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

• Published in: Nature microbiology Vol. 6; no. 5; pp. 563 - 573
• Main Authors: Yoon, Hyo Shin, Cho, Chung Hwan, Yun, Myeong Sik, Jang, Sung Jae, You, Hyun Ju, Kim, Jun-hyeong, Han, Dohyun, Cha, Kwang Hyun, Moon, Sung Hyun, Lee, Kiuk, Kim, Yeon-Ji, Lee, Sung-Joon, Nam, Tae-Wook, Ko, GwangPyo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2021; Nature Publishing Group
• Subjects: 13; 13/1; 13/21; 13/31; 13/51; 14; 14/1; 14/63; 38; 38/79; 38/91; 42; 45; 59; 631/326; 64; 64/110; 64/60; 692/699; 82; 82/51; 82/58; 82/79; 82/80; 82/83; 96; 96/1; 96/95; Adipose tissue (brown); Adipose Tissue, Brown - metabolism; Akkermansia - metabolism; Akkermansia muciniphila; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biomedical and Life Sciences; Cell adhesion; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Chromatography; Diet, High-Fat - adverse effects; Energy metabolism; Gastrointestinal Microbiome; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - genetics; Glucagon-Like Peptide 1 - metabolism; Glucose; Glucose - metabolism; Glucose tolerance; High fat diet; Homeostasis; Humans; Immune system; Immunological tolerance; Infectious Diseases; Interleukin 6; Intestinal microflora; L cells; Letter; Life Sciences; Liquid chromatography; Male; Medical Microbiology; Metabolic Diseases - genetics; Metabolic Diseases - metabolism; Metabolic Diseases - microbiology; Metabolic disorders; Mice; Mice, Inbred C57BL; Microbiology; Microbiota; Molecular modelling; Parasitology; Peptides; Proteins; Spectrophotometry; Thermogenesis; Uncoupling protein 1; Uncoupling Protein 1 - genetics; Uncoupling Protein 1 - metabolism; Virology
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-021-00880-5

The gut microbiota, which includes Akkermansia muciniphila , is known to modulate energy metabolism, glucose tolerance, immune system maturation and function in humans 1 – 4 . Although A. muciniphila is correlated with metabolic diseases and its beneficial causal effects were reported on host metabolism 5 – 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. Akkermansia muciniphila produces P9, a small protein that interacts with intercellular adhesion molecule 2 to increase thermogenesis and glucagon-like peptide-1 secretion in mice.