WO 2015/066625 Al 7 May 2015 (07.05.2015) P O P C T

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WO 2015/066625 Al 7 May 2015 (07.05.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/066625 Al 7 May 2015 (07.05.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12Q 1/04 (2006.01) G01N 33/15 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US2014/06371 1 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 3 November 20 14 (03 .11.20 14) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/898,938 1 November 2013 (01. 11.2013) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: WASHINGTON UNIVERSITY [US/US] GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, One Brookings Drive, St. Louis, Missouri 63 130 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: GORDON, Jeffrey I.; One Brookings Drive, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, St. Louis, Missouri 63 130 (US). SUBRAMANIAN, Sath- LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, ish; One Brookings Drive, St. Louis, Missouri 63 130 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, HSIAO, Ansel; One Brookings Drive, St. Louis, Missouri GW, KM, ML, MR, NE, SN, TD, TG). 63 130 (US). Published: (74) Agents: RILEY-VARGAS, Rebecca et al; Polsinelli PC, Mark Twain Plaza III, 105 West Vandalia, Suite 400, Ed- — with international search report (Art. 21(3)) wardsville, IL 62025 (US). — with sequence listing part of description (Rule 5.2(a)) (54) Title: METHODS TO ESTABLISH AND RESTORE NORMAL GUT MICROBIOTA FUNCTION OF SUBJECT IN NEED © THEREOF (57) Abstract: The present invention provides a method to define normal maturation of the gut microbiota using a limited number of o bacterial taxa found in the gut microbiota. Regressing the relative abundance of age-discriminatory taxa in their gut microbiota against the chronological age of each healthy subject at the time a sample of the gut microbiota was collected produces a regression model that may be used to characterize the maturity of another subject's gut microbiota to provide a measure of gastrointestinal health without having to query the whole microbiota. The present invention also provides composition and methods for preventing and/or treating a disease in a subject in need thereof. METHODS TO ESTABLISH AND RESTORE NORMAL GUT MICROBIOTA FUNCTION OF SUBJECT IN NEED THEREOF GOVERNMENTAL RIGHTS [0001 ] This invention was made with government support under AI043596 awarded by the National Institutes of Health. The government has certain rights in the invention. CROSS REFERENCE TO RELATED APPLICATIONS [0002] This application claims the priority of provisional application number 61/898,938, filed November 1, 2013, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0003] The present invention provides a method to define normal maturation of the gut microbiota using a limited number of bacterial taxa found in the gut microbiota. Regressing the relative abundance of age-discriminatory taxa in their gut microbiota against the chronological age of each healthy subject at the time a sample of the gut microbiota was collected produces a regression model that may be used to characterize the maturity of another subject's gut microbiota to provide a measure of gastrointestinal health without having to query the whole microbiota. The present invention also provides composition and methods for preventing and/or treating a disease in a subject in need thereof. REFERENCE TO SEQUENCE LISTING [0004] A paper copy of the sequence listing and a computer readable form of the same sequence listing are appended below and herein incorporated by reference. The information recorded in computer readable form is identical to the written sequence listing, according to 37 C.F.R. 1.821 (f). BACKGROUND OF THE INVENTION [0005] Systematic analyses of the gut microbiota in different healthy and unhealthy populations have been undertaken in the scientific community for many years. The gut microbiota comprises a complex community whose composition is in flux in infants and is generally stable in adults. Disease, illness, and diet, among other factors, have been shown to affect the proportional representation of the bacterial species comprising the gut microbiota. Accordingly, the gut microbiota is viewed as both a diagnostic and therapeutic target. There remains a need in the art, therefore, for methods to define microbiota maturity using bacterial taxonomic biomarkers that are highly discriminatory for age as a way to characterize the health status of the gut microbiota. SUMMARY OF THE INVENTION [0006] In an aspect, the present disclosure encompasses a method to determine the maturity of a subject's gut microbiota, the method comprising (a) calculating a relative abundance for each bacterial taxon in a group, from a fecal sample obtained from the subject, wherein the group comprises at least the bacterial taxa listed in rows 1 to 6 of Table A; (b) applying the relative abundances of the bacterial taxa from step (a) to a regression model to determine a microbiota age for the subject's gut microbiota, wherein the model regresses, for a group of healthy subjects, relative abundances of the same bacterial taxa, as determined from a plurality of gut microbiota samples obtained over time for each healthy subject in the group, against the chronological age of each healthy subject in the group at the time the gut microbiota sample was obtained; and (c) calculating the maturity of the subject's gut microbiota, wherein the calculation for maturity is defined as relative maturity, and relative maturity = (microbiota age of the subject ) - (microbiota age of a healthy subject of a similar chronological age. In certain embodiments, the group comprises at least the bacterial taxa listed in rows 1 to 6 of Table A and at least one bacterial taxon listed in rows 7 to 24 of Table A . [0007] In another aspect, the present disclosure encompasses a method to determine the maturity of a subject's gut microbiota, the method comprising (a) calculating a relative abundance for each bacterial taxon in a group, from a fecal sample obtained from the subject, wherein the group comprises at least 24 bacterial taxa listed in Table A; (b) applying the relative abundances of the bacterial taxa from step (a) to a regression model to determine a microbiota age for the subject's gut microbiota, wherein the model regresses, for a group of healthy subjects, relative abundances of the same bacterial taxa, as determined from a plurality of gut microbiota samples obtained over time for each healthy subject in the group, against the chronological age of each healthy subject in the group at the time the gut microbiota sample was obtained; and (c) calculating the maturity of the subject's gut microbiota, wherein the calculation for maturity is defined as relative maturity, and relative maturity = (microbiota age of the subject ) - (microbiota age of a healthy subject of a similar chronological age. In certain embodiments, the group comprises the bacterial taxa listed in Table B. [0008] In another aspect, the present disclosure encompasses a method to classify a subject, the method comprising (a) calculating a relative abundance for each bacterial taxon in a group, from a fecal sample obtained from the subject, wherein the group comprises at least the bacterial taxa listed in rows 1 to 6 of Table A ; (b) applying the relative abundances of the bacterial taxa from step (a) to a regression model to determine a microbiota age for the subject's gut microbiota, wherein the model regresses, for a group of healthy subjects, relative abundances of the same bacterial taxa, as determined from a plurality of gut microbiota samples obtained over time for each healthy subject in the group, against the chronological age of each healthy subject in the group at the time the gut microbiota sample was obtained; and (c) classifying the subject as having normal gut maturation when the microbiota age of the subject is substantially similar to the microbiota age of a healthy subject with a similar chronological age. In certain embodiments, the group comprises at least the bacterial taxa listed in rows 1 to 6 of Table A and at least one bacterial taxon listed in rows 7 to 24 of Table A . [0009] In another aspect, the present disclosure encompasses a method to classify a subject, the method comprising (a) calculating a relative abundance for each bacterial taxon in a group, from a fecal sample obtained from the subject, wherein the group comprises at least 24 bacterial taxa listed in Table A ; (b) applying the relative abundances of the bacterial taxa from step (a) to a regression model to determine a microbiota age for the subject's gut microbiota, wherein the model regresses, for a group of healthy subjects, relative abundances of the same bacterial taxa, as determined from a plurality of gut microbiota samples obtained over time for each healthy subject in the group, against the chronological age of each healthy subject in the group at the time the gut microbiota sample was obtained; and (c) classifying the subject as having normal gut maturation when the microbiota age of the subject is substantially similar to the microbiota age of a healthy subject with a similar chronological age.
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