Kynurenine pathway metabolism and the microbiota-gut-brain axis

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dc.contributor.authorKennedy, Paul J.
dc.contributor.authorCryan, John F.
dc.contributor.authorDinan, Timothy G.
dc.contributor.authorClarke, Gerard
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderHealth Research Boarden
dc.contributor.funderBrain and Behavior Research Foundationen
dc.contributor.funderSeventh Framework Programmeen
dc.date.accessioned2018-01-19T13:08:40Z
dc.date.available2018-01-19T13:08:40Z
dc.date.issued2016-07-05
dc.date.updated2018-01-18T12:53:05Z
dc.description.abstractIt has become increasingly clear that the gut microbiota influences not only gastrointestinal physiology but also central nervous system (CNS) function by modulating signalling pathways of the microbiota-gut-brain axis. Understanding the neurobiological mechanisms underpinning the influence exerted by the gut microbiota on brain function and behaviour has become a key research priority. Microbial regulation of tryptophan metabolism has become a focal point in this regard, with dual emphasis on the regulation of serotonin synthesis and the control of kynurenine pathway metabolism. Here, we focus in detail on the latter pathway and begin by outlining the structural and functional dynamics of the gut microbiota and the signalling pathways of the brain-gut axis. We summarise preclinical and clinical investigations demonstrating that the gut microbiota influences CNS physiology, anxiety, depression, social behaviour, cognition and visceral pain. Pertinent studies are drawn from neurogastroenterology demonstrating the importance of tryptophan and its metabolites in CNS and gastrointestinal function. We outline how kynurenine pathway metabolism may be regulated by microbial control of neuroendocrine function and components of the immune system. Finally, preclinical evidence demonstrating direct and indirect mechanisms by which the gut microbiota can regulate tryptophan availability for kynurenine pathway metabolism, with downstream effects on CNS function, is reviewed. Targeting the gut microbiota represents a tractable target to modulate kynurenine pathway metabolism. Efforts to develop this approach will markedly increase our understanding of how the gut microbiota shapes brain and behaviour and provide new insights towards successful translation of microbiota-gut-brain axis research from bench to bedside.en
dc.description.sponsorshipHealth Research Board (Grant number HRA-POR-2014-64); Brain and Behavior Research Foundation (Grant Number 20771)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationKennedy, P. J., Cryan, J. F., Dinan, T. G. and Clarke, G. (2016) 'Kynurenine pathway metabolism and the microbiota-gut-brain axis', Neuropharmacology, 112, pp. 399-412. doi:10.1016/j.neuropharm.2016.07.002en
dc.identifier.doi10.1016/j.neuropharm.2016.07.002
dc.identifier.endpage412en
dc.identifier.issn0028-3908
dc.identifier.journaltitleNeuropharmacologyen
dc.identifier.startpage399en
dc.identifier.urihttps://hdl.handle.net/10468/5302
dc.identifier.volume112en
dc.language.isoenen
dc.publisherElsevier Ltd.en
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2273/IE/Alimentary Pharmabiotic Centre (APC) - Interfacing Food & Medicine/en
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::KBBE/613979/EU/Microbiome Influence on Energy balance and Brain Development-Function Put into Action to Tackle Diet-related Diseases and Behavior./MYNEWGUTen
dc.rights© 2016, Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectTryptophanen
dc.subjectKynurenineen
dc.subjectStressen
dc.subjectImmune systemen
dc.subjectMicrobiota-gut-brain-axisen
dc.subjectBehaviouren
dc.titleKynurenine pathway metabolism and the microbiota-gut-brain axisen
dc.typeArticle (peer-reviewed)en
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