Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice

Gut microbiota including Akkermansia muciniphila are known to modulate energy metabolism, glucose tolerance, immune system maturation and function in humans. Although A. muciniphila is correlated with metabolic diseases and its beneficial casual effects were reported on host metabolism, the molecular mechanisms involved have not been identified. We report that A. muciniphila increases thermogenesis and glucagon-like peptide-1 (GLP-1) secretion in high-fat diet (HFD) induced C57BL/6J mice by induction of uncoupling protein 1 in brown adipose tissue (BAT) and systemic GLP-1 secretion. We apply fast protein liquid chromatography and liquid chromatography-mass spectrophotometry analysis to identify an 84-kDa protein named P9 that is secreted by A. muciniphila. Using L cells and HFD mice, we show that purified P9 alone is sufficient to induce GLP-1 secretion and BAT thermogenesis. By ligand-receptor capture analysis, we find that P9 interacts with intercellular adhesion molecule-2 (ICAM-2). Interleukin-6 deficiency abrogates the effects of P9 in glucose homeostasis and down-regulates ICAM-2 expression. Our results show that interactions between P9 and ICAM-2 could be targeted by therapeutics for metabolic diseases.