Akkermansia muciniphila suppressing nonalcoholic steatohepatitis associated tumorigenesis through CXCR6(+) natural killer T cells

INTRODUCTION: Gut microbiota plays a crucial role in the development and progression of nonalcoholic steatohepatitis (NASH) and associated hepatocellular carcinoma (HCC). Akkermansia muciniphila was reported to inhibit inflammation-associated cancer in the intestine. The anti-NASH ability of A. muciniphila has recently been found. Thus, we were to investigate whether supplementation of A. muciniphila could prevent NASH-associated HCC. METHODS: 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 A. muciniphila twice a day starting at 4 or 10 weeks of age. The effects of A. muciniphila on the immune responses were also evaluated. RESULTS: Patients and mice with NASH-related HCC showed significantly reduced gut A. muciniphila in comparison to healthy controls. Administration of breast milk-isolated A. muciniphila (AM06) but not feces-isolated A. muciniphila (AM02) could improve NASH severity. Interestingly, breast milk-isolated A. muciniphila treatment suppressed the progression of NASH to HCC, accompanied with an increased hepatic CXCR6(+) natural killer T (NKT) cell and decreased macrophage infiltration. The antitumor ability of A. muciniphila was not evident in NKT cell-deficient mice (CD1d(-/-) and CXCR6(-/-)). In vitro, A. muciniphila promoted the killing of hepG2 cells by NKT cells. DISCUSSION: Our study will provide the rationale for the application of A. muciniphila to treat NASH and for the prevention of its progression to HCC.