COMPOSITIONS COMPRISING CO-SELECTED MICROBIOTA AND METHODS FOR USE THEREOF

Abstract

Anhydrous compositions comprising a co-selected microbiota and methods for using same to treat disorders associated with dysbiosis (an imbalance of the microbial community inhabiting a subject or inhabiting a particular tissue in a subject) are described herein. In particular, anhydrous compositions comprising a co-selected microbiota and methods for treating gastrointestinal disorders associated with dysbiosis are envisioned. The use of such anhydrous compositions comprising a co-selected microbiota for treating disorders associated with dysbiosis (e.g., gastrointestinal disorders associated with dysbiosis) and the use of such anhydrous compositions comprising a co-selected microbiota in the preparation of a medicament for treating disorders associated with dysbiosis (e.g., gastrointestinal disorders associated with dysbiosis) are also embodied herein.

Claims

1. An anhydrous composition comprising a co-selected microbiota, wherein the co-selected microbiota comprises a plurality of bacterial species consisting of each of the bacterial species listed in Table 1, and optionally, at least one additional bacterial species, wherein the bacterial species listed in Table 1 are in powder-form, wherein the powder-form has a moisture content of less than 5% wt/wt in the anhydrous composition, and wherein the co-selected microbiota exhibits resistance to perturbational stress.

2-7. (canceled)

8. The anhydrous composition of claim 1, wherein the co-selected microbiota comprises at least 25% Gram-negative bacterial species.

9. The anhydrous composition of claim 1, wherein the co-selected microbiota comprises at least 50% Gram-positive bacterial species.

10. The anhydrous composition of claim 1, wherein the co-selected microbiota comprises at least 65% bacterial species within the Firmicutes phylum.

11. The anhydrous composition of claim 1, wherein the co-selected microbiota comprises at least 5% bacterial species within the Bacteroidetes phylum.

12. The anhydrous composition of claim 1, wherein the co-selected microbiota comprises a sub-group as set forth in any one of Tables 3, 4, or 5 with respect to category and/or functional properties.

13. The anhydrous composition of claim 1, wherein the bacterial species are in a state of suspended animation.

14. The anhydrous composition of claim 1, further comprising a pharmaceutically acceptable carrier.

15. The anhydrous composition of claim 14, wherein the pharmaceutically acceptable carrier is cellulose.

16. The anhydrous composition of claim 1, wherein the anhydrous composition is encapsulated in a capsule.

17. The anhydrous composition of claim 16, wherein the anhydrous composition is encapsulated in a double capsule.

18. The anhydrous composition of claim 1, wherein the at least one additional bacterial species is a species in the Acidaminococcus genus.

19. The anhydrous composition of claim 18, wherein the species in the Acidaminococcus genus is Acidaminococcus intestini or Acidaminococcus fermentans.

20. The anhydrous composition of claim 1, further comprising a prebiotic.

21. A method for treating a mammalian subject afflicted with a disease or disorder associated with dysbiosis, the method comprising: administering a therapeutically effective amount of an anhydrous composition of claim 1 to the mammalian subject, wherein the therapeutically effective amount improves relative ratios of microorganisms in the mammalian subject, thereby treating the mammalian subject.

22. The method of claim 21, wherein the disease or disorder associated with dysbiosis is Clostridium difficile (Clostridioides difficile) infection, Crohn's disease, irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, or AIDS enteropathy.

23-62. (canceled)

Description

BRIEF DESCRIPTION OF THE FIGURES

[0032] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0033] FIGS. 1A and 1B show a single-stage chemostat vessel employed in the methods according to some embodiments of the present invention.

[0034] FIG. 2 depicts a chemostat model test according to one embodiment of the present invention.

[0035] FIG. 3 shows a histogram of relative percent composition of bacterial species within each of the indicated phyla according to one embodiment of the present invention.

[0036] FIGS. 4A and 4B each show a bar graph of relative percent composition of bacterial species within each of the indicated families according to one embodiment of the present invention.

[0037] FIG. 5 (Table 2) lists the MET-2 strains with their accompanying 16S rRNA sequence fragments, designated herein SEQ ID NOs: 41-80 in order of appearance in Table 2.

[0038] FIG. 6 (Table 4) lists properties of bacterial strains in MET-2.

[0039] FIG. 7 (Table 5) lists properties of bacterial strains in MET-2, MET-2A, and MET-2B.

DETAILED DESCRIPTION OF THE INVENTION

[0040] Among those benefits and improvements that have been disclosed, other objects and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying figures. Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely illustrative of the invention that may be embodied in various forms. In addition, each of the examples given in connection with the various embodiments of the invention which are intended to be illustrative, and not restrictive.

[0041] Throughout the specification and claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. The phrases in one embodiment and in some embodiments as used herein do not necessarily refer to the same embodiment(s), though it may. Furthermore, the phrases in another embodiment and in some other embodiments as used herein do not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention.

[0042] In addition, as used herein, the term or is an inclusive or operator, and is equivalent to the term and/or, unless the context clearly dictates otherwise. The term based on is not exclusive and allows for being based on additional factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of a, an, and the include plural references. The meaning of in includes in and on.

[0043] As used herein, the term OTU refers to an operational taxonomic unit, defining a species, or a group of species via similarities in nucleic acid sequences, including, but not limited to 16S rRNA gene sequences.

[0044] The term dysbiosis as used herein refers to an imbalance of the microbial community inhabiting a subject or inhabiting a particular tissue in a subject. The term typically refers to a decrease in beneficial microbes relative to deleterious microbes or a change in the ratio of microbes such that microbes that are normally only present in small numbers proliferate to a degree whereby they are present at elevated numbers.

[0045] As used herein, the term state of suspended animation as used herein with respect to a population of bacteria refers to a population of bacteria that is metabolically quiescent, but capable of resuming normal metabolic activity and proliferating in response to suitable growth promoting conditions.

[0046] The term prebiotic as used herein refers to a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora that confers benefits upon host well-being and health. See Roberfroid (2007, J Nutri 137:8305-8375. Particular prebiotics may be chosen for optimal results when used in conjunction with compositions described herein based on the mode of administration to the subject and the target tissue/s needing treatment. Particular prebiotics used in conjunction with compositions described herein may be food grade. Particular prebiotics envisioned for use in combination with compositions described herein include: inulin, fructo-oligosaccharides, or gluco-oligosaccharides and mixtures thereof.

[0047] Solutions of bacterial species are freeze dried/lyophilized to generate anhydrous compositions comprising a plurality of bacterial species having a moisture content of less than 25%, 20%, 15%, 10% 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In a particular embodiment, anhydrous compositions described herein are freeze dried to a moisture content of less than 5%.

[0048] As used herein, the term freeze dried/lyophilized refers to a laboratory method where live microbes in aqueous suspension are rapidly frozen to <50 C., and then the majority of the frozen water content is forced to sublime under vacuum conditions, allowing this water to be efficiently removed in the gaseous phase.

[0049] As used herein, the term anhydrous composition comprising a plurality of bacterial species refers to a manmade, freeze dried/lyophilized population of bacterial species having a moisture content of less than 25%, 20%, 15%, 10% 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In one embodiment, a plurality of bacterial species is isolated from the fecal matter of a single, healthy individual wherein the plurality of bacterial species have been co-selected and co-adapted as an interactive population.

[0050] Technologies typically used for moisture determination include, without limitation: thermogravimetric analysis (oven drying, halogen/IR drying, microwave drying, etc.); chemical analysis (Karl Fischer titration, calcium carbide testing); spectroscopic analysis (IR spectroscopy, microwave spectroscopy, proton nuclear magnetic resonance spectroscopy); and other analyses (e.g. gas chromatography, density determination, refractometry, etc.). With respect to thermogravimetric analysis (TGA), for example, moisture content is derived from the loss of product weight during drying by measuring the change in mass of a sample while being heated at a controlled rate until no more change in weight is observed.

[0051] As used herein, the term co-selected microbiota refers to a plurality of bacterial species that has collectively undergone co-selection and co-adaptation in a single subject (e.g., a healthy subject). In a particular embodiment, the co-selected microbiota has collectively undergone co-selection and co-adaptation in the intestines of a single, healthy subject. In contrast, bacterial species isolated or derived from different sources (e.g., different subjects and/or cell depositories) and combined with each other have not undergone co-selection and co-adaptation in a single subject (e.g., a healthy subject). Thus, even when combined in vitro, a plurality of bacterial species that have been isolated from different sources cannot constitute a co-selected microbiota.

[0052] As used herein, the term subject or patient is preferably an animal, including but not limited to animals such as mice, rats, cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, more preferably a primate, and most preferably a human.

[0053] As used herein, the term treating or treatment of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment treating or treatment refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, treating or treatment refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, treating or treatment relates to slowing the progression of the disease.

[0054] As used herein, the term preventing or prevention refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset).

[0055] As used herein, the term prophylaxis is related to prevention and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0056] As used herein, the phrase pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.

[0057] As used herein, the phrase therapeutically effective amount is used to refer to an amount of an agent (e.g., a therapeutic agent) sufficient to reduce a pathological feature of a disease or condition by at least about 30 percent, by at least 50 percent, or by at least 90 percent. A therapeutically effective amount of an agent results in a clinically significant reduction in at least one pathological feature (e.g., a clinical symptom) of a disease or condition.

[0058] As used herein, the term complementary refers to two DNA strands that exhibit substantial normal base pairing characteristics. Complementary DNA may, however, contain one or more mismatches.

[0059] As used herein, the term hybridization refers to the hydrogen bonding that occurs between two complementary DNA strands.

[0060] As used herein, the term nucleic acid or a nucleic acid molecule refers to any DNA or RNA molecule, either single or double stranded and, if single stranded, the molecule of its complementary sequence in either linear or circular form. In discussing nucleic acid molecules, a sequence or structure of a particular nucleic acid molecule may be described herein according to the normal convention of providing the sequence in the 5 to 3 direction. With reference to nucleic acids of the invention, the term isolated nucleic acid is sometimes used. This term, when applied to DNA, refers to a DNA molecule that is separated from sequences with which it is immediately contiguous in the naturally occurring genome of the organism in which it originated. For example, an isolated nucleic acid may comprise a DNA molecule inserted into a vector, such as a plasmid or virus vector, or integrated into the genomic DNA of a prokaryotic or eukaryotic cell or host organism.

[0061] When applied to RNA, the term isolated nucleic acid refers primarily to an RNA molecule encoded by an isolated DNA molecule as defined above. Alternatively, the term may refer to an RNA molecule that has been sufficiently separated from other nucleic acids with which it is generally associated in its natural state (i.e., in cells or tissues). An isolated nucleic acid (either DNA or RNA) may further represent a molecule produced directly by biological or synthetic means and separated from other components present during its production.

[0062] As used herein, the terms natural allelic variants, mutants, and derivatives of particular sequences of nucleic acids refer to nucleic acid sequences that are closely related to a particular sequence but which may possess, either naturally or by design, changes in sequence or structure. By closely related, it is meant that at least about 60%, but often, more than 85%, of the nucleotides of the sequence match over the defined length of the nucleic acid sequence referred to using a specific SEQ ID NO. Changes or differences in nucleotide sequence between closely related nucleic acid sequences may represent nucleotide changes in the sequence that arise during the course of normal replication or duplication in nature of the particular nucleic acid sequence. Other changes may be specifically designed and introduced into the sequence for specific purposes, such as to change an amino acid codon or sequence in a regulatory region of the nucleic acid. Such specific changes may be made in vitro using a variety of mutagenesis techniques or produced in a host organism placed under particular selection conditions that induce or select for the changes. Such sequence variants generated specifically may be referred to as mutants or derivatives of the original sequence.

[0063] As used herein, the terms percent similarity, percent identity and percent homology when referring to a particular sequence are used as set forth in the University of Wisconsin GCG software program and are known in the art.

[0064] As used herein, the phrase consisting essentially of when referring to a particular nucleotide or amino acid means a sequence having the properties of a given SEQ ID NO:. For example, when used in reference to an amino acid sequence, the phrase includes the sequence per se and molecular modifications that would not affect the basic and novel characteristics of the sequence.

[0065] A replicon is any genetic element, for example, a plasmid, cosmid, bacmid, phage or virus, that is capable of replication largely under its own control. A replicon may be either RNA or DNA and may be single or double stranded.

[0066] A vector is a replicon, such as a plasmid, cosmid, bacmid, phage or virus, to which another genetic sequence or element (either DNA or RNA) may be attached so as to bring about the replication of the attached sequence or element.

[0067] An expression vector or expression operon refers to a nucleic acid segment that may possess transcriptional and translational control sequences, such as promoters, enhancers, translational start signals (e.g., ATG or AUG codons), polyadenylation signals, terminators, and the like, and which facilitate the expression of a polypeptide coding sequence in a host cell or organism.

[0068] As used herein, the term operably linked refers to a regulatory sequence capable of mediating the expression of a coding sequence and which are placed in a DNA molecule (e.g., an expression vector) in an appropriate position relative to the coding sequence so as to effect expression of the coding sequence. This same definition is sometimes applied to the arrangement of coding sequences and transcription control elements (e.g. promoters, enhancers, and termination elements) in an expression vector. This definition is also sometimes applied to the arrangement of nucleic acid sequences of a first and a second nucleic acid molecule wherein a hybrid nucleic acid molecule is generated.

[0069] As used herein, the term oligonucleotide refers to primers and probes described herein, which are defined as a nucleic acid molecule comprised of two or more ribo- or deoxyribonucleotides, preferably more than three. The exact size of the oligonucleotide will depend on various factors and on the particular application and use of the oligonucleotide.

[0070] As used herein, the term probe refers to an oligonucleotide, polynucleotide or nucleic acid, either RNA or DNA, whether occurring naturally as in a purified restriction enzyme digest or produced synthetically, which is capable of annealing with or specifically hybridizing to a nucleic acid with sequences complementary to the probe. A probe may be either single-stranded or double-stranded. The exact length of the probe will depend upon many factors, including temperature, source of probe and use of the method. For example, for diagnostic applications, depending on the complexity of the target sequence, the oligonucleotide probe typically contains 15-25 or more nucleotides, although it may contain fewer nucleotides. The probes herein are selected to be substantially complementary to different strands of a particular target nucleic acid sequence. This means that the probes must be sufficiently complementary so as to be able to specifically hybridize or anneal with their respective target strands under a set of pre-determined conditions. Therefore, the probe sequence need not reflect the exact complementary sequence of the target. For example, a non-complementary nucleotide fragment may be attached to the 5 or 3 end of the probe, with the remainder of the probe sequence being complementary to the target strand. Alternatively, non-complementary bases or longer sequences can be interspersed into the probe, provided that the probe sequence has sufficient complementarity with the sequence of the target nucleic acid to anneal therewith specifically.

[0071] As used herein, the term specifically hybridize refers to the association between two single-stranded nucleic acid molecules of sufficiently complementary sequence to permit such hybridization under pre-determined conditions generally used in the art (sometimes termed substantially complementary). In particular, the term refers to hybridization of an oligonucleotide with a substantially complementary sequence contained within a single-stranded DNA or RNA molecule of the invention, to the substantial exclusion of hybridization of the oligonucleotide with single-stranded nucleic acids of non-complementary sequence.

[0072] As used herein, the term primer refers to an oligonucleotide, either RNA or DNA, either single-stranded or double-stranded, either derived from a biological system, generated by restriction enzyme digestion, or produced synthetically which, when placed in the proper environment, is able to functionally act as an initiator of template-dependent nucleic acid synthesis. When presented with an appropriate nucleic acid template, suitable nucleoside triphosphate precursors of nucleic acids, a polymerase enzyme, suitable cofactors and conditions such as a suitable temperature and pH, the primer may be extended at its 3 terminus by the addition of nucleotides by the action of a polymerase or similar activity to yield a primer extension product. The primer may vary in length depending on the particular conditions and requirement of the application. For example, in diagnostic applications, the oligonucleotide primer is typically 15-25 or more nucleotides in length. The primer must be of sufficient complementarity to the desired template to prime the synthesis of the desired extension product, that is, to be able anneal to the desired template strand in a manner sufficient to provide the 3 hydroxyl moiety of the primer in appropriate juxtaposition for use in the initiation of synthesis by a polymerase or similar enzyme. It is not required that the primer sequence represent an exact complement of the desired template. For example, a non-complementary nucleotide sequence may be attached to the 5 end of an otherwise complementary primer. Alternatively, non-complementary bases may be interspersed within the oligonucleotide primer sequence, provided that the primer sequence has sufficient complementarity with the sequence of the desired template strand to functionally provide a template-primer complex for the synthesis of the extension product.

[0073] Primers and/or probes may be labeled fluorescently with 6-carboxyfluorescein (6-FAM). Alternatively primers may be labeled with 4, 7, 2, 7-Tetrachloro-6-carboxyfluorescein (TET). Other alternative DNA labeling methods are known in the art and are contemplated to be within the scope of the invention.

[0074] In a particular embodiment, oligonucleotides according to the present invention that hybridize to nucleic acid sequences identified as specific for one of the bacterial species and/or strains described herein, are at least about 10 nucleotides in length, more particularly at least 15 nucleotides in length, more particularly at least about 20 nucleotides in length. Further to the above, fragments of nucleic acid sequences identified as specific for one of the bacterial species and/or strains described herein represent aspects of the present invention. Such fragments and oligonucleotides specific for same may be used as primers or probes for determining the amount of the particular bacterial species and/or strain in a bacterial sample generated in vitro or in a biological sample obtained from a subject, wherein the particular species or strain may be identified by the presence of any one of SEQ ID NOs: 1-40. Primers such as those described herein (e.g., SEQ ID NOs: 81 and 82) may, moreover, be used in polymerase chain reaction (PCR) assays in methods directed to determining the amount of a particular bacterial species and/or strain in a bacterial sample generated in vitro or in a biological sample obtained from a subject, wherein the particular bacterial species and/or strain comprises any one of, for example, SEQ ID NOs: 1-40.

[0075] Further to the above, a given strain's 16S rRNA sequence is species specific and in many cases, depending on the species, strain specific as well. Further to this point, some bacterial species are highly conserved and thus, different strains may have extremely similar or even identical sequences. Most species, however, include strains wherein sequence differences are detected.

[0076] Preparation of Bacterial Samples (for 16S rRNA Sanger Sequencing)

[0077] Master Mix contents (per reaction or sample): [0078] HPLC grade ddH2O (Caledon Laboratory Chemicals)38.5 L [0079] dNTPs, working stock (Invitrogen)3 L [0080] 10 ThermoPol Reaction Buffer (NEB)5 L [0081] V3kl/V6r primers (IDT)1 L of each [0082] Taq DNA Polymerase High Purity (BioBasic)0.5 L [0083] DNA Template1 L or 1 colony

[0084] PCR, Sequencing of Products, and Analysis of PCR Products [0085] 1) Determine how much of each Master Mix component is required by multiplying each by the number of samples. Add three additional reactions to account for pipetting error. [0086] 2) Bring the required amounts of ddH2O, dNTPs (stored at 20 C.), buffer (stored at 20 C.), primers (stored at 20 C.), 2 mL flip-cap tubes (sterile, from Axygen) and a V-bottom 96-well plate (sterile, from Fisher) into the Labconco Purifier Biological Safety Cabinet (Labconco, 08018496A). UV the hood and supplies for 15 minutes. [0087] 3) Turn the UV light off. Bring Taq (stored at 20 C.) and DNA template samples (if they are in liquid form) into the safety cabinet. [0088] 4) Prepare Master Mix in a 2 mL flip-cap tube, aliquoting all of the required reagents into the same tube. Mix it by gently inverting the tube several times. [0089] 5) Aliquot Master Mix into the 96-well plate, 48 L per reaction (or sample). [0090] 6) If your DNA is in liquid or broth form, skip Steps 9) and 10). If your DNA is taken directly from colonies on media plates skip Step 7). [0091] 7) Add 1 L of your DNA template per aliquoted reaction (i.e. one PCR reaction for each of your DNA template samples). For example, 27 DNA template samples (or 27 strains to be tested)=27 PCR reactions. [0092] 8) Remove the aliquoted Master Mix in the 96-well plate from the biological safety cabinet. [0093] 9) Transfer the aliquoted Master Mix in the 96-well plate into the Whitley anaerobic chamber workstation. [0094] 10) Use a sterile wooden applicator (Puritan) to touch a colony of interest and, using a twisting motion, deposit the colony into one well of the 96-well plate that contains an aliquot of Master Mix. Repeat for all bacterial strains of interest. [0095] 11) Run PCR reactions in the 96-well plate in the Eppendorf Mastercycler epgradient (Eppendorf, 5340 014805): [0096] 12) Using, for example, a Eppendorf Mastercycler (a.k.a. thermocycler) run the following: [0097] Cycle parameters are 94 C. for (the initial) 10 minutes, (94 C. for 30s, 60 C. for 30s, 72 C. for 30s) for 30 cycles, then 72 C. for 5 minutes, and 4 C. for indefinite time. [0098] 13) Sequencing is performed via Sanger sequencing methods, which are a matter of routine practice in research-based laboratories. [0099] 14) Sequences (16S rRNA full-length rRNA sequences associated with each bacterial strain) generated are compared to databases of known sequences such as, for example, those maintained by U.S. government agencies, which can be accessed via the web (e.g., blast.ncbi.nlm.nih.gov/Blast.cgi) using known programs (e.g., BLAST). [0100] 15) When using, for example, a BLAST program and an alignment application thereof, a value of 99% or higher indicates that the template sequence and the query sequence are identical. If the template sequence and the query sequence are identical this indicates that the query sequence (which was obtained from a bacterial strain of interest) is the same identity as that which is associated with the template sequence.

TABLE-US-00001 TABLE 1 presents a list of MET 2 strains, which is an exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein if the bacterial species are derived from a co-selected microbiota. In a particular embodiment, an exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following strains listed in Table 1, but does not exceed including each and every one of the species recited in the exemplary list of Table 1. In a more particular embodiment thereof, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein consists of each of the strains listed in Table 1. Strain name Closest species match NB2A-14-DS Lachnoclostridium pacaense NB2B-20-DS [Clostridium] hathewayi NB2B-20-GAM [Clostridium] lactatifermentans NB2B-13-CNA Hespellia porcina NB2A-7-D5 [Clostridium] scindens NB2B-10-NB [Clostridium] saccharogumia NB2B-6-CNA [Eubacterium] eligens NB2B-13-BHI [Eubacterium] hallii NB2A-9-NA [Ruminococcus] obeum NB2A-14-FMU [Ruminococcus] torques 14 LG Acidaminococcus intestini NB2A-8-WC Akkermansia muciniphila NB2B-9-DCM Anaerostipes hadrus NB2A-15-BHI Anaerovorax odorimutans NB2B-14-D5 Bacteroides eggerthii NB2A-12-BBE Bacteroides ovatus NB2A-15-DCM Bacteroides timonensis NB2B-3-WC Barnesiella intestinihominis NB2B-16-TSAB Bifidobacterium adolescentis NB2B-11-FAA Bifidobacterium longum/breve NB2B-9-FAA Blautia wexlerae NB2A-5-TSAB Blautia schinkii NB2B-13-DCM Collinsella aerofaciens NB2A-13-NA Coprococcus catus NB2A-2-FAA Coprococcus comes NB2B-15-DCM Dorea formicigenerans NB2A-3-NA Dorea longicatena NB2B-BHI-1 Escherichia coli NB2B-10-MRS Agathobaculum desmolans NB2A-17-FMU [Eubacterium] rectale NB2B-19-DCM Faecalibacterium prausnitzii NB2A-20-GAM Flavonifractor plautii NB2B-AER-MRS-02 Lactobacillus paracasei NB2B-16-D5 Neglecta timonensis NB2A-10-MRS Parabacteroides distasonis NB2A-29-D6 Parabacteroides merdae NB2A-12-FMU Phascolarctobacterium succinatutens NB2B-10-FAA Roseburia intestinalis NB2B-26-FMU Roseburia inulinivorans NB2B-17-NB Ruminococcus lactaris

[0101] In a particular embodiment, an exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following strains listed in Table 1: NB2B-6-CNA, NB2A-9-NA, NB2A-14-FMU, NB2A-8-WC, NB2A-12-BBE, NB2B-16-TSAB, NB2B-11-FAA, NB2B-13-DCM, NB2A-2-FAA, NB2A-3-NA, NB2B-BHI-1, NB2A-17-FMU, NB2B-19-DCM, NB2B-AER-MRS-02, or NB2A-10-MRS, but does not exceed further including each and every one of the species recited in this exemplary list. In a particular embodiment thereof, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises the following strains listed in Table 1: NB2B-6-CNA, NB2A-9-NA, NB2A-14-FMU, NB2A-8-WC, NB2A-12-BBE, NB2B-16-TSAB, NB2B-11-FAA, NB2B-13-DCM, NB2A-2-FAA, NB2A-3-NA, NB2B-BHI-1, NB2A-17-FMU, NB2B-19-DCM, NB2B-AER-MRS-02, and NB2A-10-MRS, but does not exceed further including each and every one of the species recited in the exemplary list of Table 1. In a more particular embodiment thereof, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein consists of the following strains listed in Table 1: NB2B-6-CNA, NB2A-9-NA, NB2A-14-FMU, NB2A-8-WC, NB2A-12-BBE, NB2B-16-TSAB, NB2B-11-FAA, NB2B-13-DCM, NB2A-2-FAA, NB2A-3-NA, NB2B-BHI-1, NB2A-17-FMU, NB2B-19-DCM, NB2B-AER-MRS-02, and NB2A-10-MRS.

[0102] In a further embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following strains listed in Table 1: NB2B-20-GAM, NB2B-6-CNA, NB2A-9-NA, 14 LG, NB2A-8-WC, NB2A-12-BBE, NB2A-3-NA, NB2A-17-FMU, NB2B-19-DCM, NB2B-10-FAA, NB2B-26-FMU, but does not exceed further including each and every one of the species recited in this exemplary list. In another embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following strains listed in Table 1: NB2B-20-GAM, NB2B-6-CNA, NB2A-9-NA, 14 LG, NB2A-8-WC, NB2A-12-BBE, NB2A-3-NA, NB2A-17-FMU, NB2B-19-DCM, NB2B-10-FAA, NB2B-26-FMU, but does not exceed further including each and every one of the species recited in the exemplary list of Table 1.

[0103] Table 3 sets forth additional exemplary microbiotic communities comprising the indicated bacterial strains. These exemplary microbiotic communities are designated herein MET-2A and MET-2B

TABLE-US-00002 Strain Number designation Identity MET-2 MET-2A MET-2B 1 NB2A-29-D6 Parabacteroides merdae + + + 2 NB2B-13-BHI [Eubacterium] hallii + + + 3 NB2A-10-MRS Parabacteroides + + distasonis 4 NB2A-12-FMU Phascolarctobacterium + + + succinatutens 5 NB2B-17-NB Ruminococcus lactaris + + 6 NB2B-16-D5 Neglecta timonensis + 7 NB2B-10-NB [Clostridium] + + spiroforme 8 NB2B-10-FAA Roseburia intestinalis + + 9 NB2A-8-WC Akkermansia + + + muciniphila 10 NB2A-9-NA [Ruminococcus] obeum + 11 NB2B-20-GAM [Clostridium] + lactatifermentans 12 NB2A-15-BHI Anaerovorax + + odorimutans 13 NB2A-14-FMU [Ruminococcus] torques + + 14 NB2A-17-FMU Eubacterium rectale + + + 15 NB2B-14-D5 Bacteroides eggerthii + + 16 NB2B-26-FMU Roseburia inulinivorans + + 17 NB2B-20-DS [Clostridium] hylemonae + 18 NB2B-3-WC Barnesiella + intestinihominis 19 NB2A-14-DS [Clostridium] + aerotolerans 20 NB2A-15-DCM Bacteroides + stercorirosoris 21 NB2A-20-GAM Flavonifractor plautii + + + 22 NB2A-3-NA Dorea longicatena + + + 23 NB2A-5-TSAB Blautia stercoris + 24 NB2B-11-FAA Bifidobacterium longum + + 25 NB2A-2-FAA Coprococcus comes + 26 NB2B-6-CNA [Eubacterium] eligens + + + 27 NB2B-AER- Lactobacillus paracasei + + + MRS-02 28 NB2B-13-CNA [Clostridium] oroticum + 29 NB2B-15-DCM Dorea formicigenerans + 30 NB2B-BHI-1 Escherichia coli + + 31 NB2B-9-DCM Anaerostipes hadrus + + 32 NB2B-9-FAA Blautia luti + + + 33 NB2A-7-D5 [Clostridium] scindens + + + 34 NB2B-10-MRS Eubacterium desmolans + + + 35 NB2B-19-DCM Faecalibacterium + + + prausnitzii 36 NB2A-12-BBE Bacteroides ovatus + + 37 NB2A-13-NA Coprococcus catus + + + 38 NB2B-16-TSAB Bifidobacterium + + + adolescentis 39 NB2B-13-DCM Collinsella aerofaciens + + + 40 14 LG Acidaminococcus + + + intestini 41 NB2A-2-DS Alistipes shahii + 42 NB2A-1-D5 Bacteroides uniformis + 43 NB2B-3-FMN [Clostridium] leptum + 44 NB2A-1- Enterococcus hirae + CNA_aer 45 NB2B-20-NB Gemmiger formicilis + 46 NB2B-23-CNA Oscillibacter + valericigenes 47 NB2A-31-NB Pseudoflavonifractor + capillosus

[0104] In a further embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the MET-2A strains listed in Table 3, but does not exceed further including each and every one of the MET-2A species recited in Table 3. In another embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following MET-2A strains listed in Table 3, but does not exceed further including each and every one of the species recited in the exemplary list of Table 1. In another embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein consists of the MET-2A strains listed in Table 3.

[0105] In a further embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the MET-2B strains listed in Table 3, but does not exceed further including each and every one of the MET-2B species recited in Table 3. In another embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein comprises at least one of the following MET-2B strains listed in Table 3, but does not exceed further including each and every one of the species recited in the exemplary list of Table 1. In another embodiment, the exemplary list of bacterial species that exhibits robustness in chemostat model test assays described herein consists of the MET-2B strains listed in Table 3.

[0106] As used herein, the term ecosystem output assay refers to a method whereby the composition of a microbial ecosystem may be determined from its functional output in terms of types and quantities of selected small molecule metabolites. Small molecule metabolites are known in the art and include, without limitation: organic acids (e.g., carboxylic acids and derivatives thereof), amino acids, alcohols (e.g., polyols), phenols, and fatty acids and conjugates thereof. Metabolites are typically measured in the range of millimolar concentrations. The MET-2 community, for example, exhibits a metabolic profile that comprises tartrate and urea and significantly elevated levels of glutamate, pyroglutamate, asparagine, glycolate, choline, thymine, and formate when compared to the metabolic profiles of bacterial communities isolated from different donors. See Yen et al. (2015, J Proteome Res 14:1472-1482).

[0107] As used herein, the term microbial ecosystem refers to a plurality of different bacterial species that have been grown together either in an in vitro assay or in a biological setting such as, for example, a subject's gut. In a particular embodiment, the subject may be a human.

[0108] As used herein, the term chemostat model assay refers to an assay wherein a plurality of bacterial species is seeded into a vessel compatible with bacterial proliferation, wherein the vessel is maintained under growth promoting conditions and comprises culture medium comprising growth factors suitable for promoting proliferation of the plurality of bacterial species. In an embodiment thereof, the proliferation of each of the bacterial species seeded into the vessel may be determined after a defined time period of incubation in the chemostat model assay. Such a determination may be made using techniques known in the art such as cell counting via automated or manual means and may be facilitated by cell staining using various dyes that are taken up by cells. Such dyes may be taken up differentially by live versus dead cells and thus, provide for distinguishing viable cells from dead or dying cells. The relative proliferation of each of the bacterial species seeded into the vessel may also be determined and total numbers of each bacterial species determined after a defined time period of incubation in the chemostat model assay. Accordingly, the chemostat model assay may be used to determine proliferation and/or proliferation rate of different bacterial species in the plurality of bacterial species seeded into the vessel and thus, provide an assay for comparing proliferation and/or proliferation rate among the different bacterial species seeded into the vessel under various growth promoting conditions.

[0109] In a particular embodiment, the number of bacterial cells may be determined using a LIVE/DEAD BacLight Bacterial Viability Kit in accordance with the manufacturer's protocol. Live versus dead cells are distinguished using the LIVE/DEAD BacLight Bacterial Viability Kit, which differentially stains dead and dying cells with compromised membranes red and live cells having intact membranes green. The differential staining facilitates an accurate assessment of viable cells in a given sample.

[0110] In a more particular embodiment, the number of cells is determined via flow cytometry used in conjunction with a LIVE/DEAD BacLight Bacterial Viability Kit, which combination facilitates measuring the different colors of the differentially stained cells via fluorescence detection in a plate reader. Such an approach reveals information as to relative values of live and dead cells in a sample and generally improves accuracy of cell counting.

[0111] The chemostat model assay, therefore, provides an assay wherein the growth of the plurality of bacterial species initially seeded into a vessel (bacterial seed population) may be determined at different defined time periods of incubation in the chemostat model assay. Using the chemostat model assay, multiple vessels can be seeded with different bacterial seed populations and the growth of the different bacterial seed populations and particular species in the different bacterial seed populations can be determined at different defined time periods of incubation. Results determined from multiple vessels run in the chemostat model assay can, in turn, be compared to determine if different bacterial seed populations respond differentially to different growth conditions and perturbational stress.

[0112] As used herein, the term robustness as it relates to a microbial community refers to the resistance and resilience of the community towards external perturbation/s relative to the state of the microbial community absent or prior to exposure to the external perturbation/s. Robustness may, for example, be reflected in the ability of the microbial community to maintain relative ratios of representation (numbers) of each of the different species or phylums wherein the species are classified post-perturbation as compared to pre-perturbation. Robustness may also, for example, be reflected in the ability of the microbial community to maintain metabolic output post-perturbation relative to pre-perturbation.

[0113] As used herein, the term perturbational stress refers to a change in at least one of substrate type, substrate availability, and xenobiotic challenge in the culturing conditions in which a population of bacterial cells is grown.

[0114] As used herein, the term substrate refers to a substance or compound present in the culture medium in which a population of bacterial cells is grown that is utilized metabolically by the bacterial cells.

[0115] As used herein, the term xenobiotic challenge refers to the introduction of a chemical substance into an ecosystem, wherein the chemical substance is not naturally produced or expected to be present within the ecosystem, or is present at a much higher concentration than in the natural situation.

[0116] Compositions described herein may be formulated for oral administration as capsules, powders, tablets, granulates, chewable foods, liquids, and beverages. In a particular embodiment, the compositions are formulated into a capsule (e.g., an enteric-coated microcapsule). In another particular embodiment, the compositions are formulated into a tablet. In yet another particular embodiment, the compositions are formulated into granulated or water soluble powders. Further particular compositions may be formulated into liquids, creams, lotions, gels dispersions or ointments for topical administration.

[0117] In a particular embodiment, a composition described herein is a powder. A powder may be administered as such or may be dissolved in a fluid, for example, for oral consumption (e.g., via capsule or double capsule) or for rectal administration via an enema. With respect to oral consumption, a powder composition may be provided in a palatable form for reconstitution as a drink or for reconstitution as a food additive. A powder composition may also be dissolved in a fluid for rectal administration via an enema (colonoscopic infusion). The powder may also be reconstituted to be infused via naso-duodenal infusion. Exemplary fluids for such purposes include physiological saline solutions.

[0118] Methods described herein are applicable to animals in general (e.g., mammals), and more particularly to humans and economically significant domestic animals, such as dogs, cats, cows, pigs, horses, sheep, mice, rats, and monkeys.

[0119] When formulated, the composition may contain further ingredients, including ingredients that confer properties relating to healthfulness, flavor, formulating, or tableting. Non-limiting examples of additional ingredients that may be incorporated in compositions described herein include: prebiotics, vitamins, minerals, nutritional supplements (e.g., fiber), sweeteners, flow aids, and fillers. When formulated for oral administration, the compositions comprise at least 0.1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or more w/w % of a composition of an anhydrous composition comprising a plurality of bacterial species described herein.

[0120] Compositions of the invention are useful in methods for treating various diseases and disorders characterized by dysbiosis. Compositions described herein may be used to promote digestive health, metabolism (nutritional heath), and weight management when administered orally or rectally. Compositions described herein may be used to treat or alleviate a positive indicator or symptom of a digestive disorder including: irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, Crohn's disease, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, and AIDS enteropathy.

[0121] Compositions described herein are also envisioned for use in treating or alleviating a positive indicator or symptom of a digestive disorder including: irritable bowel syndrome (IBS) or spastic colon, idiopathic ulcerative colitis, mucous colitis, collagenous colitis, Crohn's disease, inflammatory bowel disease in general, microscopic colitis, antibiotic-associated colitis, idiopathic or simple constipation, diverticular disease, and AIDS enteropathy.

[0122] Treatment regimens may be comprise administration of compositions described herein to a subject in need thereof on a daily basis (typically once or twice per day), twice or thrice weekly, bi-weekly, or once per month. Treatment regimens may also be altered as the subject's condition changes and may, furthermore, be intermittent. A suitable treatment regimen may be determined by a medical practitioner and/or may be established based on empirical results as evaluated by a medical practitioner and/or the subject being treated.

[0123] Unless stated otherwise, all percentages referred to herein are by weight based on the total weight of the composition.

Fecal-Derived Bacterial Populations and Anhydrous Compositions Thereof

[0124] In a particular embodiment, a fecal-derived bacterial population is isolated or derived from a healthy subject.

[0125] In a particular embodiment, a fecal-derived bacterial population is derived from a subject (e.g., a healthy subject) by a method comprising: [0126] a. obtaining a freshly voided stool sample, and placing the sample in an anaerobic chamber (in an atmosphere of 90% N.sub.2, 5% CO.sub.2 and 5% H.sub.2); [0127] b. generating a fecal slurry by macerating the stool sample in a buffer; and [0128] c. removing food particles by centrifugation, and retaining the supernatant, which comprises the bacteria isolated from fecal matter and food particles. Accordingly, the supernatant comprises a purified population of intestinal bacteria that is free of fecal matter and food particles. Given that, the purified population of intestinal bacteria is a manmade product that is fecal matter-free and food particle-free.

[0129] In a further embodiment, a fecal sample (either fresh or frozen) is diluted in saline and plated onto a series of 13-20 different media types, each tailored to the isolation of particular types of species. The fecal sample may also be used undiluted as inoculum to seed a chemostat, which is grown to steady state, and then an aliquot of the steady state culture is diluted in saline and subsequently plated onto a series of 13-20 different media types, each tailored to the isolation of particular types of species. A diluted sample of bacteria may, for example, be treated with ethanol to select for sporulating bacteria. In another embodiment, antibiotics are added that exclude certain types of bacterial cells. In another embodiment, filter-sterile spent chemostat medium is added to provide growth substrates that promote proliferative or provide a selective advantage for certain types of bacterial cells. Following transfer into the 13-20 different media types, bacterial cell cultures are incubated for 3-10 days and individual colonies are picked, re-streaked to purity, and then frozen down. Frozen stocks are grown in culture to curate/characterize the strain by conducting a 16S rRNA gene sequencing read using Sanger chemistry and the obtained trace compared to the RDP database.

[0130] Once the strains have been curated/characterized, each bacterial species listed in Table 1 or a subset thereof is cultured individually to expand the population of each bacterial species to reach a threshold of biomass for each bacterial species. For bacterial species that grow poorly relative to other species listed in Table 1, a larger volume of bacterial culture is grown so as to achieve a biomass equivalent to that of faster growing species. The strains are all grown separately in Wilkins-Chalgren broth under anaerobic conditions at 37 C. The cultured bacterial population of each species is then concentrated by centrifugation, resuspended in medium optionally containing a cryoprotectant/lyoprotectant (inulin and riboflavin), and then rapidly frozen at 80 C. Frozen material is placed into a lyophilizer instrument and the cycle run to sublimate and remove the water content, leaving a fine powder representing a matrix of preserved bacterial cells and optionally cryo-lyoprotectant. The individual powders from each individual isolate are tested for purity and if pure, may be combined into desired combinations as powders via thorough mixing to generate an anhydrous composition comprising a desired plurality of bacterial species.

[0131] In certain embodiments, an anhydrous composition comprising a population of bacterial species may be derived from fecal matter in accordance with methods disclosed in U.S. Pat. Nos. 8,906,668 and 9,511,099 and in U.S. Patent Application Publication No. 20140342438, the entire content of each of which is incorporated herein by reference.

Culture Methods According to Certain Embodiments

[0132] In certain embodiments, an anhydrous composition comprising a plurality of bacterial species is cultured in a chemostat vessel. In certain embodiments, the chemostat vessel is the vessel disclosed in U.S. Patent Application Publication No. 20140342438. In some embodiments, the chemostat vessel is the vessel described in FIGS. 1A and 1B.

[0133] In certain embodiments, the chemostat vessel is converted from a fermentation system to a chemostat by blocking off the condenser and bubbling nitrogen gas through the culture. In certain embodiments, the pressure forces the waste out of a metal tube (formerly a sampling tube) at a set height and allows for the maintenance of given working volume of the chemostat culture.

[0134] In certain embodiments, the chemostat vessel is kept anaerobic by bubbling filtered nitrogen gas through the chemostat vessel. In certain embodiments, temperature and pressure are automatically controlled and maintained

[0135] In certain embodiments, the culture pH of the chemostat culture is maintained using 5% (v/v) HCl (Sigma) and 5% (w/v) NaOH (Sigma).

[0136] In certain embodiments, the culture medium of the chemostat vessel is continually replaced. In certain embodiments, the replacement occurs over a period of time equal to the retention time of the distal gut. Consequently, in certain embodiments, the culture medium is continuously fed into the chemostat vessel at a rate of 400 mL/day (16.7 mL/hour) to give a retention time of 24 hours, a value set to mimic the retention time of the distal gut. An alternate retention time can be 65 hours (approximately 148 mL/day, 6.2 mL/hour). In certain embodiments, the retention time can be as short as 12 hours.

[0137] In certain embodiments, the culture medium is a culture medium disclosed in U.S. Patent Application Publication No. 20140342438.

[0138] While a number of embodiments of the present invention have been described, it is understood that these embodiments are illustrative only, and not restrictive, and that many modifications may become apparent to those of ordinary skill in the art. Further still, the various steps may be carried out in any desired order (and any desired steps may be added and/or any desired steps may be eliminated).

[0139] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non limiting fashion.

EXAMPLES

Example 1

Comparison of Microbial Ecosystems Derived from a Single Donor Versus Those Derived from Multiple Donors

[0140] The present inventors investigated whether microbes derived from a single individual have co-adapted to the host and demonstrate cohesiveness or an ability to work efficiently together. The present inventors hypothesized that such cohesiveness may be critical to the ability of the ecosystem to best respond to commonly encountered environmental perturbations

[0141] To test this, the present inventors created 2 defined microbial communities of 27 bacterial species each, representing 6 bacterial phyla commonly found in the human gut. The first community (CC) represented a group of bacterial isolates, each representative of a different species, which had been isolated from a single donor. Accordingly, CC is a co-selected microbiota. The second community (FC) represented a group of isolates which matched the CC community in species identity (97% identity across the full length 16S rRNA gene sequences), but wherein each community member had been sourced from a different individual (i.e., 27 different individuals in total). The communities were verified for purity by individual deep sequencing of 16S rRNA genes on the Illumina Miseq platform.

[0142] Each community was separately seeded into a bioreactor vessel fed with a high fibre diet and allowed to achieve steady state (14 days), and then samples were removed for analysis. See FIG. 2.

[0143] After sample removal at steady state, the bioreactors were switched abruptly to a high protein diet to simulate a perturbational stress. Steady state was allowed to develop over a further 14 days and the ecosystems were resampled. See FIG. 2. 16S rRNA sequence profiling was carried out on the samples using the Illumina MiSeq platform.

[0144] 16S rRNA primers were used to generate 16S rRNA sequence fragments FIG. 5 (Table 2) and full length 16S rRNA sequences (Appendix A) corresponding to each bacterial strain presented in Table 1. Exemplary 16S rRNA primers with T3 and T7 tails, respectively are as follows:

TABLE-US-00003 V3klprimer (SEQIDNO:81) ATTAACCCTCACTAAAGTACGG+AG+AGGCAGCAG V6rprimer (SEQIDNO:82) AATACGACTCACTATAGGGAC+AG+ACACGAGCTGACGAC.

[0145] Full length 16S rRNA sequences for each of the MET-2 strains are presented in Appendix A (attached hereto) and designated SEQ ID NOs: 1-40.

[0146] FIG. 5 (Table 2) lists the MET-2 strains with their accompanying 16S rRNA sequence fragments. The 16S rRNA sequence fragments are designated SEQ ID NOs: 41-80 in order of their appearance in Table 2.

[0147] In accordance with the present invention there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual (1989); Current Protocols in Molecular Biology Volumes I-III [Ausubel, R. M., ed. (1994)]; Cell Biology: A Laboratory Handbook Volumes I-III [J. E. Celis, ed. (1994))]; Current Protocols in Immunology Volumes I-III [Coligan, J. E., ed. (1994)]; Oligonucleotide Synthesis (M. J. Gait ed. 1984); Nucleic Acid Hybridization [B. D. Hames & S. J. Higgins eds. (1985)]; Transcription And Translation [B. D. Hames & S. J. Higgins, eds. (1984)]; Animal Cell Culture [R. I. Freshney, ed. (1986)]; Immobilized Cells And Enzymes [IRL Press, (1986)]; B. Perbal, A Practical Guide To Molecular Cloning (1984).

[0148] Results

[0149] A switch from high fibre to high protein diet resulted in little appreciable change in the relative abundance profiles of the CC community, suggesting that the community could efficiently adapt to the perturbation. Conversely, the FC community showed a dramatic change in relative abundance with a marked increase in Proteobacteriaa common sign of dysbiosis. Proteobacteria include many microbial species that tend to be metabolically versatile and thus opportunistic feeders. See FIGS. 3 and 4.

[0150] Based on the results presented herein, the present inventors conclude that microbial communities that have been co-selected and co-adapted within a host (co-selected microbiota) demonstrate robustness during perturbational stress. This provides justification for creating MET products derived from a single selected donor rather than an amalgamation of many donors.

[0151] Protocol for Treating Humans Afflicted with Diseases or Disorders Associated with Dysbiosis

[0152] As described herein, MET-2 and exemplary subgroups thereof (e.g., MET-2A and MET-2B) are described as therapeutic agents for treating gastrointestinal diseases in subjects afflicted with such diseases, including ulcerative colitis. The bacterial isolates found in MET-2 are pure live bacterial cultures of intestinal bacteria that were isolated from a stool sample of a healthy 25-year-old male donor. The microbial ecosystem therapeutic product is comprised of 40 lyophilized pure bacterial cultures mixed in predefined ratios. The product is delivered to the patients orally, in capsule form.

[0153] MET-2 comprises 40 strains of lyophilized bacteria, originally purified from a healthy 25-year-old stool donor and further selected based on their favorable safety profile. The donor used to derive MET-2 was also successfully used as a donor for FMT in the treatment of multiple patients with Clostridium difficile. A phase la clinical trial with MET-2 in patients with rCDI is currently in progress. Preliminary evidence suggests MET-2 is well tolerated with no serious adverse events related to treatment with this therapeutic to date. Furthermore, there have been no reported cases of bacteremia, sepsis or invasive infections in rCDI patients undergoing MET-2 treatment to date.

[0154] MET-2 has modifications that reflect and incorporate novel information that has emerged from the rapidly evolving field of gut microbiota research in the context of ulcerative colitis. The donor from which MET-2 was derived was screened extensively for viral, bacterial and medical disease. Briefly, MET-2 excludes pathogenic organisms including extended spectrum beta-lactamase (ESBL), vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and Clostridium difficile (C. difficile). In addition, risk assessment for high-risk behaviors for blood-borne pathogens, a thorough detailed medical history and a physical examination to confirm the overall health of the donor were completed. There are no specific considerations for MET-2 recipients. Empiric and targeted antibiotic therapy should be guided by routine standards of care in close consultation with appropriate experts including infectious disease or medical microbiology specialists. The isolated strains were then purified by repeated subculture, initially sequenced for identification and screened for bacterial resistance to ensure no transfer of resistant strains. Within the manufacturing process, there are multiple passaging steps, where purity is subsequently examined on plate culture. Finally, MET-2 product release only occurs when each bacterial culture tests negative for impurities or any bacterial contaminant (e.g. pathogenic organisms) as determined by Sanger sequencing of the 16S rRNA gene (specific to bacteria).

[0155] MET-2 is comprised of 40 lyophilized pure bacterial cultures mixed in predefined ratios, with strengths as detailed in Table 6.

TABLE-US-00004 TABLE 6 Strength of MET-2 Capsules MET-2 Dosage MET-2 content MET-2 content by Form by weight (g) Colony Forming Units Capsule 0.5 3.59 10.sup.7 to 3.59 10.sup.11 CFU per capsule CFU = colony forming unit

[0156] Ulcerative colitis (UC) is a chronic, relapsing, idiopathic, inflammatory disease of the colorectum. In the last decade, there has been an increase in the incidence and prevalence of UC, making it an important emerging global disease. The main symptoms of UC include bloody diarrhea, abdominal pain, urgency, tenesmus, and incontinence, which cause a reduction in patient quality of life. The severity of UC symptoms ranges from mild disease (<4 stools per day with or without blood) to severe disease (>10 stools per day with intense cramping and continuous bleeding). Depending on the clinical severity of intestinal disease, patients may also develop systemic symptoms and other life-threatening complications.

[0157] Management of UC is determined by the clinical severity of disease, and current treatment strategies are focused on regulating the immune system with anti-inflammatory and immunosuppressive drugs. For mild-to-moderate disease anti-inflammatory agents, e.g. 5-aminosalicyclic acid (5-ASA), are the main treatment options with use of immunomodulators as a steroid sparing agent. While these therapies are able to maintain remission in many cases, current medical treatments are imperfect and there is a subset of patients that do not respond to topical 5-ASA alone or in combinational therapy with corticosteroids. Additionally, 20-30% of UC patients require colectomy to manage acute complications and medically intractable disease. Thus, there is a need for more efficacious drugs with a greater favorable safety profile for the treatment of UC.

[0158] Although the pathogenesis of UC is complex, multifactorial, and not fully understood, aberrant host immune responses, and a dysfunctional intestinal barrier have been associated with this condition.

[0159] The human body is host to more than 10 trillion microbial cells with the majority of these residing in the gut. The collection of microorganisms, their gene products and corresponding metabolic functions in the human gastrointestinal (GI) tract is termed the gut microbiome. Recent advances in molecular microbiology have revealed the critical role of the gut microbiome in a variety of important processes including: vitamin/nutrient production, regulation of metabolism and host energy demands, intestinal epithelial cell homeostasis, protection against pathogens, and development and maintenance of normal immune function.

[0160] Gut dysbiosis can be defined as a pathological imbalance in a microbial community characterized by a shift in the composition, diversity or function of microbes, which can result in disease. Antibiotics, toxic compounds, diet, medical interventions, and disease can all influence the gut microbiome. However, defining gut microbial dysbiosis is difficult due to the variability in bacterial composition across individuals in both in healthy and disease-states. The gut microbiome has been associated with a multitude of disease indications including, but not limited to: C. difficile infection (CDI), inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS).

[0161] The MET-2 anhydrous composition (drug product) comprises a lyophilized mixture of predetermined ratio of pure cultures of 40 diverse intestinal bacteria, derived from a stool sample of one healthy donor. Each capsule contains 0.5 g of MET-2, with a strength per capsule of 3.59 X 10.sup.7 to 3.5910.sup.11 colony forming units (CFU) per capsule. The drug product is shipped and maintained at room temperature; the capsule is sealed in anaerobic packaging and is opened only immediately prior to the subject/patient swallowing the capsule.

[0162] As indicated above, forty pure bacterial culture isolates have been selected for MET-2 composition from a stool sample of a single donor. The identities of the bacterial isolates have been confirmed microbiologically as well as using 16S ribosomal RNA (rRNA) sequencing. All isolates included in MET-2 are sensitive to imipenem, ceftriaxone, and piperacillin. Susceptibility to antimicrobials was determined by directly measuring susceptibility with e-strips and/or Kirby Bauer disks.

[0163] List of cultured isolates that have been selected for the drug substance are provided in Table 7 below.

TABLE-US-00005 TABLE 7 MET-2 Composition CFU of strain % per 3-capsule Strain ID Identity (closest match).sup.a Identity dose 14 LG Acidaminococcus 99 2.7 10.sup.5-10.sup.9 intestini NB2A-8-WC Akkermansia mucimphila 100 4.0 10.sup.6-10.sup.10 NB2B-9-DCM Anaerostipes hadrus 99.53 1.0 10.sup.2-10.sup.6 NB2A-15-BHI Anaerovorax 95.76 4.0 10.sup.5-10.sup.9 odorimutans NB2B-14-D5 Bacteroides eggerthii 99.71 2.4 10.sup.6-10.sup.10 NB2A-12-BBE Bacteroides ovatus 99 1.3 10.sup.3-10.sup.7 NB2A-15-DCM Bacteroides 100 3.5 10.sup.5-10.sup.9 stercorirosoris NB2B-3-WC Barnesiella 99 2.9 10.sup.5-10.sup.9 intestinihominis NB2B-16-TSAB Bifidobacterium 99.71 6.3 10.sup.5-10.sup.9 adolescentis NB2B-11-FAA Bifidobacterium longum 99 1.8 10.sup.3-10.sup.7 NB2B-9-FAA Blautia luti 99 3.4 10.sup.5-10.sup.9 NB2A-5-TSAB Blautia stercoris 98.6 2.0 10.sup.5-10.sup.9 NB2A-14-DS [Closfridium] 97.8 1.24 10.sup.5-10.sup.9 aerotolerans NB2B-20-DS [Closfridium] hylemonae 95.73 5.0 10.sup.3-10.sup.7 NB2B-20-GAM [Closfridium] 96.33 2.1 10.sup.5-10.sup.9 lactatifermentans NB2B-13-CNA [Closfridium] oroticum 95.91 2.0 10.sup.6-10.sup.10 NB2A-7-D5 [Closfridium] scindens 99 3.2 10.sup.5-10.sup.9 NB2B-10-NB [Closfridium] spiroforme 97.93 1.3 10.sup.6-10.sup.10 NB2B-13-DCM Collinsella aerofaciens 99.85 4.1 10.sup.6-10.sup.10 NB2A-13-NA Coprococcus catus 99 1.9 10.sup.5-10.sup.9 NB2A-2-FAA Coprococcus comes 100 5.6 10.sup.6-10.sup.10 NB2B-15-DCM Dorea formicigenerans 99 8.0 10.sup.5-10.sup.9 NB2A-3-NA Dorea longicatena 99.27 3.1 10.sup.4-10.sup.8 NB2B-BHI-1 Escherichia coli 99 4.2 10.sup.7-10.sup.11 NB2B-10-MRS Eubacterium desmolans 99 2.5 10.sup.5-10.sup.9 NB2A-17-FMU Eubacterium rectale 100 9.2 10.sup.3-10.sup.7 NB2B-6-CNA [Eubacterium] eligens 99 3.5 10.sup.6-10.sup.10 NB2B-13-BHI [Eubacterium] hallii 99 3.2 10.sup.2-10.sup.6 NB2B-19-DCM Faecalibacterium 99 3.4 10.sup.3-10.sup.7 prausnitzii NB2A-20-GAM Flavonifractor plautii 99 7.1 10.sup.5-10.sup.9 NB2B-AER- Lactobacillus paracasei 99.85 5.9 10.sup.5-10.sup.9 MRS-02 NB2B-16-D5 Neglecta timonensis 99.86 3.6 10.sup.3-10.sup.7 NB2A-10-MRS Parabacteroides 99 3.5 10.sup.3-10.sup.7 distasonis NB2A-29-D6 Parabacteroides merdae 99.85 1.7 10.sup.5-10.sup.9 NB2A-12-FMU Phascolarctobacterium 99 2.5 10.sup.4-10.sup.8 succinatutens NB2B-10-FAA Roseburia intestinalis 99.69 8.6 10.sup.4-10.sup.8 NB2B-26-FMU Roseburia inulinivorans 99.4 1.7 10.sup.3-10.sup.7 NB2B-17-NB Ruminococcus lactaris 99 1.3 10.sup.5-10.sup.9 NB2A-9-NA [Ruminococcus] obeum 99 7.5 10.sup.4-10.sup.8 NB2A-14-FMU [Ruminococcus] torques 99 2.2 10.sup.6-10.sup.10 .sup.aClosest species match was inferred by alignment of the 16S rRNA sequence to the NCBI database; note that in some cases 16S rRNA gene sequences could not resolve identity beyond genus, and that closest match does not infer definitive speciation. Note that some representative strains identify with the same species by 16S rRNA gene sequence alignment but are believed to be different strains based on observed differences in colony morphology, antibiotic resistance patterns and growth rates.

[0164] Further to the above, any potential strain having equal to or greater than 97% identity to its closest neighbor by 16S rRNA gene sequence identity is considered in the art to be of the same species. This accepted understanding applies to all percent identities described herein.

[0165] Microcrystalline cellulose is added to the mixture of lyophilized drug substances as a flow aid. Two-piece hard Vcaps Enteric Capsules (Capsugel), composed of hypromellose/hypromellose AS and titanium dioxide, are used to encapsulate the MET-2 drug substance mixture (including microcrystalline cellulose). The MET-2 product is double-encapsulated; MET-2 lyophilized material is filled into a size 0 enteric capsule, sealed, and then placed in a size 00 enteric capsule, which is then sealed again.

[0166] MET-2 capsules are administered orally in an enteric capsule, for delivery of the live bacteria to the large intestine. MET-2 capsules are to be stored at room temperature, and packaging should be opened only immediately before administration to patients in order to preserve the nitrogen atmosphere within the packages.

[0167] Preclinical Studies

[0168] Dextran sulfate sodium (DSS) is a commonly-employed mouse model of colitis which involves a chemical disruption of barrier function in the absence of involvement of any specific pathogen.

[0169] In order to explore the effects of MET-2 on barrier function and inflammation, mice may be gavaged with MET-2 following an oral antibiotic treatment and then given 3% DSS to induce colitis. Mice receiving MET-2 may be evaluated to measure serum levels of inflammatory cytokines as well as reduced histologic injury compared to controls. In addition, the effect of MET-2 administration following oral antibiotics may be measured to evaluate if MET-2 administration attenuates the DSS-mediated loss of Mucin-2, a mucin protein and major constituent of the protective mucous barrier found in the colon. Impaired gut barrier function can initiate dysbiosis which influences gut barrier integrity and innate and adaptive immune responses in the host. Maintenance of gut barrier integrity is critical in the context of gut homeostasis as inappropriate immune responses to a dysbiotic gut microbiota are hypothesized contribute to the pathogenesis of UC.

[0170] In vitro studies have already been performed with MET-2 formulations. These studies have shown that MET-2 protected human intestinal cell lines from cytoskeleton and cell barrier damage caused by C. difficile toxins C. difficile Toxin A (TcdA) and C. difficile Toxin B (TcdB). MET-2 also protected cells from apoptosis.

[0171] Results of Clinical Studies with MET-2

[0172] Preliminary evidence suggests that MET-2 is well tolerated with no serious adverse events related to treatment with this therapeutic to date. Additionally, there have been no reported cases of bacteremia, sepsis or invasive infections in rCDI patients undergoing MET-2 treatment to date.

[0173] Clinical development for MET-2 includes rigorous donor screening. To summarize, fecal material was obtained from a healthy fecal donor with informed and written consent. The donor was screened for a variety of blood borne disease such as HIV-1 and HIV-2; hepatitis A, B and C; syphilis as well as different enteric bacteria (Salmonella species, Shigella species, Campylobacter species, Escherichia coli 0157:H7 and Yersinia) and the presence of C. difficile toxins. The stool was also examined for microscopic presence of ova and parasites. The donor was further screened for colonization with Helicobacter pylori, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus species in stool. A detailed medical history, including high risk behavior and a physical examination were also completed.

[0174] Bacterial strains were purified and grown in a bioreactor modeling the conditions of the human distal gut. Susceptibility to antimicrobials was determined. Isolates representing commensal species, sensitive to a range of antimicrobials, were selected for the final stool substitute formulation. Full length 16S rRNA sequences were classified using basic local alignment search tool (BLAST) with the most specific name used to report the DNA maximum likelihood score. MET-2 constituent strains were individually grown in pure culture, snap-frozen, and subjected to lyophilization. After each strain meets CFU/g specifications, lyophilized bacterial product from all strains were combined in pre-determined ratios to make the active pharmaceutical ingredient (API).

[0175] The composition and route of delivery of METs differs based on the indication. For example, MET-2 is a lyophilized bacterial product that is given orally, in encapsulated form for UC. MET-2 for rCDI is supplied in 2 dosage forms: 1) lyophilized powder in capsules for oral ingestion and 2) lyophilized powder for rectal administration by colonoscopy (powder is resuspended in 0.9% saline). MET-1 was a live bacterial product (resuspended in 0.9% saline) also administered by colonoscopy. A recent non-inferiority trial showed that oral capsules are equally effective compared to colonoscopy-delivered FMT for rCDI. Notably, there were fewer minor adverse events in patients receiving FMT capsules compared to patients receiving FMT via colonoscopy in the above study. Additionally, several FMT studies have shown that frozen fecal material is as effective as fresh fecal material in treating rCDI. More recently, FMT has been given in lyophilized form by capsule delivery, with an 88% success rate. Accordingly, the MET-2 clinical protocol implemented changes in the route of administration with regards to these recent advances in the literature. Encapsulated lyophilized FMT material has not been studied for use in UC patients, although lyophilized bacterial product preparations are commonplace in the probiotic industry.

[0176] As described herein, MET-2 is a therapeutic composition composed of a defined microbial community of 40 bacterial strains derived from the stool of a healthy fecal donor. The bacteria are prepared as a mixture in a predetermined ratio of pure lyophilized intestinal bacteria. The bacteria are then double encapsulated in enteric capsules. MET-2 capsules contain 0.5 g of MET-2 (equivalent to 3.5910.sup.7 to 3.5910.sup.12 CFU) and are administered to patients via oral route. The donor from where MET-2 strains were derived has been rigorously screened for infectious materials and blood-borne pathogens. Stool from this donor has also been previously used as an FMT donor to successfully treat rCDI. There is no upper toxicity limit is expected due to the safety profile of the MET-2 bacterial community.

[0177] A multi-species derivative community such as that described herein will be more generally useful than a single organism probiotic or a mixed culture of such probiotic species. The microbes in MET-2 are derived from a community and are expected to retain community structure to a degree that enables them to colonize the colonic environment. A defined microbial community, isolated from a single healthy donor, may be sufficiently robust to withstand further perturbations by antibiotics as indicated by results presented herein demonstrating augmented robustness responsiveness to perturbations. See, e.g., FIGS. 3 and 4.

[0178] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

[0179] The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without undue experimentation and without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. The means, materials, and steps for carrying out various disclosed functions may take a variety of alternative forms without departing from the invention.

TABLE-US-00006 AppendixA NB2-A29D6Parabacteroidesmerdae (SEQIDNO:1) ACGAAGAGTTTGATCCTGGCTCAGGATGAACGCTAGCGACAGGCTTAACACATGCA AGTCGAGGGGCAGCATGATTTGTAGCAATACAGATTGATGGCGACCGGCGCACGGG TGAGTAACGCGTATGCAACTTACCTATCAGAGGGGGATAGCCCGGCGAAAGTCGGA TTAATACCCCATAAAACAGGGGTCCCGCATGGGAATATTTGTTAAAGATTCATCGCT GATAGATAGGCATGCGTTCCATTAGGCAGTTGGCGGGGTAACGGCCCACCAAACCG ACGATGGATAGGGGTTCTGAGAGGAAGGTCCCCCACATTGGTACTGAGACACGGAC CAAACTCCTACGGGAGGCAGCAGTGAGGAATATTGGTCAATGGCCGAGAGGCTGAA CCAGCCAAGTCGCGTGAAGGAAGAAGGATCTATGGTTTGTAAACTTCTTTTATAGGG GAATAAAGTGGAGGACGTGTCCTTTTTTGTATGTACCCTATGAATAAGCATCGGCTA ACTCCGTGCCAGCAGCCGCGGTAATACGGAGGATGCGAGCGTTATCCGGATTTATTG GGTTTAAAGGGTGCGTAGGTGGTGATTTAAGTCAGCGGTGAAAGTTTGTGGCTCAAC CATAAAATTGCCGTTGAAACTGGGTTACTTGAGTGTGTTTGAGGTAGGCGGAATGCG TGGTGTAGCGGTGAAATGCATAGATATCACGCAGAACTCCGATTGCGAAGGCAGCT TACTAAACCATAACTGACACTGAAGCACGAAAGCGTGGGGATCAAACAGGATTAGA TACCCTGGTAGTCCACGCAGTAAACGATGATTACTAGGAGTTTGCGATACAATGTAA GCTCTACAGCGAAAGCGTTAAGTAATCCACCTGGGGAGTACGCCGGCAACGGTGAA ACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGAGGAACATGTGGTTTAATTCGA TGATACGCGAGGAACCTTACCCGGGTTTGAACGTAGTCTGACCGGAGTGGAAACAC TCCTTCTAGCAATAGCAGATTACGAGGTGCTGCATGGTTGTCGTCAGCTCGTGCCGT GAGGTGTCGGCTTAAGTGCCATAACGAGCGCAACCCTTATCACTAGTTACTAACAGG TGAAGCTGAGGACTCTGGTGAGACTGCCAGCGTAAGCTGTGAGGAAGGTGGGGATG ACGTCAAATCAGCACGGCCCTTACATCCGGGGCGACACACGTGTTACAATGGCATG GACAAAGGGCAGCTACCTGGCGACAGGATGCTAATCTCCAAACCATGTCTCAGTTC GGATCGGAGTCTGCAACTCGACTCCGTGAAGCTGGATTCGCTAGTAATCGCGCATCA GCCATGGCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCAAGCCATGG GAGCCGGGGGTACCTGAAGTCCGTAACCGCAAGGATCGGCCTAGGGTAAAACTGGT GACTGGGGCTAAGTCGTAACAAGGTAGCCGTACCGGAAGGTGCGGCTGGAACACCT CCTTT NB2-B13BHI[Eubacterium]hallii (SEQIDNO:2) CTGAGTGGCGGACGGGTGAGTAACGCGTGGGTAACCTGCCCTGTACAGGGGGATAA CAGCTGGAAACGGCTGCTAATACCGCATAAGCGCACGAGGAGACATCTCCTTGTGT GAAAAACTCCGGTGGTACAGGATGGGCCCGCGTCTGATTAGCTGGTTGGCAGGGTA ACGGCCTACCAAGGCAACGATCAGTAGCCGGTCTGAGAGGATGAACGGCCACATTG GAACTGAGACACGGTCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAA TGGGGGAAACCCTGATGCAGCAACGCCGCGTGAGTGAAGAAGTATTTCGGTATGTA AAGCTCTATCAGCAGGGAAGATAATGACGGTACCTGACTAAGAAGCTCCGGCTAAA TACGTGCCAGCAGCCGCGGTAATACGTATGGAGCAAGCGTTATCCGGATTTACTGGG TGTAAAGGGTGCGTAGGTGGCAGTGCAAGTCAGATGTGAAAGGCCGGGGCTCAACC CCGGAGCTGCATTTGAAACTGCTCGGCTAGAGTACAGGAGAGGCAGGCGGAATTCC TAGTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCGGCC TGCTGGACTGTTACTGACACTGAGGCACGAAAGCGTGGGGAGCAAACAGGATTAGA TACCCTGGTAGTCCACGCCGTAAACGATGAATACTAGGTGTCGGGGCCGTATAGGCT TCGGTGCCGCCGCTAACGCAGTAAGTATTCCACCTGGGGAGTACGTTCGCAAGAATG AAACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTC GAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCCTTCTGACCGCACCTTAATCG GTGCTTTCCTTCGGGACAGAAGAGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTC GTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATCTTCAGTAGCCAGCA GGTAAGGCTGGGCACTCTGGAGAGACTGCCAGGGATAACCTGGAGGAAGGTGGGG ACGACGTCAAATCATCATGCCCCTTATGATCTGGGCGACACACGTGCTACAATGGCG GTCACAGAGTGAGGCGAACCCGCGAGGGGGAGCAAACCACAAAAAGGCCGTCCCA GTTCGGACTGTAGTCTGCAACCCGACTACACGAAGCTGGAATCGCTAGTAATCGCGA ATCAGAATGTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCA TGGGAGTCGGAAATGCCCGAAGCCAGTGACCCAACCTTTTGGAGGGAGCTGTCGAA GGTGGAGCCGGTAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCG GCTGGATCACCTCCTTT NB2-A10MRSParabacteroidesdistasonis (SEQIDNO:3) CTATCAGAGGGGGATAACCCGGCGAAAGTCGGACTAATACCGCATGAAGCAGGGGC CCCGCATGGGGATATTTGCTAAAGATTCATCGCTGATAGATAGGCATGCGTTCCATT AGGCAGTTGGCGGGGTAACGGCCCACCAAACCGACGATGGATAGGGGTTCTGAGAG GAAGGTCCCCCACATTGGTACTGAGACACGGACCAAACTCCTACGGGAGGCAGCAG TGAGGAATATTGGTCAATGGGCGTAAGCCTGAACCAGCCAAGTCGCGTGAGGGATG AAGGTTCTATGGATCGTAAACCTCTTTTATAAGGGAATAAAGTGCGGGACGTGTCCT GTTTTGTATGTACCTTATGAATAAGGATCGGCTAACTCCGTGCCAGCAGCCGCGGTA ATACGGAGGATCCGAGCGTTATCCGGATTTATTGGGTTTAAAGGGTGCGTAGGCGGC CTTTTAAGTCAGCGGTGAAAGTCTGTGGCTCAACCATAGAATTGCCGTTGAAACTGG GGGGCTTGAGTATGTTTGAGGCAGGCGGAATGCGTGGTGTAGCGGTGAAATGCTTA GATATCACGCAGAACCCCGATTGCGAAGGCAGCCTGCCAAGCCATGACTGACGCTG ATGCACGAAAGCGTGGGGATCAAACAGGATTAGATACCCTGGTAGTCCACGCAGTA AACGATGATCACTAGCTGTTTGCGATACAGTGTAAGCGGCACAGCGAAAGCGTTAA GTGATCCACCTGGGGAGTACGCCGGCAACGGTGAAACTCAAAGGAATTGACGGGGG CCCGCACAAGCGGAGGAACATGTGGTTTAATTCGATGATACGCGAGGAACCTTACC CGGGTTTGAACGCATTCGGACCGAGGTGGAAACACCTTTTCTAGCAATAGCCGTTTG CGAGGTGCTGCATGGTTGTCGTCAGCTCGTGCCGTGAGGTGTCGGCTTAAGTGCCAT AACGAGCGCAACCCTTGCCACTAGTTACTAACAGGTGATGCTGAGGACTCTGGTGG GACTGCCAGCGTAAGCTGCGAGGAAGGCGGGGATGACGTCAAATCAGCACGGCCCT TACATCCGGGGCGACACACGTGTTACAATGGCGTGGACAAAGGGATGCCACCTGGC GACAGGGAGCGAATCCCCAAACCACGTCTCAGTTCGGATCGGAGTCTGCAACCCGA CTCCGTGAAGCTGGATTCGCTAGTAATCGCGCATCAGCCATGGCGCGGTGAATACGT TCCCGGGCCTTGTACACACCGCCCGTCAAGCCATGGGAGCCGGGGGTACCTGAAGT CCGTA NB2-A12FMUPhascolarctobacteriumsuccinatutens (SEQIDNO:4) ATTGGAGAGTTTGATCCTGGCTCAGGACGAACGCTGGCGGCATGCCTAACACATGC AAGTCGAACGGAGAAAGTTCAACACCAAGTATTTCATCCGCTGAAGTGTAGCGGTA AAAATTGCGAAGCAATTTTTACTACGCATTAAAAGCATGAACTAACACGGTGGTTGA AGTATTAGGTGTTGAACTTTCTTAGTGGCGAACGGGTGAGTAACGCGTGGGCAACCT GCCCTCTAGATGGGGACAACATCCCGAAAGGGGTGCTAATACCGAATGTGACAGCA ATCTCGCATGAGGATGCTGTGAAAGATGGCCTCTATTTATAAGCTATCGCTAGAGGA TGGGCCTGCGTCTGATTAGCTAGTTGGTGGGGTAACGGCCTACCAAGGCGATGATCA GTAGCCGGTCTGAGAGGATGAACGGCCACATTGGGACTGAGACACGGCCCAGACTC CTACGGGAGGCAGCAGTGGGGAATCTTCCGCAATGGGCGAAAGCCTGACGGAGCAA TGCCGCGTGAGTGATGAAGGAATTCGTTCCGTAAAGCTCTTTTGTTTATGACGAATG TGCAGATTGTAAATAATGATCTGTAATGACGGTAGTAAACGAATAAGCCACGGCTA ACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCGAGCGTTGTCCGGAATTATTG GGCGTAAAGAGCATGTAGGCGGTTTTTTAAGTCTGGAGTGAAAATGCGGGGCTCAA CCCCGTATGGCTCTGGATACTGGAAGACTTGAGTGCAGGAGAGGAAAGGGGAATTC CCAGTGTAGCGGTGAAATGCGTAGATATTGGGAGGAACACCAGTGGCGAAGGCGCC TTTCTGGACTGTGTCTGACGCTGAGATGCGAAAGCCAGGGTAGCGAACGGGATTAG ATACCCCGGTAGTCCTGGCCGTAAACGATGGGTACTAGGTGTAGGAGGTATCGACC CCTTCTGTGCCGGAGTTAACGCAATAAGTACCCCGCCTGGGGAGTACGTCCGCAAG GATGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGTATGTGGTTTA ATTCGACGCAACGCGAAGAACCTTACCAAGGCTTGACATTGAATGACCGCTCCAGA GATGGAGCTTTCCCTTCGGGGACATGAAAACAGGTGGTGCATGGCTGTCGTCAGCTC GTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATCCTATGTTAC CAGCGGGTAATGCCGGGGACTCATAGGAGACTGCCAAGGACAACTTGGAGGAAGGC GGGGATGACGTCAAGTCATCATGCCCCTTATGTCTTGGGCTACACACGTACTACAAT GGTCGGCAACAGAGGGAAGCAAAGCCGTGAGGCAGAGCAAACCCCAGAAACCCGA TCCCAGTTCGGATTGCAGGCTGCAACTCGCCTGCATGAAGTCGGAATCGCTAGTAAT CGCAGGTCAGCATACTGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCA CACCACGAAAGTTGGTAACACCCGAAGCCGGTGGGGTAACCGTAAGGAGCCAGCCG TCTAAGGTGGGGCCGATGATTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAG GTGCGGCTGGATCACCTCCTTT NB2-B17NBRuminococcuslactaris (SEQIDNO:5) GAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCAAGTC GAGCGAAGCACTTAGGAAAGATTCTTCGGATGATTTCCTATTTGACTGAGCGGCGGA CGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATAACAGTTAGAAATG ACTGCTAATACCGCATAAGACCACAGCACCGCATGGTGCAGGGGTAAAAACTCCGG TGGTATGAGATGGACCCGCGTCTGATTAGTTAGTTGGTGGGGTAACGGCCTACCAAG GCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGACTGAGACACG GCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGAAACCCT GATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCGGTATGTAAAGCTCTATCAGC AGGGAAGAAAATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACGTGCCAGCAG CCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGATTTACTGGGTGTAAAGGGAGC GTAGACGGAGCAGCAAGTCTGATGTGAAAACCCGGGGCTCAACCCCGGGACTGCAT TGGAAACTGTTGATCTGGAGTGCCGGAGAGGTAAGCGGAATTCCTAGTGTAGCGGT GAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCGGCTTACTGGACGGTA ACTGACGTTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGGTAGT CCACGCCGTAAACGATGACTACTAGGTGTCGGGTGGCAAAGCCATTCGGTGCCGCA GCCAACGCAATAAGTAGTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTCAAAG GAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAACGC GAAGAACCTTACCTGCTCTTGACATCCCGGTGACGGCAGAGTAATGTCTGCTTTTCT TTGGAACACCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGTT GGGTTAAGTCCCGCAACGAGCGCAACCCCTATCTTCAGTAGCCAGCGGTAAGGCCG GGCACTCTGGAGAGACTGCCAGGGATAACCTGGAGGAAGGTGGGGATGACGTCAAA TCATCATGCCCCTTATGAGCAGGGCTACACACGTGCTACAATGGCGTAAACAAAGG GAAGCGAACCCGCGAGGGTGGGCAAATCCCAAAAATAACGTCTCAGTTCGGATTGT AGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATCAGAATGTC GCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTCAGT AACGCCCGAAGTCAGTGACCCAACC NB2-B16D5Neglectatimonensis (SEQIDNO:6) TTTAGAGAGTTTGATCCTGGCTCAGGACGAACGCTGGCGGCGTGCCTAACACATGCA AGTCGAACGGAGATAGACGCTGAAAGGGAGACAGCTTGCTGTAAGAATTTCTTGTT TATCTTAGTGGCGGACGGGTGAGTAACGCGTGAGTAACCTGCCTTTCAGAGGGGGA TAACGTCTGGAAACGGACGCTAATACCGCATGAGACCACAGCTTCACATGGAGCGG CGGTCAAAGGAGCAATCCGCTGAAAGATGGACTCGCGTCCGATTAGATAGTTGGCG GGGTAACGGCCCACCAAGTCGACGATCGGTAGCCGGACTGAGAGGTTGAACGGCCA CATTGGGACTGAGACACGGCCCAGACTCCTACGGGAGGCAGCAGTGAGGGATATTG GTCAATGGGGGAAACCCTGAACCAGCAACGCCGCGTGAGGGAAGACGGTTTTCGGA TTGTAAACCTCTGTCCTCTGTGAAGATAGTGACGGTAGCAGAGGAGGAAGCTCCGG CTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGGAGCGAGCGTTGTCCGGATTT ACTGGGTGTAAAGGGTGCGTAGGCGGCTCTGCAAGTCAGAAGTGAAATCCATGGGC TTAACCCATGAACTGCTTTTGAAACTGTAGAGCTTGAGTGAAGTAGAGGTAGGCGG AATTCCCGGTGTAGCGGTGAAATGCGTAGAGATCGGGAGGAACACCAGTGGCGAAG GCGGCCTACTGGGCTTTAACTGACGCTGAGGCACGAAAGCATGGGTAGCAAACAGG ATTAGATACCCTGGTAGTCCATGCCGTAAACGATGATTACTAGGTGTGGGGGGTCTG ACCCCCTCCGTGCCGGAGTTAACACAATAAGTAATCCACCTGGGGAGTACGACCGC AAGGTTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCAGTGGAGTATGTGGA TTAATTCGAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCCAACTAACGAAGC AGAGATGCATTAGGTGCCCTTCGGGGAAAGTTGAGACAGGTGGTGCATGGTTGTCG TCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTACTGT TAGTTGCTACGCAAGAGCACTCTAGCAGGACTGCCGTTGACAAAACGGAGGAAGGT GGGGACGACGTCAAATCATCATGCCCCTTATGACCTGGGCCTCACACGTACTACAAT GGCCATTAACAGAGGGAAGCAAGCCCGCGAGGTGGAGCAAAACCCTAAAAATGGT CTCAGTTCGGATCGTAGGCTGAAACCCGCCTGCGTGAAGTTGGAATTGCTAGTAATC GCGGATCAGCATGCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCAC ACCATGGGAGCCGGTAATACCCGAAGTCAGTAGTCTAACCGCAAGGGGGACGCTGC CGAAGGTAGGATTGGCGACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGG TGCGGCTGGATCACCTCCTTT NB2-B10NB[Clostridium]spiroforme (SEQIDNO:7) ATGGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAATACATGCA AGTCGAACGCTTCACTTCGGTGAAGAGTGGCGAACGGGTGAGTAATACATAAGTAA CCTGGCATCTACAGGGGGATAACTGATGGAAACGTCAGCTAAGACCGCATAGGTGT AGAGATCGCATGAACTCTATATGAAAAGTGCTACGGGACTGGTAGATGATGGACTT ATGGCGCATTAGCTGGTTGGTAGGGTAACGGCCTACCAAGGCGACGATGCGTAGCC GACCTGAGAGGGTGACCGGCCACACTGGGACTGAGACACGGCCCAGACTCCTACGG GAGGCAGCAGTAGGGAATTTTCGGCAATGGGGGAAACCCTGACCGAGCAACGCCGC GTGAAGGAAGAAGTAATTCGTTATGTAAACTTCTGTCATAGAGGAAGAACGGTGGA TATAGGGAATGATATCCAAGTGACGGTACTCTATAAGAAAGCCACGGCTAACTACG TGCCAGCAGCCGCGGTAATACGTAGGTGGCGAGCGTTATCCGGAATTATTGGGCGT AAAGAGGGAGCAGGCGGCACTAAGGGTCTGTGGTGAAAGATCGAAGCTTAACTTCG GTAAGCCATGGAAACCGTAGAGCTAGAGTGTGTGAGAGGATCGTGGAATTCCATGT GTAGCGGTGAAATGCGTAGATATATGGAGGAACACCAGTGGCGAAGGCGACGATCT GGCGCATAACTGACGCTCAGTCCCGAAAGCGTGGGGAGCAAATAGGATTAGATACC CTAGTAGTCCACGCCGTAAACGATGAGTACTAAGTGTTGGGAGTCAAATCTCAGTGC TGCAGTTAACGCAATAAGTACTCCGCCTGAGTAGTACGTTCGCAAGAATGAAACTCA AAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAA CGCGAAGAACCTTACCAGGTCTTGACATCGATCTAAAGGCTCCAGAGATGGAGAGA TAGCTATAGAGAAGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGTT GGGTTAAGTCCCGCAACGAGCGCAACCCCTGTTGCCAGTTGCCAGCATTAAGTTGGG GACTCTGGCGAGACTGCCGGTGACAAGCCGGAGGAAGGCGGGGATGACGTCAAATC ATCATGCCCCTTATGACCTGGGCTACACACGTGCTACAATGGACAGAGCAGAGGGA AGCGAAGCCGCGAGGTGGAGCGAAACCCATAAAACTGTTCTCAGTTCGGACTGCAG TCTGCAACTCGACTGCACGAAGATGGAATCGCTAGTAATCGCGAATCAGCATGTCGC GGTGAATACGTTCTCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGTCGGTAA CACCCGAAGCCGGTGGCCTAACCGCAAGGAAGGAGCTGTCTAAGGTGGGACTGATG ATTGGGGTGAAGTCGTAACAAGGTATCCCTACGGGAACGTGGGGATGGATCACCTC CTTT NB2-B10FAARoseburiaintestinalis (SEQIDNO:8) ACTGAGTGGCGGACGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATA ACAGTTGGAAACGACTGCTAATACCGCATAAGCGCACAGGGTCGCATGACCTGGTG TGAAAAACTCCGGTGGTATGAGATGGACCCGCGTCTGATTAGCCAGTTGGTGGGGT AACGGCCTACCAAAGCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATT GGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACA ATGGGGGAAACCCTGATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCGGTATGT AAAGCTCTATCAGCAGGGAAGAAGAAATGACGGTACCTGACTAAGAAGCACCGGCT AAATACGTGCCAGCAGCCGCGGTAATACGTATGGTGCAAGCGTTATCCGGATTTACT GGGTGTAAAGGGAGCGCAGGCGGTACGGCAAGTCTGATGTGAAAGCCCGGGGCTCA ACCCCGGTACTGCATTGGAAACTGTCGGACTAGAGTGTCGGAGGGGTAAGTGGAAT TCCTAGTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCG GCTTACTGGACGATTACTGACGCTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATT AGATACCCTGGTAGTCCACGCCGTAAACGATGAATACTAGGTGTCGGGGAGCATTG CTCTTCGGTGCCGCAGCAAACGCAATAAGTATTCCACCTGGGGAGTACGTTCGCAAG AATGAAACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTA ATTCGAAGCAACGCGAAGAACCTTACCAAGTCTTGACATCCCGATGACAGAACATG TAATGTGTTTTCTCTTCGGAGCATCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTC GTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATTCTTAGTAGC CAGCGGGTAAGCCGGGCACTCTAGGGAGACTGCCAGGGATAACCTGGAGGAAGGTG GGGATGACGTCAAATCATCATGCCCCTTATGACTTGGGCTACACACGTGCTACAATG GCGTAAACAAAGGGAAGCGAGCCTGCGAGGGGGAGCAAATCTCAAAAATAACGTC TCAGTTCGGACTGCAGTCTGCAACTCGACTGCACGAAGCTGGAATCGCTAGTAATCG CGAATCAGAATGTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACA CCATGGGAGTTGGTAATGCCCGAAGTCAGTGACCCAACCGCAAGGAGGGAGCTGCC GAAGGCAGGATCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGT GCGGCTGGATCACCTCCTTT NB2-A8WCAkkermansiamuciniphila (SEQIDNO:9) ATGGAGAGTTTGATTCTGGCTCAGAACGAACGCTGGCGGCGTGGATAAGACATGCA AGTCGAACGAGAGAATTGCTAGCTTGCTAATAATTCTCTAGTGGCGCACGGGTGAGT AACACGTGAGTAACCTGCCCCCGAGAGCGGGATAGCCCTGGGAAACTGGGATTAAT ACCGCATAGAATCGCAAGATTAAAGCAGCAATGCGCTTGGGGATGGGCTCGCGGCC TATTAGTTAGTTGGTGAGGTAACGGCTCACCAAGGCGATGACGGGTAGCCGGTCTG AGAGGATGTCCGGCCACACTGGAACTGAGACACGGTCCAGACACCTACGGGTGGCA GCAGTCGAGAATCATTCACAATGGGGGAAACCCTGATGGTGCGACGCCGCGTGGGG GAATGAAGGTCTTCGGATTGTAAACCCCTGTCATGTGGGAGCAAATTAAAAAGATA GTACCACAAGAGGAAGAGACGGCTAACTCTGTGCCAGCAGCCGCGGTAATACAGAG GTCTCAAGCGTTGTTCGGAATCACTGGGCGTAAAGCGTGCGTAGGCTGTTTCGTAAG TCGTGTGTGAAAGGCGCGGGCTCAACCCGCGGACGGCACATGATACTGCGAGACTA GAGTAATGGAGGGGGAACCGGAATTCTCGGTGTAGCAGTGAAATGCGTAGATATCG AGAGGAACACTCGTGGCGAAGGCGGGTTCCTGGACATTAACTGACGCTGAGGCACG AAGGCCAGGGGAGCGAAAGGGATTAGATACCCCTGTAGTCCTGGCAGTAAACGGTG CACGCTTGGTGTGCGGGGAATCGACCCCCTGCGTGCCGGAGCTAACGCGTTAAGCG TGCCGCCTGGGGAGTACGGTCGCAAGATTAAAACTCAAAGAAATTGACGGGGACCC GCACAAGCGGTGGAGTATGTGGCTTAATTCGATGCAACGCGAAGAACCTTACCTGG GCTTGACATGTAATGAACAACATGTGAAAGCATGCGACTCTTCGGAGGCGTTACAC AGGTGCTGCATGGCCGTCGTCAGCTCGTGTCGTGAGATGTTTGGTTAAGTCCAGCAA CGAGCGCAACCCCTGTTGCCAGTTACCAGCACGTGAAGGTGGGGACTCTGGCGAGA CTGCCCAGATCAACTGGGAGGAAGGTGGGGACGACGTCAGGTCAGTATGGCCCTTA TGCCCAGGGCTGCACACGTACTACAATGCCCAGTACAGAGGGGGCCGAAGCCGCGA GGCGGAGGAAATCCTAAAAACTGGGCCCAGTTCGGACTGTAGGCTGCAACCCGCCT ACACGAAGCCGGAATCGCTAGTAATGGCGCATCAGCTACGGCGCCGTGAATACGTT CCCGGGTCTTGTACACACCGCCCGTCACATCATGGAAGCCGGTCGCACCCGAAGTAT CTGAAGCCAACCGCAAGGAGGCAGGGTCCTAAGGTGAGACTGGTAACTGGGATGAA GTCGTAACAAGGTAGCCGTAGGGGAACCTGCGGCTGGATCACCTCCTTT NB2-A9NA[Ruminococcus]obeum (SEQIDNO:10) GCTTAACACATGCAAGTCGAACGAGAAGGCGTAGCAATACGCTTGTAAAGTGGCGA ACGGGTGAGNAACACNTGGGTAACCTACCCTCGAGTGGGGGATAACCCGCCGAAAG GCGGGCTAATACCGCGTACGCTTCCGATCTTGCGAGATCGGAAGGAAAGCTGTCCC AAGGGGATGGCGCTCAAGGATGGGCTCACGTCCNATCAGCTNGTTGGTGNGGTAAC GGCNNACCAAGGCGACGANGGNTAGCTGGTCTGAGAGGANGANCAGCCACACTGG GACTGNGACACGGCCCAGACTCCTACGGGAGGCAGCAGTNGGGAATCTTGCGCAAT GNGCGAAAGCNTGACGCAGCNACGCCGCGTGNGGGANGANGGCCNTCGGGTTGTA AACCNCTTTCAGNAGGGACGAATCTGACGGTACCTGCAGAAGAAGCCCCGGCNAAC TACGTGCCAGCAGCCGCGGTAATACGTAGGGGGCNAGCGTTGTCCGGATTTATTGG GCGTAAAGAGCTCGTAGGCGGCTTGGCAAGTCGGGTGTGAAACCTCCAGGCTTAAC CTGGAGACGCCACTCGATNCTGCCATGGCTAGAGTCCGGTAGGGGACCACGGAATT CCTGGTGTAGCGGTGAAATGCGCAGATATCAGGAGGAACNCCGGTGGCGAAGGCGG NGNTCTGGGNCGGNACTGACGCTGAGGNGCGAAAGCGTGGGNAGCAAACAGGATT AGATACCCTGGTAGTCCACGCCGTAAACGNTGGGCACTAGGTGTGGGACCTTATCA ACGGGTTCCGTGCCGTAGCTAACGCATTAAGTGCCCCGCCTGGGGAGTACGGCCGC AAGGCTAAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGCGGAGCATGTTGC TTAATTCGATGCAACGCGAAGAACCTTACCTGGGTTGAACTACGCGGGAAAAGCCA CAGAGATGTGGTGTCCGAAAGGGCCCGCGATAGGTGGTGCATGGCTGTCGTCAGCT CGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTNTCCNATGTTG CCAGCGGATCATGCCGGGGACTCNTGGGAGACTGCCGGGGTCAACTCGGAGGAAGG TGGGGATGACGTCAAGTCANCATGCCCCTTATGTCCAGGGCTNNAAACATGCTACA ATGGCCGGTACAAAGGGTNGCGAGNCNGCGANGNNGAGCNAATCCCATAAAGNNN GTCTNAGTNCGGATCGNAGTCTGCAACTCGACTNCGTGAAGNCGGAGTNGCTAGTA ATCNCGNATCAGCANNGNCGNGGTGAATACGTTCCCGGGCCTTGTACACACCGCCC GTCACACCACGAAAGTTGGTAACACCCGAAGCCGGTGG NB2-B20GAM[Clostridium]lactatifermentans (SEQIDNO:11) GAGTAATTCGGTATAGGATGGGCCCGCATCTGATTAGCTAGTTGGTGAGATAACAGC CCACCAAGGCGACGATCAGTAGCCGACCTGAGAGGGTGATCGGCCACATTGGGACT GAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGG GAAACCCTGATGCAGCAACGCCGCGTGAAGGAAGAAGGTTTTCGGATCGTAAACTT CTATCAACAGGGACGAAGAAAGTGACGGTACCTGAATAAGAAGCCCCGGCTAACTA CGTGCCAGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGAATTACTGGGT GTAAAGGGAGCGTAGGCGGCACGCCAAGCCAGATGTGAAAGCCCGAGGCTTAACCT CGCGGATTGCATTTGGAACTGGCGAGCTAGAGTACAGGAGAGGAAAGCGGAATTCC TAGTGTAGCGGTGAAATGCGTAGATATTAGGAAGAACACCAGTGGCGAAGGCGGCT TTCTGGACTGAAACTGACGCTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGA TACCCTGGTAGTCCACGCCGTAAACGATGAGTGCTAGGTGTCGGGGAGGAATCCTC GGTGCCGCAGCTAACGCAATAAGCACTCCACCTGGGGAGTACGACCGCAAGGTTGA AACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGTTTAATTCG AAGCAACGCGAAGAACCTTACCAAGGCTTGACATCCCGATGACCGCTCTAGAGATA GAGNTTCTCTTCGGAGCATCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTC GTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCCTTAGTAGCCATCA TTGAGTTGGGCACTCTAGGGAGACTGCCGTGGATAACACGGAGGAAGGTGGGGATG ACGTCAAATCATCATGCCCCTTATGTCTTGGGCTACACACGTGCTACAATGGCTGGT AACAGAGTGAAGCGAGACGGCGACGTTAAGCAAATCACAAAAACCCAGTCCCAGTT CGGATTGTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATC AGAATGTCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGG GAGTTGGAAGCACCCGAAGTCGGTGACCTAACCGTAAGGAAGGAGCCGCCGAAGGT GAAGCCAGTGACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCT GGATCACCTCCTTT NB2-A15BHIAnaerovoraxodorimutans (SEQIDNO:12) ATATGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAACACATGCA AGTCGAGCGAGAAGCTGATGATTGACACTTCGGTTGAGAGAATCAGTGGAAAGCGG CGGACGGGTGAGTAACGCGTAGGCAACCTGCCCTTTGCAGAGGGATAGCCTCGGGA AACCGGGATTAAAACCTCATGATGCTGTATGTCCGCATGGGCAGACGGTCAAAGAT TTATCGGCAGAGGATGGGCCTGCGTCTGATTAGTTAGTTGGTGGGGTAACGGCCTAC CAAGGCAACGATCAGTAGCCGACCTGAGAGGGTGATCGGCCACATTGGAACTGAGA CACGGTCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGAAA CCCTGATGCAGCAACGCCGCGTGAGCGAAGAAGGCCTTTGGGTCGTAAAGCTCTGT CCTTGGGGAAGAAAAAATGACGGTACCCAAGGAGGAAGCCCCGGCTAACTACGTGC CAGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGAATTATTGGGCGTAAA GAGTATGTAGGTGGTTTCTTAAGCGCAGGGTATAAGGCAATGGCTTAACCATTGTTC GCCCCGTGAACTGAGAGACTTGAGTGCTGGAGAGGAAAGCGGAATTCCTAGTGTAG CGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCGGCTTTCTGGAC AGTAACTGACACTGAGATACGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGG TAGTCCACGCCGTAAACGATGAGCACTAGGTGTCGGGCTCGCAAGAGTTCGGTGCC GGAGTTAACGCATTAAGTGCTCCGCCTGGGGAGTACGCACGCAAGTGTAAAACTCA AAGGAATTGACGGGGACCCGCACAAGCAGCGGAGCATGTGGTTTAATTCGAAGCAA CGCGAAGAACCTTACCAGGGCTTGACATCCCTCCGACCGGTCCTTAATCGGACCTTT CTACGGACGGGGGAGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATG TTGGGTTAAGTCCCGCAACGAGCGCAACCCTTGTCATTAGTTGCTAACAGTAAGATG AGAACTCTAATGAGACTGCCGTGGATAACACGGAGGAAGGTGGGGATGACGTCAAA TCATCATGCCCCTTATGTCCTGGGCTACACACGTGCTACAATGGTCGGTACAAAGAG AAGCAAGACCGCGAGGTGGAGCAAATCTCAAAAACCGATCCCAGTTCGGATTGCAG GCTGCAACTCGCCTGCATGAAGTCGGAGTTGCTAGTAATCGCAGATCAGAATGCTGC GGTGAATGCGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGAAGTTGGGGG CGCCCGAAGTCGGCTAGTAAATAGGCTGCCTAAGGCGAAATCAATGACTGGGGTGA AGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGATCACCTCCTTT NB2-A14FMU[Ruminococcus]torques (SEQIDNO:13) AACGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAACACATGCA AGTCGAGCGAAGCACTTTGCTTAGATTCTTCGGATGAAGAGGATTGTGACTGAGCGG CGGACGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATAACAGTTAGA AATGACTGCTAATACCGCATAAGACCACAGCACCGCATGGTGCGGGGGTAAAAACT CCGGTGGTATGAGATGGACCCGCGTCTGATTAGCTAGTTGGTAAGGTAACGGCTTAC CAAGGCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGACTGAGA CACGGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGAAA CCCTGATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCGGTATGTAAAGCTCTATC AGCAGGGAAGAAAATGACGGTACCTGACTAAGAAGCACCGGCTAAATACGTGCCAG CAGCCGCGGTAATACGTATGGTGCAAGCGTTATCCGGATTTACTGGGTGTAAAGGG AGCGTAGACGGATGGGCAAGTCTGATGTGAAAACCCGGGGCTCAACCCCGGGACTG CATTGGAAACTGTTCATCTAGAGTGCTGGAGAGGTAAGTGGAATTCCTAGTGTAGCG GTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCGGCTTACTGGACAG TAACTGACGTTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGGTA GTCCACGCCGTAAACGATGACTACTAGGTGTCGGGTGGCAAAGCCATTCGGTGCCG CAGCAAACGCAATAAGTAGTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTCAA AGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAAC GCGAAGAACCTTACCTGCTCTTGACATCCCGCTGACCGGACGGTAATGCGTCCTTCC CTTCGGGGCAGCGGAGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATG TTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATCTTTAGTAGCCAGCGGCCAGGCC GGGCACTCTAGAGAGACTGCCGGGGATAACCCGGAGGAAGGTGGGGATGACGTCA AATCATCATGCCCCTTATGAGCAGGGCTACACACGTGCTACAATGGCGTAAACAAA GGGAAGCGAGACCGCGAGGTGGAGCAAATCCCAAAAATAACGTCTCAGTTCGGATT GTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATCAGAAT GTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTC AGTAACGCCCGAAGTCAGTGACCCAACCGTAAGGAGGGAGCTGCCGAAGGCGG NB2-A17FMU[Eubacterium]rectale (SEQIDNO:14) ATTTTGTGACTGAGTGGCGGACGGGTGAGTAACGCGTGGGTAACCTGCCTTGTACAG GGGGATAACAGTTGGAAACGGCTGCTAATACCGCATAAGCGCACAGCATCGCATGA TGCAGTGTGAAAAACTCCGGTGGTATAAGATGGACCCGCGTTGGATTAGCTAGTTGG TGAGGTAACGGCCCACCAAGGCGACGATCCATAGCCGACCTGAGAGGGTGACCGGC CACATTGGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATAT TGCACAATGGGCGAAAGCCTGATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCG GTATGTAAAGCTCTATCAGCAGGGAAGATAATGACGGTACCTGACTAAGAAGCACC GGCTAAATACGTGCCAGCAGCCGCGGTAATACGTATGGTGCAAGCGTTATCCGGATT TACTGGGTGTAAAGGGAGCGCAGGCGGTGCGGCAAGTCTGATGTGAAAGCCCGGGG CTCAACCCCGGTACTGCATTGGAAACTGTCGTACTAGAGTGTCGGAGGGGTAAGCG GAATTCCTAGTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAA GGCGGCTTACTGGACGATAACTGACGCTGAGGCTCGAAAGCGTGGGGAGCAAACAG GATTAGATACCCTGGTAGTCCACGCCGTAAACGATGAATACTAGGTGTTGGGAAGC ATTGCTTCTCGGTGCCGTCGCAAACGCAGTAAGTATTCCACCTGGGGAGTACGTTCG CAAGAATGAAACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTG GTTTAATTCGAAGCAACGCGAAGAACCTTACCAAGTCTTGACATCCTTCTGACCGGT ACTTAACCGTACCTTCTCTTCGGAGCAGGAGTGACAGGTGGTGCATGGTTGTCGTCA GCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCTTTAG TAGCCAGCGGTTCGGCCGGGCACTCTAGAGAGACTGCCAGGGATAACCTGGAGGAA GGCGGGGATGACGTCAAATCATCATGCCCCTTATGACTTGGGCTACACACGTGCTAC AATGGCGTAAACAAAGGGAAGCAAAGCTGTGAAGCCGAGCAAATCTCAAAAATAA CGTCTCAGTTCGGACTGTAGTCTGCAACCCGACTACACGAAGCTGGAATCGCTAGTA ATCGCAGATCAGAATGCTGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGT CACACCATGGGAGTTGGGAATGCCCGAAGCCAGTGACCTAACCGAAAGGAAGGAG CTGTCGAAGGCAGGCTCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGG AAGGTGCGGCTGGATCACCTCCTTT NB2-B14D5Bacteroideseggerthii (SEQIDNO:15) ATGAAGAGTTTGATCCTGGCTCAGGATGAACGCTAGCTACAGGCTTAACACATGCA AGTCGAGGGGCAGCATGATTGAAGCTTGCTTCAATCGATGGCGACCGGCGCACGGG TGAGTAACACGTATCCAACCTGCCGATAACTCGGGGATAGCCTTTCGAAAGAAAGA TTAATACCCGATAGTATAGTATTTCCGCATGGTTTCACTATTAAAGAATTTCGGTTAT CGATGGGGATGCGTTCCATTAGATAGTTGGCGGGGTAACGGCCCACCAAGTCAACG ATGGATAGGGGTTCTGAGAGGAAGGTCCCCCACATTGGAACTGAGACACGGTCCAA ACTCCTACGGGAGGCAGCAGTGAGGAATATTGGTCAATGGACGAGAGTCTGAACCA GCCAAGTAGCGTGAAGGATGACTGCCCTATGGGTTGTAAACTTCTTTTATACGGGAA TAAAGTGGAGTATGCATACTCCTTTGTATGTACCGTATGAATAAGGATCGGCTAACT CCGTGCCAGCAGCCGCGGTAATACGGAGGATCCGAGCGTTATCCGGATTTATTGGGT TTAAAGGGAGCGTAGGCGGGTGCTTAAGTCAGTTGTGAAAGTTTGCGGCTCAACCGT AAAATTGCAGTTGATACTGGGTACCTTGAGTGCAGCATAGGTAGGCGGAATTCGTG GTGTAGCGGTGAAATGCTTAGATATCACGAAGAACTCCGATTGCGAAGGCAGCTTA CTGGACTGTAACTGACGCTGATGCTCGAAAGTGTGGGTATCAAACAGGATTAGATA CCCTGGTAGTCCACACAGTAAACGATGAATACTCGCTGTTGGCGATACACAGTCAGC GGCCAAGCGAAAGCATTAAGTATTCCACCTGGGGAGTACGCCGGCAACGGTGAAAC TCAAAGGAATTGACGGGGGCCCGCACAAGCGGAGGAACATGTGGTTTAATTCGATG ATACGCGAGGAACCTTACCCGGGCTTAAATTGCAGCGGAATGTAGTGGAAACATTA CAGCCTTCGGGCCGCTGTGAAGGTGCTGCATGGTTGTCGTCAGCTCGTGCCGTGAGG TGTCGGCTTAAGTGCCATAACGAGCGCAACCCTTATCTATAGTTACTATCAGGTCAT GCTGAGGACTCTATGGAGACTGCCGTCGTAAGATGTGAGGAAGGTGGGGATGACGT CAAATCAGCACGGCCCTTACGTCCGGGGCTACACACGTGTTACAATGGGGGGTACA GAAGGCAGCTACCTGGCGACAGGATGCTAATCCCTAAAACCTCTCTCAGTTCGGATT GGAGTCTGCAACCCGACTCCATGAAGCTGGATTCGCTAGTAATCGCGCATCAGCCAC GGCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCAAGCCATGAAAGC CGGGGGTACCTGAAGTACGTAACCGCAAGGAGCGTCCTAGGGTAAAACTGGTGATT GGGGCTAAGTCGTAACAAGGTAGCCGTACCGGAAGGTGCGGCTGGAACACCTCCTT T NB2-B26FMURoseburiainulinivorans (SEQIDNO:16) ACTGAGTGGCGGACGGGTGAGTAACGCGTGGGTAACCTGCCTCACACAGGGGGATA ACAGTTGGAAACGGCTGCTAATACCGCATAAGCGCACAGTACCGCATGGTACAGTG TGAAAAACTCCGGTGGTGTGAGATGGACCCGCGTCTGATTAGCTAGTTGGCAGGGC AACGGCCTACCAAGGCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATT GGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACA ATGGGGGAAACCCTGATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCGGTATGT AAAGCTCTATCAGCAGGGAAGAAGAAATGACGGTACCTGACTAAGAAGCACCGGCT AAATACGTGCCAGCAGCCGCGGTAATACGTATGGTGCAAGCGTTATCCGGATTTACT GGGTGTAAAGGGAGCGCAGGCGGAAGGCTAAGTCTGATGTGAAAGCCCGGGGCTCA ACCCCGGTACTGCATTGGAAACTGGTCATCTAGAGTGTCGGAGGGGTAAGTGGAAT TCCTAGTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCG GCTTACTGGACGATAACTGACGCTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATT AGATACCCTGGTAGTCCACGCCGTAAACGATGAATACTAGGTGTCGGAAAGCACAG CTTTTCGGTGCCGCCGCAAACGCATTAAGTATTCCACCTGGGGAGTACGTTCGCAAG AATGAAACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTA ATTCGAAGCAACGCGAAGAACCTTACCAAGTCTTGACATCCCGGTGACCGGACAGT AATGTGTCCTTTTCTTCGGAACACCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTC GTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCCCCAGTAGC CAGCATTTTGGATGGGCACTCTGAGGAGACTGCCAGGGATAACCTGGAGGAAGGTG GGGATGACGTCAAATCATCATGCCCCTTATGACTTGGGCTACACACGTGCTACAATG GCGTAAACAAAGGGAAGCGAGACCGTGAGGTGGAGCAAATCCCAAAAATAACGTC TCAGTTCGGACTGTAGTCTGCAACCCGACTACACGAAGCTGGAATCGCTAGTAATCG CAGATCAGAATGCTGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACA CCATGGGAGTTGGAAATGCCCGAAGTCAGTGACCCAACCGCAAGGAGGGAGCTGCC GAAGGCAGGTTCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGT GCGGCTGGATCACCTCCTTT NB2-B20DS[Clostridium]hylemonae (SEQIDNO:17) ACGAGAGTTTGATCCTGGCTCAGGACGAACGCTGGCGGCGTGCCTAACACATGCAA GTCGAACGAGAATCTTTGGGATGATTCTTTCGGGATGAATTCCAAAGAGGAAAGTG GCGGACGGGCGAGTAACGCGTGAGTAACCTGCCCATAAGAGGGGGATAATCCATGG AAACGTGGACTAATACCGCATATTGTAGTTAAGTTGCATGACTTGATTATGAAAGAT TTATCGCTTATGGATGGACTCGCGTCAGATTAGATAGTTGGTGAGGTAACGGCTCAC CAAGTCAACGATCTGTAGCCGAACTGAGAGGTTGATCGGCCGCATTGGGACTGAGA CACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCGCAATGGGGGCAA CCCTGACGCAGCAACGCCGCGTGCAGGAAGAAGGTCTTCGGATTGTAAACTGTTGTC GCAAGGGAAGAAGACAGTGACGGTACCTTGTGAGAAAGTCACGGCTAACTACGTGC CAGCAGCCGCGGTAATACGTAGGTGACAAGCGTTGTCCGGATTTACTGGGTGTAAA GGGCGCGTAGGCGGACTGTCAAGTCAGTCGTGAAATACCGGGGCTTAACCCCGGGG CTGCGATTGAAACTGACAGCCTTGAGTATCGGAGAGGAAAGCGGAATTCCTAGTGT AGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCGGCTTTCTGG ACGACAACTGACGCTGAGGCGCGAAAGTGTGGGGAGCAAACAGGATTAGATACCCT GGTAGTCCACACCGTAAACGATGGATACTAGGTGTAGGAGGTATCGACCCCTTCTGT GCCGCAGTTAACACAATAAGTATCCCACCTGGGGAGTACGACCGCAAGGTTGAAAC TCAAAGGAATTGACGGGGGCCCGCACAAGCAGTGGAGTATGTGGTTTAATTCGAAG CAACGCGAAGAACCTTACCTGGGCTTGACATCCCTGGAATCGAGTAGAGATACTTG AGTGCCTTCGGGAATCAGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTG AGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATTGTCAGTTGCCATCATTA AGTTGGGCACTCTGGCGAGACTGCCGGTGACAAATCGGAGGAAGGTGGGGACGACG TCAAATCATCATGCCCCTTATGCCCAGGGCTACACACGTACTACAATGGCCGATAAC AAAGTGCAGCGAAACCGTGAGGTGGAGCGAATCACAAAACTCGGTCTCAGTTCAGA TTGCAGGCTGCAACTCGCCTGCATGAAGTTGGAATTGCTAGTAATCGCGGATCAGAA TGCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGT CGATAACACCCGAAGCCTGTGAGCTAACCTTTTAGGAGGCAGCAGTCGAAGGTGGG GTTGATGATTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGA TCACCTCCTTT NB2-B3WCBarnesiellaintestinihominis (SEQIDNO:18) CGGCGACCGGCGCACGGGTGAGTAACACGTATGCAATCCACCTGTAACAGGGGGAT AACCCGGAGAAATCCGGACTAATACCCCATAATATGGGCGCTCCGCATGGAGAGCC CATTAAAGAGAGCAATCTTGGTTACAGACGAGCATGCGCTCCATTAGCCAGTTGGCG GGGTAACGGCCCACCAAGGCGACGATGGATAGGGGTTCTGAGAGGAAGGTCCCCCA CATTGGAACTGAGACACGGTCCAAACTCCTACGGGAGGCAGCAGTGAGGAATATTG GTCAATGGTCGGCAGACTGAACCAGCCAAGTCGCGTGAGGGAAGACGGCCCTACGG GTTGTAAACCTCTTTTGTCGGAGAGTAAAGTACGCTACGTGTAGCGTATTGCAAGTA TCCGAAGAAAAAGCATCGGCTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGAT GCAAGCGTTATCCGGATTTATTGGGTTTAAAGGGTGCGTAGGCGGCACGCCAAGTCA GCGGTGAAATTTCCGGGCTCAACCCGGAGTGTGCCGTTGAAACTGGCGAGCTAGAG TGCACAAGAGGCAGGCGGAATGCGTGGTGTAGCGGTGAAATGCATAGATATCACGC AGAACCCCGATTGCGAAGGCAGCCTGCTAGGGTGAAACAGACGCTGAGGCACGAA AGCGTGGGTATCGAACAGGATTAGATACCCTGGTAGTCCACGCAGTAAACGATGAA TACTAACTGTTTGCGATACAATGTAAGCGGTACAGCGAAAGCGTTAAGTATTCCACC TGGGGAGTACGCCGGCAACGGTGAAACTCAAAGGAATTGACGGGGGCCCGCACAA GCGGAGGAACATGTGGTTTAATTCGATGATACGCGAGGAACCTTACCCGGGCTCAA ACGCAGGGGGAATATATATGAAAGTATATAGCTAGCAATAGTCACCTGCGAGGTGC TGCATGGTTGTCGTCAGCTCGTGCCGTGAGGTGTCGGCTTAAGTGCCATAACGAGCG CAACCCCTATGGACAGTTACTAACGGGTGAAGCCGAGGACTCTGTCGAGACTGCCG GCGCAAGCCGCGAGGAAGGTGGGGATGACGTCAAATCAGCACGGCCCTTACGTCCG GGGCGACACACGTGTTACAATGGCAGGTACAGAAGGCAGCCAGTCAGCAATGACGC GCGAATCCCGAAAACCTGTCTCAGTTCGGATTGGAGTCTGCAACCCGACTCCATGAA GCTGGATTCGCTAGTAATCGCGCATCAGCCATGGCGCGGTGAATACGTTCCCGGGCC TTGTACACACCGCCCGTCAAGCCATGGAAGCCGGGAGTACCTGAAGCATGCAACCG CAAGGAGCGTACGAAGGTAATACCGGTAACTGGGGCTAAGTCGTAACAAGGTAGCC GTACCGGAAGGTGCGGCTGGAACACCTCCTTT NB2-A14DS[Clostridium]aerotolerans (SEQIDNO:19) TTCCTTAGAAAGGAGGTGATCCAGCCGCACCTTCCGATACGGCTACCTTGTTACGAC TTCACCCCAGTTATCAGTCCCGCCTTCGGCAGCTCCCTCCTTRCGGTTGGGTCACTGA CTTCGGGCGTTACCAACTCCCATGGTGTGACGGGCGGTGTGTACAAGACCCGGGAA CGTATTCACCGCGACATTCTGATTCGCGATTACTAGCGATTCCAGCTTCATGTAGTCG AGTTGCAGACTACAATCCGAACTGAGACGTTATTTTTGAGATTTGCTTAAGCTCACA CTCTCGCTTCCCTTTGTTTACGCCATTGTAGCACGTGTGTAGCCCAAGTCATAAGGGG CATGATGATTTGACGTCATCCCCACCTTCCTCCAGGTTATCCCTGGCAGTCTCTCCAG AGTGCCCGACCGAATCGCTGGCTACTGAAGATAAGGGTTGCGCTCGTTGCGGGACTT AACCCAACATCTCACGACACGAGCTGACGACAACCATGCACCACCTGTCACCGATG CTCCGAAGAGAAGGYYCCATTACRRACCGGTCATCGGGATGTCAAGACTTGGTAAG GTTCTTCGCGTTGCTTCGAATTAAACCACATGCTCCACCGCTTGTGCGGGTCCCCGTC AATTCCTTTGAGTTTCATTCTTGCGAACGTACTCCCCAGGTGGAATACTTATTGCGTT TGCGGCGGCACCGAAGAGCTGTGCTCCCCGACACCTAGTATTCATCGTTTACGGCGT GGACTACCAGGGTATCTAATCCTGTTTGCTCCCCACGCTTTCGAGCCTCAACGTCAG TTACTGTCCAGTAAGCCGCCTTCGCCACTGGTGTTCCTCCTAATATCTACGCATTTCA CCGCTACACTAGGAATTCCGCTTACCTCTCCAGCACTCTAGCCAAACAGTTTCAAAA GCAGTCCCGGGGTTGAGCCCCAGCCTTTCACTTCTGACTTGCTTARCCGTCTACGCTC CCTTTACACCCAGTAAATCCGGATAACGCTTGCCCCCTACGTATTACCGCGGCTGCT GGCACGTAGTTAGCCGGGGCTTCTTAGTCAGGTACCGTCATTTTCTTCCCTGCTGATA GAGCTTTACATACCGAAATACTTCTTCACTCACGCGGCGTCGCTGCATCAGGGTTTC CCCCATTGTGCAATATTCCCCACTGCTGCCTCCCGTAGGAGTTTGGGCCGTGTCTCA GTCCCAATGTGGCCGTTCACCCTCTCAGGCCGGCTATGGATCGTCGCCTTGGTAGGC CGTTACCCTGCCAACTAGCTAATCCAACGCGGGTCCATCTCACACCGATAAATCTTT TCCGTCCGGGCCATGCGGCCCTAGCGGGTTATGCGGTATTAGCGGTCGTTTCCAACT GTTATCCCCCTGTGTGAGGCAGGTTACCCACGCGTTACTCACCCGTCCGCCACTAAG TCGCAAGAGAAATCATCCGAAGAATCAATCTCAAGCGCTTCGTTCGACTTGCATGTG TTAAGCACGCCGCCAGCGTTCATCCTGAGCCAGGATCAAACTCTCGATTAA NB2-A15DCMBacteroidesstercorirosoris (SEQIDNO:20) ATGAAGAGTTTGATCCTGGCTCAGGATGAACGCTAGCTACAGGCTTAACACATGCA AGTCGAGGGGCAGCATGACCTAGCAATAGGTTGATGGCGACCGGCGCACGGGTGAG TAACACGTATCCAACCTACCGGTTATTCCGGGATAGCCTTTCGAAAGAAAGATTAAT ACCGGATAGTATAACGAGAAGGCATCTTCTTGTTATTAAAGAATTTCGATAACCGAT GGGGATGCGTTCCATTAGTTTGTTGGCGGGGTAACGGCCCACCAAGACATCGATGG ATAGGGGTTCTGAGAGGAAGGTCCCCCACATTGGAACTGAGACACGGTCCAAACTC CTACGGGAGGCAGCAGTGAGGAATATTGGTCAATGGACGAGAGTCTGAACCAGCCA AGTAGCGTGAAGGATGACTGCCCTATGGGTTGTAAACTTCTTTTATATGGGAATAAA GTGAGCCACGTGTGGCTTTTTGTATGTACCATACGAATAAGGATCGGCTAACTCCGT GCCAGCAGCCGCGGTAATACGGAGGATCCGAGCGTTATCCGGATTTATTGGGTTTAA AGGGAGCGTAGGCGGACTATTAAGTCAGCTGTGAAAGTTTGCGGCTCAACCGTAAA ATTGCAGTTGATACTGGTCGTCTTGAGTGCAGTAGAGGTAGGCGGAATTCGTGGTGT AGCGGTGAAATGCTTAGATATCACGAAGAACTCCGATTGCGAAGGCAGCTTACTGG ACTGTAACTGACGCTGATGCTCGAAAGTGTGGGTATCAAACAGGATTAGATACCCTG GTAGTCCACACAGTAAACGATGAATACTCGCTGTTTGCGATATACAGCAAGCGGCC AAGCGAAAGCATTAAGTATTCCACCTGGGGAGTACGCCGGCAACGGTGAAACTCAA AGGAATTGACGGGGGCCCGCACAAGCGGAGGAACATGTGGTTTAATTCGATGATAC GCGAGGAACCTTACCCGGGCTTAAATTGCAAATGAATATAGTGGAAACATTATAGC CGCAAGGCATTTGTGAAGGTGCTGCATGGTTGTCGTCAGCTCGTGCCGTGAGGTGTC GGCTTAAGTGCCATAACGAGCGCAACCCTTATCTTTAGTTACTAACAGGTCATGCTG AGGACTCTAGAGAGACTGCCGTCGTAAGATGTGAGGAAGGTGGGGATGACGTCAAA TCAGCACGGCCCTTACGTCCGGGGCTACACACGTGTTACAATGGGGGGTACAGAAG GCAGCTACACAGCGATGTGATGCTAATCCCAAAAGCCTCTCTCAGTTCGGATTGGAG TCTGCAACCCGACTCCATGAAGCTGGATTCGCTAGTAATCGCGCATCAGCCACGGCG CGGTGAATACGTTCNCGGGCCTTGTACACACCGCCCGTCAAGCCATGAAAGCCGGG GGTACCTGAAGTCCGTAACCGCAAGGAG NB2-A2OGAMFlavonifractorplautii (SEQIDNO:21) TATTGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCA AGTCGAACGGGGTGCTCATGACGGAGGATTCGTCCAACGGATTGAGTTACCTAGTG GCGGACGGGTGAGTAACGCGTGAGGAACCTGCCTTGGAGAGGGGGATAACACTCCG AAAGGAGTGCTAATACCGCATGATGCAGTTGGGTCGCATGGCTCTGACTGCCAAAG ATTTATCGCTCTGAGATGGCCTCGCGTCTGATTAGCTAGTAGGTGGGGTAACGGCCC ACCTAGGCGACGATCAGTAGCCGGACTGAGAGGTTGACCGGCCACATTGGGACTGA GACACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGGGCAATGGGCGC AAGCCTGACCCAGCAACGCCGCGTGAAGGAAGAAGGCTTTCGGGTTGTAAACTTCT TTTGTCAGGGACGAAACAAATGACGGTACCTGACGAATAAGCCACGGCTAACTACG TGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCGTTATCCGGATTTACTGGGTGTA AAGGGCGTGTAGGCGGGATTGCAAGTCAGATGTGAAAACTGGGGGCTCAACCTCCA GCCTGCATTTGAAACTGTAGTTCTTGAGTGCTGGAGAGGCAATCGGAATTCCGTGTG TAGCGGTGAAATGCGTAGATATACGGAGGAACACCAGTGGCGAAGGCGGATTGCTG GACAGTAACTGACGCTGAGGCGCGAAAGCGTGGGGAGCAAACAGGATTAGATACCC TGGTAGTCCACGCCGTAAACGATGGATACTAGGTGTGGGGGGTCTGACCCCCTCCGT GCCGCAGTTAACACAATAAGTATCCCACCTGGGGAGTACGATCGCAAGGTTGAAAC TCAAAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGTATGTGGTTTAATTCGAAG CAACGCGAAGAACCTTACCAGGGCTTGACATCCCACTAACGAAGCAGAGATGCATT AGGTGCCCTTCGGGGAAAGTGGAGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTC GTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATTGTTAGTTGCTACGC AAGAGCACTCTAGCGAGACTGCCGTTGACAAAACGGAGGAAGGTGGGGACGACGTC AAATCATCATGCCCCTTATGTCCTGGGCCACACACGTACTACAATGGTGGTTAACAG AGGGAGGCAAAACCGCGAGGTGGAGCAAATCCCTAAAAGCCATCCCAGTTCGGATT GCAGGCTGAAACCCGCCTGTATGAAGTTGGAATCGCTAGTAATCGCGGATCAGCAT GCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGTC GGGAACACCCGAAGTCCGTAGCCTAACCG NB2-A3NADorealongicatena (SEQIDNO:22) GCATGGTACAGTGGTAAAAACTCCGGTGGTATGAGATGGACCCGCGTCTGATTAGG TAGTTGGTGGGGTAACGGCCTACCAAGCCGACGATCAGTAGCCGACCTGAGAGGGT GACCGGCCACATTGGGACTGAGACACGGCCCAGACTCCTACGGGAGGCAGCAGTGG GGAATATTGCACAATGGAGGAAACTCTGATGCAGCGACGCCGCGTGAAGGATGAAG TATTTCGGTATGTAAACTTCTATCAGCAGGGAAGAAAATGACGGTACCTGACTAAGA AGCCCCGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTAT CCGGATTTACTGGGTGTAAAGGGAGCGTAGACGGCACGGCAAGCCAGATGTGAAAG CCCGGGGCTCAACCCCGGGACTGCATTTGGAACTGCTGAGCTAGAGTGTCGGAGAG GCAAGTGGAATTNCTAGTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAG TGGCGAAGGCGGCTTGCTGGACGATGACTGACGTTGAGGCTCGAAAGCGTGGGGAG CAAACAGGATTAGATACCCTGGTAGTCCACGCCGTAAACGATGACTGCTAGGTGTC GGGTGGCAAAGCCATTCGGTGCCGCAGCTAACGCAATAAGCAGTCCACCTGGGGAG TACGTTCGCAAGAATGAAACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGA GCATGTGGTTTAATTCGAAGCAACGCGAAGAACCTTACCTGATCTTGACATCCCGAT GACCGCTTCGTAATGGAAGNTTTTCTTCGGAACATCGGTGACAGGTGGTGCATGGTT GTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTA TCTTCAGTAGCCAGCAGGTTAAGCTGGGCACTCTGGAGAGACTGCCAGGGATAACC TGGAGGAAGGTGGGGATGACGTCAAATCATCATGCCCCTTATNACCAGGGCTACAC ACGTGCTACAATGGCGTAAACAAAGAGACGCGAACTCGCGAGGGTAAGCAAATCTC AAAAATAACGTCTCAGTTCGGATTGTAGTCTGCAACTCGACTACATGAAGCTGGAAT CGCTAGTAATCGCAGATCAGAATGCTGCGGTGAATACGTTCCCGGGTCTTGTACACA CCGCCCGTCACACCATGGGAGTCAGTAACGCCCGAAGTCAGTGACCCAACCGTAAG GAGGGAGCTGCCGAAGGTGGGACCGATAACTGGGGTGAAGTCGTAACAAGGTAGCC GTATCGGAAGGTGCGGCTGGATCACCTCCTTT NB2-A5TSABBlautiastercoris (SEQIDNO:23) TTCGCTTCCCTCTGTTTACGCCATTGTAGCACGTGTGTAGCCCAAATCATAAGGGGC ATGATGATTTGACGTCATCCCCACCTTCCTCCAGGTTATCCCTGGCAGTCTCCTCAGA GTGCCCACCATTACATGCTGGCTACTGGGGATAGGGGTTGCGCTCGTTGCGGGACTT AACCCAACATCTCACGACACGAGCTGACGACAACCATGCACCACCTGTCTTGCCTGT CCCGAAGGAAAGGTGACGTTACTCACCGGTCAGGCAGATGTCAAGACTTGGTAAGG TTCTTCGCGTTGCTTCGAATTAAACCACATGCTCCACCGCTTGTGCGGGTCCCCGTCA ATTCCTTTGAGTTTCATTCTTGCGAACGTACTCCCCAGGTGGAATACTTAATGCGTTT GCGGCGGCACCGAAGAGCTGTGCTCCCCGACACCTAGTATTCATCGTTTACGGCGTG GACTACCAGGGTATCTAATCCTGTTTGCTCCCCACGCTTTCGAGCCTCAACGTCAGTT ACCGTCCAGTAAGCCGCCTTCGCCACTGGTGTTCCTCCTAATATCTACGCATTTCACC GCTACACTAGGAATTCCGCTTACCCCTCCGGCACTCAAGCTTAACAGTTTCCAATGC AGTCCCGGGGTTAAGCCCCAGCCTTTCACATCAGACTTGTTATGCCGTCTACGCTCC CTTTACACCCAGTAAATCCGGATAACGCTTGCCCCCTACGTATTACCGCGGCTGCTG GCACGTAGTTAGCCGGGGCTTCTTAGTCAGGTACCGTCATTTTCTTCCCTGCTGATAG AAGTTTACATACCGAGATACTTCTTCCTTCACGCGGCGTCGCTGCATCAGGGTTTCCC CCATTGTGCAATATTCCCCACTGCTGCCTCCCGTAGGAGTCTGGGCCGTGTCTCAGT CCCAATGTGGCCGTTCACCCTCTCAGGCCGGCTATGGATCGTCGCTTTGGTAGGCCG TTACCCTGCCAACTGGCTAATCCAACGCGGGTCCATCTTATACCACCTCAGTTTTTCA CACCGGGCCATGCGGCCCTGTGCGCTTATGCGGTATTAGCAGCCATTTCTGACTGTT ATCCCCCTGTATAAGGCAGGTTACCCACGCGTTACTCACCCGTCCGCCACTAGGATT AAATCAAATCTGCCGAAGCTTCAATAAAATAATCCCCGTTCGACTTGCATGTGTTAA GCACGCCGCCAGCGTTCATCCTGAGCCAGGATCAAACTCTCTGATAAAGTTTGATGT CTCAAGACAACCAACTAGCTTAGTTATCTCTCGTCATTACTGTTTTAAAGTTCATTCT TCCGAATGTGATTGTAAAAGAATTTTCGAGAATCGTATGTGTTTCACTGTTTAGTTAT CAATGTTCATTGCTTTTTACTGTCTCTCGACAGCTTATTTACTTTACCACATCTTTTTT TGTTTGTCAACAACTTTTTTGAAGTTTTTCAAACTTTTTTTCCGAAGATGAAGTTTTGT CATCCGTGTTGACGACTTGACTACTTTATCATAGATAAGTCAGTTTGTCAACAGG NB2-B11FAABifidobacteriumlongum (SEQIDNO:24) GTGGAGGGTTCGATTCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCA AGTCGAACGGGATCCATCAGGCTTTGCTTGGTGGTGAGAGTGGCGAACGGGTGAGT AATGCGTGACCGACCTGCCCCATACACCGGAATAGCTCCTGGAAACGGGTGGTAAT GCCGGATGCTCCAGTTGATCGCATGGTCTTCTGGGAAAGCTTTCGCGGTATGGGATG GGGTCGCGTCCTATCAGCTTGACGGCGGGGTAACGGCCCACCGTGGCTTCGACGGG TAGCCGGCCTGAGAGGGCGACCGGCCACATTGGGACTGAGATACGGCCCAGACTCC TACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGCGCAAGCCTGATGCAGCGAC GCCGCGTGAGGGATGGAGGCCTTCGGGTTGTAAACCTCTTTTATCGGGGAGCAAGC GAGAGTGAGTTTACCCGTTGAATAAGCACCGGCTAACTACGTGCCAGCAGCCGCGG TAATACGTAGGGTGCAAGCGTTATCCGGAATTATTGGGCGTAAAGGGCTCGTAGGC GGTTCGTCGCGTCCGGTGTGAAAGTCCATCGCTTAACGGTGGATCCGCGCCGGGTAC GGGCGGGCTTGAGTGCGGTAGGGGAGACTGGAATTCCCGGTGTAACGGTGGAATGT GTAGATATCGGGAAGAACACCAATGGCGAAGGCAGGTCTCTGGGCCGTTACTGACG CTGAGGAGCGAAAGCGTGGGGAGCGAACAGGATTAGATACCCTGGTAGTCCACGCC GTAAACGGTGGATGCTGGATGTGGGGCCCGTTCCACGGGTTCCGTGTCGGAGCTAAC GCGTTAAGCATCCCGCCTGGGGAGTACGGCCGCAAGGCTAAAACTCAAAGAAATTG ACGGGGGCCCGCACAAGCGGCGGAGCATGCGGATTAATTCGATGCAACGCGAAGA ACCTTACCTGGGCTTGACATGTTCCCGACGGTCGTAGAGATACGGCTTCCCTTCGGG GCGGGTTCACAGGTGGTGCATGGTCGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTA AGTCCCGCAACGAGCGCAACCCTCGCCCCGTGTTGCCAGCGGATTATGCCGGGAAC TCACGGGGGACCGCCGGGGTTAACTCGGAGGAAGGTGGGGATGACGTCAGATCATC ATGCCCCTTACGTCCAGGGCTTCACGCATGCTACAATGGCCGGTACAACGGGATGCG ACGCGGCGACGCGGAGCGGATCCCTGAAAACCGGTCTCAGTTCGGATCGCAGTCTG CAACTCGACTGCGTGAAGGCGGAGTCGCTAGTAATCGCGAATCAGCAACGTCGCGG TGAATGCGTTCCCGGGCCTTGTACACACCGCCCGTCAAGTCATGAAAGTGGGCAGC ACCCGAAGCCGGTGGCCTAACCCCTTGTGGGATGGAGCCGTCTAAGGTGAGGCTCG TGATTGGGACTAAGTCGTAACAAGGTAGCCGTACCGGAAGGTGCGGCTGGATCACC TCCTTT NB2-A2FAACoprococcuscomes (SEQIDNO:25) GAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCAAGTC GAACGAAGCACCTGGATTTGATTCTTCGGATGAAGATCCTTGTGACTGAGTGGCGGA CGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATAACAGTTAGAAATG ACTGCTAATACCGCATAAGACCACAGGGTCGCATGACCTGGTGGGAAAAACTCCGG TGGTATGAGATGGACCCGCGTCTGATTAGGTAGTTGGTGGGGTAACGGCCTACCAA GCCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGACTGAGACAC GGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGAAACCC TGATGCAGCGACGCCGCGTGAGCGAAGAAGTATTTCGGTATGTAAAGCTCTATCAG CAGGGAAGAAAATGACGGTACCTGACTAAGAAGCACCGGCTAAATACGTGCCAGCA GCCGCGGTAATACGTATGGTGCAAGCGTTATCCGGATTTACTGGGTGTAAAGGGAG CGTAGACGGCTGTGTAAGTCTGAAGTGAAAGCCCGGGGCTCAACCCCGGGACTGCT TTGGAAACTATGCAGCTAGAGTGTCGGAGAGGTAAGTGGAATTCCCAGTGTAGCGG TGAAATGCGTAGATATTGGGAGGAACACCAGTGGCGAAGGCGGCTTACTGGACGAT GACTGACGTTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGGTAG TCCACGCCGTAAACGATGACTACTAGGTGTCGGGGAGCAAAGCTCTTCGGTGCCGC AGCAAACGCAATAAGTAGTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTCAAA GGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAACG CGAAGAACCTTACCTGCTCTTGACATCCCGGTGACCGGCATGTAATGATGCCTTTTC TTCGGAACACCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGT TGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCTTCAGTAGCCAGCATTTCGGGTG GGCACTCTGGAGAGACTGCCAGGGATAACCTGGAGGAAGGTGGGGATGACGTCAAA TCATCATGCCCCTTATGAGCAGGGCTACACACGTGCTACAATGGCGTAAACAAAGG GAAGCGAACCTGTGAGGGTAAGCAAATCTCAAAAATAACGTCTCAGTTCGGATTGT AGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATCAGCATGTC GCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTTGGT AACGCCCGAAGTCAGTGACTCAACCGTAAGGAGAGAGCTGCCGAAGGTGGGACCG ATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGATCAC CTCCTTT NB2-B6CNA[Eubacterium]eligens (SEQIDNO:26) TTCCTTAGAAAGGAGGTGATCCAGCCGCACCTTCCGATACGGCTACCTTGTTACGAC TTCACCCCAGTTATCAAACCTGCCTTCGGCGGCTCCTTCTTTCGTTAGGTCACCGACT TCGGGCATTTTCGACTCCCATGGTGTGACGGGCGGTGTGTACAAGACCCGGGAACGT ATTCACCGCAGCATTCTGATCTGCGATTACTAGCGATTCCAGCTTCATGTAGTCGAG TTGCAGACTACAATCCGAACTGAGACGTTATTTTTGTGATTTGCTTGGCCTCACGACT TCGCTTCACTTTGTTTACGCCATTGTAGCACGTGTGTAGCCCAAGTCATAAGGGGCA TGATGATTTGACGTCATCCCCACCTTCCTCCAGGTTATCCCTGGCAGTCTCCCTAGAG TGCCCATCTTACTGCTGGCTACTAAGGATAGGGGTTGCGCTCGTTGCGGGACTTAAC CCAACATCTCACGACACGAGCTGACGACAACCATGCACCACCTGTCTCCACTGTCCC GAAGGAAAGGACACATTACTGTCCGGTCAGTGGGATGTCAAGACTTGGTAAGGTTC TTCGCGTTGCTTCGAATTAAACCACATGCTCCACCGCTTGTGCGGGTCCCCGTCAATT CCTTTGAGTTTCATTCTTGCGAACGTACTCCCCAGGTGGAATACTTATTGCGTTTGCT GCGGCACCGAAGCCCTTATGGGCCCCGACACCTAGTATTCATCGTTTACGGCGTGGA CTACCAGGGTATCTAATCCTGTTTGCTCCCCACGCTTTCGAGCCTCAGTGTCAGTTAC AGTCCAGTGAGCCGCCTTCGCCACTGGTGTTCCTCCTAATATCTACGCATTTCACCGC TACACTAGGAATTCCACTCACCCCTCCTGCACTCCAGCCTTACAGTTTCAAAAGCAG TTCCGGGGTTGAGCCCCGGATTTTCACTTCTGACTTGCATGGCCACCTACACTCCCTT TACACCCAGTAAATCCGGATAACGCTTGCTCCATACGTATTACCGCGGCTGCTGGCA CGTATTTAGCCGGAGCTTCTTAGTCAGGTACCGTCACTATCTTCCCTGCTGATAGAGC TTTACATAACGAATTACTTCTTCACTCACGCGGCGTCGCTGCATCAGAGTTTCCTCCA TTGTGCAATATTCCCCACTGCTGCCTCCCGTAGGAGTCTGGGCCGTGTCTCAGTCCC AATGTGGCCGGTCACCCTCTCAGGTCGGCTACTGATCGTCGCCTTGGTGGGCTGTTA TCTCACCAACTAGCTAATCAGACGCGGGTCCATCTTATACCACCGGAGTTTTTCACA CCATGTCATGCAACATTGTGCGCTTATGCGGTATTACCAGCCGTTTCCAGCTGCTATC CCCCAGTACAAGGCAGGTTACCCACGCGTTACTCACCCGTCCGCCACTCAGTCATAA AGAACTTCAAACCGAAGTAATCCGTTCTAAATGCTTCGTTCGACTTGCATGTGTTAA GCACGCCGCCAGCGTTCATCCTGAGCCAGGATCAAACTCTCATA NB2-BAERMRS02Lactobacillusparacasei (SEQIDNO:27) CCAAGGCGATGATACGTAGCCGAACTGAGAGGTTGATCGGCCACATTGGGACTGAG ACACGGCCCAAACTCCTACGGGAGGCAGCAGTAGGGAATCTTCCACAATGGACGCA AGTCTGATGGAGCAACGCCGCGTGAGTGAAGAAGGCTTTCGGGTCGTAAAACTCTG TTGTTGGAGAAGAATGGTCGGCAGAGTAACTGTTGNCGNCGTGACGGTATCCAACC AGAAAGCCACGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCG TTATCCGGATTTATTGGGCGTAAAGCGAGCGCAGGCGGTTTTTTAAGTCTGATGTGA AAGCCCTCGGCTTAACCGAGGAAGCGCATCGGAAACTGGGAAACTTGAGTGCAGAA GAGGACAGTGGAACTCCATGTGTAGCGGTGAAATGCGTAGATATATGGAAGAACAC CAGTGGCGAAGGCGGCTGTCTGGTCTGTAACTGACGCTGAGGCTCGAAAGCATGGG TAGCGAACAGGATTAGATACCCTGGTAGTCCATGCCGTAAACGATGAATGCTAGGT GTTGGAGGGTTTCCGCCCTTCAGTGCCGCAGCTAACGCATTAAGCATTCCGCCTGGG GAGTACGACCGCAAGGTTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGT GGAGCATGTGGTTTAATTCGAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCTT TTGATCACCTGAGAGATCAGGTTTCCCCTTCGGGGGCAAAATGACAGGTGGTGCATG GTTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCC TTATGACTAGTTGCCAGCATTTAGTTGGGCACTCTAGTAAGACTGCCGGTGACAAAC CGGAGGAAGGTGGGGATGACGTCAAATCATCATGCCCCTTATGACCTGGGCTACAC ACGTGCTACAATGGATGGTACAACGAGTTGCGAGACCGCGAGGTCAAGCTAATCTC TTAAAGCCATTCTCAGTTCGGACTGTAGGCTGCAACTCGCCTACACGAAGTCGGAAT CGCTAGTAATCGCGGATCAGCACGCCGCGGTGAATACGTTCCCGGGCCTTGTACACA CCGCCCGTCACACCATGAGAGTTTGTAACACCCGAAGCCGGTGGCGTAACCCTTTTA GGGAGCGAGCCGTCTAAGGTGGGACAAATGATTAGGGTGAAGTCGTAACAAGGTAG CCGTAGGAGAACCTGCGGCTGGATCACCTCCTTT NB2-B13CNA[Clostridium]oroticum (SEQIDNO:28) CCTTAGAAAGGAGGTGATCCAGCCGCACCTTCCGATACGGCTACCTTGTTACGACTT CACCCCAGTTATCGGTCCCACCTTCGGCAGCTCCCTCCTTGCGGTTGGGTCACTGACT TCGGGCGTTACCAACTCCCATGGTGTGACGGGCGGTGTGTACAAGACCCGGGAACG TATTCACCGCGACATTCTGATTCGCGATTACTAGCGATTCCAGCTTCATGTAGTCGA GTTGCAGACTACAATCCGAACTGAGACGTTATTTTTGAGATTTGCTTACCCTCGCAG GCTCGCTTCCCTTTGTTTACGCCATTGTAGCACGTGTGTAGCCCTGCTCATAAGGGGC ATGATGATTTGACGTCATCCCCACCTTCCTCCAGGTTATCCCTGGCAGTCTCTCTAGA GTGCCCGGCCRWACCGCTGGCTACTAAAGATAGGGGTTGCGCTCGTTGCGGGACTT AACCCAACATCTCACGACACGAGCTGACGACAACCATGCACCACCTGTCATCCCTGT CCCGAAGGAAAGGCAACATTACTTGCCGGTCAGGGAGATGTCAAGAGCAGGTAAGG TTCTTCGCGTTGCTTCGAATTAAACCACATGCTCCACCGCTTGTGCGGGTCCCCGTCA ATTCCTTTGAGTTTCATTCTTGCGAACGTACTCCCCAGGTGGACTACTTATTGCGTTG GCTGCGGCACCGAATAGCTCTGCTACCCGACACCTAGTAGTCATCGTTTACGGCGTG GACTACCAGGGTATCTAATCCTGTTTGCTCCCCACGCTTTCGAGCCTCAACGTCAGT CATCGTCCAGCAAGCCGCCTTCGCCACTGGTGTTCCTCCTAATATCTACGCATTTCAC CGCTACACTAGGAATTCCACTTGCCTCTCCGACACTCTAGTTCGACAGTTTCCAATG CAGTCCCAGGGTTGAGCCCTGGCCTTTCACATCAGACTTGCCATACCGTCTACGCTC CCTTTACACCCAGTAAATCCGGATAACGCTTGCCCCCTACGTATTACCGCGGCTGCT GGCACGTAGTTAGCCGGGGCTTCTTAGTCAGGTACCGTCATTTTCTTCCCTGCTGATA GAAGTTTACATACCGAAATACTTCATCCTTCACGCGGCGTCGCTGCATCAGGGTTTC CCCCATTGTGCAATATTCCCCACTGCTGCCTCCCGTAGGAGTTTGGGCCGTGTCTCA GTCCCAATGTGGCCGGTCACCCTCTCAGGTCGGCTACTGATCGTCGCCTTGGTAGGC CGTTACCCCACCAACYAGCTAATCAGACGCGGGTCCATCTCATACCACCGGAGTTTT TACCCCTGCACCATGCGGTGCTGTGGTCTTATGCGGTATTAGCAGYCATTTCTAACT GTTATCCCCCTGTATGAGGCAGGTTACCCACGCGTTACTCACCCGTCCGCCACTCAG TCACAAAAGTCTTCATCCGAAGAATCAAACTTAAGTGCTTCGTTCGACTTGCATGTG TTAAGCACGCCGCCAGCGTTCATCCTGAGCCAGGATCAAACTCTCGT NB2-B15DCMDoreaformicigenerans (SEQIDNO:29) TTAAACGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATG CAAGTCGAGCGAAGCACTTAAGTTCGATTCTTCGGATGAAGACTTTTGTGACTGAGC GGCGGACGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATAACAGTTA GAAATGGCTGCTAATACCGCATAAGACCACAGTACTGCATGGTACAGTGGTAAAAA CTCCGGTGGTATGAGATGGACCCGCGTCTGATTAGGTAGTTGGTGAGGTAACGGCCC ACCAAGCCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGACTGA GACACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGCGA AAGCCTGATGCAGCGACGCCGCGTGAAGGATGAAGTATTTCGGTATGTAAACTTCTA TCAGCAGGGAAGAAAATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACGTGCC AGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGATTTACTGGGTGTAAAG GGAGCGTAGACGGCTGTGCAAGTCTGAAGTGAAAGGCATGGGCTCAACCTGTGGAC TGCTTTGGAAACTGTGCAGCTAGAGTGTCGGAGAGGTAAGTGGAATTCCTAGTGTAG CGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCGGCTTACTGGAC GATGACTGACGTTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGG TAGTCCACGCCGTAAACGATGACTGCTAGGTGTCGGGTAGCAAAGCTATTCGGTGCC GCAGCTAACGCAATAAGCAGTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTCA AAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAA CGCGAAGAACCTTACCTGATCTTGACATCCCGATGACCGCTTCGTAATGGAAGCTTT TCTTCGGAACATCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGAT GTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCTTCAGTAGCCAGCATTTAAGA TGGGCACTCTGGAGAGACTGCCAGGGATAACCTGGAGGAAGGTGGGGATGACGTCA AATCATCATGCCCCTTATGACCAGGGCTACACACGTGCTACAATGGCGTAAACAAA GGGAAGCAGAGCCGCGAGGCCGAGCAAATCTCAAAAATAACGTCTCAGTTCGGATT GTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCAGATCAGAAT GCTGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTC AGTAACGCCCGAAGTCAGTGACCCAACCGAAAGGAGGGAGCTGCCGAAGGTGGGA CCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGAT CACCTCCTTTCT NB2-BBHI1Escherichiacoli (SEQIDNO:30) ACGAGTGGCGGACGGGTGAGTAATGTCTGGGAAACTGCCTGATGGAGGGGGATAAC TACTGGAAACGGTAGCTAATACCGCATAACGTCGCAAGACCAAAGAGGGGGACCTT CGGGCCTCTTGCCATCGGATGTGCCCAGATGGGATTAGCTAGTAGGTGGGGTAACG GCTCACCTAGGCGACGATCCCTAGCTGGTCTGAGAGGATGACCAGCCACACTGGAA CTGAGACACGGTCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGG GCGCAAGCCTGATGCAGCCATGCCGCGTGTATGAAGAAGGCCTTCGGGTTGTAAAG TACTTTCAGCGGGGAGGAAGGGAGTAAAGTTAATACCTTTNCTCATTGACGTTACCC GCAGAAGAAGCACCGGCTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCA AGCGTTAATCGGAATTACTGGGCGTAAAGCGCACGCAGGCGGTTTGTTAAGTCAGA TGTGAAATCCCCGGGCTCAACCTGGGAACTGCATCTGATACTGGCAAGCTTGAGTCT CGTAGAGGGGGGTAGAATTCCAGGTGTAGCGGTGAAATGCGTAGAGATCTGGAGGA ATACCGGTGGCGAAGGCGGCCCCCTGGACGAAGACTGACGCTCAGGTGCGAAAGCG TGGGGAGCAAACAGGATTAGATACCCTGGTAGTCCACGCCGTAAACGATGTCGACT TGGAGGTTGTGCCCTTGAGGCGTGGCTTCCGGAGCTAACGCGTTAAGTCGACCGCCT GGGGAGTACGGCCGCAAGGTTAAAACTCAAATGAATTGACGGGGGCCCGCACAAGC GGTGGAGCATGTGGTTTAATTCGATGCAACGCGAAGAACCTTACCTGGTCTTGACAT CCACNGAANTTTNCAGAGATGAGAATGTGCCTTCGGGAACNGTGAGACAGGTGCTG CATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTGGGTTAAGTCCCGCAACGAGCGCA ACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGGAACTCAAAGGAGACTGCCAGTGA TAAACTGGAGGAAGGTGGGGATGACGTCAAGTCATCATGGCCCTTACGACCAGGGC TACACACGTGCTACAATGGCGCATACAAAGAGAAGCGACCTCGCGAGAGCAAGCGG ACCTCATAAAGTGCGTCGTAGTCCGGATTGGAGTCTGCAACTCGACTCCATGAAGTC GGAATCGCTAGTAATCGTGGATCAGAATGCCACGGTGAATACGTTCCCGGGCCTTGT ACACACCGCCCGTCACACCATGGGAGTGGGTTGCAAAAGAAGTAGGTAGCTTAACC TTCGGGAGGGCGCTTACCACTTTGTGATTCATGACTGGGGTGAAGTCGTAACAAGGT AACCGTAGGGGAACCTGCGGTTGGATCACCTCCTT NB2-B9DCMAnaerostipeshadrus (SEQIDNO:31) ATGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCAA GTCGAACGAAGCGCCTTATTTGATTTTCTTCGGAACTGAAGATTTGGTGACTGAGTG GCGGACGGGTGAGTAACGCGTGGGTAACCTGCCCTGTACAGGGGGATAACAATCAG AAATGACTGCTAATACCGCATAAGACCACAGCACCGCATGGTGCAGGGGTAAAAAC TCCGGTGGTACAGGATGGACCCGCGTCTGATTAGCTGGTTGGTGAGGTAACGGCTCA CCAAGGCGACGATCAGTAGCCGGCTTGAGAGAGTGAACGGCCACATTGGGACTGAG ACACGGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGGA ACCCTGATGCAGCGACGCCGCGTGAGTGAAGAAGTATTTCGGTATGTAAAGCTCTAT CAGCAGGGAAGAAAATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACGTGCCA GCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGAATTACTGGGTGTAAAGG GTGCGTAGGTGGTATGGCAAGTCAGAAGTGAAAACCCAGGGCTTAACTCTGGGACT GCTTTTGAAACTGTCAGACTGGAGTGCAGGAGAGGTAAGCGGAATTCCTAGTGTAG CGGTGAAATGCGTAGATATTAGGAGGAACATCAGTGGCGAAGGCGGCTTACTGGAC TGAAACTGACACTGAGGCACGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGG TAGTCCACGCCGTAAACGATGAATACTAGGTGTCGGGGCCGTAGAGGCTTCGGTGC CGCAGCCAACGCAATAAGTATTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTC AAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCA ACGCGAAGAACCTTACCTGGTCTTGACATCCTTCTGACCGGTCCTTAACCGGACCTT TCCTTCGGGACAGGAGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGA TGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATCTTTAGTAGCCAGCATTTAAG GTGGGCACTCTAGAGAGACTGCCAGGGATAACCTGGAGGAAGGTGGGGACGACGTC AAATCATCATGCCCCTTATGACCAGGGCTACACACGTGCTACAATGGCGTAAACAG AGGGAAGCAGCCTCGTGAGAGTGAGCAAATCCCAAAAATAACGTCTCAGTTCGGAT TGTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATCAGAAT GTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTC AGTAACGCCCGAAGTCAGTGACCCAACCGTAAGGAGGGAGCTGCCGAAGGCGGGA CCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGAT CACCTCCTTT NB2-B9FAABlautialuti (SEQIDNO:32) GTTGGTGGGGTAACGGCCCACCAAGGCGACGATCCATAGCCGGCCTGAGAGGGTGA ACGGCCACATTGGGACTGAGACACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGG AATATTGCACAATGGGGGAAACCCTGATGCAGCGACGCCGCGTGAAGGAAGAAGTA TCTCGGTATGTAAACTTCTATCAGCAGGGAAGATAGTGACGGTACCTGACTAAGAA GCCCCGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATC CGGATTTACTGGGTGTAAAGGGAGCGTAGACGGTGTGGCAAGTCTGATGTGAAAGG CATGGGCTCAACCTGTGGACTGCATTGGAAACTGTCATACTTGAGTGCCGGAGGGGT AAGCGGAATTCCTAGTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTG GCGAAGGCGGCTTACTGGACGGTAACTGACGTTGAGGCTCGAAAGCGTGGGGAGCA AACAGGATTAGATACCCTGGTAGTCCACGCCGTAAACGATGAATACTAGGTGTCGG GGAGCAAAGCTCTTCGGTGCCGTCGCAAACGCAGTAAGTATTCCACCTGGGGAGTA CGTTCGCAAGAATGAAACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGC ATGTGGTTTAATTCGAAGCAACGCGAAGAACCTTACCAAATCTTGACATCCCTCTGA CCGGTCTTTAATCGGACCTTCTCTTCGGAGCAGAGGTGACAGGTGGTGCATGGTTGT CGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATC CTCAGTAGCCAGCATTTAAGGTGGGCACTCTGGGGAGACTGCCAGGGATAACCTGG AGGAAGGCGGGGATGACGTCAAATCATCATGCCCCTTATGATTTGGGCTACACACGT GCTACAATGGCGTAAACAAAGGGAAGCGAGATCGTGAGATGGAGCAAATCCCAAA AATAACGTCCCAGTTCGGACTGTAGTCTGCAACCCGACTACACGAAGCTGGAATCG CTAGTAATCGCGGATCAGAATGCCGCGGTGAATACGTTCCCGGGTCTTGTACACACC GCCCGTCACACCATGGGAGTCAGTAACGCCCGAAGTCAGTGACCTAACTGCAAAGA AGGAGCTGCCGAAGGCGGGACCGATGACTGGGGTGAAGTCGTAACAAGGTAGCCGT ATCGGAAGGTGCGGCTGGATCAC NB2-A7D5[Clostridium]scindens (SEQIDNO:33) AACGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAACACATGCA AGTCGAACGAAGCGCTTCCGCCTGATTTTCTTCGGAGATGAAGGCGGCTGCGACTGA GTGGCGGACGGGTGAGTAACGCGTGGGCAACCTGCCTTGCACTGGGGGATAACAGC CAGAAATGGCTGCTAATACCGCATAAGACCGAAGCGCCGCATGGCGCAGCGGCCAA AGCCCCGGCGGTGCAAGATGGGCCCGCGTCTGATTAGGTAGTTGGCGGGGTAACGG CCCACCAAGCCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGAC TGAGACACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGG GGAAACCCTGATGCAGCGACGCCGCGTGAAGGATGAAGTATTTCGGTATGTAAACT TCTATCAGCAGGGAAGAAGATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACG TGCCAGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGATTTACTGGGTGT AAAGGGAGCGTAGACGGCGATGCAAGCCAGATGTGAAAGCCCGGGGCTCAACCCC GGGACTGCATTTGGAACTGCGTGGCTGGAGTGTCGGAGAGGCAGGCGGAATTCCTA GTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCGGCCTG CTGGACGATGACTGACGTTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATA CCCTGGTAGTCCACGCCGTAAACGATGACTACTAGGTGTCGGGTGGCAAGGCCATTC GGTGCCGCAGCAAACGCAATAAGTAGTCCACCTGGGGAGTACGTTCGCAAGAATGA AACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCG AAGCAACGCGAAGAACCTTACCTGATCTTGACATCCCGATGCCAAAGCGCGTAACG CGCTCTTTCTTCGGAACATCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTC GTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCCTATCTTCAGTAGCCAGCA TTCCGGATGGGCACTCTGGAGAGACTGCCAGGGACAACCTGGAGGAAGGTGGGGAT GACGTCAAATCATCATGCCCCTTATGACCAGGGCTACACACGTGCTACAATGGCGTA AACAAAGGGAGGCGAACCCGCGAGGGTGGGCAAATCCCAAAAATAACGTCTCAGTT CGGATTGTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATC AGAATGTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGG GAGTCAGTAACGCCCGAAGCCGGTGACCCAACCCGCAAGGGAGGGAGCCGTCGAA GGTGGGACCGATAACTGGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCG GCTGGATCACCTCCTTT NB2-B10MRSEubacteriumdesmolans (SEQIDNO:34) TTTAGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCCTAACACATGCA AGTCGAACGGAGTCGTTTTGGAAAATCCTTCGGGATTGGAATTCTCGACTTAGTGGC GGACGGGTGAGTAACGCGTGAGCAATCTGCCTTTAAGAGGGGGATAACAGTCGGAA ACGGCTGCTAATACCGCATAAAGCATTGAATTCGCATGTTTTCGATGCCAAAGGAGC AATCCGCTTTTAGATGAGCTCGCGTCTGATTAGCTAGTTGGTGGGGTAACGGCCCAC CAAGGCGACGATCAGTAGCCGGACTGAGAGGTTGAACGGCCACATTGGGACTGAGA CACGGCCCAGACTCCTACGGGAGGCAGCAGTGGGGAATATTGCGCAATGGGGGAAA CCCTGACGCAGCAACGCCGCGTGATTGAAGAAGGCCTTCGGGTTGTAAAGATCTTTA ATCAGGGACGAAAAATGACGGTACCTGAAGAATAAGCTCCGGCTAACTACGTGCCA GCAGCCGCGGTAATACGTAGGGAGCAAGCGTTATCCGGATTTACTGGGTGTAAAGG GCGCGCAGGCGGGCCGGCAAGTTGGAAGTGAAATCCGGGGGCTTAACCCCCGAACT GCTTTCAAAACTGCTGGTCTTGAGTGATGGAGAGGCAGGCGGAATTCCGTGTGTAGC GGTGAAATGCGTAGATATACGGAGGAACACCAGTGGCGAAGGCGGCCTGCTGGACA TTAACTGACGCTGAGGCGCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGGT AGTCCACGCCGTAAACGATGGATACTAGGTGTGGGAGGTATTGACCCCTTCCGTGCC GCAGTTAACACAATAAGTATCCCACCTGGGGAGTACGGCCGCAAGGTTGAAACTCA AAGGAATTGACGGGGGCCCGCACAAGCAGTGGAGTATGTGGTTTAATTCGAAGCAA CGCGAAGAACCTTACCAGGCCTTGACATCCCGATGACCGGCTTAGAGATAAGCCTTC TCTTCGGAGCATCGGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGAT GTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTACGGTTAGTTGATACGCAAGATCA CTCTAGCCGGACTGCCGTTGACAAAACGGAGGAAGGTGGGGACGACGTCAAATCAT CATGCCCCTTATGGCCTGGGCTACACACGTACTACAATGGCAGTCATACAGAGGGA AGCAAAATCGCGAGGTGGAGCAAATCCCTAAAAGCTGTCCCAGTTCAGATTGCAGG CTGCAACCCGCCTGCATGAAGTCGGAATTGCTAGTAATCGCGGATCAGCATGCCGC GGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCATGAGAGCCGTCAA TACCCGAAGTCCGTAGCCTAACCGCAAGGAGGGCGCGGCCGAAGGTAGGGGTGGTA ATTAGGGTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGATCACCTC CTTT NB2-B19DCMFaecalibacteriumprausnitzii (SEQIDNO:35) AGAAAGGAGGTGATCCAGCCGCAGGTTCTCCTACGGCTACCTTGTTACGACTTCACC CCAATCACCAGTTTTACCTTCGGCGGCGTCCTCCTTGCGGTTAGACTACCGACTTCG GGTCCCCCCGGCTCTCATGGTGTGACGGGCGGTGTGTACAAGGCCCGGGAACGTATT CACCGTGGCATGCTGATCCACGATTACTAGCAATTCCGACTTCGTGCAGGCGAGTTG CAGCCTGCAGTCCGAACTGGGACGTTGTTTCTGAGTTTTGCTCCACCTCGCGGTCTTG CTTCTCTTTGTTTAACGCCATTGTAGTACGTGTGTAGCCCAAGTCATAAAGGGCATG ATGATTTGACGTCATCCCCACCTTCCTCCGTTTTGTCAACGGCAGTCCTGCCAGAGTC CTCTTGCGTAGTAACTGACAGTAAGGGTTGCGCTCGTTGCGGGACTTAACCCAACAT CTCACGACACGAGCTGACGACAACCATGCACCACCTGTCTCCTTGCTCCGAAGAGA AAACATATTTCTATGTGCGTCGCAGGATGTCAAGACTTGGTAAGGTTCTTCGCGTTG CGTCGAATTAAACCACATACTCCACTGCTTGTGCGGGCCCCCGTCAATTCCTTTGAG TTTCAACCTTGCGGTCGTACTCCCCAGGTGGATTACTTATTGTGTTAACTGCGGCACT GAAGGGGTCAATCCTCCAACACCTAGTAATCATCGTTTACGGTGTGGACTACCAGGG TATCTAATCCTGTTTGCTACCCACACTTTCGAGCCTCAGCGTCAGTTGGTGCCCAGTA GGCCGCCTTCGCCACTGGTGTTCCTCCCGATATCTACGCATTCCACCGCTACACCGG GAATTCCGCCTACCTCTGCACTACTCAAGAAAAACAGTTTTGAAAGCAGTTTATGGG TTGAGCCCATAGATTTCACTTCCAACTTGTCTTCCCGCCTGCGCTCCCTTTACACCCA GTAATTCCGGACAACGCTTGTGACCTACGTTTTACCGCGGCTGCTGGCACGTAGTTA GCCGTCACTTCCTTGTTGAGTACCGTCATTATCTTCCTCAACAACAGGAGTTTACAAT CCGAAGACCTTCTTCCTCCACGCGGCGTCGCTGCATCAGGGTTTCCCCCATTGTGCA ATATTCCCCACTGCTGCCTCCCGTAGGAGTCTGGGCCGTGTCTCAGTCCCAATGTGG CCGTTCAACCTCTCAGTCCGGCTACCGATCGTTGCCTTGGTGGGCCATTACCTCACC AACTAGCTAATCGGACGCGAGGCCATCTCAAAGCGGATTGCTCCTTTTCCCTCTGGT CGATGCCGACCTGTGGGCTTATGCGGTATTAGCAGTCGTTTCCAACTGTTGTCCCCCT CTTTGAGGCAGGTTCCTCACGCGTTACTCACCCGTTCGCCACTCGCTYGAGAAAGCA AGCTCTCTCTCGCTCGTTCGACTTGCATGTGTTAGGCGCGCCGCCAGCGTTCGTCCTG AGCCAGGATCAAACTCTTTATAAA NB2-Al2BBEBacteroidesovatus (SEQIDNO:36) CCGTGTCTCAGTTCCAATGTGGGGGACCTTCCTCTCAGAACCCCTATCCATCGTTGTC TTGGTGGGCCGTTACCCCGCCAACAAACTAATGGAACGCATCCCCATCGATAACCG AAATTCTTTAATAGTAAAACCATGCGGTTTTAATATACCATCGGATATTAATCTTTCT TTCGAAAGGCTATCCCCGAGTTATCGGCAGGTTGGATACGTGTTACTCACCCGTGCG CCGGTCGCCATCTTTAGTTTGCAAGCAAACTAAAATGCTGCCCCTCGACTTGCATGT GTTAAGCCTGTAGCTAGCGTTCATCCTGAGCTATTAAAGAATTTCGGTTATCGATGG GGATGCGTTCCATTAGTTTGTTGGCGGGGTAACGGCCCACCAAGACAACGATGGAT AGGGGTTCTGAGAGGAAGGTCCCCCACATTGGAACTGAGACACGGTCCAAACTCCT ACGGGAGGCAGCAGTGAGGAATATTGGTCAATGGGCGAGAGCCTGAACCAGCCAA GTAGCGTGAAGGATGAAGGCTCTATGGGTCGTAAACTTCTTTTATATGGGAATAAAG TATTCCACGTGTGGAATTTTGTATGTACCATATGAATAAGGATCGGCTAACTCCGTG CCAGCAGCCGCGGTAATACGGAGGATCCGAGCGTTATCCGGATTTATTGGGTTTAAA GGGAGCGTAGGTGGATTGTTAAGTCAGTTGTGAAAGTTTGCGGCTCAACCGTAAAAT TGCAGTTGAAACTGGCAGTCTTGAGTACAGTAGAGGTGGGCGGAATTCGTGGTGTA GCGGTGAAATGCTTAGATATCACGAAGAACTCCGATTGCGAAGGCAGCTCACTAGA CTGTCACTGACACTGATGCTCGAAAGTGTGGGTATCAAACAGGATTAGATACCCTGG TAGTCCACACAGTAAACGATGAATACTCGCTGTTTGCGATATACAGTAAGCGGCCAA GCGAAAGCATTAAGTATTCCACCTGGGGAGTACGCCGGCAACGGTGAAACTCAAAG GAATTGACGGGGGCCCGCACAAGCGGAGGAACATGTGGTTTAATTCGATGATACGC GAGGAACCTTACCCGGGCTTAAATTGCATTTGAATAATCTGGAAACAGGTTAGCCGC AAGGCAAATGTGAAGGTGCTGCATGGTTGTCGTCAGCTCGTGCCGTGAGGTGTCGGC TTAAGTGCCATAACGAGCGCAACCCTTATCTTTAGTTACTAACAGGTTATGCTGAGG ACTCTAGAGAGACTGCCGTCGTAAGATGTGAGGAAGGTGGGGATGACGTCAAATCA GCACGGCCCTTACGTCCGGGGCTACACACGTGTTACAATGGGGGGTACAGAAGGCA GCTACCTGGCGACAGGATGCTAATCCCAAAAACCTCTCTCAGTTCGGATCGAAGTCT GCAACCCGACTTCGTGAAGCTGGATTCGCTAGTAATCGCGCATCAGCCATGGCGCG GTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCAAGCCATGAAAGCCGGGGG TACCTGAAGTACGTAACCGCAAGGAGCGTCCTAGGGTAAAACTGGTAATTGGGGCT NB2-A13NACoprococcuscatus (SEQIDNO:37) ATGAGAGTTTGATCCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCAA GTCGAACGGACGATGAAGAGCTTGCTTTTCAGAGTTAGTGGCGGACGGGTGAGTAA CGCGTGGGTAACCTGCCTCATACAGGGGGATAGCAGCTGGAAACGGCTGATAAAAC CGCATAAGCGCACAGCATCGCATGATGCAGTGTGAAAAACTCCGGTGGTATGAGAT GGACCCGCGTCTGATTAGCTGGTTGGTGAGGTAACGGCCCACCAAGGCGACGATCA GTAGCCGGCCTGAGAGGGTGACCGGCCACATTGGGACTGAGACACGGCCCAAACTC CTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGAAACCCTGATGCAGCGA CGCCGCGTGAAGGAAGAAGTATCTCGGTATGTAAACTTCTATCAGCAGGGAAGATA ATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACGTGCCAGCAGCCGCGGTAAT ACGTAGGGGGCAAGCGTTATCCGGATTTACTGGGTGTAAAGGGAGCGTAGGCGGCG GAGCAAGTCAGAAGTGAAAGCCCGGGGCTCAACCCCGGGACGGCTTTTGAAACTGC CCTGCTTGATTTCAGGAGAGGTAAGCGGAATTCCTAGTGTAGCGGTGAAATGCGTAG ATATTAGGAGGAACACCAGTGGCGAAGGCGGCTTACTGGACTGACAATGACGCTGA GGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGGTAGTCCACGCCGTAA ACGATGAATACTAGGTGTCGGGGCTCATAAGAGCTTCGGTGCCGCAGCAAACGCAA TAAGTATTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTCAAAGGAATTGACGG GGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAACGCGAAGAACCTT ACCAGGCCTTGACATCCCGGTGACCGTCCCGTAATGGGGACCTCTCTTCGGAGCACC GGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTC CCGCAACGAGCGCAACCCCTATGTTCAGTAGCCAGCAGGTAAAGCTGGGCACTCTG GACAGACTGCCGGGGATAACCCGGAGGAAGGCGGGGATGACGTCAAATCATCATGC CCCTTACGGCCTGGGCTACACACGTGCTACAATGGCGTAAACAAAGGGAAGCGAGA GGGTGACCTGGAGCGAATCCCAAAAATAACGTCCCAGTTCGGACTGTAGTCTGCAA CCCGACTACACGAAGCTGGAATCGCTAGTAATCGCGAATCAGCATGTCGCGGTGAA TACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTTGGAAATGCCCG AAGTCAGTGACCTAACCGCAAGGGAGGAGCTGCCGAAGGTGGAGCCGATGACTGGG GTGAAGTCGTAACAAGGTAGCCGTATCGGAAGGTGCGGCTGGATCACCTCCTTTCTA AGGAA NB2-B16TSABBifidobacteriumadolescentis (SEQIDNO:38) TGTGGAGGGTTCGATTCTGGCTCAGGATGAACGCTGGCGGCGTGCTTAACACATGCA AGTCGAACGGGATCCCAGGAGCTTGCTCCTGGGTGAGAGTGGCGAACGGGTGAGTA ATGCGTGACCGACCTGCCCCATACACCGGAATAGCTCCTGGAAACGGGTGGTAATG CCGGATGCTCCAGTTGACCGCATGGTCCTCTGGGAAAGCTTTTGCGGTATGGGATGG GGTCGCGTCCTATCAGCTTGATGGCGGGGTAACGGCCCACCATGGCTTCGACGGGTA GCCGGCCTGAGAGGGCGACCGGCCACATTGGGACTGAGATACGGCCCAGACTCCTA CGGGAGGCAGCAGTGGGGAATATTGCACAATGGGCGCAAGCCTGATGCAGCGACGC CGCGTGCGGGATGACGGCCTTCGGGTTGTAAACCGCTTTTGACTGGGAGCAAGCCCT TCGGGGTGAGTGTACCTTTCGAATAAGCACCGGCTAACTACGTGCCAGCAGCCGCG GTAATACGTAGGGTGCAAGCGTTATCCGGAATTATTGGGCGTAAAGGGCTCGTAGG CGGTTCGTCGCGTCCGGTGTGAAAGTCCATCGCTTAACGGTGGATCCGCGCCGGGTA CGGGCGGGCTTGAGTGCGGTAGGGGAGACTGGAATTCCCGGTGTAACGGTGGAATG TGTAGATATCGGGAAGAACACCAATGGCGAAGGCAGGTCTCTGGGCCGTCACTGAC GCTGAGGAGCGAAAGCGTGGGGAGCGAACAGGATTAGATACCCTGGTAGTCCACGC CGTAAACGGTGGATGCTGGATGTGGGGACCATTCCACGGTCTCCGTGTCGGAGCCA ACGCGTTAAGCATCCCGCCTGGGGAGTACGGCCGCAAGGCTAAAACTCAAAGAAAT TGACGGGGGCCCGCACAAGCGGCGGAGCATGCGGATTAATTCGATGCAACGCGAAG AACCTTACCTGGGCTTGACATGTTCCCGACAGCCCCAGAGATGGGGCCTCCCTTCGG GGCGGGTTCACAGGTGGTGCATGGTCGTCGTCAGCTCGTGTCGTGAGATGTTGGGTT AAGTCCCGCAACGAGCGCAACCCTCGCCCTGTGTTGCCAGCACGTCGTGGTGGGAA CTCACGGGGGACCGCCGGGGTCAACTCGGAGGAAGGTGGGGATGACGTCAGATCAT CATGCCCCTTACGTCCAGGGCTTCACGCATGCTACAATGGCCGGTACAACGGGATGC GACACCGCGAGGTGGAGCGGATCCCTTAAAACCGGTCTCAGTTCGGATTGGAGTCT GCAACCCGACTCCATGAAGGCGGAGTCGCTAGTAATCGCGGATCAGCAACGCCGCG GTGAATGCGTTCCCGGGCCTTGTACACACCGCCCGTCAAGTCATGAAAGTGGGTAGC ACCCGAAGCCGGTGGCCCAACCTTTTGGGGGGAGCCGTCTAAGGTGAGACTCGTGA TTGGGACTAAGTCGTAACAAGGTAGCCGTACCGGAAGGTGCGGCTGGATCACCTCC TTT NB2-B13DCMCollinsellaaerofaciens (SEQIDNO:39) CGGAGAGTTCGATCCTGGCTCAGGATGAACGCTGGCGGCGCGCCTAACACATGCAA GTCGAACGGCACCCACCTCCGGGTGGAAGCGAGTGGCGAACGGCTGAGTAACACGT GGAGAACCTGCCCCCTCCCCCGGGATAGCCGCCCGAAAGGACGGGTAATACCGGAT ACCCCGGGGTGCCGCATGGCACCCCGGCTAAAGCCCCGACGGGAGGGGATGGCTCC GCGGCCCATCAGGTAGACGGCGGGGTGACGGCCCACCGTGCCGACAACGGGTAGCC GGGTTGAGAGACCGACCGGCCAGATTGGGACTGAGACACGGCCCAGACTCCTACGG GAGGCAGCAGTGGGGAATCTTGCGCAATGGGGGGAACCCTGACGCAGCGACGCCGC GTGCGGGACGGAGGCCTTCGGGTCGTAAACCGCTTTCAGCAGGGAAGAGTCAAGAC TGTACCTGCAGAAGAAGCCCCGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTA GGGGGCGAGCGTTATCCGGATTCATTGGGCGTAAAGCGCGCGTAGGCGGCCCGGCA GGCCGGGGGTCGAAGCGGGGGGCTCAACCCCCCGAAGCCCCCGGAACCTCCGCGGC TTGGGTCCGGTAGGGGAGGGTGGAACACCCGGTGTAGCGGTGGAATGCGCAGATAT CGGGTGGAACACCGGTGGCGAAGGCGGCCCTCTGGGCCGAGACCGACGCTGAGGCG CGAAAGCTGGGGGAGCGAACAGGATTAGATACCCTGGTAGTCCCAGCCGTAAACGA TGGACGCTAGGTGTGGGGGGACGATCCCCCCGTGCCGCAGCCAACGCATTAAGCGT CCCGCCTGGGGAGTACGGCCGCAAGGCTAAAACTCAAAGGAATTGACGGGGGCCCG CACAAGCAGCGGAGCATGTGGCTTAATTCGAAGCAACGCGAAGAACCTTACCAGGG CTTGACATATGGGTGAAGCGGGGGAGACCCCGTGGCCGAGAGGAGCCCATACAGGT GGTGCATGGCTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAG CGCAACCCCCGCCGCGTGTTGCCATCGGGTGATGCCGGGAACCCACGCGGGACCGC CGCCGTCAAGGCGGAGGAGGGCGGGGACGACGTCAAGTCATCATGCCCCTTATGCC CTGGGCTGCACACGTGCTACAATGGCCGGTACAGAGGGATGCCACCCCGCGAGGGG GAGCGGATCCCGGAAAGCCGGCCCCAGTTCGGATTGGGGGCTGCAACCCGCCCCCA TGAAGTCGGAGTTGCTAGTAATCGCGGATCAGCATGCCGCGGTGAATGCGTTCCCGG GCCTTGTACACACCGCCCGTCACACCACCCGAGTCGTCTGCACCCGAAGTCGCCGGC CCAACCGTCAAGGGGGGAGGCGCCGAAGGTGTGGAGGGTGAGGGGGGTGAAGTCG TAACAAGGTAGCCGTACCGGAAGGTGCGGCTGGATCACCTCCTTT 14LGAcidaminococcusintestini (SEQIDNO:40) GACTTCACCCCAATCATNGGCCCCANTTAGACAGCTGACTCCTAAAAGGTTATCTCA CCGGCTTCGGGTGTTACCAACTTTCGTGGTGTGACGGGCGGTGTGTACAAGGCCCGG GAACGTATTCACCGCAGTATGCTGACCTGCGATTACTAGCGATTCCAACTTCACGTA GGCGGGTTGCAGCCTACGATCCGAACTGGGGTCGGGTTTCTGGGATTTGCTCCACCT CGCGGTTTCGCTGCCCTTTGTTGCCGACCATTGTAGTACGTGTGTAGCCCAAGACAT AAGGGGCATGATGACTTGACGTCATCCCCGCCTTCCTCCAAGTTATCCCTGGCAGTC TCCTATGAGTCCCCGCCTTTACGCGCTGGTAACATAGGATAGGGGTTGCGCTCGTTG CGGGACTTAACCCAACATCTCACGACACGAGCTGACGACAGCCATGCACCACCTGT TTTCGTGTCCCCGAAGGGAGGGACCTATCTCTAGGTCTTTCACTCAATGTCAAGCCTT GGTAAGGTTCTTCGCGTTGCGTCGAATTAAACCACATACTCCACCGCTTGTGCGGGC CCCCGTCAATTCCTTTGAGTTTCAATCTTGCGATCGTAGTCCCCAGGCGGGATACTTA TTGCGTTAACTCCGGCACAGAAGGGGTCGATACCTCCTACACCTAGTATCCATCGTT TACGGCCAGGACTACCGGGGTATCTAATCCCGTTTGCTACCCTGGCTTTCGCATCTC AGCGTCAGACACAGTCCAGAAAGGCGCCTTCGCCACTGGTGTTCCTCCCAATATCTA CGCATTTCACCGCTACACTGGGAATTCCCCTTTCCTCTCCTGCACTCAAGACTTCCAG TATCCAACGCCATACGGGGTTAAGCCCCGCATTTTCACGTCAGACTTAAAAGCCCGC CTACATGCTCTTTACGCCCAATAATTCCGGACAACGCTTGCCACCTACGTATTACCG CGGCTGCTGGCACGTAGTTAGCCGTGGCTTCCTCGTTAGGTACCGTCAACACCATGA CCTGTTCGAACACGGTGCTTTCGTCCCTAACAACAGAGTTTTACAATCCGAAGACCT TCATCACTCACGCGGCGTTGCTCCGTCAGACTTTCGTCCATTGCGGAAGATTCCCCA CTGCTGCCTCCCGTAGGAGTTTGGGCCGTGTCTCAGTCCCAATGTGGCCGTTCATCCT CTCAGACCGGCTACTGATCATCGCCTTGGTGAGCCGTTACCCCACCAACTAGCTAAT CAGACGCGGGCCCATCTTCCAGCGATAGCTTGCAAGCAGAGGCCATCTTTCCTCCCT CCTCCATGCGGAGGAGGGAGCACATTCGGTATTAGCATCCCTTTCGGAATGTTGTCC CCAACTGGAGGGCAGGTTGCCCACGCGTTACTCACCCGTTCGCCACTAAGAACTTAC CGAAATAAGTTCTCCGTTCGACTTGCATGTGTTAAGCACGCCGCCAGCGTTCGTCCT GAGCC