{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T04:18:45Z","timestamp":1793852325893,"version":"4.6.1"},"reference-count":138,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"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:sec><jats:title>Background<\/jats:title><jats:p>Sepsis is a life-threatening condition with limited therapeutic options. Emerging evidence implicates gut microbial metabolites in modulating host immunity, but the specific interactions between these metabolites and host druggable targets remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We utilized a systems biology framework integrating genetic analyses, multi-omics profiling, and structure-based virtual screening to systematically map the interaction landscape between human gut microbial metabolites and druggable G-protein-coupled receptors (GPCRs), ion channels (ICs), and kinases (termed the \u201cGIKome\u201d) in sepsis. Key findings were validated by molecular dynamics (MD) simulation, microscale thermophoresis (MST), and functional assays in a murine cecal ligation and puncture (CLP) model of sepsis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We evaluated 190,950 metabolite-protein interactions, linking 114 sepsis-related GIK targets to 335 gut microbial metabolites, and prioritized indole-3-lactic acid (ILA), a metabolite enriched in <jats:italic>Akkermansia muciniphila<\/jats:italic>, as a promising therapeutic candidate. MD simulation and MST further revealed that ILA binds stably to PFKFB2, a pivotal kinase in regulating glycolytic flux and immune activation during sepsis. <jats:italic>In vivo<\/jats:italic>, ILA administration improved survival, attenuated cytokine storm, and mitigated multi-organ injury in CLP-induced septic mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This systems-level investigation unveils previously unrecognized therapeutic targets, offering a blueprint for microbiota-based precision interventions in critical care medicine.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1597676","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T06:06:10Z","timestamp":1753077970000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis"],"prefix":"10.3389","volume":"16","author":[{"given":"Jun","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianbo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1208623","article-title":"Severe sepsis and septic 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