Daily Sepsis Research Analysis
Three impactful studies advance sepsis science across mechanisms and bedside care. FXR signaling enhances neonatal MDSC function, with the FDA-approved agonist obeticholic acid protecting against neonatal sepsis. Melatonin limits sepsis-induced acute lung injury by reducing circulating mtDNA and suppressing STING-driven necroptosis, while a prospective emergency department study shows infrared thermography core-to-peripheral temperature gradients predict short-term mortality and perfusion needs.
Summary
Three impactful studies advance sepsis science across mechanisms and bedside care. FXR signaling enhances neonatal MDSC function, with the FDA-approved agonist obeticholic acid protecting against neonatal sepsis. Melatonin limits sepsis-induced acute lung injury by reducing circulating mtDNA and suppressing STING-driven necroptosis, while a prospective emergency department study shows infrared thermography core-to-peripheral temperature gradients predict short-term mortality and perfusion needs.
Research Themes
- Bile acid-FXR signaling and immunoregulation in neonatal sepsis
- Mitochondrial DAMPs, STING, and necroptosis in sepsis-induced organ injury
- Noninvasive microcirculatory monitoring for sepsis risk stratification
Selected Articles
1. FXR protects against neonatal sepsis by enhancing the immunosuppressive function of MDSCs.
FXR is identified as a positive regulator of neonatal MDSC function. Obeticholic acid, an FDA-approved FXR agonist, confers protection against neonatal sepsis in an FXR-dependent manner, while FXR deficiency impairs MDSC immunosuppressive and antibacterial functions.
Impact: Links bile acid signaling to neonatal sepsis immunoregulation and repurposes an FDA-approved drug with strong translational potential.
Clinical Implications: Suggests FXR agonists (e.g., obeticholic acid) as candidates for clinical trials in neonatal sepsis by enhancing MDSC-mediated immunoregulation. Could inform biomarker-driven stratification based on FXR/MDSC axes.
Key Findings
- FXR acts as a positive regulator of neonatal MDSC function.
- Obeticholic acid protects against neonatal sepsis in an FXR-dependent manner.
- FXR deficiency impairs MDSC immunosuppressive and antibacterial functions, worsening sepsis severity.
- Adoptive transfer of MDSCs alleviates sepsis in mouse models.
Methodological Strengths
- Use of both pharmacologic activation (OCA) and genetic deficiency to establish FXR causality.
- Functional validation via adoptive MDSC transfer linking mechanism to phenotype.
Limitations
- Preclinical neonatal mouse work; human neonatal data are lacking.
- Safety, dosing, and pharmacokinetics of obeticholic acid in neonates were not evaluated.
Future Directions: Evaluate FXR/MDSC biomarkers in human neonatal sepsis; conduct dose-finding and safety trials of FXR agonists; dissect FXR targets within MDSCs and microbiome-bile acid interactions.
2. Melatonin alleviates sepsis-induced acute lung injury by inhibiting necroptosis via reducing circulating mtDNA release.
In CLP-induced sepsis, melatonin improved survival and attenuated acute lung injury by lowering circulating mtDNA, suppressing STING activation, and inhibiting necroptosis. mtDNA was sufficient to drive necroptosis, and RIP1 inhibition (Nec-1) rescued mtDNA-induced injury.
Impact: Defines a mechanistic link between mitochondrial DAMPs, STING signaling, and necroptosis in sepsis-induced lung injury, and identifies melatonin as a low-toxicity therapeutic candidate.
Clinical Implications: Supports evaluating melatonin as an adjunctive therapy in sepsis-induced acute lung injury, and motivates clinical biomarker studies tracking circulating mtDNA and STING activation.
Key Findings
- Melatonin improved survival and reduced ALI severity in CLP-induced sepsis.
- Melatonin reduced circulating mtDNA and inhibited STING activation and necroptosis.
- Exogenous mtDNA activated necroptosis; RIP1 inhibitor Nec-1 reversed mtDNA-induced lung injury.
Methodological Strengths
- Multi-layer validation using histology, biomarkers, genetic pathway readouts, and pharmacologic modulation (Nec-1, STING modulation).
- Causal testing with exogenous mtDNA to link DAMPs to necroptosis and injury.
Limitations
- Murine single-sex model; generalizability to both sexes and humans is uncertain.
- Optimal dosing and timing of melatonin for clinical translation were not defined.
Future Directions: Pilot clinical studies of melatonin in sepsis-associated respiratory failure; translational validation of mtDNA/STING biomarkers; exploration of combination strategies with necroptosis inhibitors.
3. Utility of core to peripheral temperature gradient using infrared thermography in the assessment of patients with sepsis and septic shock in the emergency medicine department.
In 187 ED patients with suspected sepsis or septic shock, larger core-to-peripheral temperature gradients measured by infrared thermography correlated with 7-day mortality, vasopressor requirements, lower MAP, and higher lactate and SOFA. Gradients changed after 3 hours of resuscitation, supporting use as a bedside perfusion adjunct.
Impact: Provides a rapid, noninvasive, and scalable physiological marker for risk stratification and resuscitation monitoring in sepsis, with prospectively derived thresholds.
Clinical Implications: Infrared thermography-based core-to-peripheral gradients can augment early sepsis triage and guide perfusion-targeted resuscitation, especially where invasive monitoring is limited.
Key Findings
- Core-to-knee (>8.85°F) and core-to-toe (>12.25°F) gradients on arrival predicted 7-day mortality.
- Core-to-index finger gradient correlated with vasopressor need within 48 hours (p=0.020).
- Gradients negatively correlated with MAP and positively with lactate, SOFA, and qSOFA; gradients reassessed after 3 hours of resuscitation.
Methodological Strengths
- Prospective design with predefined imaging at arrival and post-resuscitation timepoints.
- Objective thermal measurements correlated with multiple clinical perfusion markers and outcomes.
Limitations
- Single-center study with modest sample size; external validity requires multicenter validation.
- Environmental factors and skin conditions may influence thermography readings.
Future Directions: Multicenter validation of thresholds; integrate gradients into sepsis bundles and decision-support; assess predictive value versus capillary refill and peripheral perfusion index.