Microbiota-derived short-chain fatty acids mediate the effects of dengzhan shengmai in ameliorating cerebral ischemia via the gut-brain axis

Hui-Hui Guo; Hao-Ran Shen; Ming-Ze Tang; Ning Sheng; Xiao Ding; Yuan Lin; Jin-Lan Zhang; Jian-Dong Jiang; Tian-Le Gao; Lu-Lu Wang; Yan-Xing Han

doi:10.1016/j.jep.2023.116158

Microbiota-derived short-chain fatty acids mediate the effects of dengzhan shengmai in ameliorating cerebral ischemia via the gut-brain axis

J Ethnopharmacol. 2023 Apr 24:306:116158. doi: 10.1016/j.jep.2023.116158. Epub 2023 Jan 11.

Authors

Hui-Hui Guo¹, Hao-Ran Shen², Ming-Ze Tang³, Ning Sheng⁴, Xiao Ding⁵, Yuan Lin⁶, Jin-Lan Zhang⁷, Jian-Dong Jiang⁸, Tian-Le Gao⁹, Lu-Lu Wang¹⁰, Yan-Xing Han¹¹

Affiliations

¹ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: guohh@imm.ac.cn.
² State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: shenhaoran@imm.ac.cn.
³ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: tangmz@imm.ac.cn.
⁴ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: shengcc@imm.ac.cn.
⁵ State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. Electronic address: dingxiao@mail.kib.ac.cn.
⁶ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: linyuan@imm.ac.cn.
⁷ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: zhjl@imm.ac.cn.
⁸ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Laboratory of Antiviral Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: jiang.jdong@163.com.
⁹ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: tianlegao@imm.ac.cn.
¹⁰ Laboratory of Antiviral Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: wanglulu@imb.cams.cn.
¹¹ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: hanyanxing@imm.ac.cn.

PMID: 36638854
DOI: 10.1016/j.jep.2023.116158

Abstract

Ethnopharmacological relevance: Dengzhan shengmai (DZSM) formula, composed of four herbal medicines (Erigeron breviscapus, Panax ginseng, Schisandra chinensis, and Ophiopogon japonicus), is widely used in the recovery period of ischemic cerebrovascular diseases; however, the associated molecular mechanism remains unclear.

Aim of the study: The purpose of this study was to uncover the links between the microbiota-gut-brain axis and the efficacy of DZSM in ameliorating cerebral ischemic diseases.

Materials and methods: The effects of DZSM on the gut microbiota community and bacteria-derived short-chain fatty acid (SCFA) production were evaluated in vivo using a rat model of cerebral ischemia and in vitro through the anaerobic incubation with fresh feces derived from model animals. Subsequently, the mechanism underlying the role of SCFAs in the DZSM-mediated treatment of cerebral ischemia was explored.

Results: We found that DZSM treatment significantly altered the composition of the gut microbiota and markedly enhanced SCFA production. The consequent increase in SCFA levels led to the upregulation of the expression of monocarboxylate transporters and facilitated the transportation of intestinal SCFAs into the brain, thereby inhibiting the apoptosis of neurocytes via the regulation of the PI3K/AKT/caspase-3 pathway. The increased intestinal SCFA levels also contributed to the repair of the 2VO-induced disruption of gut barrier integrity and inhibited the translocation of lipopolysaccharide from the intestine to the brain, thus attenuating neuroinflammation. Consequently, cerebral neuropathy and oxidative stress were significantly improved in 2VO model rats, leading to the amelioration of cerebral ischemia-induced cognitive dysfunction. Finally, fecal microbiota transplantation could reproduce the beneficial effects of DZSM on SCFA production and cerebral ischemia.

Conclusions: Our findings suggested that SCFAs mediate the effects of DZSM in ameliorating cerebral ischemia via the gut microbiota-gut-brain axis.

Keywords: Cerebral ischemia; Dengzhan shengmai; Fecal microbiota transplantation; Gut barrier; Microbiota–gut–brain axis; Short-chain fatty acids.

MeSH terms

Animals
Brain Ischemia*
Brain-Gut Axis
Cerebral Infarction
Fatty Acids, Volatile / metabolism
Microbiota*
Phosphatidylinositol 3-Kinases
Rats

Substances

fructus schizandrae, radix ginseng, radix ophiopogonis drug combination
Phosphatidylinositol 3-Kinases
Fatty Acids, Volatile