Akkermansia muciniphila-derived hypoacylated rough-type lipopolysaccharides alleviate diet-induced obesity via activation of TLR4-IL-23-IL-22 immune axis

Lipopolysaccharides (LPS) derived from intestinal symbionts plays a critical role in modulating and maintaining mucosal immunity. In this study, we investigated the chemical characteristics and antiobesity properties of Akkermansia muciniphila HW07 LPS (ALPS). ALPS was identified as hypo-acylated, mono/bis-phosphorylated, rough-type LPS. Compared to Escherichia coli LPS (ELPS), ALPS functions as a weak agonist of TLR4/TLR2. Intraperitoneal administration of ALPS in diet-induced obese (DIO) mice suppressed weight gain, improved metabolic parameters, restored gut barrier integrity, and modulated the gut microbiota. Notably, ALPS treatment significantly increased plasma interleukin (IL)-22 levels. Furthermore, neutralizing IL-22 with an antibody eliminated the antiobesity effects of ALPS in DIO mice. Mechanistically, ALPS upregulated the expression of both IL-22 and its upstream cytokine IL-23 in a TLR4-dependent manner. These findings confirm that activation of the TLR4-IL-23-IL-22 immune axis is a key mechanism underlying the antiobesity effect of ALPS. In acute toxicity assessment, no fatalities were observed in ALPS-treated mice, whereas ELPS treatment led to a 40% mortality rate. Collectively, our results demonstrate that hypo-acylated LPS from A. muciniphila functions as a metabolically beneficial immune modulator that exerts immunomodulatory effects through the TLR4-IL-22 axis and suggests ALPS as a promising novel therapeutic strategy for metabolic disorders.