Analyzing the causal relationship between gut microbiota, metabolites, and constipation: A Mendelian randomization study

A growing body of evidence suggests that the gut microbiota (GM) and its metabolites may play a role in the development of constipation; however, further investigation is necessary to ascertain the precise relationship. Genetic instruments were derived from large-scale genome-wide association studies (GWAS) of European populations. Pooled summary statistics for GM (n = 18,340) and metabolites (n = 7824) were derived from public GWAS, while constipation data (n = 47,696) were obtained from the FinnGen database R10. Mendelian randomization (MR) analyses were performed using data from GWAS to determine a causal association between GM, metabolites, and constipation. Sensitivity analyses were performed to assess the robustness of the MR results, and reverse MR analyses were performed to determine the likelihood of reverse causality. The inverse variance weighted analysis revealed positive causal correlations with the family Rikenellaceae, genus Enterorhabdus, genus FamilyXIIIUCG001, and genus Victivallison in the development of constipation (P < .05). Conversely, the class Betaproteobacteria, class Methanobacteria, family Methanobacteriaceae, genus Coprococcus2, genus Desulfovibrio, genus Eubacteriumbrachy group, genus Haemophilus, order Methanobacteriales, and phylum Firmicutes exhibited negative causal correlations with constipation (P < .05). Furthermore, 24 significant causal relationships (P < .01) were identified between the 13 GMs and their metabolites, as mentioned above. Among the identified metabolites, the class Methanobacteria, family Methanobacteriaceae, and order Methanobacteriales exhibited positive correlations with N-α-acetylornithine, 1,2-dipalmitoyl-gpc, N-acetylhistidine, and sphingomyelin. They play critical roles in maintaining gut barrier integrity, facilitating neuronal signaling, and regulating energy metabolism. This study revealed that there is a causal relationship between intestinal microbiota, metabolites, and the development of constipation, which provides a basis for the diagnosis and treatment of constipation.