Gut microbiota and sepsis: bidirectional Mendelian study and mediation analysis

Abstract

BackgroundThere 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.MethodsIn 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.FindingsIn 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.ConclusionThe 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.

Gut microbiota, circulating metabolites, and gallstone disease: a Mendelian randomization study

“…When the regression intercept was non-zero and the p < 0.05, we regarded it as a statistically significant indicator of genetic pleiotropy. Heterogeneity was assessed using Cochran’s Q test ( Zhang et al, 2023 ). In the presence of heterogeneity, we first performed a random-effects IVW analysis.…”

Gut microbiota and sepsis and sepsis-related death: a Mendelian randomization investigation

“…The most common genetic variants are single-nucleotide polymorphisms (SNPs), which are randomly assigned to offspring along with gametes and occur before disease onset, and thus, MR is less susceptible to confounding factors and reverse causation. To date, despite several MR analyses investigating the causal relationship between gut microbiota and sepsis, the selection of genome-wide association studies (GWAS) data for sepsis outcomes is not entirely consistent ( 15 , 16 ). The GWAS outcome data for sepsis selected by Chen et al.…”

“…The most common genetic variants are single-nucleotide polymorphisms (SNPs), which are randomly assigned to offspring along with gametes and occur before disease onset, and thus, MR is less susceptible to confounding factors and reverse causation. To date, despite several MR analyses investigating the causal relationship between gut microbiota and sepsis, the selection of genome-wide association studies (GWAS) data for sepsis outcomes is not entirely consistent (15,16). The GWAS outcome data for sepsis selected by Chen et al were derived from the 2020 UK Biobank (10,154 cases; 452,764 controls), and these are not the most up-to-date GWAS data available (15), while the study conducted by Zhang et al incorporated various sepsis outcome GWAS data, which included patients below 75 years, 28-day mortality, critical care units (ICU), and 28-day mortality in ICU.…”

“…The GWAS outcome data for sepsis selected by Chen et al were derived from the 2020 UK Biobank (10,154 cases; 452,764 controls), and these are not the most up-to-date GWAS data available (15), while the study conducted by Zhang et al incorporated various sepsis outcome GWAS data, which included patients below 75 years, 28-day mortality, critical care units (ICU), and 28-day mortality in ICU. However, they did not opt for the most recent sepsis outcome data available (16). Therefore, we chose to re-perform the MR analysis of gut flora and sepsis using the most comprehensive and up-to-date sepsis GWAS outcome data to investigate the causal relationship between gut microbiota and the risk of sepsis and sepsis-related death, elucidating the etiology of sepsis and suggesting innovative ideas for earlier diagnosis and treatment of this disease.…”

Causal effect of gut microbiota on Gastroduodenal ulcer: a two-sample Mendelian randomization study

“…This is achieved by employing single-nucleotide polymorphisms (SNPs) closely linked to relevant risk factors as instrumental variables (IVs) ( Emdin et al., 2017 ). The reliability of the causal relationship within this methodology stems from the fact that the random allocation of alleles during embryonic meiosis remains largely impervious to the influence of most confounding variables ( Zhang et al., 2023 ). To address the current void in Mendelian randomization (MR) analyses concerning the causal nexus between gut microbiota and Gastroduodenal ulcer, we undertook a comprehensive genome-wide association study (GWAS) followed by a two-sample Mendelian randomization (MR) investigation.…”