METHODS OF USE & COMPOSITIONS FOR OBESITY

Abstract

This invention relates to the development of prebiotic and probiotic products that treat obesity and overweight conditions and allow people with these tendencies to covert food to lean muscle mass rather than fat.

Claims

1-2. (canceled)

3. A method for determining keystone bacterial species in the gut of a livestock animal for cross-species administration to a human subject comprising the steps of: characterizing one or more natural bacterial enterotypes of a livestock; administering one or more antibiotics to the livestock; identifying one or more antibiotic administration-induced bacterial enterotypes; comparing the antibiotic administration-induced bacterial enterotypes to the natural bacterial enterotypes to identify one or more keystone bacterial species; and administering the one or more keystone bacterial species, and/or prebiotic metabolic products produced by the one or more keystone bacterial species, to a human subject.

4. The method of claim 3 wherein each of the bacterial enterotypes are representative of the gastrointestinal microbiomes in one or more of the stomach, rumen, small intestines, or colon of the livestock, and wherein the one or more keystone bacterial species are associated with a phenotypic effect on the livestock, and wherein the phenotypic effect is deposition of lean muscle over fat.

5. The method of claim 3 wherein the one or more antibiotics are selected from the group consisting of aminoglycosides, cephalosporins, cyclic peptides, diterpines, fluoroquinolones, hydrazines, ionophores, lincosam ides, macrolides, organoarsenics, nitroimidazoles, penicillins, streptogram ins, and sulfonamides.

6. The method of claim 3, wherein the one or more keystone bacterial species are formulated as a probiotic composition for administration to the human subject.

7. The method of claim 6, wherein the probiotic is co-administered to the human subject with food.

8. The method of claim 3, wherein the livestock is selected from the group consisting of cattle, poultry, swine, fish, sheep, goat, venison, and bison.

9. The method of claim 3, wherein each enterotype is characterized by one or more of metagenomic, proteomic, transcriptomic, and metabolomic analyses.

10. The method of claim 3, wherein the human subject is overweight, suffers from obesity, or is at risk for weight gain and/or obesity.

11. The method of claim 10, wherein the administration of the one or more keystone bacterial species effects the deposition of lean muscle over fat in the human subject to mitigate obesity and fat related weight gain.

12. The method of claim 3, wherein the at least one keystone bacterial species is used as a biological factory in a bioreactor to produce the prebiotic metabolic products.

13. The method of claim 16, wherein the administration of the prebiotic metabolic products to the human subject effects in the deposition of lean muscle over fat in the human subject to mitigate obesity and fat related weight gain.

14. A cross-species screening method for recapitulating a target bacterial enterotype in the gut of a human subject comprising the steps of: characterizing a natural bacterial enterotype of a livestock; administering one or more antibiotics to the livestock to yield a desired phenotype; identifying an antibiotic administration-induced target bacterial enterotype associated with the desired phenotype; screening for one or more compounds and/or drugs that recapitulate the target bacterial enterotype; and administering the one or more compounds and/or drugs to a human subject as a prebiotic to recapitulate the target bacterial enterotype in the human subject.

15. The method of claim 14, wherein the one or more antibiotics are selected from the group consisting of aminoglycosides, cephalosporins, cyclic peptides, diterpines, fluoroquinolones, hydrazines, ionophores, lincosam ides, macrolides, organoarsenics, nitroimidazoles, penicillins, streptogram ins, and sulfonamides.

16. The method of claim 14 wherein the bacterial enterotype is representative of the gastrointestinal microbiome in one or more of the stomach, rumen, small intestines, or colon of the livestock.

17. The method of claim 14 wherein the desired phenotype is deposition of lean muscle over fat in the livestock.

18. The method of claim 14, wherein the livestock is selected from the group consisting of cattle, poultry, swine, fish, sheep, goat, venison, and bison.

19. The method of claim 14, wherein the administration of the prebiotic effects the deposition of lean muscle over fat in the human subject to mitigate obesity and fat related weight gain.

20. A cross-species metabolic composition for the deposition of lean muscle over fat in a human subject to mitigate obesity and fat related weight gain comprising one or more of a keystone bacterial species, a probiotic containing one or more keystone bacterial species, metabolic products from the one or more identified keystone bacterial species, or combinations thereof, each derived from a livestock animal.

21. The composition of claim 20, further comprising one or more components selected from the group consisting of vitamins, proteins, fatty acids, sugars, and compounds screened to modulate microbiota in various gastrointestinal microbiomes.

22. The composition of claim 20, wherein the keystone bacterial species, a probiotic containing one or more keystone bacterial species, metabolic products from the one or more identified keystone bacterial species, or combinations thereof, each derived from a livestock animal, are associated with an enterotype in the livestock animal that results in the deposition of lean muscle over fat.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0023] All publications, patents and patent applications, including any drawings and appendices therein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application, drawing, or appendix was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0024] Where appropriate, any one or more of the other active agents may be in the form of a pharmaceutically acceptable salt.

[0025] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfuric, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

[0026] It is intended that the aspects and embodiments of this invention encompasses all solid forms, including amorphous forms, as well as crystalline forms, and polymorphs thereof.

[0027] Throughout this specification the term ‘in combination’ means that one or more other actives are both administered to people over the same period of treatment. They may be administered together, i.e. at the same time. In this case they may be administered in a single formulation, (e.g. as a single tablet or capsule) or in separate formulations administered simultaneously or nearly simultaneously. Alternatively, they may be administered at separate times of day.

[0028] The combinations of the invention provide benefits which are at least additive compared to the use of either agent alone. In many embodiments, the combinations are something more than additive, e.g. synergistic, compared to the use of either agent alone.

[0029] The definition of the term ‘treatment’ in this specification encompasses deposition of lean muscle mass rather than fat as well as this purpose plus disease treatment, prophylaxis and prevention (i.e. reducing or eliminating the risk of contracting the disease). As well as meaning curing people of the disease, ‘treatment’ also includes preventing the onset of symptoms, controlling (e.g. by slowing or eliminating) progression of disease, preventing the spread of the disease to other parts of the body and/or to other persons, reducing the spread of the disease and other facets of medical practice which will be readily understood by the person skilled in the art to fall within the meaning of the term ‘treatment’.

[0030] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Formulations

[0031] For the above-mentioned therapeutic uses, the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the purpose or disorder indicated.

[0032] Compositions may be administered systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories.

[0033] For oral administration, one or more active agents may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[0034] For the preparation of soft gelatine capsules, one or more active agents may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

Methods of Bioinformatics

[0035] The bioinformatics of the present invention employs for metagenomic microbiota analysis a base of both 16S ribosomal RNA fingerprinting as well as whole genome shotgun sequencing (WGS) analysis of metagenomic data. The WGS in the present invention includes techniques that use iterative scanning of small motifs, including 12 amino-acid (36 bp) motifs, that are then compared for a comprehensive taxonomy against all 280,000 named organisms in public databases and are benchmarked against other pipelines (e.g., MetaPhlan, Phylosift, GOTTCHA and Kraken).

[0036] The present invention includes cross-species metagenomic, proteomic, transcriptomic, and metabolomic analyses of the various GI microbiomes (e.g., stomach, small intestines, colon) for each livestock production species, including, but not limited to cattle, poultry (including raised game birds), swine, fish (including farmed fish), venison, bison, sheep, and goats, both before and after administration of an antibiotic, including, but not limited to, those in the class of aminoglycosides, cephalosporins, cyclic peptides, diterpines, fluoroquinolones, hydrazines, ionophores, lincosamides, macrolides, organoarsenics, nitroimidazoles, penicillins, streptogramins, and sulfonamides in combination with various feeds used for those production species.

[0037] The present invention also includes cross-species metagenomic, proteomic, transcriptomic, and metabolomic analyses of the various GI microbiomes (e.g., stomach, rumen, small intestines, colon) for each livestock production species, including, but not limited to cattle, poultry (including raised game birds), swine, fish (including farmed fish), venison, bison, sheep, and goats, both before and after administration of combinations of antibiotics, including, but not limited to, those in the class of aminoglycosides, cephalosporins, cyclic peptides, diterpines, fluoroquinolones, hydrazines, ionophores, lincosamides, macrolides, organoarsenics, nitroimidazoles, penicillins, streptogramins, and sulfonamides in combination with various feeds used for those production species.

[0038] The present invention also includes cross-species metagenomic, proteomic, transcriptomic, and metabolomic analyses of the various GI microbiomes (e.g., stomach, rumen, small intestines, colon) for each livestock production species, including, but not limited to cattle, poultry (including raised game birds), swine, fish (including farmed fish), venison, bison, sheep, and goats, both before and after administration of combinations of antibiotics and antiprotozoal agents, including, but not limited to, those in the class of coccidiostats, aminoglycosides, cephalosporins, cyclic peptides, diterpines, fluoroquinolones, hydrazines, ionophores, lincosamides, macrolides, organoarsenics, nitroimidazoles, penicillins, streptogramins, and sulfonamides in combination with various feeds used for those production species.

[0039] The present invention includes the keystone species in enterotypes, and products derived from their administration or administration of their metabolic products, determined by cross-species comparison of the metagenomic, proteomic, transcriptomic, and metabolomic analyses of the various GI microbiomes (e.g., stomach, rumen, small intestines, colon), analysed in sequence of the passage of food in the digestive tract (first stomach or rumen, then small intestines, then colon) of the different livestock production species, including, but not limited to cattle, poultry (including raised game birds), swine, fish (including farmed fish), venison, bison, sheep, and goats, both before and after administration of an antibiotic, including, but not limited to, those in the class of aminoglycosides, cephalosporins, cyclic peptides, diterpines, fluoroquinolones, hydrazines, ionophores, lincosamides, macrolides, organoarsenics, nitroimidazoles, penicillins, streptogramins, and sulfonamides in combination with various feeds used for those production species, to determine a metabolic code for digestion through the solving of simultaneous equations with variables being bacterial strains with genes encoding metabolic products for food breakdown.

[0040] The present invention encompasses combinations of enterotype probiotic products or artificially optimized metabolic solutions (Bolsols) that are non-naturally occurring and involving inventive steps as contemplated in the intellectual property scheme described in Exhibit 1: Novel IP Regime: Patenting Microbial Ecologies and Exhibit 2: Metabols and Bolsols to Process Food.

[0041] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings, such as attached FIG. 1 Syntheses), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0042] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.