Gut Microbiota Mediates the Susceptibility of Mice to Sepsis-Associated Encephalopathy by Butyric Acid

Abstract

Purpose Neuroinflammation plays an important part in the pathophysiology of sepsis-associated encephalopathy (SAE). Gut microbiota and gut brain axis are considered as important mediators in the development of neurological diseases. The aim of this study was to investigate the role of intestinal microbiota in sepsis-related brain injury and to explore the underlying mechanisms. Methods Mouse model of SAE was established using cecal ligation and puncture (CLP). Based on the mouse mortality and the associated time of death, light SAE (LSAE) and severe SAE (SSAE) were classified. Fecal microbiota transplantation (FMT) was performed to verify the role of intestinal microbiota. Feces of mice in the two groups which collected before operation were sequenced for 16S and targeted short chain fatty acids. Results Intestinal microbiota from SSAE and LSAE mice displayed diverse functions. Interestingly, LSAE mice produced more butyric acid compared with SSAE mice. In the in vivo experiments, sodium butyrate (NaB) reduced the high oxidative stress levels in mice hippocampus and conferred a marked survival superiority to sepsis mice. In addition, NaB prevented the increase in intracellular reactive oxygen species (ROS) generation and inducible nitric-oxide synthase expression in LPS-stimulated primary microglia. The GPR109A/Nrf2/HO-1 signaling pathway was found to be involved in the activation of antioxidant response of primary microglia induced by sodium butyrate. Conclusion Our findings indicate a crucial role of gut microbiota in the susceptibility to SAE. Butyrate, a metabolite of intestinal microbiota, may have a neuroprotective effect in the process of sepsis by GPR109A/Nrf2/HO-1 pathway.

Identification of biomarkers and therapeutic targets related to Sepsis-associated encephalopathy in rats by quantitative proteomics

“…CLP-induced polymicrobial infection is the most frequently used sepsis model that can closely simulate the development and characteristics of human sepsis [ 10 ]. In our study, the survival rate of CLP rats was nearly 80% at 24 h and continuously declined to 50% in the following days, which is consistent with the previous articles using the same model [ 11 ]. Additionally, obvious manifestations like piloerection, glazed eyes, chills, inertia, and the deteriorative clinical score indicated the sepsis occurring in CLP rats [ 12 ].…”

Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy

“…Activation of the host immune mechanism may cause persistent cognitive dysfunction. Therefore, early attention to specific microbiota may later improve cognitive dysfunction ( 121 , 143 ). A recent study by Zhang et al.…”

“…A recent study by Zhang et al. ( 143 ) demonstrated for the first time the exact relationship between gut microbiota and its metabolite butyric acid and SAE. SAE mouse models of different severity were constructed by CLP and fecal microbiota transplantation(FMT) was performed on sterile mice, confirming the significant role of the gut-brain axis in SAE.…”

Indole-3-Propionic Acid as a Potential Therapeutic Agent for Sepsis-Induced Gut Microbiota Disturbance

“…Microbial metabolites are increasingly recognized as key mediators of the injury responses in multiple organs distant from the gut ( 10 – 13 ). For example, gut microbiota-generated granisetron mediates the susceptibility of sepsis-induced liver injury ( 14 ), and short-chain fatty acids exert neuroprotective effects against sepsis-induced behavioral impairment ( 15 ).…”