Akkermansia muciniphila inhibits nonalcoholic steatohepatitis by orchestrating TLR2-activated γδT17 cell and macrophage polarization

ABSTRACT

Current evidence indicates that the next-generation probiotic Akkermansia muciniphila (A. muciniphila) has therapeutic potential for nonalcoholic fatty liver disease (NAFLD), especially its inflammatory stage known as nonalcoholic steatohepatitis (NASH). However, the mechanisms of A. muciniphila in NASH prevention remain unknown. Here, A. muciniphila supplementation prevented hepatic inflammation in high-fat diet-induced NASH mice, characterized by reduced hepatic proinflammatory macrophages (M1) and γδT and γδT17 cells. Consistently, hepatic M1 and γδT cells were enriched in biopsy-proven NASH patients and high-fat/high-carbohydrate diet-induced NASH mice. Antibiotics reduced hepatic M1, γδT and γδT17 cells in NASH mice. Furthermore, A. muciniphila inhibited intestinal barrier disruption and accordingly downregulated hepatic Toll-like receptor 2 (TLR2) expression in NASH mice. The activation of TLR2 by lipoteichoic acid enriched hepatic γδT17 cells (not M1) in normal diet-fed mice and neutralized the γδT cell-lowering and liver inflammation-protecting effects of A. muciniphila in NASH mice. Additionally, activated γδT cells could promote macrophage polarization via IL−17. Our study first supported that A. muciniphila prevented NASH by modulating TLR2-activated γδT17 cells and further macrophage polarization, facilitating clinical therapeutic applications.

KEYWORDS:

• NASH
• Akkermansia muciniphila
• TLR2
• γδt cells
• macrophages

Acknowledgments

We thank Mr. Lizong Zhang (Zhejiang Chinese Medical University) for support in animal experiment. This study was supported by National Natural Science Foundation of China (No. 82170668, 81790633), Sino-German Center for Research Promotion (No.GZ1546), and CAMS Innovation Fund for Medical Sciences (No. 2019-I2M-5-045). The work was approved by Clinical research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (reference number: 2020-601) and Care and Use of Laboratory Animals and approved by the Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (reference number: 2020-848).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All relevant data are within the paper and its additional files. Raw sequence data of the 16S rRNA gene has been deposited in NCBI (https://www.ncbi.nlm.nih.gov/) under accession code PRJNA783152 and SRP347563. Other data are available on reasonable request.

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2221485

Additional information

Funding

The work was supported by the National Natural Science Foundation of China [82170668, 81790633, 81790630]; CAMS Innovation Fund for Medical Sciences [2019-I2M-5-045]; Sino-German Center for Research Promotion [GZ1546].