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

Abstract 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.