Maintaining Gut Microbiota Alleviates Brain Injury Caused by Elevated Interleukin-17 Levels During Sepsis-Associated Encephalopathy

Abstract

Background: Sepsis-associated encephalopathy (SAE) is characterized by a diffuse or multifactorial cerebral dysfunction caused by sepsis without central nervous system (CNS) infection. Gut dysbacteriosis plays a critical role in the development of SAE. However, the underlying mechanisms of gut microbiota in the progression of SAE remain unclear. The current study investigated how gut microbiota and interleukin (IL)-17 affect SAE rat models using fecal microbiota transplantation (FMT) and Y320 (IL-17 inhibitor). Additionally, we examined the link between gut microbiota and IL-17 in SAE. Methods: The cecal ligation perforation (CLP) induced sepsis rat model was established and treated with fecal microbiota transplantation (FMT) or IL-17 inhibitor (Y320). 16S rDNA genes isolated from rat Fecal Flora were analyzed using high-throughput sequencing. Simple non-postural somatomotor functions were assessed using the pinna reflex and corneal reflex tests. The simple postural somatomotor function was evaluated using the tail flexion reflex test. However, complex postural somatomotor functions were evaluated using righting reflex and escape response tests. Furthermore, the Blood-Brain Barrier Permeability was assessed. The whole blood monocytes were isolated, and the T cell proportion was evaluated using flow cytometry. The levels of inflammatory cytokines (IL-7, IL-1β, tumor necrosis factor-α (TNF-α), and IL-10) in hippocampus tissue were determined using their respective enzyme-linked immunosorbent assay (ELISA) kits. Additionally, brain injury and apoptosis rate were evaluated using Hematoxylin-Eosin staining and TdT-mediated dUT PNick-End Labeling (TUNEL) assay. Protein expression levels were assessed using western blot analysis and immunofluorescence assay. Results: The brain tissue injury, expressions of inflammatory factors, levels of apoptosis, and autophagy in the hippocampus of the SAE group were higher compared to the Sham group. Furthermore, in both the SAE+FMT and SAE+Y320 groups, brain damage was improved, inflammatory factors in the hippocampus were reduced, and apoptosis and autophagy in the hippocampus were downregulated compared to the SAE+NC group (p < 0.05). Additionally, the imbalance of T helper cell 17 (Th17)/Treg was regulated to suppress IL-17 in the hippocampus following FMT or Y320 treatment (p < 0.01). Conclusions: Reducing IL-17 levels by restoring gut microecological homeostasis might be a potential strategy to prevent and treat SAE.