Role of gut microbiota in amelioration of postoperative cognitive dysfunction in mice by ketamine: association with subdiaphragmatic vagal nerve
10.3760/cma.j.cn131073.20231014.01109
- VernacularTitle:肠道菌群在氯胺酮减轻小鼠术后认知功能障碍中的作用：与膈下迷走神经的关系
- Author:
Xiongfei RONG
1
;
Yali YANG
;
Guangzhi WANG
;
Jibing ZHANG
Author Information
1. 河南省人民医院麻醉与围术期医学科 郑州大学人民医院，郑州 450003
- Keywords:
Ketamine;
Postoperative cognitive complications;
Gastrointestinal microbiome;
Vagus nerve
- From:
Chinese Journal of Anesthesiology
2023;43(11):1322-1328
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To evaluate the role of ketamine in postoperative cognitive dysfunction (POCD) and to clarify the association with subdiaphragmatic vagus nerve in mice.Methods:One hundred and forty-four SPF healthy male C57BL/6J mice, aged 18 months, weighing 32-35 g, were divided into 8 groups ( n=18 each) using a random number table method: sham operation group (group C), surgery group (group S), ketamine + surgery group (group SK), ketamine + surgery + subdiaphragmatic vagotomy group (group SK+ SDV), pseudo germ-free mice+ normal saline group (group GM+ V), pseudo germ-free mice that received fecal microbiota transplantation (FMT) from group S mice group (group GM+ S), pseudo germ-free mice that received FMT from group SK mice group (group GM+ SK), and pseudo germ-free mice received subdiaphragmatic vagotomy and FMT from group SK mice group (group GM+ SDV+ SK). Tibial fracture internal fixation was performed under anesthesia with 2.0% isoflurane. Ketamine 50 mg/kg was intraoperatively administered at the beginning of the suture in group SK. The fecal samples were collected at 24 h after surgery to prepare fecal bacteria filtrate in S and SK groups. The dorsal and ventral branches of subdiaphragmatic vagus nerve were cut prior to ketamine administration in SK+ SDV group and prior to FMT in GM+ SDV+ SK group. Broad-spectrum antibiotics dissolved in drinking water were given ad libitum to mice for 14 consecutive days at 2 weeks before FMT or subdiaphragmatic vagotomy and replaced once every 2 days to establish the pseudo germ-free model. Pseudo germ-free mice were gavaged with normal saline or fecal suspension 200 μl obtained from mice for 14 consecutive days at fixed time starting from 14 days after antibiotic intervention in GM+ SK and GM+ SDV+ SK groups. While normal saline was given instead for 14 consecutive days in GM+ V group. The fecal samples were collected after tibial fracture internal fixation or at 24 h after completion of FMT for 16S rRNA gene sequence analysis. The contents of interleukin-6 (IL-6), IL-17, tumor necrosis factor-alpha (TNF-α), IL-4 and IL-10 in the hippocampus were measured by enzyme linked-immuno-sorbent assay at 24 h after surgery or FMT. The spatial memory and learning ability was assessed by the Morris water maze test at 24 h after surgery or FMT. Results:Compared with group Sham, Simpson′s diversity index, Shannon index and Ace index were significantly decreased, the contents of IL-6, IL-17 and TNF-α were increased, contents of IL-4 and IL-10 were decreased, the escape latency in the training and testing phases and swimming distance were prolonged, and the time spent in the target quadrant was shortened in group S ( P<0.05). Compared with group S, Simpson′s diversity index, Shannon index and Ace index were significantly increased, the contents of IL-6, IL-17 and TNF-α were decreased, contents of IL-4 and IL-10 were increased, the escape latency in the training and testing phases and swimming distance were shortened, and the time spent in the target quadrant was prolonged in group SK ( P<0.05). Compared with group SK, Simpson′s diversity index, Shannon index and Ace index were significantly decreased, the contents of IL-6, IL-17 and TNF-α were increased, contents of IL-4 and IL-10 were decreased, the escape latency in the training and testing phases and swimming distance were prolonged, and the time spent in the target quadrant was shortened in group SK+ SDV ( P<0.05). Compared with group GM+ V, the contents of IL-6, IL-17 and TNF-α were significantly increased, contents of IL-4 and IL-10 were decreased, the escape latency in the training and testing phases and swimming distance were prolonged, and the time spent in the target quadrant was shortened in group GM+ S ( P<0.05). Compared with group GM+ S, the contents of IL-6, IL-17 and TNF-α were significantly decreased, contents of IL-4 and IL-10 were increased, the escape latency in the training and testing phases and swimming distance were shortened, and the time spent in the target quadrant was prolonged in group GM+ S ( P<0.05). Compared with group GM+ SK, the contents of IL-6, IL-17 and TNF-α were significantly increased, contents of IL-4 and IL-10 were decreased, the escape latency in the training and testing phases and swimming distance were prolonged, and the time spent in the target quadrant was shortened in group GM+ SDV+ SK ( P<0.05). Conclusions:Ketamine can improve intestinal flora disorders and reduce POCD in mice, and the mechanism may be related to subdiaphragmatic vagal nerve conduction.
