有许多研究表明，某些肠道微生物的丰度变化与结直肠癌（CRC）相关。然而，由于生活方式、环境和两者之间的可能逆因果关联等混杂因素，尚未确定因果关系。此外，某些宿主基因突变也可促进CRC的发展。然而，尚未对与CRC患者肠道微生物和基因之间的关联进行广泛研究。本研究使用两样本遗传学随机化（MR）研究揭示肠道微生物与CRC之间的因果关系。我们从大规模、多种族的基因组关联研究（GWAS）中获得与肠道微生物丰度相关的SNP作为工具变量（IVs），并从东亚人群遗传学联合研究（AGWAS）和FinnGen集团的研究中提取与CRC相关的数据集。我们对总共166个细菌特征进行了分析，包括目、科、属和种。我们应用逆方差加权（IVW）方法、加权中位数方法、MR-Egger方法和简单中位数方法进行MR分析，并使用一系列敏感性分析来测试结果的稳健性。我们提取与CRC直接因果关联的肠道微生物的IVs，以进行SNP注释，以揭示这些遗传变异位于哪些基因中，从而揭示CRC患者中可能存在的宿主基因-微生物组关联。我们的MR分析结果基于来自AGWAS的CRC相关GWAS数据集显示，6个细菌类群与CRC之间存在基因座水平（P < 1 × 10-5）的因果关系。IVW方法发现Porphyromonadaceae科、Anaerotruncus属、Intestinibacter属、Slackia属、Ruminococcaceae UCG004属和Eubacterium coprostanoligenes组种与CRC风险呈正相关，这与其他互补分析结果基本一致。来自AGWAS和FinnGen数据集的MR估计的荟萃分析结果显示Porphyromonadaceae科和Slackia属、Anaerotruncus属、Intestinibacter属复制了相同的因果关联。所有因果关联的敏感性分析均未显示显著的异质性、水平型多向性或逆因果关联。我们对上述肠道菌群的基因座水平的SNPs进行了注释，并确认了可能与CRC患者中的致病性肠道微生物相关的24个宿主基因。本研究支持了肠道微生物对CRC的因果关系，并揭示了基因和CRC中的病原性微生物之间的可能相关性。这些研究结果表明，肠道微生物组及其进一步的多组学分析对于预防和治疗CRC至关重要。 © 2023. BioMed Central Ltd., part of Springer Nature.

There are many studies indicating that alterations in the abundance of certain gut microbiota are associated with colorectal cancer (CRC). However, a causal relationship has not been identified due to confounding factors such as lifestyle, environmental, and possible reverse causal associations between the two. Furthermore, certain host gene mutations can also contribute to the development of CRC. However, the association between genes and gut microbes in patients with CRC has not been extensively studied.We conducted a two-sample Mendelian randomization (MR) study to reveal the causal relationship between gut microbiota and CRC. We obtained SNPs associated with gut microbiome abundance as instrumental variables (IVs) from a large-scale, multi-ethnic GWAS study, and extracted CRC-related datasets from an East Asian Population genetic consortia GWAS (AGWAS) study and FinnGen consortium, respectively. We analyzed a total of 166 bacterial features at four taxonomic levels, including order, family, genus, and species. The inverse-variance-weighted (IVW), weighted median, MR-Egger, and simple median methods were applied to the MR analysis, and the robustness of the results were tested using a series of sensitivity analyses. We extracted IVs of gut microbiota with direct causal association with CRC for SNP annotation to identify the genes in which these genetic variants were located to reveal the possible host gene-microbiome associations in CRC patients.The findings from our MR analysis based on CRC-associated GWAS datasets from AGWAS revealed causal relationships between 6 bacterial taxa and CRC at a locus-wide significance level (P < 1 × 10-5). The IVW method found that family Porphyromonadaceae, genera Anaerotruncus, Intestinibacter, Slackia, and Ruminococcaceae UCG004, and species Eubacterium coprostanoligenes group were positively associated with CRC risk, which was generally consistent with the results of other complementary analyses. The results of a meta-analysis of the MR estimates from the AGWAS and the FinnGen datasets showed that family Porphyromonadaceae and genera Slackia, Anaerotruncus, and Intestinibacter replicated the same causal association. Sensitivity analysis of all causal associations did not indicate significant heterogeneity, horizontal pleiotropy, or reverse causal associations. We annotated the SNPs at a locus-wide significance level of the above intestinal flora and identified 24 host genes that may be related to pathogenic intestinal microflora in CRC patients.This study supported the causal relationship of gut microbiota on CRC and revealed a possible correlation between genes and pathogenic microbiota in CRC. These findings suggested that the study of the gut microbiome and its further multi-omics analysis was important for the prevention and treatment of CRC.© 2023. BioMed Central Ltd., part of Springer Nature.