Akkermansia muciniphila-Derived Hypoacylated Rough-Type Lipopolysaccharides Alleviate Diet-Induced Obesity via TLR4–IL-23–IL-22 Immune Axis Activation

This study demonstrates that hypoacylated rough-type lipopolysaccharides from Akkermansia muciniphila (ALPS) exhibit significant anti-obesity and metabolic-improving effects in diet-induced obese mice by activating the TLR4–IL-23–IL-22 immune axis, thereby regulating gut microbiota and restoring intestinal barrier function.

 

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 hypoacylated rough-type LPS from A. muciniphila in modulating metabolic disorders. Through chemical structure analysis and animal experiments, the study reveals ALPS functions as a weak TLR4 agonist that significantly improves weight gain, 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 pathogenesis involving gut microbiota dysbiosis and chronic low-grade inflammation. Intestinal commensal LPS regulates host immune homeostasis through TLR4 signaling pathways, with structural variations in LPS determining differential immune responses. While Akkermansia muciniphila, a mucin-degrading gut commensal, has demonstrated inverse correlations with metabolic disorders, its specific components like LPS remain incompletely characterized in anti-obesity mechanisms. This study focuses on ALPS from A. muciniphila HW07 strain, systematically elucidating its TLR4-dependent activation of the IL-23–IL-22 immune axis to restore intestinal barrier function and modulate microbiota composition. These findings provide novel insights for developing LPS-based immunotherapies for metabolic diseases while highlighting the importance of LPS structural diversity in immune regulation.

 

 

Research Methods and Experiments
The research team chemically characterized ALPS as tetra-acylated, mono/di-phosphorylated rough-type LPS. In vivo experiments used high-fat-diet (HFD)-induced obese mouse models to evaluate effects on weight gain, metabolic parameters, intestinal barrier function, and gut microbiota composition. In vitro stimulation assays with bone marrow-derived macrophages and dendritic cells assessed ALPS' activation capacity for TLR4 and TLR2 signaling pathways. TLR4 gene knockout mice validated the dependence on TLR4 signaling. Fecal microbiota transplantation experiments determined vertical transmission of ALPS-induced microbiota modifications and associated metabolic improvements.

Key Conclusions and Perspectives

• ALPS exhibits a tetra-acylated, mono/di-phosphorylated lipid A structure with significantly reduced TLR4/TLR2 agonistic activity compared to E. coli LPS (ELPS).
• In diet-induced obese mice, ALPS treatment significantly reduces weight gain and adiposity while improving hepatic function and insulin sensitivity.
• ALPS enhances goblet cell numbers and tight junction protein expression, promoting intestinal barrier restoration.
• ALPS administration increases IL-22 and IL-23 secretion in a TLR4-dependent manner.
• Anti-IL-22 antibody blocking experiments abolished ALPS' metabolic and barrier protective effects, confirming IL-22's central mediating role.
• ALPS restructures gut microbiota composition, reducing Firmicutes/Bacteroidetes ratios and enriching beneficial species like Clostridium cocleatum and Bacteroides acidifaciens.
• Fecal transplantation experiments demonstrate vertical transmission of ALPS-induced anti-obesity phenotypes to recipient mice.
• ALPS shows no acute toxicity in mice while ELPS treatment results in 40% mortality, highlighting ALPS' superior immunotherapeutic potential.

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

 

 

Conclusion
This study systematically elucidates the chemical structure of hypoacylated rough-type LPS from A. muciniphila and its immunomodulatory mechanisms through the TLR4–IL-23–IL-22 signaling axis in diet-induced obesity models. ALPS demonstrates non-toxic immunoregulatory properties with transplantable anti-obesity microbiota effects, suggesting promising therapeutic applications for microbiota regulation and metabolic disease treatment. The findings establish theoretical foundations for commensal bacteria LPS-based immunotherapies and warrant further clinical evaluation of ALPS' therapeutic potential 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.