Akkermansia muciniphila-derived hypoacylated rough-type LPS alleviates diet-induced obesity through the TLR4–IL-23–IL-22 immune axis

This study demonstrates that hypoacylated rough-type lipopolysaccharides from Akkermansia muciniphila (ALPS) exhibit significant anti-obesity and metabolic improvement effects in diet-induced obese mice by activating the TLR4–IL-23–IL-22 immune axis, thereby modulating gut microbiota and restoring 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 Akkermansia muciniphila-derived hypoacylated rough-type LPS in regulating metabolic disorders and elucidates 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 pathogenesis involving gut microbiota dysbiosis and chronic low-grade inflammation. Intestinal commensal bacterial LPS regulates host immune homeostasis through TLR4 signaling, where distinct LPS chemical structures elicit differential immune responses. Although Akkermansia muciniphila—a mucin-degrading gut commensal—has been inversely correlated with metabolic health, the specific roles of its components like LPS in anti-obesity mechanisms remain incompletely understood. This study focuses on LPS from Akkermansia muciniphila strain HW07 (ALPS), employing chemical structure analysis, cellular stimulation, and animal models to demonstrate its TLR4-dependent activation of the IL-23–IL-22 immune axis, which enhances intestinal barrier function and remodels microbiota composition. These findings provide novel insights for developing LPS-based immunotherapies while highlighting the importance of LPS structural diversity in immunomodulation.

 

 

Research Methods and Experiments
The research team chemically characterized ALPS as a tetra-acylated, mono/di-phosphorylated rough-type LPS. In vivo experiments were conducted using high-fat-diet (HFD)-induced obese mouse models to evaluate ALPS' effects on weight gain, metabolic parameters, intestinal barrier integrity, and microbiota composition. In vitro stimulation assays with bone marrow-derived macrophages and dendritic cells assessed ALPS' activation of TLR4 and TLR2 signaling pathways, with gene knockout mice used to validate TLR4 dependency. Fecal microbiota transplantation experiments further determined 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, exhibiting significantly weaker TLR4/TLR2 activation 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 increases goblet cell density and tight junction protein expression, promoting intestinal barrier restoration.
• ALPS administration enhances IL-22 and IL-23 secretion, which is TLR4-dependent.
• Anti-IL-22 antibody blocking experiments abolished ALPS' metabolic and barrier protective effects, confirming IL-22's central mediating role.
• ALPS remodeling of gut microbiota reduces Firmicutes/Bacteroidetes ratios and enriches beneficial taxa like Clostridium cocleatum and Bacteroides acidifaciens.
• Fecal transplantation experiments demonstrate ALPS-induced microbiota changes can vertically transfer anti-obesity phenotypes to recipients, improving metabolic outcomes and barrier function.
• ALPS shows no acute toxicity in mice, whereas ELPS treatment results in 40% mortality, highlighting ALPS' superior immunomodulatory safety profile.

Research Significance and Prospects
This study establishes molecular mechanisms for Akkermansia muciniphila LPS in metabolic disease immunomodulation, identifying the TLR4–IL-23–IL-22 axis as a critical mediator of barrier and microbiota homeostasis. Future research should explore ALPS' application in human intestinal immunity, develop LPS-targeted metabolic disease therapies, and evaluate immunomodulatory potential across diverse inflammatory or infectious disease models.

 

 

Conclusion
This study represents the first comprehensive structural characterization of Akkermansia muciniphila-derived hypoacylated rough-type LPS, mechanistically demonstrating its immunomodulatory and metabolic benefits through TLR4–IL-23–IL-22 signaling in diet-induced obese mice. ALPS exhibits favorable safety profiles with no acute toxicity observed, and its anti-obesity effects can be vertically transmitted via fecal microbiota transplantation, underscoring its therapeutic potential for microbiota-targeted interventions in metabolic diseases. These findings establish foundational insights for commensal bacteria-derived LPS immunotherapy, 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.