Liu Yarui, Zhao Peng, Cai Zheng, He Peishi, Wang Jiahan, He Haoqing, Zhu Zhibo, Guo Xiaowen, Ma Ke, Peng Kang, Zhao Jie
Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
Peng Kang National Famous Traditional Chinese Medicine Expert Inheritance Studio, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510315, Guangdong, China.
Chin Med. 2024 Sep 15;19(1):126. doi: 10.1186/s13020-024-00991-1.
Ischemic stroke belongs to "apoplexy" and its pathogenesis is characterized by qi deficiency and blood stasis combining with phlegm-damp clouding orifices. Buqi-Huoxue-Tongnao decoction (BHTD) is a traditional Chinese medicine formula for qi deficiency, blood stasis and phlegm obstruction syndrome. However, its efficacy and potential mechanism on ischemic stroke are still unclear. This study aims to investigate the protective effect and potential mechanism of BHTD against ischemic stroke.
Middle cerebral artery occlusion (MCAO) surgery was carried out to establish an ischemic stroke model in rats. Subsequently, the rats were gavaged with different doses of BHTD (2.59, 5.175, 10.35 g/kg) for 14 days. The protective effects of BHTD on the brain and gut were evaluated by neurological function scores, cerebral infarction area, levels of brain injury markers (S-100B, NGB), indicators of gut permeability (FD-4) and bacterial translocation (DAO, LPS, D-lactate), and tight junction proteins (Occludin, Claudin-1, ZO-1) in brain and colon. 16S rRNA gene sequencing and metabolomic analysis were utilized to analyze the effects on gut microecology and screen for marker metabolites to explore potential mechanisms of BHTD protection against ischemic stroke.
BHTD could effectively mitigate brain impairment, including reducing neurological damage, decreasing cerebral infarction and repairing the blood-brain barrier, and BHTD showed the best effect at the dose of 10.35 g/kg. Moreover, BHTD reversed gut injury induced by ischemic stroke, as evidenced by decreased intestinal permeability, reduced intestinal bacterial translocation, and enhanced intestinal barrier integrity. In addition, BHTD rescued gut microbiota dysbiosis by increasing the abundance of beneficial bacteria, including Turicibacter and Faecalibaculum. Transplantation of the gut microbiota remodeled by BHTD into ischemic stroke rats recapitulated the protective effects of BHTD. Especially, BHTD upregulated tryptophan metabolism, which promoted gut microbiota to produce more indole lactic acid (ILA). Notably, supplementation with ILA by gavage could alleviate stroke injury, which suggested that driving the production of ILA in the gut might be a novel treatment for ischemic stroke.
BHTD could increase gut microbiota-derived indole lactic acid to attenuate ischemic stroke via the gut-brain axis. Our current finding provides evidence that traditional Chinese medicine can ameliorate central diseases through regulating the gut microbiology.
缺血性脑卒中属于“中风”范畴，其发病机制以气虚血瘀兼夹痰湿蒙蔽清窍为特征。补气血活血通脑汤（BHTD）是一种用于治疗气虚血瘀痰阻证的中药方剂。然而，其对缺血性脑卒中的疗效及潜在机制仍不明确。本研究旨在探讨BHTD对缺血性脑卒中的保护作用及潜在机制。
采用大脑中动脉闭塞（MCAO）手术建立大鼠缺血性脑卒中模型。随后，将大鼠分别用不同剂量的BHTD（2.59、5.175、10.35 g/kg）灌胃14天。通过神经功能评分、脑梗死面积、脑损伤标志物（S-100B、NGB）水平、肠道通透性指标（FD-4）、细菌移位指标（DAO、LPS、D-乳酸）以及脑和结肠中的紧密连接蛋白（Occludin、Claudin-1、ZO-1）来评估BHTD对脑和肠道的保护作用。利用16S rRNA基因测序和代谢组学分析来分析其对肠道微生态的影响，并筛选标志物代谢物，以探索BHTD对缺血性脑卒中保护作用的潜在机制。
BHTD能有效减轻脑损伤，包括减轻神经损伤、减少脑梗死以及修复血脑屏障，且在10.35 g/kg剂量时效果最佳。此外，BHTD可逆转缺血性脑卒中诱导的肠道损伤，表现为肠道通透性降低、肠道细菌移位减少以及肠道屏障完整性增强。另外，BHTD通过增加有益菌（包括Turicibacter和Faecalibaculum）的丰度来挽救肠道微生物群失调。将经BHTD重塑的肠道微生物群移植到缺血性脑卒中大鼠体内可重现BHTD的保护作用。特别地，BHTD上调色氨酸代谢，促使肠道微生物群产生更多的吲哚乳酸（ILA）。值得注意的是，通过灌胃补充ILA可减轻脑卒中损伤，这表明促使肠道中ILA的产生可能是缺血性脑卒中的一种新的治疗方法。
BHTD可通过肠-脑轴增加肠道微生物群衍生的吲哚乳酸以减轻缺血性脑卒中。我们目前的研究结果提供了证据，表明中药可通过调节肠道微生物群来改善中枢性疾病。
