Identification of proteotoxic and proteoprotective bacteria that non-specifically affect proteins associated with neurodegenerative diseases

Abstract

Neurodegenerative protein conformational diseases (PCDs), such as Alzheimer's, Parkinson's, and Huntington's, are a leading cause of death and disability worldwide and have no known cures or effective treatments. Emerging evidence suggests a role for the gut microbiota in the pathogenesis of neurodegenerative PCDs; however, the influence of specific bacteria on the culprit proteins associated with each of these diseases remains elusive, primarily due to the complexity of the microbiota. In the present study, we employed a single-strain screening approach to identify human bacterial isolates that enhance or suppress the aggregation of culprit proteins and the associated toxicity in Caenorhabditis elegans expressing Abeta1-42, alpha-synuclein, and polyglutamine tracts. Here, we reveal the first comprehensive analysis of the human microbiome for its effect on proteins associated with neurodegenerative diseases. Our results suggest that bacteria affect the aggregation of metastable proteins by modulating host proteostasis rather than selectively targeting specific disease-associated proteins. These results reveal bacteria that potentially influence the pathogenesis of PCDs and open new promising prevention and treatment opportunities by altering the abundance of beneficial and detrimental microbes.

The Role of the Gut Microbiota in Neurodegenerative Diseases

“…Furthermore, species such as Dorea and Eubacterium rectale perform distinct functions, activating immunological responses and generating beneficial SCFAs, respectively. These findings highlight the complex relationship between the gut microbiota and host physiology, with implications for both health and illness [2][3][4][5][6][7][8][9][10].…”

“…These pathological processes are involved in a variety of neurological diseases [9]. Gut microbes affect the central nervous system (CNS) through the following three pathways, as shown in Figure 1: first, through enteric nervous system stimulation; second, by inducing the intestinal epithelial secretory cells to produce metabolites or neurotransmitters such as 5-hydroxytryptamine (5-HT), GABA, dopamine, and SCFAs; and third, gut microorganisms influence immune function by generating microbial-associated molecular patterns (MAMPs) that support immune cells or cytokines like IL-6, IL-1a, IL-1b, and TNFa, which then have an impact on the central nervous system [10]. The vagus nerve connects the enteric nervous system (ENS) and the CNS directly.…”