Gut microbiome features are associated with sepsis onset and outcomes

Abstract

BackgroundEpidemiologic studies have linked antibiotic exposure to subsequent sepsis, suggesting that microbiome disruption may be in the causal pathway and an independent risk factor. This study tests whether variation in the gut microbiota associates with risk of sepsis onset and its outcomes.MethodsUsing a validated surveillance definition, patients with an archived rectal swab from intensive care and hematology units were screened for sepsis. After confirmation by chart review, cases were matched to controls in a 1:2 ratio based on age, gender, and collection date. Relative taxon abundance was measured by sequence analysis of 16S rRNA gene amplicons; total bacterial abundance was measured by qPCR of the 23S rRNA gene. Conditional logistic regression identified clinical and microbiota variables associated with sepsis.ResultsThere were 103 sepsis cases matched to 206 controls. In a final model adjusting for exposure to broad-spectrum antibiotics and indwelling vascular catheters, high relative abundance (RA) of Enterococcus (Odds Ratio (OR) 1.36 per 10% increase, P=.016) and high total bacterial abundance (OR 1.50 per 10-fold increase in 23S copies/μL, P =.001) were independently associated with sepsis. Decreased RA of butyrate-producing bacteria also independently associated with sepsis (OR 1.20 for 10% decrease in RA, P =.041), and mortality in unadjusted analysis (OR=1.47 for 10% decrease in RA, P=.034).ConclusionsThis study indicates that the microbiota is altered at sepsis onset. The decreased RA of butyrate-producing bacteria in sepsis also associates with mortality, suggesting a therapeutic role for prebiotics and probiotics in the prevention and treatment of sepsis.ImportanceEarly detection of patients at risk for sepsis could enable interventions to prevent or rapidly treat this life-threatening condition. Prior antibiotic treatment is associated with sepsis, suggesting that disruption of the bacterial population in the gut (the intestinal microbiome) could be an important step leading to disease. To investigate this theory, we matched hospitalized patients with and without sepsis and characterized the patients’ microbiomes close to or at onset of sepsis. We found that several microbiome alterations, including having more total bacteria in the gut was associated with onset, regardless of prior antibiotic treatment. This signature of microbiome disruption brings us closer to identifying the biological causes of sepsis and could be used to develop new diagnostic tests to identify patients at risk of sepsis.

The bacterial density of clinical rectal swabs is highly variable, correlates with sequencing contamination, and predicts patient risk of extraintestinal infection

“…Our group and others have shown that gut microbiota undergo rapid and temporally dependent changes in hospitalized patients [15,75,76]; therefore, the finding that temporally discordant samples show large differences in observed microbiota is unsurprising. This study adds to the growing body of literature demonstrating the clinical utility of rectal swab specimens for the characterization of gut microbiota, and we replicate findings that admission rectal swabs are predictive of infection and outcomes in ICU patients [64,77].…”

Bacteria and Sepsis: Microbiome to the Rescue?

“…However, more subtle changes occur that have long-term consequences. Recent studies have shown that decreased microbiota diversity with increased abundance of the genus Enterococcus is observed in critically ill patients and is associated with a higher risk of sepsis, which may give credence to this line of investigation [35][36][37][38][39]. In a study involving 24 long-stay ICU patients, approximately two-thirds of patients were observed to have a loss of microbial diversity based on 16S rRNA gene sequencing of bacteria in the stool.…”

“…Furthermore, three-quarters of patients were observed to have increased abundance of pathogens Enterococcus faecium, Klebsiella pneumoniae, Enterobacter cloacae, and E. coli [38]. More specific to sepsis, a study on stool samples of 103 sepsis patients compared to matched controls on intensive care and hematology units were observed to have a higher abundance of Enterococcus based on 23S rRNA gene sequencing (to calculate total abundance) as well [39]. The differential overexpression of this taxa supports the hypothesis that components of the host microbiota can mediate or elevate sepsis risk.…”

The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia

“…Loss of diversity and imbalance in composition of the microbiota, termed dysbiosis, is clearly described but associations with mortality risks are not. Dysbiosis is likely correlated with illness severity and has been linked to increased mortality in critically ill patients including sepsis 54,55 , in patients undergoing allogeneic hematopoietic-cell transplantation 56 , in hospitalized patients with cirrhosis 57 among others. A marked insult on the microbiome is likely when children are hospitalized and exposed to nosocomial microorganisms, and to selection pressure from antimicrobials, resulting in acquisition of antimicrobial resistance genes.…”