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Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia

Olson, Christine A. and Iñiguez, Alonso J. and Yang, Grace E. and Fang, Ping and Pronovost, Geoffrey N. and Jameson, Kelly G. and Rendon, Tomiko K. and Paramo, Jorge and Barlow, Jacob T. and Ismagilov, Rustem F. and Hsiao, Elaine Y. (2021) Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia. Cell Host and Microbe, 29 (9). pp. 1378-1392. ISSN 1931-3128. doi:10.1016/j.chom.2021.07.004.

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Many genetic and environmental factors increase susceptibility to cognitive impairment (CI), and the gut microbiome is increasingly implicated. However, the identity of gut microbes associated with CI risk, their effects on CI, and their mechanisms remain unclear. Here, we show that a carbohydrate-restricted (ketogenic) diet potentiates CI induced by intermittent hypoxia in mice and alters the gut microbiota. Depleting the microbiome reduces CI, whereas transplantation of the risk-associated microbiome or monocolonization with Bilophila wadsworthia confers CI in mice fed a standard diet. B. wadsworthia and the risk-associated microbiome disrupt hippocampal synaptic plasticity, neurogenesis, and gene expression. The CI is associated with microbiome-dependent increases in intestinal interferon-gamma (IFNg)-producing Th1 cells. Inhibiting Th1 cell development abrogates the adverse effects of both B. wadsworthia and environmental risk factors on CI. Together, these findings identify select gut bacteria that contribute to environmental risk for CI in mice by promoting inflammation and hippocampal dysfunction.

Item Type:Article
Related URLs:
URLURL TypeDescription ItemQIITA repository ItemHippocampal transcriptomic data
Olson, Christine A.0000-0002-5382-1393
Iñiguez, Alonso J.0000-0002-4869-3278
Yang, Grace E.0000-0001-8346-908X
Fang, Ping0000-0003-4379-3787
Jameson, Kelly G.0000-0002-9972-9138
Barlow, Jacob T.0000-0002-1842-4835
Ismagilov, Rustem F.0000-0002-3680-4399
Hsiao, Elaine Y.0000-0002-1633-588X
Additional Information:© 2021 Elsevier. Received 21 January 2021, Revised 17 May 2021, Accepted 12 July 2021, Available online 5 August 2021. We thank members of the Hsiao laboratory for their critical review of the manuscript; Dr. Alcino Silva for helpful advice regarding behavioral testing; Drs. Thomas O’Dell and Walter Babiec for critical training and advice on hippocampal electrophysiology; Irina Zhuravka of the UCLA Behavioral Testing Core for behavioral assay training; Dr. Matteo Pellegrini (UCLA) for helpful advice regarding analysis of RNA sequencing data; Drs. Suzanne Devkota and Connie Ha (Cedars, Sinai) for generously supplying Bilophila wadsworthia; Dr. Said Bogatryev for assistance with experiments for digital PCR and serum IFNg measurements; and Dr. Timothy O’Sullivan for allowing usage of his Attune NxT flow cytometer. This work was supported by funds from an NIH Ruth L. Kirschstein National Research Service Award (#F31 AG064844) and UCLA Dissertation Year Fellowship to C.A.O., Weston Family Foundation Fellowship to P.F., the Ruth L. Kirschstein National Research Service Award (#F31 HD101270) to G.N.P., the Ruth L. Kirschstein National Research Service Award (#F31 NS118966) to K.G.J., and Army Research Office Multidisciplinary University Research Initiative (W911NF-17-1-0402 to E.Y.H. and R.F.I.). E.Y.H. is a New York Stem Cell Foundation – Robertson investigator. This research was supported in part by the New York Stem Cell Foundation. This project has been made possible in part by grant number 2018-191860 from the Chan Zuckerberg Initiative DAF, an advised fund of Silicon Valley Community Foundation. Author contributions. C.A.O., A.J.I., G.E.Y., P.F., G.N.P., K.G.J, and J.T.B.performed the experiments and analyzed the data. C.A.O., A.J.I., R.F.I., and E.Y.H. designed the study. C.A.O. and E.Y.H wrote the manuscript. All authors discussed the results and commented on the manuscript. The authors declare no competing interests. Inclusion and diversity. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Data and code availability. 16S rRNA gene sequencing data and metadata are available through QIITA repository ( with the study accession # 13510. Hippocampal transcriptomic data are available on through Gene Expression Omnibus repository ( with the identification number # GSE163099.
Funding AgencyGrant Number
NIH Postdoctoral FellowshipF31 AG064844
Weston Family FoundationUNSPECIFIED
NIH Postdoctoral FellowshipF31 HD101270
NIH Postdoctoral FellowshipF31 NS118966
Army Research Office (ARO)W911NF-17-1-0402
New York Stem Cell FoundationUNSPECIFIED
Chan-Zuckerberg Initiative2018-191860
Subject Keywords:microbiota; Bilophila; hippocampus; brain; cognition; neuroimmune
Issue or Number:9
Record Number:CaltechAUTHORS:20210908-171123816
Persistent URL:
Official Citation:Christine A. Olson, Alonso J. Iñiguez, Grace E. Yang, Ping Fang, Geoffrey N. Pronovost, Kelly G. Jameson, Tomiko K. Rendon, Jorge Paramo, Jacob T. Barlow, Rustem F. Ismagilov, Elaine Y. Hsiao, Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia, Cell Host & Microbe, Volume 29, Issue 9, 2021, Pages 1378-1392.e6, ISSN 1931-3128,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110773
Deposited By: George Porter
Deposited On:08 Sep 2021 20:00
Last Modified:08 Sep 2021 20:00

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