Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate

Alyssa C Walker; Rohan Bhargava; Alfonso S Vaziriyan-Sani; Christine Pourciau; Emily T Donahue; Autumn S Dove; Michael J Gebhardt; Garrett L Ellward; Tony Romeo; Daniel M Czyż

doi:10.1371/journal.ppat.1009510

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Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate

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Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate

Alyssa C Walker, Rohan Bhargava, Alfonso S Vaziriyan-Sani, Christine Pourciau, Emily T Donahue, Autumn S Dove, Michael J Gebhardt, Garrett L Ellward, Tony Romeo and Daniel M Czyż

PLoS pathogens, Vol.17(5), pp.e1009510-e1009510

05/2021

DOI: 10.1371/journal.ppat.1009510

PMCID: PMC8101752

PMID: 33956916

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Abstract

Protein conformational diseases are characterized by misfolding and toxic aggregation of metastable proteins, often culminating in neurodegeneration. Enteric bacteria influence the pathogenesis of neurodegenerative diseases; however, the complexity of the human microbiome hinders our understanding of how individual microbes influence these diseases. Disruption of host protein homeostasis, or proteostasis, affects the onset and progression of these diseases. To investigate the effect of bacteria on host proteostasis, we used Caenorhabditis elegans expressing tissue-specific polyglutamine reporters that detect changes in the protein folding environment. We found that colonization of the C. elegans gut with enteric bacterial pathogens disrupted proteostasis in the intestine, muscle, neurons, and the gonad, while the presence of bacteria that conditionally synthesize butyrate, a molecule previously shown to be beneficial in neurodegenerative disease models, suppressed aggregation and the associated proteotoxicity. Co-colonization with this butyrogenic strain suppressed bacteria-induced protein aggregation, emphasizing the importance of microbial interaction and its impact on host proteostasis. Further experiments demonstrated that the beneficial effect of butyrate depended on the bacteria that colonized the gut and that this protective effect required SKN-1/Nrf2 and DAF-16/FOXO transcription factors. We also found that bacteria-derived protein aggregates contribute to the observed disruption of host proteostasis. Together, these results reveal the significance of enteric infection and gut dysbiosis on the pathogenesis of protein conformational diseases and demonstrate the potential of using butyrate-producing microbes as a preventative and treatment strategy for neurodegenerative disease.

Details

Title: Subtitle: Colonization of the Caenorhabditis elegans gut with human enteric bacterial pathogens leads to proteostasis disruption that is rescued by butyrate
Creators: Alyssa C Walker - University of Florida
Rohan Bhargava - University of Florida
Alfonso S Vaziriyan-Sani - University of Florida
Christine Pourciau - University of Florida
Emily T Donahue - University of Florida
Autumn S Dove - University of Florida
Michael J Gebhardt - Boston Children's Hospital
Garrett L Ellward - University of Florida
Tony Romeo - University of Florida
Daniel M Czyż - University of Florida
Resource Type: Journal article
Publication Details: PLoS pathogens, Vol.17(5), pp.e1009510-e1009510
DOI: 10.1371/journal.ppat.1009510
PMID: 33956916
PMCID: PMC8101752
NLM abbreviation: PLoS Pathog
ISSN: 1553-7366
eISSN: 1553-7374
Publisher: Public Library of Science
Grant note: P40 OD010440 / NIH HHS
Language: English
Date published: 05/2021
Academic Unit: Microbiology and Immunology
Record Identifier: 9984297432102771

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