The Causal Role of Esophageal Cancer and Gut Microbiota: A Bidirectional Mendelian Randomization Study.

Aims: Gut microbiota are reported to be associated with the incidence and prognosis of Esophageal cancer (EC) but their genetic association is unclear. We carried out a bidirectional MR analysis to assess the causal relationship between EC and gut microbiota from fecal samples.

Methods: The microbiome genome-wide association studies (GWAS) data of 18,340 individuals provided by MiBioGen consortium and the EC GWAS data (740 esophageal cancers cases and 372 016 controls) provided by UK Biobank were respectively utilized as exposure and/or outcome data. Reliable single nucleotide polymorphisms (SNPs) were obtained after rigorous screening. A bidirectional Mendelian randomization (MR) analysis was conducted using the inverse-variance weighted (IVW) method. The sensitivity analyses including the MR-Egger method, weighted median, weighed mode and leave-one-out method were performed to examine the stability, heterogeneity and pleiotropy of the results.

Results: Forward MR analysis revealed the increase in abundance of the microbial trait by each standard deviation was associated with a higher risk of EC (Coprobacter (OR = 1.001,95%CI = 1.000-1.002, P = .0281, FDR = 0.0424); Ruminococcus1(OR = 1.001,95%CI = 1.000-1.002, P = .0318, FDR = 0.0424); Senegalimassilia (OR = 1.002,95%CI = 1.000-1.003, P = .0062, FDR = 0.0372); Veillonella (OR = 1.001,95%CI = 1.000-1.002, P = .0182, FDR = 0.0372)) or a lower risk of EC (Eubacterium oxidoreducens (OR = 0.999, 95%CI = 0.998-1.000, P = .0379, FDR = 00 433); Lachnospira (OR = 0.998,95%CI = 0.996-1.000, P = .0186, FDR = 0.0372); Romboutsia (OR = 0.999,95%CI = 0.998-1.000, P = .0482, FDR = 0.0482); Turicibacter (OR = 0.999,95%CI = 0.998-1.000, P = .0133, FDR = 0.0372)). Reverse MR analysis showed that genetic liability to EC was also causally linked toincreased susceptibility of changes in the gut microbiome (genera Eggerthella (Beta = 37.63,95%CI = 4.76-70.50, P = .0248, FDR = 0.0331); Coprococcus 2 (Beta = 23.90,95%CI = 1.65-46.15, P = .0353, FDR = 0.0353); Christensenellaceae R.7 (Beta = 22.75,95%CI = 4.22-41.28, P = .0161, FDR = 0.0322); Intestinimonas (Beta = -33.24,95%CI = -54.90-11.58, P = .0026, FDR = 0.0104)).

Conclusions: Our findings supported a bidirectionally causal relationship between gut microbiota and EC, implying the potential role of gut microbiota in preventing the occurrence and development of EC.