive feedback are motivators; and 3) screening process, high donation frequency, logistics of collection/transporting feces, lack of public awareness, and negative social perception are deterrents. Considering these variables could maximize donor recruitment and retention.
Ghani R, Gan C, Mullish B, et al., 2019, MP71-15 Prevalence of recurrent extended-spectrum beta-lactamase (ESBL) urinary tract infections (UTIs) in patients within a urology service. Introducing the concept of Faecal Microbiota transplantation (FMT) as a treatment modality., AUA 2019, Publisher: Elsevier, ISSN: 0022-5347
Forlano R, Mullish BH, Yee M, et al., 2019, Liver function tests in NAFLD: Changes in upper normal limits, does it really matter?, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: E295-E295, ISSN: 0168-8278
Tyson LD, Atkinson S, Pechlivanis A, et al., 2019, Serum bile acid profiles distinguish severe alcoholic hepatitis from decompensated alcohol-related cirrhosis, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: E108-E108, ISSN: 0168-8278
Forlano R, Mullish BH, Giannakeas N, et al., 2019, SAT-294. Automated quantitation of steatosis, inflammation, ballooningand fibrosis using machine learning in routine histologicalimages of liver biopsies of patients with NAFLD, International Liver Congress (ILC), Publisher: Elsevier, Pages: e767-e768, ISSN: 0168-8278
Abeles RD, Mullish BH, Forlano R, et al., 2019, Derivation and validation of a cardiovascular risk score for prediction of major acute cardiovascular events in non-alcoholic fatty liver disease: The importance of an elevated mean platelet volume, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: E305-E305, ISSN: 0168-8278
Mullish BH, Forlano R, Abeles RD, et al., 2019, Editorial: importance of an elevated mean platelet volume for prediction of major adverse cardiovascular events in non-alcoholic fatty liver disease - authors' reply., Aliment Pharmacol Ther, Vol: 49, Pages: 1093-1094
Abeles RD, Mullish BH, Forlano R, et al., 2019, Derivation and validation of a cardiovascular risk score for prediction of major acute cardiovascular events in non-alcoholic fatty liver disease; the importance of an elevated mean platelet volume, Alimentary Pharmacology and Therapeutics, ISSN: 0269-2813
Background: Atherosclerotic cardiovascular disease is a key cause of morbidity in non-alcoholic fatty liver disease (NAFLD) but appropriate means to predict major acute cardiovascular events (MACE) are lacking. Aims: To design a bespoke cardiovascular risk score in NAFLD. Methods: A retrospective derivation (2008-2016, 356 patients) and a prospective validation (2016- 2017, 111 patients) NAFLD cohort study was performed. Clinical and biochemical data were recorded at enrolment and mean platelet volume (MPV), Qrisk2 and Framingham scores were recorded one year prior to MACE (Cardiovascular death, acute coronary syndrome, stroke, and transient ischaemic attack). Results: The derivation and validation cohorts were well matched with MACE prevalence 12.6% and 12% respectively. On univariate analysis, age, diabetes, advanced fibrosis, collagen proportionate area >5%, MPV and liver stiffness were associated with MACE. After multivariate analysis, age, diabetes and MPV remained independently predictive. The ‘NAFLD CV-risk score’ was generated using binary logistic regression: 85860.06*(Age) + 0.963*(MPV) + 0.26*(DM1) – 16.441 Diabetes mellitus: 1: present; 2: absent. (AUROC 0.84). A cut-off of -3.98 gave a Sensitivity 97%, Specificity 27%, PPV 16%, NPV 99%. An MPV alone of >10.05 gave a sensitivity 97%, specificity 59%, PPV 24% and NPV 97% (AUROC 0.83). Validation cohort AUROCs were comparable at 0.77 (NAFLD CV-risk) and 0.72 (MPV). In the full cohort, the NAFLD CV-risk score and MPV outperformed both Qrisk2 and Framingham scores. Conclusions: The NAFLD CV risk score and MPV accurately predict 1-year risk of MACE thereby allowing better identification of patients that require optimisation of their cardiovascular risk profile.
Ovadia C, Perdones-Montero A, Mullish B, et al., 2019, Ursodeoxycholic acid treatment of cholestatic pregnancy can alter the gut microbiota to enhance bile acid modification and production of metabolically-active secondary bile acids - an explanation for 'responders' and 'non-responders'?, Publisher: WILEY, Pages: 17-17, ISSN: 1470-0328
Mcilroy JR, Segal JP, Mullish BH, et al., 2019, Current and future targets for faecal microbiota transplantation, Human Microbiome Journal, Vol: 11, ISSN: 2452-2317
Kockerling D, Nathwani R, Forlano R, et al., 2019, Current and future pharmacological therapies for managing cirrhosis and its complications., World J Gastroenterol, Vol: 25, Pages: 888-908
Due to the restrictions of liver transplantation, complication-guided pharmacological therapy has become the mainstay of long-term management of cirrhosis. This article aims to provide a complete overview of pharmacotherapy options that may be commenced in the outpatient setting which are available for managing cirrhosis and its complications, together with discussion of current controversies and potential future directions. PubMed/Medline/Cochrane Library were electronically searched up to December 2018 to identify studies evaluating safety, efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis. Non-selective beta-blockers effectively reduce variceal re-bleeding risk in cirrhotic patients with moderate/large varices, but appear ineffective for primary prevention of variceal development and may compromise renal function and haemodynamic stability in advanced decompensation. Recent observational studies suggest protective, haemodynamically-independent effects of beta-blockers relating to reduced bacterial translocation. The gut-selective antibiotic rifaximin is effective for secondary prophylaxis of hepatic encephalopathy; recent small trials also indicate its potential superiority to norfloxacin for secondary prevention of spontaneous bacterial peritonitis. Diuretics remain the mainstay of uncomplicated ascites treatment, and early trials suggest alpha-adrenergic receptor agonists may improve diuretic response in refractory ascites. Vaptans have not demonstrated clinical effectiveness in treating refractory ascites and may cause detrimental complications. Despite initial hepatotoxicity concerns, safety of statin administration has been demonstrated in compensated cirrhosis. Furthermore, statins are suggested to have protective effects upon fibrosis progression, decompensation and mortality. Evidence as to whether proton pump inhibitors cause gut-liver-brain axis dysfunction is conflicting. Emerging evidence
Ghani R, Gan C, Mullish B, et al., 2019, Prevalence of recurrent extended-spectrum beta-lactamase (ESBL) urinary tract infections (UTIs) in patients within a urology service. Introducing the concept of Faecal Microbiota transplantation (FMT) as a treatment modality., Journal of Clinical Urology
Mullish BH, McDonald JAK, Pechlivanis A, et al., 2019, Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent Clostridioides difficile infection, Gut, ISSN: 0017-5749
<jats:sec><jats:title>Objective</jats:title><jats:p>Faecal microbiota transplant (FMT) effectively treats recurrent <jats:italic>Clostridioides difficile</jats:italic> infection (rCDI), but its mechanisms of action remain poorly defined. Certain bile acids affect <jats:italic>C. difficile</jats:italic> germination or vegetative growth. We hypothesised that loss of gut microbiota-derived bile salt hydrolases (BSHs) predisposes to CDI by perturbing gut bile metabolism, and that BSH restitution is a key mediator of FMT’s efficacy in treating the condition.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Using stool collected from patients and donors pre-FMT/post-FMT for rCDI, we performed 16S rRNA gene sequencing, ultra performance liquid chromatography mass spectrometry (UPLC-MS) bile acid profiling, BSH activity measurement, and qPCR of <jats:italic>bsh</jats:italic>/<jats:italic>bai</jats:italic>CD genes involved in bile metabolism. Human data were validated in <jats:italic>C. difficile</jats:italic> batch cultures and a C57BL/6 mouse model of rCDI.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>From metataxonomics, pre-FMT stool demonstrated a reduced proportion of BSH-producing bacterial species compared with donors/post-FMT. Pre-FMT stool was enriched in taurocholic acid (TCA, a potent <jats:italic>C. difficile</jats:italic> germinant); TCA levels negatively correlated with key bacterial genera containing BSH-producing organisms. Post-FMT samples demonstrated recovered BSH activity and <jats:italic>bsh</jats:italic>/<jats:italic>bai</jats:italic>CD gene copy number compared with pretreatment (p<0.05). In batch cultures, supernatant from engineered <jats:italic>bsh</jats:italic>-expressing <jats:italic>E
Mullish BH, Ghani R, McDonald J, et al., 2019, Faecal microbiota transplant for eradication of multidrug-resistant Enterobacteriaceae: a lesson in applying best practice? Re: 'A five-day course of oral antibiotics followed by faecal transplantation to eradicate carriage of multidrug-resistant Enterobacteriaceae: A Randomized Clinical Trial', Clinical Microbiology and Infection, ISSN: 1198-743X
Segal JP, Mullish B, Quraishi MN, et al., 2019, The application of omics techniques to understand the role of the gut microbiota in inflammatory bowel disease, Therapeutic Advances in Gastroenterology, Vol: 12, Pages: 1-13, ISSN: 1756-2848
The aetiopathogenesis of inflammatory bowel diseases (IBD) involves the complex interaction between a patient’s genetic predisposition, environment, gut microbiota and immune system. Currently, however, it is not known if the distinctive perturbations of the gut microbiota that appear to accompany both Crohn’s disease and ulcerative colitis are the cause of, or the result of, the intestinal inflammation that characterizes IBD.With the utilization of novel systems biology technologies, we can now begin to understand not only details about compositional changes in the gut microbiota in IBD, but increasingly also the alterations in microbiota function that accompany these. Technologies such as metagenomics, metataxomics, metatranscriptomics, metaproteomics and metabonomics are therefore allowing us a deeper understanding of the role of the microbiota in IBD. Furthermore, the integration of these systems biology technologies through advancing computational and statistical techniques are beginning to understand the microbiome interactions that both contribute to health and diseased states in IBD.This review aims to explore how such systems biology technologies are advancing our understanding of the gut microbiota, and their potential role in delineating the aetiology, development and clinical care of IBD.
Monaghan T, Mullish BH, Patterson J, et al., 2019, Effective fecal microbiota transplantation for recurrent Clostridioides difficile infection in humans is associated with increased signalling in the bile acid-farnesoid X receptor-fibroblast growth factor pathway., Gut Microbes, Vol: 10, Pages: 142-148
The mechanisms of efficacy for fecal microbiota transplantation (FMT) in treating recurrent Clostridioides difficile infection (rCDI) remain poorly defined, with restored gut microbiota-bile acid interactions representing one possible explanation. Furthermore, the potential implications for host physiology of these FMT-related changes in gut bile acid metabolism are also not well explored. In this study, we investigated the impact of FMT for rCDI upon signalling through the farnesoid X receptor (FXR)-fibroblast growth factor (FGF) pathway. Herein, we identify that in addition to restoration of gut microbiota and bile acid profiles, FMT for rCDI is accompanied by a significant, sustained increase in circulating levels of FGF19 and reduction in FGF21. These FGF changes were associated with weight gain post-FMT, to a level not exceeding the pre-rCDI baseline. Collectively, these data support the hypothesis that the restoration of gut microbial communities by FMT for rCDI is associated with an upregulated FXR-FGF pathway, and highlight the potential systemic effect of FMT.
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