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. 2023 Sep 14:14:1190230.
doi: 10.3389/fimmu.2023.1190230. eCollection 2023.

Causal associations of gut microbiota and metabolites on sepsis: a two-sample Mendelian randomization study

Jian Zhao  1 , Xin Pan  2 , Di Hao  1 , Yi Zhao  1 , Yuanzhuo Chen  1 , Shuqin Zhou  1 , Hu Peng  1 , Yugang Zhuang  1
Affiliations

Causal associations of gut microbiota and metabolites on sepsis: a two-sample Mendelian randomization study

Jian Zhao et al. Front Immunol. .

Abstract

Background: Sepsis stands as a dire medical condition, arising when the body's immune response to infection spirals into overdrive, paving the way for potential organ damage and potential mortality. With intestinal flora's known impact on sepsis but a dearth of comprehensive data, our study embarked on a two-sample Mendelian randomization analysis to probe the causal link between gut microbiota and their metabolites with severe sepsis patients who succumbed within a 28-day span.

Methods: Leveraging data from Genome-wide association study (GWAS) and combining it with data from 2,076 European descendants in the Framingham Heart Study, single-nucleotide polymorphisms (SNPs) were employed as Instrumental Variables (IVs) to discern gene loci affiliated with metabolites. GWAS summary statistics for sepsis were extracted from the UK Biobank consortium.

Results: In this extensive exploration, 93 distinct genome-wide significant SNPs correlated with gut microbial metabolites and specific bacterial traits were identified for IVs construction. Notably, a substantial link between Coprococcus2 and both the incidence (OR of 0.80, 95% CI: 0.68-0.94, P=0.007) and the 28-day mortality rate (OR 0.48, 95% CI: 0.27-0.85, P=0.013) of sepsis was observed. The metabolite α-hydroxybutyrate displayed a marked association with sepsis onset (OR=1.08, 95% CI: 1.02-1.15, P=0.006) and its 28-day mortality rate (OR=1.17, 95% CI: 1.01-1.36, P=0.029).

Conclusion: This research unveils the intricate interplay between the gut microbial consortium, especially the genus Coprococcus, and the metabolite α-hydroxybutyrate in the milieu of sepsis. The findings illuminate the pivotal role of intestinal microbiota and their metabolites in sepsis' pathogenesis, offering fresh insights for future research and hinting at novel strategies for sepsis' diagnosis, therapeutic interventions, and prognostic assessments.

Keywords: Mendelian randomization; causal associations; gut metabolites; gut microbiota; sepsis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Directed acyclic graphs for the classical Mendelian randomization designs. The arrows denote causal relations between two variables, pointing from the cause to the effect. The causal pathway is blocked if”X”is placed in the arrowed line. MR, Mendelian randomization.
Figure 2
Figure 2
Forest plot to visualize the causal effect of Gut microbiota on the risk of Sepsis by inverse variance weighted method.
Figure 3
Figure 3
Forest plot to visualize the causal effect of Gut Metabolites on the risk of Sepsis 28-day morality by inverse variance weighted method.
See this image and copyright information in PMC

Comment in

References

    1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. . The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA (2016) 315:801. doi: 10.1001/jama.2016.0287 - DOI - PMC - PubMed
    1. Kadri SS, Rhee C, Strich JR, Morales MK, Hohmann S, Menchaca J, et al. . Estimating ten-year trends in septic shock incidence and mortality in United States academic medical centers using clinical data. Chest (2017) 151:278–85. doi: 10.1016/j.chest.2016.07.010 - DOI - PMC - PubMed
    1. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al. . Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA (2017) 318:1241. doi: 10.1001/jama.2017.13836 - DOI - PMC - PubMed
    1. Ojima M, Motooka D, Shimizu K, Gotoh K, Shintani A, Yoshiya K, et al. . Metagenomic analysis reveals dynamic changes of whole gut microbiota in the acute phase of intensive care unit patients. Dig Dis Sci (2015) 61:1628–34. doi: 10.1007/s10620-015-4011-3 - DOI - PMC - PubMed
    1. Zaborin A, Smith D, Garfield K, Quensen J, Shakhsheer B, Kade M, et al. . Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during prolonged critical illness. mBio (2014) 5:e01361-14. doi: 10.1128/mbio.01361-14 - DOI - PMC - PubMed

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