Tanshinone IIA on Gut Microbiome in Diabetes-induced Cognitive Dysfunction. Tanshinone IIA on microbiome

Diabetes-induced cognitive dysfunction (DCI) has become a major public health risk affecting the aging population. To date, the clinical attempts against the known therapeutic targets against DCI such as depleted insulin secretion, insulin resistance and hyperglycaemia have not shown satisfactory outcomes. Increasing evidence has demonstrated that the gut microbiome modulates cognitive function through the gut-brain crosstalk which plays a role in the progression of DCI. Tanshinone IIA (TAN) is shown to improve cognitive and memory function in diabetes. However, the underlying mechanism is not fully explored. This study aims to investigate the effect and underlying mechanism of TAN on improving diabetic cognitive impairment in relation to regulating the microbiome. We performed metagenomic sequencing analysis in a group of control rats, high-fat diet (HFD) and streptozotocin (STZ) induced diabetic rats (model group) and TAN-treated diabetic rats (TAN group). The cognitive and memory function was assessed by the Morris water maze test, pathological staining of brain tissues and neurological biomarkers. The fast blood glucose level was monitored throughout the experiment. The blood lipopolysaccharide (LPS) and tumor necrosis factor‐α (TNF‐ α) were measured by the ELISA assays to reflect the circulatory inflammation level. The colon barrier morphology was observed by the pathological staining. Our study confirmed the anti-hyperglycemic effect of TAN and improved the cognitive and memory function against HFD and STZ-induced diabetes. TAN protected the endothelial tight junction in the hippocampus and colon, restored neuronal survival biomarkers, lowered the levels of LPS and TNF‐α in circulation. TAN corrected the reduced abundance of Bacteroidetes in diabetic rats. At the species level, TAN reversed the diabetes-related significant changes in the abundance 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 diabetic cognitive impairment and the underlying mechanism may be associated with the gut microbiome regulation.