Daily Sepsis Research Analysis
Three impactful sepsis studies span translational mechanisms, genetic causal targets, and pragmatic bedside management. A murine mechanistic study identifies an intestinal epithelial MyD88–FXR/FGF15 axis that drives gut barrier failure in abdominal sepsis and is pharmacologically rescuable. A proteome-wide Mendelian randomization analysis implicates CD33 and LY9 as causal sepsis risk proteins, while a large enterococcal bacteremia cohort quantifies the survival benefit of early ID consultation,
Summary
Three impactful sepsis studies span translational mechanisms, genetic causal targets, and pragmatic bedside management. A murine mechanistic study identifies an intestinal epithelial MyD88–FXR/FGF15 axis that drives gut barrier failure in abdominal sepsis and is pharmacologically rescuable. A proteome-wide Mendelian randomization analysis implicates CD33 and LY9 as causal sepsis risk proteins, while a large enterococcal bacteremia cohort quantifies the survival benefit of early ID consultation, appropriate antibiotics, and rapid source control.
Research Themes
- Gut–liver crosstalk and barrier failure mechanisms in sepsis
- Genetic causal inference identifying druggable sepsis targets
- Early source control and antimicrobial stewardship in enterococcal bacteremia
Selected Articles
1. Inhibition of Farnesoid-x-receptor signaling during abdominal sepsis by dysbiosis exacerbates gut barrier dysfunction.
In murine sepsis, intestinal dysbiosis activates epithelial MyD88 signaling, suppressing the FXR–FGF15 axis and worsening gut barrier dysfunction. Pharmacologic FXR activation with INT-747 restored FXR/FGF15 expression and improved barrier integrity, implicating the MyD88–FXR pathway as a therapeutic target.
Impact: This study uncovers a mechanistic gut–liver pathway in sepsis that is modifiable with an approved FXR agonist (obeticholic acid), providing a translational rationale for targeted therapies to preserve barrier function.
Clinical Implications: Suggests testing FXR agonists and microbiome-directed strategies to mitigate gut barrier failure and downstream organ dysfunction in abdominal sepsis.
Key Findings
- CLP-induced sepsis suppressed FXR–FGF15 signaling, altered microbiota, and impaired gut barrier function.
- FXR agonist INT-747 increased intestinal FXR and FGF15 expression and improved barrier integrity.
- Intestinal epithelial MyD88 signaling linked dysbiosis to FXR/FGF15 suppression and barrier failure.
Methodological Strengths
- Use of in vivo CLP sepsis model with pharmacologic rescue via FXR agonist
- Genetic interrogation with intestinal epithelial MyD88 manipulation to dissect causality
Limitations
- Preclinical murine and cellular models may not fully recapitulate human sepsis heterogeneity
- Sample sizes and detailed quantitative barrier assays are not fully specified in the abstract
Future Directions: Conduct phase 1/2 trials of FXR agonists (e.g., obeticholic acid) in abdominal sepsis with barrier function and bile acid profiles as pharmacodynamic endpoints; evaluate microbiome-targeted interventions modulating MyD88–FXR signaling.
2. Identification of potential therapeutic drug targets for sepsis by combining the human plasma proteome and genome: a Mendelian randomization study.
Proteome-wide Mendelian randomization implicates higher plasma CD33 and LY9 levels as causally associated with increased sepsis risk. These proteins, with existing drug development activity around CD33, represent promising therapeutic targets and biomarkers for risk stratification.
Impact: By leveraging genetic instruments, the study provides causal evidence for protein targets, prioritizing CD33 and LY9 for translational development in sepsis.
Clinical Implications: Supports evaluation of CD33-directed therapeutics and development of assays for CD33/LY9 as risk biomarkers, potentially informing patient selection in future trials.
Key Findings
- Higher genetically predicted CD33 levels increased sepsis risk (OR 1.04, 95% CI 1.02–1.05).
- Higher genetically predicted LY9 levels increased sepsis risk (OR 1.10, 95% CI 1.05–1.15).
- Findings prioritize CD33 and LY9 as potential therapeutic targets and biomarkers.
Methodological Strengths
- Proteome-wide MR leveraging pQTLs across multiple datasets for causal inference
- Use of genetic instruments reduces confounding and reverse causation inherent to observational studies
Limitations
- Abstract lacks full methodological detail (e.g., sensitivity analyses for pleiotropy and exact cohorts)
- Effect sizes are modest; translation to clinical efficacy remains uncertain
Future Directions: Perform target validation in experimental sepsis models, evaluate existing CD33-directed agents, and develop LY9-targeting strategies; integrate proteogenomic risk scores for patient stratification.
3. Predictors of mortality of enterococcal bacteraemia and the role of source control interventions; a retrospective cohort study.
In 768 episodes of enterococcal bacteremia (46% with sepsis/septic shock), 30-day mortality was 19%. Early infectious diseases consultation (aHR 0.40), appropriate antimicrobials within 48 h (aHR 0.54), and timely source control within 48 h (aHR 0.22) were independently associated with improved survival.
Impact: Quantifies the time-sensitive benefits of ID consultation, appropriate antibiotics, and source control specifically in enterococcal bacteremia, offering actionable targets for care pathways.
Clinical Implications: Embed automatic ID consults and source control triggers within 48 h for enterococcal bacteremia; prioritize early appropriate therapy and escalation pathways in nosocomial cases.
Key Findings
- 30-day mortality was 19% across 768 episodes; 46% presented with sepsis or septic shock.
- Independent mortality predictors: age >60 (aHR 1.75), nosocomial infection (aHR 1.78), and sepsis/septic shock (aHR 3.67).
- Protective factors: ID consultation within 48 h (aHR 0.40), appropriate antimicrobials within 48 h (aHR 0.54), and source control within 48 h (aHR 0.22).
Methodological Strengths
- Large single-center cohort with 768 episodes and multivariable Cox regression
- Sensitivity analysis excluding limitations-of-care cases confirmed associations
Limitations
- Retrospective single-center design with potential unmeasured confounding
- Timing and appropriateness definitions may vary and limit generalizability
Future Directions: Prospective multicenter implementation studies testing care bundles (automatic ID consults, early source control pathways) with process and mortality endpoints.