Probiotics Exert Protective Effect against Sepsis-Induced Cognitive Impairment by Reversing Gut Microbiota Abnormalities.

Recent evidence has revealed that probiotics could affect neurodevelopment and cognitive function via regulating gut microbiota. However, the role of probiotics in sepsis-associated encephalopathy (SAE) remained unclear. This study was conducted to assess the effects and therapeutic mechanisms of probiotic Clostridium butyricum (Cb) against SAE in mice. The SAE model mouse was induced by cecal ligation and puncture (CLP) and was given by intragastric administration with Cb for 1 month. A series of behavioral tests, including neurological severity score, tail suspension test, and elevated maze test, were used to assess cognitive impairment. Nissl staining and Fluoro-Jade C (FJC) staining were used to assess neuronal injury. Microglia activation, the release of neuroinflammatory cytokines, and the levels of ionized calcium-binding adapter molecule 1 (Iba-1) and brain-derived neurotrophic factor (BDNF) in the brain were determined. The compositions of the gut microbiota were detected by 16S rRNA sequencing. Our results revealed that Cb significantly attenuated cognitive impairment and neuronal damage. Moreover, Cb significantly inhibited excessive activation of microglia, decreased Iba-1 level, and increased BDNF level in the SAE mice. In addition, Cb improved gut microbiota dysbiosis of SAE mice. These findings revealed that Cb exerted anti-inflammatory effects and improved cognitive impairment in SAE mice, and their neuroprotective mechanisms might be mediated by regulating gut microbiota.

A retrospective study of sepsis-associated encephalopathy: epidemiology, clinical features and adverse outcomes.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common complication of sepsis that may result in worse outcomes. This study was designed to determine the epidemiology, clinical features, and risk factors of SAE. METHODS: This was a retrospective study of all patients with sepsis who were admitted to the Critical Care Medicine Department of Hangzhou First People's Hospital Affiliated with Zhejiang University School of Medicine from January 2015 to December 2019. RESULTS: A total of 291 sepsis patients were screened, and 127 (43.6%) were diagnosed with SAE. There were significant differences in median age, proportion of underlying diseases such as hypertension, Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, gastrointestinal infections, detection rate of Enterococcus, and 28-day mortality between the SAE and non-SAE groups. Both the SOFA score and APACHE II score were independent risk factors for SAE in patients with sepsis. All 127 SAE patients were divided into survival and non-survival groups. The age, SOFA score, and APACHE II score were independently associated with 28-day mortality in SAE patients. CONCLUSION: In the present retrospective study, nearly half of patients with sepsis developed SAE, which was closely related to poor outcomes. Both the SOFA score and APACHE II score were independent risk factors for predicting the occurrence and adverse outcome of SAE.

Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment.

Sepsis-associated encephalopathy manifesting as delirium is a common problem in critical care medicine. In this study, patients that had delirium due to sepsis had significant cognitive impairments at 12-18 months after hospital discharge when compared with controls and Cambridge Neuropsychological Automated Test Battery-standardized scores in spatial recognition memory, pattern recognition memory, and delayed-matching-to-sample tests but not other cognitive functions. A mouse model of S. pneumoniae pneumonia-induced sepsis, which modeled numerous aspects of the human sepsis-associated multiorgan dysfunction, including encephalopathy, also revealed similar deficits in spatial memory but not new task learning. Both humans and mice had large increases in chemokines for myeloid cell recruitment. Intravital imaging of the brains of septic mice revealed increased neutrophil and CCR2+ inflammatory monocyte recruitment (the latter being far more robust), accompanied by subtle microglial activation. Prevention of CCR2+ inflammatory monocyte recruitment, but not neutrophil recruitment, reduced microglial activation and other signs of neuroinflammation and prevented all signs of cognitive impairment after infection. Therefore, therapeutically targeting CCR2+ inflammatory monocytes at the time of sepsis may provide a novel neuroprotective clinical intervention to prevent the development of persistent cognitive impairments.

Intestinal microbiota impact sepsis associated encephalopathy via the vagus nerve.

OBJECTIVE: The pathogenesis of sepsis associated encephalopathy (SAE) remains poorly understood. Vagus nerve plays an important role in gut-microbiota-brain axis. This study aimed to investigate whether vague nerve is a key mediator of the impact of intestinal microbiota on SAE. METHODS: Male rats were randomly divided into four groups (n=20): SHAM (SH) group, lipopolysaccharide (LPS) group, fecal microbiota transplantation (FMT) +LPS group, and vagotomy (VGX)+LPS+FMT group. The left cervical vagotomy was performed 30min before LPS administration in LPS+FMT+VGX group. LPS+ FMT and LPS+FMT+VGX groups received nasogastric infusion of feces from healthy donor three times a day. Fecal samples were collected every two days to monitor changes in microbiota composition by 16S rDNA analysis. Brain function was evaluated by behavioral tests and EEG. The levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, IL-6, IL-10 in brain cortex were detected by ELISA. The expression of Iba-1 in brain cortex was assessed by immunohistochemistry and Western blot analysis. RESULTS: Significant modification of microbiota composition, characterized by a profound increase of commensals in the Firmicutes phylum and depletion of opportunistic organisms in the Proteobacteria phylum, was observed in FMT groups compared to LPS group. Furthermore, we identified a reconstituted bacterial community enriched in Firmicutes and depleted of Proteobacteria. In both FMT groups the diversity of the fecal microbiota and the microbiota composition were similar to SH group. LPS mice treated with FMT demonstrated a better spatial memory and less EEG abnormalities, significantly attenuated levels of IL-1ß, IL-6, TNF-α, and decreased number of Iba-1 positive microglia in the cortex, but these beneficial effects of FMT were reversed by VGX. CONCLUSIONS: FMT can change intestinal microbiota in sepsis patients, and vagus nerve is a key mediator between intestinal microbiota and SAE. These findings suggest that FMT and vagus nerve are potential therapy targets for treating SAE.