Antibiotic treatment reveals the contributions of the gut microbiome to CLN2 disease in the central and enteric nervous system

Scientific Reports · 2026-04-25

Abstract The Neuronal Ceroid Lipofuscinoses (NCLs) are fatal inherited lysosomal storage diseases, with pronounced neuron loss in the central nervous system (CNS). Gastrointestinal issues are frequently reported by people with NCLs, although mechanisms underlying these symptoms are poorly understood. We recently demonstrated degeneration occurs within the enteric nervous system (ENS) in several NCLs. Given that the gut microbiome has been shown to be altered a CLN2 mouse model ( Tpp1 R207X/R207X ) and may potentially influence both CNS and ENS pathology, we investigated the long-term impact of modulating the gut microbiome in these mice. This was done by administering a VNAM antibiotic cocktail (vancomycin, neomycin, ampicillin, and metronidazole) for 1-week post-weaning, examining its effects at disease endstage. While VNAM treatment markedly altered the gut microbiome and caused significant loss of enteric neurons in wildtype mice, it did not exacerbate key pathological parameters in either bowel or brain of Tpp1 R207X/R207X mice. These included histomorphometric changes in the small intestine and neurodegeneration of enteric neurons, or CNS neuropathology. However, we did find evidence for moderate protective effects of VNAM upon enteric neurons in the ileum, and upon CNS microglia, but all other pathologies were unaltered in Tpp1 R207X/R207X mice. These findings suggest that intestinal and ENS pathology is primarily driven by TPP1-deficiency rather than changes in the gut microbiome. Indeed, these alterations to the gut microbiome may occur secondary to the impact of CLN2 disease upon the bowel.

Practice patterns for acquiring neuroimaging after pediatric in-hospital cardiac arrest

Resuscitation · 2025-01-21 · 4 citations

Abstract Or116: Association of Ventilation Rate with Outcomes of Pediatric Cardiac Arrest

Circulation · 2025-11-03 · 1 citations

Background: The optimal ventilation rate during pediatric in-hospital cardiac arrest is not known. Research Question/Hypothesis: Is guideline-compliant ventilation during cardiopulmonary resuscitation (CPR) associated with improved survival? We hypothesized that CPR events with guideline-compliant average ventilation rates would have increased rates of survival to hospital discharge. Aims: The overall objective of this study was to assess the association between pediatric CPR ventilation rates and survival outcomes. Methods/Approach: Multicenter prospective observational cohort ancillary study of the ICU-RESUS trial (NCT02837497). Hospitalized children (≤18 years) with cardiac arrest and an endotracheal tube at the onset of CPR and evaluable intra-arrest end tidal carbon dioxide (ETCO2) data to calculate ventilation rate were included. The association between the existing AHA CPR ventilation rate target (20-30 breaths per minute [bpm]) and survival to hospital discharge was evaluated with Poisson regression using generalized estimating equations, controlling for a priori covariates (initial rhythm, immediate cause of arrest). In an exploratory analysis, natural cubic splines, controlling for the same a priori covariates, stratified by age (<8 and ≥8 years), were used to identify novel target intra-arrest ventilation rates for subsequent evaluation in multivariable models. Results: Among 234 included events, 36.8% (n=86) had guideline-compliant average ventilation rates (20-30 bpm). After adjusting for confounders, there was no association between guideline-complaint ventilation rates and survival to hospital discharge (aRR 0.95, 95% CI: 0.75, 1.21, p=0.68). Our exploratory analysis identified novel age-based potential thresholds (<8 years: ≥26 bpm; ≥8 years: <26 bpm) (Figure 1). In children <8 years, an event-level average CPR ventilation rate of ≥26 bpm, compared to <26 bpm, was associated with increased survival to hospital discharge (aRR 1.32, 95% CI: 1.00, 1.73, p=0.048). Conclusions: In our multicenter study of intra-arrest ventilation in children with IHCA with an invasive airway in place at the start of CPR, we did not find an association between guideline-compliant average ventilation rate and survival. In children <8 years old we identified a target ventilation threshold of ≥26 breaths per minute, which was associated with improved survival to hospital discharge.

The Gut Microbiome as a Modulator of Traumatic Brain Injury Pathology and Symptoms

Journal of Neuroscience · 2025-11-12

Traumatic brain injuries (TBIs) affect millions annually, leading to devastating neurobehavioral consequences and increasing risk for neurodegenerative and psychiatric diseases. However, therapies are lacking. Starting in 2018, dysbiosis of the gut microbiome was identified as an acute, and potentially chronic, pathology originating from TBI. Recent studies established that the microbiome contributes to the evolution of TBI pathology and functional impairments. The gut microbiome is the collection of microorganisms that inhabit the stomach through colon and is indicated as a contributor to myriad neurological and psychiatric conditions. This makes it an intriguing target to understand in the context of TBI. Thus, this review focuses on the evidence establishing the gut as a modulator of TBI and the major potential mechanisms by which this occurs. This includes regulation of food processing into host-usable nutrients, inflammatory signaling, and vagus nerve modulation. Each of these areas provides potential for future therapeutic development and intervention but there are also multiple areas where microbiome-TBI science could be improved.

Chronic traumatic brain injury induces neurodegeneration, neuroinflammation, and cognitive deficits in a T cell-dependent manner

Brain Research · 2025-01-10 · 8 citations

Association of Early Epinephrine with Hemodynamics and Outcome in Pediatric in-Hospital Cardiac Arrest: A Secondary Analysis of a Multicenter, Cluster-randomized Clinical Trial Intensive Care Unit Resuscitation (ICU-RESUS)

Annals of the American Thoracic Society · 2025-06-04 · 1 citations

Abstract Rationale Delayed (>5 minutes) epinephrine during pediatric in-hospital cardiac arrest (IHCA) is associated with worse outcomes. Epinephrine is nearly always given earlier, limiting 5 minutes as a quality target. Objectives To assess early epinephrine administration (⩽2 minutes) on outcomes and hemodynamics during cardiopulmonary resuscitation (CPR) in pediatric IHCA from pulseless, nonshockable rhythms. Methods This study leveraged the database of the ICU-RESUS (Intensive Care Unit Resuscitation) project (clinicaltrials.gov identifier NCT 02837497). Primary exposure was the time to epinephrine bolus: early versus >2 minutes. Primary outcome was survival to discharge. Secondary outcomes included the return of spontaneous circulation (ROSC), survival with favorable neurologic outcome, change from baseline to discharge Functional Status Scale (FSS) score, total FSS score at discharge, new morbidity among survivors, and invasively measured blood pressure during the first 10 minutes of CPR. Results Among 352 CPR events, median age was 1.0 (interquartile range [IQR], 0.3–8.0) year, 186 (53%) were male, and 185 (52.6%) had cardiac disease. Early epinephrine was administered in 273 (78%), and median time to administration was 1.0 (0.0–2.0) minute. Survival to discharge was similar between patients who received early epinephrine and those who did not. Early epinephrine administration was associated with higher ROSC, a change from baseline to discharge in FSS, lower total FSS scores at discharge, and lower rates of new morbidity compared with epinephrine administration at >2 minutes. The probability of ROSC and survival to discharge with favorable neurologic outcome decreased for each minute of delay in epinephrine administration. There was no difference in the invasive blood pressure targets during the first 10 minutes of CPR. Conclusions Early epinephrine administration was common and was associated with higher ROSC and improved functional outcomes compared with epinephrine administration at >2 minutes in pediatric IHCA.

Short-chain fatty acids are a key mediator of gut microbial regulation of T cell trafficking and differentiation after traumatic brain injury

Experimental Neurology · 2025-06-15 · 8 citations

Severe intracranial hemorrhage or ischemia associated with unfavorable outcomes after pediatric in-hospital cardiac arrest

Resuscitation · 2025-11-08 · 1 citations

Neuroinflammation and Neurological Dysfunction After AKI Is Driven by Kidney-Released Osteopontin and Not Uremia

Journal of the American Society of Nephrology · 2025-10-01 · 1 citations

Outcomes, Characteristics, and Physiology of In-Hospital Cardiac Arrest in Children With Sepsis

Critical Care Medicine · 2025-06-25 · 1 citations

OBJECTIVES: Prearrest sepsis has been associated with particularly poor outcomes among children who suffer in-hospital cardiac arrest (IHCA), but there is a paucity of dedicated studies on the topic. In this study of children receiving cardiopulmonary resuscitation (CPR) in the ICU, our objective was to determine the associations of sepsis with IHCA outcomes and intraarrest physiology. DESIGN: Prospectively designed secondary analysis of the ICU Resuscitation Project clinical trial (NCT02837497). SETTING: The 18 pediatric and pediatric cardiac ICUs at ten children's hospitals in the United States. PATIENTS: Children (≤ 18 yr) with an index IHCA event. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary exposure was a prearrest diagnosis of sepsis. The primary survival outcome was survival to hospital discharge with favorable neurologic outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged from baseline). The primary physiologic outcome was average diastolic blood pressure (DBP) during CPR. Multivariable regression models controlling for a priori covariates assessed the relationship between sepsis and outcomes. Of 1129 children with index IHCAs, 184 (16.3%) had prearrest sepsis. Patients with sepsis had greater prearrest comorbidities, higher prearrest severity of illness, and higher Vasoactive-Inotropic Scores than patients without sepsis. They more frequently had hypotension as the cause of IHCA, had longer durations of CPR, and more frequently received epinephrine and sodium bicarbonate during CPR. They less frequently achieved survival with favorable neurologic outcome (52/184 [28.3%] vs. 552/945 [58.4%]; p < 0.001; adjusted relative risk, 0.54; 95% CI, 0.43-0.68; p < 0.001). Intraarrest DBPs did not differ between patients with vs. without sepsis. Following IHCA, event survivors with sepsis had higher vasoactive requirements, more frequently experienced hypotension, and continued to have greater mortality rates through 48 hours postarrest. CONCLUSIONS: Children with prearrest sepsis had worse survival outcomes, similar intraarrest DBPs, and greater pre and postarrest severity of illness than children without sepsis.