iMeta | Akkermansia muciniphila-derived hypoacylated rough-type LPS alleviates diet-induced obesity via TLR4–IL-23–IL-22 immune axis

This study demonstrates that Akkermansia muciniphila-derived hypoacylated rough-type LPS (ALPS) exhibits significant anti-obesity and metabolic improvement effects in diet-induced obese mice through TLR4–IL-23–IL-22 immune axis activation, enabling intestinal microbiota regulation and barrier function restoration.

 

Literature Overview
The article titled "Akkermansia muciniphila‐derived hypoacylated rough‐type lipopolysaccharides alleviate diet‐induced obesity via activation of TLR4−IL‐23−IL‐22 immune axis", published in iMeta, systematically reviews the role of A. muciniphila-derived hypoacylated rough-type LPS in regulating metabolic disorders and its immunomodulatory mechanisms. Through chemical structure analysis and animal experiments, the study reveals ALPS acts as a weak TLR4 agonist that significantly improves weight, liver function, intestinal barrier integrity, and microbiota composition in diet-induced obesity models.

Background Knowledge
Obesity and related metabolic syndromes represent major global health challenges, with pathogenic mechanisms involving gut microbiota dysbiosis and chronic low-grade inflammation. Gut commensal LPS regulates host immune homeostasis through TLR4 signaling, where structural variations in LPS produce differential immune responses. While Akkermansia muciniphila demonstrates mucin-degrading capabilities and its abundance correlates negatively with metabolic health, the specific role of its components like LPS in anti-obesity mechanisms remains incompletely understood. This study focuses on ALPS from A. muciniphila HW07 strain, systematically elucidating its TLR4-dependent activation of IL-23–IL-22 immune axis to improve intestinal barrier function and regulate microbiota structure. This mechanism provides novel insights for developing LPS-based immunotherapies and highlights the importance of LPS structural diversity in immunomodulation.

 

 

Research Methods and Experiments
The research team chemically characterized ALPS as tetra-acylated, mono/di-phosphorylated rough-type LPS, and conducted in vivo experiments using high-fat-diet (HFD)-induced obese mouse models to evaluate its effects on weight, metabolic parameters, intestinal barrier function, and gut microbiota. In vitro stimulation experiments with bone marrow-derived macrophages and dendritic cells assessed ALPS' activation capacity for TLR4 and TLR2 signaling pathways. TLR4 knockout mice validated the TLR4-dependent mechanism. Fecal microbiota transplantation experiments further examined vertical transmission of ALPS-induced microbiota changes and their impact on metabolic phenotypes.

Key Conclusions and Perspectives

• ALPS possesses tetra-acylated, mono/di-phosphorylated lipid A structure, showing weaker TLR4/TLR2 agonistic activity compared to E. coli LPS (ELPS).
• In diet-induced obese mice, ALPS significantly reduces weight gain and adiposity while improving liver function and insulin sensitivity.
• ALPS enhances goblet cell numbers and tight junction protein expression, promoting intestinal barrier repair.
• ALPS treatment significantly increases IL-22 and IL-23 secretion through TLR4 signaling.
• Anti-IL-22 antibody blocking experiments abolished ALPS' protective effects, confirming IL-22's central role in mediating these benefits.
• ALPS restructures gut microbiota by reducing Firmicutes/Bacteroidetes (F/B) ratio and enriching beneficial bacteria like Clostridium cocleatum and Bacteroides acidifaciens.
• Fecal transplantation experiments demonstrate ALPS-induced microbiota can vertically transfer anti-obesity phenotypes to recipient mice, improving metabolic functions and barrier integrity.
• ALPS shows no acute toxicity in mice, while ELPS causes 40% mortality, highlighting ALPS' superior immunotherapeutic potential.

Research Significance and Prospects
This study provides molecular mechanistic insights into A. muciniphila LPS' immunomodulatory functions in metabolic diseases, establishing its TLR4–IL-23–IL-22 axis-mediated microbiota regulation and barrier protection. Future research should explore ALPS' application in human gut immune regulation, develop LPS-based metabolic disease immunotherapies, and evaluate its immunomodulatory potential in other inflammatory or infectious disease models.

 

 

Conclusion
This study represents the first systematic chemical structural characterization of A. muciniphila-derived hypoacylated rough-type LPS, demonstrating its TLR4–IL-23–IL-22 signaling axis-mediated immunomodulation and metabolic improvement in diet-induced obesity mice. ALPS exhibits minimal toxicity while enabling transferable anti-obesity effects through microbiota transplantation, suggesting promising applications in gut microbiota regulation and metabolic disease treatment. These findings establish theoretical foundations for commensal bacteria-derived LPS immunotherapies and warrant further evaluation of ALPS' therapeutic potential in human gut homeostasis, inflammation, and metabolic disorders.

 

Li Sun, Yuting Zhang, Wang Dong, Shuangjiang Liu, and Hongwei Liu. Akkermansia muciniphila‐derived hypoacylated rough‐type lipopolysaccharides alleviate diet‐induced obesity via activation of TLR4−IL‐23−IL‐22 immune axis. iMeta.