AUTHOR=Zheng Yanfang , Zhou Xian , Wang Chenxiang , Zhang Jialin , Chang Dennis , Liu Wenjing , Zhu MingXing , Zhuang Shuting , Shi Hong , Wang Xiaoning , Chen Yong , Cheng Zaixing , Lin Yanxiang , Nan Lihong , Sun Yibin , Min Li , Liu Jin , Chen Jianyu , Zhang Jieping , Huang Mingqing 

TITLE=Effect of Tanshinone IIA on Gut Microbiome in Diabetes-Induced Cognitive Impairment

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.890444

DOI=10.3389/fphar.2022.890444

ISSN=1663-9812

ABSTRACT=Diabetes-induced cognitive impairment (DCI) presents a major public health risk among the aging population. Previous clinical attempts on known therapeutic targets for DCI such as depleted insulin secretion, insulin resistance and hyperglycaemia have delivered poor patient outcomes. However, recent evidence has demonstrated that the gut microbiome plays an important role in DCI by modulating cognitive function through the gut-brain crosstalk. 
Bioactive compound, Tanshinone IIA (TAN), has shown to improve cognitive and memory function in diabetes mellitus models; though the pharmacological actions are not fully understood. This study aims to investigate the effect and underlying mechanism of TAN on attenuating DCI in relation to regulating the gut microbiome. Metagenomic sequencing analyses were performed on a group of control rats, high-fat/high-glucose diet (HFD) and streptozotocin (STZ) induced diabetic rats (model group) and TAN-treated diabetic rats (TAN group). Cognitive and memory function were assessed by the Morris water maze test, histopathological assessment of brain tissues and immunoblotting of neurological biomarkers. The fasted blood glucose (FBG) level was monitored throughout the experiments. The levels of serum lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were measured by the ELISA assays to reflect the circulatory inflammation level. The morphology of colon barrier was observed by histopathological staining. 
Our study confirmed that TAN reduced FBG level and improved the cognitive and memory function against HFD and STZ-induced diabetes. TAN protected the endothelial tight junction in the hippocampus and colon, regulated neuronal biomarkers, lowered the serum levels of LPS and TNF-α. TAN corrected the reduced abundances of Bacteroidetes in diabetic rats. At the species level, TAN regulated the abundances of Bacteroides dorei, Lachnoclostridium sp. YL32 and Clostridiodes difficile. TAN modulated lipid metabolism and biosynthesis of fatty acids related pathways as the main functional components. TAN significantly restored the reduced levels of isobutyric acid and butyric acid. Our results supported TAN as a promising therapeutic agent for DCI, whereby the underlying mechanism may be associated with gut microbiome regulation.