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Akkermansia muciniphila-derived postbiotics reprogram immune balance to combat sepsis via the IDO1/Kyn/AhR metabolic
Yuting Zhang1, Ruopeng Yin1, Wang Dong1
1State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing, PR China; Medical School, University of Chinese Academy of Sciences, Beijing, PR China; The Laboratory of Microbiome and Microecological Technology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, PR China.
Introduction:
Sepsis is a life-threatening syndrome of organ dysfunction driven by a dysregulated immune response. Effective therapeutic strategies to restore immune homeostasis remain limited. Hypoacylated lipooligosaccharides (ALOS) from Akkermansia muciniphila have emerged as potential immunomodulatory postbiotics, yet their therapeutic potential in sepsis and the underlying mechanisms remain unexplored.
Objectives:
This study aims to investigate whether ALOS confers protection in experimental models of sepsis induced by toxic lipopolysaccharides (LPS) or cecal ligation and puncture (CLP), and the mechanism by which ALOS exerts its anti-inflammatory and regulatory effects.
Methods:
In LPS or CLP-induced mouse sepsis models and a porcine sepsis model, ALOS (0.2 mg/kg, i.p.) was administered once every two days before challenge or half an hour post-surgery. Survival rates, physiological and biochemical parameters were assessed. Based on 16S rRNA gene amplicon sequencing and barrier function assessment, the changes of the colonic microbiota and metabolites and anti-inflammatory capacity were analyzed. The anti-inflammatory and immunomodulatory mechanisms of ALOS were investigated through dendritic cell phenotyping, transcriptomic analysis, inhibitor assays, and conditioned medium experiments. Finally, the safety of ALOS was evaluated in C57BL/6J mice following one-week administration (0.2 mg/kg, i.p.).
Results:
ALOS pretreatment significantly suppresses sepsis, reduces the proportion of pro-inflammatory Th17 cells, and increases regulatory T cells (Treg). Mechanistically, ALOS induced semi‑mature dendritic cells with upregulated IDO1 expression, leading to enhanced production of kynurenine (Kyn). Kyn activated the aryl hydrocarbon receptor (AhR) to drive Treg differentiation. The protective effect of ALOS was completely reversed by NLG919, whereas Kyn administration mimicked the therapeutic benefit. ALOS also produced therapeutic protection on sepsis. In a porcine sepsis model, pretreatment of ALOS exerted systemic anti‑inflammatory effects and protected multiple organs.
Conclusion:
This study highlights the protective role of ALOS in sepsis and identifies the IDO1-Kyn-AhR immune axis as the major underlying mechanism.
Insights
Hypoacylated lipooligosaccharides (ALOS) from Akkermansia muciniphila protect against sepsis by modulating immune responses. ALOS therapy enhances regulatory T cells via the IDO1-Kyn-AhR pathway, offering a novel therapeutic strategy for sepsis treatment.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Sepsis is a life-threatening organ dysfunction due to dysregulated immunity.
- Current sepsis therapies are limited in restoring immune homeostasis.
- Hypoacylated lipooligosaccharides (ALOS) from Akkermansia muciniphila show potential as immunomodulatory postbiotics.
Purpose of the Study:
- To investigate ALOS protection in experimental sepsis models (LPS, CLP).
- To elucidate the anti-inflammatory and regulatory mechanisms of ALOS.
- To evaluate the safety and therapeutic potential of ALOS in sepsis.
Main Methods:
- ALOS administration in mouse and porcine sepsis models.
- Assessment of survival rates, physiological parameters, and organ protection.
- Analysis of colonic microbiota, metabolites, and immune cell populations (Th17, Treg).
- Investigation of dendritic cell function, transcriptomics, and the IDO1-Kyn-AhR pathway.
Main Results:
- ALOS pretreatment significantly improved survival and suppressed sepsis.
- ALOS increased regulatory T cells (Treg) and decreased pro-inflammatory Th17 cells.
- The IDO1-Kyn-AhR axis mediated ALOS's protective effects, with Kyn administration mimicking the benefit.
- ALOS demonstrated systemic anti-inflammatory effects and organ protection in a porcine model.
Conclusions:
- ALOS confers significant protection against sepsis in preclinical models.
- The IDO1-Kyn-AhR immune axis is a key mechanism underlying ALOS's therapeutic effects.
- ALOS represents a promising postbiotic therapeutic candidate for sepsis management.
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