Show simple item record

dc.contributor.authorLaurans, Ludivine
dc.contributor.authorVenteclef, Nicolas
dc.contributor.authorHaddad, Yacine
dc.contributor.authorChajadine, Mouna
dc.contributor.authorAlzaid, Fawaz
dc.contributor.authorMetghalchi, Sarvenaz
dc.contributor.authorSovran, Bruno
dc.contributor.authorDenis, Raphael GP
dc.contributor.authorDairou, Julien
dc.contributor.authorCardellini, Marina
dc.contributor.authorMoreno-Navarrete, Jose-Maria
dc.contributor.authorStraub, Marjolene
dc.contributor.authorJegou, Sarah
dc.contributor.authorMcQuitty, Claire
dc.contributor.authorViel, Thomas
dc.contributor.authorEsposito, Bruno
dc.contributor.authorTavitian, Bertrand
dc.contributor.authorCallebert, Jacques
dc.contributor.authorLuquet, Serge H
dc.contributor.authorFederici, Massimo
dc.contributor.authorFernandez-Real, José Manuel
dc.contributor.authorBurcelin, Remy
dc.contributor.authorLaunay, Jean-Marie
dc.contributor.authorTedgui, Alain
dc.contributor.authorMallat, Ziad
dc.contributor.authorSokol, Harry
dc.contributor.authorTaleb, Soraya
dc.date.accessioned2018-09-08T06:33:55Z
dc.date.available2018-09-08T06:33:55Z
dc.date.issued2018-08
dc.identifier.issn1078-8956
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/279896
dc.description.abstractThe association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood1,2. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells3,4. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome5-9 and may promote atherosclerosis and vascular inflammation6, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity10-13, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.subjectIntestines
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectHumans
dc.subjectFatty Liver
dc.subjectDiabetes Mellitus, Type 2
dc.subjectInsulin Resistance
dc.subjectObesity
dc.subjectInflammation
dc.subjectLipopolysaccharides
dc.subjectTryptophan
dc.subjectKynurenine
dc.subjectInterleukins
dc.subjectPrincipal Component Analysis
dc.subjectHealth
dc.subjectMale
dc.subjectIndoleamine-Pyrrole 2,3,-Dioxygenase
dc.subjectGastrointestinal Microbiome
dc.titleGenetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.
dc.typeArticle
prism.endingPage1120
prism.issueIdentifier8
prism.publicationDate2018
prism.publicationNameNat Med
prism.startingPage1113
prism.volume24
dc.identifier.doi10.17863/CAM.27264
dcterms.dateAccepted2018-04-23
rioxxterms.versionofrecord10.1038/s41591-018-0060-4
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-08
dc.contributor.orcidAlzaid, Fawaz [0000-0003-3056-3640]
dc.contributor.orcidFederici, Massimo [0000-0003-4989-5194]
dc.contributor.orcidMallat, Ziad [0000-0003-0443-7878]
dc.contributor.orcidTaleb, Soraya [0000-0002-6650-619X]
dc.identifier.eissn1546-170X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idBritish Heart Foundation (RG/15/11/31593)
cam.issuedOnline2018-06-25
rioxxterms.freetoread.startdate2019-08-31


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record