Faecalibacterium prausnitzii -associated 18β-glycyrrhetinic acid protects against sepsis via ABCC1-mediated suppression of MAPK/NF-κB signaling

Gut microbiota dysbiosis is increasingly recognized as a modifiable determinant of sepsis susceptibility and outcomes, yet protective commensals and microbiota-associated metabolites with actionable host mechanisms remain incompletely defined. Here, fecal 16S rRNA sequencing of septic and non-septic patients revealed a marked depletion of Faecalibacterium prausnitzii during sepsis. Oral administration of F. prausnitzii improved survival and alleviated multiorgan injury in mice subjected to cecal ligation and puncture. Untargeted metabolomics and liquid chromatography–tandem mass spectrometry identified 18β-glycyrrhetinic acid (18β-GA) as a major metabolite enriched in F. prausnitzii culture supernatants, and exogenous 18β-GA recapitulated key protective effects in vivo . In lipopolysaccharide-stimulated macrophages, 18β-GA reduced pro-inflammatory mediator expression and suppressed mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activation. Proteomics-guided prioritization and complementary pharmacological and genetic validation implicated ATP-binding cassette subfamily C member 1 (ABCC1) as a mediator involved in the protective effects of 18β-GA. Genetic silencing of ABCC1 attenuated the anti-inflammatory effects of 18β-GA, while pharmacological inhibition of ABCC1 by probenecid (PBN) and MK-571 partially reproduced the protective effects of 18β-GA. Collectively, these findings identify a F. prausnitzii –18β-GA-associated ABCC1 regulatory axis that contributes to the control of septic inflammation and highlight microbiota-derived metabolites as potential modulators of host inflammatory responses. IMPORTANCE Sepsis is a life-threatening syndrome with limited effective therapies beyond supportive care. Gut microbiota disruption is increasingly recognized as an important contributor to sepsis, but the protective microbes, effector metabolites, and host pathways involved are not well understood. Here, we show that F. prausnitzii is markedly depleted in sepsis and that supplementation with this commensal improves outcomes in experimental sepsis. We further identify 18β-glycyrrhetinic acid as a microbiota-associated metabolite with anti-inflammatory and organ-protective activity and implicate ABCC1 as a functionally relevant host target. Our findings provide mechanistic insight into how protective commensals can influence sepsis progression and support microbiome-informed, host-directed therapeutic strategies.