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 usedCaenorhabditis elegansexpressing tissue-specific polyglutamine reporters that detect changes in the protein folding environment. We found that colonization of theC.elegansgut 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.

Background/Objectives: Antimicrobial resistance (AMR) is a growing threat that undermines the effectiveness of global healthcare. The Centers for Disease Control and Prevention and the World Health Organization have identified numerous microbial organisms, particularly members of the ESKAPEE pathogens, as critical threats to global health and economic security. Many clinical isolates of these pathogens have become completely resistant to current antibiotics, making treatment nearly impossible. Herbal remedies, such as those found in Traditional Chinese Medicine (TCM), have been practiced for thousands of years and successfully used to treat a wide range of ailments, including infectious diseases. Surprisingly, despite this extensive knowledge of folk medicine, no plant-derived antibacterial drugs are currently approved for clinical use. As such, the objective of this study is to evaluate the antimicrobial properties of extracts derived from TCM plants. Methods: This study explores a comprehensive library comprising 664 extracts from 132 distinct TCM plant species for antimicrobial properties against gram-negative (Escherichia coli) and gram-positive (Micrococcus luteus) bacteria using liquid and solid in vitro assays. Results: Intriguingly, our results reveal 17 plant species with potent antimicrobial properties effective primarily against gram-positive organisms, including Streptococcus aureus and epidermidis. A literature search revealed that nearly 100 purified compounds from the identified TCM plants were previously isolated and confirmed for their antimicrobial properties, collectively inhibiting 45 different bacterial species. Conclusions: Our results indicate that phytobiotics from the identified plants could serve as potential candidates for novel antimicrobials.

Antimicrobial resistance (AMR) is a growing threat that undermines the effectiveness of global healthcare. The Centers for Disease Control and Prevention and the World Health Organization have identified numerous microbial organisms, particularly members of the ESKAPEE pathogens, as critical threats to global health and economic security. Many clinical isolates of these pathogens have become completely resistant to current antibiotics, making treatment nearly impossible. Herbal remedies, such as those found in Traditional Chinese Medicine (TCM), have been practiced for thousands of years and successfully used to treat a wide range of ailments, including infectious diseases. Surprisingly, despite this extensive knowledge of folk medicine, no plant-derived antibacterial drugs are currently approved for clinical use. This study explores a comprehensive library comprising 664 extracts from 132 distinct TCM plant species for antimicrobial properties against gram-negative (Escherichia coli) and gram-positive (Micrococcus luteus) bacteria using liquid and solid in vitro assays. Intriguingly, our results reveal 17 plant species with potent antimicrobial properties effective primarily against gram-positive organisms, including Streptococcus aureus and epidermidis. Our results indicate that phytobiotics from the identified plants may be potential candidates for novel antimicrobials.

Neurodegenerative protein conformational diseases (PCDs) are progressive, currently incurable disorders driven by toxic protein aggregation that leads to neuronal death. Emerging evidence supports a microbial role in PCDs, including the most prevalent: Alzheimer's and Parkinson's disease. While metagenomic studies consistently associate gut dysbiosis with these disorders, the mechanisms by which microbes influence host proteostasis remain poorly understood. In particular, considerable attention has been given to proteotoxic bacteria, but the mechanisms by which commensal microbes confer proteoprotection remain largely unexplored. We have previously employed Caenorhabditis elegans models to characterize the role of over 220 bacterial isolates on host proteostasis. Strikingly, members of the Prevotella genus exhibited proteoprotective effects. Most notably, transient exposure to P. corporis uniquely induced Hsp70, a critical molecular chaperone that maintains proteostasis, and significantly reduced aggregation of polyglutamine (polyQ), Aβ_1-42, and α-synuclein. In the present study, we expand on these findings, demonstrating that among 13 Prevotella species tested, P. corporis robustly activates the heat shock response (HSR) and confers conserved aggregate-suppressing activity in Drosophila melanogaster. We further demonstrate that transient exposure to P. corporis results in the activation of protective stress pathways and promotes disaggregation of existing intestinal polyQ aggregates in C. elegans, leading to a general enhancement of global proteostasis. This is supported by significantly improved survival and enhanced thermotolerance. Together, our findings reveal a beneficial niche for P. corporis in activating the HSR to enhance organismal proteostasis and support a microbe-mediated gut-proteostasis axis. This work underscores the therapeutic potential of targeting the gut microbiota for the management of PCDs, highlights the importance of species-level resolution in microbiome studies, and supports the emerging view of the intestine as a proteostasis-modulating organ.

Biological control strategies are increasingly being explored as sustainable alternatives for managing rice blast disease caused by Magnaporthe oryzae. In this study, we characterized three Bacillus pumilus isolates (DC01, DC09, and DC13) and evaluated their antifungal and plant-beneficial properties against M. oryzae. Whole-genome sequencing revealed multiple biosynthetic gene clusters associated with the production of antimicrobial metabolites. All three isolates inhibited fungal growth in dual-culture assays, whereas heat-stable diffusible antifungal activity was primarily associated with the cell-free supernatants of DC09 and DC13. Exposure to bacterial supernatants disrupted fungal development, inducing abnormal hyphal morphology in M. oryzae characterized by bulbous swelling, altered polarity, and increased branching. Volatile organic compound assays further revealed that the DC isolates suppress fungal growth in the absence of physical contact. The isolates additionally inhibited the growth of other phytopathogenic fungi and selected human bacterial pathogens. All strains exhibited plant growth-promoting traits, including indole-3-acetic acid production and osmotic stress tolerance, whereas DC09 also displayed phosphate-solubilizing activity. Importantly, soil inoculation with the DC isolates significantly reduced rice blast disease severity and induced expression of defense-associated genes involved in jasmonic acid/ethylene signaling and immune priming. Collectively, these findings identify the DC isolates, particularly DC09 and DC13, as promising multi-mechanistic biological control agents for sustainable rice blast management.