Daily Sepsis Research Analysis
Analyzed 48 papers and selected 3 impactful papers.
Summary
Three impactful sepsis studies span prevention, mechanistic neuroimmunology, and translational nanotherapy. A randomized trial in term PROM with negative GBS shows that adding gentamicin to ampicillin reduces chorioamnionitis and suspected early-onset sepsis. Two preclinical papers reveal targetable neuroimmune pathways: engineered nanoplatform reprogramming macrophage–neuron crosstalk improves survival in murine sepsis, and mitochondrial TRPV1 in microglia drives sepsis-associated encephalopathy.
Research Themes
- Obstetric infection prevention and early-onset neonatal sepsis risk reduction
- Neuroimmune mechanisms in sepsis-associated encephalopathy
- Immunometabolic reprogramming and nanomedicine for sepsis
Selected Articles
1. Ampicillin-gentamicin versus ampicillin alone for prolonged prelabor rupture of membranes at term in group B streptococcus-negative patients: a randomized controlled trial.
In a single-center randomized trial of 207 women with term PROM and negative GBS, adding gentamicin to ampicillin reduced clinical chorioamnionitis (1.9% vs 10.6; P=.019; NNT≈11.5) and overall postpartum infectious morbidity (1.9% vs 9.6%; P=.033). NICU admissions for suspected early-onset sepsis were lower (2.9% vs 8.7%; P=.031), and positive chorioamniotic cultures—especially Enterobacteriaceae—were reduced with combination therapy.
Impact: This RCT provides contemporary, actionable evidence that broader Gram-negative coverage reduces maternal infectious morbidity and suspected early-onset sepsis in term PROM with negative GBS.
Clinical Implications: Consider revising obstetric protocols to include ampicillin plus gentamicin for term PROM with negative GBS when prophylaxis is indicated, while balancing antimicrobial stewardship and aminoglycoside toxicity risks and local resistance patterns.
Key Findings
- Clinical chorioamnionitis was lower with ampicillin+gentamicin vs ampicillin alone (1.9% vs 10.6%; P=.019; NNT≈11.5).
- Postpartum infectious morbidity decreased with combination therapy (1.9% vs 9.6%; P=.033).
- NICU admission for suspected early-onset sepsis was reduced (2.9% vs 8.7%; P=.031).
- Positive chorioamniotic cultures were less frequent (20.9% vs 36.7%; P=.029), with fewer Enterobacteriaceae (12.1% vs 25.6%; P=.033).
- Endometritis rates were similar between groups.
Methodological Strengths
- Randomized controlled design with intention-to-treat analysis.
- Microbiologic confirmation via chorioamniotic cultures and predefined co-primary outcomes.
Limitations
- Single-center RCT with modest sample size may limit generalizability.
- Potential safety and stewardship concerns with broader-spectrum prophylaxis; blinding not reported.
Future Directions: Multicenter trials to validate efficacy, evaluate optimal dosing/duration, and assess neonatal outcomes with confirmed sepsis endpoints and antimicrobial resistance impact.
BACKGROUND: Prolonged prelabor rupture of membranes at term increases the risk of maternal and neonatal infections, yet the optimal prophylactic antibiotic regimen in patients with confirmed negative group B Streptococcus colonization remains unclear. OBJECTIVE: We compared maternal and neonatal outcomes between 2 prophylactic antibiotic regimens, ampicillin plus gentamicin vs ampicillin alone, in patients with term prelabor rupture of membranes and confirmed negative group B Streptococcus colonization. STUDY DESIGN: This single-center, randomized controlled trial was conducted at a
2. Nanotherapeutic Macrophage-Neuro Reprogramming Through Immunometabolic Crosstalk Mitigates Sepsis-Induced Lung Injury and Neurologic Damage.
A dual-functional enzyme-responsive nanoplatform (SJNPs) co-delivering JHU083 (glutamate metabolism inhibitor) and spermine reprogrammed macrophage polarization toward an anti-inflammatory phenotype, boosted NGF secretion, preserved pulmonary neuronal integrity, and reduced cytokine storms. In murine sepsis models, SJNPs mitigated alveolar damage and neurological injury and improved survival, identifying NGF-linked macrophage–neuron immunometabolic crosstalk as a therapeutic target.
Impact: Introduces a rationally engineered nanotherapy that integrates immunomodulation and neuroprotection, revealing NGF-mediated macrophage–neuron crosstalk as a tractable axis in sepsis.
Clinical Implications: While preclinical, this work supports developing immunometabolic nanomedicines that concurrently modulate innate immunity and neural integrity to treat septic lung injury and brain dysfunction.
Key Findings
- SJNPs co-delivering JHU083 and spermine shifted macrophages from pro-inflammatory M1 to M2 polarization.
- Macrophage reprogramming increased NGF secretion and preserved pulmonary neuronal integrity.
- Systemic cytokine surge and alveolar damage were attenuated; neurological injury was reduced.
- Survival improved in murine sepsis models treated with SJNPs.
- Mechanistic link established: inhibiting glutamate metabolism activated NGF-mediated neurotrophic signaling.
Methodological Strengths
- Rational nanoplatform design with dual payload and enzyme responsiveness.
- Multi-level validation: immune phenotyping, neurotrophic signaling, organ histology, and survival in vivo.
Limitations
- Preclinical murine models may not fully recapitulate human sepsis heterogeneity.
- Dose, safety, and biodistribution profiles require formal toxicology and pharmacokinetic studies.
Future Directions: Define pharmacokinetics/toxicology, optimize dosing, and evaluate efficacy across diverse sepsis etiologies and large-animal models toward first-in-human translation.
Sepsis remains a leading cause of mortality in intensive care units, with its associated organ dysfunction primarily driven by uncontrolled inflammation and neuroimmune dysregulation. Among affected organs, the lung is particularly vulnerable, with injury involving both immune-mediated tissue damage and inflammation-induced neuronal impairment. Yet, whether coordinated targeting of immune and neural compartments can achieve synergistic and durable therapeutic benefits remains unknown. Here, we report a ration
3. Mitochondrial TRPV1 exacerbates cognitive deficits in sepsis-associated encephalopathy by driving microglial metabolic reprogramming.
TRPV1 localizes to microglial mitochondria and drives neurotoxic microglial polarization in sepsis-associated encephalopathy by disrupting mitochondrial dynamics and energy metabolism. Genetic deletion or pharmacologic antagonism of TRPV1 reduces microglial inflammation, normalizes synaptic pruning, and improves cognition in vivo, identifying mitochondrial TRPV1 as a therapeutic target in SAE.
Impact: Reveals a previously unrecognized mitochondrial localization and function of TRPV1 in microglia that mechanistically links metabolic failure to neuroinflammation and cognitive deficits in sepsis.
Clinical Implications: Supports exploring BBB-penetrant TRPV1 antagonists or modulators targeting microglial mitochondria as candidate therapies for sepsis-associated encephalopathy, pending safety and translational studies.
Key Findings
- TRPV1 is localized to microglial mitochondrial membranes in the hippocampus, not primarily to neuronal or astrocytic membranes.
- TRPV1 expression increases with pro-inflammatory microglial activation during SAE; its deletion or antagonism attenuates inflammation and phagocytic dysfunction.
- Blocking TRPV1 reduces mtROS/mtDNA release, restores oxidative phosphorylation, normalizes synaptic pruning, and improves cognition in vivo.
- TRPV1 activation exacerbates mitochondrial damage and ATP depletion, driving neurotoxic microglial reprogramming.
Methodological Strengths
- Convergent genetic (knockout/silencing) and pharmacologic antagonism across in vivo and in vitro systems.
- Multi-modal readouts linking metabolism (mtROS, OXPHOS) to neuroinflammation, synaptic pathology, and behavior.
Limitations
- Preclinical model; human microglial TRPV1 localization and function need verification.
- Long-term safety and specificity of TRPV1 antagonism in the CNS remain to be established.
Future Directions: Validate TRPV1 mitochondrial localization in human microglia, test BBB-penetrant TRPV1 modulators, and map downstream metabolic nodes enabling combinational therapy in SAE.
Transient receptor potential vanilloid 1 (TRPV1), a canonical non-selective cation channel predominantly expressed on the cellular membrane of peripheral sensory neurons, is responsible for perceiving physical and chemical stimuli. Accumulating evidence indicates TRPV1 expression in the central nervous system, the role of which remains elusive. Here, we demonstrate that, distinct from neurons or astrocytes, TRPV1 is distributed on the mitochondrial membrane of microglia in the hippocampus, mediating neurotoxic microglial responses during both acute and convalescent stages of sepsis by disrupting mitochondrial dynamics. During the pathogenesis of sepsis-associated encephalopathy (SAE), hippocampal microglia exhibit elevated TRPV1 expression concurrent with a pro-inflammatory state. Genetic ablation of TRPV1 or application of TRPV1 antagonist attenuates microglial inflammatory polarization and phagocytic dysfunction both in vivo and in vitro. This mitigates immoderate neuroinflammation and aberrant synaptic pruning, thereby reshaping synaptic plasticity and ameliorating cognitive deficits in SAE. Mechanistically, TRPV1 reprograms microglial phenotype with dysregulated capability for glycometabolism by affecting their mitochondrial function. Following LPS challenge, TRPV1 activation exacerbates mitochondrial damage and impairs ATP production in microglia, resulting in bioenergetic failure and excessive generation of mitochondrial reactive oxygen species (mtROS) and mtDNA. Conversely, TRPV1 depletion enhances oxidative phosphorylation capacity of microglia to counteract LPS toxicity. TRPV1 silencing further promotes the formation of cristae-deficient mitochondria, sustaining reductive proline biosynthesis and shifting microglia toward a protective pattern. Collectively, our findings suggest that TRPV1 compromises the metabolic reprogramming of microglia by perturbing mitochondrial dynamics, revealing a novel therapeutic target for SAE intervention.