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

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. Protein conformational diseases are one of the leading causes of geriatric death and disability, worldwide. Individuals suffering from these ailments are limited to palliative care, as there are no cures or effective treatments. Correlational evidence suggests that the human gut microbiota is a culprit, but the effect of individual bacteria remains elusive, in part, due to the complexity of the microbiome. A single-bacterium approach can help to deconvolute the complexity of the microbiome and reveal the effect of individual bacterial species on organismal proteostasis. As such, we utilized the intestine of C. elegans as a “test tube” to identify the effect of bacteria on the host using tissue-specific polyglutamine repeats as protein folding sensors. We found that colonization of the C. elegans intestine with pathogenic gram-negative bacteria disrupted proteostasis in the intestine, muscle, neurons, and gonads. Furthermore, we demonstrated that butyrogenic bacteria enhanced proteostasis, which was evidenced by a decrease in polyglutamine aggregation and suppression of aggregate-dependent toxicity. Further experiments revealed that co-colonization with butyrogenic bacteria inhibited protein aggregation in C. elegans and the butyrate-mediated suppression of aggregation is dependent on SKN-1/Nrf2 and DAF-16/FOXO–two transcription factors involved in the regulation of oxidative stress responses. While the mechanism of bacteria-mediated induction of protein aggregation remains elusive, our results suggest that bacterial aggregates, in addition to the contribution of oxidative stress, are the contributing factor. These results are intriguing as they suggest that enteric bacteria directly contribute to the pathogenicity of protein conformational diseases.