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

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

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1366181

DOI=10.3389/fmicb.2024.1366181

ISSN=1664-302X

ABSTRACT=<sec id="sec1"><title>Background</title><p>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.</p></sec><sec id="sec2"><title>Methods</title><p>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.</p></sec><sec id="sec3"><title>Results</title><p>In the forward MR analysis, inverse-variance weighted (IVW) estimates suggested that Eggerthella (OR: 2.66, 95%CI: 1.23–5.74, <italic>p</italic> = 0.01) was a risk factor for HSCR, while Peptococcus (OR: 0.37, 95%CI: 0.18–0.73, <italic>p</italic> = 0.004), Ruminococcus2 (OR: 0.32, 95%CI: 0.11–0.91, <italic>p</italic> = 0.03), Clostridiaceae1 (OR: 0.22, 95%CI: 0.06–0.78, <italic>p</italic> = 0.02), Mollicutes RF9 (OR: 0.27, 95%CI: 0.09–0.8, <italic>p</italic> = 0.02), Ruminococcaceae (OR: 0.16, 95%CI: 0.04–0.66, <italic>p</italic> = 0.01), and Paraprevotella (OR: 0.45, 95%CI: 0.21–0.98, <italic>p</italic> = 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, <italic>p</italic> = 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.</p></sec><sec id="sec4"><title>Conclusion</title><p>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.</p></sec>