Investigating the role of the central metabolism in the gut-brain axis of familial dysautonomia

Abstract

Familial dysautonomia (FD) is a rare, highly debilitating, developmental, and progressive neurodegenerative disease, with recessive heritability, and primary penetrance among Eastern European Jewish populations. The disease affects both the central and peripheral nervous systems, with primary deficits in the autonomic and sensory divisions. Patients thus present with numerous complex neurological phenotypes, and those of primary interest include severe gastrointestinal dyscoordination, cardiovascular instability, baroreceptor imbalances that promote autonomic "crises" marked by uncontrollable retching, and progressive visual decline leading to blindness. There is no cure for FD, and patients are still subject to a poor quality of life despite current advances in understanding the cellular mechanisms mediating the disease. The nervous system, gut-microbial ecosystem, and central metabolism are individually complex, but ever more intricate due to the crosstalk between these systems. Thus, dysregulation or damage in one system could facilitate disruption in another, thus creating a negative feedback loop between the gut-brain-metabolism axis and ultimately perpetuating neurodegeneration, gut dysbiosis, and a dysfunctional metabolism. Understanding how each individual system is affected by the FD founder mutation could lead to methods for restoring healthy function to one of the branches of the gut-brain-metabolism axis, thus arresting the negative feedback loop and disease perpetuation. In this work, nuclear magnetic resonance-based metabolomics was employed along with targeted mass spectrometry techniques to characterize the metabolic changes of FD patients, and subsequently to interrogate the retinal metabolome of a retina specific FD mouse model (Pax6). Insights into the critical changes in FD patients' fecal metabolites were found and associated with neuronal networks and the gut-microbiome. Further avenues exploring these results and the role of metabolic dysfunction in FD led to the interrogation of the retinal metabolome of the Pax6 mouse model, and identification of altered metabolites associated with energy circuits of the eye, mitochondrial function, and retinal ganglion cell health. These data demonstrate metabolic dysfunction in FD patients, and the Pax6 model, with disruptions being analogous to clinical phenotypes, gut-dysbiosis, and the cellular degeneration of FD patients, thus providing foundational information for the generation of novel therapeutic options targeting the cellular metabolic pathways of the gut-brain-metabolism axis.