The causality of gut microbiota on onset and progression of sepsis: a bi-directional Mendelian randomization analysis

Abstract

Background: Several observational studies have proposed a potential link between gut microbiota and the onset and progression of sepsis. Nevertheless, the causality of gut microbiota and sepsis remains debatable and warrants more comprehensive exploration.

Methods: We conducted a two-sample Mendelian randomization (MR) analysis to test the causality between gut microbiota and the onset and progression of sepsis. The genome-wide association study (GWAS) summary statistics for 196 bacterial traits were extracted from the MiBioGen consortium, whereas the GWAS summary statistics for sepsis and sepsis-related outcomes came from the UK Biobank. The inverse-variance weighted (IVW) approach was the primary method used to examine the causal association. To complement the IVW method, we utilized four additional MR methods. We performed a series of sensitivity analyses to examine the robustness of the causal estimates.

Results: We assessed the causality of 196 bacterial traits on sepsis and sepsis-related outcomes. Genus Coprococcus2 [odds ratio (OR) 0.81, 95% confidence interval (CI) (0.69-0.94), p = 0.007] and genus Dialister (OR 0.85, 95% CI 0.74-0.97, p = 0.016) had a protective effect on sepsis, whereas genus Ruminococcaceae UCG011 (OR 1.10, 95% CI 1.01-1.20, p = 0.024) increased the risk of sepsis. When it came to sepsis requiring critical care, genus Anaerostipes (OR 0.49, 95% CI 0.31-0.76, p = 0.002), genus Coprococcus1 (OR 0.65, 95% CI 0.43-1.00, p = 0.049), and genus Lachnospiraceae UCG004 (OR 0.51, 95% CI 0.34-0.77, p = 0.001) emerged as protective factors. Concerning 28-day mortality of sepsis, genus Coprococcus1 (OR 0.67, 95% CI 0.48-0.94, p = 0.020), genus Coprococcus2 (OR 0.48, 95% CI 0.27-0.86, p = 0.013), genus Lachnospiraceae FCS020 (OR 0.70, 95% CI 0.52-0.95, p = 0.023), and genus Victivallis (OR 0.82, 95% CI 0.68-0.99, p = 0.042) presented a protective effect, whereas genus Ruminococcus torques group (OR 1.53, 95% CI 1.00-2.35, p = 0.049), genus Sellimonas (OR 1.25, 95% CI 1.04-1.50, p = 0.019), and genus Terrisporobacter (OR 1.43, 95% CI 1.02-2.02, p = 0.040) presented a harmful effect. Furthermore, genus Coprococcus1 (OR 0.42, 95% CI 0.19-0.92, p = 0.031), genus Coprococcus2 (OR 0.34, 95% CI 0.14-0.83, p = 0.018), and genus Ruminiclostridium6 (OR 0.43, 95% CI 0.22-0.83, p = 0.012) were associated with a lower 28-day mortality of sepsis requiring critical care.

Conclusion: This MR analysis unveiled a causality between the 21 bacterial traits and sepsis and sepsis-related outcomes. Our findings may help the development of novel microbiota-based therapeutics to decrease the morbidity and mortality of sepsis.

Keywords: Mendelian randomization; causal relationship; genetics; gut microbiota; sepsis.

Figure 1

Synopsis of MR analysis procedures and major assumptions.

Figure 2

Heatmap of gut microbiota causally associated with sepsis, sepsis requiring critical care, 28-day mortality of sepsis, and 28-day mortality of sepsis requiring critical care identified by the IVW method. Red represents risk factors, whereas blue represents protective factors.

Figure 3

Forest plot of various MR results for eight bacterial traits causally associated with sepsis.

Figure 4

Forest plot of various MR results for six bacterial traits causally associated with sepsis requiring critical care.

Figure 5

Forest plot of various MR results for 12 bacterial traits causally associated with 28-day mortality of sepsis.

Figure 6

Forest plot of various MR results for nine bacterial traits causally associated with 28-day mortality of sepsis requiring critical care.

Figure 7

Scatter plot of MR results. (A) Scatter plot of genetic correlations of eight bacterial traits and sepsis using five MR methods. (B) Scatter plot of genetic correlations of six bacterial traits and sepsis requiring critical care using five MR methods. (C) Scatter plot of genetic correlations of 12 bacterial traits and 28-day mortality of sepsis using five MR methods. (D) scatter plot of genetic correlations of nine bacterial traits and 28-day mortality of sepsis requiring critical care using five MR methods.

Figure 8

Leave-one-out analysis for (A) 8 bacterial traits on sepsis, (B) 6 bacterial traits on sepsis requiring critical care, (C) 12 bacterial traits on 28-day mortality of sepsis, and (D) 9 bacterial traits on 28-day mortality of sepsis requiring critical care.