Mechanistic study of dexmedetomidine improving sepsis-associated encephalopathy in mice via modulation of the gut microbiota/trimethylamine-N-oxide signaling
WANG Lei,XU Wen-xue,KANG Yu-mei
Department of Anesthesiology, Tianjin Union Medical Center, the First Affiliated Hospital of Nankai University, Tianjin 300121, China
Abstract:
Objective To investigate whether dexmedetomidine ameliorates sepsis-associated encephalopathy (SAE) by interfering with gut microbiota/trimethylamine N-oxide (TMAO) signaling. Methods Fifty-four adult male C57BL/6J mice were randomly divided into three groups: sham, SAE and dexmedetomidine intervention (SD). SAE and SD groups underwent cecal ligation and puncture (CLP) to establish sepsis model, while sham group received laparotomy only. SD group received an intravenous injection of dexmedetomidine (5 μg/kg) via tail vein 1 h before CLP. At 24 h post-CLP, cognitive function was assessed using the novel object recognition test (cognitive index) and the open field test (distance and time spent in the center). The extent of blood-brain barrier damage was evaluated using Evans blue (EB) extravasation. Hippocampal pathological injury was examined by hematoxylin-eosin (HE) staining. Western blot was used to measure protein expression of nerve injury-induced protein-1 (NINJ1) in hippocampus. 16S rRNA sequencing was performed to determine Chao1 index, Shannon index, and to conduct Principal Component Analysis (PCA) and Principal Coordinates Analysis (PCoA) of gut microbiota. TMAO levels in feces, serum, and hippocampal tissue were detected by ELISA. Results Compared with sham group, SAE group showed a significant decrease in the distance moved and time spent in the center, a significantly lower cognitive index, evident hippocampal pathological injury, increased EB extravasation and NINJ1 expression, reduced gut microbiota Chao1 and Shannon indices, distinct clustering in PCA and PCoA, and elevated TMAO levels in feces, serum, and hippocampal tissue. Compared with S group, SD group exhibited increased distance and time in the center, an elevated cognitive index, alleviated hippocampal pathological injury, reduced EB extravasation and NINJ1 expression, increased Chao1 and Shannon indices, more concentrated clustering in PCA and PCoA, and decreased TMAO levels in feces, serum, and hippocampal tissue. Conclusion Dexmedetomidine significantly improves SAE whose mechanism may be associated with the upregulation of gut microbiota α and β diversity and the downregulation of TMAO expression.
