Daily Ards Research Analysis
Multi-omics profiling in ARDS and sepsis delineates phenotype-specific and shared mortality pathways centered on mitochondrial dysfunction, suggesting precision therapeutic targets. Preclinical inhibition of miR-93-5p mitigates ER stress and fibrosis via Mfn2 upregulation in ARDS rats. Mendelian randomization finds no Bonferroni-significant causal effects of gut microbiota on ARDS risk, tempering expectations for microbiome-targeted prevention.
Summary
Multi-omics profiling in ARDS and sepsis delineates phenotype-specific and shared mortality pathways centered on mitochondrial dysfunction, suggesting precision therapeutic targets. Preclinical inhibition of miR-93-5p mitigates ER stress and fibrosis via Mfn2 upregulation in ARDS rats. Mendelian randomization finds no Bonferroni-significant causal effects of gut microbiota on ARDS risk, tempering expectations for microbiome-targeted prevention.
Research Themes
- Precision critical care and ARDS inflammatory phenotypes
- Mitochondrial and ER stress pathways in lung injury and fibrosis
- Genetic causal inference of gut-lung axis in ARDS
Selected Articles
1. Longitudinal multi-omic signatures of ARDS and sepsis inflammatory phenotypes identify pathways associated with mortality.
In 160 ARDS patients from the ROSE trial, integrated longitudinal plasma metabolomics and whole-blood transcriptomics identified four mortality-associated molecular signatures spanning innate immunity-glycolysis, hepatic/immune dysfunction with impaired beta-oxidation, interferon suppression with altered mitochondrial respiration, and redox/cell proliferation pathways. Signatures persisted to Day 2 and were validated in the EARLI sepsis cohort, highlighting mitochondrial dysfunction as a unifying feature.
Impact: This study links ARDS inflammatory phenotypes to discrete, validated multi-omic mortality pathways, advancing precision stratification and therapeutic target discovery in critical illness.
Clinical Implications: Findings support phenotype-guided trials testing metabolic/mitochondrial modulators and biomarker panels for risk stratification. Mitochondrial dysfunction emerges as a cross-phenotype target.
Key Findings
- Four mortality-associated multi-omic signatures were identified, three linked to the Hyperinflammatory phenotype and one phenotype-independent.
- All signatures persisted to Day 2 after enrollment and were validated in an independent sepsis cohort (EARLI).
- A unifying theme of mitochondrial dysfunction characterized all mortality-associated signatures.
- Within-phenotype analyses revealed distinct mortality pathways in Hyperinflammatory vs Hypoinflammatory groups.
Methodological Strengths
- Prospective sampling within a randomized trial cohort with high-probability phenotype assignments
- Integrated longitudinal metabolomics and transcriptomics with external validation (EARLI) using MEFISTO
Limitations
- Moderate sample size (N=160) and blood-based omics may not fully capture lung-specific biology
- Observational associations limit causal inference; no interventional testing of targets
Future Directions: Prospective interventional trials targeting mitochondrial bioenergetics and metabolic pathways stratified by inflammatory phenotype; validation in larger, diverse cohorts with lung-specific sampling.
BACKGROUND: Critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a pilot study. METHODS: We performed integrative multi-omics analysis of blood samples from 160 ARDS patients in the ROSE trial, randomly selecting 80 patients from each latent class analysis-defined inflammatory phenotype (Hyperinflammatory and Hypoinflammatory) with phenotype probability >0.9. Untargeted plasma metabolomics and whole blood transcriptomics at Day 0 and Day 2 were analyzed using multi-modal factor analysis (MEFISTO). The primary outcome was 90-day mortality, with validation in an independent critically ill sepsis cohort (EARLI). RESULTS: Multi-omics integration revealed four molecular signatures associated with mortality: (1) enhanced innate immune activation coupled with increased glycolysis (associated with Hyperinflammatory phenotype), (2) hepatic dysfunction and immune dysfunction paired with impaired fatty acid beta-oxidation (associated with Hyperinflammatory phenotype), (3) interferon program suppression coupled with altered mitochondrial respiration (associated with Hyperinflammatory phenotype), and (4) redox impairment and cell proliferation pathways (not associated with inflammatory phenotype). These signatures persisted through Day 2 of trial enrollment. Within-phenotype analysis revealed distinct mortality-associated pathways in each group. All molecular signatures were validated in the independent EARLI cohort. CONCLUSIONS: Inflammatory phenotypes of ARDS reflect distinct underlying biological processes with both phenotype-specific and phenotype-independent pathways influencing patient outcomes, all characterized by mitochondrial dysfunction. These findings suggest potential therapeutic targets for precise treatment strategies in critical illness. FUNDING: This work is the result of NIH funding.
2. Targeting of miR-93-5p/Mfn2 Axis Attenuates Lung Fibrosis in Rats With Acute Respiratory Distress Syndrome by Regulating Endoplasmic Reticulum Stress.
In an LPS-induced ARDS rat model, miR-93-5p was upregulated and inversely correlated with Mfn2. Systemic inhibition of miR-93-5p increased Mfn2, reduced ER stress and inflammation, and diminished collagen deposition, thereby attenuating ARDS-associated pulmonary fibrosis.
Impact: Identifies a modifiable miRNA-Mfn2-ER stress axis driving fibrotic remodeling after ARDS, offering a mechanistically grounded anti-fibrotic strategy.
Clinical Implications: While preclinical, targeting miR-93-5p/Mfn2 and ER stress may inspire translational anti-fibrotic therapies to improve long-term outcomes in ARDS survivors.
Key Findings
- miR-93-5p is significantly upregulated in lungs of LPS-induced ARDS rats and negatively correlates with Mfn2 expression.
- Antagomir-mediated inhibition of miR-93-5p increases Mfn2, attenuates ER stress and inflammation, and reduces collagen deposition.
- Targeting miR-93-5p/Mfn2 ameliorates ARDS-associated pulmonary fibrosis in vivo.
Methodological Strengths
- In vivo ARDS model with interventional manipulation (antagomir) and multi-level readouts (histology, molecular assays)
- Bioinformatic identification of upstream miRNAs regulating Mfn2 followed by functional validation
Limitations
- Single animal model limits generalizability; human validation is lacking
- Potential off-target effects of antagomir and absence of long-term functional outcomes
Future Directions: Validate the miR-93-5p/Mfn2 axis in human ARDS tissues and test targeted modulators in large-animal models with pulmonary function endpoints.
High mortality rates among patients with acute respiratory distress syndrome (ARDS) have been linked to pulmonary fibrosis. MicroRNAs exhibit significant potential in modulating pulmonary fibrosis. However, the specific role and underlying mechanisms of miR-93-5p in the context of ARDS-associated pulmonary fibrosis remain largely unexplored. Mitofusin 2 (Mfn2) is a highly conserved transmembrane GTPase. Our previous study demonstrated that the upregulation of Mfn2 can inhibit pulmonary fibrosis in ARDS mice. In this investigation, we identified upstream miRNAs regulating Mfn2 using bioinformatics tools such as TargetScan, miRDB, and microT-CDS. Based on the expression levels of these miRNAs in lung tissue from rats with LPS-induced ARDS, miR-93-5p was selected as the focus of our research. We modulated miR-93-5p expression in ARDS rats via tail vein injection of a miR-93-5p antagomir. Thereafter, we conducted pathological staining and molecular assays to examine the impact of miR-93-5p on pulmonary fibrosis in ARDS rats and to elucidate its potential mechanisms. The results demonstrated that the expression of miR-93-5p was significantly upregulated in the lung tissue of ARDS rats. LPS-induced ARDS rats exhibited severe pulmonary fibrosis, inflammation, and strong endoplasmic reticulum (ER) stress. Furthermore, Mfn2 expression exhibited a negative correlation with miR-93-5p expression. Inhibition of miR-93-5p markedly upregulated Mfn2 expression, attenuated ER stress and lung inflammation, and decreased collagen deposition. In conclusion, the inhibition of miR-93-5p upregulated Mfn2 expression and attenuated ER stress, consequently ameliorating pulmonary fibrosis in ARDS rats. Key words Acute respiratory distress syndrome " miR-93-5p " Pulmonary fibrosis " Endoplasmic reticulum stress " Mitofusin 2.
3. Exploring the causal relationship between acute respiratory distress syndrome and gut microbiota: Unveiling the gut-lung axis through a large-scale Mendelian randomization study.
Two-sample Mendelian randomization using multiple GM GWAS (German, Dutch, MibioGen) and ARDS GWAS (FinnGen) found no Bonferroni-significant causal effects of gut microbiota taxa on ARDS risk. Suggestive taxa (e.g., Streptococcus with OR 0.61) were robust in sensitivity analyses, but overall results argue against strong causal links given current power.
Impact: Provides a genetically informed assessment tempering claims of microbiome causality in ARDS, refining targets for future interventional and mechanistic studies.
Clinical Implications: Microbiome-targeted prevention of ARDS is not yet supported by genetic causal evidence; clinical strategies should prioritize proven risk modifiers while larger, phenotype-resolved genetic studies are pursued.
Key Findings
- No Bonferroni-significant causal effects of gut microbiota taxa on ARDS were detected across multiple MR methods.
- Suggestive protective associations (e.g., Streptococcus OR 0.610, 95% CI 0.430–0.870, P=.006) emerged and were robust in sensitivity analyses.
- Results emphasize limited power (ARDS cases N=431) and the need for cautious interpretation and further mechanistic work.
Methodological Strengths
- Use of multiple large GM GWAS and standardized two-sample MR with diverse estimators (IVW, MR-Egger, weighted median/mode)
- Multiple-testing correction and thorough sensitivity, heterogeneity, and pleiotropy assessments
Limitations
- Limited ARDS case numbers reduce power; taxa-level instruments may be weak
- Population structure and taxonomy harmonization issues may bias estimates
Future Directions: Expand ARDS GWAS case counts, integrate host genetics with longitudinal microbiome and metabolome, and test mechanistic links in experimental models to prioritize taxa for intervention.
Observational studies have linked gut microbiota (GM) to acute respiratory distress syndrome (ARDS), but the cause-and-effect relationship is yet to be determined. We acquired the latest genome-wide association study (GWAS) summary statistics on GM taxa from the German (N = 8956), Dutch (N = 7738), and MibioGen (N = 18,340) consortium GWAS catalogs, as well as ARDS (Ncase = 431, Ncontrol = 4,93,301) GWAS summary statistics from the FinnGen consortium. We employed Mendelian randomization (MR) analysis using inverse-variance weighted, MR-Egger, weighted mode, and weighted median methods to investigate the causal link between GM and ARDS. We used a Bonferroni correction to account for statistical bias resulting from repeated comparisons in order to control for false positive outcomes during multiple hypothesis testing. Meta-analyses were conducted to enhance the statistical power of the MR analysis. GM had no statistically significant impact on ARDS with Bonferroni correction. Actinobacteria, Proteobacteria, Bifidobacteriales, Bifidobacteriaceae, Rikenellaceae, Dorea, Streptococcus, Bilophila wadsworthia, Escherichia unclassified, OTU99_17 (Parabacteroides), TestASV_7 (Bacteroides), TestASV_26 (Phascolarctobacterium), and TestASV_43 (Parasutterella) are notable GM taxa with low uncorrected MR inverse-variance weighted P-values, potentially indicating a reduced risk of ARDS. Bifidobacterium longum, OTU99_30 (Parasutterella), and TestASV_16 (Bacteroides) are potentially linked to an increased risk of ARDS. Meta-analyses based on 3 GWAS summary statistics suggested that Streptococcus was potentially indicating a reduced risk of ARDS (odds ratio 0.610; 95% confidence interval 0.430-0.870; P = .006). These associations were proven to be robust through analyses of sensitivity, heterogeneity, and horizontal pleiotropy. From a genetic perspective, our findings suggest a potential relationship between the GM and ARDS rather than definitive causality. Given possible confounding and methodological constraints, the results should be interpreted with caution. Additional studies are needed to elucidate underlying mechanisms and clarify microbial interactions within the GM.