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Journal articleQuraishi MN, Cheesbrough J, Rimmer P, et al., 2024,
Open label vancomycin in primary sclerosing cholangitis-inflammatory bowel disease: improved colonic disease activity and associations with changes in host-microbiome-metabolomic signatures
, Journal of Crohn's and Colitis, ISSN: 1873-9946<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>We conducted a single-arm interventional study, to explore mucosal changes associated with clinical remission under oral vancomycin (OV) treatment, in primary sclerosing cholangitis associated inflammatory bowel disease (PSC-IBD); NCT05376228.</jats:p> </jats:sec> <jats:sec> <jats:title>Method</jats:title> <jats:p>Fifteen patients with PSC and active colitis (median faecal calprotectin 459µg/g; median total Mayo score 5) were treated with OV (125mg QID) for 4 weeks and followed-up for a further 4 weeks of treatment withdrawal (8 weeks, end-of-study). Colonic biopsies were obtained at baseline and week 4. Clinical assessments, and serum and stool samples (metagenomics, metatranscriptomics and metabolomics) were collected at weeks 0, 2, 4 and 8. The primary efficacy outcome measure was induction of clinical remission.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>OV resulted in clinical remission in 12/15 patients and significant reductions in faecal calprotectin. OV was associated with reduced abundances of Lachnospiraceae, genera Blautia and Bacteroides; and enrichment of Enterobacteriaceae, and genera Veillonella, Akkermansia and Escherichia. OV treatment was associated with downregulation of multiple metatranscriptomic pathways (including short chain fatty acid [SCFA] metabolism and bile acid [BA] biotransformation), along with host genes and multiple pathways involved in inflammatory responses and antimicrobial defence; and an upregulation of genes associated with extracellular matrix repair. OV use resulted in loss of specific faecal SCFAs and secondary BAs, including
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Journal articleAl-Shakhshir S, Quraishi MN, Mullish BH, et al., 2024,
FAecal micRobiota transplantation in primary sclerosinG chOlangitis (FARGO): Study protocol for a randomised, multicentre, phase IIa, placebo-controlled trial
, BMJ Open, ISSN: 2044-6055 -
Journal articlePorcari S, Mullish BH, Asnicar F, et al., 2024,
International consensus statement on microbiome testing in clinical practice
, The Lancet Gastroenterology & Hepatology, ISSN: 2468-1253There is growing interest in the potential exploitation of the gut microbiome as a diagnostic tool in medicine, but evidence supporting its clinical usefulness is scarce. An increasing number of commercial providers offer direct-to-consumer microbiome diagnostic tests without any consensus on their regulation or any proven value in clinical practice, which could result in considerable waste of individual and health-care resources and potential drawbacks in the clinical management of patients. We convened an international multidisciplinary expert panel to standardise best practices of microbiome testing for clinical implementation, including recommendations on general principles and minimum requirements for their provision, indications, pre-testing protocols, method of analyses, reporting of results, and potential clinical value. We also evaluated current knowledge gaps and future directions in this field. We aimed to establish a framework to regulate the provision of microbiome testing and minimise the use of inappropriate tests and pave the way for the evidence-based development and use of human microbiome diagnostics in clinical medicine.
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Journal articleMullish BH, Innes AJ, Roberts LA, et al., 2024,
Intestinal microbiota transplant prior to allogeneic stem cell transplant - (MAST) trial: study protocol for a multi-centre, double-blinded, placebo-controlled, Phase IIa Trial
, BMJ Open, ISSN: 2044-6055 -
Conference paperMullish BH, Innes AJ, Ghani R, et al., 2024,
Intestinal Microbiota Transplant Prior to Allogeneic Stem Cell Transplant (MAST): A Multi-Center Randomized Double-Blinded Placebo-Controlled Phase IIa Trial
, Publisher: American Society of Hematology, Pages: 4892.1-4892.1, ISSN: 0006-4971<jats:sec> <jats:title/> <jats:p>Background and significance: Reduced gut microbiome diversity pre-allogeneic hematopoietic cell transplantation (HCT) strongly correlates with poorer survival after the procedure. Most hematologic malignancy patients undergoing HCT have previously received intensive chemotherapy, resulting in prolonged neutropenic episodes and opportunistic infections (increasingly with multidrug-resistant organisms (MDRO)), requiring broad-spectrum antibiotics. The combination of chemotherapy and antimicrobial use has particularly been linked to reduced gut microbiome diversity.</jats:p> <jats:p>Intestinal microbiota transplant (IMT) is a novel treatment approach that can restore this perturbed diversity and has shown promise in a cohort of patients colonized with MDRO in their intestine by reducing post-HCT infection burden and improving overall survival. Given that most patients undergoing HCT will have a disrupted microbiome from prior therapies, we hypothesized that offering IMT prior to initiation of HCT conditioning could improve microbiome diversity during the early stages of HCT, with potential to reduce the frequency of infective complications, and improve outcomes of HCT. Studies using IMT post-HCT have shown variable results, but one distinctive aspect of this study is pre-HCT administration of IMT, aiming to ‘prehabilitate’ the gut prior to the microbiota insults inherent to HCT.</jats:p> <jats:p>Study Design and Methods: The trial is registered (ClinicalTrials.gov ID: NCT 6355583) and recruitment started in 2024.Fifty adult patients planned to receive allogeneic HCT for hematologic malignancies will be recruited into this phase IIa trial, and randomized 1:1 to receive capsulized IMT (10 capsules of EBX-102-02, a next generation, full-spectrum microbiome product derived from pooled screened donor stool; EnteroBiotix L
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Journal articleAllegretti JR, Khanna S, Mullish BH, et al., 2024,
The Progression of Microbiome Therapeutics for the Management of Gastrointestinal Diseases and Beyond
, Gastroenterology, Vol: 167, Pages: 885-902, ISSN: 0016-5085 -
Journal articleMullish BH, Ianiro G, 2024,
Preface to special edition: Microbiome, inflammation and cancer
, Best Practice & Research Clinical Gastroenterology, Pages: 101952-101952, ISSN: 1521-6918 -
Journal articleTurner BRH, Jenkinson PI, Huttman M, et al., 2024,
Inflammation, oxidative stress and the gut microbiome perturbation: a narrative review of mechanisms and treatment of the alcohol hangover
, Alcoholism: Clinical and Experimental Research, Vol: 48, Pages: 1451-1465, ISSN: 0145-6008Alcohol is the most widely abused substance in the world, the leading source of mortality in 15–49-year-olds, and a major risk factor for heart disease, liver disease, diabetes, and cancer. Despite this, alcohol is regularly misused in wider society. Consumers of excess alcohol often note a constellation of negative symptoms, known as the alcohol hangover. However, the alcohol hangover is not considered to have long-term clinical significance by clinicians or consumers. We undertook a critical review of the literature to demonstrate the pathophysiological mechanisms of the alcohol hangover. Hereafter, the alcohol hangover is re-defined as a manifestation of sickness behavior secondary to alcohol-induced inflammation, using the Bradford-Hill criteria to demonstrate causation above correlation. Alcohol causes inflammation through oxidative stress and endotoxemia. Alcohol metabolism is oxidative and increased intake causes relative tissue hypoxia and increased free radical generation. Tissue damage ensues through lipid peroxidation and the formation of DNA/protein adducts. Byproducts of alcohol metabolism such as acetaldehyde and congeners, sleep deprivation, and the activation of nonspecific inducible CYP2E1 in alcohol-exposed tissues exacerbate free radical generation. Tissue damage and cell death lead to inflammation, but in the intestine loss of epithelial cells leads to intestinal permeability, allowing the translocation of pathogenic bacteria to the systemic circulation (endotoxemia). This leads to a well-characterized cascade of systemic inflammation, additionally activating toll-like receptor 4 to induce sickness behavior. Considering the evidence, it is suggested that hangover frequency and severity may be predictors of the development of later alcohol-related diseases, meriting formal confirmation in prospective studies. In light of the mechanisms of alcohol-mediated inflammation, research into gut permeability and the gut microbiome may be an exciting
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Journal articlePerry R, Mullish BH, Alexander JL, et al., 2024,
3D printed rectal swabs for assessing the gut microbiome, metabolome and inflammation
, Scientific Reports, Vol: 14, ISSN: 2045-2322Investigating the gut microbiome and metabolome frequently requires faecal samples, which can be difficult to obtain. Previous studies have shown that rectal swabs are comparable to faecal samples for analysing gut microbiota composition and key metabolites. In this study, 3D printed rectal swabs were compared with conventional flocked swabs and faecal samples, due to the potential advantages 3D printing as a technique offers for swab production and development. 16S rRNA gene sequencing, qPCR and metabolite profiling (using 1H-NMR spectroscopy) were performed on swab and faecal samples from healthy participants. Faecal calprotectin and total protein analysis were performed on samples from inflammatory bowel disease (IBD) patients. There were no significant differences between both swab types and faecal samples when assessing key measures of alpha and beta diversity, and differences in the abundance of major phyla. There was a strong correlation between both swab types and faecal samples for all combined metabolites detected by NMR. In IBD patients, there was no significant difference in faecal calprotectin and total protein levels between both swab types and faecal samples. These data lead us to conclude that 3D printed swabs are equivalent to flocked swabs for the analysis of the gut microbiome, metabolome and inflammation.
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Journal articleMullish BH, Thursz MR, 2024,
Alcohol-associated liver disease: Emerging therapeutic strategies.
, HepatologyThe large and growing burden of alcohol-associated liver disease-and the considerable burden of morbidity and mortality associated with it-has been a drive toward ongoing research into novel strategies for its treatment, with a particular focus upon alcohol-associated hepatitis (AH). Management of alcohol-use disorder forms the central pillar of alcohol-associated liver disease care, with evidence-based psychological and pharmacological approaches being well established, and certain models demonstrating improved clinical outcomes when hepatology and addiction services are co-located. Corticosteroids have previously been used somewhat indiscriminately in patients with severe AH, but effective tools now exist to assess early response (and limit futile ongoing exposure). Techniques to predict risk of corticosteroid-related infection are also available, although current clinical strategies to mitigate this risk are limited. A variety of novel therapeutic approaches to AH are at different phases of trials and evidence gathering, with some of the most promising signals related to cytokine manipulation, epigenetic modulation, and targeting of the gut microbiota (ie, by means of fecal microbiota transplant). While remaining an ongoing source of debate, early liver transplant in severe AH has grown in interest and acceptability over the past decade as evidence supporting its efficacy builds, in the process challenging paradigms about mandatory pretransplant sobriety periods. However, uncertainty remains regarding the optimal selection criteria, and whether liver transplant has a role for only a highly limited proportion of patients with AH or more widespread application. This review aims to provide an overview of this fast-moving field.
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