Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis
BackgroundSepsis 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.MethodsWe utilized a syst...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1597676/full |
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| author | Jun Liu Tong Li Li Xin Xingyu Li Jianbo Zhang Peng Zhu |
| author_facet | Jun Liu Tong Li Li Xin Xingyu Li Jianbo Zhang Peng Zhu |
| author_sort | Jun Liu |
| collection | DOAJ |
| description | BackgroundSepsis 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.MethodsWe 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 “GIKome”) 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.ResultsWe 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 Akkermansia muciniphila, 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. In vivo, ILA administration improved survival, attenuated cytokine storm, and mitigated multi-organ injury in CLP-induced septic mice.ConclusionsThis systems-level investigation unveils previously unrecognized therapeutic targets, offering a blueprint for microbiota-based precision interventions in critical care medicine. |
| format | Article |
| id | doaj-art-d6574639100445c8b86c79ab2ff76b21 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-d6574639100445c8b86c79ab2ff76b212025-08-20T02:41:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.15976761597676Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsisJun Liu0Tong Li1Li Xin2Xingyu Li3Jianbo Zhang4Peng Zhu5Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaBackgroundSepsis 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.MethodsWe 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 “GIKome”) 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.ResultsWe 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 Akkermansia muciniphila, 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. In vivo, ILA administration improved survival, attenuated cytokine storm, and mitigated multi-organ injury in CLP-induced septic mice.ConclusionsThis systems-level investigation unveils previously unrecognized therapeutic targets, offering a blueprint for microbiota-based precision interventions in critical care medicine.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1597676/fullGPCRsion channelskinasesMendelian randomizationmicrobial metabolitessepsis |
| spellingShingle | Jun Liu Tong Li Li Xin Xingyu Li Jianbo Zhang Peng Zhu Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis Frontiers in Immunology GPCRs ion channels kinases Mendelian randomization microbial metabolites sepsis |
| title | Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis |
| title_full | Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis |
| title_fullStr | Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis |
| title_full_unstemmed | Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis |
| title_short | Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis |
| title_sort | comprehensive characterization of multi omics landscapes between gut microbial metabolites and the druggable genome in sepsis |
| topic | GPCRs ion channels kinases Mendelian randomization microbial metabolites sepsis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1597676/full |
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