Glutamine alleviates immunosuppression in polymicrobial sepsis by augmenting bacterial phagocytosis through sustaining the GFAT-DRP1 dependent mitochondrial calcium dynamics.

Summary

In murine polymicrobial sepsis, glutamine supplementation restored macrophage phagocytosis, reduced bacterial burden, modulated cytokines, and improved survival, effects lost with macrophage depletion. Mechanistically, glutamine activated a dual GFAT–DRP1 program—O-GlcNAcylation-driven DRP1 oligomerization and CDK1-dependent DRP1 Ser616 phosphorylation—to enhance mitochondrial fission, mitochondrial Ca2+ efflux, and sustain cytosolic Ca2+ essential for phagocytosis.

Key Findings

• Glutamine deficiency impaired macrophage phagocytosis and worsened sepsis-induced immunosuppression; supplementation restored function and improved survival in septic mice.
• Dual mechanism: GFAT-dependent O-GlcNAcylation promoted DRP1 oligomerization, and GFAT–CDK1 signaling induced DRP1 Ser616 phosphorylation independent of O-GlcNAc.
• Enhanced DRP1-mediated mitochondrial fission increased mitochondrial Ca2+ efflux and sustained cytosolic Ca2+ required for phagocytosis; benefits abrogated by macrophage depletion.

Clinical Implications

Suggests testing glutamine or GFAT/DRP1-targeted strategies to reverse sepsis-associated immunosuppression, with careful attention to timing, dosing, and patient selection, given prior mixed clinical results for glutamine in critical illness.

Limitations

• Preclinical murine and in vitro data limit direct clinical generalizability
• Prior clinical trials of glutamine in critical illness have yielded mixed or negative results, necessitating cautious translational steps

Future Directions

Prospective trials to evaluate glutamine timing/dose in immunosuppressed sepsis phenotypes; development of small-molecule modulators of the GFAT–DRP1–calcium axis with pharmacodynamic biomarkers (e.g., O-GlcNAcylation, DRP1 phosphorylation).