Association between gut microbiota and Hirschsprung disease: a bidirectional two-sample Mendelian randomization study

Area of Science:

• Gastroenterology
• Microbiome Research
• Genetics

Background:

• Hirschsprung disease (HSCR) pathogenesis is increasingly linked to gut microbiota (GM) and their metabolites.
• The precise causal relationship between GM composition and HSCR remains incompletely understood.

Purpose of the Study:

• To investigate the potential causal relationship between gut microbiota and Hirschsprung disease using a two-sample Mendelian randomization (MR) analysis.
• To identify specific bacterial taxa that may act as risk or protective factors in HSCR development.

Main Methods:

• Two-sample Mendelian randomization (MR) analysis utilizing genome-wide association study (GWAS) data for GM and HSCR.
• Sensitivity analyses including Cochran's Q-test, MR-PRESSO, and MR-Egger intercept to assess heterogeneity and pleiotropy.
• Initial validation through 16S rDNA sequencing and targeted mass spectrometry.

Main Results:

• Forward MR identified Eggerthella as a risk factor for HSCR (OR: 2.66).
• Several bacteria, including Peptococcus (OR: 0.37), Ruminococcus2 (OR: 0.32), Clostridiaceae1 (OR: 0.22), Mollicutes RF9 (OR: 0.27), Ruminococcaceae (OR: 0.16), and Paraprevotella (OR: 0.45), were found to be protective.
• Reverse MR indicated HSCR as a risk factor for Eggerthella (OR: 1.02).
• Alterations in specific microbiota and short-chain fatty acids (SCFAs) were observed in HSCR patients, correlating with disease status.

Conclusions:

• This study establishes a causal link between specific gut microbiota and Hirschsprung disease.
• Identified bacterial taxa represent potential therapeutic targets for HSCR.
• Findings highlight the importance of gut microbiome modulation in HSCR pathogenesis and treatment strategies.