Daily Sepsis Research Analysis
Analyzed 11 papers and selected 3 impactful papers.
Summary
Analyzed 11 papers and selected 3 impactful articles.
Selected Articles
1. Gut microbiota immaturity with DL-endopeptidase deficiency links antibiotic use to preterm late-onset sepsis.
Across three countries, delayed microbiome maturation marked by DL-endopeptidase deficiency explained a substantial fraction of LOS risk attributable to early antibiotics. DL-endopeptidase–producing commensals activated NOD2 via MDP, induced CYLD, tuned macrophage responses, and protected neonatal mice; a pilot RCT showed L. reuteri enhanced fecal NOD2 activation in preterm infants.
Impact: Defines a mechanistic biomarker (DL-endopeptidase deficiency) linking antibiotics to LOS and provides translational evidence for NOD2-activating probiotics.
Clinical Implications: Supports antibiotic stewardship in preterm infants, motivates development of DL-endopeptidase-based diagnostics, and justifies larger efficacy trials of NOD2-activating probiotics to prevent LOS.
Key Findings
- Analyzed 4,938 longitudinal fecal samples across China, US, and UK to chart preterm microbiome maturation.
- Delayed microbiota maturation accounted for over one-third of LOS risk linked to early antibiotics.
- DL-endopeptidase deficiency was a hallmark of delayed maturation and associated with higher LOS risk.
- DL-endopeptidase–producing E. faecium or L. reuteri activated NOD2 via MDP, induced CYLD, modulated macrophages, and protected neonatal mice from LOS.
- A pilot RCT showed L. reuteri increased fecal NOD2 activation in preterm infants.
Methodological Strengths
- Large, multi-country longitudinal sampling with cross-cohort validation
- Convergent evidence from microbiome analytics, mechanistic mouse models, and a pilot randomized trial
Limitations
- Pilot RCT assessed biomarker activation rather than clinical endpoints
- Residual confounding in observational components cannot be fully excluded
Future Directions: Validate DL-endopeptidase deficiency as a clinical biomarker, test efficacy and safety of NOD2-activating probiotics in larger multicenter RCTs, and define dosing/timing relative to antibiotic exposure.
Early antibiotic exposure increases late-onset sepsis (LOS) risk in preterm infants, potentially via gut dysbiosis. Analyzing 4,938 longitudinal fecal samples from preterm infants in China, the US, and the UK, we identified a differential pace of gut microbiota development among preterm infants. Delayed maturation correlated with over one-third of LOS risk associated with early antibiotic exposure. Deficiency of a bacterial DL-endopeptidase represented a hallmark of delayed microbiota development and correlated with elevated LOS risk. Supplementation with DL-endopeptidase-producing Enterococcus faecium or Limosilactobacillus reuteri activated the NOD2 receptor via muramyl dipeptide (MDP), regulated macrophage differentiation and polarization, restrained hyperinflammation via cylindromatosis (CYLD) induction, and protected neonatal mice from LOS. A pilot randomized controlled trial showed that L. reuteri supplementation enhanced fecal NOD2 activation in preterm infants. These findings link microbiota immaturity and reduced DL-endopeptidase activity to antibiotic exposure and LOS risk and highlight a candidate biomarker that warrants further validation for clinical translation.
2. LncRNA Gm16023 ameliorates hyperglycemia-exacerbated septic intestinal injury by modulating macrophage polarization via miR-377-3p/Sirt1 axis.
Using UK Biobank data and translational models, hyperglycemia was linked to higher sepsis risk and aggravated intestinal injury via macrophage M1 polarization. The underexpressed lncRNA Gm16023 acts through miR-377-3p/Sirt1 to suppress M1 polarization, and LNP delivery of Gm16023 protected against injury in vitro and in vivo.
Impact: Links metabolic status to sepsis pathophysiology and proposes an RNA-based therapeutic approach with in vivo delivery proof-of-concept.
Clinical Implications: Supports strict glycemic management in high-risk patients and motivates development of macrophage-targeted RNA therapeutics for diabetic sepsis.
Key Findings
- In UK Biobank (n=404,184), hyperglycemia was significantly associated with increased sepsis risk.
- Hyperglycemia increased macrophage infiltration and intestinal inflammation in septic patients and mice.
- Macrophage depletion (CD11b-DTR and clodronate liposomes) attenuated hyperglycemia-driven septic intestinal injury.
- Underexpressed lncRNA Gm16023 acted as a ceRNA for miR-377-3p to regulate Sirt1 and inhibit M1 polarization.
- LNP-encapsulated Gm16023 plasmid achieved in vivo delivery and protected against intestinal injury in vitro and in vivo.
Methodological Strengths
- Large-scale population analysis integrated with mechanistic validation in human and mouse systems
- Therapeutic proof-of-concept using LNP-mediated lncRNA delivery
Limitations
- Translational hurdles include species differences in lncRNA conservation and immunogenicity/safety of LNP delivery
- Causal inference from epidemiology remains observational despite mechanistic support
Future Directions: Clarify human ortholog relevance and cell-specific delivery, conduct preclinical safety/toxicity studies, and design early-phase clinical trials for RNA therapeutics in septic patients with diabetes/hyperglycemia.
Diabetes is closely associated with inflammation and sepsis, but its clinical significance and underlying mechanisms remain obscure. Leveraging epidemiological data from 404,184 individuals in the UK Biobank cohort, we found that hyperglycemia was significantly associated with increased sepsis risk. Phenotypically, hyperglycemia enhanced macrophage infiltration and exacerbated intestinal inflammation in both septic patients and murine models. Using both a genetic CD11b-DTR model and clodronate liposome (Cls)-mediated chemical ablation, we demonstrated that macrophage depletion markedly attenuated hyperglycemia-driven septic intestinal injury, underscoring their essential pathogenic role. Mechanistically, RNA sequencing analysis identified that underexpressed lncRNA Gm16023 acted as a ceRNA, binding miR-377-3p to regulate Sirt1 expression and inhibit M1 macrophage polarization. To facilitate therapeutic delivery, we engineered a lipid nanoparticle (LNP)-encapsulated Gm16023 plasmid system that efficiently delivered lncRNA in vivo and conferred protection against intestinal injury in both in vitro and in vivo models. Collectively, our findings indicate that hyperglycemia promotes macrophage-mediated septic intestinal injury via the lncRNA Gm16023/miR-377-3p/Sirt1 axis, highlighting a potential RNA-based therapeutic strategy for diabetic sepsis.
3. RETN exacerbates sepsis by GBP5/NLRP3 signaling pathway-mediated pyroptosis of macrophage.
Resistin is upregulated in septic patient macrophages and correlates with inflammation and severity. Functional experiments identify a RETN→GBP5→NLRP3 axis that drives macrophage pyroptosis; RETN knockdown reduces organ damage and improves survival in sepsis models, nominating new therapeutic targets.
Impact: Elucidates a novel macrophage inflammasome pathway that directly links a circulating factor (resistin) to lethal pyroptosis in sepsis.
Clinical Implications: Points to RETN, GBP5, and NLRP3 as druggable targets; encourages development of inhibitors or neutralizing strategies to blunt macrophage pyroptosis in sepsis.
Key Findings
- Single-cell data show RETN is primarily expressed in monocytes/macrophages and upregulated in septic patients.
- RETN levels correlate positively with pro-inflammatory cytokines and disease severity.
- RETN knockdown attenuates macrophage pyroptosis in vitro.
- RETN overexpression upregulates GBP5 and NLRP3; in vivo RETN knockdown reduces GBP5, inhibits NLRP3 activation, decreases organ damage, and improves survival.
- GBP5 knockdown reverses the pro-pyroptotic and lethal effects of RETN overexpression.
Methodological Strengths
- Multi-tier validation: single-cell transcriptomics, in vitro loss/gain-of-function, and in vivo survival/organ injury outcomes
- Clear pathway dissection linking RETN to GBP5/NLRP3 and pyroptosis
Limitations
- Human interventional evidence is lacking; translational feasibility and safety of targeting this axis remain untested
- Patient sample sizes and cohort details are not fully specified in the abstract
Future Directions: Quantify RETN/GBP5/NLRP3 activity in well-phenotyped sepsis cohorts, evaluate pharmacologic inhibitors or neutralizing antibodies in preclinical models, and explore biomarkers to stratify patients for inflammasome-targeted therapies.
Current therapeutic options remain insufficient for sepsis, driving the search for alternative treatment approaches. Accumulating evidence suggests that resistin (RETN) serves as a crucial factor in sepsis initiation and development. Nevertheless, the specific pathways through which RETN influences sepsis pathophysiology have yet to be elucidated. Single-cell sequencing analysis reveals RETN is primarily expressed in monocytes/macrophages. RETN in macrophages is markedly upregulated in septic patients, exhibiting a marked positive correlation with pro-inflammatory cytokines and disease severity. Bioinformatics analysis and in vitro experiments reveal that knockdown of RETN alleviated macrophage pyroptosis. RNA-Seq analysis and in vitro experiments revealed that the overexpression of RETN markedly upregulates the expression of GBP5 and NLRP3. Further in vivo experiments revealed that RETN knockdown markedly downregulates GBP5 expression, inhibits NLRP3 activation, and mitigates macrophage pyroptosis. This consequently reduces organ (lung, spleen, and heart) damage and improves survival in sepsis. Finally, knocking down GBP5 can reverse the promoting effect of overexpressed RETN on macrophage pyroptosis, organ damage and sepsis lethality. This investigation initially demonstrates that the RETN/GBP5/NLRP3 signaling axis regulates macrophage pyroptosis to aggravate sepsis, providing new potential targets and theoretical support for the research on the pathogenic mechanism of sepsis and clinical treatment.