Composition for inducing beige cells

Abstract

The present invention addresses the problem of providing a composition, preparation, pharmaceutical composition, or food containing a bacterial strain capable of inducing beige cells in mammals including humans, and a method for inducing beige cells by administering the bacterial strain. In order to solve the above problem, the present invention provides the following. A composition comprising a bacterium having a DNA sequence having at least 90% identity with the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence having at least 90% identity with the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence having at least 90% identity with the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence having at least 90% identity with the sequence of SEQ ID NO: 30.

Description

Composition for inducing beige cells

[0001] It is known that the intestinal microflora influences the living body. Patent Document 1 shows that a composition containing a specific strain of bacteria induces regulatory T cells, and Patent Document 2 shows that a composition containing a specific strain of bacteria induces CD8 + It is disclosed that T cells are induced.

[0002] Beige cells, also known as beige adipocytes, are a type of fat cell that appear in white adipose tissue. They contain many mitochondria that express UCP1 (uncoupling protein 1), and are known to burn fat and generate heat. Beige cells are known to be effective in suppressing and preventing obesity. Beige cells are described in Non-Patent Documents 1 and 2.

[0003] Patent Document 3 discloses a method for achieving energy balance in a mammalian adipocyte system, which method discloses that a garcinol-containing composition is administered to recruit beige cells, and also discloses that the method includes a step of causing a change in the intestinal microbiota. However, the method of Patent Document 3 requires the administration of a garcinol-containing composition.

[0004] Non-Patent Document 3 discloses that FGF-21 induces browning of white adipocytes, but does not disclose anything about the intestinal microbiota.

[0005] Non-Patent Document 4 discloses that the amount of protein in the diet and environmental temperature are associated with the browning of white adipocytes. On the other hand, Non-Patent Document 4 does not disclose anything about the intestinal microbiota.

[0006] Japanese Patent No. 7165218 Japanese Patent No. 7104921 JP 2021-185156 A U.S. Patent No. 4205132 International Publication No. 2014 / 029578 International Publication No. 2012 / 098358

[0007] Journal of Japanese Biochemical Society 89(6):917-920 (2017)Ann Med. 47(2):133-41(2015)Frontiers in Physiology 10, article 37Genes and Nutritioin 14, article 19Gastroenterology 126:460-8(2004)Biochem Biophys Res Commun, 163(2): 1032-1037 (1989) Diabetes 55(5): 302-305(2012)

[0008] The inventors have discovered that activating beige cells is useful for preventing and suppressing obesity and obesity-related diseases. Furthermore, the inventors have discovered that the intestinal microbiota influences the body. Therefore, an objective of the present invention is to provide a composition, formulation, or pharmaceutical composition containing a bacterial strain capable of inducing beige cells, or a method for inducing beige cells by administering the bacterial strain in mammals, including humans.

[0009] To achieve the above object, the present invention provides the following: A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium of the genus Romboutsia. A composition comprising a bacterium of the genus Bilophila and a bacterium of the genus Romboutsia. A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. A composition comprising a bacterium of the genus Adlercreutzia, the genus Anaerofustis, the genus Bilophila, and the genus Romboutsia.

[0010] Administration of the strain in mammals, including humans, has enabled the induction of beige cells and the treatment, support, reduction of severity, and prevention of diseases such as obesity, type 2 diabetes, dyslipidemia, and NAFLD (non-alcoholic fatty liver disease).

[0011] (a) shows an example of an image obtained by FDG-PET. (b) shows the vertical axis representing SUV (18F-FDG uptake) and the horizontal axis representing each subject. The results of HE staining of iWAT are shown. (a)-(e) show the results for GF mice reared under AIN conditions, and (f)-(j) show the results for GF mice reared under LP conditions. (a) and (f) show the results for GF mice without feces, (b)(g) show the results for GF mice with T17 feces, (c)(h) show the results for GF mice with T10 feces, (d)(i) show the results for GF mice with T19 feces, and (e)(j) show the results for GF mice with T18 feces. The graph shows the expression of UCP1 in iWAT cells. The horizontal axis of the graph represents each group, and the vertical axis represents the expression level of UCP1 gene normalized by the expression level of Ppib gene. The two groups on the far left, labeled GF, were not colonized with feces. The two groups labeled GF+T17, GF+T10, GF+T19, and GF+T18 were colonized with fecal microorganisms from T17, T10, T19, and T18, respectively. The groups labeled "Control diet" and "LP diet" were colonized with fecal microorganisms from T17, T10, T19, and T18, respectively. HE staining of iWAT is shown. (a), (c), and (e) represent results from AIN-fed mice, and (b), (d), and (f) represent results from LP-fed mice. (a) and (b) represent GF mice without colonization, (c) and (d) represent GF mice colonized with 33 T19-derived strains, and (e) and (f) represent GF mice colonized with 33 T10-derived strains. UCP1 expression in iWAT cells is shown. The horizontal axis of the graph represents each group, and the vertical axis represents the expression level of the UCP1 gene normalized by the expression level of the Ppib gene. GF represents a group without any strains (control diet: reared under AIN conditions, LP diet: LP conditions). GF+T19-33mix represents a group with 33 T19-derived strains (control diet: reared under AIN conditions, LP diet: LP conditions). GF+T10-33mix represents a group with 33 T10-derived strains (control diet: reared under AIN conditions, LP diet: LP conditions). The graph shows the concentrations of bile acids in the blood of mice. (a) represents CA, (b) represents 7oxoCA, (c) represents UCA, and (d) represents CDCA.The vertical axis of the graph shows the concentration of each bile acid, and the horizontal axis shows each group. GF+AIN93G is a group of GF mice reared under AIN conditions without any strains being established, GF+LP is a group of GF mice reared under LP conditions without any strains being established, GF+AIN93G+T19_33mix is ​​a group of GF mice reared under AIN conditions with 33 T19-derived strains established, and GF+LP+T19_33mix is ​​a group of GF mice reared under LP conditions with 33 T19-derived strains established. GF mice were reared under AIN conditions (GF+AIN93G+T10_33mix), GF mice were reared under AIN conditions with 33 T10-derived strains (GF+LP+T10_33mix), GF mice were reared under LP conditions with 33 T10-derived strains (GF+AIN93G), SPF mice were reared under AIN conditions without any strains (SPF+AIN93G), and SPF mice were reared under LP conditions without any strains (SPF+LP). The horizontal axis of the graph indicates each mouse group, and the vertical axis indicates the expression level of UCP1 gene normalized by the expression level of Ppib gene. On the horizontal axis, GF FXR Het+AIN represents a group of FXR+ / - GF mice reared under AIN conditions without colonization with microbial strains, GF FXR KO+AIN represents a group of FXR- / - GF mice reared under AIN conditions without colonization with microbial strains, GF FXR Het+LP represents a group of FXR+ / - GF mice reared under LP conditions without colonization with microbial strains, GF FXR KO+LP represents a group of FXR- / - GF mice reared under LP conditions without colonization with microbial strains, GF FXR Het+AIN+T19_33mix represents a group of FXR+ / - GF mice reared under AIN conditions with colonization with 33 T19-derived strains, and GF FXR KO+AIN+T19_33mix represents a group of FXR- / - GF mice reared under AIN conditions with colonization with 33 T19-derived strains. Het+LP+T19_33mix is ​​a group of FXR+ / - GF mice colonized with T19-derived 33 strains and reared under LP conditions, while GF FXR KO+LP+T19_33mix is ​​a group of FXR- / - GF mice colonized with T19-derived 33 strains and reared under LP conditions. Results of HE staining of iWAT are shown. (a)(c)(e)(g) are results from mice reared under AIN conditions, and (b)(d)(f)(h) are results from mice reared under LP conditions.(a)(b) shows the results for GF mice without any strains, (c)(d) shows the results for GF mice with 33 T19-derived strains, (e)(f) shows the results for GF mice with 19 T19-derived strains, and (g)(h) shows the results for GF mice with the other 14 strains. The graph shows the expression of UCP1 in iWAT cells. The horizontal axis of the graph indicates each group, and the vertical axis indicates the expression level of UCP1 normalized by the expression level of Ppib gene. GF is a group without any strains (control diet: reared under AIN conditions, LP diet: LP conditions), GF+T19-33mix is ​​a group with 33 T19-derived strains (control diet: reared under AIN conditions, LP diet: LP conditions), GF+T19-19mix is ​​a group with 19 T19-derived strains (control diet: reared under AIN conditions, LP diet: LP conditions), and GF+T19-14mix is ​​a group with 14 other strains (control diet: reared under AIN conditions, LP diet: LP conditions). The horizontal axis of the graph shows each mouse group, and the vertical axis shows UCP1 expression normalized by Ppib expression. On the horizontal axis, GF +AIN93G is a group of GF mice reared under AIN conditions without bacterial colonization, GF +LP is a group of GF mice reared under LP conditions without bacterial colonization, GF +AIN93G+T19_all19mix is ​​a group of GF mice reared under AIN conditions with 19 T19-derived strains colonized, GF +LP+T19_all19mix is ​​a group of GF mice reared under LP conditions with 19 T19-derived strains colonized, GF +AIN93G+T19_Other5mix is ​​a group of GF mice reared under AIN conditions with 5 T19-derived strains colonized, GF +LP+T19_Other5mix is ​​a group of GF mice reared under LP conditions with 5 T19-derived strains colonized, GF +AIN93G+T19_BEE14mix is ​​a group of GF mice reared under AIN conditions with the BEE14 strain colonized, GF +LP+T19_BEE14mix is ​​a group of GF mice colonized with the BEE14 strain and raised under LP conditions. The four left columns show gene expression of 33 strains in T19-derived 33 gnotobiotic mice raised under AIN conditions, and the four right columns show gene expression of 33 strains in T19-derived 33 gnotobiotic mice raised under LP conditions.The upper panel shows genes whose expression was increased in mice reared under AIN conditions but decreased in those reared under LP conditions. The lower panel shows genes whose expression was decreased in mice reared under AIN conditions but increased in those reared under LP conditions. Enrichment analysis results for genes from 33 strains whose expression was increased in the intestines of 33 gnotobiotic mice reared under LP conditions compared to AIN conditions. The horizontal axis shows GeneRaio (number of differentially expressed genes registered in each metabolic pathway / total number of differentially expressed genes). Circle size indicates the number of genes, and color indicates significant differences. Genes related to nitrogen metabolism were enriched among the genetic group of 19 strains whose expression was increased. Enrichment analysis results for all genes from these five strains whose expression was increased in the intestines of five T19-derived gnotobiotic mice reared under LP conditions compared to AIN conditions. The horizontal axis shows GeneRaio (number of differentially expressed genes registered in each metabolic pathway / total number of differentially expressed genes). Circle size indicates the number of genes, and color indicates significant differences. The horizontal axis of the graph represents each group, and the vertical axis represents blood nitrite ion concentration. On the horizontal axis, GF +AIN93G represents a group of GF mice reared under AIN conditions without bacterial transplantation; GF +LP represents a group of GF mice reared under LP conditions without bacterial transplantation; GF +AIN93G+T19_33strains represents a group of GF mice colonized with T19-derived 33 strains and reared under AIN conditions; GF +LP+T19_33strains represents a group of GF mice colonized with T19-derived 33 strains and reared under LP conditions; and SPF+LP represents a group of SPF mice reared under LP conditions without bacterial transplantation. (a) shows the results of UCP1 measurement, and (b) shows the results of Evolv3 measurement. The six groups on the left of each graph were reared under AIN conditions, and the six groups on the right were reared under LP conditions. The group indicated as STD0.1% was administered 0.1% tungsten solution. The group labeled T19_19mix is ​​a group colonized with 19 strains derived from T19. The horizontal axis of the graph indicates the strain administered to each group, with + indicating administration of the strain T19-03, T19-04, T19-14, T19-29, or T19-31. The leftmost group is a group administered a control sample containing no strains.The second from the left is the group administered five strains: T19-03, T19-04, T19-14, T19-29, and T19-31. The vertical axis shows the expression level of the UCP1 gene normalized by the expression level of the Ppib gene. UCP1 expression in iWAT cells is shown. The horizontal axis of the graph shows the percentage of protein in the test diet fed to each group, and the vertical axis shows the expression level of the UCP1 gene normalized by the expression level of the Ppib gene. The horizontal axis of the graph shows the percentage of protein in the test diet fed to each group, and the vertical axis shows (a) the expression level of the UCP1 gene normalized by the expression level of the Ppib gene (b) the expression level of the ELOVL3 gene normalized by the expression level of the Ppib gene. The control diet is the control group. (a) UCP1 expression in iWAT cells. The horizontal axis of the graph indicates the type of mouse (GF or SPF), the type of diet (AIN diet or LP diet), and whether or not a β3 agonist was administered (β3 agonist or control PBS). The vertical axis indicates (a) the expression level of the UCP1 gene normalized by the expression level of the Ppib gene, and (b) the expression level of the ELOVL3 gene normalized by the expression level of the Ppib gene. The control diet is the control group. (a) The vertical axis indicates the concentration of each bile acid in SPF mice under the AIN diet, and the horizontal axis indicates the distribution of the concentration of each bile acid in SPF mice under the LP diet. (b) The vertical axis indicates the concentration of each bile acid in GF mice under the LP diet, and the horizontal axis indicates the distribution of the concentration of each bile acid in SPF mice under the LP diet. UCP1 expression in iWAT cells is shown. The vertical axis of the graph indicates the expression level of the UCP1 gene normalized by the expression level of the Ppib gene, and the horizontal axis indicates the mouse group. The horizontal axis shows, from left to right, a group of SPF mice reared under AIN conditions without bile acid administration, a group of SPF mice intraperitoneally administered with control PBS and fed a 10% protein diet, a group of SPF mice administered 50 μg of bile acids each and fed a 10% protein diet, and a group of SPF mice reared under LP conditions without intravenous administration. UCP1 expression in iWAT cells is shown. The vertical axis of the graph shows UCP1 gene expression normalized by Ppib gene expression, and the horizontal axis shows the mouse group. The horizontal axis shows, from left to right, the FXR+ / - group reared under AIN conditions, the FXR+ / - group reared under LP conditions, the FXR- / - group reared under AIN conditions, and the FXR- / - group reared under LP conditions.The graph shows UCP1 expression in liver cells. The vertical axis of the graph indicates the expression level of the UCP1 gene normalized by the expression level of the Ppib gene, and the horizontal axis indicates the mouse group. From left to right, the horizontal axis indicates GF mice reared under AIN conditions, GF mice reared under LP conditions, SPF mice reared under AIN conditions, and SPF mice reared under LP conditions. The graph shows the expression of (a) UCP1 or (b) Evolv1 in iWAT. The vertical axis of the graph indicates the expression level of the UCP1 gene normalized by the expression level of the Ppib gene, and the horizontal axis indicates the mouse group. From left to right, the horizontal axis indicates PPARα+ / + SPF mice reared under AIN conditions, PPARα+ / + SPF mice reared under LP conditions, PPARα- / - SPF mice reared under AIN conditions, and PPARα- / - SPF mice reared under LP conditions. (a) FGF21 expression in liver cells. The vertical axis indicates FGF21 gene expression normalized by Ppib gene expression, and the horizontal axis indicates the mouse group. From left to right, the horizontal axis indicates PPAR+ / - SPF mice reared under AIN conditions, PPAR+ / - SPF mice reared under LP conditions, PPAR- / - SPF mice reared under AIN conditions, and PPAR- / - SPF mice reared under LP conditions. (b) The vertical axis indicates blood FGF21 levels, and the horizontal axis indicates mouse groups. From left to right, the horizontal axis indicates PPAR+ / - SPF mice reared under AIN conditions, PPAR+ / - SPF mice reared under LP conditions, PPAR- / - SPF mice reared under AIN conditions, and PPAR- / - SPF mice reared under LP conditions. Metatranscriptome analysis of bacterial RNA extracted from cecal contents of GF mice colonized with 33 T19-derived strains and reared under AIN conditions (CD) or LP conditions (LPD) is shown. (a) shows the readout of the nrfA locus for T19_14 (Bilophila wadsworthia), and (b) for T19_03 (Adlercreutzia equolifaciens). The horizontal axis of the graph indicates the strain administered to each group, with + indicating administration of the strain T19-03, T19-04, T19-14, or T19-31. The leftmost group is administered a control sample containing no strains. The second from the left is the group administered the four strains T19-03, T19-04, T19-14, and T19-31. The vertical axis shows the expression level of the UCP1 gene normalized by the expression level of the Ppib gene.UCP1 expression in iWAT cells from GF mice reared under AIN (CD) or LP (LPD) conditions is shown. The horizontal axis of the graph indicates the bacterial strains used in each group. The bacterial strains used were a combination of NrfA-deficient (ΔNrfA) or wild-type (WT) T19-14 (Bilophila wadsworthia; Bilo) and T19-31 (Romboutsia timonensis; Rombo).

[0012] The embodiments included in the present invention will be described below.

[0013] First Embodiment This embodiment defines the four T19-derived strains and five T19-derived strains described below by the genera of the strains. As described below, each of these strain sets was derived from a human with a high beige cell population, and these humans possessed these strains. Furthermore, as described below, when these strain sets were established in GF (Germ-free) mice and the mice were fed a low-protein diet (LP diet) (raised under LP conditions), beige cells were induced. Hereinafter, feeding mice a low-protein diet (LP diet) may be referred to as "raised under LP conditions" or "raised under LP conditions," and feeding mice a normal diet (AIN diet) may be referred to as "raised under AIN conditions" or "raised under AIN conditions."

[0014] That is, the present embodiment provides the following: A composition for inducing beige cells, comprising bacteria of the genus Bilophila and bacteria of the genus Romboutsia; A composition for inducing beige cells, comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia.

[0015] A composition for inducing beige cells, comprising one or more bacteria selected from the group consisting of bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia.

[0016] A composition for inducing beige cells, comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, bacteria of the genus Parasutterella, and bacteria of the genus Romboutsia.

[0017] A composition for inducing beige cells, comprising one or more bacteria selected from the group consisting of bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, bacteria of the genus Parasutterella, and bacteria of the genus Romboutsia.

[0018] Bacteria of the genus Adlercreutzia include Adlercreutzia agrestimuris, Adlercreutzia aquisgranensis, Adlercreutzia caecimuris, Adlercreutzia caecimuris B7, Adlercreutzia equolifaciens, Adlercreutzia equolifaciens subsp. celatus, Adlercreutzia equolifaciens subsp. celatus DSM 18785, Adlercreutzia equolifaciens subsp. equolifaciens, Adlercreutzia equolifaciens DSM 19450, Adlercreutzia equolifaciens UC1_BHI_P, Adlercreutzia hattorii, Adlercreutzia mucosicola, Adlercreutzia mucosicola DSM 19490, Adlercreutzia murintestinalis, Adlercreutzia muris, Adlercreutzia rubneri, unclassified Adlercreutzia, Adlercreutzia sp., Adlercreutzia sp. DFI.6.23, Adlercreutzia sp. JBNU-10, Adlercreutzia sp. Marseille-P7992, Adlercreutzia sp. S45, Adlercreutzia sp. ZJ138, Adlercreutzia sp. ZJ141, Adlercreutzia sp. ZJ154, Adlercreutzia sp. ZJ176, Adlercreutzia sp. ZJ242, Adlercreutzia sp. ZJ304, Adlercreutzia sp. ZJ305, Adlercreutzia sp. ZJ473, and uncultured Adlercreutzia sp. can be mentioned.

[0019] Examples of bacteria of the genus Anaerofustis include Anaerofustis stercorihominis, Anaerofustis stercorihominis DSM 17244, Anaerofustis sp., Anaerofustis sp. DJF_B256, Anaerofustis sp. Marseille-P2832, Anaerofustis sp. NSJ-163, and uncultured Anaerofustis sp.

[0020] Examples of bacteria of the genus Bilophila include Bilophila wadsworthia, Bilophila wadsworthia 3_1_6, Bilophila wadsworthia AC2_8_11_AN_D5_FAA_1, Bilophila wadsworthia ATCC 49260, Candidatus Bilophila faecipullorum, Bilophila sp., Bilophila sp. 4_1_30, Bilophila sp. PS240, Bilophila sp. S375, and uncultured Bilophila sp.

[0021] Bacteria of the genus Romboutsia include Romboutsia faecis, Romboutsia hominis, Romboutsia ilealis, Romboutsia lituseburensis, Romboutsia lituseburensis DSM 797, Romboutsia maritimum, Romboutsia sedimentorum, Romboutsia timonensis, Romboutsia weinsteinii, [Clostridium] dakarense, Romboutsia sp., Romboutsia sp. 1001216B_150713_G3, Romboutsia sp. 1001216sp1, Romboutsia sp. 1001285H_161024_C4, Romboutsia sp. 1001713B170131_170501_G6, Romboutsia sp. 1001713B170207_170306_H8, Romboutsia sp. 13154, Romboutsia sp. 13368, Romboutsia sp. 13432, Romboutsia sp. BSD2780061687b_171204_C1, Romboutsia sp. CE17, Romboutsia sp. D33t1_170424_H2, Romboutsia sp. G12, Romboutsia sp. KF-2016-A, Romboutsia sp. LA1, Romboutsia sp. Marseille-P6047, Romboutsia sp. MT17, Romboutsia sp. Neferana2, Romboutsia sp. WB2567, Romboutsia sp. WB2916, and uncultured Romboutsia sp.

[0022] Examples of bacteria of the genus Parasutterella include Candidatus Parasutterella gallistercoris, Parasutterella excrementihominis, Parasutterella excrementihominis CAG:233, Parasutterella excrementihominis YIT 11859, Parasutterella muris, Parasutterella secunda, Parasutterella sp., Parasutterella sp. MC1, and uncultured Parasutterella sp. In this embodiment, bacteria of the genus Bilophila can be substituted with bacteria of the phylum Desulfobacterota, bacteria having an NrfA gene, or bacteria having a DNA sequence that is at least 90%, preferably 95%, identical to the sequence of SEQ ID NO: 240.

[0023] In the compositions of this embodiment or the second to eighth embodiments described below, the bacteria are preferably each strain, and the bacteria can be in a liquid form such as a suspension, a semi-solid form such as a paste, or a solid form such as a powder or tablet. When in a solid form, the bacteria can be freeze-dried. Methods known in the art can be used for freeze-drying. For example, Patent Documents 4, 5, and 6 can be referenced. Multiple types of bacteria can be freeze-dried in combination, or each type can be frozen and combined before administration.

[0024] Bacteria can be produced by culture and fermentation methods known in the art. For example, bacteria can be produced using an anaerobic fermenter. Examples of anaerobic fermenters include stirred tank reactors and disposable wave bioreactors. Culture media such as mGAM medium and EG medium, or similar media containing devoid of animal components, can be used for the culture. After culturing, the bacteria can be purified and concentrated from the culture medium by known methods such as centrifugation and filtration, and can be dried or lyophilized as needed.

[0025] <Second embodiment> This embodiment defines compositions each consisting of two T19-derived strains, four T19-derived strains, and five T19-derived strains, which will be described later, by the genus of the strain. That is, this embodiment provides the following:

[0026] A composition comprising bacteria of the genus Bilophila and bacteria of the genus Romboutsia. A composition comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia. In this specification, a "composition comprising a plurality of bacteria" refers to a composition substantially consisting of these bacteria, and the composition may contain, for example, substances derived from the culture medium, salts, and other substances, as long as the effects of the present invention are not impaired.

[0027] A composition comprising bacteria of the genus Bilophila and bacteria of the genus Romboutsia.A composition comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia.

[0028] A composition comprising one or more bacteria selected from the group consisting of bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia. Note that, as used herein, a composition comprising one or more bacteria selected from a group consisting of a plurality of bacteria means a composition substantially consisting of one or more bacteria selected from the group consisting of these bacteria, and the composition may contain, for example, substances derived from the culture medium, salts, and other substances within the scope that does not impair the effects of the present invention.

[0029] A composition comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, bacteria of the genus Parasutterella, and bacteria of the genus Romboutsia.

[0030] A composition comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, bacteria of the genus Parasutterella, and bacteria of the genus Romboutsia.

[0031] A composition comprising one or more bacteria selected from the group consisting of bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, bacteria of the genus Parasutterella, and bacteria of the genus Romboutsia. In this embodiment, the bacteria of the genus Bilophila can be replaced with bacteria of the phylum Desulfobacterota, bacteria having an NrfA gene, or bacteria having a DNA sequence having at least 90%, preferably 95%, identity to the sequence of SEQ ID NO: 240.

[0032] <Third Embodiment> The compositions of this embodiment are defined by the bacterial species of the T19-derived 2 strains, T19-derived 4 strains, T19-derived 5 strains, T19-derived 19 strains, and T19-derived 33 strains described below. As described below, each of these strain sets is derived from a human with a large number of beige cells, and these humans with a large number of beige cells possess these bacterial strains. Furthermore, as described below, when these strain sets are colonized in GF mice and the mice are raised under LP conditions, beige cells are induced. That is, this embodiment provides the following: A composition for inducing beige cells, comprising Bilophila wadsworthia and Romboutsia timonensis.

[0033] A composition for inducing beige cells comprising Adlercreutzia equolifaciens, Anaerofustis stercorihominis, Bilophila wadsworthia, and Romboutsia timonensis.

[0034] A composition for inducing beige cells, comprising one or more bacteria selected from the group consisting of Adlercreutzia equolifaciens, Anaerofustis stercorihominis, Bilophila wadsworthia, and Romboutsia timonensis.

[0035] Alternatively, the present embodiment provides the following: a composition for inducing beige cells, comprising Bilophila wadsworthia, Parasutterella excrementihominis, and Romboutsia timonensis; a composition for inducing beige cells, comprising Adlercreutzia equolifaciens, Anaerofustis stercorihominis, Bilophila wadsworthia, Parasutterella excrementihominis, and Romboutsia timonensis.

[0036] A composition for inducing beige cells, comprising one or more bacteria selected from the group consisting of Adlercreutzia equolifaciens, Anaerofustis stercorihominis, Bilophila wadsworthia, Parasutterella excrementihominis, and Romboutsia timonensis.

[0037] Alternatively, the present embodiment provides the following: a composition for inducing beige cells, comprising Thomasclavelia spiroformis, Adlercreutzia equolifaciens subsp. celatus, Anaerofustis stercorihominis, Bacteroides fragilis, Bacteroides ovatus, Bacteroides uniformis, Phocaeicola dorei, Bacteroides stercoris, Bacteroides thetaiotaomicron, Phocaeicola vulgatus, Bilophila wadsworthia, Clostridium innocuum, Coprobacillus cateniformis, Enterococcus hirae, Enterococcus gallinarum, Thomasclavelia ramosa, Parasutterella excrementihominis, Romboutsia timonensis, and Bacteroides xylanisolvens.

[0038] Alternatively, the present embodiment provides the following. Thomasclavelia spiroformis, Clostridium transplantifaecale, Adlercreutzia equolifaciens subsp.celatus, Anaerofustis stercorihominis, Anaerostipes caccae, Anaerotruncus colihominis, Bacteroides fragilis, Bacteroides ovatus, Bacteroides uniformis, Phocaeicola dorei, Bacteroides stercoris, Bacteroides thetaiotaomicron, Phocaeicola vulgatus, Bilophila wadsworthia, Agathobaculum desmolans, Clostridium phoceensis, [Clostridium] innocuum, Coprobacillus cateniformis, Eisenbergiella massiliensis, Enterococcus hirae, Enterococcus gallinarum, Thomasclavelia ramosa, Extibacter and a composition for inducing beige cells, comprising: Bacillus subtilis, Flavonifractor plautii, Fournierella massiliensis, Hungatella hathewayi, Hungatella hathewayi, Parasutterella excrementihominis, Coprococcus phoceensis, Romboutsia timonensis, Ruthenibacterium lactatiformans, Bacteroides xylanisolvens, and Blautia coccoides. In this embodiment, Bilophila wadsworthia can be substituted with bacteria of the phylum Desulfobacterota, bacteria having an NrfA gene, or bacteria having a DNA sequence that is at least 90%, preferably 95%, identical to the sequence of SEQ ID NO: 240.

[0039] <Fourth embodiment> The compositions of this embodiment are defined by the bacterial species considered to be the same, and each of the compositions comprises 4 T19-derived strains, 5 T19-derived strains, 19 T19-derived strains, and 33 T19-derived strains, which will be described later. That is, this embodiment provides the following.

[0040] A composition comprising Bilophila wadsworthia, and Romboutsia timonensis.A composition comprising Adlercreutzia equolifaciens, Anaerofustis stercorihominis, Bilophila wadsworthia, and Romboutsia timonensis.

[0041] A composition comprising Bilophila wadsworthia, and Romboutsia timonensis.A composition comprising Adlercreutzia equolifaciens, Anaerofustis stercorihominis, Bilophila wadsworthia, and Romboutsia timonensis.

[0042] A composition comprising one or more bacteria selected from the group consisting of Adlercreutzia equolifaciens, Anaerofustis stercorihominis, Bilophila wadsworthia, and Romboutsia timonensis.

[0043] Alternatively, the present embodiment provides the following: a composition consisting of Adlercreutzia equolifaciens, Anaerofustis stercorihominis, Bilophila wadsworthia, Parasutterella excrementihominis, and Romboutsia timonensis.

[0044] A composition comprising Adlercreutzia equolifaciens, Anaerofustis stercorihominis, Bilophila wadsworthia, Parasutterella excrementihominis and Romboutsia timonensis.

[0045] A composition comprising one or more bacteria selected from the group consisting of Adlercreutzia equolifaciens, Anaerofustis stercorihominis, Bilophila wadsworthia, Parasutterella excrementihominis, and Romboutsia timonensis.

[0046] Alternatively, this embodiment provides the following. Thomasclavelia spiroformis, Adlercreutzia equolifaciens subsp.celatus, Anaerofustis stercorihominis, Bacteroides fragilis, Bacteroides ovatus, Bacteroides uniformis, Phocaeicola dorei, Bacteroides stercoris, Bacteroides thetaiotaomicron, Phocaeicola vulgatus, Bilophila A composition comprising wadsworthia, [Clostridium] innocuum, Coprobacillus cateniformis, Enterococcus hirae, Enterococcus gallinarum, Thomasclavelia ramosa, Parasutterella excrementihominis, Romboutsia timonensis, and Bacteroides xylanisolvens.

[0047] Alternatively, the present embodiment provides the following. Thomasclavelia spiroformis, Clostridium transplantifaecale, Adlercreutzia equolifaciens subsp.celatus, Anaerofustis stercorihominis, Anaerostipes caccae, Anaerotruncus colihominis, Bacteroides fragilis, Bacteroides ovatus, Bacteroides uniformis, Phocaeicola dorei, Bacteroides stercoris, Bacteroides thetaiotaomicron, Phocaeicola vulgatus, Bilophila wadsworthia, Agathobaculum desmolans, Clostridium phoceensis, [Clostridium] innocuum, Coprobacillus cateniformis, Eisenbergiella massiliensis, Enterococcus hirae, Enterococcus gallinarum, Thomasclavelia ramosa, Extibacter A composition comprising: Bacillus subtilis, Flavonifractor plautii, Fournierella massiliensis, Hungatella hathewayi, Hungatella hathewayi, Parasutterella excrementihominis, Coprococcus phoceensis, Romboutsia timonensis, Ruthenibacterium lactatiformans, Bacteroides xylanisolvens, and Blautia coccoides. In this embodiment, Bilophila wadsworthia can also be substituted with bacteria of the phylum Desulfobacterota, bacteria having an NrfA gene, or bacteria having a DNA sequence that is at least 90%, preferably 95%, identical to the sequence of SEQ ID NO: 240.

[0048] Fifth Embodiment In this embodiment, the T19-derived strains 2, 4, 5, 19, and 33 described below are defined by the DNA sequences corresponding to the 16rSRNA of the bacterial species identified as the same. SEQ ID NOs: 34 to 64 are the DNA sequences corresponding to the 16rSRNA of each of the species identified as strains T19-1 to T19-33, as described below. That is, this embodiment provides the following:

[0049] A composition for inducing beige cells, comprising a bacterial strain having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. A composition for inducing beige cells, comprising a bacterial strain having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterial strain having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterial strain having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.

[0050] A composition for inducing beige cells, comprising one or more bacteria selected from the group consisting of a bacterial strain having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 36, a bacterial strain having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 37, a bacterial strain having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 62.

[0051] Alternatively, this embodiment provides the following: a composition for inducing beige cells, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 60, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.

[0052] A composition for inducing beige cells, comprising one or more bacteria selected from the group consisting of bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 60, and bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.

[0053] Alternatively, this embodiment provides the following: a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 34, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 40, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 41, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 42, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 43, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 44, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 45, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 46. A composition for inducing beige cells, comprising a bacterium having sequence A, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 50, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 51, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 53, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 54, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 55, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 60, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 64.

[0054] Alternatively, the present embodiment provides the following: A composition for inducing beige cells, comprising a bacterium having a DNA sequence having at least 90% identity to each of the sequences of SEQ ID NOs: 34 to 65.

[0055] In this embodiment, the identity of at least 90% is more preferably at least 91%, more preferably at least 95%, more preferably at least 97%, more preferably at least 97.5%, and more preferably completely identical. Each bacterium is preferably a strain. In this embodiment, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 can be substituted for a bacterium of the Desulfobacterota phylum, a bacterium having an NrfA gene, or a bacterium having a DNA sequence at least 90%, preferably 95%, identical to the sequence of SEQ ID NO: 240.

[0056] Sixth Embodiment In this embodiment, compositions consisting of 2 T19-derived strains, 4 T19-derived strains, 5 T19-derived strains, 19 T19-derived strains, and 33 T19-derived strains, which will be described later, are defined by DNA sequences corresponding to the 16rSRNA of the bacterial species considered to be the same.

[0057] A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.

[0058] A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.

[0059] A composition comprising one or more bacteria selected from the group consisting of bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 36, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 37, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 47, and bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 62.

[0060] Alternatively, this embodiment provides the following: a composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 60, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.

[0061] A composition comprising a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 47, a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 60, and a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 62.

[0062] A composition comprising one or more bacteria selected from the group consisting of bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 36, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 37, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 47, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 60, and bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 62.

[0063] Alternatively, this embodiment provides a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 34, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 40, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 41, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 42, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 43, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 44, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 45, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 46 a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 47, a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 50, a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 51, a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 53, a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 54, a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 55, a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 60, a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 62, and a composition comprising: a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 64.

[0064] Alternatively, this embodiment provides the following: A composition comprising a bacterium having a DNA sequence that has at least 90% identity to each of the sequences of SEQ ID NOs: 34 to 65.

[0065] In this embodiment, the identity of at least 90% is more preferably at least 91%, more preferably at least 95%, more preferably at least 97%, more preferably at least 97.5%, and more preferably completely identical. Each bacterium is preferably a strain. In this embodiment, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 can be substituted for a bacterium of the Desulfobacterota phylum, a bacterium having an NrfA gene, or a bacterium having a DNA sequence at least 90%, preferably 95%, identical to the sequence of SEQ ID NO: 240.

[0066] Seventh Embodiment This embodiment is defined by the 16rSRNA sequences of the T19-derived 2 strains, T19-derived 4 strains, T19-derived 5 strains, T19-derived 19 strains, and T19-derived 33 strains described below. SEQ ID NOs: 1 to 33 are DNA sequences corresponding to the 16rSRNA of each of the strains T19-1 to T19-33, as described below. That is, this embodiment provides the following:

[0067] A composition for inducing beige cells, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. A composition for inducing beige cells, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30.

[0068] Alternatively, this embodiment provides the following: a composition for inducing beige cells, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO:3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO:4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO:14, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO:28, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO:30.

[0069] A composition for inducing beige cells comprising bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 28, and bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30.

[0070] A composition for inducing beige cells, comprising one or more bacteria selected from the group consisting of bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 28, and bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30.

[0071] Alternatively, this embodiment provides the following: a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 1, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 7, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 8, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 9, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 10, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 11, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 12, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 13. a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 14, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 17, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 18, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 20, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 21, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 22, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 28, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 30, and a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 32.

[0072] Alternatively, the present embodiment provides the following: A composition for inducing beige cells, comprising a bacterium having a DNA sequence having at least 90% identity to each of the sequences of SEQ ID NOs: 1 to 33.

[0073] In this embodiment, the identity of at least 90% is more preferably at least 91% for all sequences, more preferably at least 95% for all sequences, more preferably at least 97% for all sequences, more preferably at least 97.5% for all sequences, and more preferably completely identical for all sequences. Each bacterium is preferably a bacterial strain. In this embodiment, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 can be substituted for a bacterium of the Desulfobacterota phylum, a bacterium having an NrfA gene, or a bacterium having a DNA sequence at least 90%, preferably 95%, identical to the sequence of SEQ ID NO: 240.

[0074] Eighth Embodiment This embodiment provides compositions comprising two T19-derived strains, four T19-derived strains, five T19-derived strains, 19 T19-derived strains, and 33 T19-derived strains, which are defined by the DNA sequences corresponding to the 16rSRNA of the strains.

[0075] A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30.

[0076] A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30.

[0077] A composition comprising one or more bacteria selected from the group consisting of bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 3, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 4, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 14, and bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 30.

[0078] Alternatively, this embodiment provides the following: a composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO:3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO:4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO:14, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO:28, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO:30.

[0079] A composition comprising a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO:3, a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO:4, a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO:14, a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO:28, and a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO:30.

[0080] A composition comprising one or more bacteria selected from the group consisting of bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 3, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 4, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 14, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 28, and bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 30.

[0081] Alternatively, this embodiment provides the following: a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 1, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 7, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 8, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 9, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 10, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 11, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 12, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 13, A composition comprising a bacterium having sequence A, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 14, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 17, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 18, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 20, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 21, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 22, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 28, a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 30, and a bacterium having a DNA sequence at least 90% identical to SEQ ID NO: 32.

[0082] Alternatively, this embodiment provides the following: A composition comprising a bacterium having a DNA sequence that has at least 90% identity to each of the sequences of SEQ ID NOs: 1 to 33.

[0083] In this embodiment, the identity of at least 90% is more preferably at least 91% for all sequences, more preferably at least 95% for all sequences, more preferably at least 97% for all sequences, more preferably at least 97.5% for all sequences, and more preferably completely identical for all sequences. Each bacterium is preferably a bacterial strain. In this embodiment, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 can be substituted for a bacterium of the Desulfobacterota phylum, a bacterium having an NrfA gene, or a bacterium having a DNA sequence at least 90%, preferably 95%, identical to the sequence of SEQ ID NO: 240.

[0084] <Ninth embodiment> This embodiment provides a composition comprising any one of the compositions described in embodiments 1 to 8 and a pharmaceutically acceptable excipient or food additive. In the composition of this embodiment or the pharmaceutical composition of the tenth embodiment described below, the number of bacteria in the composition or pharmaceutical composition is 10 or more, 10 or less, or 2 That's it, 10 3 That's it, 10 4 That's it, 10 5 That's it, 10 6 That's it, 10 7 That's it, 10 8 That's it, 10 9 That's it, 10 10 That's it, 10 11 That's it, 10 12 or more, while the number of each bacterium can be 10 13 Below, 10 12 Below, 10 11 Below, 10 10 Below, 10 9 Below, 10 8 Below, 10 7 Below, 10 6 Below, 10 5 Below, 10 4 Below, 10 3Below, 10 2 Preferably, the number of bacteria administered per day is 10 per kg of body weight or less. 7 ~10 12 The number of bacteria in the composition is (1 x 10^7 to 1 x 10^12). Because bacteria can survive and grow in the intestines, it is possible to expect bacteria to grow in the intestines by reducing the number of bacteria in the composition.

[0085] The composition or pharmaceutical composition may contain a pharmaceutically acceptable excipient or food additive. Examples of excipients and food additives include sterilized water, physiological saline, solvents, bases, emulsifiers, suspending agents, surfactants, stabilizers, flavorings, fragrances, excipients, vehicles, preservatives, binders, diluents, isotonicity agents, soothing agents, bulking agents, disintegrants, buffers, coating agents, lubricants, coloring agents, sweeteners, thickeners, and solubilizers. The composition or pharmaceutical composition may further contain a carrier or stabilizer. Examples of carriers and stabilizers include buffers, antioxidants, preservatives, polymers, chelating agents, and surfactants. The form of the pharmaceutical composition is not particularly limited, and examples include capsules, tablets, pills, sachets, liquids, powders, granules, fine granules, film-coated preparations, pellets, troches, sublingual preparations, chewable tablets, buccal preparations, pastes, syrups, and suspensions. However, the composition or pharmaceutical composition is not limited to these and may include any substance that can be used for administration to humans or mammals, as long as it does not interfere with obtaining the effects of the present invention.

[0086] The composition, or pharmaceutical composition, is preferably prepared or formulated for delivery to the intestine, including the large intestine, small intestine, or colon, and is preferably formulated for oral administration or formulated for rectal administration.

[0087] When formulated for oral administration, the pharmaceutical composition is preferably formulated with an enteric coating to ensure that the bacteria survive passage through the stomach and are delivered to the intestine. Formulations for rectal administration include preparations or formulations for delivery via suppository, colonoscopy, endoscopy, sigmoidoscopy, or enema. To enable effective delivery to the intestine, the pharmaceutical composition may contain, for example, a pH-sensitive composition, an enteric coating, etc. When a pH-sensitive composition is used, the sensitive pH threshold can be, for example, about 6.8 to about 7.5, the range in which the pH in the stomach shifts to alkaline distally. Examples of enteric coatings include those that dissolve upon contact with intestinal fluid, and can be based on polymers known in the art, such as hypromellose phthalate ceracephate and methacrylic acid copolymer. For delivery to the intestine, e.g., the colon, the pharmaceutical composition may be formulated as a delayed-release formulation that delays release of the contents for up to several hours after administration. For delayed release, methods known in the art can be used, such as forming a shell structure or coating using a hydrogel, an in vivo degradable polymer, a slowly hydrating polymer, a slowly water-soluble polymer, an enzymatically degradable polymer, or the like.

[0088] The dosage of the active ingredient in the composition, or pharmaceutical composition, can be varied to obtain an amount of the active ingredient that is effective to achieve the desired pharmaceutical response without being toxic or having side effects to the subject.

[0089] <Tenth Embodiment> This embodiment provides a pharmaceutical composition or food for treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, which contains any of the compositions described in Embodiments 1 to 8 as an active ingredient.

[0090] Beige cells are known to be effective in suppressing and preventing obesity, as shown in Non-Patent Document 1, etc. Obesity refers to a state in which one's weight is heavy relative to one's height, and in this specification, it includes, without any particular limitation, obesity based on a healthy perspective, obesity based on beauty or slimming, but preferably refers to obesity based on a healthy perspective, in which case obesity is defined as a body mass index (BMI = weight [kg] / height [m] 2 ) can be determined based on the

[0091] According to the Japan Society for Obesity Prevention, a body mass index of 25 or higher is defined as obesity, and health disorders (complications) related to obesity based on this standard include diabetes / impaired glucose tolerance, obesity-related kidney disease, high blood pressure, myocardial infarction / angina pectoris, cerebral infarction, gout / hyperuricemia, dyslipidemia, fatty liver, sleep apnea syndrome / obesity hypoventilation syndrome, orthopedic diseases, menstrual disorders / complications of pregnancy. In this embodiment, the above 11 diseases can be mentioned as diseases related to obesity.

[0092] The present embodiment also provides a pharmaceutical composition containing the composition of any one of embodiments 1 to 8 as an active ingredient, for treating any one of diseases selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, assisting in the treatment of diseases selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, reducing the severity of diseases selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, or preventing diseases selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD.

[0093] Obesity, type 2 diabetes, dyslipidemia, and NASH (non-alcoholic steatohepatitis) are closely correlated with each other. Non-Patent Document 5 indicates a positive correlation between the amount of visceral fat and the amount of fat in liver cells in patients with NAFLD. Non-Patent Document 6 also indicates that the underlying causes of NAFLD include worsening insulin resistance, obesity, and the associated development of type 2 diabetes, dyslipidemia, and hypertension.

[0094] Type 2 diabetes is a disease characterized by elevated blood glucose levels due to insulin resistance, which can lead to complications such as retinopathy, nephropathy, and neuropathy. Furthermore, diabetes is known to promote the onset and progression of cardiovascular diseases such as stroke and ischemic heart disease. Type 2 diabetes is highly correlated with obesity. Obesity reduces insulin receptors, resulting in increased insulin secretion from the pancreas. Furthermore, free fatty acids and adipocytokines such as TNF-α secreted from obese enlarged adipocytes suppress insulin action, increasing insulin secretion and resulting in insulin resistance. Diabetes can be diagnosed based on fasting blood glucose levels, 1-hour values ​​in a glucose tolerance test, and HbA1c values, as well as diabetic symptoms such as dry mouth, polydipsia, polyuria, and weight loss, as well as diabetic retinopathy.

[0095] Dyslipidemia includes high LDL cholesterol, low HDL cholesterol, and hypertriglyceridemia. Excessive LDL cholesterol or triglyceride lipids, or low HDL cholesterol, can cause lipid deposition in blood vessel walls, resulting in the formation of plaque (atheroma), thickening the walls, and increasing the risk of blockage. This condition is called atherosclerosis. Among dyslipidemias, low HDL cholesterol and hypertriglyceridemia in particular are highly correlated with obesity. Obese individuals may consume excessive amounts of foods high in triglycerides and cholesterol, and obesity can lead to insulin resistance, which in turn promotes the liver's synthesis of triglycerides, which is thought to be the cause of low HDL cholesterol and hypertriglyceridemia. Hypertriglyceridemia is not only caused by excessive release of VLDL (very low density lipoprotein), which contains a lot of triglycerides, from the liver into the bloodstream, but also by insufficient activation of LPL (lipoprotein lipase) due to insulin resistance, which makes it difficult for VLDL to be metabolized into HDL, resulting in low HDL cholesterol levels in the blood. Dyslipidemia can be diagnosed by fasting blood tests. For example, high LDL cholesterol levels of 140 mg / dL or higher, low HDL cholesterol levels of less than 40 mg / dL, and triglyceride levels of 150 mg / dL or higher are sometimes considered to be dyslipidemia. However, these criteria are not absolute.

[0096] NAFLD is a type of fatty liver disease characterized by fatty liver disease similar to alcoholic liver disease, even in patients without a history of alcohol consumption. Fatty liver disease is a condition characterized by the deposition of triglycerides in hepatocytes, resulting in liver damage. Fatty liver disease is defined as a condition in which a certain number of hepatocytes (e.g., 30% or more) contain lipid droplets. NAFLD encompasses simple fatty liver, characterized by the deposition of fat in hepatocytes alone, and steatohepatitis, characterized by the deposition of fat accompanied by inflammation and fibrosis. Fatty liver can be diagnosed through imaging tests such as abdominal ultrasound and abdominal CT scans, as well as blood tests. Abdominal ultrasound uses hepatorenal contrast, attenuation of deep echoes in the liver, and obscuration of hepatic vascularity as indicators. Abdominal CT scans evaluate the liver's CT value, which decreases with the presence of fat. Therefore, if this value is below a certain value (e.g., 0.9), a diagnosis of fatty liver can be made. If blood tests show elevations in ALT (GPT), AST (GOT), γ-GTP, cholinesterase, etc., it is determined that there is a tendency toward NAFLD / NASH.

[0097] Eleventh Embodiment This embodiment provides a diet comprising any one of the compositions described in Embodiments 1 to 8. This embodiment also provides a diet for inducing beige cells comprising any one of the compositions described in Embodiments 1 to 8. This embodiment also provides a diet for treating, assisting in the treatment of, reducing the severity of, or preventing any one of diseases selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, which comprises any one of the compositions described in Embodiments 1 to 8 as an active ingredient.

[0098] Diets include foods for humans and animal feeds. Foods can be foods for specified health uses (FOSHU), nutritionally functional foods, functional food claims, foods or beverages for people on diets, people seeking to reduce obesity, infants, pregnant women, athletes, the elderly, and other dietary supplements. Foods can be of any type, including beverages such as juice, milk drinks, and jelly drinks; alcoholic beverages such as wine and beer; carbohydrate-containing foods such as rice dishes and noodles; confectioneries such as chocolate, ice cream, biscuits, and snacks; dairy products such as ice cream, processed cheese, and butter; instant foods such as noodles and soups; frozen foods such as hamburger steaks, curry, and meat sauce; and retort pouch foods. Feeds can be used for any mammal, including pets such as dogs, cats, rabbits, ferrets, and guinea pigs; livestock such as cows, pigs, sheep, and horses; and laboratory animals such as mice, rats, rabbits, guinea pigs, dogs, and chimpanzees. The feed may take any form, such as solid, semi-solid, pelleted, liquid, flake, or fibrous, depending on the animal species and purpose.

[0099] Since the composition of the present invention is expected to induce beige cells more effectively through a synergistic effect with a low-protein diet, it is preferable that the diet contain any of the compositions described in embodiments 1 to 8 and be a low-protein diet.

[0100] A low-protein diet is a diet that, when consumed alone, contains less than 40% of the protein recommended for a typical individual. Because a low-protein diet regulates protein intake, it is recommended that a person consume no other foods besides the low-protein diet, with the exception of water.

[0101] Therefore, it is preferable that the low-protein diet allows the intake of standard amounts of nutrients other than the protein content. In a preferred example, the low-protein diet limits the daily protein intake per kg of the subject's body weight to 0.0 g or more and 0.4 g or less, and in a more preferred example, limits the daily protein intake per kg of the subject's body weight to 0.1 g or more and 0.35 g or less.

[0102] In a preferred example, the low-protein diet has a protein calorie percentage (calorie %) of the total calories of the diet ingested by the subject of 0 to 10 calorie%, in a more preferred example, 2 to 8 calorie%, and in an even more preferred example, 2.5 to 7.0 calorie%.

[0103] In a preferred example, the low-protein diet has a protein content of 0% by mass or more and 10% by mass or less of the total weight of the diet ingested by the subject, and in a more preferred example, 2% by mass or more and 8% by mass or less, and in an even more preferred example, 2.5% by mass or more and 7.0% by mass or less.

[0104] A low-protein diet has a total daily calorie intake of between 1200 and 3000 kcal, of which protein accounts for between 0 and 10 calorie%, more preferably between 2 and 8 calorie%, and even more preferably between 2.5 and 7.0 calorie%, or the proportion of protein by mass is preferably between 0 and 10% by mass, and even more preferably between 2.5 and 7.0% by mass, and the amount of protein intake per serving is preferably between 400 and 1000 kcal.

[0105] The low-protein diet may be packaged for individual servings. In this case, each serving contains between 400 and 1000 kcal. The low-protein diet may be solid, liquid, or liquid, as long as it satisfies the total calorie and protein requirements. It may also consist of multiple dishes, such as a combination of rice, soup, a main dish, and a side dish. However, if the low-protein diet is solid, the patient must ingest the necessary amount of fluids separately. The low-protein diet should preferably include instructions or packaging warning patients not to consume any other foods except for fluids, or the patient should receive such instructions from a doctor, pharmacist, nurse, or other such person. The low-protein diet may also contain amino acids as protein. Essential amino acids are preferred.

[0106] <Twelfth embodiment> This embodiment provides compositions for inducing beige cells, which contain culture supernatants of 2 T19-derived strains, 4 T19-derived strains, 5 T19-derived strains, 19 T19-derived strains, and 33 T19-derived strains.

[0107] Furthermore, this embodiment provides compositions comprising culture supernatants of 2 T19-derived strains, 4 T19-derived strains, 5 T19-derived strains, 19 T19-derived strains, and 33 T19-derived strains.

[0108] Each set of strains may be defined by the genus of each of the bacteria T19-1 to T19-33 as in embodiments 1 and 2, by the species identified as each of the strains T19-1 to T19-33 as in embodiments 3 and 4, by the DNA sequence corresponding to each of the 16rSRNAs of the species identified as each of the strains T19-1 to T19-33 as in embodiments 5 and 6, or by the DNA sequence corresponding to each of the 16rSRNAs of each of the strains T19-1 to T19-33 as in embodiments 7 and 8.

[0109] <Thirteenth Embodiment> The following examples demonstrate that the establishment of a set of T19-derived strains is important for the induction of beige cells. In experiments using GF mice established with a set of T19-derived strains, beige cells were significantly induced when reared under LP conditions, whereas beige cell induction was low when reared under AIN conditions (Example 4). On the other hand, humans (T19) carrying T19-derived strains had abundant beige cells even without low-protein conditions (Example 1). This suggests that, while the induction of beige cells in GF mice requires an additional trigger, such as a low-protein diet, in addition to the establishment of a set of T19-derived strains, humans are exposed to various stimuli in their environment, and it is therefore possible to induce beige cells using T19-derived strains alone. Therefore, if beige cells cannot be sufficiently induced using T19-derived strains alone, it is preferable to have a second composition that provides LP conditions or a similar trigger.

[0110] The second composition may be (a) a low-protein diet, (b) one or more selected from the group consisting of nitrate ions, nitrite ions, arginine, and ammonium ions, (c) FGF21 (fibroblast growth factor 21), (d) bile acid, (e) FXR (funnelloid X receptor) agonist, or (f) PPARα (peroxisome proliferator-activated receptor α) agonist.

[0111] As described below, GF mice colonized with a set of T19-derived strains showed lower induction of nitrite ions under AIN conditions compared to LP conditions. This suggests that supplementing the blood with nitrate ions, nitrite ions, or their precursor, arginine, could act as a trigger to replace LP conditions. Furthermore, the inventors have found that nrfA, an enzyme that reduces nitrite to ammonia, increases in the intestines of mice colonized with T19-derived strains and raised under LP conditions, suggesting that ammonium ions could act as a trigger to replace LP conditions. Furthermore, FGF-21 is involved in the induction of beige cells. GF ​​mice colonized with a set of T19-derived strains showed elevated FGF-21 levels under LP conditions but not under AIN conditions. Therefore, supplementing with FGF-21 could be a trigger to replace LP conditions. Furthermore, LP conditions increase the concentrations of the bile acids cholic acid (CA), 7-oxocholic acid (7oxoCA), ursocholic acid (UCA), and chenodeoxycholic acid (CDCA) in the blood. Furthermore, administration of bile acids significantly increases UCP1 expression in iWAT. Therefore, administration of bile acids, particularly CA, 7oxoCA, UCA, and CDCA, may act as a trigger to replace LP conditions. Furthermore, knockout of the bile acid receptor FXR reduces beige cell induction, suggesting that FXR agonists may act as a trigger to replace LP conditions. Furthermore, PPARα knockout (PPARα- / -) mice show reduced beige cell induction and reduced FGF21 production, suggesting that PPARα agonists may act as a trigger to replace LP conditions.

[0112] That is, this embodiment provides the following: A second composition comprising any one of the compositions according to embodiments 1 to 8 and at least one selected from the group consisting of the following (a) to (f): (a) a low-protein diet, (b) one or more selected from the group consisting of nitrate ions, nitrite ions, arginine, and ammonium ions, (c) FGF21, (d) a bile acid, (e) an FXR agonist, and (f) a PPARα (peroxisome proliferator-activated receptor α) agonist.

[0113] The present embodiment also provides the following: A second composition comprising any one of the compositions according to embodiments 1 to 8 and at least one selected from the group consisting of the following (a) to (f): (a) a low-protein diet, (b) one or more selected from the group consisting of nitrate ions, nitrite ions, arginine, and ammonium ions, (c) FGF21, (d) a bile acid, (e) an FXR agonist, or (f) a PPARα agonist.

[0114] A composition for treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, comprising: any of the compositions described in embodiments 1 to 8; and a second composition comprising at least one selected from the group consisting of the following (a) to (f): (a) a low-protein diet; (b) one or more selected from the group consisting of nitrate ions, nitrite ions, arginine, and ammonium ions; (c) FGF21; (d) a bile acid; (e) an FXR agonist; or (f) a PPARα agonist.

[0115] In a preferred example of this embodiment, the second composition is (a) a low-protein diet, and the first composition and the second composition are each formulated for oral administration.

[0116] In a preferred example of this embodiment, the second composition is (a) a low-protein diet.

[0117] The low protein diet is as described above.

[0118] In a preferred example of this embodiment, the second composition comprises (b) one or more selected from the group consisting of nitrate ions, nitrite ions, arginine, and ammonium ions, (c) FGF21, (d) a bile acid, (e) an FXR agonist, or (f) a PPARα agonist, and the first composition and the second composition are each formulated for oral administration.

[0119] In a preferred example of this embodiment, the second composition comprises: (b) one or more selected from the group consisting of nitrate ions, nitrite ions, arginine, and ammonium ions; (c) FGF21; (d) a bile acid; (e) an FXR agonist; or (f) a PPARα agonist; the first composition is formulated for oral administration; and the second composition is formulated for intravascular administration.

[0120] In a preferred example of this embodiment, the second composition contains (b) one or more selected from the group consisting of nitrate ions, nitrite ions, arginine, and ammonium ions, the first composition is formulated for oral administration, and the second composition is formulated for oral administration or intravascular administration.

[0121] In a preferred example of this embodiment, the second composition comprises (c) FGF21, the first composition is formulated for oral administration, and the second composition is formulated for vascular administration.

[0122] In a preferred example of this embodiment, the second composition comprises (d) a bile acid, the first composition is formulated for oral administration, and the second composition is formulated for oral administration or intravascular administration.

[0123] In a preferred example of this embodiment, the second composition comprises (e) an FXR agonist, the first composition is formulated for oral administration, and the second composition is formulated for oral administration or intravascular administration.

[0124] In addition, in a preferred example of this embodiment, the second composition contains (f) a PPARα agonist, the first composition is formulated for oral administration, and the second composition is formulated for oral administration or intravascular administration.

[0125] Nitrate ions are NO3 - The nitrate ion may be derived from a nitrate salt, such as sodium nitrate, potassium nitrate, calcium nitrate, or ammonium nitrate. The nitrite ion is expressed as NO2 - The nitrite ion may be derived from a nitrite salt, such as sodium nitrite, potassium nitrite, or ammonium nitrite. Arginine is known to be a precursor of the nitrate ion or nitrite ion (see, for example, Non-Patent Document 6). The ammonium ion is NH4 +- The ammonium ion may be derived from an ammonium salt, and examples of the ammonium salt include ammonium chloride, ammonium nitrate, and ammonium nitrite.

[0126] FGF21 is known to be involved in the regulation of glucose metabolism and promotes the uptake of blood glucose by adipocytes.

[0127] The bile acid may be a primary bile acid such as CA or CDCA, or a secondary bile acid such as ursocholic acid or ursodeoxycholic acid.

[0128] FXR agonists can be used without any particular limitation as long as they can induce FXR-mediated signals. They are also commercially available, and examples thereof include EYP001 (Vonafexor), LJN452 (Tropifexor), MB763 (Nidufexor), GS-9674 (Cilofexor), PLX007, PX-102 (PX-20606), PX-104 (Phenex 104), OCA (Ocaliva), EDP-297, EDP-305, TERN-101 (LY2562175), MET-409, MET-642, GW4064, WAY362450 (Tulofexolate isopropyl), fexaramine, AGN242266, AKN-083, and BAR502.

[0129] The PPARα agonist can be used without any particular limitation as long as it can induce a signal mediated by PPARα. Commercially available products include fenofibrate, bezafibrate, lanifibranor, seladelpar, and elafibranor.

[0130] <Fourteenth Embodiment> This embodiment provides the following: Any of the composition, pharmaceutical composition, food, or diet according to any one of Embodiments 1 to 12, for use in a method for inducing beige cells in a living body.

[0131] The present embodiment also provides the following: Any of the compositions, pharmaceutical compositions, foods, or diets according to embodiments 1 to 12 for use in treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD.

[0132] <Fifteenth Embodiment> This embodiment is a method for inducing beige cells, characterized by administering any of the compositions, pharmaceutical compositions, foods, or diets described in embodiments 1 to 14 to a subject.

[0133] Furthermore, this embodiment is a method for treating any disease selected from the group consisting of obesity, diabetes / impaired glucose tolerance, obesity-related kidney disease, hypertension, myocardial infarction / angina pectoris, cerebral infarction, gout / hyperuricemia, dyslipidemia, fatty liver, sleep apnea syndrome / obesity hypoventilation syndrome, orthopedic diseases, and menstrual disorders / complications of pregnancy, characterized by administering to a subject the composition, pharmaceutical composition, food, or diet of any of embodiments 1 to 14.

[0134] In a preferred example of this embodiment, the subject's daily protein intake per kg of body weight is 0.0 g or more and 0.4 g or less, and in a more preferred example, the subject's daily protein intake per kg of body weight is 0.1 g or more and 0.35 g or less.

[0135] In addition, in a preferred example of this embodiment, the proportion of protein in the total calories of the diet ingested by the subject is 0 calorie% or more and 10 calorie%, in a more preferred example, 2 calorie% or more and 8 calorie% or less, and in an even more preferred example, 2.5 calorie% or more and 7.5 calorie% or less.

[0136] In addition, in a preferred example of this embodiment, the proportion of protein in the total weight of the diet ingested by the subject is 0% by mass or more and 10% by mass or less, and in a more preferred example, it is 2 calorie% or more and 8 calorie% or less, and in an even more preferred example, it is 2.5 calorie% or more and 7.5 calorie% or less.

[0137] <16th Embodiment> This embodiment provides the following: A composition for inducing beige cells, comprising any of the compositions described in Embodiments 1 to 8, characterized in that the composition described in Embodiments 1 to 8 is administered to a subject in a low-protein environment.

[0138] A method for treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, characterized by administering any of the compositions described in embodiments 1 to 8 to a subject in a low-protein environment.

[0139] A low-protein environment is an environment in which the subject's daily protein intake per kg of body weight is between 0.0 g and 0.4 g, and in a more preferred example, the subject's daily protein intake per kg of body weight is between 0.1 g and 0.35 g.

[0140] In addition, in a low-protein environment, the proportion of protein in the total calories of the diet ingested by the subject is preferably between 0 calorie% and 10 calorie% inclusive, and in a more preferred example, between 2 calorie% and 8 calorie% inclusive, and in an even more preferred example, between 2.5 calorie% and 7.5 calorie% inclusive.

[0141] In addition, in a low-protein environment, the proportion of protein in the total weight of the diet ingested by the subject is preferably between 0% and 10% by mass, and in a more preferred example, the proportion of protein in the total calories ingested by the subject is between 2% and 7% by mass.

[0142] It is also preferable that the low-protein environment be maintained for at least 4 weeks.

[0143] As will be described in more detail in the Examples below, the inventors have made the following findings.

[0144] <Induction of beige cells and effects on weight loss, etc.> Seven NAFLD patients were given a low-protein diet (LP diet) for two weeks, replacing their normal diet with a protein content adjusted to 0.6-0.8g per body weight per day while maintaining total calories. Reductions in the patients' weight, blood ALT (alanine aminotransferase), body fat percentage, AST (aspartate aminotransferase), triglycerides, HDL (high-density lipoprotein cholesterol), LDL (low-density lipoprotein cholesterol), and other levels were observed.

[0145] When mice raised under conventional conditions were fed an AIN diet instead of an LP diet, the expression level of UCP1 increased in the inguinal white adipose tissue (iWAT), and beige cells were induced. This suggests that the LP condition induces beige cells, resulting in weight loss and other benefits.

[0146] When SPF (specific-pathogen-free) mice were fed test diets with varying protein content, it was shown that a protein content of 10 calorie% or less can trigger beige cell induction, and that a protein content of 2.5 to 7 calorie% was a strong trigger (Reference Example 1, Figure 17). To investigate the relationship between the duration of LP diet administration and the expression of beige cells, mice were fed an AIN diet and an LP diet for various periods. It was shown that a low-protein environment for 1 week or more can trigger beige cell induction, and that a low-protein environment for 4 weeks or more was a strong trigger (Reference Example 1, Figure 18).

[0147] Relationship between microbiota and beige cell induction: When SPF mice and GF mice were reared under LP conditions, the expression level of UCP1 in iWAT of SPF mice, which possess gut microbes, was elevated, and beige cell induction was observed. However, in GF mice, UCP1 expression in iWAT was not elevated, and beige cell induction was not observed. This suggests that beige cell induction under LP conditions is, at least in part, dependent on the gut microbiota.

[0148] When GF mice were intravenously administered an adrenergic β3 agonist (hereinafter referred to as "β3 agonist") and then reared under LP conditions, induction of beige cells was observed to the same extent as in SPF mice. This suggests that GF mice also contain cells that can serve as beige cell precursors, and that beige cells can be induced using appropriate methods (Reference Example 2, Figure 19).

[0149] SPF mice reared under LP conditions had increased concentrations of the bile acids CA, 7oxoCA, UCA, and CDCA in their blood. These increased bile acid concentrations were not observed in GF mice, suggesting that the increased bile acid concentrations depend on the intestinal microbiota (Reference Example 3, Figure 20). Furthermore, when mice were reared on a diet containing 10% protein, administration of bile acids significantly increased UCP1 expression in iWAT (Figure 21).

[0150] In mice lacking the nuclear receptor FXR (Funnelloid X receptor), a bile acid receptor, beige cell induction was lower when reared under LP conditions than in mice expressing FXR (Reference Example 4, Figure 22). On the other hand, unlike the FXR knockout mice, mice lacking the bile acid receptor TGR showed similar levels of beige cell induction when reared under LP conditions, without a reduction in beige cell induction. These results suggest that rearing under LP conditions leads to the production of bile acids by the intestinal microbiota, which then activates FXR, thereby inducing beige cells. In particular, adipose tissue-specific FXR knockout mice showed a significant reduction in beige cell induction when reared under LP conditions, suggesting that FXR in adipose tissue is involved in beige cell induction.

[0151] In SPF mice reared under LP conditions, increased expression of FGF21 (fibroblast growth factor 21) was observed in the liver. In GF mice reared under LP conditions, increased expression of FGF21 was not observed in the liver, suggesting that the intestinal microflora contributes to the increased expression of FGF21 in mice reared under LP conditions (Reference Example 5, Figure 23).

[0152] Furthermore, when PPARα- / - mice, in which peroxisome proliferator-activated receptor (PPARα) is knocked out, were reared under LP conditions, the induction of beige cells was found to be lower than that of PPARα+ / - mice reared under LP conditions (Reference Example 6, Figure 24). Furthermore, when PPARα- / - mice were reared under LP conditions, the levels of FGF21 in the liver and blood were found to be lower than that of PPARα+ / - mice reared under LP conditions (Reference Example 6, Figure 25). These findings indicate that the induction of beige cells is partly dependent on the α-type peroxisome proliferator-activated receptor (PPARα).

[0153] These results suggest that the induction of beige cells under LP conditions is, at least in part, dependent on the gut microbiota and occurs via two pathways: activation of FXR via the secretion of bile acids by microorganisms, and induction of FGF21. It is also thought to be partially dependent on peroxisome proliferator-activated receptor α (PPARα).

[0154] Induction of beige cells by colonization with microbiota derived from beige cell-bearing individuals. Among 25 healthy individuals (T1-T20, A, B, D, F2, H), four individuals (T17, T10, T19, and T18) with high beige cell abundance were selected based on fluorodeoxyglucose (FDG) accumulation near the clavicles as measured by FDG-PET (fluorodeoxyglucose-positronemission tomography) (Example 1, Figure 1). Fecal suspensions from these four individuals were orally administered to SPF or GF mice at a microbial dose of 1x10^7-1x10^8 CFU / mouse, allowing colonization in the intestines. GF ​​mice colonized with feces from T17, T10, and T19 and reared under LP conditions showed high UCP1 expression in iWAT and abundant beige cells (Example 2, Figures 2 and 3).

[0155] <Induction of beige cells by a mixture of isolated bacterial strains> Thirty-three strains derived from T19 (T19_01-T19_16, T19_18-32, T19_34, T19_35) and 33 strains derived from T10 (T10_01-T10_06, T10_08-T10_33, T10_35) were isolated. Each isolated strain was cultured and mixed to prepare a mixed suspension of 33 T10-derived strains and 33 T19-derived strains. These were orally administered to GF mice to allow the strains to colonize the intestines. When the mice were reared under LP conditions, numerous beige cells were detected in the iWAT (Example 3, Figures 4 and 5). Increases in the bile acids cholic acid (CA), 7-oxocholic acid (7oxoCA), ursocholic acid (UCA), and chenodeoxycholic acid (CDCA) were also confirmed (Example 3, Figure 6). On the other hand, when FXR knockout (FXR- / -) or FXR heterozygous (FXR+ / -) GF mice were colonized with T19-derived strain 33 and reared under LP conditions, UCP1 expression in iWAT was lower in FXR knockout (FXR- / -) mice than in FXR heterozygous (FXR+ / -) mice (Example 3, Figure 7).

[0156] Induction of beige cells by 19 strains and further narrowing down the selection: 19 strains (T19-derived 19 strains) selected from the 33 T19-derived strains and the remaining 14 strains were colonized in GF mice and reared under LP conditions. In the group of GF mice colonized with the 19 T19-derived strains and reared under LP conditions, induction of beige cells was observed in iWAT, similar to the group colonized with the 33 T19-derived strains (Example 4, Figures 8 and 9). Furthermore, five T19-derived strains (T19_03, T19_04, T19_14, T19_29, and T19_31) were narrowed down from the 19 T19-derived strains, and these five T19-derived strains were found to induce beige cells in GF mice (Example 4, Figure 10). Furthermore, four T19-derived strains (T19_03, T19_04, T19_14, and T19_31) were narrowed down from the five T19-derived strains and were found to induce beige cells in GF mice (Example 9, Figure 16). Genome sequence analysis was performed on each of the 33 T19-derived strains, and the closest species to each strain was identified based on the base sequence of the 16S rRNA gene in the analyzed genome sequence. The species correspondences for the 33 T19-derived strains, 19 T19-derived strains, 5 T19-derived strains, 4 T19-derived strains, and the two T19-derived strains described below are shown in Table 1.

[0157]

[0158] Each of the identified species is classified as shown in Table 2. Among the 33 T19-derived strains, five T19-derived strains, four T19-derived strains, and two T19-derived strains (described below) are unique in that they do not overlap in genus with the other 33 T19-derived strains. Although data are not shown, the classification of each species identified from the 16S rRNA gene sequence in the genome sequence of each strain is also supported by the results of the whole genome sequence of the 33 T19-derived strains.

[0159]

[0160] <Relationship with Nitrate Reductase> Differentially expressed genes (DEGs) were analyzed. The results showed that when host mice were reared under LP conditions, the expression of genes related to nitrogen metabolism, in particular, increased in the T19-derived 33 strain. Similarly, the expression of genes related to nitrogen metabolism was also increased in the T19-derived 5 strains (Example 7, Figures 11, 12, and 13). Furthermore, in a group of GF mice colonized with the T19-derived 33 strain and reared under LP conditions, elevated blood nitrite ion concentrations were observed (Example 8, Figure 14). This increase was eliminated by administration of tungsten, which inhibits molybdenum coenzymes. These results suggest that nitrate reductase is involved in the induction of beige cells by the T19-derived 19 strain.

[0161] Example 1 <Search for humans with beige cells> 25 healthy men in their 20s to 40s (T1 to T20, A, B, D, F2, H) were selected as subjects. 18 F-FDG (fluorodeoxyglucose F18)-PET (positron emission tomography) was performed. The measurements were performed as follows: the subjects were fasted and 18 F-FDG was administered intravenously, and PET measurements were performed one hour later. 18 An example of an image obtained with F-FDG-PET is shown below. In the subject on the left, the area around the clavicle was 18 The amount of F-FDG accumulation was low, while in the right-sided subjects, the accumulation of F-FDG near the clavicle 18 It can be seen that the amount of F-FDG accumulated is high. 18 F-FDG accumulates in cells that consume a lot of glucose, such as those in the brain, fat cells, kidneys, and cancer cells. In addition, beige cells are distributed around the collarbone and chest area, so 18 F-FDG is an indicator of beige cells (Non-patent Document 7).

[0162] Figure 1 (b) shows the actual measurement results for the area around the clavicle. 18The standardized uptake value (SUV), which is the degree of F-FDG accumulation, is shown for each subject. Four subjects, T17, T10, T19, and T18, had high SUVs, and were determined to have a high number of beige cells.

[0163] Example 2 Induction of beige cells by colonization of human-derived microbiota bearing beige cells T20 mg of feces from four subjects (T17, T10, T19, and T18) was suspended in mGAM medium (Accudia® Modified GAM Bouillon 05433, Shimadzu Diagnostics Co., Ltd.) and passed through a cell strainer. The resulting samples (suspensions) from each subject were orally administered to GF mice or SPF mice, and the subject-derived microbiota was allowed to colonize the intestines.

[0164] SPF (specific-pathogen-free) mice and GF (germ-free) mice were maintained in the absence of specific pathogens (SPF environment) and in a germ-free environment (GF environment), respectively. Unless otherwise noted, SPF mice were maintained in an SPF environment even after the start of the experiment, and GF mice were maintained in a GF environment or a gnotobiotic environment. Unless otherwise noted, C57BL / 6 mice maintained in an SPF or GF environment were used in this example.

[0165] Approximately half of the SPF mice and GF mice were fed a low protein (LP) diet (hereinafter referred to as "LP conditions"), and the remaining half were fed an AIN diet (hereinafter referred to as "AIN conditions"). Details of the LP and AIN diets are shown in Table 3. The LP and AIN diets were prepared by Research Diets, Inc., upon request. After 6 weeks of feeding under these conditions, the iWAT of each mouse was collected and subjected to hematoxylin and eosin staining (HE staining). RNA was prepared from iWAT cells of each mouse using Trizol (Invitrogen). cDNA was synthesized from the prepared RNA using the ReverTra Ace® qPCR RT Kit (TOYOBO). The obtained cDNA was analyzed by real-time RT-PCR (Roche LightCycler® 480 System) using the UCP1 primer set or PPIB primer set as primers and THUNDERBIRD® Next SYBR™ qPCR Mix (TOYOBO). For each sample, the expression level of UCP1 was normalized to that of PPIB. The primer sets used were as follows: UCP1 Ucp1_F: 5'-CACCTTCCCGCTGGACACT-3' (SEQ ID NO: 99) Ucp1_R: 5'-CCCTAGGACACCTTTATACCTAATGG-3' (SEQ ID NO: 100) PPIB Ppib_F: 5'-GGAGATGGCACAGGAGGAA-3' (SEQ ID NO: 101) Ppib_R: 5'-GCCCGTAGTGCTTCAGCTT-3' (SEQ ID NO: 102)

[0166]

[0167] The results of HE staining are shown in Figure 2. Specifically, in the groups of GF mice colonized with fecal microorganisms from subjects T17, T10, and T19 and reared under LP conditions, HE staining confirmed the presence of many multivesicular beige cells in the iWAT (Figure 2 (g) to (j)).

[0168] The expression of UCP1 was as shown in Figure 3. In the groups of GF mice colonized with fecal microorganisms from the subjects T19, T10, and T17 and raised under LP conditions, increased expression of UCP1 was observed, indicating that beige cells had been induced in these mice.

[0169] Example 3 <Induction of beige cells using a mixture of isolated microbial strains> Thirty-three microbial strains derived from T19 (T19_01 to T19_16, T19_18 to T19_32, T19_34 to T19_35) and 33 microbial strains derived from T10 (T10_01 to T10_06, T10_08 to T10_33, T10_35) were isolated as follows. In this example, feces from GF mice, which had been transplanted with feces derived from T19 or T10 in Example 2, established a microbiota, and then reared under LP conditions, were used. This feces was serially diluted in mGAM medium (Accudia® Modified GAM Bouillon 05433, Shimadzu Diagnostics Co., Ltd.) and plated on non-selective agar plates. The mice were then cultured at 37°C under anaerobic conditions for 4 days, after which independent colonies were collected. Each strain was individually cultured in mGAM medium supplemented with 0.1% fumaric acid, 0.1% formic acid, 0.1 mg / mL sodium sulfite, and 0.5 μg / mL vitamin K3 under anaerobic conditions (80% nitrogen, 10% hydrogen, 10% carbon dioxide). Thirty-three T10-derived strains (T10-derived 33 strains) and 33 T19-derived strains (T19-derived 33 strains) were individually cultured and then suspended and mixed in mGAM medium at a microbial dose of 1x10^7-1x10^8 CFU / GF mouse to prepare a mixed suspension of the 33 T10-derived strains and the 33 T19-derived strains.

[0170] GF mice were orally administered 0.2-0.5 ml of each of the suspensions obtained above to each mouse, allowing the microbial strains to colonize the intestines. These GF mice were then bred, and their iWAT samples were collected and subjected to HE staining in the same manner as in Example 2. UCP1 expression was also observed. The results of HE staining of GF mice bred with the 33 T19-derived strains are shown in Figure 4. Specifically, HE staining confirmed the presence of numerous beige cells in the iWAT of all GF mice bred under LP conditions and bred with the 33 T19-derived strains.

[0171] The results of UCP1 expression are shown in Figure 5. A significant increase in UCP1 expression was observed in the group of GF mice colonized with 33 T19-derived strains and reared under LP conditions.

[0172] Furthermore, bile acids in the blood of each mouse group were measured. The bile acids measured were cholic acid (CA), 7-oxocholic acid (7oxoCA), ursocholic acid (UCA), and chenodeoxycholic acid (CDCA). Blood samples were collected from the mice and diluted appropriately. Deuterium-labeled substances were added as internal standards. The samples were eluted using ISOLUTE® C18(EC) 100 mg / 3 mL (Biotage). LC-MS / MS analysis was performed using an InertSustain C18 column (150 mm x 2.1 mm inner dimension, 3 μm particle size, GL Sciences). LC-MS / MS analysis was performed using a TripleQuad 6500 Sciex column. The analysis results are shown in Figure 6. In GF mice administered a mixed suspension of 33 T19-derived strains and then reared under LP conditions, elevated blood concentrations of CA, 7oxoCA, UCA, and CDCA were observed. These results suggest that T19-derived bacteria transplanted into GF mice produced more CA, 7oxoCA, UCA, and CDCA under LP conditions than under AIN conditions.

[0173] FXR- / - or FXR+ / - GF mice were established from FXR (Funnelloid X receptor) knockout mice (Jackson Laboratory Nr1h4tm1Gonz / J Strain #:004144), and the T19-derived 33 strain was established in the same manner as described above. The results are shown in Figure 7. When these mice were reared under LP conditions, the expression of UCP1, a beige cell marker, was lower in the FXR- / - mice compared to the FXR+ / - mice. This suggests that bile acids produced by the T19-derived 33 strain induced beige cells via FXR.

[0174] Example 4 Induction of beige cells using 19 T19-derived strains The 33 T19-derived strains were divided into 19 strains (hereinafter referred to as "19 T19-derived strains") and 14 strains other than the 19 strains (hereinafter referred to as "other 14 strains"). Table 4 shows, among the 33 T19-derived strains, bacterial strains included in the 19 T19-derived strains, bacterial strains included in the 5 T19-derived strains described below, and bacterial strains included in the 4 T19-derived strains and 2 T19-derived strains (described below) with circles.

[0175]

[0176] GF mice were colonized with 33 T19-derived strains, 19 T19-derived strains, or 14 other strains as in Example 4, and the GF mice were housed under LP conditions. The iWAT of the mice was collected and subjected to HE staining as in Example 2, and UCP1 expression was observed. The results of HE staining are shown in Figure 8. Specifically, in the groups of GF mice colonized with 33 T19-derived strains or 19 T19-derived strains and housed under LP conditions, HE staining of iWAT demonstrated induction of beige cells. However, in the groups of GF mice colonized with the other 14 strains and housed under LP conditions, almost no beige cell induction was observed in iWAT.

[0177] The expression of UCP1 is shown in Figure 9. In the groups of GF mice colonized with 33 T19-derived strains or 19 T19-derived strains and reared under LP conditions, a significant increase in UCP1 expression was observed, but in the groups of GF mice colonized with the other 14 strains and reared under LP conditions, the increase in UCP1 expression was low.

[0178] Example 5 <Induction of beige cells using 5 T19-derived strains> The 19 T19-derived strains were further narrowed down, and 5 of them were selected. These 5 strains are referred to as the 5 T19-derived strains. The 5 T19-derived strains are shown in Table 4. Furthermore, 14 strains other than the 5 T19-derived strains among the 19 T19-derived strains are referred to as the BEE14 strain. The 19 T19-derived strains, the 5 T19-derived strains, and the BEE14 strain were transplanted and established in GF mice as in Example 4. These GF mice were kept under LP conditions, and the expression of UCP1 in the mouse iWAT was observed as in Example 2. The results are shown in Figure 10. In the groups of GF mice colonized with 19 T19-derived strains and 5 T19-derived strains and reared under LP conditions (GF+LP+T19_all19mix and GF+LP+T19_other5mix, respectively), a significant increase in UCP1 expression was observed. However, in the group of GF mice colonized with the BEE14 strain and reared under LP conditions (GF+LP+BEE14mix), the increase in UCP1 expression was low.

[0179] Although the data are not shown, the expression of ELOVL3 (ELOVL fatty acid elongase 3), an adipocyte-specific expression marker, was also measured in the same manner as UCP1. A significant increase in ELOVL3 expression was observed in the groups of GF mice colonized with 19 T19-derived strains or 5 T19-derived strains and reared under LP conditions, whereas the increase in ELOVL3 expression was low in the groups of GF mice colonized with the BEE14 strain and reared under LP conditions.

[0180] Furthermore, although data are not shown, the blood FGF21 concentration of each mouse was measured. As a result, the group of GF mice colonized with 19 or 5 T19-derived strains and reared under LP conditions showed a significant increase in the expression of FGF21, which is thought to be involved in the induction of beige cells, but the group of GF mice colonized with the BEE14 strain and reared under LP conditions showed a low increase in FGF21 expression.

[0181] Example 6 <Gene Sequencing and Strain Identification of 33 T19-Derived Strains> Genome sequencing of 33 T19-derived strains was performed. Each colony was cultured in liquid or agar medium, and the bacteria were harvested. High-molecular-weight DNA was extracted according to standard procedures. Genome sequencing was performed using the MiSeq™ system (Illumina) and PacBio Sequel (PacBio) using a whole-genome shotgun method according to the protocol. The 16S rRNA gene sequences in the analyzed genome sequences were SEQ ID NOS: 1-33 and 103-233, and the correspondence between each strain and its 16S rRNA gene sequence is shown in Table 5. Based on SEQ ID NOS: 1-33 (33 T19-derived strains), each strain was identified to its closest known bacterial species. The results are shown in Table 6. For each of the 33 T19-derived strains, the 16S rRNA gene sequences of the bacterial species identified as having the closest 16S rRNA sequence were SEQ ID NOS: 34-65. The gene sequences corresponding to each sequence number are given at the end of the specification.

[0182]

[0183]

[0184] Example 7 <Expression Gene Analysis> Thirty-three T19-derived strains were colonized in GF mice, four of which were reared under AIN conditions and the other four under LP conditions. RNA was extracted from the cecal contents of each mouse, and the cDNA obtained by reverse transcription was analyzed using a HiseqX PE150 (Ilumina). The results were analyzed for differentially expressed genes (DEGs). The results are shown in Figure 11. It was found that the gene expression patterns of the 33 T19-derived strains differed between host mice reared under LP and AIN conditions. When mice were reared under LP conditions, the expression of 6,125 genes derived from bacteria present in the cecum was increased and the expression of 4,507 genes was decreased compared to mice reared under AIN conditions. Furthermore, although data are not shown, of the 6,125 genes whose expression increased when GF mice colonized with the above-mentioned 33 T19-derived strains were raised under LP conditions, 2,245 genes were derived from the 19 T19-derived strains, and 3,680 genes were derived from the BEE14 strain.

[0185] The gene expression analysis revealed that when host mice were reared under LP conditions, the expression of genes related to nitrogen metabolism (ko00910) was particularly elevated in the 33 T19-derived strains. The results are shown in Figure 12. Furthermore, among the 33 T19-derived strains, nrfA transcription was significantly increased in the T19-14 and T19-03 strains. The results are shown in Figure 26. Furthermore, these nrfA gene sequences were characterized by containing a lipoprotein signal peptide (LSP). Furthermore, nrfA gene expression was found to be high in the Desulfobacterota phylum, to which T19-14 B. wadsworthia belongs.

[0186] Similar experiments were performed on the five T19-derived strains, and elevated expression of nitrogen metabolism-related genes was also observed. The results are shown in Figure 13.

[0187] Example 8 <Quantification of Nitrite Ions> Blood samples were collected from GF mice colonized with the T19-derived 33 strain and reared under LP conditions, as well as from other groups of mice, and the amount of nitrite ions in the blood was quantified. Quantification was performed by colorimetry based on the diazotization method using a Nitrate / Nitrite Assay Kit, Colorimetric (23479, Cayman). The results are shown in Figure 14. Increased blood nitrite ion concentrations were observed in the GF mice colonized with the T19-derived 33 strain and reared under LP conditions.

[0188] Nitrate reductase requires a molybdenum cofactor. Therefore, we investigated the effect of tungsten administration, which inhibits the molybdenum cofactor, on beige cell induction in mice colonized with the T19-derived 19 strain. The experiment was performed as follows. GF ​​mice were colonized with the T19-derived 19 strain, and 5 days later, 0.1% tungsten solution was orally administered. They were then housed under AIN or LP conditions. 14 days after tungsten administration, iWAT was collected and UCP1 expression was observed. The results are shown in Figure 15. In the group without tungsten administration, colonization of the T19-derived 19 strain resulted in increased UCP1 expression in GF mice housed under LP conditions. However, in the tungsten-administered group, there was little increase in UCP1 expression. A similar experiment was performed with Evolv3, and no increase in Evolv3 expression was observed in the tungsten-administered group. The primer sequences used to analyze EVOLV3 expression were as follows: Elovl3_417Fwd: 5'-TGTTGGCCAGACCTACATGA-3' (SEQ ID NO: 236) Elovl3_562Rv: 5'-GGCCCACTGTAAACATCACTG-3' (SEQ ID NO: 237)

[0189] This indicates that the induction of beige cells by T19-derived strain 19 is related to molybdenum cofactor-dependent enzymes, including nitrate reductase, and the production of nitrite by these enzymes.

[0190] Example 9 <Induction of Beige Cells with Four T19-Derived Strains> To further narrow down the five T19-derived strains, a mixed suspension consisting of four strains, excluding one of the five T19-derived strains, was prepared. This suspension was administered to GF mice as in Example 4 to allow the bacterial strains to colonize. The GF mice were then housed under LP conditions, and UCP1 expression in the mouse iWAT was monitored as in Example 2. The results are shown in Figure 16. Increased UCP1 expression was observed in groups colonized with the five T19-derived strains or the four strains other than T19_29, but not in groups colonized with the four strains excluding any one of T19_29. These results demonstrate that the four T19-derived strains (T19_03, T19_04, T19_14, and T19_31) excluding T19_29 are particularly important for beige cell induction.

[0191] Reference Example 1: Study of Protein Ratio and Low-Protein Diet Administration Period. Test diets 1 to 7 were prepared with varying protein ratios. The protein ratio per calorie, i.e., the percentage of calories derived from protein relative to the total calories of the diet, for each diet was 40% (Test Diet 1), 20% (Test Diet 2), 15% (Test Diet 3), 10% (Test Diet 4), 7% (Test Diet 5), 5% (Test Diet 6), and 2.5% (Test Diet 7). These diets were fed to SPF mice (5 mice per group). Test Diet 2 was identical to the AIN diet and had the composition shown in Table 3. Test Diet 5 was identical to the LP diet and had the composition shown in Table 3. The increase or decrease in protein ratio for each test diet was substituted with carbohydrates. SPF mice were fed each test diet, and iWAT samples were collected and UCP1 expression was observed in the same manner as in Example 2. The results are shown in Figure 17. It was shown that a protein content of 10 calorie percent or less can trigger beige cell induction, and that a protein content of 2.5 calorie percent to 7 calorie percent is a strong trigger. Although the results are not shown, similar results were obtained when the same experiment was performed replacing protein with essential amino acids.

[0192] Furthermore, to examine the relationship between the duration of LP diet administration and beige cell expression, SPF mice were initially fed the AIN diet for 8 weeks as controls. Alternatively, SPF mice were fed the AIN diet for 7, 6, 5, 4, 2, and 0 weeks, then switched to the LP diet for 1, 2, 3, 4, 6, or 8 weeks, respectively. The iWAT of the mice was then collected and the expression of UCP1 and Evolv3 was examined as in Examples 2 and 8. The results are shown in Figures 18(a) and 18(b), respectively. It was shown that a low-protein environment for 1 week or longer can trigger beige cell induction, and that a low-protein environment for 4 weeks or longer is a strong trigger.

[0193] Reference Example 2 GF mice or SPF mice were housed under AIN conditions for 6 weeks, and during the final week, CL316243 was administered daily by intraperitoneal injection as a β3 agonist. PBS was administered intraperitoneally as a control. iWAT was collected from the mice, and the expression of UCP1 and Evolv3 was observed in the same manner as in Examples 2 and 8. The results are shown in Figures 19(a) and (b), respectively. When the β3 agonist was administered, an increase in the expression of UCP1 and Evolv3 was observed in GF mice to the same extent as in SPF mice.

[0194] Reference Example 3: Bile acids in the blood of GF mice or SPF mice reared under LP or AIN conditions were measured. The method was the same as in Example 3. The results are shown in Figure 20. In SPF mice reared under LP conditions, the concentrations of cholic acid (CA), 7-oxocholic acid (7oxoCA), ursocholic acid (UCA), and chenodeoxycholic acid (CDCA) were increased compared to mice reared under AIN conditions or GF mice.

[0195] Four types of bile acids (CA, CDCA, DCA, and UDCA) were intraperitoneally administered to GF mice at a dose of 50 μg each, and the mice were fed a diet with a 10% protein content. iWAT was collected from the mice, and UCP1 expression was observed in the same manner as in Example 2. The results are shown in Figure 21. UCP1 expression was significantly elevated in the bile acid-administered group compared to the PBS-administered control group.

[0196] Reference Example 4 GF mice established from FXR- / - mice (Jackson Laboratory Nr1h4tm1Gonz / J Strain #: 004144) in which the nuclear receptor FXR (Funnelloid X receptor), a bile acid receptor, was knocked out were raised under LP conditions, and iWAT from the mice was collected and UCP1 expression was observed as in Example 2. Expression of UCP1 was found to be lower in FXR- / - mice than in GF mice established from FXR+ / - mice expressing FXR. The results are shown in Figure 22.

[0197] Reference Example 5: Livers were excised from SPF mice raised under LP conditions and GF mice raised under LP conditions, and cDNA was prepared from the cells in the same manner as in Example 2, and FGF21 expression was observed. The sequences of the FGF21 primers were as follows: mFgf21_466Fwd: 5'-CCTGGGTGTCAAAGCCTCTA-3' (SEQ ID NO: 238) mFgf21_576Rv: 5'-TCCTCCAGCAGCAGTTCTCT-3' (SEQ ID NO: 239)

[0198] The results are shown in Figure 23. In GF mice reared under LP conditions, FGF21 expression in the liver was significantly lower than in SPF mice reared under LP conditions, suggesting that the intestinal microflora contributes to the increased expression of FGF21.

[0199] Reference Example 6: PPARα- / - mice (Jackson Laboratory 129S4-Pparatm1Gonz / J Strain #: 008154), in which the α-type peroxisome proliferator-activated receptor (PPARα) was knocked out, were raised under LP conditions. The expression of UPC1 and Evolv3 in iWAT was observed, and it was found that the PPARα- / - mice had lower expression of both genes and lower induction of beige cells compared to PPARα+ / + mice. The results are shown in Figure 24.

[0200] Furthermore, PPAR+ / - SPF mice or PPAR- / - SPF mice were raised under AIN or LP conditions. Livers were removed from each mouse, and cDNA was prepared from the cells in the same manner as in Reference Example 5, and FGF21 expression was observed. The results are shown in Figure 25(a). The amount of FGF21 in the blood of each mouse was also measured. The results are shown in Figure 25(b). Both results indicated that FGF21 production was lower in PPARα- / - SPF mice than in PPARα+ / - SPF mice, even under LP conditions.

[0201] Reference Example 7 <Gene Sequencing and Strain Identification of 33 T10-Derived Strains> Expression analysis of the 16S rRNA sequences of 33 T10-derived strains was performed. PCR amplification was performed using KOD plus Neo (TOYOBO) with the F27 and R1492 primers, using each colony suspension as a template, and Sanger sequencing of the PCR amplified product was performed using the F27 primer. The sequences of each primer were as follows: 27Fmod primer: 5'-AGRGTTTGATYMTGGCTCAG-3' (SEQ ID NO: 234) 1492R primer: 5'-TACGGYTACCTTGTTACGACTT-3' (SEQ ID NO: 235) The 16S rRNA gene sequences obtained by Sanger sequencing were SEQ ID NOs: 66 to 98. The correspondence is shown in Table 7.

[0202] Example 10: NrfA-deficient T19_14 (ΔnrfAT19_14) was constructed. The construction method followed the methods disclosed in Appl Environ Microbiol 75, 7682-7691 (2009). https: / / doi.org:10.1128 / AEM.01839-09 and Proc Natl Acad Sci USA 111, 14822-14827 (2014). https: / / doi.org:10.1073 / pnas.1407986111. Specifically, a strain (Δupp) lacking the upp gene encoding uracil phosphoribosyltransferase (upp) was constructed, which is resistant to 5-fluorouracil (5-FU), a drug that is toxic to wild-type strains. First, a Δupp plasmid containing sequences adjacent to the upstream and downstream of the upp gene in wild-type T19_14 was constructed on an E. coli plasmid vector by PCR. E. coli cells transfected with this plasmid were screened for viability in medium containing 5-FU. The constructed plasmid was then transfected into T19_14 cells by electroporation to generate a Δupp cell line (ΔuppT19_14). Next, a plasmid containing sequences adjacent to the upstream nrfA gene in wild-type T19_14, the chloramphenicol resistance gene (cat) sequence and its promoter sequence, the kanamycin resistance gene promoter (PaphII) sequence, the upp gene sequence, and the sequence adjacent to the downstream nrfA gene in wild-type T19_14 was constructed on an E. coli plasmid vector. This plasmid was then introduced into cells by electroporation. Because the upstream and downstream sequences of the NrfA gene in the DNA of the plasmid and ΔuppT19_14 were identical, the wild-type nrfA gene in ΔuppT19_14 was exchanged by homologous recombination with the cat sequence and its promoter sequence, the PaphII sequence, and the upp gene sequence of the plasmid.Specifically, the upp gene was restored and the nrfA gene was deleted in the DNA of ΔuppT19_14 (ΔnrfAT19_14). These cells were chloramphenicol resistant and sensitive to 5-FU, allowing for screening. Furthermore, gene insertion was confirmed in the plasmid construct by PCR. The gene sequence of NrfA is shown in SEQ ID NO: 240. The primer sequences used were as follows: 27FmodAGRGTTTGATYMTGGCTCAG (SEQ ID NO: 234) 1492RTACGGYTACCTTGTTACGACTT (SEQ ID NO: 235) Elovl3_417FwdTGTTGGCCAGACCTACATGA (SEQ ID NO: 236) Elovl3_562RvGGCCCACTGTAAACATCACTG (SEQ ID NO: 237) mFgf21_466FwdCCTGGGTGTCAAAGCCTCTA (SEQ ID NO: 238) mFgf21_576RvTCCTCCAGCAGCAGTTCTCT (SEQ ID NO: 239) Wild-type T19_14 and ΔnrfAT19_14 alone were unable to colonize the intestines of GF mice, but co-administration with T19_31 enabled colonization. Furthermore, when wild-type T19_14 and T19_31 were co-administered into GF mice, only these two strains were found to induce beige cells. Two T19-derived strains, T19_14 and T19_31, were used. The results are shown in Figure 27. The induction of beige cells by the two T19-derived strains was weaker than that by the four T19-derived strains. On the other hand, the induction of beige cells by T19_31 and ΔnrfAT19_14 was not observed. The results are shown in Figure 28. These results demonstrate that the induction of beige cells is possible with the two strains, T19_14 and T19_31. Furthermore, the induction of beige cells via T19_14 was found to be dependent on NrfA, suggesting that T19_14 may be substituted by bacteria containing NrfA. Furthermore, although not shown, replacing T19_14 with ΔnrfAT19_14 did not result in the increase in FGF21 expression observed above, but did not affect the expression of Csad and Cyp39a1 or plasma bile acid levels. It is thought that nitrogen metabolism by NrfA promoted the induction of beige cells through the improvement of FGF21.

[0203] The present application includes the following embodiments: (1-A) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (2-A) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (3-A) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, and a pharmaceutically acceptable excipient or food additive. (4-A) A pharmaceutical composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, and a pharmaceutically acceptable excipient. (5-A) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, for use in a method for inducing beige cells in a living body. (6-A) A composition for inducing beige cells, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (7-A) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, for use in treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD.(8-A) A pharmaceutical composition for use in treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (9-A) Any of the compositions described above, wherein the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 is a bacterium of the genus Bilophila, and the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30 is a bacterium of the genus Romboutsia. (10-A) Any of the compositions described above, wherein the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 is Bilophila wadsworthia, and the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30 is Romboutsia timonensis. (11-A) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (12-A) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (13-A) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62, and a pharmaceutically acceptable excipient or food additive. (14-A) A pharmaceutical composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62, and a pharmaceutically acceptable excipient. (15-A) A composition comprising a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 62 for use in a method for inducing beige cells in a living body.(16-A) A composition for inducing beige cells, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (17-A) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62 for use in treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD. (18-A) A pharmaceutical composition for use in treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (19-A) The composition according to any one of the above, wherein the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 is a bacterium of the genus Bilophila, and the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62 is a bacterium of the genus Romboutsia. (20-A) The composition according to any one of the above, wherein the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 is Bilophila wadsworthia, and the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62 is Romboutsia timonensis. (21-A) The composition according to any one of (1-A) to (20-A), wherein the at least 90% identity is at least 95% identity in each case. (22-A) The composition according to any one of (1-A) to (20-A), wherein the at least 90% identity is at least 97% identity in each case. (23-A) The composition according to any one of (1-A) to (20-A), wherein the at least 90% identity is completely identical. (24-A) A composition comprising a bacterium having an NrfA gene and a bacterium of the genus Romboutsia.(25-A) A composition comprising bacteria having the NrfA gene and bacteria of the genus Romboutsia. (26-A) A composition consisting of bacteria having the NrfA gene, bacteria of the genus Romboutsia, and a pharmaceutically acceptable excipient or food additive. (27-A) A pharmaceutical composition consisting of bacteria having the NrfA gene, bacteria of the genus Romboutsia, and a pharmaceutically acceptable excipient. (28-A) A composition comprising bacteria having the NrfA gene and bacteria of the genus Romboutsia for use in a method for inducing beige cells in a living body. (29-A) A composition for inducing beige cells, comprising a composition consisting of bacteria having the NrfA gene and bacteria of the genus Romboutsia. (30-A) A composition comprising bacteria having the NrfA gene and bacteria of the genus Romboutsia for use in treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD. (31-A) A pharmaceutical composition for treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, comprising a composition comprising a bacterium having the NrfA gene and a bacterium of the genus Romboutsia. (32-A) The composition according to any one of (24-A) to (31-A), wherein the bacterium having the NrfA gene is Bilophila wadsworthia and the bacterium of the genus Romboutsia is Romboutsia timonensis. (1-B) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (2-B) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (3-B) A composition comprising a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 14, a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 30, and a pharmaceutically acceptable excipient or food additive.(4-B) A pharmaceutical composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, and a pharmaceutically acceptable excipient. (5-B) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, for use in a method for inducing beige cells in a living body. (6-B) A composition for inducing beige cells, comprising a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (7-B) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, for use in treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD. (8-B) A pharmaceutical composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, for use in treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD. (9-B) Any of the above compositions, wherein the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 is a bacterium of the genus Bilophila, and the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30 is a bacterium of the genus Romboutsia. (10-B) Any of the above compositions, wherein the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 is Bilophila wadsworthia, and the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30 is Romboutsia timonensis.(11-B) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (12-B) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (13-B) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62, and a pharmaceutically acceptable excipient or food additive. (14-B) A pharmaceutical composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62, and a pharmaceutically acceptable excipient. (15-B) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62, for use in a method for inducing beige cells in a living body. (16-B) A composition for inducing beige cells, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (17-B) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62, for use in treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD. (18-B) A pharmaceutical composition for use in treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.(19-B) The composition according to any one of the above, wherein the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 is a bacterium of the genus Bilophila, and the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62 is a bacterium of the genus Romboutsia. (20-B) The composition according to any one of the above, wherein the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47 is Bilophila wadsworthia, and the bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62 is Romboutsia timonensis. (21-B) The composition according to any one of (1-B) to (20-B), wherein the at least 90% identity is at least 95% identity in each case. (22-B) The composition according to any one of (1-B) to (20-B), wherein the at least 90% identity is at least 97% identity in each case. (23-B) The composition according to any one of (1-B) to (20-B), wherein the identity is at least 90% and the composition is completely identical. (24-B) A composition comprising bacteria of the genus Bilophila and bacteria of the genus Romboutsia. (25-B) A composition comprising bacteria of the genus Bilophila and bacteria of the genus Romboutsia. (26-B) A composition comprising bacteria of the genus Bilophila and bacteria of the genus Romboutsia, and a pharmaceutically acceptable excipient or food additive. (27-B) A pharmaceutical composition comprising bacteria of the genus Bilophila and bacteria of the genus Romboutsia, and a pharmaceutically acceptable excipient. (28-B) A composition comprising bacteria of the genus Bilophila and bacteria of the genus Romboutsia for use in a method for inducing beige cells in vivo. (29-B) A composition for inducing beige cells, comprising a composition comprising bacteria of the genus Bilophila and bacteria of the genus Romboutsia. (30-B) A composition comprising a bacterium of the genus Bilophila and a bacterium of the genus Romboutsia for use in treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD.(31-B) A pharmaceutical composition for treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, comprising a composition comprising a bacterium of the genus Bilophila and a bacterium of the genus Romboutsia. (32-B) The composition according to (24-B) to (31-B), wherein the bacterium of the genus Bilophila is Bilophila wadsworthia and the bacterium of the genus Romboutsia is Romboutsia timonensis. (1-C) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (2-C) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (3-C) A composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, and a pharmaceutically acceptable excipient or food additive. (4-C) A pharmaceutical composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, or a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, and a pharmaceutically acceptable excipient.(5-C) A composition for use in a method for inducing beige cells in a living body, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (6-C) A composition for inducing beige cells, comprising a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30. (7-C) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, for use in treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD. (8-C) A pharmaceutical composition for use in treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30.(9-C) Any of the above compositions, wherein the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 3 is a bacterium of the genus Adlercreutzia, the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 4 is a bacterium of the genus Anaerofustis, the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 14 is a bacterium of the genus Bilophila, and the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 30 is a bacterium of the genus Romboutsia. (10-C) Any of the above compositions, wherein the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 3 is Adlercreutzia equolifaciens, the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 4 is Anaerofustis stercorihominis, the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 14 is Bilophila wadsworthia, and the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 30 is Romboutsia timonensis. (11-C) A composition comprising a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 62. (12-C) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.(13-C) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62, and a pharmaceutically acceptable excipient or food additive. (14-C) A pharmaceutical composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62, and a pharmaceutically acceptable excipient. (15-C) A composition for use in a method for inducing beige cells in vivo, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (16-C) A composition for inducing beige cells, comprising a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.(17-C) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62, for use in treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD. (18-C) A pharmaceutical composition for use in treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (19-C) The composition described in any of the above, wherein the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 36 is a bacterium of the genus Adlercreutzia, the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 37 is a bacterium of the genus Anaerofustis, the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 47 is a bacterium of the genus Bilophila, and the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 62 is a bacterium of the genus Romboutsia.(20-C) The composition described in any of the above, wherein the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 36 is Adlercreutzia equolifaciens, the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 37 is Anaerofustis stercorihominis, the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 47 is Bilophila wadsworthia, and the bacterium having a DNA sequence having at least 90% identity to the sequence of SEQ ID NO: 62 is Romboutsia timonensis. (21-C) The composition described in any of (1-C) to (20-C), wherein the at least 90% identity is at least 95% identity in each case. (22-C) The composition described in any of (1-C) to (20-C), wherein the at least 90% identity is at least 97% identity in each case. (23-C) The composition according to any one of (1-C) to (20-C), wherein the identity is at least 90% and the composition is completely identical. (24-C) A composition comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia. (25-C) A composition comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia. (26-C) A composition comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia, and a pharmaceutically acceptable excipient or food additive. (27-C) A pharmaceutical composition comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia, and a pharmaceutically acceptable excipient. (28-C) A composition comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia for use in a method for inducing beige cells in vivo.(29-C) A composition for inducing beige cells, comprising a composition consisting of bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia. (30-C) A composition consisting of bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia for use in treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD. (31-C) A pharmaceutical composition consisting of a composition consisting of bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia for treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD. (32-C) The composition according to any one of (24-C) to (31-C), wherein the bacterium of the genus Adlercreutzia is Adlercreutzia equolifaciens, the bacterium of the genus Anaerofustis is Anaerofustis stercorihominis, the bacterium of the genus Bilophila is Bilophila wadsworthia, and the bacterium of the genus Romboutsia is Romboutsia timonensis. (33) A composition comprising: a composition according to any one of (1) to (32) (first composition); and a second composition containing at least one selected from the group consisting of the following (a) to (f): (a) a low-protein diet, (b) one or more selected from the group consisting of nitrate ions, nitrite ions, arginine, and ammonium ions, (c) FGF21, (d) a bile acid, (e) an FXR agonist, or (f) a PPARα agonist. (34) The composition according to (30), wherein the second composition is (a) a low-protein diet, and the first composition and the second composition are each formulated for oral administration. (35) The composition according to (33) or (34), wherein the second composition is (a) a low-protein diet, and the low-protein diet has a protein content of 10% or less of total calories.(36) The composition according to (33) or (34), wherein the second composition is (a) a low-protein diet, wherein the proportion of protein in the total calories is 2.5 calorie% or more and 7.0 calorie% or less. (37) A method for inducing beige cells in a living body, comprising a step of administering or ingesting an effective amount of the composition according to any of (1) to (32) above. (38) The method according to (37), further comprising a step of administering or ingesting a second composition containing at least one selected from the group consisting of the following (a) to (f): (a) a low-protein diet, (b) one or more selected from the group consisting of nitrate ions, nitrite ions, arginine, and ammonium ions, (c) FGF21, (d) a bile acid, (e) an FXR agonist, or (f) a PPARα agonist. (39) The method according to (37), further comprising controlling the daily protein intake per kg of body weight to be 0.1 g or more and 0.35 g or less. (40) The method according to (39), wherein the period for controlling protein intake is 4 weeks or longer. (41) Use of the composition according to any of (1) to (36) above in the manufacture of a pharmaceutical composition for inducing beige cells in a living body. (42) Use of the composition according to any of (1) to (36) above in the manufacture of a pharmaceutical composition for treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD. (43A) A pharmaceutical composition comprising any of the following (IA) to (IIIA) and a pharmaceutically acceptable excipient: (IA) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30; (IIA) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium of the genus Romboutsia; (IIIA) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.(44A) A composition for use in a method for inducing beige cells in a living body, comprising any of the following (IA) to (IIIA): (IA) a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30; (IIA) a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium of the genus Romboutsia; (IIIA) a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (45A) A composition comprising any of the following (IA) to (IIIA) for use in treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD: (IA) a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, (IIA) a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium of the genus Romboutsia, (IIIA) a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (43B) A pharmaceutical composition comprising any of the following (IB) to (IIIB) and a pharmaceutically acceptable excipient.(IB) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14 and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30; (IIB) A composition comprising a bacterium of the genus Bilophila and a bacterium of the genus Romboutsia; (IIIB) A composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (44B) A composition for use in a method for inducing beige cells in a living body, comprising any of the following (I) to (III): (IB) a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30; (IIB) a composition consisting of a bacterium of the genus Bilophila and a bacterium of the genus Romboutsia; (IIIB) a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.(45B) A composition comprising any of the following (IB) to (IIIB) for use in treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD: (IB) a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30, (IIB) a composition consisting of a bacterium of the genus Bilophila and a bacterium of the genus Romboutsia, (IIIB) a composition consisting of a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (43C) A pharmaceutical composition comprising any of the following (IC) to (IIIC) and a pharmaceutically acceptable excipient. (IC) A composition comprising bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30; (IIC) A composition comprising bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia; (IIIC) A composition comprising bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62.(44C) A composition for use in a method for inducing beige cells in a living body, comprising any of the following (IC) to (IIIC): (IC) a composition consisting of bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30; (IIC) a composition consisting of bacteria of the genus Adlercreutzia, bacteria of the genus Anaerofustis, bacteria of the genus Bilophila, and bacteria of the genus Romboutsia; (IIIC) a composition consisting of bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 36, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 37, bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 47, and bacteria having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 62. (45C) A composition comprising any of the following (IC) to (IIIC) for use in treating, assisting in the treatment of, reducing the severity of, or preventing a disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD: (IC) a composition comprising a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 3, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 4, a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence at least 90% identical to the sequence of SEQ ID NO: 30; (IIC) a composition comprising a bacterium of the genus Adlercreutzia, a bacterium of the genus Anaerofustis, a bacterium of the genus Bilophila, and a bacterium of the genus Romboutsia; (IIIC) A composition comprising bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 36, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 37, bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 47, and bacteria having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 62.

[0204]

Claims

1. A composition comprising a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 14, and a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO:

30.

2. A composition comprising a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO:

30.

3. A composition comprising a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 47, and a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO:

62.

4. A composition comprising a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO: 240, and a bacterium having a DNA sequence that is at least 90% identical to the sequence of SEQ ID NO:

62.

5. A composition comprising bacteria of the genus Bilophila and bacteria of the genus Romboutsia.

6. The composition according to claim 3, wherein the bacterium of the genus Bilophila is Bilophila wadsworthia and the bacterium of the genus Romboutsia is Romboutsia timonensis.

7. A composition comprising the composition according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient or food additive.

8. A composition for inducing beige cells, comprising the composition of any one of claims 1 to 6.

9. A pharmaceutical composition or food for treating, assisting in the treatment of, reducing the severity of, or preventing any disease selected from the group consisting of obesity, type 2 diabetes, dyslipidemia, and NAFLD, comprising the composition according to any one of claims 1 to 6 as an active ingredient.

10. A composition comprising the composition (first composition) according to any one of claims 1 to 6, and a second composition comprising at least one selected from the group consisting of the following (a) to (f): (a) a low-protein diet, (b) one or more selected from the group consisting of nitrate ions, nitrite ions, arginine, and ammonium ions, (c) FGF21, (d) bile acids, (e) an FXR agonist, and (f) a PPARα agonist.

11. The composition of claim 10, wherein the second composition is (a) a low-protein diet, and the first composition and the second composition are each formulated for oral administration.

12. The composition of claim 10, wherein the second composition is (a) a low protein diet, the low protein diet having less than 10% of total calories from protein.

13. The composition of claim 10, wherein the second composition is (a) a low-protein diet, the low-protein diet having a protein content of 2.5 calorie% to 7.0 calorie% of total calories.

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