Abstract:

Objective

To explore the causal link among gut microbiome， blood metabolites and gastric cancer by mediated Mendelian randomization （MR） analysis in East Asian population.

Methods

At first， summary statistics of 500 gut microbiomes， 112 blood metabolites， 7 921 gastric cancer patients， and 159 201 controls were obtained from the publicly available genome-wide association studies （GWAS） database for two-sample MR analysis.In addition， a two-step approach was used to quantify the proportion of blood metabolite-mediated effects of gut microbiome on gastric cancer.The inverse variance weighted （IVW）method was the primary effect estimation method， while the MR-Egger， weighted median， simple mode，and weighted mode were used as supplements to the IVW method， and sensitivity analyses were utilized to validate the reliability of the MR results.

Results

14 gut microbes were significantly associated with gastric cancer in East Asians， of which 8 were identified as risk factors.Two-step MR analysis identified three metabolic functional pathways （rhamnose degradation， arginine degradation I， and pentose phosphate pathway of non-oxidative branch） that were causally associated with gastric cancer in East Asians through the mediation of two blood metabolites （hydrocortisone and vitamin K）， with vitamin K showing the highest mediation proportion （13.5% and 16.2%）.

Conclusion

Blood metabolites represented by hydrocortisone and vitamin K， may mediate the pathogenic process of gastric cancer by gut microbiota， providing new ideas for the diagnosis， treatment， and early prevention of gastric cancer.

Key words: Gastrointestinal microbiome, Stomach neoplasms, Blood metabolites, Mendelian randomization analysis, Mediation analysis