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Journal articleCammarota G, Ianiro G, Kelly CR, et al., 2019,
International consensus conference on stool banking for faecal microbiota transplantation in clinical practice
, Gut, Vol: 68, Pages: 2111-2121, ISSN: 0017-5749<jats:p>Although faecal microbiota transplantation (FMT) has a well-established role in the treatment of recurrent <jats:italic>Clostridioides difficile</jats:italic> infection (CDI), its widespread dissemination is limited by several obstacles, including lack of dedicated centres, difficulties with donor recruitment and complexities related to regulation and safety monitoring. Given the considerable burden of CDI on global healthcare systems, FMT should be widely available to most centres.</jats:p><jats:p>Stool banks may guarantee reliable, timely and equitable access to FMT for patients and a traceable workflow that ensures safety and quality of procedures. In this consensus project, FMT experts from Europe, North America and Australia gathered and released statements on the following issues related to the stool banking: general principles, objectives and organisation of the stool bank; selection and screening of donors; collection, preparation and storage of faeces; services and clients; registries, monitoring of outcomes and ethical issues; and the evolving role of FMT in clinical practice,</jats:p><jats:p>Consensus on each statement was achieved through a Delphi process and then in a plenary face-to-face meeting. For each key issue, the best available evidence was assessed, with the aim of providing guidance for the development of stool banks in order to promote accessibility to FMT in clinical practice.</jats:p>
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Journal articlePinato DJ, Gramenitskaya D, Altmann DM, et al., 2019,
Antibiotic therapy and outcome from immune-checkpoint inhibitors
, Journal for ImmunoTherapy of Cancer, Vol: 7 -
PatentMarchesi JR, McDonald JAK, Mullish BH, 2019,
Clostridioides difficile
The invention relates to Clostridioides difficile, and in particular to compounds, polypeptides and mixtures for the treatment of C. difficile infections. The invention also relates to nucleic acids, vectors comprising these nucleic acids and microorganisms for the treatment of C. difficile infections, and to methods of identifying and matching faecal microbiota transplant (FMT) donors to FMT recipients.
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Journal articleAllegretti JR, Mullish B, Nativ L, et al., 2019,
185 Evaluating Dynamics of Bile Acid Metabolism to Predict Recurrence of Clostridioides difficile Infection
, American Journal of Gastroenterology, Vol: 114, Pages: S113-S113, ISSN: 0002-9270<jats:sec> <jats:title>INTRODUCTION:</jats:title> <jats:p>Recurrent <jats:italic toggle="yes">Clostridioides difficile</jats:italic> infection (CDI) is a major public health problem. The ability of commensal gut microbiota to metabolize primary into secondary bile acids plays a role in protection against this infection. Current clinical prediction tools for CDI recurrence do not incorporate biomarkers predictive of protective microbiota functionalities. We investigated metabolomic predictors of <jats:italic toggle="yes">C. difficile</jats:italic> recurrence.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>We conducted a prospective longitudinal study of patients experiencing a first CDI episode. Patients testing positive with either enzyme immunoassay (EIA) toxin or polymerase chain reaction (PCR), and being treated for CDI, were eligible for inclusion. Serial stool samples were collected at diagnosis through week-8 post-completion of anti-CDI therapy if no recurrence, or until the point of recurrence (defined as diarrhea with positive <jats:italic toggle="yes">C</jats:italic>. <jats:italic toggle="yes">difficile</jats:italic> EIA toxin stool test). Liquid chromatography-mass spectrometry was performed to profile fecal bile acids. The week 1 post-antibiotic time point was chosen to assess for potential predictors. We derived a univariate logistic regression model predicting recurrence and computed the AUC (c-statistic) on discriminatory ability. The Youden index was calculated as the value that maximizes sensitivity and specificity.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>29 first episode CDI patients were enrolled. 10 patient
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Journal articleAllegretti JR, Mullish B, Hurtado J, et al., 2019,
837 Short Chain Fatty Acid Profiles Are Altered by Fecal Microbiota Transplantation for the Treatment of Inflammatory Bowel Disease and Recurrent Clostridioides difficile Infection
, American Journal of Gastroenterology, Vol: 114, Pages: S484-S485, ISSN: 0002-9270<jats:sec> <jats:title>INTRODUCTION:</jats:title> <jats:p>Recurrent <jats:italic toggle="yes">C. difficile</jats:italic> infection (rCDI) is a major challenge among patients with inflammatory bowel disease (IBD). Perturbation of microbiota-mediated metabolism of short chain fatty acids (SCFA) has been reported in IBD patients. Fecal microbiota transplantation (FMT), an established therapy for rCDI, alters gut microbiota composition, but effects on SCFA are unclear. Accordingly, this study assessed SCFA profiles in IBD patients with rCDI pre- and post-FMT.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>This open-label, prospective, single-arm multi-center cohort study enrolled patients from 4 tertiary care centers. Patients with IBD and ≥2 episodes of CDI received a single colonoscopic FMT from a universal stool bank. The primary outcome was CDI recurrence up to week 8 defined as diarrhea and EIA-positive toxin testing for <jats:italic toggle="yes">C. difficile</jats:italic>. Stool for metabolomic profiling was collected pre-FMT and week 1, 8 and 12 weeks post-FMT. A targeted gas chromatography-mass spectrometry protocol was used for the identification and quantification of SCFA. SCFA concentrations were analyzed via univariate analysis, comparing groups (e.g. pre- <jats:italic toggle="yes">vs</jats:italic> post-FMT).</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>37 participants were enrolled, with mean age of 37.6 years (range 20-76) and primarily female (n = 21, 57%). 14 had Crohn’s disease (CD) (mean HBI = 6.4) and 23 had ulcerative colitis (UC) (mean Partial Mayo Score = 4.5). Mean baseline fecal calprotectin was 1804.8 +/- 2307.7 Overall, 3
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Journal articleMullish BH, McDonald JAK, Pechlivanis A, et al., 2019,
Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent <i>Clostridioides difficile</i> infection
, Gut, Vol: 68, Pages: 1791-1800, 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
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Journal articleSinganayagam A, Glanville N, Cuthbertson L, et al., 2019,
Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease
, Science Translational Medicine, Vol: 11, Pages: 1-13, ISSN: 1946-6234Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp-/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.
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Journal articleBates KA, Shelton JMG, Mercier VL, et al., 2019,
Captivity and infection by the fungal pathogen batrachochytrium salamandrivorans perturb the amphibian skin microbiome
, Frontiers in Microbiology, Vol: 10, ISSN: 1664-302XThe emerging fungal pathogen, Batrachochytrium salamandrivorans (Bsal) is responsible for the catastrophic decline of European salamanders and poses a threat to amphibians globally. The amphibian skin microbiome can influence disease outcome for several host-pathogen systems, yet little is known of its role in Bsal infection. In addition, many experimental in-vivo amphibian disease studies to date have relied on specimens that have been kept in captivity for long periods without considering the influence of environment on the microbiome and how this may impact the host response to pathogen exposure. We characterized the impact of captivity and exposure to Bsal on the skin bacterial and fungal communities of two co-occurring European newt species, the smooth newt, Lissotriton vulgaris and the great-crested newt, Triturus cristatus. We show that captivity led to significant losses in bacterial and fungal diversity of amphibian skin, which may be indicative of a decline in microbe-mediated protection. We further demonstrate that in both L. vulgaris and T. cristatus, Bsal infection was associated with changes in the composition of skin bacterial communities with possible negative consequences to host health. Our findings advance current understanding of the role of host-associated microbiota in Bsal infection and highlight important considerations for ex-situ amphibian conservation programmes.
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Journal articleAllegretti 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: 420-431Developments 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.
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Conference paperRiaz 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
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