Baicalin ameliorates neuropathology in repeated cerebral ischemia-reperfusion injury model mice by remodeling the gut microbiota

Abstract

We investigated the neuroprotective effects of baicalin and the role of gut microbiota in a mouse model of cerebral ischemia-reperfusion injury. Repeated cerebral ischemia-reperfusion significantly increased plasma levels of trimethylamine (TMA), trimethylamine-N-oxide (TMAO), and clusterin (a neuroinflammation biomarker). These changes correlated with cognitive decline; short-term memory deficits; abnormal long term potentiation (LTP); decreased functional connectivity (FC) between various brain regions; reduced plasticity and dendritic spine density in the hippocampus; increased levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNFα; and altered the gut microbial composition. Treatment with 50-100 mg/Kg baicalin for 7 days after cerebral ischemia-reperfusion significantly restored normal plasma levels of TMA, TMAO, and clusterin. Baicalin treatment also suppressed neuroinflammation, remodeled the gut microbial composition back to normal, and improved cognition, memory, LTP, cerebral FC, and hippocampal neuronal plasticity. The neuroprotective effects of baicalin were diminished when mice undergoing repeated cerebral ischemia-reperfusion were pretreated with broad-spectrum antibiotics to deplete gut microbial populations. This suggests the neuroprotective effects of baicalin in cerebral ischemiareperfusion injury are mediated by the gut microbiota. It thus appears that baicalin ameliorates neuropathology in a repeated cerebral ischemia-reperfusion model mice by remodeling the gut microbiota.

Implication of Gut Microbiota in Cardiovascular Diseases

“…Considered a complex organ, the microbial community is required in the committed step through which food would be converted into small compounds and metabolites, thus modulating intestine structure, gut barrier integrity, inflammatory status, and host metabolism both directly and indirectly [ 4 ]. Since Hippocrates claimed that “all diseases begin in the gut” centuries ago, a great body of research has demonstrated the interplay between intestinal microbiota and diseases, including colorectal cancer [ 5 ], cerebral ischemia-reperfusion injury [ 6 ], liver fibrosis [ 7 ], and CVDs [ 8 ]. The gut microbiota accounts for 0.2–2.0 kg of the weight of an adult and approximately 50% of the dry weight of adult feces.…”

Flavonoids as a Natural Enhancer of Neuroplasticity—An Overview of the Mechanism of Neurorestorative Action

“…Baicalein (5,6,7-trihydroxy-2-phenylchromen-4-one), and its 7- O -glucuronide baicalin ((2S,3S,4S,5R,6S)-6-(5,6-dihydroxy-4-oxo-2-phenylchromen-7-yl)oxy-3,4,5-trihydroxyoxane-2-carboxylic acid), are flavonoids extracted from Scutellaria , widely used in Chinese medicine as anti-inflammatory, -viral, -bacterial, -apoptotic -oxidant and -coagulant substances [ 56 ]. The administration of baicalein and baicalin to rats with induced stroke reduced the infarct volume, and improved motor, cognitive and behavioral skills, and neurological deficit [ 57 , 58 , 59 , 60 , 61 ]. The neuroprotective effects of these flavonoids were related to the inhibition of CaMKII phosphorylation, as well as the modulation of mitochondrial function.…”

“…The neuroprotective effects of these flavonoids were related to the inhibition of CaMKII phosphorylation, as well as the modulation of mitochondrial function. Moreover, baicalin supplementation (50–100 mg/kg for 7 days) has been shown to increase synaptic plasticity in a dose-depended manner in the hippocampus of mice with I/R injury [ 59 ]. Another study suggested that the neurorestorative properties of baicalin may be associated with toll-like receptor 2 and 4 (TLR 2/4) pathways.…”

Role of gut microbiota‐derived metabolites on vascular calcification in CKD

“…In summary, the elevated TMAO level in CKD is a considerable promoter of VC. Several approaches are being explored to reduce TMAO levels, like oral broad‐spectrum antibiotics or promoting the growth of bacteria that use TMAO as matrix and baicalin 62‐64 …”