Sepsis Research Analysis
In 2025, sepsis science pivoted to mechanism-led, precision frameworks that redefine susceptibility, monitoring, and intervention. A Cell-scale organ-origin plasma proteome atlas enabled organ-specific readouts from blood, while a conserved 42-gene SoM signature operationalized precision endotyping and predicted treatment response. Foundational host–pathogen ecology emerged, showing pathogen siderophores sabotaging microbiota–AhR signaling and TLR4/ROS-driven luminal redox shifts precipitating o
Summary
In 2025, sepsis science pivoted to mechanism-led, precision frameworks that redefine susceptibility, monitoring, and intervention. A Cell-scale organ-origin plasma proteome atlas enabled organ-specific readouts from blood, while a conserved 42-gene SoM signature operationalized precision endotyping and predicted treatment response. Foundational host–pathogen ecology emerged, showing pathogen siderophores sabotaging microbiota–AhR signaling and TLR4/ROS-driven luminal redox shifts precipitating opportunistic blooms. Methodologically, a JAMA reinforcement-learning policy for vasopressin timing and context-aware antimicrobial testing revived colistin activity under physiologic conditions. Cardiometabolic breakthroughs linked lactate-driven HADHA lactylation to septic cardiomyopathy, and trial design advanced through goal-directed subgroup identification. Rapid, time-resolved host transcriptomics delivered 24-hour readouts of antibiotic response, and chemistry-enabled antimicrobial polymers achieved intracellular uptake against MDR pathogens. Together, these advances chart a path from one-size-fits-all protocols to biomarker-timed, organ- and phenotype-aligned interventions.
Selected Articles
1. Human proteome distribution atlas for tissue-specific plasma proteome dynamics.
A mass-spectrometry atlas maps plasma proteins to their tissue and cell origins across 18 organs and major blood cell types, validating organ-enriched panels in clinical cohorts (including sepsis) and enabling organ-specific plasma signatures for precision diagnostics.
Impact: Provides a validated, foundational resource to infer organ origin from plasma, accelerating organ-specific phenotyping, monitoring, and trial enrichment in sepsis.
Clinical Implications: Enables rational design of plasma panels (e.g., liver, kidney, endothelium) to refine diagnosis, track responses, and select organ-directed therapies.
Key Findings
- Constructed a proteome atlas across 18 vascularized organs and major blood cell types.
- Validated organ-enriched plasma panels across multiple clinical cohorts including sepsis.
- Enabled inference of organ-origin signals for precision diagnostics and monitoring.
Methodological Strengths
- Atlas-scale mass spectrometry with organ/cell-of-origin resolution
- External validation across multiple independent clinical cohorts
Limitations
- Predominantly observational resource without interventional testing
- Standardization and assay portability to rapid clinical platforms remain to be established
Future Directions: Develop CLIA-ready organ panels and integrate organ-origin signals into adaptive trials and bedside monitoring for sepsis.
Abstract not available in provided dataset.
2. Optimal Vasopressin Initiation in Septic Shock: The OVISS Reinforcement Learning Study.
An externally validated reinforcement-learning policy recommended earlier vasopressin at lower norepinephrine; rule-concordant care across 227 hospitals was associated with lower in-hospital mortality under off-policy causal evaluation.
Impact: Delivers practice-ready, data-driven guidance on vasopressor sequencing at scale with robust external validation and causal inference.
Clinical Implications: Supports pragmatic RCTs and EHR-integrated decision support for earlier vasopressin at lower norepinephrine with protocolized safety monitoring.
Key Findings
- RL policy recommended vasopressin in 87% vs 31% under usual care and at lower norepinephrine doses.
- Rule-concordant initiation associated with lower in-hospital mortality (adjusted OR ~0.81).
- Off-policy causal evaluation supported observed benefits.
Methodological Strengths
- Large, multi-center external validation across 227 hospitals
- Off-policy causal evaluation (e.g., importance sampling/IPW)
Limitations
- Observational RL evaluation cannot fully replace randomized trials
- Generalizability depends on local practices and EHR integration
Future Directions: Conduct pragmatic, cluster-randomized implementation trials of RL-guided vasopressor timing with safety endpoints.
Abstract not available in provided dataset.
3. A rapid time-resolved host gene expression signature predicts responses to antibiotic treatment in neonatal bacterial sepsis.
Time-resolved transcriptomics in culture-confirmed neonatal sepsis identified a host-response signature reversing within 24 hours of vancomycin, tracking clinical improvement and showing conservation across pediatric and adult cohorts.
Impact: Introduces a rapid, biologically grounded readout of antibiotic efficacy with potential to transform stewardship and serve as an early endpoint.
Clinical Implications: If adapted to rapid platforms and prospectively validated, can guide early de-escalation and duration, and enable adaptive enrollment based on response trajectories.
Key Findings
- 24-hour reversal of host-response signature following antibiotic initiation
- Signature dynamics conserved across age groups
- Signature trajectories correlate with clinical improvement
Methodological Strengths
- Time-series transcriptomics in microbiologically confirmed sepsis
- Cross-cohort validation across pediatric and adult datasets
Limitations
- Requires translation to rapid, point-of-care platforms
- Initial development in neonatal population may limit immediate generalizability
Future Directions: Prospective trials to validate de-escalation and duration decisions guided by dynamic host-response signatures.
Abstract not available in provided dataset.
4. Enterobactin inhibits microbiota-dependent activation of AhR to promote bacterial sepsis in mice.
Microbiota-derived indoles activate macrophage AhR to improve clearance and survival, whereas pathogen-secreted enterobactin inhibits AhR signaling and worsens outcomes; dietary tryptophan restored survival, defining a targetable microbiota–host–pathogen axis.
Impact: Offers a unified, targetable pathway integrating microbiome metabolites and pathogen siderophores in sepsis susceptibility.
Clinical Implications: Supports microbiome-preserving stewardship and development of AhR agonists or siderophore-neutralizing interventions; motivates nutrition strategies.
Key Findings
- Microbiota-derived indoles increased survival via macrophage AhR.
- Macrophage-specific AhR knockout impaired bacterial clearance and survival.
- Enterobactin suppressed AhR signaling and increased mortality; tryptophan restored survival.
Methodological Strengths
- Mechanistic dissection with genetic knockouts and dietary rescue
- Integration of microbiome metabolites and pathogen factors
Limitations
- Predominantly murine models; limited direct human validation
- Translational dosing and safety of AhR-targeting or siderophore blockade remain untested
Future Directions: Develop AhR-preserving or siderophore-neutralizing strategies with early-phase human studies and embed nutritional modulation in trials.
Abstract not available in provided dataset.
5. A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response.
An integrative analysis across 68 cohorts (12,026 samples) validated a conserved 42-gene Severe-or-Mild (SoM) signature linking baseline risk to infection severity, predicting mortality and differential treatment response, and modifiable by drugs and lifestyle.
Impact: Provides a robust, cohort-validated immune score enabling precision endotyping and informing benefit or harm from immunomodulators.
Clinical Implications: SoM scoring could guide steroid use and immunomodulator selection and enrich trials for likely responders/non-responders.
Key Findings
- 42-gene SoM signature links baseline risk to infection severity.
- Predicts mortality and differential treatment response (e.g., hydrocortisone harm signals).
- Signature is modifiable by drugs and lifestyle changes.
Methodological Strengths
- Large-scale, multi-cohort integration with external validation
- Treatment-response association testing across datasets
Limitations
- Observational meta-analysis subject to confounding and platform heterogeneity
- Prospective, interventional validation is needed before clinical deployment
Future Directions: Prospective trials stratified by SoM to test immunomodulator benefit/harm and to integrate into EHR-based triage.
Abstract not available in provided dataset.
6. Sublethal systemic LPS in mice enables gut-luminal pathogens to bloom through oxygen species-mediated microbiota inhibition.
Systemic LPS rapidly drives large expansions of facultative gut pathogens via TLR4-dependent increases in luminal ROS that halt fermentation and favor oxidative respiration, without enteropathy.
Impact: Explains host-driven opportunistic blooms during systemic inflammation, nominating TLR4/redox modulation and luminal antioxidants as preventive strategies.
Clinical Implications: Motivates host-directed strategies (TLR4 modulation, antioxidants, fermentation support) to reduce nosocomial blooms and secondary infections.
Key Findings
- Systemic LPS induced 100–10,000-fold expansion of gut pathogens within 24 hours.
- Mechanism required TLR4-driven luminal ROS increases halting fermentation.
- Bloom occurred without overt mucosal injury, indicating ecological shift.
Methodological Strengths
- Mechanistic dissection of TLR4–ROS axis in controlled models
- Quantitative bloom dynamics with clear ecological readouts
Limitations
- Animal models; human validation and safety of interventions remain to be shown
- Interplay with antibiotic exposure and nutrition requires clinical testing
Future Directions: Evaluate luminal antioxidant strategies and TLR4/redox modulation in high-risk ICU populations with microbiome endpoints.
Abstract not available in provided dataset.
7. Colistin exerts potent activity against mcr+ Enterobacteriaceae via synergistic interactions with the host defense.
Under physiologic media and in fresh human blood ex vivo, colistin retained bactericidal activity against mcr-1+ strains via enhanced complement deposition and serum synergy, and was effective in a murine bacteremia model, challenging conventional AST conclusions.
Impact: Reveals that standard AST can miss clinically relevant host–drug synergies, reopening therapeutic options for select drug-resistant bacteremias.
Clinical Implications: Encourages physiologic-condition AST or context-aware interpretation (e.g., complement competence) and supports prospective evaluation of colistin in selected mcr-1+ bacteremias.
Key Findings
- Colistin killed mcr-1+ strains in bicarbonate-containing media despite conventional AST suggesting inactivity.
- Enhanced complement deposition and synergized with human serum; killed mcr-1+ strains in fresh human blood ex vivo.
- Demonstrated efficacy in a murine bacteremia model.
Methodological Strengths
- Use of physiologic media and fresh human blood to mimic in vivo conditions
- In vivo validation in murine bacteremia model
Limitations
- Lacks randomized clinical data in humans
- Host factor variability (e.g., complement deficits) may limit generalizability
Future Directions: Prospective trials incorporating physiologic-condition AST and host-factor assessment to guide colistin use.
Abstract not available in provided dataset.
8. Deriving consensus sepsis clusters via goal-directed subgroup identification in multi-omics study.
A goal-directed subgroup identification framework integrated longitudinal multi-omics from 1,327 patients to derive subgroups optimized for differential treatment response, predicting survival differences for fluid strategy and ulinastatin with external validation.
Impact: Transforms heterogeneity into actionable design by operationalizing predictive enrichment for interventional trials.
Clinical Implications: Enables therapy allocation by omics-derived benefit scores and may reduce negative trials via biologically aligned enrollment.
Key Findings
- Introduced goal-directed framework discovering subgroups with differential treatment effects.
- Predicted survival differences for fluid strategies and ulinastatin.
- Externally validated across international critical care datasets.
Methodological Strengths
- Longitudinal multi-omics integration with external validation
- Explicit optimization for differential treatment effects (predictive enrichment)
Limitations
- Requires prospective deployment to test clinical utility
- Complexity and data requirements may limit immediate scalability
Future Directions: Embed GD-SI into adaptive RCTs to allocate fluids/immunomodulators and test pre-specified benefit hypotheses.
Abstract not available in provided dataset.
9. Lactylation of HADHA Promotes Sepsis-Induced Myocardial Depression.
Extensive lysine lactylation was mapped in septic myocardium; HADHA K166/K728 lactylation inhibited HADHA activity, impaired mitochondrial function, reduced ATP, and decreased contractility. SIRT1/3 regulated these modifications, and site-directed mutagenesis established causality in LPS/CLP models.
Impact: Defines a tractable post-translational mechanism linking lactate signaling to septic cardiomyopathy, highlighting the HADHA lactylation/SIRT1-3 axis as a target.
Clinical Implications: Motivates therapies targeting lactylation (e.g., SIRT1/3 modulators) or restoring HADHA function to prevent/treat septic myocardial depression.
Key Findings
- 1,127 lysine lactylation sites mapped; 83 sites differentially lactylated in sepsis.
- HADHA K166/K728 lactylation inhibited activity, impaired mitochondria/ATP, reduced contractility.
- SIRT1/3 regulate HADHA lactylation; mutagenesis established causality.
Methodological Strengths
- Site-specific mutagenesis linking modification to function and phenotype
- Multi-layer evidence (proteomics, biochemistry, functional assays) across models
Limitations
- Preclinical models; human myocardial data and translational biomarkers are needed
- Potential off-target effects with global sirtuin modulation require caution
Future Directions: Develop selective modulators of lactylation/SIRT1-3, and measure cardiac lactylation in human sepsis for target engagement.
Abstract not available in provided dataset.
10. Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers.
Oligoimidazolium carbon-acid polymers transiently form N-heterocyclic carbenes enabling non-lytic membrane translocation and potent activity against colistin- and multidrug-resistant bacteria; amide derivatives improved outcomes in murine sepsis and infection models.
Impact: Offers a generalizable, non-lytic uptake mechanism that addresses a key translational barrier for antimicrobial polymers with in vivo efficacy against MDR pathogens.
Clinical Implications: Supports development of intracellular-targeting antimicrobials for MDR sepsis pathogens; next steps include PK/PD, toxicity, and dosing studies.
Key Findings
- Transient N-heterocyclic carbene formation enables non-lytic membrane translocation.
- Carbon-acid polymers active against colistin- and multidrug-resistant bacteria.
- Amide derivatives improved outcomes in murine sepsis models.
Methodological Strengths
- Mechanistic chemistry elucidation linked to biological efficacy
- Demonstrated in vivo efficacy against MDR pathogens
Limitations
- Comprehensive safety, PK/PD, and manufacturability not yet established
- Resistance evolution and off-target effects require evaluation
Future Directions: Advance medicinal chemistry optimization and large-animal studies to enable first-in-human evaluation.
Abstract not available in provided dataset.
11. Human proteome distribution atlas for tissue-specific plasma proteome dynamics.
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Abstract not available in provided dataset.