Causal relationship between GM, immune cells and esophageal adenocarcinoma: a mediation analysis based on MR

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BACKGROUND: Modulating the immune system represents a pivotal mechanism through which the gut microbiome (GM) exerts influence over disease progression. However, Further investigation is necessary to ascertain the causal role of GM in Esophageal Adenocarcinoma (EAC) and the potential for immune cell mediation. METHODS: Initially, a two-stage, two-sample Mendelian randomization (MR) analysis using the Inverse Variance Weighted (IVW) method was performed to assess the causal effects of GM conditions on EAC, while exploring the potential mediating role of immune cells in the GM-EAC association. RESULTS: A MR analysis identified 5 types of GM and 9 types of GM metabolic pathway abundances with potential causal relationships to EAC. Furthermore, 26 immune cell characteristics(ICTs) were identified as closely associated with EAC. Mediation MR analysis revealed that ICTs negatively influenced the relationship between Rothia and EAC. CONCLUSION: Our MR and mediation analyses suggest that specific gut microbes, microbial pathway abundances, and peripheral immune traits are associated with EAC susceptibility. Immune mediation was modest (-6–15%), implying predominantly direct microbiota effects with secondary immune modulation, and providing hypotheses for mechanistic validation and potential microbiome/immune intervention targets.

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