The mediating effect of circulating inflammatory proteins on the relationship between gut microbiota and FD: a bidirectional Mendelian randomization study

Abstract

Functional dyspepsia (FD) is known to be influenced by gut microbiota (GM) and circulating inflammatory proteins (CIPs), however, the causal relationship between GM, CIPs and FD haven't been investigated. This study employed two-sample Mendelian Randomization (TSMR) to investigate their associations using data from Genome-Wide Association Studies (GWAS). In this study, Inverse-variance weighted (IVW) method was employed as the primary analysis, with supplementary approaches including weighted median, weighted mode, simple mode, and MR-Egger. Heterogeneity and pleiotropy were assessed using the Cochrane Q test, MR-Egger intercept test, and MR-PRESSO global test. Totally, 196 GM traits and 91 CIPs were analyzed, and the results uncovered the causal impact of 12 GM taxa and 5 proteins on functional dyspepsia (FD). 9 GM genera were linked to a reduced risk of FD, while 3 GM genera were associated with an increased risk of FD.Additionally, reverse analysis revealed no FD-GM causation. Furthermore, IL-12, IL-10, CXCL10, CXCL9 and VEGFA were significantly correlated with FD, with CXCL9 and VEGFA acting as mediators in the association between GM traits and FD. Taken together, our findings established a link between specific GM and CIPs in the pathogenesis of FD, offering novel insights for its diagnosis and treatment.

Keywords: Circulating inflammatory proteins; Functional dyspepsia; Gut microbiota; Mediation analysis; Mendelian randomization.

Fig. 1

Flow chart of the MR study.

Fig. 2

Forest plots of MR results for 12 gut microbiota on functional dyspepsia. Abbreviation: MR, Mendelian Randomization; NSNP, number of SNPs; OR, odds ratio.

Fig. 3

MR analysis of gut microbiota and functional dyspepsia (A) Circular heatmap of the causal relationship between GM and FD. (B) Circular heatmap of the causal relationship between FD and GM.

Fig. 4

Forest plot depicting the effects of circulating inflammatory proteins on FD.

Fig. 5

Forest plot of the MVMR analysis of the association between GM, CIPs and FD.

Fig. 6

Mulberry Plot of GM and circulating inflammatory proteins.