# US 2021/0275600 A1 · Methods for diagnosis and treatment of type 1 diabetes

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- Number: US 2021/0275600 A1
- Document ID: US20210275600A1
- Status: Published application
- Kind: A1
- Application number: 17/256,428
- Filed: 2019-06-28
- Published: 2021-09-09
- Earliest claimed: 2018-06-29
- Assignees: Viktor Veniaminovich TETS; Georgy Viktorovich TETS
- Inventors: Viktor Veniaminovich TETS; Georgy Viktorovich TETS
- Web page: https://patentgrep.com/patent/US20210275600A1

## CPC

- A61K 35/74: Bacteria (therapeutic use of a bacterial protein A61K38/00)
- A61K 31/65: Tetracyclines
- A61K 31/7004: Monosaccharides having only carbon, hydrogen and oxygen atoms
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 33/06: Aluminium, calcium or magnesium; Compounds thereof {, e.g. clay}
- A61K 35/745: Bifidobacteria
- A61K 35/747: Lactobacilli, e.g. L. acidophilus or L. brevis
- A61K 35/76: Viruses; Subviral particles; Bacteriophages
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/1709: {from mammals}
- A61K 38/465: {acting on ester bonds (3.1), e.g. lipases, ribonucleases}
- A61K 39/0008: {Antigens related to auto-immune diseases; Preparations to induce self-tolerance}
- A61K 39/0258: {Escherichia}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07K 16/1232: Escherichia (G)
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 1/689: for bacteria
- C12Q 1/70: involving virus or bacteriophage {(immunoassay for viruses G01N33/56983)}
- G01N 33/6893: {related to diseases not provided for elsewhere}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/58: {raising an immune response against a target which is not the antigen used for immunisation}
- C12N 2310/14: interfering nucleic acids [NA]
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/172: Haplotypes
- G01N 2800/042: Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Methods for preventing, treating or diagnosing Type 1 Diabetes (T1D) are described. Amyloid-producing bacteria within microbiota are inactivated. Amyloid-producing bacteria are inactivated in microbiota, gastrointestinal tract, bodily fluids or tissues. Type-1 Diabetes associated microbial product production or release by microbiota is prevented. Also described is inactivation of bacteria-derived T1DAMP present in microbiota, bodily fluids or tissues of a mammal. Release of bacteria-derived T1DAMP from biofilm or bacteria to gastrointestinal tract is inhibited. Entry of bacteria-derived T1DAMP to microbiota, gastrointestinal tract, bodily fluids or tissues of a mammal is inhibited.

## Claims

### Claim 1

A method for preventing or treating Type 1 Diabetes (T1D) or consequences thereof in a mammal in need thereof, said method comprising one or more of (i) inactivating amyloid-producing bacteria within microbiota in the mammal, (ii) preventing amyloid-producing bacteria from entering the microbiota, the gastrointestinal tract, a bodily fluid or a tissue of the mammal from an environment outside the mammal, (iii) inactivating a T1D-associated microbial product (T1DAMP) that is released by microbiota of the mammal, (iv) inactivating a T1DAMP present, a bodily fluid or a tissue of the mammal, (v) inhibiting release of a T1DAMP from a biofilm and/or bacteria in the gastrointestinal tract, a bodily fluid or a tissue of the mammal, (vi) inhibiting entry of T1DAMP to microbiota, the gastrointestinal tract, a bodily fluid or a tissue of the mammal, (vii) inhibiting the triggering of T1D by bacteria, T1DAMP derived from the bacteria, or a complex comprising the bacteria or the T1DAMP, (viii) administering to the mammal E. coli that do not produce an amyloid protein, (ix) administering to the mammal a pilocene or a curlicide, and (x) inhibiting the activity of a bacteriophage (xi)) inhibiting the prophage inductors.

### Claim 2 (depends on 1)

The method of claim 1, wherein the mammal expresses a T1D susceptible HLA allele.

### Claim 3 (depends on 2)

The method of claim 2, wherein the T1D susceptible HLA allele is selected from an HLA allele having a DR4-DQ8 and/or DRB1 haplotype, an HLA allele having a DR3-DQ2 haplotype, HLA allele DQB1*02/*0302-DRB1*0404, HLA allele DQB1*0302/*0501-DRB1*0401, and
DQB1*0302/*04-DRB1*0401*.

### Claim 4 (depends on 1, 2, 3)

The method of any of claims 1-3, wherein the mammal comprises an increased amount of E. coli or Salmonella in the gastrointestinal tract as compared to a second mammal that does not develop T1D, and optionally wherein the mammal and the second mammal both express a T1D susceptible HLA allele, and optionally wherein the mammal and the second mammal both express the same T1D susceptible HLA allele.

### Claim 5 (depends on 4)

The method of claim 4, wherein the second mammal is age-matched and/or gender-matched to the mammal comprising the increased amount of E. coli or Salmonella in the gastrointestinal tract.

### Claim 6 (depends on 1, 2, 3, 4)

The method of any one of claims 1-4, wherein the method comprises administering to the mammal E. coli in a manner effective to populate the microbiota with the E. coli, wherein the administered E. coli do not produce an amyloid protein or produce a reduced amount of the amyloid protein as compared to a wild-type E. coli.

### Claim 7 (depends on 6)

The method of claim 6, wherein the administered E. coli comprises a mutation in a gene encoding for an amyloid protein.

### Claim 8 (depends on 6)

The method of claim 6, wherein the method comprises administering to the mammal E. coli that comprises a mutation in a sequence regulating expression of a gene encoding for an amyloid protein.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6)

The method of any one of claims 1-6, wherein inactivation of amyloid-producing bacteria within microbiota comprises preventing transfer of amyloid-producing bacteria to the mammal from a mother of the mammal during birth or breastfeeding.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6)

The method of any one of claims 1-6, wherein the inactivation of amyloid-producing bacteria within microbiota comprises administering to the mammal a microorganism or a by-product of the microorganism, wherein the microorganism or the byproduct is effective to prevent colonization of the amyloid-producing bacteria in the gastrointestinal tract of the mammal.

### Claim 11 (depends on 11)

The method of claim 11, wherein said microorganism is from an order selected from Bacteroidales, Lactobacillales, Erysipelotrichales, Coriobacteriales, Clostridiales, Bacillales, and Bifidobacteriales.

### Claim 12 (depends on 11)

The method of claim 11, wherein the microorganism is a non-amyloid-producing strain of bacteria or a strain of bacteria that synthesizes a reduced amount of amyloid.

### Claim 13

A method for preventing or treating Type 1 Diabetes (T1D) or consequences thereof in a mammal in need thereof, said method comprising vaccination of the mammal against Enterobacteriales bacteria.

### Claim 14 (depends on 13)

The method of claim 13, further comprising vaccination of the mammal against E. coli or Salmonella.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

The method of any one of claims 1-12, further comprising vaccination of the mammal against Enterobacteriales bacteria.

### Claim 16 (depends on 15)

The method of claim 15, further comprising vaccination of the mammal against E. coli or Salmonella.

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15)

The method any one of claims 1-12 and 15, wherein the inactivation of amyloid-producing bacteria within microbiota comprises i) colonization of gastrointestinal microbiota of the mammal with non-amyloid-producing bacteria and/or ii) administering an anti-amyloid antibody to the mammal.

### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 17)

The method any one of claims 1-12 and 15-17, wherein the inactivation of amyloid-producing bacteria within microbiota comprises editing one or more genes in the genome of the amyloid-producing bacteria, wherein the inactivation inhibits adhesion of the amyloid-producing bacteria, wherein the one or more genes are selected from afa-dra, daaD, tsh, vat, ibeA, fyuA, mat, sfa-foc, malX, pic, irp2, papC, fimH; PapAH papEF, bmaE, sfa/focDE, papC, focG, sfaI, sfa II, sfaS, aah, aidA, fasA, faeG, bfpA, eaeA, Paa, fasA, faeG, fedA, fanC, sfaY, and a gene in the Cpx pathway.

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 17)

The method any one of claims 1-12 and 15-17, wherein the inactivation of the amyloid-producing bacteria within microbiota comprises administering to the mammal a composition comprising one or more of fosfomycin, Doxycycline, Ciprofloxacin, Trimethoprim/sulfamethoxazole, Levofloxacin, Amoxicillin, Aztreonam, Nitrofurantoin, Ceftriaxone, imipenem, and Rifaximin, a FimH antagonist, and a pilicide.

### Claim 20 (depends on 19)

The method of claim 19, wherein the FimH antagonist is an n-Heptyl α-D-mannose glycopolymer, methyl R-D-mannoside, or a thiazolylmannoside.

### Claim 21 (depends on 19)

The method of claim 19, wherein the pilicide is selected from
i) 7-(1-naphthylmethyl)-5-oxo-8-phenyl-2,3,6,7-tetrahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid
ii) 8-cyclopropyl-7-(1-naphthylmethyl)-5-oxo-2,3,6,7-tetrahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid
iii) 7-(1-naphthylmethyl)-5-oxo-8-pentyl-2,3,6,7-tetrahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid
iv) 8-(4-bromophenyl)-7-(1-naphthylmethyl)-5-oxo-2,3,6,7-tetrahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid
v) 7-(1-naphthylmethyl)-5-oxo-8-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt
vi) 8-cyclopropyl-7-(1-naphthylmethyl)-5-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt
vii) 7-methyl-5-oxo-8-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt
viii) 6-dimethylaminomethyl-7-(1-naphthylmethyl)-5-oxo-8-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt
ix) 6-morpholinomethyl-7-(1-naphthylmethyl)-5-oxo-8-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt
x) 8-cyclopropyl-6-morpholinomethyl-7-(1-naphthylmethyl)-5-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt, and
xi) 6-dimethylaminomethyl-7-methyl-5-oxo-8-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt.

### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)

The method of any one of claims 1-21, wherein the mammal expresses one or more of T1D-susceptible HLA alleles.

### Claim 23 (depends on 22)

The method of claim 22, wherein the T1D-susceptible HLA allele is a DR4-DQ8 haplotype, an HLA allele having a DR3-DQ2 haplotype, HLA allele DQB1*02/*0302-DRB1*0404, HLA allele DQB1*0302/*0501-DRB1*0401, and DQB1*0302/*04-DRB1*0401*.

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

The method of any one of claims 1-22, comprising (i) inactivating amyloid-producing bacteria within microbiota in the mammal, and wherein the microbiota is gut microbiota.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

The method of any one of claims 1-22 comprising (iii) inactivating a T1D-associated microbial product (T1DAMP) that is released by microbiota of the mammal, and wherein the microbiota is gut microbiota.

### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

The method of any one of claims 1-22 comprising (vi) inhibiting entry of T1DAMP to microbiota, the gastrointestinal tract, a bodily fluid or a tissue of the mammal, (vii) inhibiting the triggering of T1D by bacteria, T1DAMP derived from the bacteria, or a complex comprising the bacteria or the T1DAMP, and wherein the microbiota is gastrointestinal microbiota.

### Claim 27

A method for determining susceptibility to T1D in a mammal, said method comprising (a) detecting the expression in the mammal of at least one T1D susceptible HLA allele, and (b) (i) detecting increased intestinal permeability in the mammal as compared to the intestinal permeability in one or more mammals from an age-matched and sex-matched reference population, and/or (ii) detecting an increased level of E. coli or Salmonella in gastrointestinal microbiota of the mammal, wherein the E. coli or Salmonella release a T1D-associated microbial product (T1DAMP) that enters the bloodstream of the mammal and binds to a β-cell or dendritic cells expressing a Toll-like 2 receptor or a Toll-like 9 receptor and promotes death of the β-cell to thereby increase susceptibility to T1D.

### Claim 28 (depends on 27)

The method of claim 27, wherein the T1D susceptible HLA allele is selected from an HLA allele having a DR4-DQ8 haplotype, an HLA allele having a DR3-DQ2 haplotype, HLA allele DQB1*02/*0302-DRB1*0404, HLA allele DQB1*0302/*0501-DRB1*0401, and HLA allele DQB1*0302/*04-DRB1*0401*.

### Claim 29 (depends on 27, 28)

The method of claim 27 or claim 28, wherein the detection of an increased level of E. coli comprises performing one or more of the assays selected from i) analysis of 16S rRNA from the E. coli, ii) PCR of a nucleic acid from the E. coli, iii) sequencing of a gene from the E. coli, iv) a metagenomic assay, v) cultivation of the E. coli, and vi) biochemical identification of the E. coli.

### Claim 30

A method for determining susceptibility to T1D in a mammal, said method comprising detecting the level of E. coli bacteriophages in the gastrointestinal microbiota of the mammal by performing one or more of assays selected from i) PCR of a nucleic acid from the E. coli bacteriophages, ii) sequencing of a gene from the E. coli bacteriophages, iii) a metagenomic assay, iv) cultural identification of the E. coli bacteriophages, and v) biochemical identification of the E. coli bacteriophages.

### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

The method of any one of claims 1-30, wherein the mammal is a human.

### Claim 32 (depends on 31)

The method of claim 31, wherein the detecting of an increased level of E. coli and/or an increase or decrease in the level of E. coli bacteriophages and/or a microbial inducer of E. coli prophages in the gastrointestinal microbiota is conducted at 100-200 days after birth of the human.

### Claim 33 (depends on 32)

The method of claim 32, wherein the detecting is conducted at 130-180 days after birth of the human.

### Claim 34 (depends on 27, 31, 32, 33)

The method of any one of claims 27 and 31-33, further comprising detecting a decrease in the level of E. coli and/or an increase or a decrease in the level of E. coli bacteriophages and/or microbial inducers of E. coli prophages subsequent to the detecting of the increased level of E. coli.

### Claim 35 (depends on 34)

The method of claim 34, wherein the mammal is a human and wherein the detecting of a decrease in the level of E. coli is performed when the human is between 9 months of age and 30 months of age.

### Claim 36

A method for detecting susceptibility to T1D in a mammal, said method comprising detecting the amount of T1DAMP in feces from the mammal, wherein an increased level of T1DAMP in the feces indicates an increased likelihood to T1DAMP binding to β-cell or dendritic cell expressing a Toll-like 2 receptor or a Toll-like 9 receptor and promotes death of the β cell to thereby increase susceptibility to T1D.

### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)

The method of any one of claims 1-36, wherein the T1DAMP is an amyloid protein, a bacterial amyloid protein, an amyloid-like protein, a bacterial amyloid curli protein, an amyloid precursor, a bacterial curli, an amyloid-DNA complex, an amyloid-nucleic acid complex, or a bacterial DNA.

### Claim 38 (depends on 36, 37)

The method of claim 36 or claim 37, wherein the mammal is human.

### Claim 39

A composition for preventing or treating Type 1 Diabetes, wherein the composition comprises one or more of a microorganism or a by-product of the microorganism, an anti-amyloid antibody, fosfomycin, Doxycycline, Ciprofloxacin, Trimethoprim/sulfamethoxazole, Levofloxacin, Amoxicillin, Aztreonam, Nitrofurantoin, Ceftriaxone, imipenem, and Rifaximin, a FimH antagonist, and a pilicide.

### Claim 40 (depends on 39)

The composition of claim 39, wherein said microorganism is from an order selected from Bacteroidales, Lactobacillales, Erysipelotrichales, Coriobacteriales, Clostridiales, Bacillales, and Bifidobacteriales.

### Claim 41 (depends on 39, 40)

The composition of claim 39 or claim 40, wherein the FimH antagonist is an n-Heptyl α-D-mannose glycopolymer, methyl R-D-mannoside, or a thiazolylmannoside.

### Claim 42 (depends on 39, 40, 41)

The composition of any of claims 39 to 41, wherein the pilicide is selected from
i) 7-(1-naphthylmethyl)-5-oxo-8-phenyl-2,3,6,7-tetrahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid
ii) 8-cyclopropyl-7-(1-naphthylmethyl)-5-oxo-2,3,6,7-tetrahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid
iii) 7-(1-naphthylmethyl)-5-oxo-8-pentyl-2,3,6,7-tetrahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid
iv) 8-(4-bromophenyl)-7-(1-naphthylmethyl)-5-oxo-2,3,6,7-tetrahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid
v) 7-(1-naphthylmethyl)-5-oxo-8-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt
vi) 8-cyclopropyl-7-(1-naphthylmethyl)-5-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt
vii) 7-methyl-5-oxo-8-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt
viii) 6-dimethylaminomethyl-7-(1-naphthylmethyl)-5-oxo-8-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt
ix) 6-morpholinomethyl-7-(1-naphthylmethyl)-5-oxo-8-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt
x) 8-cyclopropyl-6-morpholinomethyl-7-(1-naphthylmethyl)-5-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt, and
xi) 6-dimethylaminomethyl-7-methyl-5-oxo-8-phenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid, lithium salt.

### Claim 43

A composition comprising an antagonist of an amyloid-producing bacteria, the composition comprising a defined microbial consortia of amyloid-producing bacteria antagonists selected from the group consisting of Bacteroidetes, Firmicutes, Proteobacteria, Verrucomicrobiae, and Actinobacteria, wherein the composition is formulated for oral administration, for parenteral administration by nasogastric tube, or administration by colonoscopy.

### Claim 44 (depends on 43)

The composition of claim 43, wherein the amyloid-producing bacteria are Enterobacteriales bacteria or E. coli.

### Claim 45

A composition comprising an antagonist of an amyloid-producing bacteria, the composition comprising a microorganism, an excipient, and a defined microbial consortia of non-amyloid producing strains selected from the group Enterobacteriales and/or E. coli, wherein the composition is formulated for oral administration, for parenteral administration by nasogastric tube, or administration by colonoscopy.

### Claim 46 (depends on 45)

The composition of claim 45, wherein the amyloid-producing bacteria are Enterobacteriales bacteria or E. coli.

### Claim 47

A composition comprising a fecal or non-fecal microbiome transplantation material and an antagonist of an amyloid-producing bacteria, wherein the transplantation material comprises one or more microorganisms belong to any one of Actinomycetales, Bacteroidales, Flavobacteriales, Bacillales, Lactobacillales, Clostridiales, Erysipelotrichales, Selenomonadales, Fusobacteriales, Neisseriales, Campylobacterales or Pasteurellales.

### Claim 48 (depends on 47)

The composition of claim 47, wherein the amyloid-producing bacteria are Enterobacteriales bacteria or E. coli.

### Claim 49

A composition for the inactivating amyloid-producing bacteria within microbiota by inhibition of curli assembly and their effects on macroorganisms by Transthyretin, as anti-α-sheet inhibitors, parthenolides, benzoquinone derivatives, (2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-p-benzoquinone, 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone), or tafamidis, wherein the composition is formulated for oral administration, parenteral administration by nasogastric tube, or IV, or administration by colonoscopy.

### Claim 50

A method of preventing a T1DAMP effect on macroorganisms, the method comprising administering an effective amount of deoxyribonuclease to a subject by oral administration, parenteral administration by nasogastric tube, IV, or administration by colonoscopy, wherein the composition is administered once per day, more than once per day, once per week, multiple times per week, once per month, or multiple times per month for a year, for 2 years, 3 years, 4, years, 5 years, from 5 years to 20 years, or for a period exceeding 20 years.

### Claim 51

A composition comprising one or more anti-amyloid-producing bacterial antibodies, wherein the composition is formulated for oral administration, for parenteral administration by nasogastric tube, or IV, or for administration by colonoscopy.

### Claim 52 (depends on 51)

The composition of claim 51, wherein the composition is formulated for administration to a subject once, once per day, multiple times per day, once per week, multiple times per week, once per month, or multiple times per month for a year, for 2 years, 3 years, 4, years, 5 years, from 5 years to 20 years, or for a period exceeding 20 years, optionally wherein the composition is formulated for administration before or after the development of T1D autoimmunity.

### Claim 53

A composition comprising one or more antibodies against bacterial amyloid protein and/or DNA-amyloid complexes and/or their components, wherein the composition is formulated for oral administration, for parenteral administration by nasogastric tube, or for administration by colonoscopy or IV.

### Claim 54 (depends on 53)

The composition of claim 53, wherein the composition is formulated for administration to a subject once, once per day, multiple times per day, once per week, multiple times per week, once per month, or multiple times per month for a year, for 2 years, 3 years, 4, years, 5 years, from 5 years to 20 years, optionally wherein the composition is formulated for administration before or after the development of T1D autoimmunity.

### Claim 55 (depends on 49, 50, 51, 52, 53, 54)

A method for vaccinating a mammal against bacterial-amyloid and/or amyloid complexes, the method comprising administering to the mammal the composition of any one of claims 49-54 before or after the development of T1D autoimmunity.

### Claim 56

A composition comprising siRNA effective against components of amyloid proteins, in the appropriate excipients and are administered before or after the development of T1D autoimmunity.

### Claim 57 (depends on 56)

The composition of claim 56, wherein the siRNA is against CsgA and CsgB.

### Claim 58

A composition comprising a vaccine, wherein the vaccine comprises conjugates of antigens to serotypes of an amyloid-producing bacterium within the microbiota of a patient, wherein the bacteria belongs to Bacteroidetes, Firmicutes, Proteobacteria, Verrucomicrobiae, and Actinobacteria, before or after the development of T1D autoimmunity.

### Claim 59

A method for preventing, delaying or treating Type 1 Diabetes (T1D) or consequences thereof in a mammal in need thereof, said method comprising one or more of
(i) inactivating amyloid-producing bacteria within microbiota in the mammal;
(ii) preventing amyloid-producing bacteria from entering the microbiota, the gastrointestinal tract, a bodily fluid or a tissue of the mammal, from an environment outside the mammal;
(iii) preventing amyloid-producing bacteria to release amyloid, DNA, a complex of an amyloid or DNA to microbiota, the gastrointestinal tract, bodily fluids or a tissue of the mammal;
(iv) inactivating a T1D-associated microbial product (T1DAMP) that is released by microbiota of the mammal;
(v) inactivating a T1DAMP present, a bodily fluid or a tissue of the mammal;
(vi) inhibiting release of a T1DAMP from a biofilm and/or bacteria in the gastrointestinal tract, a bodily fluid or a tissue of the mammal;
(vii) inhibiting entry of T1DAMP to microbiota, the gastrointestinal tract, a bodily fluid or a tissue of the mammal;
(viii) inhibiting the triggering of T1D by bacteria, T1DAMP derived from the bacteria, or a complex comprising the bacteria or the T1DAMP;
(ix) administering to the mammal E. coli that do not produce an amyloid protein;
(x) administering to the mammal a pilocene or a curlicide; and
(xi) inhibiting the activity of a bacteriophage (xii) inhibiting the prophage inductors.

### Claim 60 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 25, 26, 36, 37, 38, 50, 59)

The method of any one of claims 1-12, 25, 26, 36-38, 50 and 59, wherein the T1DAMP is an amyloid protein, a bacterial amyloid protein, an amyloid-like protein, a bacterial amyloid curli protein, an amyloid precursor, a bacterial curli, an amyloid-DNA complex, an amyloid-nucleic acid complex, or a bacterial DNA.

### Claim 61 (depends on 60)

The method of claim 60, wherein the bacterial DNA is either genomic DNA or extracellular DNA.

### Claim 62

A method for preventing or treating Type 1 Diabetes in a subject, the method comprising administering to the subject a composition effective to inactivate bacterial amyloid-DNA complexes, extracellular nucleic acids, and/or extracellular amyloid, wherein the composition comprises one or more of an antibody, a nuclease, a protease, an intercalator, and an oligonucleotide.

### Claim 63

A method for preventing or treating Type 1 Diabetes in a mammalian subject, the method comprising vaccinating the subject against amyloid-producing bacteria, amyloid-DNA complexes, amyloid, and/or extracellular nucleic acids.

### Claim 64 (depends on 63)

The method of claim 63, wherein the amyloid-producing bacteria are Enterobacteriales bacteria or E. coli.

### Claim 65

A method for preventing or treating Type 1 Diabetes in a mammalian subject, the method comprising vaccinating the subject against bacteriophages of amyloid-producing bacteria.