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

Abstract

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 Shigella 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 Shigella infections. However, conventional research methodologies encounter inherent challenges in identifying antagonistic microbial agents against Shigella, necessitating a comprehensive and in-depth analysis of the causal relationship between Shigella infections and the gut microbiota. 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 Shigella infections. This investigation also involved 83 cases of Shigella 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 Shigella infections and genetically predicted compositions of the gut microbiota. 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 Shigella infections and the phylum Tenericutes (OR: 0.18, 95% CI: 0.04-0.74, p = 0.02), class Mollicutes (OR: 0.18, 95% CI: 0.04-0.74, p = 0.02), genus Intestinimonas (OR: 0.16, 95% CI: 0.04-0.63, p = 0.01), genus Gordonibacter (OR: 0.39, 95% CI: 0.16-0.93, p = 0.03), and genus Butyrivibrio (OR: 0.44, 95% CI: 0.23-0.87, p = 0.02). Conversely, a positive correlation was observed between the occurrence of Shigella infections and genus Sutterella (OR: 10.16, 95% CI: 1.87-55.13, p = 0.01) and genus Alistipes (OR: 12.24, 95% CI: 1.71-87.34, p = 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, Shigella infections resulted in an upregulation of four bacterial genera and a downregulation of three bacterial genera. In summation, the MR analysis outcomes corroborate the presence of bidirectional causal relationships between the gut microbiota and Shigella infections. This study not only unveils novel perspectives for the prevention and treatment of Shigella infections but also furnishes fresh insights into the mechanistic underpinnings of how the gut microbiota contributes to the pathogenesis of Shigella 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 Shigella infections, thereby paving the way for innovative therapeutic interventions and preventive strategies in the realm of Shigella-related diseases.