AUTHOR=Wang Zhe , Gao Bingjun , Liu Xiao , Li Aiwu 

TITLE=The mediating role of metabolites between gut microbiome and Hirschsprung disease: a bidirectional two-step Mendelian randomization study

JOURNAL=Frontiers in Pediatrics

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2024.1371933

DOI=10.3389/fped.2024.1371933

ISSN=2296-2360

ABSTRACT=<sec><title>Background</title><p>Gut microbiome (GM) was observed to be associated with the incidence of Hirschsprung disease (HD). However, the effect and mechanism of GM in HD is still unclear. To investigate the relationship between GM and HD and the effect of metabolites as mediators, a bidirectional two-step Mendelian randomization (MR) study was conducted.</p></sec><sec><title>Methods</title><p>The study selected instrument variables (IVs) from summary-level genome-wide association studies (GWAS). The MiBioGen consortium provided the GWAS data for GM, while the GWAS data for metabolites and HD were obtained from the GWAS Catalog consortium. Two-sample MR analyses were performed to estimate bidirectional correlations between IVs associated with GM and HD. Then, genetic variants related to 1,400 metabolite traits were selected for further mediation analyses using the Product method.</p></sec><sec><title>Results</title><p>This study found that seven genus bacteria had a significant causal relationship with the incidence of HD but not vice versa. 27 metabolite traits were significantly correlated with HD. After combining the significant results, three significant GM-metabolites-HD lines have been identified. In the <italic>Peptococcus</italic>-Stearoyl sphingomyelin (d18:1/18:0)-HD line, the Stearoyl sphingomyelin (d18:1/18:0) levels showed a mediation proportion of 14.5%, while in the <italic>Peptococcus</italic>-lysine-HD line, the lysine levels had a mediation proportion of 12.9%. Additionally, in the <italic>Roseburia</italic>-X-21733-HD line, the X-21733 levels played a mediation proportion of 23.5%.</p></sec><sec><title>Conclusion</title><p>Our MR study indicates a protective effect of <italic>Peptococcus</italic> on HD risk that is partially mediated through serum levels of stearoyl sphingomyelin (d18:1/18:0) and lysine, and a risk effect of <italic>Roseburia</italic> on HD that is partially mediated by X-21733 levels. These findings could serve as novel biomarkers and therapeutic targets for HD.</p></sec>