Frontiers in Microbiology (Mar 2024)

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

  • Wei Liu,
  • Wei Liu,
  • Hanlei Yan,
  • Hanlei Yan,
  • Wanying Jia,
  • Wanying Jia,
  • Jingjing Huang,
  • Jingjing Huang,
  • Zihao Fu,
  • Zihao Fu,
  • Wenyao Xu,
  • Wenyao Xu,
  • Hui Yu,
  • Hui Yu,
  • Weili Yang,
  • Weikang Pan,
  • Baijun Zheng,
  • Yong Liu,
  • Xinlin Chen,
  • Ya Gao,
  • Donghao Tian,
  • Donghao Tian

DOI
https://doi.org/10.3389/fmicb.2024.1366181
Journal volume & issue
Vol. 15

Abstract

Read online

BackgroundSeveral studies have pointed to the critical role of gut microbiota (GM) and their metabolites in Hirschsprung disease (HSCR) pathogenesis. However, the detailed causal relationship between GM and HSCR remains unknown.MethodsIn this study, we used two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between GM and HSCR, based on the MiBioGen Consortium’s genome-wide association study (GWAS) and the GWAS Catalog’s HSCR data. Reverse MR analysis was performed subsequently, and the sensitivity analysis, Cochran’s Q-test, MR pleiotropy residual sum, outlier (MR-PRESSO), and the MR-Egger intercept were used to analyze heterogeneity or horizontal pleiotropy. 16S rDNA sequencing and targeted mass spectrometry were developed for initial validation.ResultsIn the forward MR analysis, inverse-variance weighted (IVW) estimates suggested that Eggerthella (OR: 2.66, 95%CI: 1.23–5.74, p = 0.01) was a risk factor for HSCR, while Peptococcus (OR: 0.37, 95%CI: 0.18–0.73, p = 0.004), Ruminococcus2 (OR: 0.32, 95%CI: 0.11–0.91, p = 0.03), Clostridiaceae1 (OR: 0.22, 95%CI: 0.06–0.78, p = 0.02), Mollicutes RF9 (OR: 0.27, 95%CI: 0.09–0.8, p = 0.02), Ruminococcaceae (OR: 0.16, 95%CI: 0.04–0.66, p = 0.01), and Paraprevotella (OR: 0.45, 95%CI: 0.21–0.98, p = 0.04) were protective factors for HSCR, which had no heterogeneity or horizontal pleiotropy. However, reverse MR analysis showed that HSCR (OR: 1.02, 95%CI: 1–1.03, p = 0.049) is the risk factor for Eggerthella. Furthermore, some of the above microbiota and short-chain fatty acids (SCFAs) were altered in HSCR, showing a correlation.ConclusionOur analysis established the relationship between specific GM and HSCR, identifying specific bacteria as protective or risk factors. Significant microbiota and SCFAs were altered in HSCR, underlining the importance of further study and providing new insights into the pathogenesis and treatment.

Keywords