东亚人群口腔微生物群与肝细胞癌的因果关系：一项孟德尔随机化研究

doi:10.12122/j.issn.1673-4254.2026.07.01

摘要/Abstract

摘要：

目的多项新研究表明，口腔微生物群在胃癌、结直肠癌、胰腺癌等多种恶性肿瘤中发挥关键作用，但它与肝细胞癌的因果关联仍尚不明确。本研究采用孟德尔随机化分析法，探究东亚人群口腔微生物群落构成与肝细胞癌发病风险间的潜在因果关系。方法基于东亚人群口腔微生物全基因组关联研究的最新汇总数据，本研究针对舌背 309 种微生物、唾液 285 种微生物与肝癌病变开展两样本孟德尔随进行分析。选取不受混杂因素干扰的单核苷酸多态性作为因果推断工具变量，运用多种孟德尔随机化统计方法展开分析，并检验工具变量的异质性与多效性。结果本研究揭示了口腔微生物组的特定细菌属与肝癌之间的复杂关联，其中Streptococcus与肝细胞癌表现出混合关联，而Oribacterium和Centipeda与肝细胞癌呈正相关，Gemella属与肝细胞癌呈负相关。在敏感性分析中未检测到异质性和多效性。结论本研究通过孟德尔随机化研究证实东亚人群口腔微生物群与肝细胞癌患病风险存在因果关联，提示特定口腔菌种可影响肝细胞癌变的进程，为阐释口-肝轴作用机制、挖掘肝癌防治的潜在微生物靶点提供了新的思路。

关键词: 因果关系, 口腔菌群, 孟德尔随机化, 肝细胞癌, 东亚人群

Abstract:

Objective Emerging evidence highlights the crucial role of the oral microbiota in various malignancies, but its causal relationship with hepatocellular carcinoma (HCC) remains largely unexplored. This study aimed to investigate the causal association between oral microbiota composition and HCC risk in East Asian populations using Mendelian randomization (MR) analysis. Methods We performed a two-sample Mendelian randomization to investigate the causal association of 309 tongue dorsum microbiomes and 285 salivary microbiomes with liver cancer progression using the latest pooled data from genome-wide association study (GWAS) of oral microbiomes in East Asian populations. We selected single nucleotide polymorphism (SNP) independent of confounders as the instrumental variable (IV) for causal inference analysis using various Mendelian randomization statistical techniques. The heterogeneity and pleiotropy of the IV was evaluated to ensure the reliability of the results. Results Our analysis revealed a complex association between specific bacterial genera in the oral microbiome and liver cancer. Streptococcus showed a mixed association with hepatocellular carcinoma, while Oribacterium and Centipeda showed a positive correlation with HCC occurrence. Gemella genus was negatively correlated with HCC. Heterogeneity or pleiotropy of the IV was not detected in the sensitivity analysis. Conclusion This study provides the first Mendelian randomization evidence linking oral microbiota to HCC susceptibility in East Asian populations. Our findings suggest causal roles of specific oral bacterial taxa in hepatocarcinogenesis, and offer new insights into the mechanisms of the oral-liver axis and potential microbial targets for HCC prevention and treatment.

Key words: causal association, oral microbiota, Mendelian randomization, hepatocellular carcinoma, East Asian populations

钟瀚翔, 赵渊宇, 傅宏, 董家勇, 丁国善, 陈瑶, 郭闻渊. 东亚人群口腔微生物群与肝细胞癌的因果关系：一项孟德尔随机化研究[J]. 南方医科大学学报, 2026, 46(7): 1467-1473.

Hanxiang ZHONG, Yuanyu ZHAO, Hong FU, Jiayong DONG, Guoshan DING, Yao CHEN, Wenyuan GUO. Causal association between oral microbiota and hepatocellular carcinoma in East Asian populations: a Mendelian randomization study[J]. Journal of Southern Medical University, 2026, 46(7): 1467-1473.

图/表 5

Fig.1 Three main assumptions for Mendelian randomization (MR) analysis.

Fig.2 MR estimation of the association between oral microbiota and HCC, showing the estimated values of the 'Inverse variance weighted', 'MR Egger', 'Simple mode', 'Weighted media', and 'Weighted mode' methods from the inner to the outer circles. The depth of the color indicates the magnitude of the P value.

Fig.3 MR results of the causal association between oral microbiota and HCC. NSNP: Number of single nucleotide polymorphisms.

Fig.4 Scatter plots of MR analysis of the association between 5 oral microbiota and HCC. SNP: Single-nucleotide polymorphism.

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