Akkermansia muciniphila-Derived Hypoacylated Rough-Type LPS Alleviates Diet-Induced Obesity via TLR4–IL-23–IL-22 Immune Axis

This study reveals that hypoacylated rough-type lipopolysaccharides (ALPS) derived from Akkermansia muciniphila demonstrate significant anti-obesity and metabolic improvement effects in diet-induced obese mice, achieved through activation of the TLR4–IL-23–IL-22 immune axis for microbiota regulation and barrier function restoration.

 

Literature Overview
This study 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 metabolic regulation and elucidates its immunomodulatory mechanisms. Through chemical structural analysis and animal experiments, the research demonstrates that ALPS acts as a weak TLR4 agonist, significantly improving 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 pathogenesis involving gut microbiota dysbiosis and chronic low-grade inflammation. Intestinal commensal LPS regulates host immune homeostasis through TLR4 signaling, where structural variations in LPS produce differential immunological responses. While A. muciniphila, a mucin-degrading gut commensal, exhibits negative correlation with metabolic disorders, the specific mechanisms of its components like LPS in anti-obesity functions remain incompletely understood. This study focuses on ALPS from A. muciniphila HW07 strain, using structural characterization, cellular assays, and animal models to demonstrate TLR4-dependent activation of the IL-23–IL-22 axis, which enhances intestinal barrier function and modulates microbiota composition. These findings provide molecular insights for developing LPS-based immunotherapies while highlighting structural diversity of LPS in immune regulation.

 

 

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

Key Conclusions and Perspectives

• ALPS possesses tetra-acylated, mono/di-phosphorylated lipid A structure, showing reduced TLR4/TLR2 agonistic activity compared to E. coli LPS (ELPS).
• In diet-induced obese mice, ALPS significantly reduces weight gain, fat mass accumulation, while improving hepatic function and insulin sensitivity.
• ALPS enhances goblet cell density and tight junction protein expression, promoting intestinal barrier repair.
• ALPS treatment specifically induces IL-22 and IL-23 secretion through TLR4 signaling.
• Anti-IL-22 antibody blocking experiments abrogated ALPS' metabolic benefits and barrier protection, confirming IL-22's central mediating role.
• ALPS remodels gut microbiota composition, decreasing Firmicutes/Bacteroidetes ratio while enriching beneficial species like Clostridium cocleatum and Bacteroides acidifaciens.
• Fecal transplantation experiments demonstrate vertical transmission of ALPS-induced microbiota conferring anti-obesity phenotypes with improved barrier function in recipient mice.
• ALPS shows no acute toxicity in mice versus 40% mortality in ELPS-treated groups, highlighting its superior immunotherapeutic potential.

Research Significance and Prospects
This study provides molecular evidence for A. muciniphila LPS as an immunomodulator in metabolic diseases, establishing its TLR4–IL-23–IL-22 mediated gut barrier and microbiota regulation. Future research should explore ALPS' applications in human gut immune regulation, develop LPS-based metabolic disease therapies, and evaluate its immunomodulatory potential in other inflammatory or infectious disease models.

 

 

Conclusion
This study presents the first systematic structural characterization of A. muciniphila-derived hypoacylated rough-type LPS, demonstrating its TLR4–IL-23–IL-22 signaling axis-dependent immunomodulation and metabolic improvement in diet-induced obesity models. ALPS exhibits minimal toxicity while enabling transferable anti-obesity effects through microbiota transplantation, suggesting therapeutic potential for gut microbiota-targeted interventions. These findings establish theoretical foundations for commensal bacteria-derived LPS immunotherapy, warranting further evaluation of its therapeutic applications 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.