{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:37:39Z","timestamp":1793147859969,"version":"4.5.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"ERC Advanced","award":["833247"],"award-info":[{"award-number":["833247"]}]},{"name":"Netherlands Organization for Scientific Research","id":[{"id":"https:\/\/ror.org\/04jsz6e67","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 DK043351"],"award-info":[{"award-number":["P30 DK043351"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Center for Microbiome Informatics and Therapeutics"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Genome Biol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The bacillus Calmette-Gu\u00e9rin (BCG) vaccine protects against tuberculosis and heterologous infections but elicits high inter-individual variation in specific and nonspecific, or trained, immune responses. While the gut microbiome is increasingly recognized as an important modulator of vaccine responses and immunity in general, its potential role in BCG-induced protection is largely unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Stool and blood were collected from 321 healthy adults before BCG vaccination, followed by blood sampling after 2 weeks and 3 months. Metagenomics based on de novo genome assembly reveals 43 immunomodulatory taxa. The nonspecific, trained immune response is detected by altered production of cytokines IL-6, IL-1\u03b2, and TNF-\u03b1 upon ex vivo blood restimulation with\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      and negatively correlates with abundance of\n                      <jats:italic>Roseburia<\/jats:italic>\n                      . The specific response, measured by IFN-\u03b3 production upon\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                      stimulation, is associated positively with\n                      <jats:italic>Ruminococcus<\/jats:italic>\n                      and\n                      <jats:italic>Eggerthella lenta<\/jats:italic>\n                      . The identified immunomodulatory taxa also have the strongest effects on circulating metabolites, with\n                      <jats:italic>Roseburia<\/jats:italic>\n                      affecting phenylalanine metabolism. This is corroborated by abundances of relevant enzymes, suggesting alternate phenylalanine metabolism modules are activated in a\n                      <jats:italic>Roseburia<\/jats:italic>\n                      species-dependent manner.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Variability in cytokine production after BCG vaccination is associated with the abundance of microbial genomes, which in turn affect or produce metabolites in circulation.\n                      <jats:italic>Roseburia<\/jats:italic>\n                      is found to alter both trained immune responses and phenylalanine metabolism, revealing microbes and microbial products that may alter BCG-induced immunity. Together, our findings contribute to the understanding of specific and trained immune responses after BCG vaccination.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13059-021-02482-0","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T04:04:06Z","timestamp":1632283446000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["The influence of the gut microbiome on BCG-induced trained immunity"],"prefix":"10.1186","volume":"22","author":[{"given":"Martin","family":"Stra\u017ear","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera P.","family":"Mourits","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie A. C. M.","family":"Koeken","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":"Leo A. B.","family":"Joosten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinout","family":"van Crevel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hera","family":"Vlamakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihai G.","family":"Netea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5630-5167","authenticated-orcid":false,"given":"Ramnik J.","family":"Xavier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"issue":"21-22","key":"2482_CR1","doi-asserted-by":"publisher","first-page":"2782","DOI":"10.1016\/S0264-410X(03)00181-6","volume":"21","author":"ML Garly","year":"2003","unstructured":"Garly ML, Martins CL, Bale C, Balde MA, Hedegaard KL, Gustafson P, et al. BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG? Vaccine. 2003;21(21-22):2782\u201390. https:\/\/doi.org\/10.1016\/S0264-410X(03)00181-6.","journal-title":"Vaccine"},{"issue":"5","key":"2482_CR2","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1111\/j.1365-3083.1992.tb03132.x","volume":"36","author":"JW van\u2019t Wout","year":"1992","unstructured":"van\u2019t Wout JW, Poell R, van Furth R. The role of BCG\/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand J Immunol. 1992;36(5):713\u20139. https:\/\/doi.org\/10.1111\/j.1365-3083.1992.tb03132.x.","journal-title":"Scand J Immunol"},{"issue":"5","key":"2482_CR3","first-page":"902","volume":"172","author":"J Tribouley","year":"1978","unstructured":"Tribouley J, Tribouley-Duret J, Appriou M. Effect of Bacillus Callmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni. C R Seances Soc Biol Fil. 1978;172(5):902\u20134.","journal-title":"C R Seances Soc Biol Fil"},{"issue":"5","key":"2482_CR4","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.chom.2011.04.006","volume":"9","author":"MG Netea","year":"2011","unstructured":"Netea MG, Quintin J, van der Meer JW. Trained immunity: a memory for innate host defense. Cell Host Microbe. 2011;9(5):355\u201361. https:\/\/doi.org\/10.1016\/j.chom.2011.04.006.","journal-title":"Cell Host Microbe"},{"issue":"6","key":"2482_CR5","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/s41577-020-0285-6","volume":"20","author":"MG Netea","year":"2020","unstructured":"Netea MG, Dominguez-Andres J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20(6):375\u201388. https:\/\/doi.org\/10.1038\/s41577-020-0285-6.","journal-title":"Nat Rev Immunol"},{"issue":"43","key":"2482_CR6","doi-asserted-by":"publisher","first-page":"17537","DOI":"10.1073\/pnas.1202870109","volume":"109","author":"J Kleinnijenhuis","year":"2012","unstructured":"Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012;109(43):17537\u201342. https:\/\/doi.org\/10.1073\/pnas.1202870109.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"2482_CR7","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.clim.2014.10.005","volume":"155","author":"J Kleinnijenhuis","year":"2014","unstructured":"Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Jacobs C, Xavier RJ, et al. BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin Immunol. 2014;155(2):213\u20139. https:\/\/doi.org\/10.1016\/j.clim.2014.10.005.","journal-title":"Clin Immunol"},{"issue":"1-2","key":"2482_CR8","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.cell.2017.12.031","volume":"172","author":"E Kaufmann","year":"2018","unstructured":"Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonca LE, Pacis A, et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell. 2018;172(1-2):176\u201390.e19. https:\/\/doi.org\/10.1016\/j.cell.2017.12.031.","journal-title":"Cell"},{"issue":"2","key":"2482_CR9","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1016\/j.chom.2020.05.014","volume":"28","author":"B Cirovic","year":"2020","unstructured":"Cirovic B, de Bree LCJ, Groh L, Blok BA, Chan J, van der Velden W, et al. BCG vaccination in humans elicits trained immunity via the hematopoietic progenitor compartment. Cell Host Microbe. 2020;28(2):322\u201334.e5. https:\/\/doi.org\/10.1016\/j.chom.2020.05.014.","journal-title":"Cell Host Microbe"},{"issue":"2","key":"2482_CR10","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1159\/000355628","volume":"6","author":"J Kleinnijenhuis","year":"2014","unstructured":"Kleinnijenhuis J, Quintin J, Preijers F, Benn CS, Joosten LA, Jacobs C, et al. Long-lasting effects of BCG vaccination on both heterologous Th1\/Th17 responses and innate trained immunity. J Innate Immun. 2014;6(2):152\u20138. https:\/\/doi.org\/10.1159\/000355628.","journal-title":"J Innate Immun"},{"issue":"10","key":"2482_CR11","doi-asserted-by":"publisher","first-page":"5591","DOI":"10.1172\/JCI133935","volume":"130","author":"VA Koeken","year":"2020","unstructured":"Koeken VA, de Bree LCJ, Mourits VP, Moorlag SJ, Walk J, Cirovic B, et al. BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner. J Clin Invest. 2020;130(10):5591\u2013602. https:\/\/doi.org\/10.1172\/JCI133935.","journal-title":"J Clin Invest"},{"issue":"4","key":"2482_CR12","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1016\/j.cell.2016.10.020","volume":"167","author":"M Schirmer","year":"2016","unstructured":"Schirmer M, Smeekens SP, Vlamakis H, Jaeger M, Oosting M, Franzosa EA, et al. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell. 2016;167(4):1125\u201336.e8. https:\/\/doi.org\/10.1016\/j.cell.2016.10.020.","journal-title":"Cell"},{"issue":"4","key":"2482_CR13","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/nri.2017.7","volume":"17","author":"M Levy","year":"2017","unstructured":"Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17(4):219\u201332. https:\/\/doi.org\/10.1038\/nri.2017.7.","journal-title":"Nat Rev Immunol"},{"issue":"6","key":"2482_CR14","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.1073\/pnas.1322269111","volume":"111","author":"PV Chang","year":"2014","unstructured":"Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2014;111(6):2247\u201352. https:\/\/doi.org\/10.1073\/pnas.1322269111.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"2482_CR15","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.cell.2015.08.058","volume":"163","author":"K Atarashi","year":"2015","unstructured":"Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y, Narushima S, et al. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell. 2015;163(2):367\u201380. https:\/\/doi.org\/10.1016\/j.cell.2015.08.058.","journal-title":"Cell"},{"key":"2482_CR16","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.3389\/fmicb.2019.01305","volume":"10","author":"A Ciabattini","year":"2019","unstructured":"Ciabattini A, Olivieri R, Lazzeri E, Medaglini D. Role of the microbiota in the modulation of vaccine immune responses. Front Microbiol. 2019;10:1305. https:\/\/doi.org\/10.3389\/fmicb.2019.01305.","journal-title":"Front Microbiol"},{"issue":"30","key":"2482_CR17","doi-asserted-by":"publisher","first-page":"4433","DOI":"10.1016\/j.vaccine.2018.04.066","volume":"36","author":"P Zimmermann","year":"2018","unstructured":"Zimmermann P, Curtis N. The influence of the intestinal microbiome on vaccine responses. Vaccine. 2018;36(30):4433\u20139. https:\/\/doi.org\/10.1016\/j.vaccine.2018.04.066.","journal-title":"Vaccine"},{"issue":"5","key":"2482_CR18","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.chom.2018.04.009","volume":"23","author":"MA Lynn","year":"2018","unstructured":"Lynn MA, Tumes DJ, Choo JM, Sribnaia A, Blake SJ, Leong LEX, et al. Early-life antibiotic-driven dysbiosis leads to dysregulated vaccine immune responses in mice. Cell Host Microbe. 2018;23(5):653\u201360.e5. https:\/\/doi.org\/10.1016\/j.chom.2018.04.009.","journal-title":"Cell Host Microbe"},{"key":"2482_CR19","doi-asserted-by":"publisher","first-page":"726","DOI":"10.3389\/fimmu.2020.00726","volume":"11","author":"S Nadeem","year":"2020","unstructured":"Nadeem S, Maurya SK, Das DK, Khan N, Agrewala JN. Gut dysbiosis thwarts the efficacy of vaccine against Mycobacterium tuberculosis. Front Immunol. 2020;11:726. https:\/\/doi.org\/10.3389\/fimmu.2020.00726.","journal-title":"Front Immunol"},{"issue":"2","key":"2482_CR20","doi-asserted-by":"publisher","first-page":"e362","DOI":"10.1542\/peds.2013-3937","volume":"134","author":"MN Huda","year":"2014","unstructured":"Huda MN, Lewis Z, Kalanetra KM, Rashid M, Ahmad SM, Raqib R, et al. Stool microbiota and vaccine responses of infants. Pediatrics. 2014;134(2):e362\u201372. https:\/\/doi.org\/10.1542\/peds.2013-3937.","journal-title":"Pediatrics"},{"issue":"1","key":"2482_CR21","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41564-017-0072-8","volume":"3","author":"PI Costea","year":"2018","unstructured":"Costea PI, Hildebrand F, Arumugam M, Backhed F, Blaser MJ, Bushman FD, et al. Enterotypes in the landscape of gut microbial community composition. Nat Microbiol. 2018;3(1):8\u201316. https:\/\/doi.org\/10.1038\/s41564-017-0072-8.","journal-title":"Nat Microbiol"},{"issue":"2","key":"2482_CR22","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.3892\/mmr.2019.10327","volume":"20","author":"W Luo","year":"2019","unstructured":"Luo W, Shen Z, Deng M, Li X, Tan B, Xiao M, et al. Roseburia intestinalis supernatant ameliorates colitis induced in mice by regulating the immune response. Mol Med Rep. 2019;20(2):1007\u201316. https:\/\/doi.org\/10.3892\/mmr.2019.10327.","journal-title":"Mol Med Rep"},{"issue":"1","key":"2482_CR23","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1093\/advances\/nmx009","volume":"9","author":"H Liu","year":"2018","unstructured":"Liu H, Wang J, He T, Becker S, Zhang G, Li D, et al. Butyrate: a double-edged sword for health? Adv Nutr. 2018;9(1):21\u20139. https:\/\/doi.org\/10.1093\/advances\/nmx009.","journal-title":"Adv Nutr"},{"issue":"7","key":"2482_CR24","doi-asserted-by":"publisher","first-page":"2099","DOI":"10.1128\/JB.186.7.2099-2106.2004","volume":"186","author":"P Louis","year":"2004","unstructured":"Louis P, Duncan SH, McCrae SI, Millar J, Jackson MS, Flint HJ. Restricted distribution of the butyrate kinase pathway among butyrate-producing bacteria from the human colon. J Bacteriol. 2004;186(7):2099\u2013106. https:\/\/doi.org\/10.1128\/JB.186.7.2099-2106.2004.","journal-title":"J Bacteriol"},{"issue":"7867","key":"2482_CR25","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/s41586-021-03707-9","volume":"595","author":"S Han","year":"2021","unstructured":"Han S, Van Treuren W, Fischer CR, Merrill BD, DeFelice BC, Sanchez JM, et al. A metabolomics pipeline for the mechanistic interrogation of the gut microbiome. Nature. 2021;595(7867):415\u201320. https:\/\/doi.org\/10.1038\/s41586-021-03707-9.","journal-title":"Nature"},{"issue":"1","key":"2482_CR26","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1189\/jlb.3MR0316-118RR","volume":"101","author":"JJ Seeley","year":"2017","unstructured":"Seeley JJ, Ghosh S. Molecular mechanisms of innate memory and tolerance to LPS. J Leukoc Biol. 2017;101(1):107\u201319. https:\/\/doi.org\/10.1189\/jlb.3MR0316-118RR.","journal-title":"J Leukoc Biol"},{"issue":"3","key":"2482_CR27","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1111\/j.1365-2249.2009.03926.x","volume":"156","author":"JH van der Meer","year":"2009","unstructured":"van der Meer JH, Netea MG, Dinarello CA. Modulation of muramyl dipeptide stimulation of cytokine production by blood components. Clin Exp Immunol. 2009;156(3):428\u201333. https:\/\/doi.org\/10.1111\/j.1365-2249.2009.03926.x.","journal-title":"Clin Exp Immunol"},{"key":"2482_CR28","doi-asserted-by":"publisher","first-page":"5812743","DOI":"10.1155\/2020\/5812743","volume":"2020","author":"VP Mourits","year":"2020","unstructured":"Mourits VP, Koeken V, de Bree LCJ, Moorlag S, Chu WC, Xu X, et al. BCG-induced trained immunity in healthy individuals: the effect of plasma muramyl dipeptide concentrations. J Immunol Res. 2020;2020:5812743\u20138. https:\/\/doi.org\/10.1155\/2020\/5812743.","journal-title":"J Immunol Res"},{"issue":"1","key":"2482_CR29","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1111\/j.1749-6632.2012.06813.x","volume":"1277","author":"JW Johnson","year":"2013","unstructured":"Johnson JW, Fisher JF, Mobashery S. Bacterial cell-wall recycling. Ann N Y Acad Sci. 2013;1277(1):54\u201375. https:\/\/doi.org\/10.1111\/j.1749-6632.2012.06813.x.","journal-title":"Ann N Y Acad Sci"},{"issue":"1","key":"2482_CR30","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1111\/1462-2920.13589","volume":"19","author":"P Louis","year":"2017","unstructured":"Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2017;19(1):29\u201341. https:\/\/doi.org\/10.1111\/1462-2920.13589.","journal-title":"Environ Microbiol"},{"issue":"1","key":"2482_CR31","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/s41598-018-37246-7","volume":"9","author":"MCP Cleophas","year":"2019","unstructured":"Cleophas MCP, Ratter JM, Bekkering S, Quintin J, Schraa K, Stroes ES, et al. Effects of oral butyrate supplementation on inflammatory potential of circulating peripheral blood mononuclear cells in healthy and obese males. Sci Rep. 2019;9(1):775. https:\/\/doi.org\/10.1038\/s41598-018-37246-7.","journal-title":"Sci Rep"},{"issue":"12","key":"2482_CR32","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1038\/s41564-018-0272-x","volume":"3","author":"K Kasahara","year":"2018","unstructured":"Kasahara K, Krautkramer KA, Org E, Romano KA, Kerby RL, Vivas EI, et al. Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model. Nat Microbiol. 2018;3(12):1461\u201371. https:\/\/doi.org\/10.1038\/s41564-018-0272-x.","journal-title":"Nat Microbiol"},{"issue":"1","key":"2482_CR33","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1161\/ATVBAHA.120.314216","volume":"41","author":"D Flores-Gomez","year":"2021","unstructured":"Flores-Gomez D, Bekkering S, Netea MG, Riksen NP. Trained immunity in atherosclerotic cardiovascular disease. Arterioscler Thromb Vasc Biol. 2021;41(1):62\u20139.","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"1","key":"2482_CR34","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s13073-016-0299-7","volume":"8","author":"J Chen","year":"2016","unstructured":"Chen J, Wright K, Davis JM, Jeraldo P, Marietta EV, Murray J, et al. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome Med. 2016;8(1):43. https:\/\/doi.org\/10.1186\/s13073-016-0299-7.","journal-title":"Genome Med"},{"issue":"40","key":"2482_CR35","doi-asserted-by":"publisher","first-page":"10713","DOI":"10.1073\/pnas.1711235114","volume":"114","author":"E Cekanaviciute","year":"2017","unstructured":"Cekanaviciute E, Yoo BB, Runia TF, Debelius JW, Singh S, Nelson CA, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci U S A. 2017;114(40):10713\u20138. https:\/\/doi.org\/10.1073\/pnas.1711235114.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"2482_CR36","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1016\/j.cell.2014.08.006","volume":"158","author":"NW Palm","year":"2014","unstructured":"Palm NW, de Zoete MR, Cullen TW, Barry NA, Stefanowski J, Hao L, et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell. 2014;158(5):1000\u201310. https:\/\/doi.org\/10.1016\/j.cell.2014.08.006.","journal-title":"Cell"},{"issue":"2","key":"2482_CR37","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1128\/JCM.02926-14","volume":"53","author":"BJ Gardiner","year":"2015","unstructured":"Gardiner BJ, Tai AY, Kotsanas D, Francis MJ, Roberts SA, Ballard SA, et al. Clinical and microbiological characteristics of Eggerthella lenta bacteremia. J Clin Microbiol. 2015;53(2):626\u201335. https:\/\/doi.org\/10.1128\/JCM.02926-14.","journal-title":"J Clin Microbiol"},{"issue":"10","key":"2482_CR38","doi-asserted-by":"publisher","first-page":"4212","DOI":"10.1172\/JCI72333","volume":"124","author":"SR Modi","year":"2014","unstructured":"Modi SR, Collins JJ, Relman DA. Antibiotics and the gut microbiota. J Clin Invest. 2014;124(10):4212\u20138. https:\/\/doi.org\/10.1172\/JCI72333.","journal-title":"J Clin Invest"},{"issue":"4","key":"2482_CR39","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1249\/MSS.0000000000001495","volume":"50","author":"JM Allen","year":"2018","unstructured":"Allen JM, Mailing LJ, Niemiro GM, Moore R, Cook MD, White BA, et al. Exercise alters gut microbiota composition and function in lean and obese humans. Med Sci Sports Exerc. 2018;50(4):747\u201357. https:\/\/doi.org\/10.1249\/MSS.0000000000001495.","journal-title":"Med Sci Sports Exerc"},{"issue":"12","key":"2482_CR40","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1136\/gutjnl-2013-306541","volume":"63","author":"SF Clarke","year":"2014","unstructured":"Clarke SF, Murphy EF, O'Sullivan O, Lucey AJ, Humphreys M, Hogan A, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014;63(12):1913\u201320. https:\/\/doi.org\/10.1136\/gutjnl-2013-306541.","journal-title":"Gut"},{"issue":"1","key":"2482_CR41","doi-asserted-by":"publisher","first-page":"48","DOI":"10.5534\/wjmh.190009","volume":"38","author":"YS Kim","year":"2020","unstructured":"Kim YS, Unno T, Kim BY, Park MS. Sex differences in gut microbiota. World J Mens Health. 2020;38(1):48\u201360. https:\/\/doi.org\/10.5534\/wjmh.190009.","journal-title":"World J Mens Health"},{"issue":"1","key":"2482_CR42","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1136\/gutjnl-2015-309618","volume":"65","author":"D Vandeputte","year":"2016","unstructured":"Vandeputte D, Falony G, Vieira-Silva S, Tito RY, Joossens M, Raes J. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut. 2016;65(1):57\u201362. https:\/\/doi.org\/10.1136\/gutjnl-2015-309618.","journal-title":"Gut"},{"issue":"1","key":"2482_CR43","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s12866-019-1489-4","volume":"19","author":"X Shen","year":"2019","unstructured":"Shen X, Wang M, Zhang X, He M, Li M, Cheng G, et al. Dynamic construction of gut microbiota may influence allergic diseases of infants in Southwest China. BMC Microbiol. 2019;19(1):123. https:\/\/doi.org\/10.1186\/s12866-019-1489-4.","journal-title":"BMC Microbiol"},{"issue":"5","key":"2482_CR44","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1136\/gutjnl-2015-309940","volume":"66","author":"T Lee","year":"2017","unstructured":"Lee T, Clavel T, Smirnov K, Schmidt A, Lagkouvardos I, Walker A, et al. Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD. Gut. 2017;66(5):863\u201371. https:\/\/doi.org\/10.1136\/gutjnl-2015-309940.","journal-title":"Gut"},{"issue":"9","key":"2482_CR45","doi-asserted-by":"publisher","first-page":"fiy125","DOI":"10.1093\/femsec\/fiy125","volume":"94","author":"Y Saito","year":"2018","unstructured":"Saito Y, Sato T, Nomoto K, Tsuji H. Identification of phenol- and p-cresol-producing intestinal bacteria by using media supplemented with tyrosine and its metabolites. FEMS Microbiol Ecol. 2018;94(9):fiy125.","journal-title":"FEMS Microbiol Ecol"},{"issue":"2","key":"2482_CR46","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.cell.2015.02.047","volume":"161","author":"JM Yano","year":"2015","unstructured":"Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161(2):264\u201376. https:\/\/doi.org\/10.1016\/j.cell.2015.02.047.","journal-title":"Cell"},{"issue":"2","key":"2482_CR47","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1002\/jsfa.10010","volume":"100","author":"V Coman","year":"2020","unstructured":"Coman V, Vodnar DC. Hydroxycinnamic acids and human health: recent advances. J Sci Food Agric. 2020;100(2):483\u201399. https:\/\/doi.org\/10.1002\/jsfa.10010.","journal-title":"J Sci Food Agric"},{"issue":"5","key":"2482_CR48","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.cmet.2014.10.016","volume":"20","author":"G Sharon","year":"2014","unstructured":"Sharon G, Garg N, Debelius J, Knight R, Dorrestein PC, Mazmanian SK. Specialized metabolites from the microbiome in health and disease. Cell Metab. 2014;20(5):719\u201330. https:\/\/doi.org\/10.1016\/j.cmet.2014.10.016.","journal-title":"Cell Metab"},{"issue":"1","key":"2482_CR49","doi-asserted-by":"publisher","first-page":"13670","DOI":"10.1038\/s41598-017-13722-4","volume":"7","author":"T Pallister","year":"2017","unstructured":"Pallister T, Jackson MA, Martin TC, Zierer J, Jennings A, Mohney RP, et al. Hippurate as a metabolomic marker of gut microbiome diversity: modulation by diet and relationship to metabolic syndrome. Sci Rep. 2017;7(1):13670. https:\/\/doi.org\/10.1038\/s41598-017-13722-4.","journal-title":"Sci Rep"},{"key":"2482_CR50","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.bbrep.2018.04.008","volume":"14","author":"V Jaswal","year":"2018","unstructured":"Jaswal V, Palanivelu J, Ramalingam C. Effects of the Gut microbiota on Amygdalin and its use as an anti-cancer therapy: substantial review on the key components involved in altering dose efficacy and toxicity. Biochem Biophys Rep. 2018;14:125\u201332. https:\/\/doi.org\/10.1016\/j.bbrep.2018.04.008.","journal-title":"Biochem Biophys Rep"},{"issue":"1","key":"2482_CR51","doi-asserted-by":"publisher","first-page":"3294","DOI":"10.1038\/s41467-018-05470-4","volume":"9","author":"HM Roager","year":"2018","unstructured":"Roager HM, Licht TR. Microbial tryptophan catabolites in health and disease. Nat Commun. 2018;9(1):3294. https:\/\/doi.org\/10.1038\/s41467-018-05470-4.","journal-title":"Nat Commun"},{"issue":"2","key":"2482_CR52","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1161\/CIRCRESAHA.119.315800","volume":"127","author":"C van der Heijden","year":"2020","unstructured":"van der Heijden C, Groh L, Keating ST, Kaffa C, Noz MP, Kersten S, et al. Catecholamines induce trained immunity in monocytes in vitro and in vivo. Circ Res. 2020;127(2):269\u201383. https:\/\/doi.org\/10.1161\/CIRCRESAHA.119.315800.","journal-title":"Circ Res"},{"issue":"1","key":"2482_CR53","first-page":"31","volume":"29","author":"RA Williams","year":"2008","unstructured":"Williams RA, Mamotte CD, Burnett JR. Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev. 2008;29(1):31\u201341.","journal-title":"Clin Biochem Rev"},{"issue":"2","key":"2482_CR54","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/s41579-020-0438-4","volume":"19","author":"KA Krautkramer","year":"2021","unstructured":"Krautkramer KA, Fan J, Backhed F. Gut microbial metabolites as multi-kingdom intermediates. Nat Rev Microbiol. 2021;19(2):77\u201394. https:\/\/doi.org\/10.1038\/s41579-020-0438-4.","journal-title":"Nat Rev Microbiol"},{"key":"2482_CR55","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.trsl.2016.04.007","volume":"179","author":"A Nallu","year":"2017","unstructured":"Nallu A, Sharma S, Ramezani A, Muralidharan J, Raj D. Gut microbiome in chronic kidney disease: challenges and opportunities. Transl Res. 2017;179:24\u201337. https:\/\/doi.org\/10.1016\/j.trsl.2016.04.007.","journal-title":"Transl Res"},{"issue":"9","key":"2482_CR56","doi-asserted-by":"publisher","first-page":"1897","DOI":"10.1681\/ASN.2013101062","volume":"25","author":"R Vanholder","year":"2014","unstructured":"Vanholder R, Schepers E, Pletinck A, Nagler EV, Glorieux G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol. 2014;25(9):1897\u2013907. https:\/\/doi.org\/10.1681\/ASN.2013101062.","journal-title":"J Am Soc Nephrol"},{"issue":"5","key":"2482_CR57","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.cell.2020.02.016","volume":"180","author":"I Nemet","year":"2020","unstructured":"Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, et al. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell. 2020;180(5):862\u201377.e22. https:\/\/doi.org\/10.1016\/j.cell.2020.02.016.","journal-title":"Cell"},{"issue":"12","key":"2482_CR58","doi-asserted-by":"publisher","first-page":"6992","DOI":"10.1073\/pnas.1236794100","volume":"100","author":"BA Manjasetty","year":"2003","unstructured":"Manjasetty BA, Powlowski J, Vrielink A. Crystal structure of a bifunctional aldolase-dehydrogenase: sequestering a reactive and volatile intermediate. Proc Natl Acad Sci U S A. 2003;100(12):6992\u20137. https:\/\/doi.org\/10.1073\/pnas.1236794100.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"18","key":"2482_CR59","doi-asserted-by":"publisher","first-page":"7074","DOI":"10.1021\/ac201267k","volume":"83","author":"T Fuhrer","year":"2011","unstructured":"Fuhrer T, Heer D, Begemann B, Zamboni N. High-throughput, accurate mass metabolome profiling of cellular extracts by flow injection-time-of-flight mass spectrometry. Anal Chem. 2011;83(18):7074\u201380. https:\/\/doi.org\/10.1021\/ac201267k.","journal-title":"Anal Chem"},{"issue":"10","key":"2482_CR60","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1093\/bioinformatics\/btv033","volume":"31","author":"D Li","year":"2015","unstructured":"Li D, Liu CM, Luo R, Sadakane K, Lam TW. MEGAHIT: an ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph. Bioinformatics. 2015;31(10):1674\u20136. https:\/\/doi.org\/10.1093\/bioinformatics\/btv033.","journal-title":"Bioinformatics"},{"issue":"1","key":"2482_CR61","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1186\/1471-2105-11-119","volume":"11","author":"D Hyatt","year":"2010","unstructured":"Hyatt D, Chen GL, Locascio PF, Land ML, Larimer FW, Hauser LJ. Prodigal: prokaryotic gene recognition and translation initiation site identification. BMC Bioinformatics. 2010;11(1):119. https:\/\/doi.org\/10.1186\/1471-2105-11-119.","journal-title":"BMC Bioinformatics"},{"issue":"23","key":"2482_CR62","doi-asserted-by":"publisher","first-page":"3150","DOI":"10.1093\/bioinformatics\/bts565","volume":"28","author":"L Fu","year":"2012","unstructured":"Fu L, Niu B, Zhu Z, Wu S, Li W. CD-HIT: accelerated for clustering the next-generation sequencing data. Bioinformatics. 2012;28(23):3150\u20132. https:\/\/doi.org\/10.1093\/bioinformatics\/bts565.","journal-title":"Bioinformatics"},{"issue":"14","key":"2482_CR63","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754\u201360. https:\/\/doi.org\/10.1093\/bioinformatics\/btp324.","journal-title":"Bioinformatics"},{"issue":"9","key":"2482_CR64","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1093\/bioinformatics\/bty830","volume":"35","author":"F Plaza Onate","year":"2019","unstructured":"Plaza Onate F, Le Chatelier E, Almeida M, Cervino ACL, Gauthier F, Magoules F, et al. MSPminer: abundance-based reconstitution of microbial pan-genomes from shotgun metagenomic data. Bioinformatics. 2019;35(9):1544\u201352. https:\/\/doi.org\/10.1093\/bioinformatics\/bty830.","journal-title":"Bioinformatics"},{"issue":"8","key":"2482_CR65","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1038\/nbt.2942","volume":"32","author":"J Li","year":"2014","unstructured":"Li J, Jia H, Cai X, Zhong H, Feng Q, Sunagawa S, et al. An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol. 2014;32(8):834\u201341. https:\/\/doi.org\/10.1038\/nbt.2942.","journal-title":"Nat Biotechnol"},{"issue":"D1","key":"2482_CR66","doi-asserted-by":"publisher","first-page":"D309","DOI":"10.1093\/nar\/gky1085","volume":"47","author":"J Huerta-Cepas","year":"2019","unstructured":"Huerta-Cepas J, Szklarczyk D, Heller D, Hernandez-Plaza A, Forslund SK, Cook H, et al. eggNOG 5.0: a hierarchical, functionally and phylogenetically annotated orthology resource based on 5090 organisms and 2502 viruses. Nucleic Acids Res. 2019;47(D1):D309\u2013D14. https:\/\/doi.org\/10.1093\/nar\/gky1085.","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"2482_CR67","doi-asserted-by":"publisher","first-page":"2500","DOI":"10.1038\/s41467-020-16366-7","volume":"11","author":"F Asnicar","year":"2020","unstructured":"Asnicar F, Thomas AM, Beghini F, Mengoni C, Manara S, Manghi P, et al. Precise phylogenetic analysis of microbial isolates and genomes from metagenomes using PhyloPhlAn 3.0. Nat Commun. 2020;11(1):2500.","journal-title":"Nat Commun"},{"issue":"8","key":"2482_CR68","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/nmeth.2066","volume":"9","author":"N Segata","year":"2012","unstructured":"Segata N, Waldron L, Ballarini A, Narasimhan V, Jousson O, Huttenhower C. Metagenomic microbial community profiling using unique clade-specific marker genes. Nat Methods. 2012;9(8):811\u20134. https:\/\/doi.org\/10.1038\/nmeth.2066.","journal-title":"Nat Methods"},{"key":"2482_CR69","volume-title":"The influence of the gut microbiome on BCG-induced trained immunity","author":"M Strazar","year":"2021","unstructured":"Strazar M, Mourits VP, Koeken VACM, de Bree LCJ, Moorlag SJCFM, Joosten LAB, et al. The influence of the gut microbiome on BCG-induced trained immunity: Github; 2021. https:\/\/gitlab.com\/xavier-lab-computation\/public\/bcg300"},{"key":"2482_CR70","volume-title":"The influence of the gut microbiome on BCG-induced trained immunity","author":"M Strazar","year":"2021","unstructured":"Strazar M, Mourits VP, Koeken VACM, de Bree LCJ, Moorlag SJCFM, Joosten LAB, et al. The influence of the gut microbiome on BCG-induced trained immunity: Zenodo; 2021. https:\/\/zenodo.org\/record\/5148664#.YSz6I4hKiks"},{"key":"2482_CR71","volume-title":"The influence of the gut microbiome on BCG-induced trained immunity","author":"M Strazar","year":"2020","unstructured":"Strazar M, Mourits VP, Koeken VACM, de Bree LCJ, Moorlag SJCFM, Joosten LAB, et al. The influence of the gut microbiome on BCG-induced trained immunity: NCBI SRA; 2020. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA685797"}],"container-title":["Genome Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13059-021-02482-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13059-021-02482-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13059-021-02482-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,8]],"date-time":"2024-09-08T13:56:52Z","timestamp":1725803812000},"score":1,"resource":{"primary":{"URL":"https:\/\/genomebiology.biomedcentral.com\/articles\/10.1186\/s13059-021-02482-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,22]]},"references-count":71,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2482"],"URL":"https:\/\/doi.org\/10.1186\/s13059-021-02482-0","relation":{},"ISSN":["1474-760X"],"issn-type":[{"value":"1474-760X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,22]]},"assertion":[{"value":"23 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Arnhem-Nijmegen Medical Ethical Committee (NL58553.091.16) and performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants prior to sample collection.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"275"}}