{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:33:32Z","timestamp":1791408812565,"version":"4.3.3"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The microbiome is an important immune regulator, but the mechanisms by which commensal microbes shape systemic host defense during bloodstream infection remain poorly defined and commonly used pre-clinical models have practical, ethical and scientific limitations. Here, we establish a gnotobiotic zebrafish larval model to investigate microbiome-dependent protection against systemic blood infection by\n                    <jats:italic>Escherichia coli (E. coli)<\/jats:italic>\n                    bacteria, an important cause of early onset neonatal sepsis. We also use nontuberculous mycobacteria to infect zebrafish larvae to investigate the contribution of Toll-like receptor 2 (TLR2) in the defense responses. Germ-free (GF) and conventionalized (CONVD) larvae derived from the same clutches were systemically infected with\n                    <jats:italic>E. coli<\/jats:italic>\n                    , revealing that microbiome colonization significantly reduces early mortality. RNAseq revealed a conserved core immune activation program in both GF and CONVD larvae, but the absence of a microbiome was associated with a broader transcriptional response and stronger repression of metabolic pathways, suggesting that commensal microbes buffer infection-induced metabolic suppression. Extending this framework to nontuberculous mycobacteria, we performed systemic infections with fluorescent\n                    <jats:italic>Mycobacterium marinum<\/jats:italic>\n                    and\n                    <jats:italic>M. avium<\/jats:italic>\n                    in\n                    <jats:italic>tlr2<\/jats:italic>\n                    wild-type and mutant larvae under GF and CONVD conditions. While survival was largely unchanged, imaging-based quantification demonstrated increased bacterial proliferation in\n                    <jats:italic>tlr2<\/jats:italic>\n                    mutants and in GF larvae, with microbiome-mediated restriction of bacterial burden evident in wild-type but not\n                    <jats:italic>tlr2<\/jats:italic>\n                    -deficient hosts. Together, these data show that microbiome colonization buffers septic outcomes by reshaping systemic inflammatory and metabolic programs and identify TLR2 as a key node linking microbial colonization to effective host defense during nontuberculous mycobacterial infection.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1837804","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T04:24:41Z","timestamp":1782966281000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The microbiome protects against septic hyperinflammation and bacterial proliferation in a zebrafish model of blood infection with Escherichia coli and mycobacteria"],"prefix":"10.3389","volume":"17","author":[{"given":"Li","family":"Liu","sequence":"first","affiliation":[{"name":"Institute of Biology Leiden, Animal Science and Health, Leiden University","place":["Leiden, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f8rn E. V.","family":"Koch","sequence":"additional","affiliation":[{"name":"Institute of Biology Leiden, Animal Science and Health, Leiden University","place":["Leiden, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke H. J.","family":"Krekels","sequence":"additional","affiliation":[{"name":"Leiden Academic Centre for Drug Research, Leiden University","place":["Leiden, Netherlands"]},{"name":"Certara Inc.","place":["Princeton, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herman P.","family":"Spaink","sequence":"additional","affiliation":[{"name":"Institute of Biology Leiden, Animal Science and Health, Leiden University","place":["Leiden, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2024.2361490","article-title":"Gut microbiota dysbiosis-related susceptibility to nontuberculous mycobacterial lung disease","volume":"16","author":"Lin","year":"2024","journal-title":"Gut Microbes"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad9378","article-title":"How colonization by microbiota in 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