Publications
98 results found
Hegade VS, Pechlivanis A, McDonald JA, et al., 2019, Autotaxin, bile acid profile and effect of IBAT inhibition in primary biliary cholangitis patients with pruritus, Liver International, Vol: 39, Pages: 967-975, ISSN: 1478-3223
BACKGROUND &AIMS: Pruritus is a common symptom in patients with primary biliary cholangitis (PBC) for which ileal bile acid transporter (IBAT) inhibition is emerging as a potential therapy. We explored the serum metabonome and gut microbiota profile in PBC patients with pruritus and investigated the effect of GSK2330672, an IBAT inhibitor. METHODS: We studied fasting serum bile acids (BAs), autotaxin and faecal microbiota in 22 PBC patients with pruritus at baseline and after two weeks of GSK2330672 treatment. Control group included 31 asymptomatic PBC patients and 18 healthy volunteers. BA profiling was done by ultraperformance liquid chromatography coupled to a mass spectrometry (UPLC-MS). Faecal microbiomes were analysed by 16S ribosomal RNA gene sequencing. RESULTS: In PBC patients with pruritus serum levels of total and glyco-conjugated primary BAs and autotaxin were significantly elevated. Autotaxin activity correlated significantly with tauro- and glyco-conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA), both at baseline and after GSK2330672. GSK2330672 significantly reduced autotaxin and all tauro- and glyco- conjugated BAs and increased faecal levels of CA (p=0.048) and CDCA (p=0.027). Gut microbiota of PBC patients with pruritus was similar to control groups. GSK2330672 increased relative abundance of Firmicutes (p=0.033) and Clostridia (p=0.04) and decreased Bacteroidetes (p=0.033) and Bacteroidia (p=0.04). CONCLUSIONS: Pruritus in PBC does not show a distinct gut bacterial profile but is associated with elevated serum bile acid and autotaxin levels which decrease after IBAT inhibition. In cholestatic pruritus, a complex interplay between BAs and ATX is likely and may be modified by IBAT inhibition. This article is protected by copyright. All rights reserved.
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-S-129, 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, Pages: S-2-S-3, ISSN: 0016-5085
Maurice JB, Garvey L, Tsochatzis EA, et al., 2019, Monocyte-macrophage activation is associated with nonalcoholic fatty liver disease and liver fibrosis in HIV monoinfection independently of the gut microbiome and bacterial translocation., AIDS, Vol: 33, Pages: 805-814, ISSN: 0269-9370
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is common among people living with HIV. There are limited data available on the pathophysiology of NAFLD and the development of fibrosis in this population. OBJECTIVES: The aim of this study was to investigate the association of bacterial translocation, adipose tissue dysfunction, monocyte activation and gut dysbiosis in patients with HIV monoinfection and NAFLD. METHODS: Cases with biopsy-proven NAFLD and HIV monoinfection were age and sex-matched to HIV-positive and HIV-negative controls. Markers of bacterial translocation [lipopolysaccharide-binding protein (LBP), bacterial DNA and lipopolysaccharide (LPS)], adipose tissue dysfunction (leptin, adiponectin) and monocyte activation (sCD14 and sCD163) were measured by ELISA. Hepatic patterns of macrophage activation were explored with immunohistochemistry. 16 s rRNA sequencing was performed with stool. RESULTS: Thirty-three cases were included (≥F2 fibrosis n = 16), matched to HIV-positive (n = 29) and HIV-negative (n = 17) controls. Cases with NAFLD were more obese (BMI 31.0 ± 4.4 vs. 24.1 ± 2.8 kg/m, P < 0.001) and had significantly increased levels of sCD14, sCD163 and higher leptin to adiponectin ratio vs. HIV-positive controls. Cases with ≥F2 verses < F2 fibrosis had increased sCD14 (1.4 ± 0.4 vs. 1.1 ± 0.3 μg/ml, P = 0.023) and sCD163 (1.0 ± 0.3 vs. 0.8 ± 0.3 μg/ml, P = 0.060), which correlated with waist circumference (sCD14 P = 0.022, sCD163 P = 0.011). Immunohistochemistry showed increased hepatic portal macrophage clusters in patients with fibrosis. No markers of bacterial translocation or changes to the microbiome were associated with NAFLD or fibrosis. CONCLUSION: NAFLD fibrosis stage in HIV monoinfected patients is associated with monocyte activation in the context of obesity, which may be independent of bacterial translocation and gut microbiome.
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'?, British Maternal & Fetal Medicine Society (BMFMS) 21st Annual Conference 2019, Publisher: WILEY, Pages: 17-17, ISSN: 1470-0328
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, Vol: 25, Pages: 912-913, ISSN: 1198-743X
McDonald JAK, Mullish BH, Pechlivanis A, et al., 2018, Inhibiting growth of clostridioides difficile by restoring valerate, produced by the intestinal microbiota, Gastroenterology, Vol: 155, Pages: 1495-1507.e15, ISSN: 0016-5085
Background & AimsFecal microbiota transplantation (FMT) is effective for treating recurrent Clostridioides difficile infection (CDI), but there are concerns about its long-term safety. Understanding the mechanisms of the effects of FMT could help us design safer, targeted therapies. We aimed to identify microbial metabolites that are important for C difficile growth.MethodsWe used a CDI chemostat model as a tool to study the effects of FMT in vitro. The following analyses were performed: C difficile plate counts, 16S rRNA gene sequencing, 1H-NMR spectroscopy, and UPLC mass spectrometry bile acid profiling. FMT mixtures were prepared using fresh fecal samples provided by donors enrolled in an FMT program in the United Kingdom. Results from chemostat experiments were validated using human stool samples, C difficile batch cultures, and C57BL/6 mice with CDI. Human stool samples were collected from 16 patients with recurrent CDI and healthy donors (n=5) participating in an FMT trial in Canada.ResultsIn the CDI chemostat model, clindamycin decreased valerate and deoxycholic acid concentrations and increased C difficile total viable counts (TVC) and valerate precursors, taurocholic acid, and succinate concentrations. After we stopped adding clindamycin, levels of bile acids and succinate recovered, whereas levels of valerate and valerate precursors did not. In the CDI chemostat model, FMT increased valerate concentrations and decreased C difficile TVC (94% reduction), spore counts (86% reduction), and valerate precursor concentrations—concentrations of bile acids were unchanged. In stool samples from patients with CDI, valerate was depleted before FMT, but restored after FMT. C difficile batch cultures confirmed that valerate decreased vegetative growth, and that taurocholic acid is required for germination but had no effect on vegetative growth. C difficile TVC were decreased by 95% in mice with CDI given glycerol trivalerate compared to phosphate-buffered sali
Mullish BH, Pechlivanis A, Barker GF, et al., 2018, Functional microbiomics: evaluation of gut microbiota-bile acid metabolism interactions in health and disease, Methods, Vol: 149, Pages: 49-58, ISSN: 1046-2023
There is an ever-increasing recognition that bile acids are not purely simple surfactant molecules that aid in lipid digestion, but are a family of molecules contributing to a diverse range of key systemic functions in the host. It is now also understood that the specific composition of the bile acid milieu within the host is related to the expression and activity of bacterially-derived enzymes within the gastrointestinal tract, as such creating a direct link between the physiology of the host and the gut microbiota. Coupled to the knowledge that perturbation of the structure and/or function of the gut microbiota may contribute to the pathogenesis of a range of diseases, there is a high level of interest in the potential for manipulation of the gut microbiota-host bile acid axis as a novel approach to therapeutics. Much of the growing understanding of the biology of this area reflects the recent development and refinement of a range of novel techniques; this study applies a number of those techniques to the analysis of human samples, aiming to illustrate their strengths, drawbacks and biological significance at all stages. Specifically, we used microbial profiling (using 16S rRNA gene sequencing), bile acid profiling (using liquid chromatography–mass spectrometry), bsh and baiCD qPCR, and a BSH enzyme activity assay to demonstrate differences in the gut microbiota and bile metabolism in stool samples from healthy and antibiotic-exposed individuals.
Guzman-Rodriguez M, McDonald JAK, Hyde R, et al., 2018, Using bioreactors to study the effects of drugs on the human microbiota, METHODS, Vol: 149, Pages: 31-41, ISSN: 1046-2023
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- Citations: 23
Mullish BH, Osborne LS, Marchesi JR, et al., 2018, The implementation of omics technologies in cancer microbiome research, Ecancermedicalscience, Vol: 12, Pages: 1-11, ISSN: 1754-6605
Whilst the interplay between host genetics and the environment plays a pivotal role in the aetiopathogenesis of cancer, there are other key contributors of importance as well. One such factor of central and growing interest is the contribution of the microbiota to cancer. Even though the field is only a few years old, investigation of the ’cancer microbiome’ has already lead to major advances in knowledge of the basic biology of cancer risk and progression, opened novel avenues for biomarkers and diagnostics, and given better understanding of mechanisms underlying response to therapy. Recent developments in microbial DNA sequencing techniques (and the bioinformatics required for analysis of these datasets) has allowed much more in-depth profiling of the structure of microbial communities than was previously possible. However, for more complete assessment of the functional implications of microbial changes, there is a growing recognition of the importance of the integration of microbial profiling with other ‘omics modalities, with metabonomics (metabolite profiling) and proteomics (protein profiling) both gaining particular recent attention. In this review, we give an overview of some of the key scientific techniques being used to unravel the role of the cancer microbiome. We have aimed to highlight practical aspects related to sample collection and preparation, choice of modality of analysis, and examples of where different ‘omics technologies have been complementary to each other to highlighting the significance of the cancer microbiome.
Mullish BH, McDonald JAK, Thursz MR, et al., 2018, Antibiotic‐associated disruption of microbiota composition and function in cirrhosis is restored by fecal transplant, Hepatology, Vol: 68, Pages: 1205-1205, ISSN: 0270-9139
McDonald JAK, Kimhofer T, West K, et al., 2018, Role of the gut microbiota in autism spectrum disorder, ISME17, Publisher: Nature Publishing Group
McDonald JAK, Mullish BH, Pechlivanis A, et al., 2018, A novel route for controlling Clostridioides difficile growth via bile acid and short chain fatty acid modulation, ISME17
Allegretti JR, Mullish BH, Bogart E, et al., 2018, 25 - Microbiome and metabolic markers of Clostridium Difficile recurrance, Digestive Diseases Week, Publisher: Elsevier, Pages: S8-S9, ISSN: 0016-5085
McDonald JAK, Mullish BH, Pechlivanis A, et al., 2018, 24 - A novel route to controlling Clostridioides Difficile growth via short chain fatty acid and bile acid modulation, Digestive Diseases Week, Publisher: Elsevier, Pages: S8-S8, ISSN: 0016-5085
Alexander JL, Scott A, Poynter LR, et al., 2018, Sa1840 - The colorectal cancer mucosal microbiome is defined by disease stage and the tumour metabonome, Digestive Disease Week 2018, Publisher: Elsevier, Pages: S415-S415, ISSN: 0016-5085
Alexander JL, Scott A, Poynter LR, et al., 2018, THE COLORECTAL CANCER MUCOSAL MICROBIOME IS DEFINED BY DISEASE STAGE AND THE TUMOUR METABONOME, Annual Meeting of the American-Society-for-Gastrointestinal-Endoscopy / Digestive Disease Week, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S415-S415, ISSN: 0016-5085
Alexander JL, Scott A, Poynter LR, et al., 2018, THE EFFECT OF BOWEL PURGATIVE MEDICATION ON THE MUCOSA-ASSOCIATED MICROBIOTA MAY BE LESS SIGNIFICANT THAN WE THOUGHT, Annual Meeting of the American-Society-for-Gastrointestinal-Endoscopy / Digestive Disease Week, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S1044-S1045, ISSN: 0016-5085
McDonald JAK, 2017, <i>In vitro</i> models of the human microbiota and microbiome, EMERGING TOPICS IN LIFE SCIENCES, Vol: 1, Pages: 373-384, ISSN: 2397-8554
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- Citations: 6
Hegade VS, Pechlivanis A, McDonald JA, et al., 2017, Serum Metabonomic and Gut Microbial Profile in Patients with Primary Biliary Cholangitis with Pruritus and the Effect of Ileal Bile Acid Transporter Inhibition, 68th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, Publisher: WILEY, Pages: 171A-171A, ISSN: 0270-9139
Mullish BH, McDonald JAK, Thursz MR, et al., 2017, Fecal Microbiota Transplant From a Rational Stool Donor Improves Hepatic Encephalopathy: A Randomized Clinical Trial, HEPATOLOGY, Vol: 66, Pages: 1354-1355, ISSN: 0270-9139
Kuang Y-S, Lu J-H, Li S-H, et al., 2017, Connections between human gut microbiome and gestational diabetes mellitus, GIGASCIENCE, Vol: 6, ISSN: 2047-217X
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- Citations: 159
McDonald J, Gordon H, Blad W, et al., 2017, FIRST ANALYSIS FROM UK IBD TWIN BIOBANK; 16S RRNA GENE SEQUENCING IDENTIFIES REDUCED DIVERSITY IN ACTIVE IBD AND TAXA ASSOCIATED WITH ACTIVE DISEASE PHENOTYPE TO LEVEL OF SPECIES, Annual General Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A249-A249, ISSN: 0017-5749
Mullish BH, McDonald JAK, Kao DH, et al., 2017, OC-063 Gut microbiota-host bile acid metabolism interactions in clostridium difficile infection: the explanation for the efficacy of faecal microbiota transplantation?, British Society of Gastroenterology Annual Meeting, Publisher: BMJ Publishing Group, Pages: A33-A34, ISSN: 1468-3288
Mullish BH, McDonald J, Kao DH, et al., 2017, Understanding the mechanisms of efficacy of fecal microbiota transplantation in the treatment of Clostridium difficile Infection: the potential role of bile metabolising enzymes, Digestive Diseases Week, Publisher: Elsevier, Pages: S47-S47, ISSN: 0016-5085
Gordon H, McDonald JA, Orchard T, et al., 2017, FIRST ANALYSIS FROM UK IBD TWIN BIOBANK: 16S RRNA GENE SEQUENCING IDENTIFIES REDUCED DIVERSITY IN IBD AND BACTERIAL TAXA ASSOCIATED WITH DISEASE, Digestive Disease Week (DDW), Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S992-S993, ISSN: 0016-5085
McDonald J, Gordon H, Blad W, et al., 2017, First analysis from UK IBD Twin Biobank; 16S rRNA gene sequencing identifies reduced diversity in IBD and bacterial taxa associated with disease, Journal of Crohns & Colitis, Vol: 11, Pages: S474-S475, ISSN: 1873-9946
Mullish BH, Mcdonald JA, Pechlivanis A, et al., 2016, Understanding the efficacy of faecal microbiota transplantation in Clostridium difficile infection: re-establishment of gut microbiota with the ability to degrade bile?, British Society of Gastroenterology Annual Meeting 2016, Publisher: BMJ Publishing Group, ISSN: 1468-3288
Kindinger LM, MacIntyre DA, Lee YS, et al., 2016, Relationship between vaginal microbial dysbiosis, inflammation and pregnancy outcomes in cervical cerclage, Science Translational Medicine, Vol: 8, ISSN: 1946-6242
Preterm birth, the leading cause of death in children under five, may be caused by inflammation triggered by ascending vaginal infection. About two million cervical cerclages are performed annually to prevent preterm birth. The procedure is thought to provide structural support and maintain the endocervical mucus plug as a barrier to ascending infection. Two types of suture material are used for cerclage: monofilament or multifilament braided. Braided sutures are most frequently used, though no evidence exists to favor them over monofilament sutures. In this study we assessed birth outcomes in a retrospective cohort of 678 women receiving cervical cerclage in 5 UK university hospitals and showed that braided cerclage was associated with increased intrauterine death (15% v 5%, P = 0.0001) and preterm birth (28% v 17%, P = 0.0006) compared to monofilament suture. To understand the potential underlying mechanism, we performed a prospective, longitudinal study of the vaginal microbiome in women at risk of preterm birth because of short cervical length (≤25 mm) who received braided (n=25) or monofilament (n=24) cerclage under otherwise comparable circumstances. Braided suture induced a persistent shift towards vaginal microbiome dysbiosis characterized by reduced Lactobacillus spp. and enrichment of pathobionts. Vaginal dysbiosis was associated with inflammatory cytokine and interstitial collagenase excretion into cervicovaginal fluid and premature cervical remodeling. Monofilament suture had comparatively minimal impact upon the vaginal microbiome and its interactions with the host. These data provide in vivo evidence that a dynamic shift of the human vaginal microbiome toward dysbiosis correlates with preterm birth.
Santiago-Rodriguez TM, Ly M, Daigneault MC, et al., 2015, Chemostat culture systems support diverse bacteriophage communities from human feces., Microbiome, Vol: 3, ISSN: 2049-2618
BACKGROUND: Most human microbiota studies focus on bacteria inhabiting body surfaces, but these surfaces also are home to large populations of viruses. Many are bacteriophages, and their role in driving bacterial diversity is difficult to decipher without the use of in vitro ecosystems that can reproduce human microbial communities. RESULTS: We used chemostat culture systems known to harbor diverse fecal bacteria to decipher whether these cultures also are home to phage communities. We found that there are vast viral communities inhabiting these ecosystems, with estimated concentrations similar to those found in human feces. The viral communities are composed entirely of bacteriophages and likely contain both temperate and lytic phages based on their similarities to other known phages. We examined the cultured phage communities at five separate time points over 24 days and found that they were highly individual-specific, suggesting that much of the subject-specificity found in human viromes also is captured by this culture-based system. A high proportion of the community membership is conserved over time, but the cultured communities maintain more similarity with other intra-subject cultures than they do to human feces. In four of the five subjects, estimated viral diversity between fecal and cultured communities was highly similar. CONCLUSIONS: Because the diversity of phages in these cultured fecal communities have similarities to those found in humans, we believe these communities can serve as valuable ecosystems to help uncover the role of phages in human microbial communities.
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