{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:29:46Z","timestamp":1791854986565,"version":"4.3.4"},"reference-count":42,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T00:00:00Z","timestamp":1657756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R35 GM130385 (G.S.)"],"award-info":[{"award-number":["R35 GM130385 (G.S.)"]}]},{"name":"National Institutes of Health","award":["P30 MH062261 (G.S.)"],"award-info":[{"award-number":["P30 MH062261 (G.S.)"]}]},{"name":"National Institutes of Health","award":["P01 DA026146 (G.S.)"],"award-info":[{"award-number":["P01 DA026146 (G.S.)"]}]},{"name":"National Institutes of Health","award":["U01 CA235493 (G.S.)"],"award-info":[{"award-number":["U01 CA235493 (G.S.)"]}]},{"name":"National Institutes of Health","award":["R01 GM114368-03 (B.M.S.)"],"award-info":[{"award-number":["R01 GM114368-03 (B.M.S.)"]}]},{"name":"National Institutes of Health","award":["R21 AI145374 (B.M.S.)"],"award-info":[{"award-number":["R21 AI145374 (B.M.S.)"]}]},{"name":"National Institutes of Health","award":["DE-AC02-05CH11231 (G.S.)"],"award-info":[{"award-number":["DE-AC02-05CH11231 (G.S.)"]}]},{"name":"US Department of Energy","award":["R35 GM130385 (G.S.)"],"award-info":[{"award-number":["R35 GM130385 (G.S.)"]}]},{"name":"US Department of Energy","award":["P30 MH062261 (G.S.)"],"award-info":[{"award-number":["P30 MH062261 (G.S.)"]}]},{"name":"US Department of Energy","award":["P01 DA026146 (G.S.)"],"award-info":[{"award-number":["P01 DA026146 (G.S.)"]}]},{"name":"US Department of Energy","award":["U01 CA235493 (G.S.)"],"award-info":[{"award-number":["U01 CA235493 (G.S.)"]}]},{"name":"US Department of Energy","award":["R01 GM114368-03 (B.M.S.)"],"award-info":[{"award-number":["R01 GM114368-03 (B.M.S.)"]}]},{"name":"US Department of Energy","award":["R21 AI145374 (B.M.S.)"],"award-info":[{"award-number":["R21 AI145374 (B.M.S.)"]}]},{"name":"US Department of Energy","award":["DE-AC02-05CH11231 (G.S.)"],"award-info":[{"award-number":["DE-AC02-05CH11231 (G.S.)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA\u2019s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8+ T cells, reveal a potential role of 3-IPA in these responses. T-cell exhaustion was examined via infection of two genetically related mouse strains, DBA\/1J and DBA\/2J, with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13). The different mouse strains produced disparate outcomes driven by their T-cell responses. Infected DBA\/2J presented with exhausted T cells and persistent infection, and DBA\/1J mice died one week after infection from cytotoxic T lymphocytes (CTLs)-mediated pulmonary failure. Metabolomics revealed over 70 metabolites were altered between the DBA\/1J and DBA\/2J models over the course of the infection, most of them in mice with a fatal outcome. Cognitive-driven prioritization combined with statistical significance and fold change were used to prioritize the metabolites. 3-IPA, a tryptophan-derived metabolite, was identified as a high-priority candidate for testing. To test its activity 3-IPA was added to the drinking water of the mouse models during LCMV Cl13 infection, with the results showing that 3-IPA allowed the mice to survive longer. This negative immune-modulation effect might be of interest for the modulation of CTL responses in events such as autoimmune diseases, type I diabetes or even COVID-19. Moreover, 3-IPA\u2019s bacterial origin raises the possibility of targeting the microbiome to enhance CTL responses in diseases such as cancer and chronic infection.<\/jats:p>","DOI":"10.3390\/metabo12070645","type":"journal-article","created":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T01:57:11Z","timestamp":1657850231000},"page":"645","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7993-3388","authenticated-orcid":false,"given":"Carlos","family":"Guijas","sequence":"first","affiliation":[{"name":"Scripps Center for Metabolomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy E.","family":"Horton","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linh","family":"Hoang","sequence":"additional","affiliation":[{"name":"Scripps Center for Metabolomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0133-6863","authenticated-orcid":false,"given":"Xavier","family":"Domingo-Almenara","sequence":"additional","affiliation":[{"name":"Computational Metabolomics for Systems Biology Lab, Omics Sciences Unit, Eurecat\u2014Technology Centre of Catalonia, 08005 Barcelona, Catalonia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4320-3276","authenticated-orcid":false,"given":"Elizabeth M.","family":"Billings","sequence":"additional","affiliation":[{"name":"Scripps Center for Metabolomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C.","family":"Ware","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4749-0014","authenticated-orcid":false,"given":"Gary","family":"Siuzdak","sequence":"additional","affiliation":[{"name":"Scripps Center for Metabolomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"name":"Departments of Chemistry, Molecular, and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3698","DOI":"10.1073\/pnas.0812874106","article-title":"Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites","volume":"106","author":"Wikoff","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Konopelski, P., and Mogilnicka, I. (2022). Biological Effects of Indole-3-Propionic Acid, a Gut Microbiota-Derived Metabolite, and Its Precursor Tryptophan in Mammals\u2019 Health and Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031222"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat. Immunol"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"E7814","DOI":"10.1073\/pnas.1804674115","article-title":"Lymphocytic choriomeningitis virus Clone 13 infection causes either persistence or acute death dependent on IFN-1, cytotoxic T lymphocytes (CTLs), and host genetics","volume":"115","author":"Oldstone","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1084\/jem.188.12.2205","article-title":"Viral immune evasion due to persistence of activated T cells without effector function","volume":"188","author":"Zajac","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nature04444","article-title":"Restoring function in exhausted CD8 T cells during chronic viral infection","volume":"439","author":"Barber","year":"2006","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1200\/JCO.2009.26.7609","article-title":"Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates","volume":"28","author":"Brahmer","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Patil, N.K., Guo, Y., Luan, L., and Sherwood, E.R. (2017). Targeting Immune Cell Checkpoints during Sepsis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18112413"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3389\/fimmu.2019.00111","article-title":"Is There a Positive Side to T Cell Exhaustion?","volume":"10","author":"Pawelec","year":"2019","journal-title":"Front. Immunol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8925","DOI":"10.1073\/pnas.1408148111","article-title":"Type I interferon is a therapeutic target for virus-induced lethal vascular damage","volume":"111","author":"Baccala","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1073\/pnas.1712107115","article-title":"Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion","volume":"115","author":"Avery","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.molimm.2014.11.019","article-title":"TIPE2 protein negatively regulates HBV-specific CD8(+) T lymphocyte functions in humans","volume":"64","author":"Zhang","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3025","DOI":"10.1016\/j.ajpath.2015.07.019","article-title":"Endogenous Il10 alleviates the systemic antiviral cellular immune response and T cell-mediated immunopathology in select organs of acutely LCMV-infected mice","volume":"185","author":"Jakobshagen","year":"2015","journal-title":"Am. J. Pathol"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nri3859","article-title":"Eicosanoid storm in infection and inflammation","volume":"15","author":"Dennis","year":"2015","journal-title":"Nat. Reviews. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature13479","article-title":"Pro-resolving lipid mediators are leads for resolution physiology","volume":"510","author":"Serhan","year":"2014","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nature25986","article-title":"Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1","volume":"556","author":"Mills","year":"2018","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/ni.3796","article-title":"alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming","volume":"18","author":"Liu","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.chembiol.2016.04.012","article-title":"Foamy Monocytes Are Enriched in cis-7-Hexadecenoic Fatty Acid (16:1n-9), a Possible Biomarker for Early Detection of Cardiovascular Disease","volume":"23","author":"Guijas","year":"2016","journal-title":"Cell Chem. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.cell.2016.09.031","article-title":"L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity","volume":"167","author":"Geiger","year":"2016","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/s41586-018-0701-2","article-title":"The metabolite BH4 controls T cell proliferation in autoimmunity and cancer","volume":"563","author":"Cronin","year":"2018","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nbt.4101","article-title":"Metabolomics activity screening for identifying metabolites that modulate phenotype","volume":"36","author":"Guijas","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s41580-019-0108-4","article-title":"Identification of bioactive metabolites using activity metabolomics","volume":"20","author":"Rinschen","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11505","DOI":"10.1021\/acs.analchem.7b02759","article-title":"Exposome-Scale Investigations Guided by Global Metabolomics, Pathway Analysis, and Cognitive Computing","volume":"89","author":"Warth","year":"2017","journal-title":"Anal. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.clinthera.2015.12.001","article-title":"IBM Watson: How Cognitive Computing Can Be Applied to Big Data Challenges in Life Sciences Research","volume":"38","author":"Chen","year":"2016","journal-title":"Clin. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nprot.2017.151","article-title":"Data Processing, Pathway Mapping and Multi-Omic Systems Analysis using XCMS Online","volume":"13","author":"Forsberg","year":"2018","journal-title":"Nat. Protoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nmeth.4260","article-title":"Systems biology guided by XCMS Online metabolomics","volume":"14","author":"Huan","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1194\/jlr.M800244-JLR200","article-title":"Differences in DBA\/1J and DBA\/2J reveal lipid QTL genes","volume":"49","author":"Stylianou","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/ng1666","article-title":"Genetic variation in laboratory mice","volume":"37","author":"Wade","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/0306-4522(94)00400-Y","article-title":"Differences of CA3 bursting in DBA\/1 and DBA\/2 inbred mouse strains with divergent shuttle box performance","volume":"64","author":"Yanovsky","year":"1995","journal-title":"Neuroscience"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1002\/art.11273","article-title":"Dependence on interferon-gamma for the spontaneous occurrence of arthritis in DBA\/1 mice","volume":"48","author":"Matthys","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e82","DOI":"10.1161\/ATVBAHA.117.309522","article-title":"DBA\/2J Haplotype on Distal Chromosome 2 Reduces Mertk Expression, Restricts Efferocytosis, and Increases Susceptibility to Atherosclerosis","volume":"37","author":"Kayashima","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.yebeh.2015.06.008","article-title":"Abnormalities of serotonergic neurotransmission in animal models of SUDEP","volume":"71","author":"Feng","year":"2017","journal-title":"Epilepsy Behav."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.brainres.2011.08.043","article-title":"Differences in serotonin receptor expression in the brainstem may explain the differential ability of a serotonin agonist to block seizure-induced sudden death in DBA\/2 vs. DBA\/1 mice","volume":"1418","author":"Faingold","year":"2011","journal-title":"Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12757","DOI":"10.1038\/srep12757","article-title":"Arteriovenous Blood Metabolomics: A Readout of Intra-Tissue Metabostasis","volume":"5","author":"Ivanisevic","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1021\/acs.analchem.7b03929","article-title":"Annotation: A Computational Solution for Streamlining Metabolomics Analysis","volume":"90","author":"Benton","year":"2018","journal-title":"Anal. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3246","DOI":"10.1021\/acs.analchem.8b03126","article-title":"Autonomous METLIN-Guided In-source Fragment Annotation for Untargeted Metabolomics","volume":"91","author":"Guijas","year":"2019","journal-title":"Anal. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3156","DOI":"10.1021\/acs.analchem.7b04424","article-title":"METLIN: A Technology Platform for Identifying Knowns and Unknowns","volume":"90","author":"Guijas","year":"2018","journal-title":"Anal. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10666","DOI":"10.1073\/pnas.1806643115","article-title":"Literature-based automated discovery of tumor suppressor p53 phosphorylation and inhibition by NEK2","volume":"115","author":"Choi","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nri.2016.4","article-title":"Purinergic regulation of the immune system","volume":"16","author":"Cekic","year":"2016","journal-title":"Nat. Reviews. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"39884","DOI":"10.1038\/srep39884","article-title":"Soluble Uric Acid Activates the NLRP3 Inflammasome","volume":"7","author":"Braga","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4372","DOI":"10.1128\/jvi.67.7.4372-4378.1993","article-title":"Vaccination to prevent persistent viral infection","volume":"67","author":"Oldstone","year":"1993","journal-title":"J. Virol"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Serger, E., Luengo-Gutierrez, L., Chadwick, J.S., Kong, G., Zhou, L., Crawford, G., Danzi, M.C., Myridakis, A., Brandis, A., and Bello, A.T. (2022). The gut metabolite indole-3 propionate promotes nerve regeneration and repair. Nature.","DOI":"10.1038\/s41586-022-04884-x"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/12\/7\/645\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:50:05Z","timestamp":1760140205000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/12\/7\/645"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,14]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["metabo12070645"],"URL":"https:\/\/doi.org\/10.3390\/metabo12070645","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,14]]}}}