BACKGROUND: Diabetic Ischemic Stroke (DIS) is a devastating complication of diabetes, associated with high morbidity and mortality. Huang-Lian-Jie-Du Decoction (HLJDD), a renowned traditional Chinese medicine prescription, has demonstrated diverse pharmacological activities, including ameliorating diabetes, neurological disorders, and intestinal dysbiosis. However, the therapeutic effects of HLJDD and its underlying mechanisms against DIS remain elusive.
PURPOSE: To investigate the therapeutic effects of HLJDD on DIS and explore its underlying mechanisms, focusing on gut microbiota-derived short-chain fatty acids (SCFAs) and the TLR4/NF-κB pathway.
METHODS: A DIS rat model was established using high-fat diet (HFD) and streptozotocin (STZ), followed by middle cerebral artery occlusion/reperfusion (MCAO/R). Rats were treated with HLJDD or SCFAs. Neurological function, infarct size, lipid metabolism, inflammation, and gut microbiota were assessed. 16S rDNA sequencing, GC-MS, RT-qPCR, and Western blotting were used to analyze SCFAs, microbiota composition, and TLR4/NF-κB pathway. A pseudo-germ-free (PGF) model validated microbiota dependency.
RESULTS: HLJDD reduced cerebral infarct size, improved neurological deficits, and alleviated dyslipidemia and nitrative stress. It restored gut microbiota balance, increased SCFAs, and enhanced intestinal barrier integrity. HLJDD inhibited TLR4/NF-κB pathway activation in the gut-brain axis, reducing systemic and neuroinflammation. SCFAs administration replicated these benefits, while microbiota depletion diminished HLJDD's efficacy.
CONCLUSIONS: Our findings provide the first evidence that HLJDD alleviates DIS by modulating the gut-brain axis via enhancement of microbiota-derived SCFAs and inhibition of TLR4/NF-κB pathway, highlighting its potential as a novel therapeutic strategy for DIS.
