Daily Sepsis Research Analysis

BACKGROUND: Sepsis-induced myocardial dysfunction (SIMD) is a critical complication of sepsis, and ferroptosis has been identified as a key contributor to its pathogenesis. Emerging evidence suggests that sepsis profoundly disrupts the gut microbiota composition, leading to dysbiosis. Butyrate, a short-chain fatty acid produced by gut microbiota, has been implicated in ferroptosis regulation; however, its role in SIMD remains controversial. This study aims to elucidate the protective effects of gut microbiota-derived butyrate against SIMD through ferroptosis modulation. METHODS: This study assessed cardiac function using echocardiography and quantified myocardial injury biomarkers via ELISA. Myocardial iron deposition was evaluated using Prussian blue staining. The gut microbiota composition was analyzed using 16S rRNA gene sequencing. Ferroptosis-related protein expression in SIMD heart tissues and H9C2 cardiomyocytes was examined via western blotting to determine the regulatory role of butyrate. RESULTS: Sepsis-induced gut microbiota dysbiosis was characterized by a significant reduction in butyrate-producing bacteria. Echocardiographic assessments (CO, EF), myocardial injury markers (BNP, cTnI), histopathological analysis (H&E staining), and cardiomyocyte ultrastructure (TEM) demonstrated that butyrate administration significantly alleviated myocardial injury in SIMD. Mechanistically, butyrate mitigated oxidative stress by increasing GSH levels and reducing MDA levels. Furthermore, butyrate treatment reversed the sepsis-induced downregulation of GPX4 and suppressed the upregulation of ACSL4 and PTGS2, thereby inhibiting ferroptosis. CONCLUSION: These findings highlight the protective role of butyrate in SIMD, with ferroptosis inhibition serving as a key cardioprotective mechanism. Targeting gut microbiota-derived butyrate may represent a promising therapeutic strategy for sepsis-induced myocardial injury.

BACKGROUND: Hereditary spastic paraplegia (HSP) denotes a heterogeneous group of neurodegenerative spastic gait disorders. Variants in SPG11 cause the most common autosomal recessive HSP also known as SPG11. The gene product Spatacsin interacts with the adaptor protein complex 5 (AP5). Because neurodegeneration in SPG11 is accompanied by marked neuro-inflammation, we hypothesised that Spatacsin may play a cell-autonomous role in pro-inflammatory cells. METHODS: Inflammasome activation was assessed in primary microglia and bone-marrow-derived-macrophages (BMDMs) from wild-type, Spg11, and Ap5z1 knockout (KO) mice and monocyte-derived-macrophages (MDMs) from patients with SPG11 mutations. Wild-type and Spg11 KO mice were used to study microglia activation and LPS-induced inflammatory responses in vivo. FINDINGS: We show that microglia activation is more pronounced in pre-symptomatic Spg11 KO compared with control mice following systemic lipopolysaccharide (LPS) challenge. Our subsequent studies demonstrate that the activation of the non-canonical inflammasome results in a stronger inflammatory response in primary microglia and BMDMs from Spg11 KO mice, while the canonical pathway is unaffected. These findings are also observed in MDMs isolated from patients carrying loss-of-function SPG11 mutations. In vivo, LPS triggers a much stronger inflammatory response and leads to drastically increased lethality in Spg11 KO mice. Mass spectrometry of activated BMDMs unveils a massive downregulation of AP5 subunits upon disruption of Spg11. Notably, the disruption of its ζ-subunit Ap5z1, which is associated with SPG48, also sensitises the non-canonical inflammasome. INTERPRETATION: Our findings suggest that a hyper-reactivity of the non-canonical inflammasome in innate immune cells contributes to neuro-inflammation in SPG11 and SPG48. FUNDING: Please see Acknowledgements.

STUDY OBJECTIVE: Among emergency department (ED) patients with septic shock, assess the association between high- versus low-priority triage assignment on delays in care. METHODS: Retrospective cohort study of ED encounters from 2016 to 2020 across 21 community EDs. All EDs used the Emergency Severity Index (ESI) to triage patients. Patients were included if they had an ED or hospital diagnosis of septic shock and received intravenous antibiotics and vasopressors in the ED. Patients were categorized as receiving a high- (ESI I or II) versus low- priority triage assignment (ESI III - V). Outcomes included four measures of timeliness of care and 30-day mortality. RESULTS: Among 8601 patient encounters; median age was 71.0, 4452 (51.8 %) were male and 1159 (13.5 %), 887 (10.3 %), 4611 (53.6 %), 1287 (15.0 %), and 657 (7.6 %) were Asian, Black, Non-Hispanic White, Hispanic, and other, respectively. We found 7071 (82.2 %) patients received a high-priority triage assignment. The mean adjusted differences between high- and low-priority patients in initial orders, antibiotic delivery, vasopressor delivery, and ED length of stay were 4.6 min (95 % CI 4.2-4.9 min), 34.4 min (95 % CI 31.0-37.8 min), 27.5 min (95 % CI 25.5 min - 29.5 min), and 51.6 min (95 % CI 44.8 min - 58.2 min), respectively. The mean adjusted 30-day mortality rates among high- and low-priority triage patients were 36.3 % (95 % CI 24.5% - 53.8 %) and 32.7 % (21.9 % - 48.9 %), respectively. CONCLUSION: Lower triage priority is associated with delays in care for patients with septic shock. Early identification is critical to ensure timely care and improved outcomes.