Weekly Sepsis Research Analysis
This week’s sepsis literature emphasizes rapid diagnostic advances, mechanistic target discovery from host–microbiome interactions, and novel endothelial–immune pathways driving organ injury. High-yield diagnostic studies show plasma microbial cfDNA metagenomic sequencing greatly outperforms blood cultures and could change antimicrobial choices, while systems multi-omics map microbiota metabolites to druggable targets with in vivo validation. Mechanistic preclinical work identifies endothelial c
Summary
This week’s sepsis literature emphasizes rapid diagnostic advances, mechanistic target discovery from host–microbiome interactions, and novel endothelial–immune pathways driving organ injury. High-yield diagnostic studies show plasma microbial cfDNA metagenomic sequencing greatly outperforms blood cultures and could change antimicrobial choices, while systems multi-omics map microbiota metabolites to druggable targets with in vivo validation. Mechanistic preclinical work identifies endothelial chemokine and STING–GSDMD mitochondrial axes as actionable targets for sepsis lung injury, and several large cohorts refine prognostic and stewardship tools (CRP dynamics, sTREM1, ML risk models).
Selected Articles
1. Endothelial-Derived CCL7 Promotes Macrophage Polarization and Aggravates Septic Acute Lung Injury via CCR1-Mediated STAT1 Succinylation.
Preclinical work shows endothelial CCL7 drives CCR1+ macrophage metabolic reprogramming and M1 polarization through KAT2A-dependent STAT1 succinylation, amplifying inflammation in septic acute lung injury; endothelial-specific CCL7 inhibition reduced lung injury severity in murine sepsis models.
Impact: Identifies a novel endothelial–macrophage epigenetic–metabolic axis (CCL7–CCR1–KAT2A–STAT1) that causally links vascular signaling to macrophage-driven lung injury and offers several druggable nodes for translational development.
Clinical Implications: Supports testing CCR1 antagonists, KAT2A modulators, or interventions that reduce endothelial CCL7 release in translational models; suggests measuring endothelial/macrophage signatures in human ALI cohorts to enable biomarker-guided trials.
Key Findings
- Endothelial-derived CCL7 induces metabolic reprogramming and M1 polarization of CCR1+ macrophages.
- CCL7–CCR1 signaling increases KAT2A expression leading to STAT1 succinylation and enhanced glycolytic gene transcription.
- Endothelial-specific inhibition of CCL7 reduced severity of septic acute lung injury in vivo.
2. Improved pathogen identification in sepsis or septic shock by clinical metagenomic sequencing.
In a prospective multicenter cohort (n=491), plasma microbial cell-free DNA metagenomic NGS detected pathogens in 70.5% of septic patients within 3 days of onset versus 19.4% by blood culture; expert adjudication found 98.6% of NGS findings plausible and estimated that NGS results would have prompted anti-infective treatment changes in 32.6% of patients.
Impact: Demonstrates major diagnostic yield gains over standard blood cultures and quantifies potential treatment impact (approx. one-third of patients), addressing a core bottleneck in sepsis management: timely pathogen identification.
Clinical Implications: Supports integration of plasma mcfDNA NGS alongside blood cultures—especially for culture-negative and pretreated patients—and prioritizes randomized/implementation trials to demonstrate outcome and cost-effectiveness benefits.
Key Findings
- NGS positivity 70.5% vs blood cultures 19.4% within 3 days after sepsis onset (n=491).
- 98.6% of NGS-identified pathogens were judged plausible by an independent expert panel.
- NGS findings could have led to anti-infective treatment adaptations in 32.6% of patients; inadequately treated NGS+/BC- patients had worse outcomes.
3. Comprehensive characterization of multi-omics landscapes between gut microbial metabolites and the druggable genome in sepsis.
A systems biology pipeline mapped ~190,950 metabolite–protein interactions linking 335 gut microbial metabolites to 114 sepsis-relevant druggable targets (GPCRs, ion channels, kinases). Indole-3-lactic acid was prioritized and target engagement/function validated by MD simulation, MST biophysics, and murine CLP models, providing a blueprint for microbiota-based therapeutic discovery in sepsis.
Impact: Provides a scalable, validated framework to translate microbiome chemistry into host-targeted interventions, nominating concrete metabolite–target pairs with orthogonal biophysical and in vivo validation—bridging microbiome science and therapeutic discovery.
Clinical Implications: Motivates early-phase translation of prioritized microbiota-derived ligands and host targets (e.g., ILA-related pathways) with pharmacodynamic biomarkers; encourages integration of metabolome profiling into sepsis drug-discovery pipelines.
Key Findings
- Mapped 190,950 metabolite–protein interactions linking 335 gut metabolites to 114 druggable sepsis targets (GPCRs, ion channels, kinases).
- Prioritized indole-3-lactic acid (ILA) and validated target engagement using MD simulation and MST.
- Functional validation in murine CLP sepsis model supported in vivo relevance of prioritized metabolite–target interactions.