Genetic causal association between gut microbiota and sepsis: Evidence from a two-sample bidirectional Mendelian randomization analysis

Background: Sepsis is a severe and potentially life-threatening condition characterized by a dysregulated host response and organ dysfunction. The causal relationship between intestinal microbiota and sepsis is unclear. Methods: A two-sample Mendelian randomization (MR) study was performed to proxy the causal association between gut microbiota and sepsis. The genome-wide association study (GWAS) data of sepsis and gut microbiome were collected from the Integrative Epidemiology Unit (IEU) OpenGWAS, with summary-level data obtained from the UK Biobank. Five traditional methods were used to estimate the potential causal relationships between gut microbiota and sepsis, including the inverse-variance weighted method, weighted median method, MR-Egger regression, simple mode, and weighted mode. Reverse MR analysis was performed on the bacteria that were found to be causally associated with sepsis in forward MR analysis. Cochran's Q statistic was used to quantify the heterogeneity of instrumental variables. Results: The inverse-variance weighted estimate suggested that class Lentisphaeria (odds ratio [OR]=0.86, 95% confidence interval [CI]: 0.78 to 0.94, P=0.0017, q=0.1596) and order Victivallales (OR=0.86, 95% CI: 0.78 to 0.94, P=0.0017, q=0.1596) have a protective effect on sepsis. The genus Eubacterium eligens group (OR=1.34, 95% CI: 1.11 to 1.63, P=0.0029, q=0.1881) was positively associated with the risk of sepsis. Sepsis may be a significant risk factor for genus Odoribacter (OR=1.18, 95% CI: 1.10 to 1.39, P=0.0415, q=0.9849) and Phascolarctobacterium (OR=1.21, 95% CI: 1.00 to 1.46, P=0.0471, q=0.9849), but this effect was not statistically significant after false discovery rate correction. There was a suggestive association between sepsis and Faecalibacterium (OR=0.85, 95% CI: 0.73 to 0.98, P=0.0278) and Ruminococcus 1 (OR=0.85, 95% CI: 0.73 to 1.00, P=0.0439), which were not significant after false discovery rate correction (q>0.2). Conclusions: This study found that class Lentisphaeria, order Victivallales, and genus Eubacterium eligens group may have a causal relationship with the risk of sepsis.