Daily Sepsis Research Analysis
Multi-omic analyses advanced sepsis endotyping and mechanistic understanding: a JCI study linked inflammatory phenotypes in ARDS/sepsis to four mortality-associated molecular signatures centered on mitochondrial dysfunction, validated in an independent sepsis cohort. Complementary work identified mitophagy-related biomarkers and molecular subtypes with functional validation of NUP93, while a real-world study showed blood mNGS substantially increases pathogen detection and guides therapy in hemat
Summary
Multi-omic analyses advanced sepsis endotyping and mechanistic understanding: a JCI study linked inflammatory phenotypes in ARDS/sepsis to four mortality-associated molecular signatures centered on mitochondrial dysfunction, validated in an independent sepsis cohort. Complementary work identified mitophagy-related biomarkers and molecular subtypes with functional validation of NUP93, while a real-world study showed blood mNGS substantially increases pathogen detection and guides therapy in hematologic malignancy patients with sepsis after antibiotics.
Research Themes
- Mitochondria-centric biology and endotypes in sepsis/ARDS
- Mitophagy-related biomarkers and molecular subtyping
- Metagenomic next-generation sequencing to guide therapy in immunocompromised sepsis
Selected Articles
1. Longitudinal multi-omic signatures of ARDS and sepsis inflammatory phenotypes identify pathways associated with mortality.
Integrating plasma metabolomics and whole-blood transcriptomics from 160 ARDS patients stratified by inflammatory phenotype, the authors defined four mortality-associated molecular signatures that largely converged on mitochondrial dysfunction. These longitudinal signatures persisted to Day 2 and were validated in an independent critically ill sepsis cohort, revealing phenotype-specific and phenotype-independent pathways that may inform precision therapies.
Impact: This paradigm-advancing, validated multi-omic work links clinical inflammatory phenotypes to mechanistic, mortality-associated pathways centered on mitochondrial dysfunction, directly informing endotype-driven interventions in sepsis/ARDS.
Clinical Implications: Supports endotype-based risk stratification and prioritizes mitochondrial bioenergetics, fatty acid oxidation, interferon signaling, and redox pathways as therapeutic targets; enables longitudinal biomarker panels for early prognosis.
Key Findings
- Four mortality-associated molecular signatures were identified, including innate immune activation with glycolysis, hepatic/immune dysfunction with impaired fatty acid β-oxidation, interferon suppression with altered mitochondrial respiration, and redox/proliferation pathways.
- Signatures persisted from Day 0 to Day 2 and were validated in an independent critically ill sepsis cohort (EARLI).
- Within-phenotype analyses revealed distinct mortality-associated pathways, indicating both phenotype-specific and phenotype-independent biology centered on mitochondrial dysfunction.
Methodological Strengths
- Prospective trial-derived cohort with random selection by high phenotype probability and longitudinal sampling (Day 0, Day 2).
- Integrated untargeted metabolomics and transcriptomics with external validation (EARLI) using advanced multi-modal factor analysis (MEFISTO).
Limitations
- Secondary analysis of trial biospecimens with modest sample size (n=160) may limit generalizability.
- Causal inference is limited; therapeutic targets require interventional validation.
Future Directions: Prospective, multi-center validation of signature-based risk models and interventional trials targeting mitochondrial bioenergetics, fatty acid oxidation, and interferon/redox pathways in endotype-enriched populations.
2. Integrated multi-omics of mitophagy-related molecular subtype characterization and biomarker identification in sepsis.
Integrative analyses identified four mitophagy-associated gene biomarkers (RPL18, PRPF8, NUP93, CUL1) with excellent diagnostic performance and defined sepsis molecular subtypes with distinct immune landscapes. Functional experiments showed NUP93 overexpression rescues LPS-induced mitophagy impairment by restoring PINK1 and LC3B, linking biomarkers to mechanism.
Impact: Bridges computational endotyping with bench validation to position mitophagy as a diagnostic and therapeutic axis in sepsis, offering actionable biomarker candidates and a stratification framework.
Clinical Implications: Proposes a high-AUC diagnostic panel and mitophagy-informed subtypes that could guide precision diagnostics and selection of candidates for mitophagy-targeted therapies.
Key Findings
- Machine learning identified four MAG biomarkers (RPL18, PRPF8, NUP93, CUL1) with individual AUCs 0.957–0.975 and a nomogram AUC of 0.990.
- Consensus clustering based on MAG stratified sepsis into molecular subtypes with distinct immune landscapes and pathways.
- NUP93 overexpression restored PINK1 and LC3B levels in LPS-stimulated macrophages, rescuing mitophagy impairment in vitro.
Methodological Strengths
- Integration of bulk and single-cell transcriptomics with WGCNA, ssGSEA, ESTIMATE, and consensus clustering.
- Functional validation linking biomarker (NUP93) to mitophagy rescue in LPS-stimulated macrophages.
Limitations
- Predominantly in silico, retrospective dataset integration without prospective clinical validation.
- Functional assays limited to in vitro macrophage models; no in vivo validation or clinical assay readiness.
Future Directions: Prospective, multi-center validation of biomarker panels and subtypes, development of rapid assays, and preclinical/in vivo testing of mitophagy-targeted interventions.
3. Application of metagenomic next-generation sequencing technology in hematologic malignancy patients with sepsis following antibiotic use.
In 119 hematologic malignancy patients with sepsis unresponsive to ≥3 days of antibiotics, blood mNGS detected pathogens far more frequently than culture (89.36% vs 25.53%) and prompted antimicrobial regimen changes in 39.49% of cases; antitumor therapy–related granulocytopenia was a risk factor for polymicrobial infection.
Impact: Demonstrates real-world utility of blood mNGS to guide therapy in immunocompromised sepsis where cultures underperform post-antibiotics, highlighting both clinical impact and interpretive challenges.
Clinical Implications: Supports incorporating blood mNGS to augment pathogen detection and tailor antimicrobials in complex, culture-negative or polymicrobial sepsis, with stewardship frameworks to manage specificity and contamination concerns.
Key Findings
- mNGS positivity for bacteria/fungi was 89.36% versus 25.53% for blood culture.
- Therapeutic modifications based on mNGS occurred in 39.49% of patients.
- Agreement with culture was low (kappa −0.202), with reported sensitivity 58.33% and specificity 0% relative to reference used.
- Granulocytopenia from antitumor therapy was a high-risk factor for polymicrobial infections.
Methodological Strengths
- Head-to-head comparison of simultaneous blood mNGS and culture in a high-risk, clinically relevant population.
- Actionability assessed via documented antimicrobial regimen changes.
Limitations
- Single-center design with no definitive gold standard and very low agreement with culture complicates performance interpretation.
- Potential contamination/background signals and lack of outcome-adjusted utility (e.g., mortality/LOS) limit conclusions.
Future Directions: Establish composite clinical/microbiologic adjudication standards, define quantitative thresholds for actionability, integrate host-response markers, and test mNGS-guided care pathways in randomized trials.