Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis

Jun Liu¹Tong Li¹Li Xing¹Xingyu Li²Jianbo Zhang^1*Peng Zhu^1*

• ¹Department of Gastrointestinal Anorectal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
• ²Department of Cardiology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

Background: 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.Methods: 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 "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.Results: 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 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.Conclusions: This systems-level investigation unveils previously unrecognized therapeutic targets, offering a blueprint for microbiota-based precision interventions in critical care medicine.