{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:51:52Z","timestamp":1792191112115,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.pbio.3001765","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000}}],"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T00:00:00Z","timestamp":1662940800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["948207"],"award-info":[{"award-number":["948207"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006209","name":"Radboud Universitair Medisch Centrum","doi-asserted-by":"publisher","award":["Hypatia grant 2018"],"award-info":[{"award-number":["Hypatia grant 2018"]}],"id":[{"id":"10.13039\/501100006209","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Helmholtz Initiative and Networking Fund","award":["1800167"],"award-info":[{"award-number":["1800167"]}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["833247"],"award-info":[{"award-number":["833247"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["Spinoza grant"],"award-info":[{"award-number":["Spinoza grant"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>The antituberculosis vaccine Bacillus Calmette\u2013Gu\u00e9rin (BCG) induces nonspecific protection against heterologous infections, at least partly through induction of innate immune memory (trained immunity). The amplitude of the response to BCG is variable, but the factors that influence this response are poorly understood. Metabolites, either released by cells or absorbed from the gut, are known to influence immune responses, but whether they impact BCG responses is not known. We vaccinated 325 healthy individuals with BCG, and collected blood before, 2 weeks and 3 months after vaccination, to assess the influence of circulating metabolites on the immune responses induced by BCG. Circulating metabolite concentrations after BCG vaccination were found to have a more pronounced impact on trained immunity responses, such as the increase in IL-1\u03b2 and TNF-\u03b1 production upon <jats:italic>Staphylococcus aureus<\/jats:italic> stimulation, than on specific adaptive immune memory, assessed as IFN-\u03b3 production in response to <jats:italic>Mycobacterium tuberculosis<\/jats:italic>. Circulating metabolites at baseline were able to predict trained immunity responses at 3 months after vaccination and enrichment analysis based on the metabolites positively associated with trained immunity revealed enrichment of the tricarboxylic acid (TCA) cycle and glutamine metabolism, both of which were previously found to be important for trained immunity. Several new metabolic pathways that influence trained immunity were identified, among which taurine metabolism associated with BCG-induced trained immunity, a finding validated in functional experiments. In conclusion, circulating metabolites are important factors influencing BCG-induced trained immunity in humans. Modulation of metabolic pathways may be a novel strategy to improve vaccine and trained immunity responses.<\/jats:p>","DOI":"10.1371\/journal.pbio.3001765","type":"journal-article","created":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T17:42:14Z","timestamp":1663004534000},"page":"e3001765","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":52,"title":["Plasma metabolome predicts trained immunity responses after antituberculosis BCG vaccination"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5783-9013","authenticated-orcid":true,"given":"Valerie A. C. M.","family":"Koeken","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cancan","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera P.","family":"Mourits","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. Charlotte J.","family":"de Bree","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone J. C. F. M.","family":"Moorlag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidhisha","family":"Sonawane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Lemmers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga","family":"Dijkstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6166-9830","authenticated-orcid":true,"given":"Leo A. B.","family":"Joosten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6607-4075","authenticated-orcid":true,"given":"Arjan","family":"van Laarhoven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1586-4672","authenticated-orcid":true,"given":"Cheng-Jian","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6233-6410","authenticated-orcid":true,"given":"Reinout","family":"van Crevel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihai G.","family":"Netea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,9,12]]},"reference":[{"issue":"6","key":"pbio.3001765.ref001","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41577-020-0285-6","article-title":"Defining trained immunity and its role in health and disease","volume":"20","author":"MG Netea","year":"2020","journal-title":"Nat Rev Immunol"},{"issue":"2","key":"pbio.3001765.ref002","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1093\/infdis\/jir240","article-title":"Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?","volume":"204","author":"P Aaby","year":"2011","journal-title":"J Infect Dis"},{"issue":"7","key":"pbio.3001765.ref003","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1093\/cid\/cix525","article-title":"Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial","volume":"65","author":"S Biering-Sorensen","year":"2017","journal-title":"Clin Infect Dis"},{"issue":"43","key":"pbio.3001765.ref004","doi-asserted-by":"crossref","first-page":"17537","DOI":"10.1073\/pnas.1202870109","article-title":"Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes","volume":"109","author":"J Kleinnijenhuis","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pbio.3001765.ref005","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.clim.2014.10.005","article-title":"BCG-induced trained immunity in NK cells: Role for non-specific protection to infection","volume":"155","author":"J Kleinnijenhuis","year":"2014","journal-title":"Clin Immunol"},{"issue":"1","key":"pbio.3001765.ref006","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/s41588-018-0298-2","article-title":"Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments","volume":"51","author":"S Fanucchi","year":"2019","journal-title":"Nat Genet"},{"issue":"11","key":"pbio.3001765.ref007","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1089\/ars.2017.7310","article-title":"Epigenetics and Trained Immunity","volume":"29","author":"C van der Heijden","year":"2018","journal-title":"Antioxid Redox Signal"},{"issue":"10","key":"pbio.3001765.ref008","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1016\/j.celrep.2016.11.011","article-title":"Immunometabolic Pathways in BCG-Induced Trained Immunity.","volume":"17","author":"RJW Arts","year":"2016","journal-title":"Cell Rep"},{"issue":"6","key":"pbio.3001765.ref009","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.cmet.2016.10.008","article-title":"Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity.","volume":"24","author":"RJ Arts","year":"2016","journal-title":"Cell Metab."},{"issue":"1","key":"pbio.3001765.ref010","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.chom.2017.12.010","article-title":"BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity","volume":"23","author":"RJW Arts","year":"2018","journal-title":"Cell Host Microbe"},{"issue":"1","key":"pbio.3001765.ref011","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1038\/s41467-019-08659-3","article-title":"Outcomes of controlled human malaria infection after BCG vaccination.","volume":"10","author":"J Walk","year":"2019","journal-title":"Nat Commun."},{"issue":"4","key":"pbio.3001765.ref012","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1093\/cid\/cit790","article-title":"Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials","volume":"58","author":"P Mangtani","year":"2014","journal-title":"Clin Infect Dis"},{"issue":"10","key":"pbio.3001765.ref013","doi-asserted-by":"crossref","first-page":"5591","DOI":"10.1172\/JCI133935","article-title":"BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner","volume":"130","author":"VA Koeken","year":"2020","journal-title":"J Clin Invest"},{"issue":"10","key":"pbio.3001765.ref014","doi-asserted-by":"crossref","first-page":"5603","DOI":"10.1172\/JCI133934","article-title":"Circadian rhythm influences induction of trained immunity by BCG vaccination","volume":"130","author":"LCJ de Bree","year":"2020","journal-title":"J Clin Invest"},{"issue":"9","key":"pbio.3001765.ref015","doi-asserted-by":"crossref","first-page":"e1701062","DOI":"10.1002\/mnfr.201701062","article-title":"The Influence of Dietary Habits and Meat Consumption on Plasma 3-Methylhistidine-A Potential Marker for Muscle Protein Turnover.","volume":"62","author":"B Kochlik","year":"2018","journal-title":"Mol Nutr Food Res"},{"issue":"7","key":"pbio.3001765.ref016","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.bbamcr.2006.05.005","article-title":"Biosynthesis of heme in mammals.","volume":"1763","author":"RS Ajioka","year":"2006","journal-title":"Biochim Biophys Acta"},{"issue":"67","key":"pbio.3001765.ref017","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1111\/j.1467-9868.2005.00527.x","article-title":"Regularization and variable selection via the elastic net (vol B 67, pg 301, 2005).","author":"H Zou","year":"2005","journal-title":"J R Stat Soc B"},{"issue":"7","key":"pbio.3001765.ref018","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/s41590-018-0121-3","article-title":"Integration of multi-omics data and deep phenotyping enables prediction of cytokine responses","volume":"19","author":"OB Bakker","year":"2018","journal-title":"Nat Immunol"},{"issue":"1","key":"pbio.3001765.ref019","doi-asserted-by":"crossref","first-page":"100365","DOI":"10.1016\/j.xpro.2021.100365","article-title":"In vitro induction of trained immunity in adherent human monocytes","volume":"2","author":"J Dominguez-Andres","year":"2021","journal-title":"STAR Protoc"},{"issue":"7","key":"pbio.3001765.ref020","article-title":"Meat and Seafood Consumption in Relation to Plasma Metabolic Profiles in a Chinese Population: A Combined Untargeted and Targeted Metabolomics Study.","volume":"9","author":"Y Lu","year":"2017","journal-title":"Nutrients"},{"issue":"7444","key":"pbio.3001765.ref021","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha","volume":"496","author":"GM Tannahill","year":"2013","journal-title":"Nature"},{"issue":"7","key":"pbio.3001765.ref022","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1093\/infdis\/jis012","article-title":"A human challenge model for Mycobacterium tuberculosis using Mycobacterium bovis bacille Calmette-Guerin","volume":"205","author":"AM Minassian","year":"2012","journal-title":"J Infect Dis"},{"issue":"1","key":"pbio.3001765.ref023","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00726-012-1361-4","article-title":"Taurine and inflammatory diseases","volume":"46","author":"J Marcinkiewicz","year":"2014","journal-title":"Amino Acids"},{"issue":"2","key":"pbio.3001765.ref024","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0378-1097(03)00611-6","article-title":"Taurine: new implications for an old amino acid","volume":"226","author":"GB Schuller-Levis","year":"2003","journal-title":"FEMS Microbiol Lett"},{"issue":"3","key":"pbio.3001765.ref025","doi-asserted-by":"crossref","first-page":"225","DOI":"10.4062\/biomolther.2017.251","article-title":"Effects and Mechanisms of Taurine as a Therapeutic Agent.","volume":"26","author":"S Schaffer","year":"2018","journal-title":"Biomol Ther (Seoul)"},{"issue":"6","key":"pbio.3001765.ref026","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1007\/s00726-011-0962-7","article-title":"Mechanism underlying the antioxidant activity of taurine: prevention of mitochondrial oxidant production","volume":"42","author":"CJ Jong","year":"2012","journal-title":"Amino Acids"},{"key":"pbio.3001765.ref027","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1146\/annurev-immunol-032712-095956","article-title":"Metabolic regulation of T lymphocytes","volume":"31","author":"NJ MacIver","year":"2013","journal-title":"Annu Rev Immunol"},{"issue":"1","key":"pbio.3001765.ref028","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s13059-021-02413-z","article-title":"Integration of metabolomics, genomics, and immune phenotypes reveals the causal roles of metabolites in disease","volume":"22","author":"X Chu","year":"2021","journal-title":"Genome Biol"},{"issue":"5","key":"pbio.3001765.ref029","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.molcel.2016.05.029","article-title":"Interplay between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes","volume":"62","author":"JP Etchegaray","year":"2016","journal-title":"Mol Cell"},{"issue":"1","key":"pbio.3001765.ref030","first-page":"6","article-title":"Protection against tuberculosis by Bacillus Calmette-Gu\u00e9rin (BCG) vaccination: A historical perspective.","volume":"3","author":"TP Setiabudiawan","year":"2022","journal-title":"Medicina"},{"issue":"2","key":"pbio.3001765.ref031","article-title":"Op weg naar eliminatie van tuberculose in Nederland.","volume":"31","author":"J van den Boogaard","year":"2020","journal-title":"Infectieziekten. Dengue Bull"},{"issue":"18","key":"pbio.3001765.ref032","doi-asserted-by":"crossref","first-page":"7074","DOI":"10.1021\/ac201267k","article-title":"High-throughput, accurate mass metabolome profiling of cellular extracts by flow injection-time-of-flight mass spectrometry","volume":"83","author":"T Fuhrer","year":"2011","journal-title":"Anal Chem"},{"issue":"12","key":"pbio.3001765.ref033","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1128\/CVI.00349-16","article-title":"In Vitro Experimental Model of Trained Innate Immunity in Human Primary Monocytes.","volume":"23","author":"S Bekkering","year":"2016","journal-title":"Clin Vaccine Immunol"},{"issue":"3","key":"pbio.3001765.ref034","doi-asserted-by":"crossref","first-page":"e0173615","DOI":"10.1371\/journal.pone.0173615","article-title":"The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age.","volume":"12","author":"S Trabado","year":"2017","journal-title":"PLoS ONE"},{"key":"pbio.3001765.ref035","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"P Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"pbio.3001765.ref036","doi-asserted-by":"crossref","first-page":"e86","DOI":"10.1002\/cpbi.86","article-title":"Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis.","volume":"68","author":"J Chong","year":"2019","journal-title":"Curr Protoc Bioinformatics"}],"updated-by":[{"DOI":"10.1371\/journal.pbio.3001765","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000}}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3001765","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T18:37:08Z","timestamp":1663871828000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3001765"}},"subtitle":[],"editor":[{"given":"Jason W.","family":"Locasale","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,9,12]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9,12]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3001765","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pbio.3001765","asserted-by":"object"}]},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,12]]}}}