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

This study demonstrates that hypoacylated rough-type lipopolysaccharides (ALPS) from Akkermansia muciniphila significantly improve metabolic disorders and reshape gut microbiota through activation of the TLR4-IL-23-IL-22 immune axis in diet-induced obese mouse models, providing novel insights for obesity and related metabolic disease therapies.

 

Literature Overview
This 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 potential role of Akkermansia muciniphila in metabolic diseases, particularly focusing on the immunomodulatory functions and anti-obesity effects of its derived hypoacylated rough-type lipopolysaccharides (ALPS). Through chemical structural analysis, cellular experiments, and animal models, the study reveals that ALPS regulate intestinal barrier function, microbiota balance, and metabolic disorders via the TLR4-IL-23-IL-22 signaling pathway, establishing theoretical foundations for developing novel immunomodulatory probiotic components.

Background Knowledge
Lipopolysaccharides (LPS), as critical components of Gram-negative bacterial outer membranes, mediate key interactions between host immune systems and gut microbiota. LPS from different bacterial species vary in acylation patterns, phosphorylation states, and carbohydrate chain structures, affecting their binding capabilities to TLR4/TLR2 and subsequent immune responses. Akkermansia muciniphila, a mucin-degrading bacterium highly abundant in healthy individuals, has well-established anti-obesity, anti-inflammatory, and immunomodulatory properties through active components like the outer membrane protein Amuc_1100. However, its LPS chemical structure and immunological mechanisms in metabolic regulation remain incompletely characterized. This study focuses on ALPS structural features and their roles in diet-induced obesity models to elucidate their immunomodulatory mechanisms, particularly TLR4−IL-23−IL-22 axis activation, offering new targets for metabolic disease interventions.

 

 

Research Methods and Experiments
The research team extracted and purified LPS (ALPS) from healthy human-origin Akkermansia muciniphila HW07, analyzing its chemical structure through SDS-PAGE, LC-MS, and genomic comparisons. Physiological effects of ALPS were evaluated in diet-induced obese (DIO) mouse models, including weight changes, lipid metabolism, liver function, intestinal barrier integrity, and microbiota alterations. TLR4/TLR2 specificity was validated using receptor antagonists and TLR4 knockout mice. Finally, IL-22 neutralization experiments confirmed its central role in ALPS-mediated metabolic improvements.

Key Conclusions and Perspectives

• ALPS was identified as a hypoacylated, mono/di-phosphorylated, rough-type lipopolysaccharide with weaker TLR4/TLR2 activation compared to E. coli LPS (ELPS)
• In DIO mouse models, ALPS intraperitoneal injection significantly inhibited weight gain while improving lipid metabolism, liver function, and intestinal barrier integrity
• ALPS treatment markedly elevated plasma IL-22 and IL-23 levels, with IL-22 neutralization reversing anti-obesity effects, demonstrating IL-22 as a key effector
• ALPS upregulates IL-23 and IL-22 expression through TLR4-dependent mechanisms, activating intestinal immune defenses and promoting antimicrobial peptides, mucins, and tight junction protein expression
• ALPS reshaped gut microbiota composition in mice, increasing beneficial bacteria like Clostridium cocleatum and Bacteroides acidifaciens while reducing pathogenic Frod, with fecal microbiota transplantation experiments confirming metabolic improvements
• Compared to ELPS, ALPS showed superior safety profiles with no mortality in acute mouse toxicity tests versus 40% mortality in ELPS-treated groups

Research Significance and Prospects
This study provides molecular immunological mechanisms explaining Akkermansia muciniphila's metabolic benefits, supporting its application as next-generation probiotics for obesity and related disorders. Future research should explore ALPS safety and efficacy in humans, and evaluate its potential as an immunomodulatory agent for other metabolic diseases like diabetes and non-alcoholic fatty liver disease.

 

 

Conclusion
This study systematically characterizes the immunomodulatory and metabolic benefits of Akkermansia muciniphila-derived hypoacylated rough-type lipopolysaccharides (ALPS) in diet-induced obese mice. ALPS activate the TLR4-dependent IL-23−IL-22 signaling axis, promoting intestinal barrier repair, antimicrobial peptide secretion, and microbiota equilibrium to alleviate obesity and associated metabolic disorders. Compared to conventional E. coli LPS, ALPS demonstrate reduced pro-inflammatory activity and enhanced safety profiles, offering new molecular foundations for LPS-based immunomodulatory therapies. This research establishes scientific basis for probiotic-derived LPS applications in metabolic disease interventions and provides theoretical support for future clinical translations.

 

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.