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Dissecting Microbiota-Gut-Brain Interactions for the Anti-Seizure Effects of the Ketogenic Diet

Award Number: R01NS115537
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Mammals are colonized with a vast and diverse consortium of microorganisms, collectively called the microbiota, that influence a wide array of biological processes. Recent studies demonstrate that in addition to their roles in nutrition, immunity and metabolism, the intestinal microbiota plays a fundamental role in the development and activity of the nervous system, influencing several complex host behaviors. The proposed research plan aims to uncover molecular and cellular mechanisms underlying the interaction between specific gut microbes and the brain, and to elucidate the impact of these relationships on host physiology. This research plan will investigate microbiome-gut-brain interactions that mediate the antiseizure effects of the ketogenic diet (KD). The KD is an effective treatment for refractory epilepsy and an increasing number of other brain disorders. However, use of the KD remains low due to difficulties with implementation, compliance and adverse side effects, and exactly how the diet succeeds in treating neural dysfunction in cases when drugs fail remains unknown. Understanding the molecular bases for KD-mediated protection against seizures will reveal new insights into signaling mechanisms from gut microbes to the nervous system and novel pathways for treating neurological disease. Notably, a previous publication from our laboratory reported that the KD results in striking changes in the gut microbiota, and these changes are required for the anti-seizure effects of the diet in two seizure models. We now propose to i) determine how the clinical KD influences the human gut microbiota in children with refractory epilepsy, ii) evaluate whether the KD-associated human gut microbiota regulates seizure susceptibility in mouse models for epilepsy, iii) uncover molecular and cellular mechanisms for microbial influences on neuronal activity. In doing so, we will consider the ability of microbes to modulate metabolomic profiles, sensory neuronal activity, ketone body levels and/or immune homeostasis as potential pathways for any microbiota-dependent host phenotypes. This work will push the frontiers of microbiota-gut-brain research toward uncovering new molecular pathways for treating neurological disease. The proposed research tests the transformative hypothesis that alterations in the human gut microbiome contribute to the anti-seizure effects of the ketogenic diet and could inspire novel strategies for enhancing the protective effects of the KD while overcoming major obstacles of strict dietary therapy. It is methodologically integrative in its study of neurobiology, drawing from advancements in functional genomics, metabolomics, gnotobiotics, imaging, molecular biology and neuroscience.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $277,033 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/10/2024	NON-COMPETING CONTINUATION	$19,993
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10920 WILSHIRE BLVD STE 500	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/16/2024	NON-COMPETING CONTINUATION	$257,040
														Subtotal = $277,033

Issue Date FY: 2023 ( Subtotal = $290,749 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/26/2023	NON-COMPETING CONTINUATION	$290,749
														Subtotal = $290,749

Issue Date FY: 2022 ( Subtotal = $335,469 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/25/2022	NON-COMPETING CONTINUATION	$301,922
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/31/2022	NON-COMPETING CONTINUATION	$33,547
														Subtotal = $335,469

Issue Date FY: 2021 ( Subtotal = $385,316 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/5/2021	NON-COMPETING CONTINUATION	$385,316
														Subtotal = $385,316

Issue Date FY: 2020 ( Subtotal = $385,316 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/7/2020	NEW	$385,316
														Subtotal = $385,316

Grand Total All Awards = $1,673,883

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Dissecting Microbiota-Gut-Brain Interactions for the Anti-Seizure Effects of the Ketogenic Diet

Award Number: R01NS115537

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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