GLP-1RA Liraglutide Attenuates Sepsis by Modulating Gut Microbiota and Associated Metabolites.

Liraglutide significantly improved survival in a murine cecal ligation and puncture (CLP) sepsis model.

• A murine CLP model was used to evaluate liraglutide treatment effects on survival.
• Liraglutide treatment resulted in significantly improved survival rates compared to untreated septic mice.
• The survival benefit was abolished in microbiota-depleted (antibiotic-treated) mice, indicating gut microbiota dependency.

Liraglutide reduced pro-inflammatory cytokines and alleviated organ injury in septic mice.

• Liraglutide treatment reduced pro-inflammatory cytokines in the CLP sepsis model.
• Organ damage in the lung, liver, and colon was alleviated following liraglutide treatment.
• Public transcriptomic data analysis identified overlapping targets between liraglutide and sepsis-related genes, supporting mechanistic relevance.

Liraglutide partially restored sepsis-induced gut dysbiosis and modulated fecal metabolites, including increasing citrulline levels.

• Gut microbiota composition was assessed via 16S rRNA sequencing and fecal metabolome via UPLC-MS.
• Liraglutide partially restored the gut microbiota composition disrupted by sepsis.
• Citrulline was identified as a key metabolite increased by liraglutide treatment.
• Additional associated metabolic pathways were modulated by liraglutide treatment.

The therapeutic effects of liraglutide in sepsis are critically mediated by the gut microbiota, as demonstrated by microbiota-depletion and fecal microbiota transplantation (FMT) experiments.

• The survival benefit of liraglutide was abolished in antibiotic-depleted (microbiota-depleted) mice.
• FMT from liraglutide-treated mice conferred protection against sepsis in recipient mice.
• These experiments confirmed the gut microbiota as a critical mediator of liraglutide's protective effects.

Citrulline exhibited direct anti-inflammatory properties in cellular assays and its plasma levels were negatively correlated with sepsis biomarkers in patients.

• Citrulline's anti-inflammatory properties were validated in vitro in cellular assays.
• Plasma citrulline levels were negatively correlated with procalcitonin (PCT) and C-reactive protein (CRP) in a clinical cohort of sepsis patients.
• These findings suggest citrulline may represent a potential microbial mediator or exploratory biomarker within the liraglutide-gut microbiota axis.

Plasma GLP-1 levels were measured in sepsis patients as part of the clinical investigation.

• Plasma GLP-1 was measured in sepsis patients to characterize the endogenous GLP-1 response in sepsis.
• This measurement was conducted alongside examination of microbiota-dependency of liraglutide's effects.
• The study used both a murine CLP model and a clinical cohort to provide translational context.