Gut microbiome dysbiosis drives metabolic dysfunction in Familial dysautonomia

Alexandra M. Cheney, Stephanann M. Costello, Nicholas V. Pinkham, Annie Waldum, Susan C. Broadaway, Maria Cotrina-Vidal, Marc Mergy, Brian Tripet, Douglas J. Kominsky, Heather M. Grifka-Walk, Horacio Kaufmann, Lucy Norcliffe-Kaufmann, Jesse T. Peach, Brian Bothner, Frances Lefcort (), Valérie Copié () and Seth T. Walk ()
Additional contact information
Alexandra M. Cheney: Montana State University
Stephanann M. Costello: Montana State University
Nicholas V. Pinkham: Montana State University
Annie Waldum: Montana State University
Susan C. Broadaway: Montana State University
Maria Cotrina-Vidal: New York University School of Medicine
Marc Mergy: Montana State University
Brian Tripet: Montana State University
Douglas J. Kominsky: Montana State University
Heather M. Grifka-Walk: Montana State University
Horacio Kaufmann: New York University School of Medicine
Lucy Norcliffe-Kaufmann: New York University School of Medicine
Jesse T. Peach: Montana State University
Brian Bothner: Montana State University
Frances Lefcort: Montana State University
Valérie Copié: Montana State University
Seth T. Walk: Montana State University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Familial dysautonomia (FD) is a rare genetic neurologic disorder caused by impaired neuronal development and progressive degeneration of both the peripheral and central nervous systems. FD is monogenic, with >99.4% of patients sharing an identical point mutation in the elongator acetyltransferase complex subunit 1 (ELP1) gene, providing a relatively simple genetic background in which to identify modifiable factors that influence pathology. Gastrointestinal symptoms and metabolic deficits are common among FD patients, which supports the hypothesis that the gut microbiome and metabolome are altered and dysfunctional compared to healthy individuals. Here we show significant differences in gut microbiome composition (16 S rRNA gene sequencing of stool samples) and NMR-based stool and serum metabolomes between a cohort of FD patients (~14% of patients worldwide) and their cohabitating, healthy relatives. We show that key observations in human subjects are recapitulated in a neuron-specific Elp1-deficient mouse model, and that cohousing mutant and littermate control mice ameliorates gut microbiome dysbiosis, improves deficits in gut transit, and reduces disease severity. Our results provide evidence that neurologic deficits in FD alter the structure and function of the gut microbiome, which shifts overall host metabolism to perpetuate further neurodegeneration.

Date: 2023
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DOI: 10.1038/s41467-023-35787-8

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