iMeta | Hypoacylated LPS from Akkermansia muciniphila Alleviates Diet-Induced Obesity via TLR4–IL-23–IL-22 Immune Axis

This study demonstrates that hypoacylated rough-type LPS derived from Akkermansia muciniphila (ALPS) exhibits significant anti-obesity and metabolic-improving effects in diet-induced obese mice by modulating gut microbiota and restoring barrier function through activation of the TLR4–IL-23–IL-22 immune axis.

 

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

Background Knowledge
Obesity and associated metabolic syndromes represent major global health challenges, with pathogenesis involving gut microbiota dysbiosis and chronic low-grade inflammation. Gut symbiotic bacterial LPS regulates host immune homeostasis via TLR4 signaling pathways, where structural variations in LPS molecules determine differential immunological responses. Akkermansia muciniphila, a mucin-degrading intestinal commensal, shows negative correlation with metabolic disorders, yet the specific anti-obesity mechanisms of its components like LPS remain incompletely understood. This study focuses on ALPS from A. muciniphila strain HW07, characterizing its chemical structure and demonstrating through in vitro cellular assays and murine models that ALPS activates the IL-23–IL-22 immune axis in a TLR4-dependent manner, enhancing intestinal barrier function and restructuring gut microbiota. These findings provide novel insights for developing LPS-based immunotherapies and emphasize the critical role of LPS structural diversity in immune regulation.

 

 

Research Methods and Experiments
The research team conducted chemical characterization to confirm ALPS as tetra-acylated, mono/di-phosphorylated rough-type LPS. In vivo experiments used high-fat-diet (HFD)-induced obese mice to evaluate ALPS effects on weight gain, metabolic parameters, intestinal barrier function, and microbiota composition. In vitro stimulation assays employed bone marrow-derived macrophages and dendritic cells to assess ALPS-induced TLR4/TLR2 signaling activation. TLR4-knockout mice validated the receptor dependency mechanism. Fecal microbiota transplantation experiments determined whether ALPS-induced microbiota changes could vertically transmit metabolic benefits to recipient mice.

Key Conclusions and Perspectives

• ALPS possesses a tetra-acylated, mono/di-phosphorylated lipid A structure, exhibiting weaker TLR4/TLR2 agonistic activity compared to E. coli LPS (ELPS).
• In diet-induced obese mice, ALPS significantly reduces weight gain, fat mass accumulation, and improves liver function and insulin sensitivity.
• ALPS enhances intestinal goblet cell numbers and tight junction protein expression, promoting intestinal barrier repair.
• ALPS treatment specifically induces IL-22 and IL-23 secretion through TLR4-dependent signaling.
• Anti-IL-22 antibody blockade experiments confirm IL-22 mediates ALPS metabolic and barrier protective effects.
• ALPS restructures gut microbiota by reducing Firmicutes/Bacteroidetes ratios and enriching beneficial species like Clostridium cocleatum and Bacteroides acidifaciens.
• Fecal transplant recipients exhibit transmitted anti-obesity phenotypes with improved metabolic parameters and barrier integrity.
• ALPS shows no acute toxicity in mice versus 40% mortality in ELPS-treated groups, demonstrating superior immunomodulatory safety.

Research Significance and Prospects
This work provides molecular mechanistic insights into A. muciniphila LPS immunomodulation in metabolic diseases, establishing its TLR4–IL-23–IL-22 axis-mediated intestinal barrier repair and microbiota stabilization. Future research should evaluate ALPS applications in human intestinal immunity, develop LPS-targeted metabolic disease immunotherapies, and explore its immunoregulatory potential in inflammatory and infectious disease models.

 

 

Conclusion
This study presents the first comprehensive structural characterization of A. muciniphila-derived hypoacylated rough-type LPS and mechanistically demonstrates its TLR4–IL-23–IL-22 signaling axis-mediated immunomodulatory and metabolic benefits in obese mice. The absence of ALPS toxicity and its transmissible anti-obesity effects via microbiota transplantation highlight its therapeutic potential for microbiota regulation and metabolic disease intervention. These findings establish a foundation for symbiotic bacteria LPS-based immunomodulatory therapies, warranting further clinical evaluation in human intestinal 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.