Emerging evidence suggests that gut microbiota is associated with functional gastrointestinal disorders (FGIDs). However, findings regarding microbial alterations in FGIDs have been inconsistent across observational studies, and the direction and causality of these associations remain unclear. We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate potential causal associations between gut microbiota and two common FGIDs, irritable bowel syndrome (IBS) and functional dyspepsia (FD). Genome-wide association study (GWAS) summary statistics of gut microbiota, IBS, and FD were obtained from public databases and applied to our MR analysis. The inverse-variance-weighted method was used as the primary analysis, with weighted median and complementary sensitivity analyses used to assess the consistency and robustness of the findings. Higher genetically predicted abundances of
order Bifidobacteriales
(OR: 0.741, 95% CI: 0.570 to 0.963,
P
= 0.025) and
genus Eubacterium ventriosum group
(OR: 0.684, 95% CI: 0.524 to 0.893,
P
= 0.005) were associated with a lower risk of IBS.
Genus Lachnospiraceae NK4A136 group
(OR: 1.368, 95% CI: 1.086 to 1.722,
P
= 0.008) correlated to a high risk of FD while
family Desulfovibrionaceae
and
order Desulfovibrionales
(OR: 0.649, 95% CI: 0.471 to 0.893,
P
= 0.008) were protective for FD. In the reverse MR analysis, genetically predicted IBS risk was associated with lower abundances of
Turicibacter
and
Slackia
, whereas no robust reverse associations were observed for FD. These findings identify several microbial taxa as candidates for further mechanistic and clinical validation rather than established risk factors or therapeutic targets. Further experimental research to investigate the underlying mechanisms is warranted.
Yu-Tong Cheng, Qiu-Ai Shu, Zi-Wei Wang et al.· Experimental biology and med...· 0 citations
Observational studies have frequently reported an association between primary biliary cirrhosis (PBC) and inflammatory bowel disease (IBD). In this study, we leveraged summary-level data from genome-wide association studies (GWAS) to conduct a two-sample bidirectional Mendelian randomization (MR) analysis, with the primary objective of investigating the genetic causal relationship between PBC and IBD, comprising ulcerative colitis (UC) and Crohn’s disease (CD). Additionally, a validation analysis was performed by repeating the bidirectional MR framework, alternately defining PBC and IBD as the exposure and outcome variables to confirm the directionality of the observed associations. A comprehensive panel of sensitivity analyses was implemented to test the robustness of the findings. We first examined the genetic causality at the subtype level. In the forward MR, PBC exerted a significant positive causal effect on UC (P < 0.001, OR 95% CI = 1.081 [1.037–1.127]) and on CD (P = 0.002, OR 95% CI = 1.136 [1.047–1.232]). In the reverse MR, only UC showed a significant negative causal influence on PBC (P > 0.003, OR 95% CI = 0.788 [0.672–0.924]), whereas no significant effect was detected from CD on PBC (P = 0.431, OR 95% CI = 0.956 [0.856–1.068]). We then extended the analysis to the overall IBD phenotype. The forward MR demonstrated a significant positive genetic relationship between PBC on IBD (P < 0.001, OR 95% CI = 1.076 [1.042–1.110]). Conversely, the reverse MR did not support a causal effect of IBD on PBC (P = 0.357, OR 95% CI = 0.898 [0.714–1.129]). The robustness of all these findings was confirmed by comprehensive sensitivity analyses, which showed no evidence of heterogeneity, horizontal pleiotropy, or undue influence from individual instrumental variables. Our MR analysis demonstrates that PBC serves as a genetic determinant of IBD as a whole and of UC/CD separately, whereas reverse causation is limited to a protective effect of UC on PBC. This direction-dependent and subtype-specific causal architecture provides novel insights into the shared etiological pathways between PBC and IBD.
Ming-Yi Yang, Jia-Le Xie, Jing Hu et al.· Experimental biology and med...· 0 citations
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