AUTHOR=Li Tao , Lin Xinlong , Shen Binhai , Zhang Wujian , Liu Yangyang , Liu Hongbin , Wang Ye , Zheng Lijun , Zhi Fachao 

TITLE=Akkermansia muciniphila suppressing nonalcoholic steatohepatitis associated tumorigenesis through CXCR6+ natural killer T cells

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1047570

DOI=10.3389/fimmu.2022.1047570

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Gut microbiota plays a crucial role in the development and progression of nonalcoholic steatohepatitis (NASH) and associated hepatocellular carcinoma (HCC). <italic>Akkermansia muciniphila</italic> was reported to inhibit inflammation-associated cancer in the intestine. The anti-NASH ability of <italic>A. muciniphila</italic> has recently been found. Thus, we were to investigate whether supplementation of <italic>A. muciniphila</italic> could prevent NASH-associated HCC.</p></sec><sec><title>Methods</title><p>In a model we called STAM, male C57BL/6J mice were subcutaneously injected with 200 µg streptozotocin at 4 days after birth, and fed with high-fat diet at 4 weeks of age to induce NASH-associated HCC. Faeces from mice and patients with NASH-related HCC were collected for 16S rRNA sequencing. STAM mice were orally administered either saline or <italic>A. muciniphila</italic> twice a day starting at 4 or 10 weeks of age. The effects of <italic>A. muciniphila</italic> on the immune responses were also evaluated.</p></sec><sec><title>Results</title><p>Patients and mice with NASH-related HCC showed significantly reduced gut <italic>A. muciniphila</italic> in comparison to healthy controls. Administration of breast milk-isolated <italic>A. muciniphila</italic> (AM06) but not feces-isolated <italic>A. muciniphila</italic> (AM02) could improve NASH severity. Interestingly, breast milk-isolated <italic>A. muciniphila</italic> treatment suppressed the progression of NASH to HCC, accompanied with an increased hepatic CXCR6<sup>+</sup> natural killer T (NKT) cell and decreased macrophage infiltration. The antitumor ability of <italic>A. muciniphila</italic> was not evident in NKT cell-deficient mice (CD1d<sup>-/-</sup> and CXCR6<sup>-/-</sup>). <italic>In vitro</italic>, <italic>A. muciniphila</italic> promoted the killing of hepG2 cells by NKT cells.</p></sec><sec><title>Discussion</title><p>Our study will provide the rationale for the application of <italic>A. muciniphila</italic> to treat NASH and for the prevention of its progression to HCC.</p></sec>