WO2025076308A1 - Compositions et méthodes pour analyser l'effet du microbiote sur la conformation des protéines hôtes et pour traiter des maladies neurodégénératives - Google Patents

Compositions et méthodes pour analyser l'effet du microbiote sur la conformation des protéines hôtes et pour traiter des maladies neurodégénératives Download PDF

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WO2025076308A1
WO2025076308A1 PCT/US2024/049907 US2024049907W WO2025076308A1 WO 2025076308 A1 WO2025076308 A1 WO 2025076308A1 US 2024049907 W US2024049907 W US 2024049907W WO 2025076308 A1 WO2025076308 A1 WO 2025076308A1
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prevotella
composition
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gut
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Daniel CZYZ
Alyssa WALKER
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University of Florida
University of Florida Research Foundation Inc
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University of Florida Research Foundation Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor

Definitions

  • 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.
  • PCDs Neurodegenerative protein conformational diseases
  • 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.
  • Neurodegenerative PCDs are characterized by disturbances in proteostasis that result in the aggregation of disease-associated proteins, ultimately leading to tissue death.
  • AD Alzheimer's disease
  • PD Parkinson’s disease
  • HD Huntington’s disease
  • ALS amyotrophic lateral sclerosis
  • AD recognized by the World Health Organization (WHO) as one of the leading causes of death worldwide.
  • WHO World Health Organization
  • HGM human gut microbiota
  • the HGM is considered an “organ’' due to its production of essential proteins and metabolites, including vitamins, hormones, and neurotransmitters.
  • 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).
  • compositions for use in treating or preventing a protein conformational disease (PCD) in a subject 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.
  • the composition comprises a pharmaceutical composition.
  • the pharmaceutical composition comprises an excipient and/or one or more 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.
  • 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.
  • 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.
  • the one or more additional active ingredients comprises at least one bacteriophage.
  • 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.
  • 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.
  • 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.
  • the composition comprises a pharmaceutical composition.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition comprises a pharmaceutical composition.
  • 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.
  • 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;
  • composition that specifically decreases the abundance or inhibits the growth of a Pseudomonas species in the gut of the subject;
  • composition that specifically decreases the abundance or inhibits the growth of a Shigella species in the gut of the subject.
  • compositions 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.
  • composition that specifically decreases the abundance or inhibits the growth of a Klebsiella species in the gut of the subject.
  • composition that specifically decreases the abundance or inhibits the grow th of an Escherichia species in the gut of the subject.
  • the methods for treating a subject suffering from a PCD or at risk of developing a PCD comprise administering to the subject:
  • 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;
  • 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.
  • 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.
  • the Pseudomonas species is Pseudomonas aeruginosa or Pseudomonas stutzeri.
  • the Shigella species is Shigella flexneri, Shigella sonnei, Shigella dysenteriae. or Shigella boydii.
  • the Achromobacter species is Achromobacter xylosoxidans, Achromobacter rubefaciens, Achromobacter insuavis, Achromobacter dolens, or Achromobacter spanius.
  • the Ralstonia species is Ralstonia pickettii or Ralstonia mannitolilytica.
  • the Klebsiella species is Klebsiella pneumoniae, Klebsiella oxytoca, or Klebsiella ozaenae.
  • the Arcobacter species is Arcobacter butzleri, Arcobacter cryaerophilus , or Arcobacter skirrowii.
  • the Citrobacter species is Citrobacter portucalensis .
  • Citrobacter freundii Citrobacter freundii, Citrobacter koseri, or Citrobacter braakii.
  • the Escherichia species is Escherichia coli.
  • the subject is human.
  • 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.
  • 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
  • the methods further comprise:
  • 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/
  • the methods further comprise:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the one or more therapeutic treatments comprise bacteriophages that specifically target the one or more identified bacteria that disrupt proteostasis.
  • 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.
  • 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.
  • 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.
  • 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;
  • composition that specifically decreases the abundance or inhibits the grow th of a Pseudomonas species in the gut of the subject;
  • composition that specifically decreases the abundance or inhibits the growth of a Shigella species in the gut of the subject.
  • 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.
  • 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.
  • 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.
  • FIG. 1 Schematic illustrating the method used to assess the effect of bacterial isolates on C. elegans proteostasis.
  • 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.
  • 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 by multiple comparison Dunnett's post-hoc test (*p ⁇ 0.05. **p ⁇ 0.01, ***p ⁇ 0.001, ****p ⁇ 0.0001).
  • 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.
  • 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).
  • 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.
  • 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).
  • FIG. 8 Graph illustrating effect of various enteric bacteria on host proteostasis assessed by polyQ aggregation in the C. elegans intestine.
  • 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).
  • 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.
  • 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).
  • Designation of a range of values includes all integers within or defining the range, and all subranges defined by integers within the range.
  • 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.
  • the term “about” means within the typical ranges of tolerances in the art.
  • the term “about” means within 1 or 2 standard deviations from the mean.
  • the term “about” means ⁇ 10%.
  • the term “about” means ⁇ 5%.
  • subject refers 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.
  • rodents e.g., rats, mice, and guinea pigs
  • rabbits cows, pigs, horses, and other mammalian species.
  • the subject is a human.
  • 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.
  • treat means 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.
  • 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 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.
  • 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.
  • 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.
  • a “therapeutically effective amount” of an agent 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.
  • 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.
  • 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.
  • 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, intradermal deliver ⁇ ', intramuscular deliver ⁇ ', intrathecal deliver ⁇ ', colonic delivery, rectal delivery, or intraperitoneal delivery.
  • 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.
  • a pharmaceutically acceptable 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.
  • compositions and methods of using the compositions to treat PCDs in a host 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.
  • Described are methods of decreasing protein misfolding in a subject 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 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.
  • the bacterial species that disrupts proteostasis in the subject is a Pseudomonas species and/or a Shigella species.
  • a composition that decreases the abundance of a Pseudomonas species and/or a Shigella species comprises a bacteriophage.
  • the composition that decreases the abundance of the Pseudomonas species comprises a bacteriophage that specifically targets (infects) the Pseudomonas species.
  • the Pseudomonas species is Pseudomonas aeruginosa.
  • the composition that decreases the abundance of the Shigella species comprises a bacteriophage that specifically targets (infects) the Shigella species.
  • 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.
  • the bacterial species that enhances proteostasis in the subject is aPrevotella species.
  • the Prevotella species is P. corporis.
  • 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.
  • 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 growth, in the gut of the subject, of one or more bacterial species that disrupts or decreases proteostasis in the subject.
  • the bacterial species that enhances proteostasis in the subject is a Prevotella species.
  • the Prevotella species is P. corporis.
  • 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.
  • 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.
  • 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.
  • 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.
  • enhancing proteostasis comprises increasing expression of heat shock protein (HSP) and/or activation of a heat shock response in a subject.
  • HSP heat shock protein
  • 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.
  • 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.
  • Described are methods for treating PCD 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.
  • 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 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.
  • the Prevotella sp. is Prevotella corporis.
  • the Prevotella species is Prevotella amnii, Prevotella bivia, Prevotella buccae.
  • the bacterial species that disrupts proteostasis in the subject is a Pseudomonas species and/or a Shigella species.
  • a composition that decreases the abundance of a Pseudomonas species and/or a Shigella species comprises a bacteriophage.
  • a composition that decreases the abundance of a Pseudomonas species and/or a Shigella species comprises a lytic bacteriophage.
  • the composition that decreases the abundance of the Pseudomonas species comprises a bacteriophage that specifically targets (infects) the Pseudomonas species.
  • the Pseudomonas species is Pseudomonas aeruginosa.
  • the composition that decreases the abundance of the Shigella species comprises a bacteriophage that specifically targets (infects) the Shigella species.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a Pseudomonas 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.
  • 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.
  • the bacterial species that enhances proteostasis in the subject is a Prevotella species.
  • the Prevotella species is P. corporis.
  • 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.
  • 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.
  • the bacterial species that enhances proteostasis in the subject is a Prevotella species.
  • the Prevotella species is / ⁇ corporis.
  • 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.
  • 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.
  • 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.
  • methods for increasing expression of HSP in a subject are described, the methods comprising: administering to the subject killed Prevotella sp.
  • the 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.
  • the Prevotella species is Prevotella corporis.
  • the Prevotella species is Prevotella amnii.
  • kits for increasing expression of MUC3 and/or MUC4 in a subject 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.
  • methods for increasing expression of MUC3 and/or MUC4 in a subject 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.
  • 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.
  • compositions that specifically increases the abundance or growth or aPrevotella species in the gut of the subject 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.
  • methods for activating a heat shock response in a subject are described, the methods comprising: administering to the subject killed Prevotella sp.
  • the Prevotella species is Prevotella corporis.
  • the Prevotella species is Prevotella amnii, Prevotella bivia, Prevotella buccae, Prevotella denticola, Prevotella disiens, Prevotella histicola.
  • 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) a composition 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).
  • the composition comprises a pharmaceutical composition.
  • the pharmaceutical composition comprises an excipient.
  • 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).
  • the composition comprises a pharmaceutical composition.
  • the pharmaceutical composition comprises an excipient.
  • 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;
  • composition comprising a Prevotella corporis lysate or an extract or a fraction thereof;
  • composition comprises a pharmaceutical composition.
  • pharmaceutical composition comprises an excipient.
  • 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).
  • the composition comprises a pharmaceutical composition.
  • the pharmaceutical composition comprises an excipient.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the agent or composition comprises a bacteriophage.
  • 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.
  • the agent or composition comprises a bacteriophage.
  • 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;
  • 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.
  • 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.
  • 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.
  • 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 grow th of a Pseudomonas species or a Shigella species in the gut of the subject.
  • 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.
  • 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.
  • 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 Citrobacter species, 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.
  • a control population e.g., a population of healthy
  • 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.
  • 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
  • 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.
  • 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.
  • 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).
  • a protein folding disease e.g. , Alzheimer’s disease or Parkinson’s disease
  • 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.
  • compositions and methods can be used to treat or prevent a PCD in a subject.
  • 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.
  • the subject has or has been diagnosed with a PCD or is at increased risk of developing a PCD.
  • 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 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.
  • 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.
  • 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.
  • Heat map generation 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.
  • 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-second period. 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.
  • 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.
  • E. coli OP50 aerobic
  • 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.
  • 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.
  • FIG. 1 The method used to conduct this experiment is illustrated in FIG. 1 .
  • 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.
  • NNM nematode growth media
  • Intestinal polyQ aggregates were quantified by manual counting and western blotting the insoluble fractions.
  • the collection encompasses isolates from a range of diverse phyla and a variety of anatomical sites (FIG. 2).
  • FOG. 2 The collection encompasses isolates from a range of diverse phyla and a variety of anatomical sites.
  • C. elegans as a model organism for studying the effect of gut bacteria on host organism protein folding.
  • 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.
  • 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.
  • enterobacteriaceae ⁇ E. coll. Klebsiella species, Proteus species, Citrobacter species, Shigella species, and Salmonella species
  • other pathogenic species ⁇ Pseudomonas species and Acinetobacter species
  • the human microbiota is comprised of a diverse array of bacterial species that coexist and interact within a complex polymicrobial community.

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Abstract

L'invention concerne des compositions et des méthodes utilisant Prevotella corporis pour traiter ou prévenir des protéinopathies.
PCT/US2024/049907 2023-10-06 2024-10-04 Compositions et méthodes pour analyser l'effet du microbiote sur la conformation des protéines hôtes et pour traiter des maladies neurodégénératives Pending WO2025076308A1 (fr)

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