Application of Mendelian randomization to assess host gene-gut microbiota correlations in patients with esophageal cancer

Zhenhu Zhang; Guodong Zhang; Zhulan Huang; Yamin Shi; Dong Wang

doi:10.3389/fmicb.2023.1309596

Application of Mendelian randomization to assess host gene-gut microbiota correlations in patients with esophageal cancer

Front Microbiol. 2023 Dec 21:14:1309596. doi: 10.3389/fmicb.2023.1309596. eCollection 2023.

Authors

Zhenhu Zhang^#¹, Guodong Zhang^#¹, Zhulan Huang², Yamin Shi³, Dong Wang¹

Affiliations

¹ Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
² Department of Ultrasound Medicine, Longgang District Maternity and Child Healthcare Hospital of Shenzhen City, Shenzhen, Guangdong, China.
³ Department of Foreign Languages, Shandong University of Finance and Economics, Jinan, China.

^# Contributed equally.

Abstract

Background: Increasing evidence suggests that esophageal cancer (ESCA) may be correlated with gut flora. However, their causal connection remains unclear. This study aimed to evaluate potential causal linkages and gene-gut microbiome associations between the gut microbiota and ESCA using Mendelian randomization (MR).

Methods: We analyzed the data using genome-wide association studies. The exposure factor and outcome variable were the gut microbiota and ESCA, respectively. The MR-Egger method, weighted median, inverse-variance weighted method, heterogeneity test, sensitivity analysis, and multiplicity analysis were used for the MR analysis. And it was validated using an external dataset. Further meta-analysis was performed to validate the robustness of this relationship. Finally, we annotated single nucleotide polymorphisms in the gut microbiota that were causally associated with ESCA to explore possible host gene-gut microbiota correlations in patients with ESCA.

Results: We identified four species with potential associations with ESCA. Three of these species had a negative causal relationship with ESCA (odds ratio (OR): 0.961; 95% confidence interval (CI): 0.923-0.971; p = 0.047 for Romboutsia; OR: 0.972; 95% CI: 0.921-0.961; p = 0.018 for Lachnospira; OR: 0.948; 95% CI: 0.912-0.970; p = 0.032 for Eubacterium). A positive causal relationship was observed between one bacterial group and ESCA (OR: 1.105; 95% CI: 1.010-1.072; p = 0.018 for Veillonella). External datasets show the same trend. This is further supported by meta-analysis. None of the data showed pleiotropy, and leave-one-out analysis indicated the reliability of these findings. The gut microbiomes of patients with ESCA may correlate with the 19 identified genes.

Conclusion: Our data indicate a potential causal link between these four gut bacteria and ESCA and identify a correlation between host genes and gut microbiota in ESCA, offering novel therapeutic options.

Keywords: Mendelian randomization; esophageal cancer; gut microbiota; meta-analysis; single nucleotide polymorphism.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National Science Foundation of Shandong Province of China (no. ZR2019MH092).