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Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent Clostridioides difficile infection

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Title: Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent Clostridioides difficile infection
Authors: Mullish, BH
McDonald, JAK
Pechlivanis, A
Allegretti, JR
Kao, D
Barker, GF
Kapila, D
Petrof, EO
Joyce, SA
Gahan, CGM
Glegola-Madejska, I
Williams, HRT
Holmes, E
Clarke, TB
Thursz, MR
Marchesi, JR
Item Type: Journal Article
Abstract: Objective 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.
Issue Date: 11-Feb-2019
Date of Acceptance: 15-Jan-2019
URI: http://hdl.handle.net/10044/1/67139
DOI: https://dx.doi.org/10.1136/gutjnl-2018-317842
ISSN: 0017-5749
Publisher: BMJ Publishing Group
Journal / Book Title: Gut
Copyright Statement: © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Wellcome Trust
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council
Medical Research Council (MRC)
Imperial College London Joint Translational Fund
Funder's Grant Number: 107660/Z/15/Z
RDA27
RDA02
MR/R00875/1
MR/R000875/1
Keywords: 1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
Gastroenterology & Hepatology
Publication Status: Published online
Online Publication Date: 2019-02-11
Appears in Collections:Division of Surgery
Department of Medicine
Faculty of Medicine



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