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Journal articleAllegretti JR, Mullish BH, 2020,
Faecal microbiota transplantations and urinary tract infections – Authors' reply
, The Lancet, Vol: 395, Pages: 271-271, ISSN: 0140-6736 -
Journal articleSegal JP, Mullish BH, Quraishi MN, et al., 2020,
Mechanisms underpinning the efficacy of faecal microbiota transplantation in treating gastrointestinal disease
, Therapeutic Advances in Gastroenterology, Vol: 13, ISSN: 1756-2848<jats:p> Faecal microbiota transplantation (FMT) is currently a recommended therapy for recurrent/refractory Clostridioides difficile infection (CDI). The success of FMT for CDI has led to interest in its therapeutic potential in many other disorders. The mechanisms that underpin the efficacy of FMT are not fully understood. Importantly, FMT remains a crucial treatment in managing CDI and understanding the mechanisms that underpin its success will be critical to improve its clinical efficacy, safety and usability. Furthermore, a deeper understanding of this may allow us to expose FMT’s full potential as a therapeutic tool for other disease states. This review will explore the current understanding of the mechanisms underlying the efficacy of FMT across a variety of diseases. </jats:p>
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Journal articleSegal JP, Mak JWY, Mullish BH, et al., 2020,
The gut microbiome: an under-recognised contributor to the COVID-19 pandemic?
, Therapeutic Advances in Gastroenterology, Vol: 13, ISSN: 1756-2848<jats:p> The novel coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus has spread rapidly across the globe, culminating in major global morbidity and mortality. As such, there has been a rapid escalation in scientific and clinical activity aimed at increasing our comprehension of this virus. This volume of work has led to early insights into risk factors associated with severity of disease, and mechanisms that underpin the virulence and dynamics involved in viral transmission. These insights ultimately may help guide potential therapeutics to reduce the human, economic and social impact of this pandemic. Importantly, the gastrointestinal (GI) tract has emerged as an important organ influencing propensity to, and potentially severity of, COVID-19 infection. Furthermore, the gut microbiome has been linked to a variety of risk factors for COVID-19 infection, and manipulation of the gut microbiome is an attractive potential therapeutic target for a number of diseases. While data profiling the gut microbiome in COVID-19 infection to date are limited, they support the possibility of several routes of interaction between COVID-19, the gut microbiome, angiotensin converting enzyme 2 (ACE-2) expression in the small bowel and colon and gut inflammation. This article will explore the evidence that implicates the gut microbiome as a contributing factor to the pathogenesis, severity and disease course of COVID-19, and speculate about the gut microbiome’s capability as a therapeutic avenue against COVID-19. </jats:p><jats:sec><jats:title>Lay summary</jats:title><jats:p> It has been noted that certain baseline gut profiles of COVID-19 patients are associated with a more severe disease course, and the gut microbiome impacts the disease course of several contributory risk factors to the severity of COVID-19. A protein called ACE-2, which is found in the small intestine among other sites, is a key receptor for COVID-19 virus entry
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Journal articleMcSweeney B, Allegretti JR, Fischer M, et al., 2020,
In search of stool donors: a multicenter study of prior knowledge, perceptions, motivators, and deterrents among potential donors for fecal microbiota transplantation.
, Gut Microbes, Vol: 11, Pages: 51-62Fecal 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.
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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 -
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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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 Clostridioides difficile infection
, Gut, Vol: 68, Pages: 1791-1800, ISSN: 0017-5749Objective Faecal microbiota transplant (FMT) effectively treats recurrent Clostridioides difficile infection (rCDI), but its mechanisms of action remain poorly defined. Certain bile acids affect C. difficile 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.Design 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 bsh/baiCD genes involved in bile metabolism. Human data were validated in C. difficile batch cultures and a C57BL/6 mouse model of rCDI.Results 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 C. difficile germinant); TCA levels negatively correlated with key bacterial genera containing BSH-producing organisms. Post-FMT samples demonstrated recovered BSH activity and bsh/baiCD gene copy number compared with pretreatment (p<0.05). In batch cultures, supernatant from engineered bsh-expressing E. coli and naturally BSH-producing organisms (Bacteroides ovatus, Collinsella aerofaciens, Bacteroides vulgatus and Blautia obeum) reduced TCA-mediated C. difficile germination relative to culture supernatant of wild-type (BSH-negative) E. coli. C. difficile total viable counts were ~70% reduced in an rCDI mouse model after administration of E. coli expressing highly active BSH relative to mice administered BSH-negative E. coli (p<0.05).Conclusion Restoration of gut BSH functionality contributes to the efficacy of FMT in treating rCDI.
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