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 , 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. , 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.