Julie A K McDonald1, Benjamin H Mullish1, Alexandros Pechlivanis1, Zhigang Liu1, Jerusa Brignardello1, Dina Kao2, Elaine Holmes1, Jia V Li1, Thomas B Clarke3, Mark R Thursz1, Julian R Marchesi4. 1. Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom. 2. Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. 3. MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom. 4. Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom; School of Biosciences, Cardiff University, Cardiff, United Kingdom. Electronic address: j.marchesi@imperial.ac.uk.
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, proton nuclear magnetic resonance spectroscopy, and ultra-performance liquid chromatography and 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 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 total viable counts (94% decrease), spore counts (86% decrease), 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. Clostridioides difficile batch cultures confirmed that valerate decreased vegetative growth, and that taurocholic acid was required for germination but had no effect on vegetative growth. Clostridioides difficile total viable counts were decreased by 95% in mice with CDI given glycerol trivalerate compared with 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.
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, proton nuclear magnetic resonance spectroscopy, and ultra-performance liquid chromatography and 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 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 total viable counts (94% decrease), spore counts (86% decrease), 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. Clostridioides difficile batch cultures confirmed that valerate decreased vegetative growth, and that taurocholic acid was required for germination but had no effect on vegetative growth. Clostridioides difficile total viable counts were decreased by 95% in mice with CDI given glycerol trivalerate compared with 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.
Authors: Simon D Baines; Rachael O'Connor; Katie Saxton; Jane Freeman; Mark H Wilcox Journal: J Antimicrob Chemother Date: 2008-09-04 Impact factor: 5.790
Authors: Rosemarie Peri; Rebeca Cruz Aguilar; Kester Tüffers; Andreas Erhardt; Alexander Link; Philipp Ehlermann; Wolfgang Angeli; Thorsten Frank; Martin Storr; Thomas Glück; Andreas Sturm; Ulrich Rosien; Frank Tacke; Oliver Bachmann; Philipp Solbach; Andreas Stallmach; Felix Goeser; Maria Jgt Vehreschild Journal: United European Gastroenterol J Date: 2019-03-21 Impact factor: 4.623
Authors: Tanya M Monaghan; Niharika A Duggal; Elisa Rosati; Ruth Griffin; Jamie Hughes; Brandi Roach; David Y Yang; Christopher Wang; Karen Wong; Lynora Saxinger; Maja Pučić-Baković; Frano Vučković; Filip Klicek; Gordan Lauc; Paddy Tighe; Benjamin H Mullish; Jesus Miguens Blanco; Julie A K McDonald; Julian R Marchesi; Ning Xue; Tania Dottorini; Animesh Acharjee; Andre Franke; Yingrui Li; Gane Ka-Shu Wong; Christos Polytarchou; Tung On Yau; Niki Christodoulou; Maria Hatziapostolou; Minkun Wang; Lindsey A Russell; Dina H Kao Journal: Cells Date: 2021-11-19 Impact factor: 6.600
Authors: Jorge E Vidal; Meagan N Wier; Uriel A Angulo-Zamudio; Erin McDevitt; Ana G Jop Vidal; Babek Alibayov; Anna Scasny; Sandy M Wong; Brian J Akerley; Larry S McDaniel Journal: Infect Immun Date: 2021-09-20 Impact factor: 3.441
Authors: Daniel A Schupack; Ruben A T Mars; Dayne H Voelker; Jithma P Abeykoon; Purna C Kashyap Journal: Nat Rev Gastroenterol Hepatol Date: 2021-08-27 Impact factor: 46.802
Authors: Jessica R Allegretti; Colleen R Kelly; Ari Grinspan; Benjamin H Mullish; Jonathan Hurtado; Madeline Carrellas; Jenna Marcus; Julian R Marchesi; Julie A K McDonald; Ylaine Gerardin; Michael Silverstein; Alexandros Pechlivanis; Grace F Barker; Jesus Miguens Blanco; James L Alexander; Kate I Gallagher; Will Pettee; Emmalee Phelps; Sara Nemes; Sashidhar V Sagi; Matthew Bohm; Zain Kassam; Monika Fischer Journal: Inflamm Bowel Dis Date: 2021-08-19 Impact factor: 5.325
Authors: Yannick D N Tremblay; Benjamin A R Durand; Audrey Hamiot; Isabelle Martin-Verstraete; Marine Oberkampf; Marc Monot; Bruno Dupuy Journal: ISME J Date: 2021-06-21 Impact factor: 10.302
Authors: Anthony M Buckley; Ines B Moura; Norie Arai; William Spittal; Emma Clark; Yoshihiro Nishida; Hannah C Harris; Karen Bentley; Georgina Davis; Dapeng Wang; Suparna Mitra; Takanobu Higashiyama; Mark H Wilcox Journal: Front Cell Infect Microbiol Date: 2021-07-02 Impact factor: 5.293