Gut microbiota and sepsis: bidirectional Mendelian study and mediation analysis

BACKGROUND: There is a growing body of evidence that suggests a connection between the composition of gut microbiota and sepsis. However, more research is needed to better understand the causal relationship between the two. To gain a deeper insight into the association between gut microbiota, C-reactive protein (CRP), and sepsis, we conducted several Mendelian randomization (MR) analyses. METHODS: In this study, publicly available genome-wide association study (GWAS) summary statistics were examined to determine the correlation between gut microbiota and sepsis, including various sepsis subgroups (such as under 75, 28-day death, Critical Care Units (ICU), 28-day death in ICU). Initially, two-sample and reverse Mendelian randomization (MR) analyses were conducted to identify causality between gut microbiota and sepsis. Subsequently, multivariable and two-step MR analyses revealed that the relationship between microbiota and sepsis was mediated by CRP. The robustness of the findings was confirmed through several sensitivity analyses. FINDINGS: In our study, we revealed positive correlations between 24 taxa and different sepsis outcomes, while 30 taxa demonstrated negative correlations with sepsis outcomes. Following the correction for multiple testing, we found that the Phylum Lentisphaerae (OR: 0.932, p = 2.64E-03), class Lentisphaeria, and order Victivallales (OR: 0.927, p = 1.42E-03) displayed a negative relationship with sepsis risk. In contrast, Phylum Tenericutes and class Mollicutes (OR: 1.274, p = 2.89E-03) were positively related to sepsis risk and death within 28 days. It is notable that Phylum Tenericutes and class Mollicutes (OR: 1.108, p = 1.72E-03) also indicated a positive relationship with sepsis risk in individuals under 75. From our analysis, it was shown that C-reactive protein (CRP) mediated 32.16% of the causal pathway from Phylum Tenericutes and class Mollicutes to sepsis for individuals under 75. Additionally, CRP was found to mediate 31.53% of the effect of the genus Gordonibacter on sepsis. Despite these findings, our reverse analysis did not indicate any influence of sepsis on the gut microbiota and CRP levels. CONCLUSION: The study showcased the connection between gut microbiota, CRP, and sepsis, which sheds new light on the potential role of CRP as a mediator in facilitating the impact of gut microbiota on sepsis.