AUTHOR=Peng Jingyi , Cai Kun , Chen Guanglei , Liu Linxiao , Peng Lili 

TITLE=Genetic evidence strengthens the bidirectional connection between gut microbiota and Shigella infection: insights from a two-sample Mendelian randomization study

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1361927

DOI=10.3389/fmicb.2024.1361927

ISSN=1664-302X

ABSTRACT=<sec id="sec1"><title>Background</title><p>In recent investigations, substantial strides have been made in the precise modulation of the gut microbiota to prevent and treat a myriad of diseases. Simultaneously, the pressing issue of widespread antibiotic resistance and multidrug resistance resulting from <italic>Shigella</italic> infections demands urgent attention. Several studies suggest that the antagonistic influence of the gut microbiota could serve as a novel avenue for impeding the colonization of pathogenic microorganisms or treating <italic>Shigella</italic> infections. However, conventional research methodologies encounter inherent challenges in identifying antagonistic microbial agents against <italic>Shigella</italic>, necessitating a comprehensive and in-depth analysis of the causal relationship between <italic>Shigella</italic> infections and the gut microbiota.</p></sec><sec id="sec2"><title>Materials and methods</title><p>Utilizing the aggregated summary statistics from Genome-Wide Association Studies (GWAS), we conducted Mendelian Randomization (MR) analyses encompassing 18,340 participants to explore the interplay between the gut microbiota and <italic>Shigella</italic> infections. This investigation also involved 83 cases of <italic>Shigella</italic> infection patients and 336,396 control subjects. In the positive strand of our findings, we initially performed a preliminary analysis using the Inverse Variance Weighting (IVW) method. Subsequently, we undertook sensitivity analyses to assess the robustness of the results, addressing confounding factors’ influence. This involved employing the Leave-One-Out method and scrutinizing funnel plots to ensure the reliability of the MR analysis outcomes. Conclusively, a reverse MR analysis was carried out, employing the Wald ratio method due to the exposure of individual Single Nucleotide Polymorphisms (SNPs). This was undertaken to explore the plausible associations between <italic>Shigella</italic> infections and genetically predicted compositions of the gut microbiota.</p></sec><sec id="sec3"><title>Results</title><p>In this study, we employed 2,818 SNPs associated with 211 species of gut microbiota as instrumental variables (IVs). Through IVW analysis, our positive MR findings revealed a significant negative correlation between the occurrence of <italic>Shigella</italic> infections and the phylum Tenericutes (OR: 0.18, 95% CI: 0.04–0.74, <italic>p</italic> = 0.02), class Mollicutes (OR: 0.18, 95% CI: 0.04–0.74, p = 0.02), genus <italic>Intestinimonas</italic> (OR: 0.16, 95% CI: 0.04–0.63, <italic>p</italic> = 0.01), genus <italic>Gordonibacter</italic> (OR: 0.39, 95% CI: 0.16–0.93, <italic>p</italic> = 0.03), and genus <italic>Butyrivibrio</italic> (OR: 0.44, 95% CI: 0.23–0.87, <italic>p</italic> = 0.02). Conversely, a positive correlation was observed between the occurrence of <italic>Shigella</italic> infections and genus <italic>Sutterella</italic> (OR: 10.16, 95% CI: 1.87–55.13, <italic>p</italic> = 0.01) and genus <italic>Alistipes</italic> (OR: 12.24, 95% CI: 1.71–87.34, <italic>p</italic> = 0.01). In sensitivity analyses, utilizing MR-Egger regression analysis and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) detection, all outcomes demonstrated robust stability. Simultaneously, in the reverse MR analysis, <italic>Shigella</italic> infections resulted in an upregulation of four bacterial genera and a downregulation of three bacterial genera.</p></sec><sec id="sec4"><title>Conclusion</title><p>In summation, the MR analysis outcomes corroborate the presence of bidirectional causal relationships between the gut microbiota and <italic>Shigella</italic> infections. This study not only unveils novel perspectives for the prevention and treatment of <italic>Shigella</italic> infections but also furnishes fresh insights into the mechanistic underpinnings of how the gut microbiota contributes to the pathogenesis of <italic>Shigella</italic> infections. Consequently, the established dual causal association holds promise for advancing our understanding and addressing the complexities inherent in the interplay between the gut microbiota and <italic>Shigella</italic> infections, thereby paving the way for innovative therapeutic interventions and preventive strategies in the realm of <italic>Shigella</italic>-related diseases.</p></sec>