Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice
Gregory R. Lum,
Sung Min Ha,
Christine A. Olson,
Montgomery Blencowe,
Jorge Paramo,
Beck Reyes,
Joyce H. Matsumoto,
Xia Yang,
Elaine Y. Hsiao
Affiliations
Gregory R. Lum
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author
Sung Min Ha
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Christine A. Olson
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Montgomery Blencowe
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Jorge Paramo
UCLA Goodman-Luskin Microbiome Center, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA 90095, USA
Beck Reyes
Department of Pediatrics, Division of Pediatric Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Joyce H. Matsumoto
Department of Pediatrics, Division of Pediatric Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Xia Yang
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Elaine Y. Hsiao
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Goodman-Luskin Microbiome Center, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA 90095, USA; Corresponding author
Summary: The gut microbiome modulates seizure susceptibility and the anti-seizure effects of the ketogenic diet (KD) in animal models, but whether these relationships translate to KD therapies for human epilepsy is unclear. We find that the clinical KD alters gut microbial function in children with refractory epilepsy. Colonizing mice with KD-associated microbes promotes seizure resistance relative to matched pre-treatment controls. Select metagenomic and metabolomic features, including those related to anaplerosis, fatty acid β-oxidation, and amino acid metabolism, are seen with human KD therapy and preserved upon microbiome transfer to mice. Mice colonized with KD-associated gut microbes exhibit altered hippocampal transcriptomes, including pathways related to ATP synthesis, glutathione metabolism, and oxidative phosphorylation, and are linked to susceptibility genes identified in human epilepsy. Our findings reveal key microbial functions that are altered by KD therapies for pediatric epilepsy and linked to microbiome-induced alterations in brain gene expression and seizure protection in mice.
