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

Nat Microbiol. 2021 May;6(5):563-573. doi: 10.1038/s41564-021-00880-5. Epub 2021 Apr 5.


The gut microbiota, which includes Akkermansia muciniphila, is known to modulate energy metabolism, glucose tolerance, immune system maturation and function in humans1-4. Although A. muciniphila is correlated with metabolic diseases and its beneficial causal effects were reported on host metabolism5-8, the molecular mechanisms involved have not been identified. Here, 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 and systemic GLP-1 secretion. We apply fast protein liquid chromatography and liquid chromatography coupled to mass spectrophotometry analysis to identify an 84 kDa protein, named P9, that is secreted by A. muciniphila. Using L cells and mice fed on an HFD, we show that purified P9 alone is sufficient to induce GLP-1 secretion and brown adipose tissue thermogenesis. Using 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 downregulates ICAM-2 expression. Our results show that the interactions between P9 and ICAM-2 could be targeted by therapeutics for metabolic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Akkermansia / metabolism
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Diet, High-Fat / adverse effects
  • Gastrointestinal Microbiome*
  • Glucagon-Like Peptide 1 / genetics
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucose / metabolism*
  • Homeostasis
  • Humans
  • Male
  • Metabolic Diseases / genetics
  • Metabolic Diseases / metabolism
  • Metabolic Diseases / microbiology*
  • Mice
  • Mice, Inbred C57BL
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism


  • Antigens, CD
  • Bacterial Proteins
  • Cell Adhesion Molecules
  • ICAM-2 protein, mouse
  • Uncoupling Protein 1
  • Glucagon-Like Peptide 1
  • Glucose

Supplementary concepts

  • Akkermansia muciniphila