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.
Myeloid-derived suppressor cells (MDSCs) play a protective role against neonatal inflammation during the early postnatal period. However, the mechanisms regulating neonatal MDSC function remain to be fully elucidated. In this study, we report that the bile acid receptor farnesoid X receptor (FXR) acts as a positive regulator of neonatal MDSC function. The FDA-approved FXR agonist obeticholic acid (OCA) protects against neonatal sepsis in an FXR-dependent manner. Genetic deficiency of FXR impairs the immunosuppressive and antibacterial functions of MDSCs, thereby exacerbating the severity of neonatal sepsis. Adoptive transfer of MDSCs alleviates sepsis in both Fxr
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.
BACKGROUND: Sepsis is a life-threatening condition that often leads to severe complications, including acute lung injury (ALI), which carries high morbidity and mortality in critically ill patients. Melatonin (Mel) has shown significant protective effects against sepsis-induced ALI, but its precise mechanism remains unclear. METHODS: A cecal ligation and puncture (CLP) model was used to induce sepsis in male C57BL/6 mice, which were divided into four groups: Control, Sham, CLP, and CLP + Mel. ALI severity was evaluated via hematoxylin and eosin (H&E) staining, lung wet/dry ratio, and serum biomarkers (SP-D, sRAGE). Inflammatory cytokines (IL-1β, IL-6, TNF-α) were measured in serum and bronchoalveolar lavage fluid using ELISA. Circulating mitochondrial DNA (mtDNA) subtypes (D-loop, mt-CO1, mMito) were quantified by real-time PCR. TUNEL staining was performed to assess lung cell apoptosis. Necroptosis and STING pathway activation were analyzed via Western blot and immunofluorescence. RESULTS: Sepsis led to increased circulating mtDNA levels and activation of necroptosis signaling pathways. Melatonin treatment alleviated sepsis-induced ALI, improving survival, reducing inflammatory cytokines and mtDNA release, and suppressing necroptosis. Intraperitoneal injection of mtDNA in mice activated necroptosis, while RIP1 inhibitor Nec-1 counteracted mtDNA-induced lung damage and necroptosis in sepsis-induced ALI. Additionally, melatonin significantly inhibited STING pathway activation. Further experiments revealed that STING modulation influenced necroptosis protein expression and mediated melatonin's protective effects in sepsis-induced ALI. CONCLUSION: Melatonin mitigates sepsis-induced ALI by suppressing necroptosis through inhibition of STING activation and reduction of mtDNA release. These findings suggest melatonin as a potential therapeutic strategy for sepsis-induced ALI.
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.
OBJECTIVE: Sepsis is a disease affecting microcirculation, reflected in temperature changes between the core and the skin. This study explores correlation of this gradient using infrared thermography (IRT) with mortality and markers of hypoperfusion in patients admitted with sepsis and septic shock and its changes with resuscitation. DESIGN: We conducted a prospective, single center observational study on patients admitted in the Department of Emergency Medicine of a tertiary care center in Karnataka, India. These patients were enrolled based on the inclusion criteria and infrared thermography was performed and cases were followed up after 28 days. Adults presenting to the emergency medicine department with clinically suspected sepsis or septic shock were enrolled and infrared thermography was performed. A final sample size of 187 cases was analyzed after retrospectively excluding patients with any exclusion criteria. INTERVENTIONS: Patients underwent thermal imaging of all four limbs on arrival and after 3 hours of resuscitation. Core temperature was measured using a tympanic thermometer. Infrared thermography was performed, and limb temperature was extracted from the images. Other parameters including mean arterial pressure and lactate were recorded and SOFA score was calculated. OUTCOME MEASURE(S): The temperature gradients were correlated with 7 and 28-day mortality along with markers of hypoperfusion including mean arterial pressure and serum lactate levels. RESULTS: A total of 187 patients were included, with a mean SOFA score of 5. Forty four patients (23.5%) died within 7-days. 28-day mortality was 31%. Temperature gradients of core to knee > 8.85°F (p = 0.003) and core to great toe > 12.25°F (p = 0.020) on arrival were found to be correlated with 7-day mortality. Core to knee temperature gradient was found to correlate with 48-hour mortality(p < 0.013). Core to index finger gradient on arrival correlated with vasopressor requirement within 48h (p = 0.020). Core to index finger temperature gradient had a negative correlation with mean arterial pressure (spearman coefficient - 0.286, p = < 0.001), and a positive correlation with lactate (0.281, p = < 0.001), SOFA score (0.242, p = 0.001), qSOFA score (0.167, p = 0.023). CONCLUSIONS: Core-to-knee and core-to-toe temperature gradients using IRT significantly correlate with 7-day mortality. IRT can be a useful adjunct to predict clinical courses in patients with sepsis and septic shock.