BBB dysfunction further leads to reduced CBF and impaired clearance of amyloid-beta (Aβ) plaques, a hallmark of Alzheimer’s disease (AD) 1, 6. muciniphila can alter the microbial ecology of the mucus layer 10 and lead to damage of tight junctions of BBB and the gut 7, 11. Similarly, Akkermansia muciniphila can produce SCFAs such as acetate and propionate 9, and the lack of A. recently showed that BBB permeability is increased in germ-free mice due to lack of butyrate, a short chain fatty acid (SCFA) produced by microorganisms such as Clostridium tyrobutyricum 8. Specifically, reduced cerebral blood flow (CBF) is linked to increased risk for anxiety, depression, and dementia 3, 4, 5, while impaired blood-brain-barrier (BBB) function is associated with neuroinflammation, synaptic dysfunction, and psychiatric disorders 6, 7.Įmerging evidence suggests that gut microbiota play an important role in determining brain vascular integrity. Studies have shown that neurovascular risk is highly associated with accelerated decline in language ability, verbal memory, attention and visuospatial abilities 2, 3. Neurovascular functions play a critical role in determining cognitive capability and mental health 1. Our findings suggest that KD intervention started in the early stage may enhance brain vascular function, increase beneficial gut microbiota, improve metabolic profile, and reduce risk for AD. We also observed that KD reduced blood glucose levels and body weight, and increased blood ketone levels, which might be associated with gut microbiome alteration. KD also increased the relative abundance of putatively beneficial gut microbiota ( Akkermansia muciniphila and Lactobacillus), and reduced that of putatively pro-inflammatory taxa ( Desulfovibrio and Turicibacter). These neurovascular enhancements were associated with reduced mechanistic target of rapamycin (mTOR) and increased endothelial nitric oxide synthase (eNOS) protein expressions. Here we show that with 16 weeks of KD, mice had significant increases in CBF and P-glycoprotein transports on BBB to facilitate clearance of amyloid-beta, a hallmark of Alzheimer’s disease (AD). The purpose of the study was to identify if ketogenic diet (KD) intervention would alter gut microbiome and enhance neurovascular functions, and thus reduce risk for neurodegeneration in young healthy mice (12–14 weeks old). Recent studies suggest that neurovascular integrity could be regulated by the gut microbiome.

Neurovascular integrity, including cerebral blood flow (CBF) and blood-brain barrier (BBB) function, plays a major role in determining cognitive capability.

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