Amomum tsao‐ko Attenuates Hyperglycemia and Cognitive Impairment via Regulating Gut Microbiota, SCFAs , and CREB / BDNF / TrkB Signaling Pathway in T2DM Mice

BACKGROUND: As a medicine-food fruit, Amomum tsao-ko has been reported to be beneficial for the management of diabetes. However, its effects and mechanisms in the cognitive impairment caused by diabetes remain unclear. This study aimed to investigate the influences of A. tsao-ko on cognitive impairment in type 2 diabetes mellitus (T2DM) mice and associated mechanisms. METHODS: A. tsao-ko was characterized using UHPLC-Q-Orbitrap-MS/MS. T2DM mice induced by a high-fat diet combined with streptozotocin were treated with ethanol extract of A. tsao-ko (EEAT) for 8 weeks. The cognitive function was evaluated by the Morris water maze (MWM) test, open field test (OFT), and novel object recognition test (NORT). Hippocampus and colon tissues were used for histopathology, biochemical assays, or protein expression analysis. Additionally, fecal samples were subjected to 16S rRNA gene sequencing and short-chain fatty acids (SCFAs) detection. KEY RESULTS: The findings demonstrated that EEAT significantly reversed glucose metabolism disorders and cognitive deficits in T2DM mice. It promoted the protein expression of the CREB/BDNF/TrkB pathway and reduced hippocampal inflammatory responses, thereby improving neuronal damage. It inhibited the loss of colonic tight junction proteins, decreased the levels of inflammatory factors in the colon, and also reshaped the gut microbiota and increased SCFAs. Notably, Spearman's correlation analysis indicated that the Lachnospiraceae NK4A136 group, Ruminococcaceae UCG-014, Lactobacillus, Blautia, and Lachnoclostridium were obviously correlated (positive or negative) with glucose homeostasis indexes, behavioral indexes, tissue inflammatory factors, and SCFAs. CONCLUSIONS: The regulating effects of Amomum tsao-ko on gut microbiota, SCFAs, and the CREB/BDNF/TrkB pathway may be potential mechanisms for alleviating cognitive impairment in diabetes, which provides a potential option to treat diabetic cognitive impairment.