Akkermansia muciniphila-derived postbiotics reprogram immune balance to combat sepsis via the IDO1/Kyn/AhR metabolic axis.

Summary

In mouse LPS/CLP and a porcine sepsis model, hypoacylated lipooligosaccharides from Akkermansia muciniphila protected against sepsis by inducing semi-mature dendritic cells with IDO1 upregulation, increasing kynurenine and AhR signaling to drive Treg differentiation and suppress Th17 responses. Effects were abrogated by an IDO1 inhibitor and mimicked by kynurenine, and safety was demonstrated in mice.

Key Findings

• ALOS protected against sepsis in LPS and CLP mouse models and in a porcine model, reducing systemic inflammation and organ injury.
• Mechanism: ALOS induced semi-mature dendritic cells with increased IDO1, elevating kynurenine to activate AhR and promote Treg differentiation while reducing Th17 cells.
• Reversal and mimicry: The IDO1 inhibitor NLG919 abolished protection, whereas exogenous kynurenine reproduced benefits; short-term safety of ALOS was shown in mice.

Clinical Implications

While preclinical, findings support advancing microbiome-derived postbiotics and IDO1–kynurenine–AhR modulators as candidate adjuvants for sepsis, with biomarker-guided designs.

Limitations

• Preclinical models may not fully recapitulate human sepsis heterogeneity and timing of intervention
• Dosing schedule and route (i.p.) may not translate directly to clinical practice

Future Directions

Phase 1 safety/pharmacokinetic studies of ALOS or analogs, followed by biomarker-enriched early-phase trials targeting the IDO1–Kyn–AhR axis in sepsis; exploration of combinatorial strategies with antibiotics and source control.