Sulfated bile acid produced by a human gut commensal alleviates paediatric sepsis in mice.

Summary

Multi-omics in two pediatric sepsis cohorts pinpointed DCA-3S, produced largely by Enterococcus raffinosus, as linked to disease progression and capable of attenuating sepsis in mice and organoids by strengthening intestinal barrier and dampening inflammation. This uncovers a microbial route to bile acid sulfation and nominates DCA-3S as a biomarker and therapeutic candidate.

Key Findings

• Targeted bile acid metabolomics integrated with gut metagenomes in two pediatric sepsis cohorts identified DCA-3S as associated with sepsis progression.
• Enterococcus raffinosus was shown in vitro/in vivo to account for at least 80% of DCA-3S production, challenging hepato-centric sulfation dogma.
• Exogenous DCA-3S administration alleviated sepsis in mouse and intestinal organoid models by improving intestinal barrier function and reducing inflammatory responses.

Clinical Implications

DCA-3S could evolve into a noninvasive biomarker for pediatric sepsis risk stratification and a candidate metabolite therapy; however, human interventional data, dosing, pharmacokinetics, and safety are needed before clinical adoption.

Limitations

• Predominantly preclinical efficacy; no human interventional data yet
• Cohort sample sizes and generalizability across diverse pediatric populations are not detailed in the abstract

Future Directions

Validate DCA-3S as a biomarker in larger, longitudinal pediatric cohorts; delineate microbial sulfation enzymes and regulation; assess dosing, PK/PD, and safety of DCA-3S or microbiome-based interventions in early-phase trials.