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

Hyo Shin Yoon, Chung Hwan Cho, Myeong Sik Yun, Sung Jae Jang, Hyun Ju You, Jun hyeong Kim, Dohyun Han, Kwang Hyun Cha, Sung Hyun Moon, Kiuk Lee, Yeon Ji Kim, Sung Joon Lee, Tae Wook Nam, Gwang Pyo Ko

Research output: Contribution to journalArticlepeer-review

255 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)563-573
Number of pages11
JournalNature Microbiology
Volume6
Issue number5
DOIs
Publication statusPublished - 2021 May

Bibliographical note

Funding Information:
We thank P. Helbling and M. Pavlou (Dualsystems Biotech) for their discussion regarding the LRC assay and proteomics analysis; K. Ge (National Institutes of Health, USA), J. B. Kim (Seoul National University, Korea) and O. J. Kwon (Catholic University, Korea) for providing the immortalized BACs; B. L. Roth (The University of North Carolina at Chapel Hill, USA) for providing HTLA cells; S. J. Lee (Korea University, Korea) for providing the calcium inhibitors; W. K. Huh (Seoul National University, Korea) for providing the GPCR inhibitors; J. S. Han (Seoul National University, Korea) for FPLC usage; Y. K. Oh (Seoul National University, Korea) for infrared camera usage; Y. Chung (Seoul National University, Korea) for temperature-controlled chamber usage; S. H. Yoon, L. Song, J. W. Kim and S. E. Choi (Seoul National University, Korea) for their technical assistance with the tissue sampling and preparation for FACS analysis; T. J. Ahn (KoBioLabs, Inc.) for cytokine analysis of bacterial isolates in cell lines; I. S. Cho (KoBioLabs, Inc.) for producing EcPrc; and the staff at the Samsung Medical Center for providing infant faecal samples. This work was supported by the National Research Foundation of Korea (NRF) (no. NRF-2018R1A2A1A05078258). C.H.C. was supported by the Global Ph.D. Fellowship program and a NRF grant funded by the Korean government (no. NRF-2018H1A2A1061914).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

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