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

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

doi:10.3389/fimmu.2022.1047570

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

Front Immunol. 2022 Dec 1:13:1047570. doi: 10.3389/fimmu.2022.1047570. eCollection 2022.

Authors

Tao Li¹, Xinlong Lin¹, Binhai Shen¹, Wujian Zhang², Yangyang Liu³, Hongbin Liu¹, Ye Wang³, Lijun Zheng³, Fachao Zhi¹

Affiliations

¹ Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China.
² Department of General Surgery of the First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Haerbin, China.
³ Guangzhou ZhiYi Biotechnology Co. Ltd., Guangzhou, China.

Abstract

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.

Keywords: Akkermansia muciniphila; cancer progression; hepatocellular carcinoma - metabolic syndrome - non-alcoholic fatty liver disease (NAFLD) - non-alcoholic steatohepatitis - NASH-HCC; nonalcoholic fatty liver disease; tumor immune surveillance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis
Carcinoma, Hepatocellular* / pathology
Cell Transformation, Neoplastic
Liver Neoplasms* / etiology
Liver Neoplasms* / prevention & control
Male
Mice
Mice, Inbred C57BL
Natural Killer T-Cells*
Non-alcoholic Fatty Liver Disease*
RNA, Ribosomal, 16S
Receptors, CXCR6

Substances

RNA, Ribosomal, 16S
Cxcr6 protein, mouse
Receptors, CXCR6

Supplementary concepts

Akkermansia muciniphila

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 82102684), China Postdoctoral Science Foundation (No. 2021M691472), Guangdong Science and Technology Project (No. 2017B020209003), Innovation Leader Team Program of Guangzhou (No. 201809010014) and R & D Plan for Key Areas in Guangdong Province (No. 2019B020204003).