UCLA

The gut microbiota varies in a host of human neurological disorders and in murine models is critical to proper neurodevelopment and in neuropathologies. However, current mechanistic evidence is lacking for how microbes related to homeostatic and/or pathological signaling affect these processes. The incidence of neurological disorders without viable treatment options, including epileptic disorders and cognitive impairment, is increasing which raises the impetus in searching for novel biological pathways and mechanisms by which these disorders may be prevented or treated. The gut microbiota has gained attention as a modifier of neurological risk for disorders in development, adulthood, and aging. The work described in this thesis isolates molecular mechanisms by which the gut microbiota mediates environmental protection or risk in murine models of epileptic episodes, cognitive impairment, and host metabolic dysfunction. Specifically, we report that the ketogenic diet, which provides protection against intractable epileptic seizures, mediates this effect in mice through the gut microbiota, more specifically through modifying gamma-glutamylated amino acids. We characterize cognitive and neurophysiological responses in mice mediated by dietary and stressor-induced changes in the gut microbiota, which is mediated by microbial changes in host immune pathways. Together, our findings provide mechanistic evidence that the host microbiota prevents and contributes to murine neurological dysfunction.