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

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

doi:10.3389/fmicb.2024.1366181

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

Front Microbiol. 2024 Mar 7:15:1366181. doi: 10.3389/fmicb.2024.1366181. eCollection 2024.

Authors

Wei Liu^{1

2}, Hanlei Yan^{1

2}, Wanying Jia^{1

2}, Jingjing Huang^{1

2}, Zihao Fu^{1

2}, Wenyao Xu^{1

2}, Hui Yu^{1

2}, Weili Yang¹, Weikang Pan¹, Baijun Zheng¹, Yong Liu², Xinlin Chen², Ya Gao¹, Donghao Tian^{1

2}

Affiliations

¹ Department of Pediatric Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
² Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi'an Jiaotong University, Xi'an, China.

Abstract

Background: Several 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.

Methods: In 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.

Results: In 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.

Conclusion: Our 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: Hirschsprung disease; Mendelian randomization analysis; bidirectional; causality; gut microbiota.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The study was supported by grants from the National Natural Science Foundation of China (nos: 82300575, 82071692, and 82170531), Xi’an Jiaotong University (no: YXJLRH2022053), and the General Project of Shaanxi Science and Technology Department (no: 2022SF-133/033).