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

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dc.contributor.authorMullish, Benjamin H.
dc.contributor.authorMcDonald, Julie A. K.
dc.contributor.authorPechlivanis, Alexandros
dc.contributor.authorAllegretti, Jessica R.
dc.contributor.authorKao, Dina
dc.contributor.authorBarker, Grace F.
dc.contributor.authorKapila, Diya
dc.contributor.authorPetrof, Elaine O.
dc.contributor.authorJoyce, Susan A.
dc.contributor.authorGahan, Cormac G.
dc.contributor.authorGlegola-Madejska, Izabela
dc.contributor.authorWilliams, Horace R. T.
dc.contributor.authorHolmes, Elaine
dc.contributor.authorClarke, Thomas B.
dc.contributor.authorThursz, Mark R.
dc.contributor.authorMarchesi, Julian R.
dc.contributor.funderNational Institute for Health Researchen
dc.contributor.funderBiomedical Research Centreen
dc.date.accessioned2019-11-26T05:46:55Z
dc.date.available2019-11-26T05:46:55Z
dc.date.issued2019-02-11
dc.description.abstractObjective: 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.en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMullish, B.H., McDonald, J.A., Pechlivanis, A., Allegretti, J.R., Kao, D., Barker, G.F., Kapila, D., Petrof, E.O., Joyce, S.A., Gahan, C.G.M., Glegola-Madejska, I., Williams, H.R.T., Holmes, E., Clarke, T.B., Thursz, M.R. and Marchesi, J.R. (2019) ‘Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent Clostridioides difficile infection’. Gut, 68, pp.1791-1800. doi:10.1136/gutjnl-2018-317842en
dc.identifier.doi10.1136/gutjnl-2018-317842en
dc.identifier.eissn1468-3288
dc.identifier.endpage1800en
dc.identifier.issn0017-5749
dc.identifier.journaltitleGuten
dc.identifier.startpage1791en
dc.identifier.urihttps://hdl.handle.net/10468/9227
dc.identifier.volume68en
dc.language.isoenen
dc.publisherBMJ Publishing Groupen
dc.relation.urihttps://gut.bmj.com/content/early/2019/02/11/gutjnl-2018-317842
dc.rights© 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/.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectFaecal microbiota transplant (FMT)en
dc.subjectRecurrent Clostridioides difficile infection (rCDI)en
dc.subjectBile salt hydrolases (BSHs)en
dc.titleMicrobial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent Clostridioides difficile infectionen
dc.typeArticle (peer-reviewed)en
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