Zheng Linyi, Li Yuqiang, Güngör Cenap, Ge Heming
Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, 410013, China.
Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Discov Oncol. 2025 May 13;16(1):747. doi: 10.1007/s12672-025-02486-3.
Colorectal cancer (CRC) is the most prevalent malignant tumor of the digestive system globally, posing a significant threat to human health and quality of life. Recent studies have established associations between gut microbiota and immune cells with CRC; however, the mechanisms by which gut microbiota influence the development and progression of CRC through immune mediators remain poorly understood.
We conducted a two-sample, bidirectional Mendelian randomization analysis. We utilized 731 immune cell types and 473 gut microbial species along with colorectal cancer statistics from published summary statistics from genome-wide association studies (GWAS).The analysis employed several methodologies, including inverse variance-weighted (IVW) analysis, MR-Egger regression, the weighted median method, and both weighted and simple model approaches.Sensitivity analyses were performed to confirm the reliability of the Mendelian randomization results, and reverse Mendelian randomization was used to assess the overall impact of CRC on gut microbiota and immune cells.
Our findings suggest a causal relationship involving nine immunophenotypes and five specific gut microbial taxa with CRC. Notably, the gut microbes Alloprevotella and Holdemania, along with immune cell types CD3 on CD28- CD8br and CD4 + T cells, demonstrated significant causal associations with CRC. Mediation analysis revealed that the association between Alloprevotella and CRC was mediated by CD4 + T cells, with a mediation effect of 6.48%. Additionally, Holdemania was found to mediate its association with CRC through CD3 on CD28- CD8br, exhibiting a mediation effect of 9.29%. Reverse Mendelian randomization did not indicate any causal effect of CRC on specific immune cells or gut microbiota. Two-sided sensitivity analyses revealed no evidence of heterogeneity or horizontal pleiotropy in our findings.
This comprehensive Mendelian randomization study enhances our understanding of the mechanisms by which gut microbiota affects CRC through immune cell interactions. Further investigations are warranted to unravel the underlying mechanisms linking gut microbiota, immune cells, and colorectal cancer.
结直肠癌（CRC）是全球消化系统中最常见的恶性肿瘤，对人类健康和生活质量构成重大威胁。最近的研究已经确定了肠道微生物群和免疫细胞与CRC之间的关联；然而，肠道微生物群通过免疫介质影响CRC发生发展的机制仍知之甚少。
我们进行了一项两样本双向孟德尔随机化分析。我们利用了731种免疫细胞类型和473种肠道微生物物种以及来自全基因组关联研究（GWAS）已发表汇总统计数据中的结直肠癌统计信息。该分析采用了多种方法，包括逆方差加权（IVW）分析、MR-Egger回归、加权中位数法以及加权和简单模型方法。进行敏感性分析以确认孟德尔随机化结果的可靠性，并使用反向孟德尔随机化来评估CRC对肠道微生物群和免疫细胞的总体影响。
我们的研究结果表明，九种免疫表型和五种特定肠道微生物分类群与CRC之间存在因果关系。值得注意的是，肠道微生物Alloprevotella和Holdemania，以及免疫细胞类型CD28-CD8br上的CD3和CD4+T细胞，与CRC表现出显著的因果关联。中介分析表明，Alloprevotella与CRC之间的关联由CD4+T细胞介导，中介效应为6.48%。此外，发现Holdemania通过CD28-CD8br上的CD3介导其与CRC的关联，中介效应为9.29%。反向孟德尔随机化未表明CRC对特定免疫细胞或肠道微生物群有任何因果效应。双侧敏感性分析表明，我们的研究结果中没有异质性或水平多效性的证据。
这项全面的孟德尔随机化研究增进了我们对肠道微生物群通过免疫细胞相互作用影响CRC机制的理解。有必要进一步研究以阐明肠道微生物群、免疫细胞和结直肠癌之间的潜在机制。
