Causal association between Parkinson disease, gut microbiota, and constipation: A Mendelian study

This study utilized multiple 2-sample Mendelian randomization (MR) approaches to evaluate the causal effects of gut microbiota on the risk of constipation and Parkinson disease (PD) and further investigated the mediating role of gut microbiota in the pathway linking PD to constipation. Two-sample MR analysis was conducted to identify gut microbiota with significant causal associations with constipation. These identified gut microbiota, along with PD, were incorporated as exposure variables into a MVMR framework. A comprehensive model encompassing gut microbiota, PD, and constipation was then established to perform mediation analysis, aiming to quantify the indirect effect of PD on constipation through gut microbiota. The 2-sample MR analysis identified statistically significant causal associations (P <.05) between specific gut microbiota and the development of constipation. Notable findings included c_Betaproteobacteria (OR = 0.899188), c_Methanobacteria (OR = 0.950024), f_Methanobacteriaceae (OR = 0.950024), g_Eubacterium rectale group (OR = 0.893372), and o_Methanobacteriales (OR = 0.950024). In the MVMR analysis, the association between PD and constipation was significant in Models 1 and 5 (P <.05). Mediation effect analysis revealed that the Eubacterium rectale group (g_Eubacterium rectale group) and Methanobacteriales (o_Methanobacteriales) exerted an indirect influence on the development of constipation through PD, with mediation effect proportions of 193.17% and 128.44%. This study revealed the potential causal effects of specific gut microbiota on constipation and, for the first time, proposed a mediating mechanism whereby PD indirectly influences constipation through certain gut microbiota. These findings provide novel insights into the complex relationships among PD, gut microbiota, and constipation, offering potential targets for gut microbiota-based interventions to address PD-associated constipation.