Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice

David Ma,Jared D Hoffman,Ishita Parikh,M Paul Murphy,Ai-Ling Lin,George Chlipala,Anika M S Hartz,Brent S Sokola,Björn Bauer,Stefan J Green,Amy C Wang

doi:10.1038/s41598-018-25190-5

David Ma, Jared D Hoffman + Show 9 more

Open Access

https://doi.org/10.1038/s41598-018-25190-5

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Abstract

Neurovascular integrity, including cerebral blood flow (CBF) and blood-brain barrier (BBB) function, plays a major role in determining cognitive capability. Recent studies suggest that neurovascular integrity could be regulated by the gut microbiome. 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). 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). These neurovascular enhancements were associated with reduced mechanistic target of rapamycin (mTOR) and increased endothelial nitric oxide synthase (eNOS) protein expressions. 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). 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. 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.

Highlights

Neurovascular functions play a critical role in determining cognitive capability and mental health[1]
Data are presented as mean ± SEM, ***p < 0.001. (c) Western blot (WB) images for mechanistic target of rapamycin (mTOR), P-gp, and endothelial nitric oxide synthase (eNOS) from the cortical vasculature, β-Actin was used as loading control. (d) The corresponding values of the levels of protein expression
We found that ketogenic diet (KD)-fed mice had significantly elevated cerebral blood flow (CBF) globally and regionally, in ventromedial hypothalamus (VMH) (11.82%; p < 0.0001; Fig. 1b)

Summary

Introduction

Neurovascular functions play a critical role in determining cognitive capability and mental health[1]. 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]. Interventions that maintain gut microbiome and neurovascular integrity may be crucial for impeding neurological disorders. (e) Representative confocal images showing increased luminal accumulation of NBD-CSA fluorescence in brain capillaries isolated from KD mice compared to control mice, indicating higher P-gp transport activity. A recent study showed that KD significantly increased regional CBF in a mouse model with ischemic stroke[19]. KD may be protective against various neurological disorders, possibly through the restoration of neurovascular function and by maintaining healthy gut microbiome

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