Compositions and methods for analyzing the effect of microbiota on host protein conformation and treating neurodegenerative diseases

Abstract

Described are compositions and methods comprising Prevotella corporis for treating or preventing protein conformational diseases.

Description

Compositions and Methods for Analyzing the Effect of Microbiota on Host Protein Conformation and Treating Neurodegenerative DiseasesCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 588,409, filed October 6, 2023, and U.S. Provisional Application No. 63 / 619.365, filed January 10, 2024, each of which is incorporated herein by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under Grant No. AG070580 awarded by the National Institutes of Health. The government has certain nghts in the invention.

[0003] This invention was created in part from funding received from the IDSA Foundation.

[0004] This invention was created in part while Dr. Daniel Czyz was a Glenn Foundation for Medical Research and AFAR Grant for Junior Faculty awardee.BACKGROUND

[0005] Neurodegenerative protein conformational diseases (PCDs), such as Alzheimer's, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, 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.

[0006] Neurodegenerative PCDs are characterized by disturbances in proteostasis that result in the aggregation of disease-associated proteins, ultimately leading to tissue death. Alzheimer's disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) are among the most prevalent neurodegenerative diseases, with AD recognized by the World Health Organization (WHO) as one of the leading causes of death worldwide. However, despite their increasing prevalence, the etiology and potential therapeutic targets remain obscure. The sporadic onset and variable severity of neurodegenerative diseases, along with their idiopathic nature, suggest the possibility of a triggering factor for their onset and progression. Multiple factors have been associated with the pathogenicity of PCDs, including an expanding body of evidence that suggests the involvement of microbes, but primarily those within the human gut microbiota (HGM). The HGM is considered an “organ’' due to its production of essential proteins and metabolites, includingvitamins, hormones, and neurotransmitters. Hence, dysbiosis of the gut microbiota has been linked to various ailments, including neurodegenerative diseases (Intili G et al. "From Dysbiosis to Neurodegenerative Diseases through Different Communication Pathways: An Overview.” Biology 2023, 12(2): 195).

[0007] The complexity of the microbiome has made it challenging to determine the precise role of bacteria in the pathogenesis of neurodegenerative diseases. In addition, most of the evidence that associates bacteria with the occurrence of neurodegenerative diseases is based on correlation (Fang, P et al. “The Microbiome as a Modifier of Neurodegenerative Disease Risk.” Cell Host Microbe 2020, 28(2):201-222). Interestingly, correlational evidence does not demonstrate any selectivity between different neurodegenerative diseases, despite each disease featuring a unique, specific culprit protein species. For example, a lower abundance of Prevotella species has been observed in patients with different PCDs, including PD and ALS. Due to this lack of specificity, we hypothesized that bacteria could be affecting these diseases through the host proteostasis network — upstream of protein aggregate formation. This hypothesis is further supported by our previous study in which we identified gram-negative enteropathogens that significantly disrupt proteostasis across tissues in C. elegans (Walker AC et al. 2021). The utility of C. elegans as a model to study host-microbe interaction is strengthened by its unique ability7to be colonized by a single bacterial strain. Such a feature simplifies the complexity of the microbiome, allowing us to study the effect of individual species on host proteostasis.

[0008] Here, we characterized the effect bacterial isolates on the aggregation of disease- associated proteins in C. elegans, using transgenic nematodes expressing Afh-42, a-synuclein, and polyglutamine (PolyQ), proteins that adopt amyloidal conformation and are associated with AD, PD, and HD. respectively, in which their toxic aggregation culminates in neurodegeneration.SUMMARY

[0009] Described are compositions for use in treating or preventing a protein conformational disease (PCD) in a subject. The compositions comprise: Prevotella corporis: a composition containing Prevotella corporis; a composition comprising killed Prevotella corporis or a Prevotella corporis lysate or an extract or a fraction thereof; a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject; or combinations thereof. In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an excipient and / or one ormore additional active ingredients. The PCD can be, but is not limited to, a neurodegenerative disease. The neurodegenerative disease can be, but is not limited to, Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease, amyotrophic lateral sclerosis, multiple system atrophy, Lewy body dementia, Creutzfeldt-Jakob disease, prion disease, or amyloidosis.

[0010] A composition comprising Prevotella corporis can be provided as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, or a granular powder. A composition comprising killed Prevotella corporis or a Prevotella corporis lysate or an extract or a fraction thereof, or a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject, can be provided as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, a granular powder, a food additive, a food composition, or a nutraceutical, or a supplement.

[0011] In some embodiments, the composition further comprises one or more additional active ingredients that decrease the abundance or inhibit the growth of one or more of a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species in the gut of the subject. In some embodiments, the one or more additional active ingredients comprises at least one bacteriophage. In some embodiments, the phage is a lytic phage specific for a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species.

[0012] Also described are compositions for use in treating a PCD in a subject, wherein the composition specifically decreases the abundance or inhibits the growth of a Pseudomonas species in the gut of the subject and / or specifically decreases the abundance or inhibits the growth of a one or more of Shigella species in the gut of the subject. In some embodiments, the composition comprises at least one bacteriophage. The composition can be provided as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, a granular pow der, a food additive, a food composition, a nutraceutical, or a supplement. In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an excipient and / or one or more additional active ingredients. The one or more additional active ingredients can be, but is not limited to. Prevotella corporis, a composition containing Prevotella corporis, a composition comprising killed Prevotella corporis or a Prevotella corporis lysate or an extract or a fraction thereof, or a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject. The PCD can be, but is not limited to, a neurodegenerative disease. Theneurodegenerative disease can be, but is not limited to, Alzheimer’s disease. Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple system atrophy, Lewy body dementia, Creutzfeldt-Jakob disease, prion disease, or amyloidosis.

[0013] Also described are compositions for use in treating a PCD in a subject, wherein the composition specifically decreases the abundance or inhibits the growth of one or more of a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species. a Citrobacter species, and an Escherichia species in the gut of the subject. In some embodiments, the composition comprises at least one bacteriophage. The composition can be provided as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, a granular powder, a food additive, a food composition, a nutraceutical, or a supplement. In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an excipient and / or one or more additional active ingredients. The one or more additional active ingredients can be, but is not limited to, a Prevotella species, a composition containing Prevotella species, a composition comprising a Prevotella species lysate or an extract or a fraction thereof, or a composition that increases abundance or supports growth of Prevotella species in the gut of the subject. The PCD can be, but is not limited to, a neurodegenerative disease. The neurodegenerative disease can be, but is not limited to, Alzheimer's disease, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple system atrophy, Lewy body dementia, Creutzfeldt-Jakob disease, prion disease, or amyloidosis.

[0014] Also described are methods of treating a subject suffering from a PCD or at risk of developing a PCD, the methods comprising: administering to the subject one or more of:(a) a Prevotella species, a composition containing the Prevotella species, a composition containing killed Prevotella species, a composition comprising a lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject;(b) a composition that specifically decreases the abundance or inhibits the growth of a Pseudomonas species in the gut of the subject; and(c) a composition that specifically decreases the abundance or inhibits the growth of a Shigella species in the gut of the subject.(d) a composition that specifically decreases the abundance or inhibits the growth of an Achromobacter species in the gut of the subject.(e) a composition that specifically decreases the abundance or inhibits the growth of aRalstonia species in the gut of the subject.(f) a composition that specifically decreases the abundance or inhibits the growth of a Klebsiella species in the gut of the subject.(g) a composition that specifically decreases the abundance or inhibits the growth of an Arcobacter species in the gut of the subject.(h) a composition that specifically decreases the abundance or inhibits the growth of a Citrobacter species in the gut of the subject.(i) a composition that specifically decreases the abundance or inhibits the grow th of an Escherichia species in the gut of the subject.

[0015] In some embodiments, the methods for treating a subject suffering from a PCD or at risk of developing a PCD, comprise administering to the subject:(a) a Prevotella species, a composition containing the Prevotella species, a composition containing killed Prevotella species, a composition comprising a lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject; and(b) a composition that specifically decreases the abundance or inhibits the growth of one or more of: a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, or an Escherichia species in the gut of the subject.

[0016] In some embodiments, the Prevotella species is Prevotella corporis. In some embodiments, the Prevotella species is Prevotella amnii. Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens. Prevotella histicola, Prevotella melaninogencia, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella timonensis, or Prevotella ver oralis.

[0017] In some embodiments, the Pseudomonas species is Pseudomonas aeruginosa or Pseudomonas stutzeri.

[0018] In some embodiments, the Shigella species is Shigella flexneri, Shigella sonnei, Shigella dysenteriae. or Shigella boydii.

[0019] In some embodiments, the Achromobacter species is Achromobacter xylosoxidans, Achromobacter rubefaciens, Achromobacter insuavis, Achromobacter dolens, or Achromobacter spanius.

[0020] In some embodiments, the Ralstonia species is Ralstonia pickettii or Ralstonia mannitolilytica.

[0021] In some embodiments, the Klebsiella species is Klebsiella pneumoniae, Klebsiella oxytoca, or Klebsiella ozaenae.

[0022] In some embodiments, the Arcobacter species is Arcobacter butzleri, Arcobacter cryaerophilus , or Arcobacter skirrowii.

[0023] In some embodiments, the Citrobacter species is Citrobacter portucalensis . Citrobacter freundii, Citrobacter koseri, or Citrobacter braakii.

[0024] In some embodiments, the Escherichia species is Escherichia coli.

[0025] In some embodiments, the subject is human. In some embodiments, the PCD comprises a neurodegenerative disease. The neurodegenerative disease can be, but is not limited to: Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease, multiple system atrophy, Lewy body dementia, Creutzfeldt-Jakob disease, prion disease, or amyloidosis.

[0026] In some embodiments, the methods further comprise: monitoring the abundance of one or more of the Prevotella species, Pseudomonas species, and the Shigella species in the gut of the subject and. (a) if the abundance of Prevotella species in the gut of the subject is below a predetermined value, then administering to the subject the Prevotella species, the composition containing Prevotella species, the composition comprising the Prevotella species lysate or the extract or the fraction thereof, or the composition that increases abundance or supports growth of the Prevotella species in the gut of the subject; and / or (b) if the abundance of the Pseudomonas species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Pseudomonas species in the gut of the subject; and / or (c) if the abundance of the Shigella species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Shigella species in the gut of the subject.

[0027] In some embodiments, the methods further comprise:(a) analyzing a sample of a microbiota from a gut or a stool sample from the subject to determine an amount of one or more of the Prevotella species, the Pseudomonas species, and the Shigella species in the sample;(b) comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, and the Shigella species in the sample to a predetermined control; and(i) if the amount of the Prevotella species in the gut of the subject is below a predetermined value, then administering to the subject the Prevotella species, the composition containing Prevotella species, the composition comprising the Prevotella species lysate or the extract or the fraction thereof, or the composition that increases abundance or supports growth of the Prevotella species in the gut of the subject;(ii) if the amount of the Pseudomonas species in the gut of the subj ect is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Pseudomonas species in the gut of the subject; and / or(iii) if the amount of the Shigella species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Shigella species in the gut of the subject.

[0028] In some embodiments, the methods further comprise: monitoring the abundance of one or more of the Prevotella species, the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and the Escherichia species in the gut of the subject and, (a) if the abundance of Prevotella species in the gut of the subject is below a predetermined value, then administering to the subject the Prevotella species, the composition containing Prevotella species, the composition comprising the Pre votella species lysate or the extract or the fraction thereof, or the composition that increases abundance or supports growth of the Prevotella species in the gut of the subject; and / or (b) if the abundance of the Pseudomonas species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Pseudomonas species in the gut of the subject; (c) if the abundance of the Shigella species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Shigella species in the gut of the subject; (d) if the abundance of the Achromobacter species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Achromobacter species in the gut of the subject; (e) if the abundance of the Ralstonia species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Ralstonia species in the gut of the subject; (f) if the abundance of the Klebsiella species in the gut of the subject is above apredetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Klebsiella species in the gut of the subject; (g) if the abundance of the Arcobacter species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the grow th of the Arcobacter species in the gut of the subject; (h) if the abundance of the Citrobacter species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Citrobacter species in the gut of the subject; and / or (i) if the abundance of the Escherichia species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Escherichia species in the gut of the subject.

[0029] In some embodiments, the methods further comprise:(a) analyzing a sample of a microbiota from a gut or a stool sample from the subject to determine an amount of one or more of the Prevotella species, the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and the Escherichia species in the sample;(b) comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, the Shigella species the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and the Escherichia species in the sample to a predetermined control; and(i) if the amount of the Prevotella species in the gut of the subject is below a predetermined value, then administering to the subject the Prevotella species, the composition containing Prevotella species, the composition comprising the Prevotella species lysate or the extract or the fraction thereof, or the composition that increases abundance or supports growth of the Prevotella species in the gut of the subject;(ii) if the amount of the Pseudomonas species in the gut of the subj ect is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Pseudomonas species in the gut of the subject;(iii) if the amount of the Shigella species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Shigella species in the gut of the subject.(iv) if the amount of the Achromobacter species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Achromobacter species in the gut of the subject;(v) if the amount of the Ralstonia species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Ralstonia species in the gut of the subject;(vi) if the amount of the Klebsiella species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Klebsiella species in the gut of the subject;(vii) if the amount of the Arcobacter species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Arcobacter species in the gut of the subject;(viii) if the amount of the Citrobacter species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Citrobacter species in the gut of the subject; and / or(ix) if the amount of the Escherichia species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Escherichia species in the gut of the subject.

[0030] In some embodiments, the sample is a microbial sample or a fecal sample. Monitoring the abundance or analyzing the sample can comprise analyzing nucleic acid in the sample.

[0031] Treating PCD include, but is not limited to, reducing or ameliorating the severity of the disease, reducing or ameliorating the severity of one or more symptoms associated with the disease, slowing progression of the disease, slowing progression of one or more symptoms associated with the disease, reducing severity of the disease, reducing severity of one or more symptoms of the disease, delaying onset of the disease, delaying onset of one or more symptoms associated with the disease, preventing the disease, preventing one or more symptoms associated with the disease, reduce the duration of a symptom associated with a disease, regressing the disease, regressing one or more symptoms associated with the disease,reducing recurrence of one or more symptom associated with the disease, or increasing or prolonging survival of a subject with a disease.

[0032] Described are methods of determining a risk of developing a PCD or one or more symptoms of a PCD comprising: (a) analyzing a sample of a microbiota from a gut or a stool sample of a subject to determine an amount of one or more of a Prevotella species, a Pseudomonas species, and a Shigella species in the sample; and (b) comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, and the Shigella species in the sample to a predetermined control; wherein an amount of the Prevotella species in the sample lower than the predetermined control, and / or an amount of Pseudomonas species and / or the Shigella species in the sample that is higher than the predetermined control, indicates the subject is at increased risk of developing the PCD. In some embodiments, the PCD comprises a neurodegenerative disease. The neurodegenerative disease can be, but is not limited to, Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease, amyotrophic lateral sclerosis, multiple system atrophy, Lewy' body dementia, Creutzfeldt-Jakob disease, prion disease, or amyloidosis.

[0033] Described are methods of determining a risk of developing a PCD or one or more symptoms of a PCD comprising: (a) analyzing a sample of a microbiota from a gut or a stool sample of a subject to determine an amount of one or more of a Prevotella species, a Pseudomonas species, and a Shigella species, an Achromobacler species, a. Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and a Escherichia species in the sample; and (b) comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and the Escherichia species in the sample to a predetermined control; wherein an amount of the Prevotella species in the sample lower than the predetermined control, and / or an amount of Pseudomonas species, the Shigella species the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and / or the Escherichia species in the sample that is higher than the predetermined control, indicates the subject is at increased risk of developing the PCD. In some embodiments, the PCD comprises a neurodegenerative disease. The neurodegenerative disease can be, but is not limited to, Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease, amyotrophic lateral sclerosis, multiple system atrophy, Lewy body dementia, Creutzfeldt-Jakob disease, prion disease, or amyloidosis.

[0034] Described are methods of treating or preventing a PCD in a subject, the methods comprising: administering to the subject one or more therapeutic treatments that target one or more identified bacteria that disrupt proteostasis. In some embodiments, the one or more therapeutic treatments comprise bacteriophages that specifically target the one or more identified bacteria that disrupt proteostasis. In some embodiments, the bacteria are a Pseudomonas species, a Shigella species, or a combination thereof. In some embodiments, the bacteria are a Pseudomonas species, a Shigella species, an Achromobacter species, aRalstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, an Escherichia species, or a combination two or more thereof. The therapeutic can be, but is not limited to, a bacteriophage. In some embodiments, the one or more therapeutics comprises a bacteriophage that specifically targets the Pseudomonas species. In some embodiments, the one or more therapeutics comprises a bacteriophage that specifically targets the Shigella species. In some embodiments, the one or more therapeutics comprises a bacteriophage that specifically targets the Pseudomonas species and a bacteriophage that specifically targets the Shigella species. In some embodiments, the PCD is a neurodegenerative disease. The PCD can be, but is not limited to, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or a prion disease.

[0035] Described are methods of decreasing protein misfolding in a subject, the methods comprising administering to the subject one or more of:(a) a Prevolella species, a composition containing the Prevotella species, a composition comprising lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject;(b) a composition that specifically decreases the abundance or inhibits the grow th of a Pseudomonas species in the gut of the subject; and(c) a composition that specifically decreases the abundance or inhibits the growth of a Shigella species in the gut of the subject.In some embodiments, the method comprises (a) and (b). In some embodiments, the method comprises (a) and (c). In some embodiments, the methods comprise (a), (b) and (c). In some embodiments, the composition that specifically decreases the abundance or inhibits the growth of a Pseudomonas species comprises a bacteriophage. In some embodiments, the composition that specifically decreases the abundance or inhibits the growth of a Shigella species comprises a bacteriophage.

[0036] Described are methods for increasing expression of HSP and / or activation of a heat shock response in a subject comprising: administering to the subject Prevotella corporis; a composition containing Prevotella corporis; a composition comprising killed Prevotella corporis or a Prevotella corporis lysate or an extract or a fraction thereof; a composition that increases abundance or supports grow th of Prevotella corporis in the gut of the subject; or combinations thereof.

[0037] Described are methods for increasing expression of mucin-associated membrane proteins MUC3 and / or MUC4 in a subject comprising: administering to the subject Prevotella corporis; a composition containing Prevotella corporis; a composition comprising killed Prevotella corporis or a Prevotella corporis lysate or an extract or a fraction thereof; a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject; or combinations thereof.

[0038] Described are methods for inhibiting proteotoxicity caused by a bacterial species in a subject, comprising administering to the subj ect Prevotella corporis; a composition containing Prevotella corporis; a composition comprising killed Prevotella corporis or a Prevotella corporis lysate or an extract or a fraction thereof; a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject; or combinations thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG. 1. Schematic illustrating the method used to assess the effect of bacterial isolates on C. elegans proteostasis.

[0040] FIG. 2. Heat map showing the extent of the screen that identified the effect of human bacterial isolates on C. elegans intestinal polyQ aggregation using a biophysical method (fluorescent aggregate count) and a biochemical method (Western blotting). Aggregation data are normalized to worms fed control E. coll OP50.

[0041] FIG. 3. The effect of Prevotella species on proteins associated with neurodegenerative diseases. A) The effect of Prevotella species on C. elegans intestinal polyQ aggregation (“Aggregates”) and the associated toxicity (“Motility”). Checkered bars represent bacteria-associated developmental delay. The three strongest suppressors of polyQ aggregation that did not affect development were tested using intestinal polyQ, B) neuronal polyQ, C) muscle polyQ, D) muscle Ap l -42. and E) muscle a-synuclein. Data are represented as the average number of aggregates or TOP (seconds) per worm obtained from at least two independent experiments for a total of 30-60 worms. Error bars represent standard error of the mean (SEM). Statistical significance was calculated using one-way ANOVA followed bymultiple comparison Dunnett's post-hoc test (*p<0.05. **p<0.01, ***p<0.001, ****p<0.0001).

[0042] FIG. 4. Graphs illustrating the effect of proteotoxic bacteria on proteins associated with neurodegenerative diseases. A) The effect of gram-negative, aerobic bacteria on C. elegans intestinal polyQ aggregation (“Aggregates”) and the associated toxicity ("Motility"). Three robust enhancers of polyQ aggregation were tested using intestinal polyQ, B) neuronal polyQ. C) muscle polyQ, D) muscle A(3I-42. and E) muscle a-synuclein. Data are represented as the average number of aggregates or TOP (seconds) per worm obtained from at least two independent experiments for a total of 30-60 worms. Error bars represent SEM. Statistical significance was calculated using one-way ANOVA followed by multiple comparison Dunnet’s post-hoc test (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

[0043] FIG. 5. Image (panel A) illustrating aggregation of A01-42 in worms fed various bacteria and graphs (panel B) illustrating time-off-pick (TOP) in control worms or worms expressing muscle AP1-42.

[0044] FIG. 6. Graphs illustrating age dependence of aggregation of muscle A(3I-42 (panel A) and a-synuclein (panel B). Data are represented as the average TOP (seconds) per worm. Each data point represents two independent experiments for a total of 20 worms. Error bars represent SEM. Statistical significance was calculated using one-way analysis of variants (ANOVA) followed by multiple comparison Dunnett’s post-hoc test (***p<0.001, ****p<0.0001).

[0045] FIG. 7. Graph illustrating effect of P. corporis on motility in worms expressing an endogenous temperature-sensitive mutation that leads to protein misfolding in muscle or neuronal tissue at the restrictive temperature of 25 °C . Wild-ty pe (WT) indicates the N2 control worms. Data are represented as the average TOP (seconds) per worm. Each data point represents three independent expenments for a total of 30 worms. Error bars represent SEM. Statistical significance was calculated using Student's t-test (***p<0.001, ****p<0.0001).

[0046] FIG. 8. Graph illustrating effect of various enteric bacteria on host proteostasis assessed by polyQ aggregation in the C. elegans intestine.

[0047] FIG. 9. Workflow for identification of bacterial proteins that affect host proteostasis.

[0048] FIG. 10. Graphs and images illustrating the effect of P. corporis on bacteria-induced polyQ aggregation and activation of the heat-shock response. The effect of co-colonizing intestinal polyQ44 worms with (A) K. pneumoniae HM-751 and P. corporis HM-1294, (B) E. coli OP50 and P. corporis HM-12924, and (C) K. pneumoniae HM-751 and / :, coli OP50. Data are represented as the average number of aggregates per intestinal polyQ44 worm obtainedfrom three independent experiments for a total of 60 worms. Statistical significance was calculated using one-way analysis of variants (ANOVA) followed by multiple comparison Dunnett's post-hoc test (****p<0.0001). (D) Nomarski and fluorescent (EGFP) images of transgenic worms expressing transcriptional fusion reporter hsp70p'. :GFP, fed E. coll OP50, P. corporis HM-1294, K. pneumoniae HM-751, and as a positive control, heat-shocked worms fed E. coli OP50. Scale bar is 200 pm.

[0049] FIG. 11. Graph illustrating the effect of P. corporis on phary ngeal pumping. Data are represented as the average number of pharyngeal pumps per 30 seconds for a total of ten data points per worm (N2) and three independent experiments for a total of 20 worms per condition. Mean pumping rates of worms fed P. corporis HM-1294 (101.22 pumps / 30 sec ± SEM 1.28) are not significantly different from those fed E. coli OP50 control (89.97 ± 1.68 SEM) as determined by t-test (p>0.9999); distribution of pumping rates of worms fed P. corporis HM- 1294 are not significantly different from those fed E. coli OP50 control as determined by Kolmogorov-Smirnov test (p=0.9639).

[0050] FIG. 12. Graph illustrating the effect of PFA-killed P. corporis on intestinal polyQ aggregation. Data are represented as the average number of aggregates per intestinal polyQ44 worm. Each bar represents two independent experiments for a total of 60 worms. Error bars represent SEM. Statistical significance was calculated using Student's t-test (****p<0.0001).

[0051] FIG. 13. Graph illustrating colonization of proteotoxic bacteria in the C. elegans intestine. Data are represented as the average bacterial load per N2 worm [Log(CFU / worm)]. Each bar represents three independent experiments for a total of 30 worms. Error bars represent SEM.

[0052] FIG. 14. Graph illustrating the effect of bacterial supernatants on intestinal polyQ aggregation in C. elegans. Data are represented as the average number of aggregates per intestinal polyQ44 worm. Each bar represents three independent experiments for a total of 98 worms. Error bars represent SEM. Statistical significance was calculated using one-way analysis of variants (ANOVA) followed by Dunnett's post-hoc test (**p<0.01, ***p<0.001).DETAI ED DESCRIPTION

[0053] The scope of the present invention is defined by the claims appended hereto and is not limited by certain embodiments described herein. Those skilled in the art, reading the present specification, will be aware of various modifications that may be equivalent to such described embodiments, or otherwise within the scope of the claims. In general, terms used herein are in accordance with their understood meaning in the art, unless clearly indicatedotherwise. Explicit definitions of certain terms are provided below; meanings of these and other terms in particular instances throughout this specification will be clear to those skilled in the art from context. Additional definitions for the following and other terms are set forth throughout the specification. Patent and non-patent literature references cited within this specification, or relevant portions thereof, are incorporated herein by reference in their entireties.

[0054] The singular forms of the articles “a.” “an,” and ‘‘the” include plural references unless the context clearly dictates otherwise. For example, the term “an element” or “at least one element” can include a plurality of elements, including mixtures thereof.

[0055] The term “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0056] The term “or” refers to any one member of a particular list.

[0057] Designation of a range of values includes all integers within or defining the range, and all subranges defined by integers within the range.

[0058] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not.

[0059] As used herein, the terms “about” and “approximately,” when used to modify an amount specified in a numeric value or range, indicates the numeric value as well as reasonable deviations from the value known to the skilled person in the art. In some embodiments, the term “about” means within the typical ranges of tolerances in the art. In some embodiments, the term “about” means within 1 or 2 standard deviations from the mean. In some embodiments, the term “about” means ±10%. In some embodiments, the term “about” means ±5%. When the term “about” is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range.

[0060] The term “subject,” “individual,” and “patient,” as used interchangeably herein, refer to a mammal, including but not limited to humans, non-human primates, rodents (e.g., rats, mice, and guinea pigs), rabbits, cows, pigs, horses, and other mammalian species. In some embodiments, the subject is a human.

[0061] A “protein conformational disease” (PCD) (also termed proteinopathy) is a disease where one or more cellular functions are compromised because of misfolded proteins or nonnative protein conformations. Disease can be caused by loss of function of the protein and / oraggregation or accumulation of misfolded proteins. PCD can be genetic, age-related, or infectious (e.g., prion diseases). For some proteins, the misfolded conformation is able to interact with other copies of the same protein and induce their transition into the misfolded state. Inherited genetic defects that result in the misfolding of proteins may lead to recessive disorders if the proteins in question are totally or partly eliminated or to dominant diseases if the misfolded proteins accumulate in the cell. Misfolding may also occur in proteins with an intrinsic ability to aggregate and in oxidatively damaged proteins, which accumulate by aging. Misfolding of proteins is a contributing factor in the development of late onset neurodegenerative disorders.

[0062] “Proteotoxicity” refers to the adverse effects of damaged or misfolded proteins on a cell. Proteotoxicity also refers to the process by which a protein or proteins misfold and exert atoxic effect on cells or cellular metabolism.

[0063] The terms “treat,” “treatment,” and the like, mean the methods or steps taken to provide relief from, or amelioration or alleviation of the number, severity, adverse effect, and / or frequency of one or more symptoms or pathological consequences of a disease, disorder, or condition in a subject. Treatment can be prophylactic in terms of preventing or partially preventing a disease, or a symptom or condition of the disease. Preventing includes providing prophylaxis with respect to the occurrence or recurrence of a disease in a subject that may be predisposed to the disease but has not yet been diagnosed with the disease. Preventing also includes providing prophylaxis with respect to the occurrence or recurrence of a symptom or pathological consequence of a disease in a subject that may be predisposed symptom or pathological consequence of the disease but has not yet been diagnosed with the symptom or pathological consequence the disease. Treatment can also be prophylactic in terms of delaying onset of a disease, or a symptom or condition of the disease. Delaying development of a disease or symptom or pathological consequence of the disease indicates deferring, hindering, slowing, retarding, stabilizing, suppressing, and / or postponing development of the disease or symptom or pathological consequence of the disease. The delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. Treating can include inhibiting the disease, disorder, or condition, e.g.. impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. Treatment can also mean prolonging survival as compared to expected survival in the absence of treatment. Treatment can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, orcondition. The term treatment can include: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. Treating can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those previously diagnosed with a disease, disorder, or condition, or those identified as being at risk of developing a disease, disorder, or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected.

[0064] The term "‘pharmaceutically acceptable excipient’" refers to a non-active pharmaceutical ingredient that is biologically or pharmacologically compatible for use in humans or animals, such as but not limited to a buffer, carrier, or preservative.

[0065] An “effective amount'’ of an agent, e.g., a dual transporter or a pharmaceutical formulation containing a dual transporter, in the context of administration, refers to an amount effective, at dosages / amounts and for periods of time necessary, to achieve a desired result, such as a therapeutic or prophylactic result.

[0066] A “therapeutically effective amount” of an agent, e.g., a dual transporter or a pharmaceutical formulation containing a dual transporter, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result, such as for treatment of a disease, condition, or disorder, and / or pharmacokinetic or pharmacodynamic effect of the treatment. The therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the subject, and the populations of cells administered.

[0067] A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. A prophylactically effective amount may be less than the therapeutically effective amount of the same drug.

[0068] A “dose,” “unit dose.” or “dosage” refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of active pharmaceutical ingredient and / or a pharmaceutical composition.

[0069] The term “administer” refers to a method of delivering agents, compounds, or compositions to the desired site of biological action. These methods include, but are not limited to, oral delivery’, topical delivery, parenteral delivery, intravenous delivery, intradermaldeliver}', intramuscular deliver}', intrathecal deliver}', colonic delivery, rectal delivery, or intraperitoneal delivery. In one embodiment, the compositions described herein are administered intravenously. A molecule that is ‘‘administered peripherally” means that the molecule is not administered directly to CNS (e.g., not administered intrathecally or directly into the brain, such as intracerebroventricularly). Thousands of bacterial species colonize the human body. Genetic analyses have identified 1473 genomes in the human mouth and 2182 genomes in the human gut. Bacterial species have also been identified on skin, vagina, and other body parts. In addition, the human microbiota is affected by lifestyle, diet, drugs, and aging.

[0070] A pharmaceutically acceptable excipient (excipient) is a substance other than an active pharmaceutical ingredient (API, therapeutic product) that is intentionally included with the API. Excipients do not exert or are not intended to exert a therapeutic effect at the intended dosage. Excipients may act to a) aid in processing of the API during manufacture, b) protect, support, or enhance stability', bioavailability or subject acceptability of the API, c) assist in product identification, and / or d) enhance any other attribute of the overall safety, effectiveness, of delivery of the API during storage or use. A pharmaceutically acceptable excipient may or may not be an inert substance. Excipients include, but are not limited to: absorption enhancers, anti-adherents, anti-foaming agents, anti-oxidants, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, delivery polymers, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavors, glidants, humectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repelling agents, and wetting agents

[0071] Described are compositions and methods of using the compositions to treat PCDs in a host. The compositions include formulations that increase beneficial bacteria (bacteria that enhance proteostasis in the host) in the gut, formulations comprising a component of a bacterial species that enhances proteostasis, and / or formulations that decrease detrimental bacteria (bacteria that disrupt or decrease proteostasis in the host) in the gut.

[0072] Described are methods of decreasing protein misfolding in a subject, the methods comprising administering to the subject one or more compositions that specifically increase the abundance or grow th, in the gut of the subject, of one or more bacterial species that enhances proteostasis in the subject; one of more compositions comprising a component of a bacterial species that enhances proteostasis in the subject, and / or one or more compositions thatspecifically decrease the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject.

[0073] In some embodiments, the bacterial species that enhances proteostasis in the subject is a Prevotella species. Compositions that increase the abundance of a Prevotella sp. in the gut include but are not limited to, isolated Prevotella sp. bacteria, a composition comprising the isolated Prevotella sp. bacteria, or a composition that increases or supports growth of the Prevotella species in the gut of the subject. Compositions comprising a component of a bacterial species that enhances proteostasis in the subject include, but are not limited to, a purified Prevotella sp. protein, killed Prevotella sp. bacteria, a Prevotella sp. lysate or a fraction thereof, or a Prevotella sp. extract or fraction thereof. In some embodiments, the Prevotella sp. is Prevotella corporis. In some embodiments, the Prevotella species is Prevotella amnii, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella histicola, Prevotella melaninogencia, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella timonensis, or Prevotella veroralis.

[0074] In some embodiments, the bacterial species that disrupts proteostasis in the subject is a Pseudomonas species and / or a Shigella species. In some embodiments, a composition that decreases the abundance of a Pseudomonas species and / or a Shigella species comprises a bacteriophage. In some embodiments, the composition that decreases the abundance of the Pseudomonas species comprises a bacteriophage that specifically targets (infects) the Pseudomonas species. In some embodiments, the Pseudomonas species is Pseudomonas aeruginosa. In some embodiments, the composition that decreases the abundance of the Shigella species comprises a bacteriophage that specifically targets (infects) the Shigella species.

[0075] In some embodiments, the bacterial species that disrupts proteostasis in the subject is a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, or an Escherichia species. In some embodiments, a composition that decreases the abundance of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, or the Escherichia species comprises a bacteriophage. In some embodiments, the composition that decreases the abundance of the Pseudomonas species comprises a bacteriophage that specifically targets (infects) the Pseudomonas species. In some embodiments, the composition that decreases the abundance of the Shigella species comprises a bacteriophage that specifically targets (infects) the Shigellaspecies. In some embodiments, the composition that decreases the abundance of the Achromobacter species comprises a bacteriophage that specifically targets (infects) the Achromobacter species. In some embodiments, the composition that decreases the abundance of the Ralstonia species comprises a bacteriophage that specifically targets (infects) the Ralstonia species. In some embodiments, the composition that decreases the abundance of the Klebsiella species comprises a bacteriophage that specifically targets (infects) the Klebsiella species. In some embodiments, the composition that decreases the abundance of the Arcobacter species comprises a bacteriophage that specifically targets (infects) the Arcobacter species. In some embodiments, the composition that decreases the abundance of the Citrobacter species comprises a bacteriophage that specifically targets (infects) the Citrobacter species. In some embodiments, the composition that decreases the abundance of the Escherichia species comprises a bacteriophage that specifically targets (infects) the Escherichia species.

[0076] In some embodiments, the methods comprise administering to the subject (a) one or more compositions that specifically increases the abundance or growth, in the gut of the subject, of one or more bacterial species that enhances proteostasis in the subject or one of more compositions comprising a component of a bacterial species that enhances proteostasis in the subject, and (b) one or more compositions that specifically decreases the abundance or grow th, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject. In some embodiments, the bacterial species that enhances proteostasis in the subject is aPrevotella species. In some embodiments, the Prevotella species is P. corporis. In some embodiments, the one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject comprises a bacteriophage that specifically targets a Pseudomonas species. In some embodiments, the one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject comprises a bacteriophage that specifically targets a Shigella species. In some embodiments, the one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject comprises a bacteriophage that specifically targets a Pseudomonas species and bacteriophage that specifically targets a Shigella species.

[0077] In some embodiments, the methods comprise administering to the subject (a) one or more compositions that specifically increases the abundance or growth, in the gut of the subject, of one or more bacterial species that enhances proteostasis in the subject or one ofmore compositions comprising a component of a bacterial species that enhances proteostasis in the subject, and (b) one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject. In some embodiments, the bacterial species that enhances proteostasis in the subject is a Prevotella species. In some embodiments, the Prevotella species is P. corporis. In some embodiments, the Prevotella species is Prevotella amnii, Prevotella bivia, Prevotella buccae. Prevotella denticola. Prevotella disiens. Prevotella histicola. Prevotella melaninogencia, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella timonensis, or Prevotella veroralis. In some embodiments, the one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject comprises a bacteriophage that specifically targets a Pseudomonas species. In some embodiments, the one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject comprises one or more bacteriophages that specifically target one or more of a Shigella species, a Pseudomonas species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, an Escherichia" or combination of two or more thereof.

[0078] Specifically increases the abundance or supports grow th of a bacterial species in the gut of a subject indicates the composition increases the abundance or growth of the target bacterial species in the gut of the subject without substantially increasing the abundance or growth of bacteria of a different genus or species in the gut of the subject. In some embodiments, a composition that specifically increases the abundance or growth of a Prevotella species in the gut of a subject increases abundance or supports growth of the Prevotella corporis relative to other species in the gut, particularly a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species.

[0079] Specifically decreases the abundance or growth of a bacterial species in the gut of a subject indicates the composition decreases the abundance or growth of the target bacterial species in the gut of the subject without substantially decreasing the abundance or growth of bacteria of a different genus or species in the gut of the subject.

[0080] Enhances proteostasis indicates the level or rate of protein misfolding in the subject is less when the bacterial species that enhances proteostasis is present in the gut of the subject,or present in the gut above a predetermined amount, relative to the level or rate of protein misfolding in the subject is the absence of the bacteria species in the gut or when the abundance of the bacteria species is below a predetermined amount in the gut. Enhances proteostasis indicates ability of a cell to buffer misfolded proteins.

[0081] In some embodiments, enhancing proteostasis comprises increasing expression of heat shock protein (HSP) and / or activation of a heat shock response in a subject. Increasing expression of heat shock protein (HSP) and / or activation of a heat shock response in a subject can comprise administrating to the subject: Prevotella corporis; a composition containing Prevotella corporis; a composition comprising killed Prevotella corporis or a Prevotella corporis lysate or an extract or a fraction thereof; a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject; or combinations thereof.

[0082] In some embodiments, enhancing proteostasis comprises increasing expression of mucin-associated membrane proteins MUC3 and / or MUC4 in a subject. Increasing expression of MUC3 and / or MUC4 in a subject can comprise administrating to the subject: Prevotella corporis; a composition containing Prevotella corporis; a composition comprising killed Prevotella corporis or a Prevotella corporis lysate or an extract or a fraction thereof; a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subj ect; or combinations thereof.

[0083] Disrupts proteostasis indicates the level or rate of protein misfolding in the subject is greater when the bacterial species that disrupts proteostasis is present in the gut of the subject, or present in the gut above a predetermined amount, relative to the level or rate of protein misfolding in the subject is the absence of the bacteria species in the gut or when the abundance of the bacteria species is below- a predetermined amount in the gut.

[0084] Described are methods for treating PCD, the methods comprising administering to the subject one or more compositions that specifically increases the abundance or growth, in the gut of the subject, of one or more bacterial species that enhances proteostasis in the subject; one of more compositions comprising a component of a bacterial species that enhances proteostasis in the subject, and / or one or more compositions that specifically decrease the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject.

[0085] In some embodiments, the bacterial species that enhances proteostasis in the subject is a Prevotella species. Compositions that increase the abundance of a Prevotella sp. in the gut include but are not limited to. isolated Prevotella sp. bacteria, a composition comprising theisolated Prevotella sp. bacteria, or a composition that specifically increases or supports growth of the Prevotella species in the gut of the subject. Compositions comprising a component of a bacterial species that enhances proteostasis in the subject include, but are not limited to, killed Prevotella sp. bacteria, a composition comprising killed Prevotella sp. bacteria, a purified Prevotella sp. protein, a Prevotella sp. lysate or a fraction thereof, or a Prevotella sp. extract or fraction thereof. In some embodiments, the Prevotella sp. is Prevotella corporis. In some embodiments, the Prevotella species is Prevotella amnii, Prevotella bivia, Prevotella buccae. Prevotella denticola, Prevotella disiens, Prevotella histicola, Prevotella melaninogencia, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella timonensis, or Prevotella ver oralis.

[0086] In some embodiments, the bacterial species that disrupts proteostasis in the subject is a Pseudomonas species and / or a Shigella species. In some embodiments, a composition that decreases the abundance of a Pseudomonas species and / or a Shigella species comprises a bacteriophage. In some embodiments, a composition that decreases the abundance of a Pseudomonas species and / or a Shigella species comprises a lytic bacteriophage. In some embodiments, the composition that decreases the abundance of the Pseudomonas species comprises a bacteriophage that specifically targets (infects) the Pseudomonas species. In some embodiments, the Pseudomonas species is Pseudomonas aeruginosa. In some embodiments, the composition that decreases the abundance of the Shigella species comprises a bacteriophage that specifically targets (infects) the Shigella species.

[0087] In some embodiments, the bacterial species that disrupts proteostasis in the subject is a an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species. In some embodiments, a composition that decreases the abundance of the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and / or the Escherichia species comprises a one or more bacteriophages that specifically target (infect) the Achromobacter, Ralstonia, Klebsiella, Arcobacter, Citrobacter, and / or the Escherichia bacterial species. In some embodiments, a composition that decreases the abundance of the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and / or the Escherichia species comprises a one or more lytic bacteriophages that specifically target (infect) the Achromobacter, Ralstonia, Klebsiella, Arcobacter, Citrobacter, and / or the Escherichia bacterial species.

[0088] In some embodiments, the methods for treating a PCD comprise administering to the subject one or more compositions that specifically increases the abundance or growth, in the gut of the subject, of one or more bacterial species that enhances proteostasis in the subject or one of more compositions comprising a component of a bacterial species that enhances proteostasis in the subject. In some embodiments, the bacterial species that enhances proteostasis in the subject is a Prevotella species. In some embodiments, the Prevotella species is Prevotella corporis. In some embodiments, the Prevotella species is Prevotella amnii. Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella histicola, Prevotella melaninogencia, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella timonensis, or Prevotella veroralis.

[0089] In some embodiments, the methods for treating a PCD comprise administering to the subject one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject. In some embodiments, the bacterial species that disrupts proteostasis in the subject is a Pseudomonas species and / or a Shigella species. In some embodiments, a composition that decreases the abundance of a Pseudomonas species and / or a Shigella species comprises a bacteriophage (e.g., a lytic bacteriophage). In some embodiments, the composition that decreases the abundance of the Pseudomonas species comprises a bacteriophage that specifically targets (infects) the Pseudomonas species. In some embodiments, the Pseudomonas species is Pseudomonas aeruginosa. In some embodiments, the composition that decreases the abundance of the Shigella species comprises a bacteriophage that specifically targets (infects) the Shigella species.

[0090] In some embodiments, the methods for treating a PCD comprise administering to the subject one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject. In some embodiments, the bacterial species that disrupts proteostasis in the subject is a Pseudomonas species, a Shigella species, an Achromobacter species, aRalstonia species, a Klebsiella species, an Arcobacter species. a Citrobacter species, or an Escherichia species. In some embodiments, a composition that decreases the abundance of the bacterial species that disrupts or decreases proteostasis in the subject comprises one or more bacteriophage (e.g., a lytic bacteriophage) that infects one or more of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, or the Escherichia species.

[0091] In some embodiments, the methods for treating a PCD comprise administering to the subject one or more compositions that inhibits the proteotoxicity of one or more bacterial species that disrupts or decreases proteostasis in the subject. In some embodiments, the bacterial species that disrupts proteostasis in the subject is a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, o an Escherichia species. In some embodiments, a composition that that inhibits the proteotoxicity caused by a bacterial species (e.g.. a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, or an Escherichia species) comprises a composition comprising Prevotella corporis^ a composition containing Prevotella corporis,' a composition comprising killed Prevotella corporis ox a Prevotella corporis lysate or an extract or a fraction thereof; a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject; or combinations thereof.

[0092] In some embodiments, the methods for treating a PCD comprise administering to the subject (a) one or more compositions that specifically increases the abundance or growth, in the gut of the subject, of one or more bacterial species that enhances proteostasis in the subject or one of more compositions comprising a component of a bacterial species that enhances proteostasis in the subject, and (b) one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject. In some embodiments, the bacterial species that enhances proteostasis in the subject is a Prevotella species. In some embodiments, the Prevotella species is P. corporis. In some embodiments, the one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject comprises a bacteriophage that specifically targets a Pseudomonas species. In some embodiments, the one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject comprises a bacteriophage that specifically targets a Shigella species. In some embodiments, the one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject comprises a bacteriophage that specifically targets a Pseudomonas species and bacteriophage that specifically targets a Shigella species.

[0093] In some embodiments, the methods for treating a PCD comprise administering to the subject (a) one or more compositions that specifically increases the abundance or growth, in the gut of the subject, of one or more bacterial species that enhances proteostasis in the subject or one of more compositions comprising a component of a bacterial species that enhances proteostasis in the subject, and (b) one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject. In some embodiments, the bacterial species that enhances proteostasis in the subject is a Prevotella species. In some embodiments, the Prevotella species is / < corporis. In some embodiments, the Prevotella species is Prevotella amnii, Prevotella bivia, Prevotella buccae, Prevotella deniicola. Prevotella disiens, Prevotella histicola. Prevotella melaninogencia, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella timonensis, or Prevotella veroralis. In some embodiments, the one or more compositions that specifically decreases the abundance or growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject comprises one or more bacteriophages that specifically target one or more of a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species.

[0094] In some embodiments, methods for increasing expression of HSP in a subject are described, the methods comprising administering to the subj ect one or more compositions that specifically increase the abundance or growth of & Prevotella species in the gut of the subject. Compositions that increase the abundance of Prevotella sp. in the gut include but are not limited to, isolated Prevotella sp. bacteria, a composition comprising the isolated Prevotella sp. bacteria, or a composition that specifically increases or supports growth of the Prevotella species in the gut of the subject. In some embodiments, methods for increasing expression of HSP in a subject are described, the methods comprising: administering to the subject killed Prevotella sp. bacteria, a composition comprising killed Prevotella sp. bacteria, a purified Prevotella sp. protein, a Prevotella sp. lysate or a fraction thereof, or a Prevotella sp. extract or fraction thereof, or combinations thereof. In some embodiments, the Prevotella species is Prevotella corporis. In some embodiments, the Prevotella species is Prevotella amnii. Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella histicola, Prevotella melaninogencia, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella timonensis, or Prevotella veroralis.

[0095] In some embodiments, methods for increasing expression of MUC3 and / or MUC4 in a subject are described, the methods comprising: administering to the subject one or more compositions that specifically increases the abundance or growth or aPrevotella species in the gut of the subject. Compositions that increase the abundance of a Prevotella sp. in the gut include but are not limited to, isolated Prevotella sp. bacteria, a composition comprising the isolated Prevotella sp. bacteria, or a composition that specifically increases or supports growth of the Prevotella species in the gut of the subj ect. In some embodiments, methods for increasing expression of MUC3 and / or MUC4 in a subject are described, the methods comprising: administering to the subject killed Prevotella sp. bacteria, a composition comprising killed Prevotella sp. bacteria, a purified Prevotella sp. protein, a Prevotella sp. lysate or a fraction thereof, or a Prevotella sp. extract or fraction thereof, or combinations thereof. In some embodiments, the Prevotella species is Prevotella corporis. In some embodiments, the Prevotella species is Prevotella amnii, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella histicola, Prevotella melaninogencia, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella timonensis, or Prevotella veroralis.

[0096] In some embodiments, methods for activating or inducing a heat shock response in a subject are described, the methods comprising: administering to the subject one or more compositions that specifically increases the abundance or growth or aPrevotella species in the gut of the subject. Compositions that increase the abundance of a Prevotella sp. in the gut include but are not limited to. isolated Prevotella sp. bacteria, a composition comprising the isolated Prevotella sp. bacteria, or a composition that specifically increases or supports growth of the Prevotella species in the gut of the subject. In some embodiments, methods for activating a heat shock response in a subject are described, the methods comprising: administering to the subject killed Prevotella sp. bacteria, a composition comprising killed Prevotella sp. bacteria, a purified Prevotella sp. protein, a Prevotella sp. lysate or a fraction thereof, or a Prevotella sp. extract or fraction thereof, or combinations thereof. In some embodiments, the Prevotella species is Prevotella corporis. In some embodiments, the Prevotella species is Prevotella amnii, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella histicola. Prevotella melaninogencia, Prevotella nigrescens, Prevotella oralis, Prevotella oris. Prevotella timonensis, ox Prevotella veroralis.

[0097] Described are compositions use in treating a PCD in a subject, the composition comprising: (a) isolated Prevotella species bacteria; (b) a composition containing Prevotella species bacteria: (c) a composition comprising killed Prevotella species bacteria; (d) acomposition comprising a Prevotella species lysate or an extract or a fraction thereof; (e) a composition that increases abundance or supports growth of Prevotella species in the gut of the subject; or (f) combinations of two or more of (a)-(e). In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an excipient.

[0098] Described are compositions use in treating a PCD in a subject, the composition comprising: (a) isolated Prevotella corporis bacteria; (b) a composition containing Prevotella corporis bacteria; (c) a composition comprising killed Prevotella corporis bacteria; (d) a composition comprising a Prevotella corporis lysate or an extract or a fraction thereof; (e) a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject; or (I) combinations of two or more of (a)-(e). In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an excipient.

[0099] Described are compositions use in increasing expression of HSP in a subject, the composition comprising: (a) isolated Pre votella corporis bacteria; (b) a composition containing Prevotella corporis bacteria' (c) a composition comprising killed Prevotella corporis bacteria;(d) a composition comprising a Prevotella corporis lysate or an extract or a fraction thereof;(e) a composition that increases abundance or supports grow th of Prevotella corporis in the gut of the subject; or (f) combinations of two or more of (a)-(e). In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an excipient.

[0100] Described are compositions use in increasing expression of MUC3 and / or MUC4 in a subject, the composition comprising: (a) isolated Prevotella corporis bacteria; (b) a composition containing Prevotella corporis bacteria; (c) a composition comprising killed Prevotella corporis bacteria; (d) a composition comprising a Prevotella corporis lysate or an extract or a fraction thereof; (e) a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject; or (f) combinations of two or more of (a)-(e). In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an excipient.

[0101] Described are compositions use in activating or inducing a heat shock response in a subject, the compositions comprising: (a) isolated Prevotella corporis bacteria; (b) a composition containing Prevotella corporis bacteria; (c) a composition comprising killed Prevotella corporis bacteria; (d) a composition comprising a Prevotella corporis lysate or anextract or a fraction thereof; (e) a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject; or (f) combinations of two or more of (a)-(e). In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an excipient.

[0102] In some embodiments, the isolated Prevotella species bacteria or the composition containing Prevotella species bacteria can be provided or formulated as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, or a granular pow der. The isolated Prevotella species bacteria can be cultured bacteria. The Prevotella species can be genetically modified.

[0103] In some embodiments, the isolated Prevotella corporis bacteria or the composition containing Prevotella corporis bacteria can be provided or formulated as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, or a granular powder. The isolated Prevotella corporis bacteria can be cultured bacteria. The Prevotella corporis can be genetically modified.

[0104] In some embodiments, the composition comprising killed Prevotella species bacteria or the composition containing Prevotella species bacteria can be provided or formulated as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, or a granular powder. The Prevotella species can be genetically modified.

[0105] In some embodiments, the isolated Prevotella corporis bacteria or the composition containing Prevotella corporis bacteria can be provided or formulated as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, or a granular powder. The Prevotella corporis can be genetically modified.

[0106] In some embodiments, the composition comprising the Prevotella species lysate or an extract or a fraction thereof, or the composition that increases abundance or supports growth of Prevotella species in the gut of the subject, can be provided or formulated as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, a granular powder, a food additive, a food composition, or a nutraceutical, or a supplement. The Prevotella species can be genetically modified.

[0107] In some embodiments, the composition comprising the Prevotella corporis lysate or an extract or a fraction thereof, or the composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject, can be provided or formulated as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, a granular powder, a food additive, a food composition, or a nutraceutical, or a supplement. The Prevotella corporis can be genetically modified.

[0108] In some embodiments, the composition comprises one or more additional active ingredients. The one or more additional active ingredients can comprise an agent or composition that decreases the abundance or inhibits the growth of a Pseudomonas species and / or a Shigella species in the gut of the subject. In some embodiments, the agent or composition comprises a bacteriophage.

[0109] In some embodiments, the composition comprises one or more additional active ingredients. The one or more additional active ingredients can comprise an agent or composition that decreases the abundance or inhibits the growth of one or more of a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species in the gut of the subject. In some embodiments, the agent or composition comprises a bacteriophage.

[0110] Described are compositions for use in treating a PCD in a subject, the compositions comprising: a composition that specifically decreases the abundance or inhibits the grow th of ^Pseudomonas species in the gut of the subject and / or a composition that specifically decreases the abundance or inhibits the growth of a Shigella species in the gut of the subject. In some embodiments, the compositions comprise a composition that specifically decreases the abundance or inhibits the growth of a Pseudomonas species in the gut of the subject and a composition that specifically decreases the abundance or inhibits the growth of a Shigella species in the gut of the subject. In some embodiments, the composition comprises at least one bacteriophage. In some embodiments, the composition comprises a bacteriophage that specifically targets the Pseudomonas species. In some embodiments, the composition comprises a bacteriophage that specifically targets the Shigella species. In some embodiments, the composition comprises a bacteriophage that specifically targets the Pseudomonas species and a bacteriophage that specifically targets the Shigella species. In some embodiments, the Pseudomonas species is Pseudomonas aeruginosa. The composition can be provided or formulated as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, a granular powder, a food additive, a food composition, or a nutraceutical, or a supplement. In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises one or more additional active ingredients. The one or more addition active ingredients can be, but is not limited to: Prevotella corporis, a composition containing Prevotella corporis, acomposition comprising a Prevotella corporis lysate or an extract or a fraction thereof, or a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject.[OHl] Described are compositions for use in treating a PCD in a subject, the compositions comprising: a composition that specifically decreases the abundance or inhibits the grow th of one or more of a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species in the gut of the subject. In some embodiments, the composition comprises at least one bacteriophage. In some embodiments, the composition comprises one or more bacteriophage that specifically target one or more of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and the Escherichia species. The composition can be provided or formulated as a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, a granular powder, a food additive, a food composition, or a nutraceutical, or a supplement. In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises one or more additional active ingredients. The one or more addition active ingredients can be, but is not limited to: a Prevotella species, a composition containing Prevotella species, a composition comprising a Prevotella species lysate or an extract or a fraction thereof, or a composition that increases abundance or supports growth of Prevotella species in the gut of the subj ect.

[0112] A bacteriophage is virus that infects bacteria. In some embodiments, the bacteriophage specifically infects a Pseudomonas species. In some embodiments, the bacteriophage specifically infects a Shigella species. In some embodiments, the bacteriophage specifically infects an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, or an Escherichia species. In some embodiments, the bacteriophage is a lytic bacteriophage. The bacteriophage can be a genetically modified bacteriophage. The bacteriophage can be genetically modified to increase killing of the target bacteria. Lytic bacteriophages have been identified for several bacterial species, including, but not limited to, Achromobacter xylosoxidans, Bacteroides dorei, Bacteroides finegoldii, Bacteroides fragilis, Citrobacter portucalensis, Citrobacter sp., Clostridiales bacterium, Clostridioides difficile, Clostridium cadaveris, Enterococcus faecalis, Escherichia coll,Klebsiella pneumoniae, Neisseria flavescens, Pseudomonas sp., Pseudomonas aeruginosa, Ralstonia sp., Shigella sp.. and Treponema denticola. Bacteriophage that target Pseudomonas aeruginosa have been described by Chegini Z et al. (‘'Bacteriophage therapy against Pseudomonas aeruginosa biofilms: a review.” Annals of Clinical Microbiology and Antimicrobials 2020 19(45). Bacteriophage that target Shigella species have been described by Goodridge LD (“Bacteriophages for managing Shigella in various clinical and non-clinical settings.” Bacteriophage. 2013 3(l):e25098.) Bacteriophage that target an Achromobacter species have been described by Wittmann et al. 2014 (“Isolation and Characterization of Numerous Novel Phages Targeting Diverse Strains of the Ubiquitous and Opportunistic Pathogen Achromobacter xylosoxidans" PLoS One 9(l):e86935) and Lebeaux et al. 2021 (“A Case of Phage Therapy against Pandrug-Resistant Achromobacter xylosoxidans in a 12-Year- Old Lung-Transplanted Cystic Fibrosis Patient” Viruses 13(1 ): 60). Bacteriophage that target a Ralstonia species have been described by Fujiwara et al. 2011 (“Biocontrol of Ralstonia solanacearum by Treatment with Lytic Bacteriophages” Appl. Environ. Microbiol. 77(12):4155-4162). Bacteriophage that target Klebsiella species have been described by Cao et al. 2015 (“Evaluation of the Efficacy of a Bacteriophage in the Treatment of Pneumonia Induced by Multidrug Resistance Klebsiella pneumoniae in Mice” BioMed Research International, Article ID 752930). Bacteriophage that target a Citrobacter species have been described by Tikhe et al. 2015 (“Complete Genome Sequence of Citrobacter Phage CVT22 Isolated from the Gut of the Formosan Subterranean Termite, Coptotermes formosanus Shiraki” Genome Announc. 3(4):e00408). Bacteriophage that target a Escherichia species have been described by Cieplak et al. 2018 (“A bacteriophage cocktail targeting Escherichia coli reduces E. coli in simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota” Gut Microbes 9(5): 391-399). Bacteriophage that target a Escherichia species have been described by

[0113] Described are methods of treating a subject suffering from a PCD or at risk of developing a PCD, the methods comprising: administering to the subject one or more of:(a) a Prevotella species, a composition containing the Prevotella species, a composition comprising killed Prevotella species bacteria, a composition comprising a lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject;(b) a composition that specifically decreases the abundance or inhibits the growth of a. Pseudomonas species in the gut of the subject; and(c) a composition that specifically decreases the abundance or inhibits the grow th of a Shigella species in the gut of the subject.

[0114] Described are methods of treating a subject suffering from a PCD or at risk of developing a PCD, the methods comprising: administering to the subject one or more of:(a) a Prevotella species, a composition containing the Prevotella species, a composition comprising killed Prevotella species bacteria, a composition comprising a lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject;(b) a composition that specifically decreases the abundance or inhibits the grow th of one or more of a Pseudomonas species, a Shigella specie, an Achromobact er species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species in the gut of the subject.

[0115] In some embodiments, the methods comprise administering to the subject a Prevotella species, a composition containing the Prevotella species, a composition comprising killed Prevotella species bacteria, a composition comprising a lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject.

[0116] In some embodiments, the methods comprise administering to the subject a composition that specifically decreases the abundance or inhibits the growth of a Pseudomonas species in the gut of the subject.

[0117] In some embodiments, the methods comprise administering to the subject a composition that specifically decreases the abundance or inhibits the growth of a Shigella species in the gut of the subject.

[0118] In some embodiments, the methods comprise administering to the subject a composition that specifically decreases the abundance or inhibits the growth of one or more of a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species in the gut of the subject.

[0119] In some embodiments, the methods comprise administering to the subject (a) a Prevotella species, a composition containing the Prevotella species, a composition comprising killed Prevotella species bacteria, a composition comprising a lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject; and (b) a composition that specificallydecreases the abundance or inhibits the grow th of a Pseudomonas species or a Shigella species in the gut of the subject.

[0120] In some embodiments, the methods comprise administering to the subject (a) a Prevotella species, a composition containing the Prevotella species, a composition comprising killed Prevotella species bacteria, a composition comprising a lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject; and (b) a composition that specifically decreases the abundance or inhibits the growth of a Pseudomonas species and a Shigella species in the gut of the subject.

[0121] In some embodiments, subjects suitable for treatment with the described compositions, or using the described methods, are identified by having a low relative abundance of Prevotella species in the gut. In some embodiments, subjects suitable for treatment with the described compositions, or using the described methods, are identified by having a high relative abundance of one or more of a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, or an Escherichia species in the gut. In some embodiments, subjects suitable for treatment with the described compositions, or using the described methods, are identified by having a low relative abundance of Prevotella species in the gut and a high relative abundance of one or more of a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, or an Escherichia species in the gut.

[0122] A low relative abundance of the Prevotella species (e.g., Prevotella corporis) in the gut of a subj ect indicates the abundance of the Prevotella species in the subj ect is lower relative to the abundance of the Prevotella species in the gut of a control population (e.g.. a population of healthy subjects) or is lower than a predetermined control. A high relative abundance of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, or the Escherichia species in the gut of a subject indicates the abundance of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, or the Escherichia species in the subject is higher relative to the abundance of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacterspecies, or the Escherichia species in the gut of a control population (e.g., a population of healthy subjects) or is higher than a predetermined control.

[0123] In some embodiments, the method further comprises monitoring the abundance of one or more of the Prevotella species, Pseudomonas species, and the Shigella species in the gut of the subject. In some embodiments, if the abundance of Prevotella species in the gut of the subject is below a predetermined value, then the Prevotella species, the composition containing Prevotella species, the composition comprising the killed Prevotella species bacteria, the composition comprising the Prevotella species lysate or the extract or the fraction thereof, or the composition that increases abundance or supports growth of the Prevotella species in the gut of the subject is administered to the subject. In some embodiments, if the abundance of the Pseudomonas species in subject is above a predetermined value, then the composition that specifically decreases the abundance or inhibits the growth of the Pseudomonas species in the gut of the subject is administered to the subject. In some embodiments, if the abundance of the Shigella species in the gut of the subject is above a predetermined value, then the composition that specifically decreases the abundance or inhibits the growth of the Shigella species in the gut of the subject is administered to the subject. In some embodiments, the Prevotella species is Prevotella corporis. In some embodiments, the Pseudomonas species is Pseudomonas aeruginosa or Pseudomonas stutzeri. In some embodiments, the Shigella species is Shigella Jlexneri. Shigella sonnei, Shigella dysenteriae, or Shigella boydii.

[0124] In some embodiments, the method further comprises monitoring the abundance of one or more of a Prevotella species, a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species in the gut of the subject. In some embodiments, if the abundance of Prevotella species in the gut of the subject is below a predetermined value, then the Prevotella species, the composition containing Prevotella species, the composition comprising the killed Prevotella species bacteria, the composition comprising the Prevotella species lysate or the extract or the fraction thereof, or the composition that increases abundance or supports growth of the Prevotella species in the gut of the subject is administered to the subject. In some embodiments, if the abundance of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and / or the Escherichia species in subject is above a predetermined value, then the composition that specifically decreases the abundance orinhibits the grow th of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and / or the Escherichia species in the gut of the subject is administered to the subject.

[0125] In some embodiments, the methods further comprise analyzing a sample of a microbiota from a gut or a stool sample from the subject to determine an amount of one or more of the Prevotella species, the Pseudomonas species, and the Shigella species in the sample and comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, and the Shigella species in the sample to a predetermined control; and (i) if the amount of the Prevotella species in the gut of the subject is below a predetermined value, then administering to the subject the Prevotella species, the composition containing Prevotella species, the composition comprising the killed Prevotella species bacteria, the composition comprising the Prevotella species lysate or the extract or the fraction thereof, or the composition that increases abundance or supports growth of the Prevotella species in the gut of the subject; (ii) if the amount of the Pseudomonas species in the gut of subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Pseudomonas species in the gut of the subject; and / or (iii) if the amount of the Shigella species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Shigella species in the gut of the subject. The sample can be. but is not limited to, a gut microbial sample, a mucosal biopsy, an intestinal fluid, or a fecal sample.

[0126] In some embodiments, the methods further comprise analyzing a sample of a microbiota from a gut or a stool sample from the subject to determine an amount of one or more of the Prevotella species, the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and the Escherichia species in the sample and comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and the Escherichia species in the sample to a predetermined control; and (i) if the amount of the Prevotella species in the gut of the subject is below a predetermined value, then administering to the subject the Prevotella species, the composition containing Prevotella species, the composition comprising the killed Prevotella species bacteria, the composition comprising the Prevotella species lysate or the extract or the fractionthereof, or the composition that increases abundance or supports growth of the Prevotella species in the gut of the subject; (ii) if the amount of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and / or the Escherichia species in the gut of subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and / or the Escherichia species that is above the predetermined value in the gut of the subject. The sample can be, but is not limited to, a gut microbial sample, a mucosal biopsy, an intestinal fluid, or a fecal sample.

[0127] Any method available in the art for detecting, measuring, or monitoring bacterial levels in the gut can be used to determine the amount the Prevotella species, the Pseudomonas species, and / or the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and / or the Escherichia species in the sample. The relative abundance of microbial taxa can be measured using techniques based on DNA sequencing, quantitative PCR, DNA microarray, by using test beds utilizing arrays or other suitable platforms, including microfluidic solutions, techniques based on droplet PCR, or any other suitable method wherein the abundance of taxa is expressed as read count, percentage, cell count, or value expressing intensity of any other suitable signal. Exemplary methods include, but are not limited to, analyzing nucleic acid in the sample.

[0128] Described are methods for determining a risk of developing a PCD or one or more symptoms of a PCD comprising: analyzing a sample of a microbiota from a gut or a stool sample of a subject to determine an amount of one or more of a Prevotella species, a Pseudomonas species, and a Shigella species in the sample; and comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, and the Shigella species in the sample to a predetermined control; wherein an amount of the Prevotella species in the sample lower than the predetermined control, and / or an amount of Pseudomonas species and / or the Shigella species in the sample that is higher than the predetermined control, indicates the subject is at increased risk of developing the PCD.

[0129] Described are methods for determining a risk of developing a PCD or one or more symptoms of a PCD comprising: analyzing a sample of a microbiota from a gut or a stool sample of a subject to determine an amount of one or more of a Prevotella species, a Pseudomonas species, and a Shigella species, an Achromobacter species, a Ralstonia species,a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia in the sample; and comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and the Escherichia species in the sample to a predetermined control; wherein an amount of the Prevotella species in the sample lower than the predetermined control, and / or an amount of the Pseudomonas species, the Shigella species. the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and / or the Escherichia species in the sample that is higher than the predetermined control, indicates the subject is at increased risk of developing the PCD.

[0130] In some embodiments, the predetermined value comprises a standard derived from a population of subjects known to suffer from a protein folding disease (e.g. , Alzheimer’s disease or Parkinson’s disease) or a population of subjects known to not suffer from the protein folding disease (i.e., healthy subjects). The abundance of Prevotella species, (e.g., Prevotella corporis , Pseudomonas species, (e.g, Pseudomonas aeruginosa), Shigella species, Achromobacter species, Ralstonia species, Klebsiella species. Arcobacter species, Citrobacter species, and / or Escherichia species as determined for the population is measured using the same or substantially the same method as used to measure the abundance of Prevotella species, (e.g, Prevotella corporis), Pseudomonas species, (e.g, Pseudomonas aeruginosa). Shigella species, Achromobacter species, Ralstonia species, Klebsiella species. Arcobacter species, Citrobacter species, and / or Escherichia species in an individual subject or subject to be treated. An abundance of Prevotella species (e.g. , Prevotella corporis) in the gut of a subject that is the lower relative to the abundance of the Prevotella species (e.g. , Prevotella corporis) determined for a population of healthy subjects indicates the subject is likely to respond to composition comprising: a Prevotella species (e.g, Prevotella corporis), a composition containing the Prevotella species (e.g, Prevotella corporis), a composition comprising lysate of the Prevotella species (e.g., Prevotella corporis) or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species (e.g, Prevotella corporis) in the gut of the subject. An abundance of Achromobacter species. Ralstonia species, Klebsiella species, Arcobacter species, Citrobacter species, and / or Escherichia species in the gut of a subject that is the higher relative to the abundance of the Pseudomonas species, Shigella species, Achromobacter species, Ralstonia species, Klebsiella species, Arcobacter species, Citrobacter species, and / or Escherichia species determined for apopulation of healthy subjects indicates the subject is likely to respond to composition comprising: a composition that specifically decreases the abundance or inhibits the growth of the Pseudomonas species, Shigella species, Achromobacter species, Ralstonia species, Klebsiella species, Arcobacter species, Citrobacter species, and / or Escherichia species in the gut of the subject.

[0131] The described compositions and methods can be used to treat or prevent a PCD in a subject. In some embodiments, the PCD is aneurodegenerative disease. Protein conformational diseases include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, cystic fibrosis, amyotrophic lateral sclerosis, alphal -antitrypsin deficiency liver disease, cerebral P-amyloid angiopathy, tauopathies. frontotemporal lobar degeneration, CADASIL, Alexander disease, Pelizaeus-Merzbacher disease, seipinopathies, familial amyloidotic neuropathy, serpinopathies, amyloidosis, hereditary cerebral hemorrhage with amyloidosis, senile systemic amyloidosis, aortic medial amyloidosis, ApoAI amyloidosis, ApoAII amyloidosis, ApoAIV amyloidosis, familial amyloidosis of the Finnish ty pe (FAF), lysozyme amyloidosis, fibrinogen amyloidosis, dialysis amyloidosis, cardiac atrial amyloidosis, cutaneous lichen amyloidosis, corneal lactoferrin amyloidosis, apolipoprotein C2 amyloidosis, apolipoprotein C3 amyloidosis, Lect2 amyloidosis, insulin amyloidosis, galectin- 7 amyloidosis, comeodesmosin amyloidosis, enfuvirtide amyloidosis, type II diabetes, inclusion body myositis / myopathy, cataracts, retinitis pigmentosa with rhodopsin mutations, retinal ganglion cell degeneration, medullary thyroid carcinoma, pituitary prolactinoma, hereditary lattice comeal dystrophy, mallory bodies, pulmonary alveolar proteinosis, odontogenic tumor amyloid, seminal vesicle amyloid, sickle cell disease, plasma cell dyscrasias, exfoliation syndrome, autism, Creutzfeldt-Jakob disease, multiple system atrophy, Lewy body dementia, and certain dementias.

[0132] In some embodiments, the subject is a human subject.

[0133] In some embodiments, the subject has or has been diagnosed with a PCD or is at increased risk of developing a PCD.

[0134] Treating a PCD include, but is not limited to, reducing or ameliorating the severity of the disease, reducing or ameliorating the severity of one or more symptoms associated with the disease, slowing progression of the disease, slowing progression of one or more symptoms associated with the disease, reducing severity of the disease, reducing severity of one or more symptoms of the disease, delaying onset of the disease, delaying onset of one or more symptoms associated with the disease, preventing the disease, preventing one or moresymptoms associated with the disease, reduce the duration of a symptom associated with a disease, regressing the disease, regressing one or more symptoms associated with the disease, reducing recurrence of one or more symptom associated with the disease, or increasing or prolonging survival of a subject with a disease.

[0135] The one or more symptoms of a PCT include, but are not limited to: anosmia, hyposmia, bradykinesia, ataxia, tremor, muscle rigidity, impaired gait, impaired posture and balance, loss of automatic movements, dysarthria or other speech changes, handwriting changes, orthostatic hypotension, memory deficit, dysphagia, incontinence, sleep disruption, cardiac arrhythmia, visual disturbance, psychiatric problems including depression and visual, auditory, olfactory, or tactile hallucinations, vertigo, cognitive dysfunction, altered dopamine levels, altered serotonin levels, altered kynurenine levels, and / or any combination thereof.

[0136] Also described are compositions and methods that can used to identify bacterial signals that disrupt host proteostasis, characterize bacterial genes that disrupt host proteostasis; and analyze bacterial influence on host stress responses and lifetime.EXAMP ESExample 1. Methods

[0137] A. C. elegans maintenance and strains. For experiments that generated the data represented in the heat-map (FIG. 2), nematodes were kept on E. coli OP50 for two days at 20°C, washed three times and transferred to indicated bacteria, where they were kept at 22.5°C for three days. For all other experiments, nematodes were plated on indicated bacteria as Lis at 22.5°C, where they remained until the time of assay, except for the experiment in FIG. 7, in which worms were cultured in temperatures indicated in the figure.

[0138] B. Bacterial culture conditions. All bacteria were cultured at 37°C. Bacteria were grown: 1) anaerobically in reinforced clostridial broth (RCB) with Oxyrase; 2) in facultative conditions (no shaking, tube filled to top) in brain heart infusion broth (BHI), 3) in aerobic conditions, shaking at 220 revolutions per minute (RPM) in BHI; 4) in anaerobic conditions on tryptic soy agar (TSA) supplemented with 5% defibrinated sheep’s blood; or 5) in aerobic conditions on TSA supplemented with 5% defibrinated sheep’s blood. E. coli OP50 controls were grown in a manner consistent with which experiment was performed. Bacteria were washed and resuspended in M9 before being seeded on NGM. All follow-up experiments were performed with bacteria grown on TSA supplemented with 5% defibrinated sheep’s blood at 37°C except for the intestinal confirmation experiment of the proteotoxic bacteria (FIG. 4 PanelA, “Aggregates”). Except for Prevotella species which were grown under anaerobic conditions, bacteria were grown aerobically in follow-up experiments.

[0139] C. Aggregate quantification. Fluorescent aggregates were quantified using Leica MZ10F Modular Stereo Microscope equipped with CoolLED pE3001ite 365 dir mount STEREO with filter set ET GFP-MZ10F. Fluorescent aggregates in worms used to generate data for the heat-map (FIG. 2) were manually quantified after having been cultured as indicated in “C. elegans maintenance and strains”. For all other experiments, worms were plated on indicated bacteria as Lis and fluorescent aggregates were manually quantified after four days (intestinal polyQ44) or three days (muscle polyQ35, 40) of life. Aggregates of worms that were quantified to generate the data used in the heat map were quantified blind.

[0140] D. Motility assays. All motility assays were performed at room temperature as described in Walker AC et al. 2021 (“Colonization of the Caenorhabditis Elegans Gut with Human Enteric Bacterial Pathogens Leads to Proteostasis Disruption That Is Rescued by Butyrate. PLOS Pathog. 2021, 17(5):el009510) and Walker AC et al. 2022 (Time-off-Pick Assay to Measure Caenorhabditis Elegans Motility. Bio-Protoc. 2022, 12(12):e4436). In brief, the time-off-pick (TOP) assay entailed sliding a worm pick made with an eyebrow hair under the mid-section of the w orm and using a ticking second timer to count the number of seconds it took for the worm to crawl off entirely. TOP (seconds) of transgenic nematodes harboring tissue-specific aggregating protein species was assessed at three days (muscle polyQ, muscle A[3I-42, unc-54(ts). dyn-l(ts), TSA, and respective controls) or four days (intestine polyQ, neuron polyQ, muscle a-synuclein and control) after having been plated on indicated bacteria as Lis. Worms carrying the temperature-sensitive mutation in dyn-1 (ts) were assayed before and after a one-hour shift to the restrictive temperature.

[0141] E. Live imaging. Nematodes expressing muscle-specific A|3I-42 were plated as Lis on NGM containing E. coli OP50, P. corporis HM-1294, and P. aeruginosa PAO1 for three days were mounted on a 3% agarose pad, frozen to reduce background fluorescence, and imaged. Nematodes expressing hsp70p .G¥P were plated as Lis onto NGM containing E. coli OP50 for two days, washed with M9 and transferred onto NGM containing indicated bacteria for 24 h, and were paralyzed with 2 mM levamisole. mounted on a 3% agarose pad. and imaged. Fluorescent and Nomarski images were taken using Zeiss Axio Observer 7 microscope equipped with Axiocam 503 mono camera, Solid-State Light Source Colibri 7, and a 1 Ox EC Plan-Neofluar objective (0.3 NA) and were processed using ZEN Tiles & Positions Module in Zeiss ZenPro Software.

[0142] F. Gel electrophoresis and western blotting. Worms were prepared for gel electrophoresis and western blotting. In brief, M9 was used to lift worms from NGM which were washed until superficial bacteria was removed. Worms were plated on unseeded NGM, were allowed to dry briefly and 50 worms were picked into 10 pL M9 with 1 mM phenylmethylsulfonyl fluoride (PMSF) in non-skirted screw-cap microcentrifuge tubes and frozen overnight or longer at -80°C. Tubes were pulse-centrifuged and three, 1 ,5mm zirconium beads were added to each tube. The following two steps were repeated a minimum of two times; if large worm particulates were observed, these steps were repeated again with the entire sample set until no tubes contained worm pieces that were visible under a dissecting microscope: Samples were homogenized by placing tubes in a Bead Bug homogenizer at 280x 10 rates per minute (RPM) for 90 seconds. Tubes were cooled on ice and centrifuged for 1-2 minutes at a low speed to re-settle worms and worm particulates. Samples were prepped for gel electrophoresis and entire samples were loaded on 4-12% gradient sodium dodecylsulfate-polyacrylamide gels (SDS-PAGE) to separate proteins through electrophoresis. Proteins were transferred onto polyvinyl difluoride (PDVF) membrane, blocked with 5% nonfat milk powder in PBS-Tween-20 (PBST) and probed with Living Colors JL-8 monoclonal primary antibody (1 : 1000) for 48 h at 4°C on an orbital shaker and underwent three, five- minute washes with 0.1% PBST followed by incubation with a 1 :10,000 dilution of goat-anti- mouse horse-radish peroxidase (HRP) conjugated secondary antibody for at least two h followed by three, ten-minute washes with 0. 1% PBST. Chemiluminescence was achieved by incubation with Clarity Western ECL substrate. Image J (vl .52) or ChemiDox XRS+System with Image Lab Image Capture and Analysis Software was used to analyze insoluble fractions.

[0143] G. Quantification and statistical analysis. Quantification of aggregate counts per worm in FIG. 2 were performed on a cohort of ten worms to corroborate the findings from the w estern blot analysis. In the rest of the figures, data are represented as the average number of aggregates, TOP (seconds), or otherwise specified per w orm obtained from two independent experiments for a total of 60 w orms (FIG. 3 Panel A “Aggregates”), 45-60 worms normalized to the control (FIG. 4 Panel A “Aggregates”); three independent experiments for a total of 98 worms (FIG. 14) or 60 worms (FIG. 5) or 45 worms (FIG. 3 Panel A “Motility”. FIG. 3 Panel A "Motility" (polyQ44, polyQ33), FIG. 3 Panels B and C, FIG. 4 Panel A “Motility”, FIG. 4 Panel C “Aggregates”) or 30 worms (FIG. 3 Panel A "Motility" (N2), FIG. 3 Panels D and E, FIG. 4 Panels B and C “Motility”, FIG. 4 Panels D and E, FIG. 5, FIG. 7) or 20 worms (FIG. 11); two independent experiments for a total of 20 worms (FIG. 6). Data are described asstatistically significant when p<0.05 as determined by Student’s t-test or one-way ANOVA followed by multiple comparison Dunnetf s post-hoc test (statistical tests used are indicated in figure legends) performed using Graphpad Prism 8.4.3 or later. Degrees of significance are denoted by the use of asterisks such that *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. The heat map (FIG. 2) is represented as data normalized to the control E. coli OP50. Error bars represent standard error of the mean.

[0144] H. Heat map generation. Heatmap was constructed in R-studio using the ComplexHeatmap package from the Bioconductor project. The experimental data were fed into R-studio as an organized .CSV file. The heatmap is the graphical representation of this data, clustering the bacteria by phylum.

[0145] I. Phylogenetic tree generation. Whole genome sequences were assembled using the Bacterial and Viral Bioinformatics Resources Center (BV-BCR) via Unicycler. All genomes were annotated in BV-BRC using Prokka. Phylogenetic analysis was conducted in BV-BRC based on concatenated alignments of 100 single-copy genes using mafft, and the results were assessed for maximum likelihood using RAxML. Sequences that did not have 100 complete single-copy genes due to poor sequencing quality were excluded.

[0146] J. Feeding worms PFA-killed bacteria. Bacteria were cultured on TSA-blood plates under aerobic (E. coli OP50) or anaerobic (P. corporis) conditions. Bacterial lawns were washed and resuspended in M9 and adjusted to ODeoo = 2. PFA was added at a final concentration of 0.5% and incubated at 37°C. shaking at 220 RPM for 1 h. After incubation, samples were washed 4* by centrifugation at 5,000xg for 10 min and resuspension in M9. Bacterial killing was confirmed by spotting 20 pL of each sample onto TSA-blood plates and incubating under the above-specified conditions. Dead bacterial samples were seeded onto NGM and allowed to dry overnight. Once dried, age-synchronized LI worms expressing intestinal polyQ44 were plated onto them and maintained for four days in a 22.5°C incubator. PolyQ aggregates were quantified as described in "Aggregate quantification".

[0147] K. Pharyngeal pumping. Pharyngeal pumping was assessed using a modified protocol from Raizen et al. (‘'Methods for Measuring Pharyngeal Behaviors.” In WormBook The C. elegans Research Community, Ed.; WormBook, 2012). Bacteria were cultured on TSA-blood plates in anaerobic conditions and seeded. Age-synchronized LI N2s were plated onto NGM containing indicated bacteria and kept at 22.5°C for four days until the assay. After four days, each w orm was picked onto a fresh plate of NGM seeded with the indicated bacteria and was given 10-15 min to acclimate. The number of pharyngeal pumps w as counted over a 30-secondperiod. A single pump was scored as a complete backward motion of the terminal bulb grinder. This was repeated on the same worm for a total of 10 times per worm.

[0148] L. Exposing worms to bacterial supernatants. Bacteria were grown on TSA-blood plates under aerobic (E. coli OP50, K. pneumoniae, A. xylosoxidans) or anaerobic (P. corporis) conditions. E. coli OP50 pellets and bacterial supernatants were obtained as follows: bacterial lawns were resuspended in M9, adjusted to ODeoo = 2, centrifuged at 5,000 xg for 15 minutes and sterile filtered. E. coli OP50 pellets were washed and resuspended in M9 (No SN) or supernatants from indicated bacteria. Suspensions were seeded onto NGM and allowed to dry overnight prior to having worms (intestinal polyQ44) plated on them.

[0149] M. Co-colonization assays. Bacteria were grown on TSA-blood plates under aerobic (E. coli OP50. K. pneumoniae or anaerobic (P. corporis) conditions. Bacterial lawns were resuspended in M9 and indicated bacteria were mixed 1 : 1 (CFU / mL) and seeded on NGM. The seeded plates were allowed to dry for 6-8 h in ambient conditions prior to having worms (intestinal polyQ44) plated on them.

[0150] N. Quantification of intestinal bacteria. Bacterial loads in the C. elegans intestine (N2, WT) were quantified as previously. C. elegans were lysed using the BeadBug. Bacteria were cultured on TSA-blood plates in aerobic conditions. Age-synchronized LI N2s were plated onto NGM containing indicated bacteria and kept at 22.5°C for four days until the assay.Example 2. Characterization of the human microbiome on host proteostasis.

[0151] We obtained a comprehensive Human Microbiome Project collection of 229 unique bacterial isolates from BEI Resources and assessed their effect on C. elegans proteostasis. The method used to conduct this experiment is illustrated in FIG. 1 . In brief, anaerobic bacteria were cultured on TSA-blood plates using anaerobic gas packs or in liquid broth supplemented with oxyrase for 2-7 days, while aerobic bacteria were cultured on TSA-blood plates or in liquid broth for one day. Cultured bacteria were transferred to nematode growth media (NGM) plates and incubated overnight with (for anaerobic bacteria) or without (aerobic bacteria) anaerobic gas packs. Worms were synchronized by the bleaching method and cultured on control E. coli OP50 until young adults (2 d), w ashed and transferred to NGM plates containing anaerobically or aerobically grown test bacteria, and cultured for an additional three days. Intestinal polyQ aggregates were quantified by manual counting and western blotting the insoluble fractions.

[0152] The collection encompasses isolates from a range of diverse phyla and a variety of anatomical sites (FIG. 2). In a previous study, we used aggregation-prone polyQ tracts as asensor of the protein folding environment to demonstrate that gram-negative pathogens disrupt host proteostasis (Walker AC et al. 2021). Among animals carrying intestine-, muscle-, and neuron-specific polyQ::YFP, we previously found that proteostasis in the intestine was significantly affected by the colonizing bacteria (Walker AC et al. 2021). As such, we performed our initial screen using the intestinal polyQ model (FIG. 2). To eliminate the possibility that bacteria will affect C. elegans development, worms were grown to adulthood prior to being transferred to the bacterial strains of interest. polyQ aggregation was assessed by fluorescent microscopy. To ensure the validity of our results, we also assessed polyQ aggregation by western blotting. Validating our approach, both quantitative methods yielded similar results.

[0153] Bacteria from the isolate collection exhibited a differential effect on C. elegans proteostasis as indicated by increases and decreases in polyQ aggregation compared to worms fed control E. coll OP50 (FIG. 2). FIG. 2 summarizes the screen revealing bacteria that most robustly affected host proteostasis. For example, Prevotella was the only genus that consistently resulted in low polyQ aggregation across all 229 strains tested (FIG. 2). Conversely, significant host proteotoxicity was observed in nematodes that were fed Achromobacter xylosoxidans and Arcobacter butzleri, as well as Citrobacter, Escherichia, Klebsiella, Pseudomonas, and Ralstonia species (FIG. 2). A detailed list of all bacterial strains and their effect on polyQ aggregation is summarized in Table 1.

[0154] We screened a collection of 229 unique bacterial isolates from the Human Microbiome Project for their ability to affect host proteostasis from within the intestinal milieu. Our follow-up experiments on the most robust beneficial and detrimental bacteria confirmed their influence on proteostasis across host tissues, affecting the stability of proteins associated with Alzheimer’s, Parkinson’s, and Huntington’s diseases. The phylogenetic analysis revealed clustering of select proteotoxic and proteoprotective bacteria, indicating that genetically related bacteria affect host proteostasis in a similar manner, but with a different magnitude. To our knowledge, this is the first comprehensive characterization of bacteria from human microbiomes on host proteostasis. Surprisingly, our data suggest that bacteria do not selectively target any specific host proteins associated with PCDs, but rather affect proteostasis in general, leading to the aggregation and proteotoxicity of any destabilized proteins present within the proteome, such as exogenous polyQ, A(3I-42, and a-synuclein, tested in our experiments. While this is a generalized mechanism, there could be microbes that exclusively affect a specific disease.Example 3. Prevotella species mitigate the proteotoxic aggregation of diverse culprit proteins.

[0155] Out of the 229 strains tested, the Prevotella genus had the highest number of members that suppressed polyQ aggregation. We further retested 17 Prevotella species using the intestinal polyQ44 model. To increase the robustness of the response, we started feeding animals test bacteria immediately after hatching. Although we observed an enhanced suppression of aggregation for most retested strains, there were few isolates that did not significantly inhibit polyQ aggregation, likely due to the timing of feeding. Furthermore, as expected, feeding worms test bacteria beginning at the LI larval stage affected development (FIG. 3 Panel A, “Aggregates'’). Out of all strains, P. buccae, P. oris, and P. corporis significantly suppressed polyQ aggregation without causing any detectable developmental delay (FIG. 3 Panel A, “Aggregates”). Motility defects are associated with neurodegenerative PCDs. As such, we assessed whether the three Prevotella species alleviated aggregatedependent motility defects caused by culprit proteins expressed in the intestine and distal tissues. We used our well-established and validated time-off-pick (TOP) assay that relies on C. elegans motihty as a readout of proteotoxicity. Consistent with their suppression of polyQ aggregation, all three strains alleviated aggregate-dependent motility defects with P. corporis having the strongest effect (FIG. 3 Panel A, “Motility”). To determine whether the observed suppression is dependent on polyQ, we used N2 wild-type worms and a model expressing a shorter poly glutamine tract, polyQ33. The results revealed no effect on the N2 worms and a less robust suppression of the motility defect for polyQ33, indicating that Prevotella suppressed proteotoxicity.

[0156] To determine whether Prevotella also affects polyQ in distal tissues, we employed the neuronal and muscle models. Because worms expressing the neuronal polyQ do not exhibit quantifiable aggregates, we used the TOP assay as a motility readout. Our results show7that of the three strains, only P. corporis showed significant suppression of the motility defect in worms expressing neuronal polyQ40 (FIG. 3 Panel B). Unexpectedly, P. buccae, P. oris, and P. corporis increased motility defects in the neuronal empty vector control (polyQO); the reason for this is unknown, but importantly does not diminish the observed beneficial effects of Prevotella on neuronal polyQ. In a manner similar to the intestinal polyQ, we observed Prevotella-mediated suppression of aggregation and proteotoxicity in worms expressing muscle-specific polyQ (FIG. 3 Panel C).

[0157] The association between the low abundance of gut Prevotella and diverse neurodegenerative PCDs suggests that the bacterial influence on these diseases is independent of the culprit protein species. As such, we hypothesized that bacteria might affect protein aggregation by modulating host proteostasis, and if this is the case, Prevotella species should enhance proteostasis in worms expressing various aggregation-prone proteins. To test the effect of Prevotella on other disease-associated proteins, we chose three muscle-specific models: one expressing A|3I-42, and two expressing a-synuclein. These culprit proteins model Alzheimer's and Parkinson’s diseases, respectively. Additionally, these models exhibit age-dependent proteotoxicity. which is consistent with the age-dependent progression of neurodegenerative diseases. To investigate progressive proteotoxicity in the A|3I-42 and a-synuclein models, we assessed their motility between days three to five post-hatching (FIG. 6). Nematodes expressing AP1-42 and a-synuclein had age-dependent motility defects that were markedly greater than those of the controls (FIG. 6). We examined the effect of P. buccae, P. oris, and P. corporis on proteotoxicity associated with each of these three models. In a manner similar to the polyQ models. P. buccae, P. oris, and P. corporis reduced aggregate-dependent toxicity compared to wild-type control (FIG. 3 Panel A), particularly with P. corporis having the strongest effect (FIG. 3 Panels D and E). Bacteria that strongly enhanced or suppressed host proteostasis induced notable differences in the aggregation of Afh-42, which parallels the extent of the motility defect (FIG. 5). Both A01-42 aggregation and the associated toxicity were suppressed by P. corporis and enhanced by Pseudomonas aeruginosa (FIG. 5), a bacterium that strongly disrupted host proteostasis in our previous studies (Walker et al. 2021 and Walker AC et a; 2022b (“Bacteria-Derived Protein Aggregates Contribute to the Disruption of Host Proteostasis.'’ Int. J. Mol. Sci. 2022, 23(9): 4807)). All of our transgenic worms expressed exogenous proteins. To determine whether Prevotella can also provide protection against misfolding of endogenous proteins, we used a strain that carried a temperature-sensitive mutation in myosin heavy chain (UNC-54) that leads to its misfolding and paralysis at the restrictive temperature (25°C) (“Muscle”) and DYN-1, featuring a modified GTPase domain that is highly expressed in motor neurons, resulting in loss of coordination at the restrictive temperature (25°C) (“Neuronal”). In agreement with the proteoprotective effect against misfolding and aggregation of exogenous proteins, Prevotella suppressed the temperaturedependent motility defect at the restrictive temperature, further supporting its beneficial role (FIG. 7). Collectively, our findings indicate that Prevotella can mitigate the pathogenesis of PCDs, including neurodegenerative diseases.

[0158] Given that dietary restriction enhances proteostasis and suppresses polyQ aggregation, we assessed pharyngeal pumping to determine whether the proteoprotective effect mediated by P. corporis was the result of caloric restriction. The results showed no significant difference in phary ngeal pumping between worms fed E. coli OP50 and those fed P. corporis (FIG. 11), indicating that the observed proteoprotection was not caused by caloric restriction.Example 4. Proteotoxic bacteria enhance the aggregation and toxicity) of PCD-associated proteins.

[0159] To confirm the effect of the most robust proteotoxic strains identified in our original screen (FIG. 2), we assessed polyQ44 aggregation in animals fed gram-negative aerobes (FIG. 4A, ‘'Aggregates”). We concentrated on these specific bacteria because they did not affect worm development, which is known to influence proteostasis. We found that Ralstonia sp., Achromobacter xylosoxidans , Pseudomonas sp., and K. pneumoniae were the strongest inducers of polyQ aggregation (FIG. 4 Panel A). As we have already demonstrated the proteotoxic potential of P. aeruginosa in our previous work, 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. While we detected a significant enhancement in the motility defect in animals expressing polyQ44, no significant changes were observed in wild-type or in animals expressing polyQ33 (FIG. 4 Panel A). These results indicate that the impairment of motility induced by bacteria is contingent on polyQ aggregation rather than general bacterial pathogenicity’. The aggregate-dependent motility defects were also observed in worms expressing neuronal and muscle-specific polyQ; although, the phenotype was less robust as we did detect some decrease in motility in control animals (FIG. 4 Panels B and C). K. pneumoniae Ralstonia sp., and A. xylosoxidans also elevated muscle-specific polyQ aggregation (FIG. 4 Panel C). To test the microbial influence on other disease-associated proteins, we employed worms expressing muscle-specific A[3I-42 and a-synuclein. In agreement with the intestinal polyQ model, all of these bacterial isolates also induced proteotoxicity associated with these additional culprit proteins (FIGs. 4 Panels D and E). These results demonstrate that bacteria can enhance the proteotoxicity of diverse disease-associated proteins, supporting their role in the pathogenesis of neurodegenerative PCDs.

[0160] To determine whether the observed proteotoxicity is attributed to increased bacterial colonization, we quantified intestinal bacteria. The results indicated that K. pneumoniae, Ralstonia sp., and A. xylosoxidans colonized less than A coli OP50 (FIG. 13), indicating thatthe proteotoxicity mediated by these strains was not explained by their colonization efficiencies.

[0161] Worms were exposed to spent culture supernatants from K. pneumoniae and A. xylosoxidans. The results demonstrated that supernatants from these bacteria significantly increased polyQ aggregation, whereas supernatants from P. corporis and E. coli OP50 had no effect (FIG. 14).Example 5. Analysis

[0162] Numerous studies that employed genomic analyses of microbial compositions in affected patients revealed a connection between comparable gut dysbioses and diverse neurodegenerative PCDs (Fang P et al. The Microbiome as a Modifier of Neurodegenerative Disease Risk. Cell Host Microbe 2020, 28(2):201-222 and Walker A et al. “Oh My Gut! Is the Microbial Origin of Neurodegenerative Diseases Real?” Infect. Immun. 2023).

[0163] We screened a collection of 229 unique bacterial isolates from the Human Microbiome Project for their ability to affect host proteostasis from within the intestinal milieu. Follow-up experiments on the most robust beneficial and detrimental bacteria confirmed their influence on proteostasis across host tissues, affecting the stability of proteins associated with Alzheimer’s. Parkinson’s, and Huntington’s diseases. The phylogenetic analysis revealed clustering of select proteotoxic and proteoprotective bacteria, indicating that genetically related bacteria affect host proteostasis in a similar manner, but with a different magnitude. Surprisingly, our data suggest that bacteria do not selectively target any specific host proteins associated with PCDs, but rather affect proteostasis in general, leading to the aggregation and proteotoxicity of any destabilized proteins present within the proteome, such as exogenous polyQ, API-42, and a-synuclein, tested in our experiments.

[0164] In our screen (FIG. 2), Prevotella stood out as the only genus devoid of any species that exhibit proteotoxicity towards the host. Furthermore, our findings indicate that Prevotella species have a broad and suppressive effect on host protein aggregation, regardless of the specific disease-associated protein (FIG. 3). Sequencing data suggest that a low abundance of Prevotella in the guts of patients with PCDs enhances disease pathogenesis. Our data indicate that various Prevotella species exhibit a differential effect on host proteostasis (FIG. 3 panel A). Such various effects of individual species could be explained by large variability in their genomes (Tett A et al. “Prevotella Diversity, Niches and Interactions with the Human Host. Nat. Rev. Microbiol. 2021, 19 (9), 585-599).

[0165] The robust induction of proteotoxicity by K. pneumoniae across all C. elegans models expressing different aggregation-prone protein species (FIG. 4), is in agreement with a previous study that identified an overabundance of K. pneumoniae in the gut microbiota of individuals with AD (Haran JP et al. “Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Gly coprotein Pathway. mBio 2019, 10(3)). A. xylosoxidans induced proteotoxicity in all our disease models (FIG. 4). along with Pseudomonas , which displayed a notable increase in polyQ aggregation (FIG. 4 Panel A, “Aggregates”). Furthermore, we previously demonstrated that P. aeruginosa exerts robust proteotoxic effects on C. elegans (Walker AC et al. 2022 and Walker AC 2022b). It is remarkable that the various bacteria induce proteotoxicity consistently across all our C. elegans models expressing distinct disease proteins.Example 6. Effect of bacteria on host protein folding

[0166] To decipher the effect of individual microbes on host proteostasis. we employed Caenorhabditis elegans models that express fluorescent polyglutamine (polyQ) tracts across different tissues, including intestine, muscle, and neurons. A polyglutamine aggregation model has been used as a sensor for changes in proteostasis in various tissue (Muscle (Morley et al 2002); Intestine (Mohri-Shiomi. Garsin 2008); and neurons (Brignull et al. 2006)) for various proteins, including, A0I-42, Tau, a-Syn, and TDP-43. We use these reporters as proxies to detect bacteria-induced changes in the folding environment. We used C. elegans as a model organism for studying the effect of gut bacteria on host organism protein folding. We found that colonization of the C. elegans intestine with gram-negative enteropathogenic bacteria led to disruption of the folding environment and consequently aggregation of polyQ not only in that tissue but in the muscle and neuronal tissues as well. We demonstrated that bacteria- derived aggregates contribute to the observed disruption of proteostasis. Co-colonization with butyrogenic bacteria or the presence of butyrate inhibited polyQ aggregation and alleviated the associated proteotoxicity. Genetic experiments revealed that the protective response mediated by butyrate required SKN-1 / Nrf2 and DAF-16 / FOXO transcription factors. We further deciphered the effect of all culturable bacterial isolates from the Human Microbiome Project on host proteostasis and found species that either disrupt or enhance host proteostasis. We tested the most robust bacterial isolates using C. elegans models expressing A01-42. a-syn, and a novel tauopathy model. Our results indicate that bacteria do not discriminate between different metastable proteins but rather generally affect host proteostasis. Collectively, ourstudy characterized the effect of the culturable microbiome on host proteostasis revealing proteoprotective and proteotoxic species.

[0167] By analyzing the effect of culturable bacterial isolates from the Human Microbiome Project on protein folding homeostasis, we have identified bacteria that disrupt the protein folding environment and contribute to the pathogenesis of neurodegenerative diseases by inducing toxic protein aggregation. We observed that bacteria-derived protein aggregates contribute to the disruption of host proteostasis. Protein aggregates could migrate from the gut into the brain and contribute to the disruption of host proteostasis.

[0168] We looked at the effect of various enteric bacteria on host proteostasis. The enteric bacteria included: Enterobacteriaceae {E. coll. Klebsiella species, Proteus species, Citrobacter species, Shigella species, and Salmonella species) and other pathogenic species {Pseudomonas species and Acinetobacter species) (FIG. 8).

[0169] We then examined whether bacteria or their products contribute to the pathogenesis of neurodegenerative PCDs. We observed that bacteria-derived protein aggregates contributed to the disruption of host proteostasis. We further showed that protein aggregates could migrate from the gut into the brain and contribute to the disruption of host proteostasis.

[0170] To analyze how bacteria-derived protein aggregates affect host proteostasis, we performed a genome-wide screen for bacterial signals that affect host proteostasis. A screen of about 10,000 P. aeruginosa mutants revealed bacterial genes and pathways that affect host proteostasis (FIG. 9).Example 7. Mitigation of proteot oxicity by P. corporis.

[0171] The human microbiota is comprised of a diverse array of bacterial species that coexist and interact within a complex polymicrobial community. We investigated the potential of a proteoprotective species to mitigate bacterial rot eotoxi city by co-colonizing worms with P. corporis and either K. pneumoniae or E. coli OP50. Our findings demonstrated that P. corporis suppressed the polyQ aggregation associated with K. pneumoniae and E. coli OP50 (FIG. 10 Panels A and B). We tested whether the same suppressive effect would result from cocolonizing worms with K. pneumoniae and E. coli OP50 and found that the resulting aggregation profile w as an integrative reflection of the individual effects observed when each strain was introduced in isolation (FIG. 10 Panel C). P. corporis completely inhibited the proteotoxicity of l. pneumoniae (FIG. 10 Panel A) and A. coli (FIG. 10 Panel B). Collectively, these results indicate that, in addition to suppressing proteotoxicity from intrinsic factors likeaging and host-encoded metastable proteins, P. corporis also suppresses host proteotoxicity mediated by extrinsic factors such as proteotoxic bacteria.Example 8. P corporis activates heat shock response.

[0172] To investigate the mechanistic basis behind the ability of P. corporis to safeguard against host proteotoxicity, we investigated its potential to activate the heat shock response (HSR), a critical and evolutionary conserved cellular defense mechanism that responds to protein misfolding and proteotoxic stress. Using C. elegans expressing a transcriptional fluorescent reporter, fe / ?70p::GFP, we monitored HSR activation in worms fed P. corporis. While control E. coli OP50 and proteotoxic K. pneumoniae did not elicit any detectable response, P. corporis induced the reporter, indicating HSR activation (FIG. 10 Panel D).

[0173] The results demonstrate that P corporis can be used to induce expression of Heat Shock proteins and heat shock response. The results reinforce the ability of bacteria such as P. corporis to target components of the host proteostasis network.Example 9. Killed P. corporis retain proteoprotective properties.

[0174] Because Prevotella spp. are anaerobic and may not thrive well in the ambient conditions in which C. elegans are cultured, we investigated whether dead bacteria retain their proteoprotective properties. To accomplish this, we fed worms paraformaldehyde (PFA)-killed bacteria and found that P. corporis still significantly suppressed polyQ aggregation relative to E. coli OP50 control (FIG. 12). indicating that live bacteria are not necessary to elicit protection. The data also indicate that Prevotella lysate, extract, or fraction will also elicit protection.Table 1. Bacterial strains and their effect on polyQ aggregation.

Claims

Claims:

1. A composition for use in treating a protein conformational disease (PCD) in a subject, the composition comprising:(a) Prevotella corporis;(b) a composition containing Prevotella corporis;(c) a composition comprises killed Prevotella corporis bacteria;(d) a composition comprising a Prevotella corporis lysate or an extract or a fraction thereof;(e) a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject; or(f) combinations of two or more of (a)-(e).

2. The composition of claim 1 , wherein the Prevotella corporis or the composition containing Prevotella corporis comprises, a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, or a granular powder.

3. The composition of claim 1, wherein the composition comprising the killed Prevotella corporis bacteria, composition comprising the Prevotella corporis lysate or an extract or a fraction thereof, or the composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject, comprises a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, a granular powder, a food additive, a food composition, or a nutraceutical, or a supplement.

4. The composition of any one of claims 1-3, wherein the composition comprises a pharmaceutical composition.

5. The composition of claim 4, wherein the pharmaceutical composition comprises an excipient and / or one or more additional active ingredients.

6. The composition of claim 5, wherein the one or more additional active ingredients comprises a second composition that decreases the abundance or inhibits the growth of a Pseudomonas species and / or a Shigella species in the gut of the subject.

7. The composition of claim 6, wherein the second composition comprises one or more bacteriophages.

8. A composition for use in treating a PCD in a subject, the composition comprising: a composition that specifically decreases the abundance or inhibits the growth of a Pseudomonas species in the gut of the subject and / or specifically decreases the abundance or inhibits the growth of a Shigella species in the gut of the subject.

9. The method of claim 8, wherein the composition comprises at least one bacteriophage.

10. The composition of claim 8 or 9, wherein the composition comprises a liquid, a suspension, a solid dosage form, a pill, a capsule, a tablet, a granular powder, a food additive, a food composition, or a nutraceutical, or a supplement.

11. The composition of claim 10, wherein the composition comprises a pharmaceutical composition.

12. The composition of claim 11, wherein the pharmaceutical composition comprises an excipient and / or one or more additional active ingredients.

13. The composition of claim 12, wherein the one or more addition active ingredients comprises: Prevotella corporis, a composition containing Prevotella corporis, a composition comprises killed Prevotella corporis bacteria, a composition comprising a Prevotella corporis lysate or an extract or a fraction thereof, or a composition that increases abundance or supports growth of a Prevotella corporis in the gut of the subject.

14. The method of claim of any one of claims 1-13, wherein the PCD comprises a neurodegenerative disease.

15. The method of claim 14. wherein the neurodegenerative disease comprises Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease, multiple system atrophy, Lewy body dementia, Creutzfeldt-Jakob disease, prion disease, or amyloidosis.

16. A method of treating a subject suffering from a PCD or at risk of developing a PCD, the method comprising: administering to the subject one or more of:(a) a Prevotella species, a composition containing the Prevotella species, a composition comprises killed Prevotella species bacteria, a composition comprising a lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject;(b) a composition that specifically decreases the abundance or inhibits the growth of a Pseudomonas species in the gut of the subject; and(c) a composition that specifically decreases the abundance or inhibits the growth of a Shigella species in the gut of the subject.

17. The method of claim 16, wherein the method further comprises: monitoring the abundance of one or more of the Prevotella species. Pseudomonas species, and the Shigella species in the gut of the subject and(a) if the abundance of Prevotella species in the gut of the subject is below a predetermined value, then administering to the subject the Prevotella species, the composition containing Prevotella species, the composition comprising the killed Prevotella species bacteria, the composition comprising the Prevotella species lysate or the extract or the fraction thereof, or the composition that increases abundance or supports growth of the Prevotella species in the gut of the subject; and / or(b) if the abundance of the Pseudomonas species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Pseudomonas species in the gut of the subject; and / or(c) if the abundance of the Shigella species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Shigella species in the gut of the subject.

18. The method of claim 16, wherein the method further comprises:(a) analyzing a sample of a microbiota from a gut or a stool sample from the subject to determine an amount of one or more of the Prevotella species, the Pseudomonas species, and the Shigella species in the sample;(b) comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, and the Shigella species in the sample to a predetermined control; and(i) if the amount of the Prevotella species in the gut of the subject is below a predetermined value, then administering to the subject the Prevotella species, the composition containing Prevotella species, the composition comprising the killed Prevotella species bacteria, the composition comprising the Prevotella species lysate or the extract or the fraction thereof, or the composition that increases abundance or supports growth of the Prevotella species in the gut of the subject;(ii) if the amount of the Pseudomonas species in the gut of subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the grow th of the Pseudomonas species in the gut of the subject; and / or(iii) if the amount of the Shigella species in the gut of the subject is above a predetermined value, then administering to the subject the composition that specifically decreases the abundance or inhibits the growth of the Shigella species in the gut of the subject.

19. The method of claim 18, wherein the sample is a microbial sample or a fecal sample.

20. The method of any one of claims 16-19, wherein monitoring the abundance or analyzing the sample comprises analyzing nucleic acid in the sample.

21. The method of any one of claims 16-20, wherein the Prevotella species is Prevotella corporis.

22. The method of any one of claims 16-21, wherein the Pseudomonas species is Pseudomonas aeruginosa, and / or the Shigella species is Shigella flexneri , Shigella sonnet. Shigella dysenteriae, or Shigella boydii.

23. The method of any one of claims 16-22, wherein subject is human.

24. The method of claim 23. wherein the PCD comprises a neurodegenerative disease.

25. The method of claim 24, wherein the neurodegenerative disease comprisesAlzheimer's disease, Parkinson's disease, or Huntington’s disease, multiple system atrophy, Lewy body dementia, Creutzfeldt-Jakob disease, prion disease, or amyloidosis.

26. The composition of claim 1 or 8, or the method of claim 16, wherein the treating comprising: reducing or ameliorating the severity of the disease, reducing or ameliorating theseverity of one or more symptoms associated with the disease, slowing progression of the disease, slowing progression of one or more symptoms associated with the disease, reducing severity of the disease, reducing severity of one or more symptoms of the disease, delaying onset of the disease, delaying onset of one or more symptoms associated with the disease, preventing the disease, preventing one or more symptoms associated with the disease, reduce the duration of a symptom associated with a disease, regressing the disease, regressing one or more symptoms associated with the disease, reducing recurrence of one or more symptom associated with the disease, or increasing or prolonging survival of a subject with a disease.

27. A method for determining a risk of developing a PCD or one or more symptoms of a PCD comprising:(a) analyzing a sample of a microbiota from a gut or a stool sample of a subject to determine an amount of one or more of a Prevotellci species, a Pseudomonas species, and a Shigella species in the sample; and(b) comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, and the Shigella species in the sample to a predetermined control; wherein an amount of the Prevotella species in the sample lower than the predetermined control, and / or an amount of Pseudomonas species and / or the Shigella species in the sample that is higher than the predetermined control, indicates the subject is at increased risk of developing the PCD.

28. The method of claim 27, wherein the PCD comprises a neurodegenerative disease.

29. The method of claim 28, wherein the neurodegenerative disease comprises Alzheimer's disease, Parkinson’s disease, or Huntington’s disease, multiple system atrophy, Lewy body dementia, Creutzfeldt-Jakob disease, prion disease, or amyloidosis.

30. A method of decreasing protein misfolding in a subject, the method comprising administering to the subject one or more of:(a) a Prevotella species, a composition containing the Prevotella species, a composition containing killed Prevotella species bacteria, a composition comprising a lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject;(b) a composition that specifically decreases the abundance or inhibits the grow th of a Pseudomonas species in the gut of the subject; and(c) a composition that specifically decreases the abundance or inhibits the growth of a Shigella species in the gut of the subject.

31. A composition for use in treating a protein conformational disease (PCD) in a subject, the composition comprising:(a) Prevotella species;(b) a composition containing a Prevotella species;(c) a composition containing killed Prevotella species bacteria;(d) a composition comprising a Prevotella species lysate or an extract or a fraction thereof;(e) a composition that increases abundance or supports grow th of Prevotella species in the gut of the subject; or(f) combinations of two or more of (a)-(e); wherein the Prevotella species is Prevotella amnii, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella histicola, Prevotella melaninogencia, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella timonensis. or Prevotella veroralis.

32. A composition for use in treating a PCD in a subject, the composition comprising: a composition that specifically decreases the abundance or inhibits the grow th of one or more of a Pseudomonas species, a Shigella species, an Achromobacter species, aRalstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species in the gut of the subject.

33. A method of treating a subject suffering from a PCD or at risk of developing a PCD, the method comprising: administering to the subject one or more of:(a) a Prevotella species, a composition containing the Prevotella species, a composition containing killed Prevotella species bacteria a composition comprising a lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports growth of the Prevotella species in the gut of the subject; and(b) a composition that specifically decreases the abundance or inhibits the growth of one or more of a Pseudomonas species, a Shigella species, an Achromobacter species, aRalstonia species, a Klebsiella species, an Ar cobacter species, a Citrobacter species, and an Escherichia species in the gut of the subject.

34. The method of claim 33, wherein the composition comprises one or more lytic bacteriophage that infect one or more of the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and the Escherichia species.

35. A method for determining a risk of developing a PCD or one or more symptoms of a PCD comprising:(a) analyzing a sample of a microbiota from a gut or a stool sample of a subject to determine an amount of one or more of a Prevotella species, a Pseudomonas species, a Shigella species, an Achromobacter species, a Ralstonia species, a Klebsiella species, an Arcobacter species, a Citrobacter species, and an Escherichia species in the sample; and(b) comparing the amount of the one or more of the Prevotella species, the Pseudomonas species, the Shigella species, the Achromobacter species, the Ralstonia species, the Klebsiella species, the Arcobacter species, the Citrobacter species, and the Escherichia species in the sample to a predetermined control; wherein an amount of the Prevotella species in the sample lower than the predetermined control, and / or an amount of the Pseudomonas species, the Shigella species, the Achromobacter species, Axe Ralstonia species, Axe Klebsiella species, the Arcobacter species, the Citrobacter species, and / or the Escherichia species in the sample that is higher than the predetermined control, indicates the subject is at increased risk of developing the PCD.

36. A method of decreasing protein misfolding in a subject, the method comprising administering to the subject one or more of:(a) a Prevotella species, a composition containing the Prevotella species, a composition comprising lysate of the Prevotella species or an extract or a fraction thereof, or a composition that increases abundance or supports grow th of the Prevotella species in the gut of the subject;(b) a composition that specifically decreases the abundance or inhibits the growth of one or more of a Pseudomonas species a Shigella species, an Achromobacter species, aRalstonia species, a Klebsiella species, an Ar cobacter species, a Citrobacter species, and an Escherichia species in the gut of the subject.

37. A method activating or inducing a heat shock response in a subject, the method comprising administering to the subject:(a) isolated Prevotella corporis bacteria;(b) a composition containing Prevotella corporis bacteria;(c) a composition comprising killed Prevotella corporis bacteria;(d) a composition comprising a Prevotella corporis lysate or an extract or a fraction thereof;(e) a composition that increases abundance or supports growth of Prevotella corporis in the gut of the subject; or(f) combinations of two or more of (a)-(e). In some embodiments, the composition comprises a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises an excipient.

38. A method increasing expression of a heat shock protein, mucin-associated membrane protein 3, or mucin-associated membrane protein 4 in a subject, the method comprising administering to the subject:(a) isolated Prevotella corporis bacteria;(b) a composition containing Prevotella corporis bacteria;(c) a composition comprising killed Prevotella corporis bacteria;(d) a composition comprising a Prevotella corporis lysate or an extract or a fraction thereof;(e) a composition that increases abundance or supports grow th of Prevotella corporis in the gut of the subject; or(!) combinations of two or more of (a)-(e).

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