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Intraperitoneal hypertension, a novel risk factor for sepsis-associated encephalopathy in sepsis mice.

ABSTRACT: Sepsis associated encephalopathy (SAE), appears often indicates the deterioration of the sepsis disease and which have high risk of death. Although several mechanism and hypotheses have been proposed and studied, there is no breakthrough in the treatment of SAE. We performed a systematic research to evaluate the effect of intraperitoneal pressure on SAE. A mice model of sepsis was established by intraperitoneal injection of endotoxin. A total of 48 female BALB/c mouse (30 days old) were randomly divided into a control group (n?=?12) and an injection of endotoxin referred to bacterial lipopolysaccharide (LPS) group (n?=?12). Intraperitoneal hypertension (IAH) referred to IAH group (n?=?12), and LPS?+?IAH group (n?=?12). Following sepsis induction, diagnosis, the brains were analyzed for both function and ultrastructural morphology.We determined that IAH exacerbated sepsis induces sepsis-associated encephalopathy when examining low score of neurological function and more delta wave in EEG, increased neuronal edema in LPS?+?IAH group, as well as an escalation of Bax and Cleaved-caspase-3, Cleaved-parp, and reduction of Bcl-2 and Mfsd2a in LPS?+?IAH group. Therefore, IAH can exacerbate and increase incident rate of sepsis-related encephalopathy in sepsis mice by promoting neuronal apoptosis and destruction of the blood-brain barrier.

SUBMITTER: He YJ

PROVIDER: S-EPMC5970176 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Intraperitoneal hypertension, a novel risk factor for sepsis-associated encephalopathy in sepsis mice.

He Yu-Jing YJ Xu Hao H Fu Yao-Jie YJ Lin Ji-Yan JY Zhang Min-Wei MW

Scientific reports 20180525 1

Sepsis associated encephalopathy (SAE), appears often indicates the deterioration of the sepsis disease and which have high risk of death. Although several mechanism and hypotheses have been proposed and studied, there is no breakthrough in the treatment of SAE. We performed a systematic research to evaluate the effect of intraperitoneal pressure on SAE. A mice model of sepsis was established by intraperitoneal injection of endotoxin. A total of 48 female BALB/c mouse (30 days old) were randomly ...[more]

PMID: 29802336

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Project description:Sepsis-associated encephalopathy (SAE) is common in septic patients and is associated with adverse outcomes. The gut microbiota has been recognized as a key mediator of neurological disease development. However, the exact role of the gut microbiota in regulating SAE remains elusive. Here, we investigated the role of the gut microbiota in SAE and its underlying mechanisms. Cecal ligation and puncture (CLP) was conducted to induce sepsis in mice. Neurological scores were recorded to distinguish SAE-resistant (SER) (score of >6 at 36 h postoperatively) from SAE-susceptible (SES) (score of ≤6 at 36 h postoperatively) mice. 16S rRNA gene sequencing and metabolomics analyses were used to characterize the gut microbiota in the two groups. Fecal microbiota transplantation was performed to validate the role of the gut microbiota in SAE progression. The gut microbiota was more severely disrupted in SES mice than in SER mice after sepsis modeling. Interestingly, mice receiving postoperative feces from SES mice exhibited more severe cortical inflammation than mice receiving feces from SER mice. Indole-3-propionic acid (IPA), a neuroprotective molecule, was more enriched in feces from SER mice than in feces from SES mice. IPA alleviated CLP-induced anxiety and spatial memory impairment in septic mice. Moreover, IPA markedly inhibited NLRP3 inflammasome activation and interleukin-1β (IL-1β) secretion in lipopolysaccharide-stimulated microglia. These responses were attenuated after antagonizing the aryl hydrocarbon receptor. Our study indicates that the variability in sepsis-induced gut dysbiosis mediates the differential susceptibility to SAE in CLP-induced experimental sepsis mice, and microbially derived IPA is possibly involved in SAE development as a neuroprotective compound. IMPORTANCE The bidirectional interactions between the gut microbiota and sepsis-associated encephalopathy (SAE) are not well characterized. We found that the gut microbiota was more severely disturbed in SAE-susceptible (SES) mice than in SAE-resistant (SER) mice after sepsis modeling. Mice gavaged with postoperative feces from SES mice exhibited more severe neuroinflammation than mice gavaged with feces from SER mice. The gut microbiota from SER mice enriched a neuroprotective metabolite, IPA, which appeared to protect mice from SAE. The potential underlying mechanism of the protective effect of IPA may be mediated via the inhibition of NLRP3 inflammasome activation and IL-1β secretion in microglia. These anti-inflammatory effects of IPA may be regulated by aryl hydrocarbon receptors. These results enhance our understanding of the role of the intestinal microbiota in sepsis. In particular, gut microbiota-derived IPA may serve as a potential therapeutic agent to prevent neuroinflammation in SAE.

Project description:ObjectiveThis study aims to analyze the changes of fecal short chain fatty acids (SCFAs) content and gut microbiota composition in sepsis associated encephalopathy (SAE) mice, further evaluating the effect of SCFAs on cognitive function and the underlying mechanism in SAE mice.MethodsA total of 55 male adult C57BL/6 mice (2-3 months of age, 20-25 g) were divided into four groups randomly: sham group (n = 10), cecal ligation and puncture group (CLP group, n = 15), CLP+SCFAs group (n = 15), and CLP+SCFAs+GLPG0974 group (n = 15). Seven days after surgery, fecal samples were collected for microbiota composition and SCFA analysis from 6 mice in each group randomly. Behavioral test was applied to assess cognitive impairment at the same time. After that, mice were sacrificed and brain tissue was harvested for inflammatory cytokines analysis.ResultsThe levels of acetic acid (.57 ± 0.09 vs 2.00 ± 0.24, p < 0.001) and propionic acid (.32 ± 0.06 vs .66 ± 0.12, p = 0.002) were significantly decreased in the CLP group compared with the sham group. The administration of SCFAs significantly increased the levels of acetic acid (1.51 ± 0.12 vs. 0.57 ± 0.09, p < 0.001) and propionic acid (0.54 ± 0.03 vs. 0.32 ± 0.06, p = 0.033) in CLP+SCFAs group compared with CLP group. Relative abundance of SCFAs-producing bacteria, including Allobaculum (0.16 ± 0.14 vs. 15.21 ± 8.12, p = 0.037), Bacteroides (1.82 ± 0.38 vs. 15.21 ± 5.95, p = 0.002) and Bifidobacterium (0.16 ± 0.06 vs. 2.24 ± 0.48, p = 0.002), significantly decreased in the CLP group compared with the sham group. The behavioral tests suggested that cognitive function was impaired in SAE mice, which could be alleviated by SCFAs pretreatment. ELISA tests indicated that the levels of IL-1β, IL-6, and TNF-α were elevated in SAE mice and SCFAs could lower them. However, the GPR43 antagonist, GLPG0974, could reverse the cognitive protective effect and anti-neuroinflammation effect of SCFAs.ConclusionOur study suggested that in SAE, the levels of acetate and propionate decreased significantly, accompanied by gut microbiota dysbiosis, particularly a decrease in SCFAs-producing bacteria. GPR43 was essential for the anti-neuroinflammation and cognitive protective effect of SCFAs in SAE.

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Intraperitoneal hypertension, a novel risk factor for sepsis-associated encephalopathy in sepsis mice.

Publications

Intraperitoneal hypertension, a novel risk factor for sepsis-associated encephalopathy in sepsis mice.

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