Bacteria-Derived Protein Aggregates Contribute to the Disruption of Host Proteostasis

Abstract

Neurodegenerative protein conformational diseases are characterized by the misfolding and aggregation of metastable proteins encoded within the host genome. The host is also home to thousands of proteins encoded within exogenous genomes harbored by bacteria, fungi, and viruses. Yet, their contributions to host protein-folding homeostasis, or proteostasis, remain elusive. Recent studies, including our previous work, suggest that bacterial products contribute to the toxic aggregation of endogenous host proteins. We refer to these products as bacteria-derived protein aggregates (BDPAs). Furthermore, antibiotics were recently associated with an increased risk for neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis—possibly by virtue of altering the composition of the human gut microbiota. Other studies have shown a negative correlation between disease progression and antibiotic administration, supporting their protective effect against neurodegenerative diseases. These contradicting studies emphasize the complexity of the human gut microbiota, the gut–brain axis, and the effect of antibiotics. Here, we further our understanding of bacteria’s effect on host protein folding using the model Caenorhabditis elegans. We employed genetic and chemical methods to demonstrate that the proteotoxic effect of bacteria on host protein folding correlates with the presence of BDPAs. Furthermore, the abundance and proteotoxicity of BDPAs are influenced by gentamicin, an aminoglycoside antibiotic that induces protein misfolding, and by butyrate, a short-chain fatty acid that we previously found to affect host protein aggregation and the associated toxicity. Collectively, these results increase our understanding of host–bacteria interactions in the context of protein conformational diseases.

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

“…Both Aβ 1-42 aggregation and the associated toxicity were suppressed by P. corporis and enhanced by Pseudomonas aeruginosa (Figure S1), a bacterium that strongly disrupted host proteostasis in our previous studies. 16,23 All of our transgenic worms express exogenous proteins. To determine whether Prevotella can also provide protection against misfolding of endogenous proteins, we used a strain that carries a temperature-sensitive mutation in myosin heavy chain (UNC-54) that leads to its misfolding and paralysis at the restrictive temperature (25°C).…”

“…26 We found that Ralstonia sp., Achromobacter xylosoxidans , Pseudomonas sp., and K. pneumoniae were the strongest inducers of polyQ aggregation (Figure 4A). As we have already demonstrated the proteotoxic potential of P. aeruginosa in our previous work, 16,23 we focused on the three remaining species in follow-up experiments. To assess the proteotoxic effect of these bacteria, we employed the TOP assay to measure the motility of worms expressing aggregating polyQ44 and non-aggregating polyQ33.…”

“…Furthermore, we previously demonstrated that P. aeruginosa exert robust proteotoxic effects on C. elegans. 16,23 The presence of Pseudomonas, in conjunction with another bacterial genus, was successfully used to differentiate individuals with AD from control subjects. 71 Collectively, the aforementioned studies are in agreement with our results and further support the wide-ranging impact of bacteria on protein folding diseases.…”

“…74 Our previous work demonstrated that P. aeruginosa and E. coli can also disrupt host proteostasis through the production of bacteria-derived protein aggregates. 16,23 Additionally, P. aeruginosa FapC amyloids were shown to cross-seed with Aβ 1-42 . 75 Interestingly, the fap operon is also present in the genomes of Burkholderiales, which include Ralstonia and Achromobacter.…”

Oh my gut! Is the microbial origin of neurodegenerative diseases real?

“…While the mechanisms underlying the neuroprotective role of Prevotella spp. remain unknown, recent work revealed that specific species (i.e., disiens and corporis ) decrease toxic polyglutamine (polyQ) aggregation in Caenorhabditis elegans ( 71 , 72 ). Studies in pigs and rats have shown that antibiotic use reduces the relative abundance of Prevotella spp.…”