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Journal articleMullish BH, Pechlivanis A, Barker GF, et al., 2018,
Functional microbiomics: Evaluation of gut microbiota-bile acid metabolism interactions in health and disease.
, Methods (San Diego, Calif.), Vol: 149, Pages: 49-58, ISSN: 1046-2023There 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.
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- Citations: 52
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Journal articleMonaghan T, Mullish BH, Patterson J, et al., 2018,
Effective fecal microbiota transplantation for recurrent Clostridioides difficile in humans is associated with increased signalling in bile acid-farnesoid X receptor-fibroblast growth factor pathway
, Gut Microbes, Vol: 10, Pages: 142-148, ISSN: 1949-0984The 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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Journal articleMullish BH, Osborne LS, Marchesi JR, et al., 2018,
The implementation of omics technologies in cancer microbiome research
, Ecancermedicalscience, Vol: 12, Pages: 1-11, ISSN: 1754-6605Whilst 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.
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Journal articleAbdolrasouli A, Bercusson AC, Rhodes JL, et al., 2018,
Airway persistence by the emerging multi-azole-resistant Rasamsonia argillacea complex in cystic fibrosis
, Mycoses, Vol: 61, Pages: 665-673, ISSN: 0933-7407Infections caused by Rasamsonia argillacea complex have been reported in various clinical settings. Cystic fibrosis (CF) is one of the main underlying conditions. An observational cohort study of CF patients with Rasamsonia in respiratory samples was conducted. Eight isolates from six patients were identified as R. argillacea complex and tested for antifungal susceptibility. All isolates had high MICs to voriconazole and posaconazole and low MECs to echinocandins. Four patients experienced lung function decline in the year preceding first Rasamsonia isolation. This continued in the year following first isolation in three out of four cases. Antifungal therapy was initiated in two patients, to which only one exhibited a clinical response. Three out of six patients died within three years of isolating Rasamsonia. Genotyping suggests that similar genotypes of Rasamsonia can persist in CF airways. Consistent with other fungi in CF, the clinical impact of airway colonization by Rasamsonia is variable. In certain patients, Rasamsonia may be able to drive clinical decline. In others, though a clear impact on lung function may be difficult to determine, the appearance of Rasamsonia acts as a marker of disease severity. In others it does not appear to have an obvious clinical impact on disease progression.
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Journal articleMullish BH, Quraishi MN, Segal JP, et al., 2018,
The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines
, Journal of Hospital Infection, Vol: 100, Pages: S1-S31, ISSN: 0195-6701Interest in the therapeutic potential of faecal microbiota transplant (FMT) has been increasing globally in recent years, particularly as a result of randomised studies in which it has been used as an intervention. The main focus of these studies has been the treatment of recurrent or refractory Clostridium difficile infection (CDI), but there is also an emerging evidence base regarding potential applications in non-CDI settings. The key clinical stakeholders for the provision and governance of FMT services in the United Kingdom (UK) have tended to be in two major specialty areas: gastroenterology and microbiology/infectious diseases. While the National Institute for Health and Care Excellence (NICE) guidance (2014) for use of FMT for recurrent or refractory CDI has become accepted in the UK, clear evidence-based UK guidelines for FMT have been lacking. This resulted in discussions between the British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS), and a joint BSG/HIS FMT working group was established. This guideline document is the culmination of that joint dialogue.
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Journal articleMullish 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 -
Journal articleAhmed B, Cox MJ, Cuthbertson L, et al., 2018,
Comparison of the upper and lower airway microbiota in children with chronic lung diseases
, PLoS ONE, Vol: 13, ISSN: 1932-6203RationaleThe lower airway microbiota is important in normal immunological development and chronic lung diseases (CLDs). Young children cannot expectorate and because of the uncertainty whether upper airway samples reflect the lower airway microbiota, there have been few longitudinal paediatric studies to date.ObjectivesTo assess whether throat swabs (TS) and cough swabs (CS) are representative of the lower airway microbiota.MethodsTS, CS, bronchoalveolar lavage and bronchial brushings were prospectively collected from 49 children undergoing fibreoptic bronchoscopy for CLDs. Bacterial DNA was extracted and the 16S rRNA gene V4 region sequenced using the Illumina MiSeq.Results5.97 million high quality reads were obtained from 168 samples (47 TS, 37 CS, 42 BALF and 42 bronchial brushings). CS sequenced poorly. At a community level, no difference in alpha diversity (richness, evenness or Shannon Diversity Index) was seen between lower airway samples and TS (P > 0.05). Less than 6.31% of beta diversity variation related to sampling method for TS (P = 0.001). Variation between pathologies and individual patients was greater (20%, 54% respectively P ≤ 0.001) than between TS and lower airway samples. There was strong correlation in the relative abundance of genera between samples (r = 0.78, P < 0.001). Similarity between upper and lower airway samples was observed to be less for individuals where one sample type was dominated by a single organism.ConclusionsAt the community structure level, TS correlate with lower airway samples and distinguish between different CLDs. TS may be a useful sample for the study of the differences in longitudinal changes in the respiratory microbiota between different CLDs. Differences are too great however for TS to be used for clinical decision making.
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Journal articleHoyles L, Fernández-Real JM, Federici M, et al., 2018,
Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women
, Nature Medicine, Vol: 24, Pages: 1-17, ISSN: 1078-8956Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.
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Journal articleCanessa S, Bozzuto C, Campbell Grant EH, et al., 2018,
Decision-making for mitigating wildlife diseases: From theory to practice for an emerging fungal pathogen of amphibians
, Journal of Applied Ecology, Vol: 55, Pages: 1987-1996, ISSN: 0021-8901Conservation science can be most effective in its decision-support role when seeking answers to clearly formulated questions of direct management relevance. Emerging wildlife diseases, a driver of global biodiversity loss, illustrate the challenges of performing this role: in spite of considerable research, successful disease mitigation is uncommon. Decision analysis is increasingly advocated to guide mitigation planning, but its application remains rare. Using an integral projection model, we explored potential mitigation actions for avoiding population declines and the ongoing spatial spread of the fungus Batrachochytrium salamandrivorans (Bsal). This fungus has recently caused severe amphibian declines in north-western Europe and currently threatens Palearctic salamander diversity. Available evidence suggests that a Bsal outbreak in a fire salamander (Salamandra salamandra) population will lead to its rapid extirpation. Treatments such as antifungals or probiotics would need to effectively interrupt transmission (reduce probability of infection by nearly 90%) in order to reduce the risk of host extirpation and successfully eradicate the pathogen. Improving the survival of infected hosts is most likely to be detrimental as it increases the potential for pathogen transmission and spread. Active removal of a large proportion of the host population has some potential to locally eradicate Bsal and interrupt its spread, depending on the presence of Bsal reservoirs and on the host's spatial dynamics, which should therefore represent research priorities. Synthesis and applications. Mitigation of Batrachochytrium salamandrivorans epidemics in susceptible host species is highly challenging, requiring effective interruption of transmission and radical removal of host individuals. More generally, our study illustrates the advantages of framing conservation science directly in the management decision context, rather than adapting to it a posteriori.
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Journal articleMullish BH, Williams HRT, 2018,
Clostridium difficile infection and antibiotic-associated diarrhoea.
, Clinical Medicine, Vol: 18, Pages: 237-241, ISSN: 1470-2118Antibiotic-associated diarrhoea is amongst the most common adverse events related to antibiotic use. Most cases are mild, but Clostridium difficile infection causes a spectrum of disease ranging from occasional diarrhoea to colitis, toxic megacolon, and potentially death. Recent developments in our understanding of the biology of the gut microbiota have given new insights into the pathogenesis of these conditions, as well as revealing a role for manipulation of the gut microbiota as a novel therapeutic approach. This CME review will give an overview of assessment of these conditions, before particularly focusing on the rapidly-developing area of their treatment.
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