Daily Sepsis Research Analysis
Three sepsis studies stand out today: a large two-cohort analysis shows the De Ritis (AST/ALT) ratio robustly stratifies 30-day mortality in sepsis-associated liver injury; a mechanistic study identifies Mac-1–dependent endothelial–neutrophil adhesion as a driver of NETs and lung injury; and a multi-omics, germ-free/knockout mouse study shows time-restricted feeding protects against septic liver injury via gut microbiota and 3-hydroxybutyrate.
Summary
Three sepsis studies stand out today: a large two-cohort analysis shows the De Ritis (AST/ALT) ratio robustly stratifies 30-day mortality in sepsis-associated liver injury; a mechanistic study identifies Mac-1–dependent endothelial–neutrophil adhesion as a driver of NETs and lung injury; and a multi-omics, germ-free/knockout mouse study shows time-restricted feeding protects against septic liver injury via gut microbiota and 3-hydroxybutyrate.
Research Themes
- Simple bedside biomarkers for risk stratification in sepsis-associated liver injury
- Mechanistic targeting of neutrophil–endothelium interactions to limit NET-driven lung injury
- Immunometabolic and microbiome-mediated protection via time-restricted feeding and 3-hydroxybutyrate
Selected Articles
1. Time-restricted feeding protects against septic liver injury by reshaping gut microbiota and metabolite 3-hydroxybutyrate.
In murine sepsis models, time-restricted feeding protected the liver by reshaping gut microbiota and elevating the ketone body 3-hydroxybutyrate (3-HB). The study used germ-free and Hmgcs2/Lpin1 knockout mice, multi-omics, and hepatocyte experiments to implicate a microbiota–metabolite axis in mitigating septic liver injury.
Impact: This work links dietary timing to sepsis organ protection via a defined microbiome–metabolite mechanism, offering testable immunometabolic targets (e.g., 3-HB) for translation.
Clinical Implications: Although preclinical, the data support evaluating time-restricted feeding paradigms or exogenous ketone/3-HB strategies as adjuncts to protect the liver in sepsis, while carefully considering ICU feasibility and nutrition risks.
Key Findings
- Time-restricted feeding (TRF) mitigated septic liver injury in mice.
- TRF reshaped gut microbiota and increased 3-hydroxybutyrate (3-HB).
- Mechanistic support came from germ-free and Hmgcs2/Lpin1 knockout mice plus multi-omics and hepatocyte assays.
Methodological Strengths
- Use of germ-free and gene knockout mice to establish causality.
- Integrated multi-omics (16S rRNA sequencing, targeted metabolomics, transcriptomics) with cellular validation.
Limitations
- Preclinical animal study; human generalizability is unknown.
- Feasibility and safety of time-restricted feeding in critically ill patients remain uncertain.
Future Directions: Pilot human studies to test ketone/3-HB supplementation and circadian-aligned feeding in sepsis, with microbiome and metabolomic endpoints.
Liver injury is an independent risk factor for multiple organ dysfunction and high mortality in patients with sepsis. However, the pathological mechanisms and therapeutic strategies for sepsis-associated liver injury have not been fully elucidated. Time-restricted feeding (TRF) is a promising dietary regime, but its role in septic liver injury remains unknown. Using 16S rRNA gene sequencing, Q200 targeted metabolomics, transcriptomics, germ-free mice, Hmgcs2/Lpin1 gene knockout mice, and Aml12 cells experiments, we revealed that TRF can mitigate septic liver injury by modulating the gut microbiota, particularly by increasing
2. Subphenotypes and the De Ritis ratio for mortality risk stratification in sepsis-associated acute liver injury: a retrospective cohort study.
Across two ICU databases, sepsis patients with liver injury had markedly higher 30-day mortality. The De Ritis (AST/ALT) ratio most strongly stratified mortality risk: ≤1 showed no significant increase, 1–2 increased risk (HR 1.56), and ≥2 had the highest risk (HR 2.46), with external validation.
Impact: A simple, widely available ratio provides robust, validated risk stratification for sepsis-associated liver injury, enabling immediate bedside application.
Clinical Implications: Incorporate the De Ritis ratio into early assessment of sepsis with suspected liver injury to identify high-risk patients (AST/ALT ≥1), prioritize monitoring, and consider targeted interventions.
Key Findings
- Sepsis-associated liver injury doubled 30-day mortality risk versus no SALI (HR 1.73).
- De Ritis ratio stratified mortality: ≤1 (no significant increase), 1–2 (HR 1.56), ≥2 (HR 2.46).
- Findings replicated in an external ICU cohort; R-factor and ALT elevation also stratified but were weaker.
Methodological Strengths
- Large retrospective cohorts with external validation across two ICU databases.
- Multivariable Cox models and Kaplan–Meier analyses with clear, reproducible lab-based thresholds.
Limitations
- Retrospective design with potential residual confounding.
- AST/ALT can be influenced by extrahepatic sources (e.g., muscle injury), potentially affecting specificity.
Future Directions: Prospective validation and integration of De Ritis ratio into sepsis risk scores; evaluate whether ratio-guided protocols improve outcomes.
BACKGROUND: Sepsis-associated liver injury (SALI) is associated with poor outcomes and increased mortality. However, effectively stratifying SALI patients according to prognosis remains challenging. This study evaluates laboratory-based clustering filters for stratifying SALI patients by 30-day mortality risk, utilizing data mining techniques for novel pattern discovery. METHODS: This retrospective cohort study analyzed SALI patients from two ICU databases: Medical Information Mart for Intensive Care (MIMIC)-IV database (n = 73,181, study period: 2008 to 2019) and Amsterdam UMC (n = 16,194, study period: 2003 to 2016). Patients were identified using Sepsis-3 criteria and liver injury markers. Risk stratification employed three laboratory-based approaches: (I) De Ritis ratio (aspartate aminotransferase/alanine aminotransferase), (II) R-factor (alanine aminotransferase and alkaline phosphatase relative to their upper limits of normal), and (III) alanine aminotransferase elevation. Kaplan-Meier analysis and multivariable Cox regression assessed the association between stratification methods and 30-day mortality risk. FINDINGS: SALI patients had almost a 2-fold higher risk of 30-day mortality than those without SALI (hazard ratio: 1.73; 95%-CI: 1.58-1.90, p < 0.0001). Each stratification method (I-III) successfully classified patients into statistically distinct risk strata. The De Ritis ratio emerged as the strongest prognostic differentiation method: a ratio ≤1 indicated no significant increase in mortality risk (hazard ratio: 0.86; 95%-CI: 0.68-1.09, p = 0.21), whereas ratios of 1-2 and ≥2 were significantly associated with higher mortality (hazard ratio: 1.56; 95%-CI: 1.37-1.78, p < 0.0001 and hazard ratio: 2.46; 95%-CI: 2.18-2.77, p < 0.0001, respectively). All findings were confirmed in the validation cohort. INTERPRETATION: The De Ritis ratio serves as a valuable prognostic tool for 30-day mortality in SALI patients. Our findings indicate that patients with a ratio ≥1 face significantly worse outcomes, highlighting the need for targeted interventions. These results refine risk stratification in SALI subphenotypes, enhancing our understanding of its prognostic implications. FUNDING: This study received no external funding and was solely financed through the departmental resources of the authors.
3. Mac-1 blockade impedes adhesion-dependent neutrophil extracellular trap formation and ameliorates lung injury in LPS-induced sepsis.
Direct endothelial–neutrophil adhesion is essential for NET formation in response to LPS/LTA/septic plasma. Blocking Mac-1, but not PSGL-1 or LFA-1, reduced NETs in vitro and attenuated cytokines, endothelial damage, and lung injury in LPS sepsis mice, highlighting Mac-1 as a therapeutic target.
Impact: It refines the mechanistic link between neutrophil–endothelium interactions and NET-driven lung injury and nominates Mac-1 as a druggable target.
Clinical Implications: Suggests testing Mac-1–targeted strategies to mitigate NET-mediated lung injury in sepsis-induced ARDS, while recognizing current evidence is preclinical.
Key Findings
- Endothelial adhesion is required for NET formation with LPS/LTA/septic plasma stimulation.
- Mac-1 blockade, but not PSGL-1 or LFA-1 inhibition, reduced NETs in vitro.
- In LPS-induced sepsis mice, Mac-1 blockade decreased cytokines, endothelial damage, NET release, and lung injury.
- Adhesion-dependent NETs required extracellular calcium and PAD4-mediated H3 citrullination; Mac-1 blockade did not alter calcium influx.
Methodological Strengths
- Combined in vitro co-culture systems with in vivo LPS sepsis models.
- Mechanistic dissection of adhesion molecules and PAD4 dependence.
Limitations
- LPS-induced sepsis may not capture the complexity of polymicrobial or CLP models.
- Translational relevance requires testing in additional models and species.
Future Directions: Evaluate Mac-1 targeting in polymicrobial sepsis (e.g., CLP) and explore safety/efficacy of integrin-modulating agents in large animals.
BACKGROUND: Sepsis is a common critical condition that can lead to multiple organ injury. Sepsis-induced acute respiratory distress syndrome (ARDS) is frequently an important cause of poor prognosis and is associated with high mortality rates, despite existing therapeutic interventions. Neutrophil infiltration and extracellular traps (NET) are implicated in acute lung injury (ALI) and ARDS following sepsis. As circulating neutrophils infiltrate infected tissues, they come into direct contact with vascular endothelial cells (ECs). Although the ability of NETs to induce endothelial damage is well established, the specific role of direct EC-neutrophil interactions in NET formation and lung injury during sepsis is not fully understood. METHODS: In this study, NET formation was assessed when neutrophils were co-culture with ECs or separated from them and stimulated with phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide (LPS), lipoteichoic acid (LTA), or septic plasma. RESULTS: We found that adhesion of neutrophils on ECs is critical in NET formation in response to LPS, LTA, or septic plasma in vitro. Blocking the macrophage-1 antigen (Mac-1) impeded NET formation, while inhibiting P-selectin glycoprotein ligand-1 (PSGL-1) or leukocyte function-associated antigen-1 (LFA-1) did not. This adhesion-dependent NET formation was reliant on the influx of extracellular calcium and peptidylarginine deiminase 4 (PAD4)-mediated citrullination of histone H3. However, Mac-1 blockade did not alter calcium influx. In a murine model of LPS-induced sepsis, Mac-1 blockade reduced NET release, lowered inflammatory cytokine levels, mitigated endothelial damage, and attenuated lung injury. CONCLUSION: Our findings offer insights into the critical role of EC-neutrophil direct contact in NET formation during sepsis and propose Mac-1 as a potential therapeutic target.