Weekly Sepsis Research Analysis
This week’s sepsis literature emphasizes mechanistic immunometabolism and translational targets, microbiome–metabolite immunomodulation, and vascular/cardiac protective signaling. High-quality preclinical studies identify FGF13-driven ERK/HIF‑1α glycolytic reprogramming and CNP–NPR‑C vascular protection as druggable axes, while a cross-species ketogenic diet study revealed a gut‑lung metabolite (azelaic acid) that resolves lung inflammation. These findings converge with advances in proteome-wide
Summary
This week’s sepsis literature emphasizes mechanistic immunometabolism and translational targets, microbiome–metabolite immunomodulation, and vascular/cardiac protective signaling. High-quality preclinical studies identify FGF13-driven ERK/HIF‑1α glycolytic reprogramming and CNP–NPR‑C vascular protection as druggable axes, while a cross-species ketogenic diet study revealed a gut‑lung metabolite (azelaic acid) that resolves lung inflammation. These findings converge with advances in proteome-wide causal inference and bedside hemodynamic biomarkers to accelerate precision diagnostics and targeted interventions.
Selected Articles
1. FGF 13 functions as a regulator of the ERK/aerobic glycolysis axis in the inflammatory state during septic lung injury.
Using conditional knockout and overexpression mouse models plus pharmacologic inhibition, this study shows FGF13 scaffolds TAK1/MEK/ERK signaling to amplify HIF‑1α–driven aerobic glycolysis in endothelial cells and macrophages, thereby worsening septic lung inflammation and injury. ERK inhibition abrogated FGF13-induced effects and HIF‑1α overexpression reversed protection from Fgf13 deletion.
Impact: Identifies FGF13 as a nodal regulator linking ERK signaling to immunometabolic reprogramming in septic lung injury and demonstrates targetability with ERK inhibition, revealing a translational axis for therapeutic development.
Clinical Implications: Supports investigating ERK pathway inhibitors or approaches that limit HIF‑1α–driven glycolysis as interventions to mitigate septic lung injury; FGF13 expression may become a biomarker for risk stratification.
Key Findings
- FGF13 is downregulated in lung endothelial cells and macrophages of septic patients and mice, but conditional manipulation shows causal effects on injury.
- FGF13 scaffolds TAK1/MEK/ERK signaling to enhance HIF‑1α–regulated aerobic glycolysis in inflammatory conditions.
- ERK inhibitor SCH772984 abolishes FGF13-driven inflammatory exacerbation; HIF‑1α overexpression negates protection from Fgf13 knockout.
2. Ketogenic diet alleviates septic lung injury via microbial gut-lung axis.
This cross-species study shows a ketogenic diet reshapes the gut microbiota to enrich FMO‑expressing strains that convert dietary oleic acid into azelaic acid; during sepsis azelaic acid traffics to the lung, promotes neutrophil apoptosis and expands MerTK+ macrophages, resolving inflammation and reducing lung injury in mice, with supportive human microbiome observations.
Impact: Uncovers a diet–microbe–metabolite–immune circuit (azelaic acid) with translational potential, suggesting dietary, probiotic, or metabolite-based adjuncts to mitigate sepsis lung pathology.
Clinical Implications: Motivates evaluation of ketogenic-like nutritional strategies, FMO-bearing probiotics, or azelaic acid administration as adjunctive therapies in sepsis, with safety and metabolic monitoring required before clinical adoption.
Key Findings
- Ketogenic diet (KD) alters gut microbiota in mice and humans, enriching Limosilactobacillus reuteri and Lactiplantibacillus plantarum.
- Specific FMO‑expressing bacterial strains convert oleic acid to azelaic acid, which traffics to the lung during sepsis.
- Azelaic acid promotes neutrophil apoptosis and expansion of MerTK+ macrophages, resolving inflammation and reducing lung injury in preclinical models.
3. C-Type Natriuretic Peptide Preserves Vascular and Cardiac Function in Sepsis.
Translational analyses combining human NT‑proCNP biomarker data and endothelial‑restricted genetic models indicate endogenous CNP preserves microvascular perfusion, endothelial integrity, and cardiac function via NPR‑C signaling in sepsis. The findings nominate the CNP/NPR‑C axis as a therapeutic target and NT‑proCNP as a potential stratification biomarker.
Impact: Bridges human biomarker associations with mechanistic models to highlight NPR‑C–mediated CNP signaling as a protective, druggable axis in sepsis with direct translational potential.
Clinical Implications: Supports early-phase evaluation of CNP pathway agonists and use of NT‑proCNP for patient stratification in trials aiming to improve microvascular perfusion and cardiac function in sepsis.
Key Findings
- Circulating NT‑proCNP is elevated in sepsis patients and associates with reduced disease severity.
- Endogenous and endothelial-derived CNP preserve microvascular perfusion, endothelial integrity, and cardiac function in preclinical models.
- Protective effects are mediated via NPR‑C signaling, indicating pharmacologic tractability.