A. muciniphila-Derived Hypoacylated Rough-Type LPS Alleviates Diet-Induced Obesity via the 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 activation of the TLR4-IL-23-IL-22 immune axis, enabling gut microbiota regulation and intestinal barrier 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 reviews the role of A. muciniphila-derived hypoacylated rough-type LPS in modulating metabolic disorders and its immune regulatory mechanisms. Through chemical structure analysis and animal experiments, the study reveals ALPS acts as a weak TLR4 agonist that significantly improves weight gain, liver function, intestinal barrier integrity, and modulates gut microbiota 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. Gut commensal LPS regulates host immune homeostasis via TLR4 signaling, while distinct LPS chemical structures generate differential immune responses. Akkermansia muciniphila, an intestinal mucus-degrading bacterium, demonstrates negative correlation with metabolic disorders, but the specific roles of its components like LPS in anti-obesity mechanisms remain incompletely understood. This study focuses on LPS from A. muciniphila strain HW07 (ALPS), using chemical structure analysis, cell experiments, and animal models to demonstrate that ALPS activates the IL-23-IL-22 immune axis through TLR4-dependent mechanisms, thereby improving intestinal barrier function and modulating microbiota composition. These findings provide new insights for developing LPS-based immunotherapies for metabolic diseases, highlighting the importance of LPS structural diversity in immune regulation.

 

 

Research Methods and Experiments
The research team chemically characterized ALPS as a rough-type LPS with tetra-acylation and mono/di-phosphorylation features. In vivo experiments were conducted using high-fat-diet-induced obese mouse models to evaluate its effects on weight management, metabolic parameters, intestinal barrier integrity, and microbiota composition. In vitro stimulation assays employed bone marrow-derived macrophages and dendritic cells to assess ALPS activation of TLR4 and TLR2 signaling pathways, with TLR4 knockout mice used to validate the TLR4-dependent mechanism. Fecal microbiota transplantation experiments further tested whether ALPS-induced microbiota changes could vertically transmit metabolic improvements to recipient mice.

Key Conclusions and Perspectives

• ALPS possesses 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 substantially reduces weight gain, decreases adiposity, and improves hepatic function and insulin sensitivity.
• ALPS enhances goblet cell proliferation and tight junction protein expression, promoting intestinal barrier repair.
• ALPS administration significantly increases IL-22 and IL-23 secretion, which is TLR4-dependent.
• Anti-IL-22 antibody blocking experiments abolished ALPS-mediated metabolic improvements and barrier protection, confirming IL-22's central role.
• ALPS modulates gut microbiota composition by reducing Firmicutes/Bacteroidetes ratios and increasing beneficial bacteria including Clostridium cocleatum and Bacteroides acidifaciens.
• Fecal transplantation experiments demonstrate that ALPS-modulated microbiota can vertically transfer anti-obesity phenotypes to recipient mice, improving metabolic function and enhancing intestinal barrier integrity.
• ALPS shows no acute toxicity in mice, whereas ELPS treatment caused 40% mortality, highlighting ALPS' superior safety profile and immunomodulatory potential.

Research Significance and Prospects
This study provides molecular mechanistic insights into A. muciniphila LPS-mediated immune regulation in metabolic diseases, demonstrating its TLR4-IL-23-IL-22 axis-dependent restoration of gut barrier and microbiota homeostasis. Future investigations should explore ALPS' application in human intestinal immunity, develop LPS-based immunotherapies for metabolic disorders, and evaluate its immunomodulatory potential in other inflammatory or infectious disease models.

 

 

Conclusion
This research represents the first systematic characterization of A. muciniphila-derived hypoacylated rough-type LPS chemical structure, elucidating its TLR4-IL-23-IL-22 signaling axis-mediated immune regulation and metabolic improvement in diet-induced obese mice. ALPS exhibits minimal toxicity while demonstrating transmissible anti-obesity effects through microbiota modulation, suggesting promising therapeutic applications in gut microbiota regulation and metabolic disease treatment. The findings establish a theoretical foundation for commensal bacteria LPS-based immunotherapies, warranting further clinical evaluation of its 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.