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Inhibiting growth of clostridioides difficile by restoring valerate, produced by the intestinal microbiota

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Title: Inhibiting growth of clostridioides difficile by restoring valerate, produced by the intestinal microbiota
Authors: McDonald, JAK
Mullish, BH
Pechlivanis, A
Liu, Z
Brignardello, J
Kao, D
Holmes, E
Li, JV
Clarke, TB
Thursz, MR
Marchesi, JR
Item Type: Journal Article
Abstract: Background & Aims Fecal 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. Methods We 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. Results In 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 saline. Conclusions We identified valerate as a metabolite that is depleted with clindamycin and only recovered with FMT. Valerate is a target for a rationally designed recurrent CDI therapy.
Issue Date: Nov-2018
Date of Acceptance: 9-Jul-2018
URI: http://hdl.handle.net/10044/1/62121
DOI: https://doi.org/10.1053/j.gastro.2018.07.014
ISSN: 0016-5085
Publisher: Elsevier
Start Page: 1495
End Page: 1507.e15
Journal / Book Title: Gastroenterology
Volume: 155
Issue: 5
Copyright Statement: © 2018 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor/Funder: Medical Research Council
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Wellcome Trust
Medical Research Council (MRC)
Medical Research Council (MRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust- BRC Funding
Kristian Gerhard Jebsen Foundation
Bowel & Cancer Research
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Seattle ChildrensHospital Research Foundation
The Academy of Medical Sciences
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare Charity
Imperial College London
St Stephen's Aids Trust
Imperial College London Joint Translational Fund
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
National Institute for Health Research
Funder's Grant Number: MR/R00875/1
MR/R000875/1
RDA27
RDA02
107660/Z/15/Z
MR/L009226/1
MR/L009226/1
BB/L020858/1
BH124127
RDA01 79560
None Given
N/A
EME/13/121/07
RDA05 79560
RDB04
N/A
Springboard
RDA27
RDA27
RDA27
RF17/1011
SSAT054
RDB01
MR/P028225/1
EME/13/121/07
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
Bacteria
Stool Transplant
Gut Microbiome
Pathogen
HUMAN GUT MODEL
CHAIN FATTY-ACIDS
TOXIN PRODUCTION
IN-VITRO
PROLINE REDUCTASE
MASS-SPECTROMETRY
CHEMOSTAT MODEL
UNITED-STATES
INFECTION
TRANSPLANTATION
Bacteria
Gut Microbiome
Pathogen
Stool Transplant
Animals
Bile Acids and Salts
Chromatography, High Pressure Liquid
Clindamycin
Clostridium Infections
Clostridium difficile
Feces
Female
Gas Chromatography-Mass Spectrometry
Gastrointestinal Microbiome
Magnetic Resonance Spectroscopy
Mice, Inbred C57BL
Spores, Bacterial
Triglycerides
Valerates
Feces
Animals
Mice, Inbred C57BL
Clostridium difficile
Spores, Bacterial
Clostridium Infections
Valerates
Clindamycin
Bile Acids and Salts
Triglycerides
Chromatography, High Pressure Liquid
Magnetic Resonance Spectroscopy
Female
Gas Chromatography-Mass Spectrometry
Gastrointestinal Microbiome
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
1109 Neurosciences
Gastroenterology & Hepatology
Publication Status: Published
Online Publication Date: 2018-07-17
Appears in Collections:Department of Infectious Diseases