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

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

doi:10.1038/s41598-018-25190-5

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

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

Research output: Contribution to journal › Article › peer-review

151 Scopus citations

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.

Original language	English
Article number	6670
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-25190-5
State	Published - Dec 1 2018

Bibliographical note

Funding Information:
This research was supported by NIH/NIA grants R01AG054459 and K01AG040164, NIH/CTSA grant UL1TR000117, and American Federation for Aging Research Grant #A12474 to A-LL, NIH/NIA grant R01AG039621 to AMSH, NIH/NINDS grant R01NS079507 to BB, and NIH/NIDDK Training Grant T32DK007778 to JDH.

Funding Information:
This research was supported by NIH/NIA grants R01AG054459 and K01AG040164, NIH/CTSA grant UL1TR000117, and American Federation for Aging Research Grant #A12474 to A-LL, NIH/NIA grant R01AG039621 to AMSH, NIH/NINDS grant R01NS079507 to BB, and NIH/NIDDK Training Grant T32DK007778 to JDH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. The MRI imaging and data were processed using MANGO software developed by the Research Imaging Institute of the University of Texas Health Science Center at San Antonio. The 7 T ClinScan small animal MRI scanner of UK was funded by the S10 NIH Shared Instrumentation Program Grant (1S10RR029541-01). We thank Vikas Bakshi, Janet Guo, Max Baker, Stephanie Edelmann, and Ralf Rempe of the University of Kentucky for assisting the experiments.

Publisher Copyright:
© 2018 The Author(s).

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title = "Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice",

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.",

author = "David Ma and Wang, {Amy C.} and Ishita Parikh and Green, {Stefan J.} and Hoffman, {Jared D.} and George Chlipala and Murphy, {M. Paul} and Sokola, {Brent S.} and Bj{\"o}rn Bauer and Hartz, {Anika M.S.} and Lin, {Ai Ling}",

note = "Funding Information: This research was supported by NIH/NIA grants R01AG054459 and K01AG040164, NIH/CTSA grant UL1TR000117, and American Federation for Aging Research Grant #A12474 to A-LL, NIH/NIA grant R01AG039621 to AMSH, NIH/NINDS grant R01NS079507 to BB, and NIH/NIDDK Training Grant T32DK007778 to JDH. Funding Information: This research was supported by NIH/NIA grants R01AG054459 and K01AG040164, NIH/CTSA grant UL1TR000117, and American Federation for Aging Research Grant #A12474 to A-LL, NIH/NIA grant R01AG039621 to AMSH, NIH/NINDS grant R01NS079507 to BB, and NIH/NIDDK Training Grant T32DK007778 to JDH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. The MRI imaging and data were processed using MANGO software developed by the Research Imaging Institute of the University of Texas Health Science Center at San Antonio. The 7 T ClinScan small animal MRI scanner of UK was funded by the S10 NIH Shared Instrumentation Program Grant (1S10RR029541-01). We thank Vikas Bakshi, Janet Guo, Max Baker, Stephanie Edelmann, and Ralf Rempe of the University of Kentucky for assisting the experiments. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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AU - Ma, David

AU - Wang, Amy C.

AU - Parikh, Ishita

AU - Green, Stefan J.

AU - Hoffman, Jared D.

AU - Chlipala, George

AU - Murphy, M. Paul

AU - Sokola, Brent S.

AU - Bauer, Björn

AU - Hartz, Anika M.S.

AU - Lin, Ai Ling

N1 - Funding Information: This research was supported by NIH/NIA grants R01AG054459 and K01AG040164, NIH/CTSA grant UL1TR000117, and American Federation for Aging Research Grant #A12474 to A-LL, NIH/NIA grant R01AG039621 to AMSH, NIH/NINDS grant R01NS079507 to BB, and NIH/NIDDK Training Grant T32DK007778 to JDH. Funding Information: This research was supported by NIH/NIA grants R01AG054459 and K01AG040164, NIH/CTSA grant UL1TR000117, and American Federation for Aging Research Grant #A12474 to A-LL, NIH/NIA grant R01AG039621 to AMSH, NIH/NINDS grant R01NS079507 to BB, and NIH/NIDDK Training Grant T32DK007778 to JDH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. The MRI imaging and data were processed using MANGO software developed by the Research Imaging Institute of the University of Texas Health Science Center at San Antonio. The 7 T ClinScan small animal MRI scanner of UK was funded by the S10 NIH Shared Instrumentation Program Grant (1S10RR029541-01). We thank Vikas Bakshi, Janet Guo, Max Baker, Stephanie Edelmann, and Ralf Rempe of the University of Kentucky for assisting the experiments. Publisher Copyright: © 2018 The Author(s).

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N2 - 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.

AB - 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.

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

Abstract

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