Causal effects of gut microbiota on 28-day mortality in patients with sepsis: a Mendelian randomization analysis

Background Sepsis, characterized by multiple organ failure, is the leading cause of death in intensive care units. Extensive research has highlighted a significant association between sepsis and the gut microbiota (GM). However, the causal relationship between these factors, particularly their impact on 28-day mortality, remains unclear. Methods We conducted a Mendelian randomization (MR) study using genome-wide association study (GWAS) summary statistics. The primary analytical method to establish causality was the inverse-variance weighted (IVW) method, supplemented by four additional MR approaches. Heterogeneity and horizontal pleiotropy were assessed using Cochran’s Q test and the MR-Egger intercept test, respectively. Results The IVW method revealed that seven GM taxa, primarily including class Bacteroidia (OR 1.565, 95% CI 1.161-2.108, P= 0.003), genus Methanobrevibacter (OR 1.347, 95% CI 1.045-1.736, P= 0.022), and others, were positively associated with 28-day sepsis mortality. Conversely, genetically predicted levels of four GM taxa, including class Lentisphaeria (OR 0.751, 95% CI 0.588-0.960, P = 0.022), genus Coprococcus2 (OR 0.537, 95% CI 0.315-0.917, P = 0.023), and others, were negatively associated with 28-day sepsis mortality. Heterogeneity and pleiotropy analyses confirmed the robustness of these findings (all P > 0.05). Conclusion Our MR study provides genetic evidence supporting a causal relationship between GM composition and 28-day mortality in sepsis. These findings suggest potential targets for future microbiome-based therapeutic interventions in sepsis management.