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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $385,316

## Abstract

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.

## Key facts

- **NIH application ID:** 10047679
- **Project number:** 1R01NS115537-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Elaine Hsiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,316
- **Award type:** 1
- **Project period:** 2020-05-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047679

## Citation

> US National Institutes of Health, RePORTER application 10047679, Dissecting Microbiota-Gut-Brain Interactions for the Anti-Seizure Effects of the Ketogenic Diet (1R01NS115537-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10047679. Licensed CC0.

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