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    • 专利摘要:
    COMPOSITION TO IMPROVE THE INTESTINAL MICROBIOTA POPULATION, USE OF COMPOSITION, NON-THERAPEUTIC METHODS AND USE OF BERBERINE. Method and composition for improving the structure of the intestinal microbiota, to selectively increase a first population of the intestinal microbiota while simultaneously decreasing a second population of the intestinal microbiota, in a subject. The first population of the intestinal microbiota includes a short-chain fatty acid-producing bacteria (AGCC), and the second population of the intestinal microbiota includes an endotoxin-producing bacteria.
    公开号:BR112014030578B1
    申请号:R112014030578-1
    申请日:2013-06-04
    公开日:2021-04-06
    发明作者:Liping Zhao；Guang Ning；Linghua Wang；Menghui Zhang；Xiaojun Zhang；Xiaoyan Pang；Xiaoying Li；Xu Zhang；Yifei Zhang；Yufeng Zhao
    申请人:Shanghai Jiao Tong University；Perfect (China) Co., Ltd；
    IPC主号:
    专利说明:

    [0001] [0001] This application claims priority benefit from the filing date of Chinese patent application No. 201210185004.2, filed on June 6, 2012, the disclosure of which is fully incorporated herein by reference. FIELD OF THE INVENTION
    [0002] [0002] This application relates to compositions and methods for improving intestinal microbiota populations and related applications with drugs, food supplements, health care products, foods and beverages. BACKGROUND OF THE INVENTION
    [0003] [0003] Unless otherwise stated, the materials described in this section are not part of the state of the art for the claims of this application and are not admitted as part of the state of the art by inclusion in this section.
    [0004] [0004] Within the human body lives a large number of symbiotic microbes, among which the intestinal microbiota acts as an important environmental factor for the health of the host. There are more than 1000 species of bacteria, whose number exceeds 10 times the number of human cells, and whose number of genes is about 150 times that found in human cells. In this context, the human body as a "superorganism" made up of host cells and symbiotic microbes, including the intestinal microbiota, and the genome encoding a consortium of intestinal microbes (microbiome) is considered as the second human genome, also known as "metagenome. human". When there are changes in the state of human health, the composition of the symbiotic microbes changes accordingly. On the other hand, changes in the composition of symbiotic microbes lead to changes in human health status. Together, the diversity in the human genome and in the intestinal microbial genome affects immunity, nutrition, metabolism, and the human host's state of health and disease. However, until now, it is not clear by what mechanisms the intestinal microbiota contributes to the etiology of diseases and pathology, what type of bacteria correlates positively with the health status of the host, and what type of bacteria correlates negatively with the state health of the host. BRIEF DESCRIPTION OF THE INVENTION
    [0005] [0005] The following summary is illustrative only and is not intended to be limiting in any way. In addition to the illustrative aspects, examples of realization and features described, other aspects, examples of realization and additional features will be evident with reference to the drawings and the detailed description below.
    [0006] [0006] In one aspect, the present application provides methods for improving the population of the intestinal microbiota. In one embodiment, the method includes administering to a subject a composition to increase a first population of the intestinal microbiota while simultaneously decreasing a second population of the intestinal microbiota in the subject. The first population of the intestinal microbiota may include a short-chain fatty acid-producing bacteria (AGCC). The second population of the intestinal microbiota may include an endotoxin-producing bacteria.
    [0007] [0007] In another aspect, the application provides methods for screening a test compound that can be active in improving the population of the intestinal microbiota. In one embodiment, the method includes administering to a control individual an effective amount of a control composition to increase a first population of the intestinal microbiota while simultaneously decreasing a second population of the control subject's intestinal microbiota, and administration to a subject testing a quantity of a test compound and comparing the population of the control subject's intestinal microbiota with the population of the test subject's intestinal microbiota. The similarity of at least about 80% is indicative that the test compound is active in improving the intestinal microbiota population. The first population of the intestinal microbiota may include a short-chain fatty acid-producing bacteria (AGCC). The second population of the intestinal microbiota may include an endotoxin-producing bacteria.
    [0008] [0008] In an additional aspect, the present application provides compositions for improving the population of the intestinal microbiota. In one embodiment, the composition is capable of selectively increasing a first population of the intestinal microbiota and at the same time decreasing a second population of the intestinal microbiota in a subject. The first population of the intestinal microbiota may include a short-chain fatty acid-producing bacteria (AGCC). The second population of the intestinal microbiota may include an endotoxin-producing bacteria. In one embodiment, the composition is administered to the subject in a dosage of between about 50 mg / kg of body weight to about 400 mg / kg of body weight and with a schedule of administration once a day for at least two weeks. BRIEF DESCRIPTION OF THE FIGURES
    [0009] [0009] The exposed characteristics and other characteristics of the present disclosure will become more evident from the following description and attached claims, considered in conjunction with the attached drawings. Understanding that these drawings describe only several examples of realization arranged in accordance with the disclosure and, therefore, should not be considered as limiting the scope of the present invention, the disclosure will be described with additional details and specificity by the use of the attached drawings, in which:
    [0010] - A Figura 1 ilustra o efeito da berberina sobre a estrutura da microbiota intestinal de rato; a Figura 1A é o gráfico de pontuação (escore) PCoA de alterações na estrutura da microbiota intestinal de ratos em resposta à alimentação HFD e à administração de berberina; a Figura 1B mostra o agrupamento da microbiota intestinal com base nas distâncias de Mahalanobis calculadas usando MANOVA; e Figura 1C mostra o índice de Shannon-Wiener, calculado após a rarefação a um número igual de leituras de sequências para todas as amostras; - A Figura 2 ilustra algumas diferenças representativas na estrutura da microbiota intestinal causada pelo tratamento com berberina usando a análise de redundância da distância (RDA) tipo triplot da microbiota intestinal; - A Figura 3 ilustra o efeito sobre o conteúdo de ácidos graxos de cadeia curta nas fezes de ratos quando os ratos foram alimentados com uma dieta rica em gordura ou dieta normal; a Figura 3A mostra os níveis de ácidos graxos de cadeia curta totais (AGCCs); a Figura 3B mostra o nível de ácido acético; a Figura 3C mostra o nível de ácido propiônico; e a Figura 3D mostra o nível de ácido butírico (D); - A Figura 4 ilustra o efeito da berberina sobre fenótipos de obesidade e ingestão de alimentos em ratos; a Figura 4A mostra o efeito da berberina sobre o ganho de peso corporal; a Figura 4B mostra o efeito da berberina sobre o índice de adiposidade, calculado como o peso do panículo adiposo (do epidídimo e soma dos panículos adiposos perirenais) por 100 g de peso corporal total; e Figura 4C mostra a ingestão de alimentos pelos ratos durante todo o estudo; - A Figura 5 ilustra o efeito da berberina sobre a sensibilidade à insulina em ratos; a Figura 5A mostra o efeito da berberina sobre a glicemia em jejum (FBG); a Figura 5B mostra o efeito da berberina sobre a insulina sérica em jejum (FINS); a Figura 5C mostra o efeito da berberina sobre a avaliação da homeostase de resistência à insulina (HOMA-IR), calculado segundo a fórmula insulina em jejum (mU/mL) x glicose em jejum (mmol/L)/22,5; a Figura 5D mostra o efeito da berberina sobre o teste de tolerância à glicose oral (OGTT); e a Figura 5E mostra o efeito da berberina sobre o teste de tolerância à insulina intraperitoneal (ITT); e - A Figura 6 ilustra o efeito da berberina sobre o nível de fatores inflamatórios em ratos; a Figura 6A mostra o efeito da berberina sobre a proteína de ligação ao lipopolissacarídeo (LPS) sérico (LBP); a Figura 6B mostra o efeito da berberina sobre a leptina no soro; a Figura 6C mostra o efeito da berberina sobre a MCP-1 sérica; e a Figura 6D mostra o efeito da berberina sobre a adiponectina no soro corrigida pela gordura corporal. [0010] - Figure 1 illustrates the effect of berberine on the structure of the rat intestinal microbiota; Figure 1A is the PCoA score graph (score) of changes in the structure of the intestinal microbiota of rats in response to HFD feeding and berberine administration; Figure 1B shows the clustering of the intestinal microbiota based on Mahalanobis distances calculated using MANOVA; and Figure 1C shows the Shannon-Wiener index, calculated after rarefaction at an equal number of sequence readings for all samples; - Figure 2 illustrates some representative differences in the structure of the intestinal microbiota caused by treatment with berberine using the distance redundancy analysis (RDA) type triplot of the intestinal microbiota; - Figure 3 illustrates the effect on the content of short-chain fatty acids in the feces of rats when the rats were fed a high-fat diet or normal diet; Figure 3A shows the levels of total short-chain fatty acids (AGCCs); Figure 3B shows the level of acetic acid; Figure 3C shows the level of propionic acid; and Figure 3D shows the level of butyric acid (D); - Figure 4 illustrates the effect of berberine on obesity and food intake phenotypes in rats; Figure 4A shows the effect of berberine on body weight gain; Figure 4B shows the effect of berberine on the adiposity index, calculated as the weight of the adipose panicle (of the epididymis and sum of the perirenal adipose panicles) per 100 g of total body weight; and Figure 4C shows the food intake by the rats throughout the study; - Figure 5 illustrates the effect of berberine on insulin sensitivity in rats; Figure 5A shows the effect of berberine on fasting blood glucose (FBG); Figure 5B shows the effect of berberine on fasting serum insulin (FINS); Figure 5C shows the effect of berberine on the assessment of insulin resistance homeostasis (HOMA-IR), calculated according to the fasting insulin formula (mU / mL) x fasting glucose (mmol / L) / 22.5; Figure 5D shows the effect of berberine on the oral glucose tolerance test (OGTT); and Figure 5E shows the effect of berberine on the intraperitoneal insulin tolerance test (ITT); and - Figure 6 illustrates the effect of berberine on the level of inflammatory factors in rats; Figure 6A shows the effect of berberine on serum lipopolysaccharide (LPS) binding protein (LBP); Figure 6B shows the effect of berberine on leptin in serum; Figure 6C shows the effect of berberine on serum MCP-1; and Figure 6D shows the effect of berberine on adiponectin in serum corrected by body fat.
    [0011] [0011] In the following detailed description, reference is made to the attached drawings, which form part of the present. In the drawings, similar symbols usually identify similar components, unless the context indicates otherwise. The illustrative embodiments described in the detailed description, drawings and claims are not intended to limit the scope of the invention. Other examples of realization can be used, and other changes can be made without departing from the spirit or scope of the material presented here. It will be easily understood that aspects of the present disclosure, as described in general and illustrated in the figures, can be arranged, replaced, combined, separated, and designed in a wide variety of different configurations, all of which are expressly contemplated in the present invention.
    [0012] [0012] The present application is generally prepared, inter alia, for compositions, methods, processes, devices, systems, devices and / or products related to the improvement of the intestinal microbiota population.
    [0013] [0013] The application provides new compositions and methods to improve the population of the intestinal microbiota. The application identifies families of bacteria that are closely related to host metabolism using, for example, high-throughput sequencing and multivariate statistical methods.
    [0014] [0014] In one aspect, the present application provides methods for improving the population of the intestinal microbiota. In an example of an embodiment, the method may include selective enrichment of a first population of the intestinal microbiota. The first population of the intestinal microbiota may include, for example, a short-chain fatty acid-producing bacteria (AGCC). In an example of an embodiment, the method may include the suppression of a second population of the intestinal microbiota. The second population of the intestinal microbiota may include, for example, an endotoxin-producing bacteria.
    [0015] [0015] In an example of an embodiment, the method may include the step of administering a composition to a subject. The composition can be an oral or parenteral formulation. The composition can selectively increase the first population of the intestinal microbiota
    [0016] [0016] The enrichment of the first population of the intestinal microbiota and the suppression of the second population of the microbiota can be carried out simultaneously. The method can result in the prevention or treatment of metabolic syndrome including, without limitation, obesity, diabetes mellitus, insulin resistance, hyperlipoproteinemia, hyperuricemia, hepatic steatosis, hypercholesterolemia, hypertriglyceridemia, inflammation, and others disorders.
    [0017] [0017] Short-chain fatty acid-producing bacteria (AGCC) within the intestine are mainly beneficial bacteria. These bacteria, either directly or indirectly by the increase of short chain fatty acids in the intestine, perform functions that include, without limitation, anti-inflammatory action, protecting the function of the intestinal barrier, and regulating the metabolism and the immune system. These functions lead to the prevention or treatment of obesity, insulin resistance, diabetes, and other metabolic diseases.
    [0018] [0018] Using the disclosed methods to improve the intestinal microbiota population, the increased intestinal microbiota population may include Alistipes, Allobaculum, Bacteroides, Barnesiella, Blautia, Butyricicoccus, Butyricimonas, Dorea, Helicobacter, Hespellia, Holdemania, Lawsonia, Oscillides , Phascolarctobacterium, Prevotella, or Sedimentibacter. In an example of an embodiment, the population of the increased intestinal microbiota may include Bacteroidaceae, Coriobacteriaceae, Desulfovibrionaceae, Erysipelotrichaceae, Fla vobacteriaceae, Helicobacteracea, Incertae Sedis XI, Incertae Sedis XIV, Lachnospiraceae, Porotelrome alternatively, the increased intestinal bacteria population comprises Campylobacterales, Desulfovibrionales, Bacteroidales, Coriobacteriales, Flavobacteriales, Clostridiales, or Erysipelotrichales; alternatively, the increased intestinal bacteria population comprises Epsilonproteobacteria, Deltaproteobacteria, Bacteroidia, Coriobacteridae, Flavobacteria, Clostridiales, or Erysipelotrichi; alternatively, the increased intestinal bacteria population comprises Proteobacteria, Bacteroidetes, Actinobacteria, or Firmicutes.
    [0019] [0019] For example, the population increase in the intestinal microbiota may include a bacterium whose V3 region of the 16S rRNA gene sequence is at least about 70%, at least about 75%, at least about 80%, at least at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% similarity to a nucleic acid sequence selected from a group consisting of SEQ ID NO: 1-93.
    [0020] [0020] The bacteria producing endotoxin bacteria inside the intestine are mainly harmful bacteria, which directly or indirectly by increasing the endotoxin, promote inflammation, impair the function of the intestinal barrier, and increase disturbances in the metabolism and the immune system as a result they induce obesity, insulin resistance, diabetes and other metabolic diseases.
    [0021] [0021] According to the methods for improving the intestinal microbiota population disclosed in the present invention, the decreased intestinal bacteria population may comprise Alistipes, Anaeroplasma, Barnesiella, Bifidobacterium, Butyricimonas, Butyrivibrio, Coprococcus, Fastidiosipila, Helicobacter, Hespellia, Marvinbryantia, Oribacterium, Oscillibacter, Prevotella, Roseburia, Ruminococcus, or TM7_genera_incertae_sedis; alternatively, the diminished intestinal bacteria population may comprise Helicobacteraceae, Lachnospiraceae, Porphyromonadaceae, Prevotellaceae, Rikenellaceae, Ruminococcaceae, Anaeroplasmataceae, or Bifidobacteriaceae. In one embodiment, the diminished intestinal microbiota population may include Campylobacterales, Bacteroidales, Clostridiales, Anaeroplasmatales, Bifidobacteriales or, alternatively, the diminished intestinal bacteria population may include Epsilonproteobacteria, Alphaaproteobacteria, Bacteroidia, Clostridia, Actinobicutes, or Actinobollutes. In one embodiment, the diminished intestinal microbiota population may include Proteobacteria, Bacteroidetes, Actinobacteria, Firmicutes, or Tenericutes.
    [0022] [0022] For example, the decrease in the population of intestinal bacteria may include a bacterium whose V3 region of the 16S rRNA gene sequence is at least about 70%, at least about 75%, at least about 80%, at least at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% similarity to a nucleic acid sequence selected from a group consisting of SEQ ID NO: 94-268.
    [0023] [0023] These methods can cause a decrease in the serum level of pro-inflammatory factors. Example proinflammatory factors include, without limitation, cytokines such as the lipopolysaccharide-binding protein, monocyte-1 chemotactic protein, or leptin. Additionally and optionally, the methods can increase the serum level of cytokines, such as adiponectin.
    [0024] [0024] The level of short-chain fatty acids in the intestine can be increased using the methods disclosed in the present invention. Short-chain fatty acids can include, without limitation, acetic acid, propionic acid, butyric acid, valeric acid, isobutyric acid and isovaleric acid.
    [0025] [0025] To improve the intestinal microbiota population, the compositions can be administered orally or parenterally. In an example of an embodiment, the composition can be a food, a drink, a supplement, or a pharmaceutical formulation. In one embodiment, the composition may be in the form of a suppository, tablet, pill, granule, powder, film, microcapsule, aerosol, distillate, tincture, tonic, liquid suspension or syrup. The composition can be administered in a dosage from about 50 mg / kg of body weight to about 400 mg / kg of body weight.
    [0026] [0026] In one example, the composition including berberine was administered to a subject. The subject's intestinal microbiota population was then analyzed using pyrosequencing techniques 454 and the short chain fatty acid level was assessed by gas chromatography. The results showed that berberine is capable of altering the population of the intestinal microbiota: enriching certain bacteria, including those that produce short-chain fatty acids, while simultaneously suppressing or eliminating certain bacteria, including those that produce endotoxins. It has further been shown that orally administered berberine is able to increase the level of short-chain fatty acid within the intestine, and the increase is more pronounced in individuals suffering from metabolic syndrome. Further experimentation and observation further demonstrated that the effects of berberine described above on the intestinal microbiota population have beneficial results, including, without limitation, improving insulin sensitivity, reducing inflammation, controlling weight gain, and the prevention of obesity induced by overeating, chronic inflammation and insulin resistance.
    [0027] [0027] In another aspect, the present application provides methods for screening drugs, compounds, compositions, extracts, or formulations capable of improving the population of the intestinal microbiota. The methods can be used in the development of drugs, nutritional supplements, health care products, foods and beverages that improve health and / or prevent obesity or other associated metabolic syndromes by targeting the population of the intestinal microbiota in a subject.
    [0028] [0028] In one embodiment, the screening method may include administering to a control individual an effective amount of a control composition to increase a first population of the intestinal microbiota while simultaneously decreasing a second population of the control subject's intestinal microbiota, and administering to a test subject an amount of a test composition and comparing the population of the control subject's intestinal microbiota with the population of the test subject's intestinal microbiota.
    [0029] [0029] As used in the present invention, the term "subject" refers to an animal, such as a mammal, for example a human. In some embodiments, the subject may be a rat. In some embodiments , the subject may be a mouse. In some embodiments, the subject may be a human.
    [0030] [0030] If the test compound demonstrates an effect on the intestinal microbiota similar to that of the control, the test compound is active in improving the population of the intestinal microbiota. As used in the present invention, the terms "similar" and "similar" refer to a similarity of about at least 75%, of about at least 80%, of about at least 90%, of about at least 95%, about at least 98%, or about at least 99%.
    [0031] [0031] The test composition can be a single compound, a mixture, a food, a food additive, nutritional supplement, health care products, a pharmaceutical formulation or a drink.
    [0032] [0032] In an additional aspect, the present application provides compositions for improving the intestinal microbiota population. In one embodiment, the composition may be able to selectively increase the first population of the intestinal microbiota and at the same time decrease the second population of the intestinal microbiota in a subject.
    [0033] [0033] The composition can include a chemical compound, a natural medicine, a natural product, or herbal extract. In an example of an embodiment, the chemical compound can include, without limitation, berberine, derivatives of berberine, isoquinoline alkaloids, or any combinations thereof.
    [0034] [0034] In one embodiment, the composition may include natural medicines, whole, fragmented or powdered herbs, or plant extracts derived from Berberis, Coptis, Scutellaria, Phellodendron, Momordica, Ilex, Sophora, Gentiana, Anemarrhena, Gardenia, plants Rheum, or Taraxacum. In an example embodiment, the composition may include natural medicines, whole, fragmented or powdered herbs, or plant extracts derived from the Berberidaceae, Ranunculaceae, Lamiaceae, Rutaceae, Cucurbitacea, Aquifoliaceae, Leguminosae, Gentianaceae, Agavaceae, Rubiaceae, Polygonaceae, Asteraceae , Menispermaceae or Cucurbitaceae. In one embodiment, the composition may include natural medicines, whole, fragmented or powdered herbs, or plant extracts derived from Berberis vulgaris, Coptis chinensis, Scutellaria baicalensis, Phellodendri Chinensis, Momordica charantia, Ilex kudingcha, Sophora flavescens, Gentiana scabra, Anemarrhena asphodeloides, Gardenia jasminoides, Rheum palmatum or Herba Taraxaci.
    [0035] [0035] The following examples are provided for purposes of illustrating the execution and method properties representative of the application. These examples are not intended to limit the scope of the request. EXAMPLES
    [0036] [0036] These examples use Wistar rats (8 weeks old, male) as test subjects and berberine as a representative compound. 40 Wistar rats were acclimatized for two weeks and were subsequently randomly divided into four groups: normal diet group (NCD), normal diet plus berberine treatment (NCD + BBR), high fat diet (HFD), and high fat diet more treatment with berberine (HFD + BBR). Each group continued for another 18 weeks. During these 18 weeks, the NCD + BBR group received berberine by intragastric administration at the established levels. Stool samples from each animal were collected at various points in time. Pyrosequencing 454 was performed to analyze the structure of the intestinal microbiota. Gas chromatography was used to assess the level of short-chain fatty acids in the stool. In addition, weight, food intake, insulin sensitivity and levels of systemic inflammation were monitored and measured over the 18-week period. BERBERINE ALTERED THE INTESTINAL MICROBIOT POPULATION UNDER CONDITIONS OF A NORMAL DIET AND A FAT-RICH DIET
    [0037] [0037] Intestinal microbiota populations in rats from all four experimental groups were analyzed by 454 pyrosequencing and multivariate statistical analyzes. The results based on the Principal Coordinate Analysis (PCoA), based on the uniFrac distance matrix unweighted, demonstrated that berberine altered the structure of the intestinal microbiota both in the group that received a normal diet and in the group with a high-fat diet at one level. statistically significant; and berberine represents 12.6% of the global changes in the intestinal microbiota population (Figure 1A). Diet also had a statistically significant influence on the population of the intestinal microbiota. Figure 1a reveals a statistically significant difference (3.7%) in the population of the intestinal microbiota between the two different diets (NCD versus HFD) along the vertical axis. Multivariate analysis of variance (MANOVA) on the four groups showed that berberine or the diet has a statistically significant influence on the intestinal microbiota (P <0.01), but the most pronounced difference derives from the presence of berberine (Figure 1B) . The Shannon-Wiener parameter indicates that berberine reduces the diversity of the intestinal microbiota population at a statistically significant level (P <0.05). BERBERINE ENRICHES THE POPULATION OF SHORT CHAIN FATTY ACID PRODUCING BACTERIA AND REDUCES THE POPULATION OF ENDOTOXIN PRODUCING BACTERIA IN THE INTESTINAL MICROBIOTA
    [0038] [0038] 268 OTUs (operational taxonomic units) related to drinking were identified by redundancy analysis (RDA) and detailed results are shown in Figure 2, Table 1, and Table 2. 93 OTUs (SEQ_ID_NO 1-93) (Table 1) are enriched with berberine, while 175 OTUs (SEQ_ID_NO 94-268) (Table 2) have been suppressed or eliminated.
    [0039] [0039] The taxonomy of these 268 OTUs was analyzed using an RDP classifier with the representative sequence of the OTU. The bacteria suppressed by berberine were revealed to include Alistipes, Anaeroplasma, Barnesiella, Bifidobacterium, Butyricimonas, Butyrivibrio, Coprococcus, Fastidiosipila, Helicobacter, Hespellia, Marvinbryantia, Oribacterium, Oscillibacter, Prevotella, Among them, Helicobacter, belonging to the phylum Proteobacteria, is capable of producing highly active endotoxin. In addition, it was revealed that bacteria increased by drinking included Alistipes, Allobaculum, Bacteroides, Barnesiella, Blautia, Butyricicoccus, Butyricimonas, Dorea, Helicobacter, Hespellia, Holdemania, Lawsonia, Oscillibacter, Parabacteroides, Phascolarctobacterium, Prev. Among them, the bacteria Blautia, Allobaculum, Prevotella, Bacteroides, and Butyricimonas are relatively abundant and capable of producing short-chain fatty acids.
    [0040] Consequently, when administered to a subject, berberine is able to enrich short-chain fatty acid-producing bacteria and reduce endotoxin-producing bacteria in the intestinal microbiota population. BERBERINE INCREASES SHORT CHAIN FATTY ACID LEVELS IN THE INTESTINE OF RATS FEEDING A NORMAL OR FAT-RICH DIET
    [0041] [0041] The levels of short-chain fatty acids (including acetic acid, propionic acid, butyric acid, valeric acid, isobutyric acid, isovaleric acid, etc.) in rat feces were analyzed by gas chromatography. The result demonstrated that oral administration of 100 mg / kg of body weight can increase the level of short-chain fatty acids in the intestine of rats fed a normal diet or a diet rich in fat. The effect on acetic acid and propionic acid levels is especially pronounced (Figure 3). Therefore, berberine is able to increase the level of short-chain fatty acid in the intestines of rats fed a normal or high-fat diet. BERBERINE REDUCES THE PHENOTYPE OF OBESITY IN RATS
    [0042] [0042] The body weight of all four groups of rats was monitored during the experiment period and analyzed. The results showed that after 18 weeks of a high-fat diet, the HFD group had a significantly higher body weight than the group with a normal diet (P <0.01); and the intragastric administration of berberine at a dose of 100 mg / kg effectively limited the increase in body weight in rats, especially in rats fed a high-fat diet. The result is especially surprising due to the fact that throughout the experimental process, the body weight of the HFD + BBR group was limited to a level similar to that of the group that received a normal diet, with no statistically significant difference (P> 0.05). Berberine also influenced, to some degree, the body weight of rats fed a normal diet (Figure 4).
    [0043] [0043] At the end of the experiment, the animals were sacrificed. Fasting body weight, epididymal fat weight, and perirenal fat weight were measured. Adiposity index ([weight of epididymal fat + perirenal fat] / fasting weight χ 100) is shown in Figure 4B. After 18 weeks of a high-fat diet, the adiposity index in the HFD group is significantly higher than in the NCD group, and treatment with berberine significantly reduces the adiposity index. In addition, neither a high-fat diet nor berberine had a significant effect on the liver and pancreas, surprisingly indicating that long-term use of berberine has no obvious side effect on the rat's normal physiological functions. The results of calorie intake in these rats demonstrated that oral administration of berberine at 100 mg / kg body weight has a significant inhibitory effect on food intake, particularly in rats fed a high-fat diet (Figure 4C). BERBERINE REDUCES INSULIN SENSITIVITY IN RATS FEEDING A NORMAL OR FAT-RICH DIET
    [0044] [0044] Fasting blood glucose (FBG) and fasting serum insulin (FINS) were measured in the four experimental groups of rats. The rats fed with HFD for 18 months had a significantly higher level of FBG than the rats in the NCD group. Surprisingly, berberine effectively reduced FBG in NCD and HFD rats, especially in HFD rats where the reduction in FBG was significant (p <0.05) (Figure 5A). The result of the effect of berberine on insulin level is shown in Figure 5B. The FINS of rats fed the HFD diet was significantly higher than that of the NCD group; however, after 18 months of intervention with 100 mg / kg body weight of berberine, the level of FINS was significantly reduced even in rats fed with HFD (HFD + BBR), reaching a level comparable to that of the normal diet. Figure 5C shows the result of the HOMA insulin resistance index to assess the state of insulin resistance in rats, which demonstrates that after 18 weeks of HFD induction, they evidently exhibit insulin resistance; and the intervention with berberine at 100 mg / kg of body weight prevented the formation of insulin resistance (P <0.05).
    [0045] [0045] In order to continue the analysis of insulin sensitivity, the tests of oral glucose tolerance and intraperitoneal injection of insulin tolerance were performed, and the results are shown in Figure 5D and 5E, respectively. Consistent with the results of FBG and FINS, after 18 weeks of induction with a high-fat diet, oral glucose tolerance and intraperitoneal injection of insulin tolerance were significantly impaired, in turn, the intervention with 100 mg / kg berberine of body weight significantly prevented loss of glucose tolerance and insulin tolerance, demonstrating that berberine can play an important role in improving glucose metabolism. BERBERINE REDUCES THE LEVEL OF SYSTEMIC INFLAMMATION IN RATS FEEDING A FAT-RICH DIET
    [0046] [0046] In order to assess the levels of systemic inflammation in all four experimental groups of rats, the serum levels of the lipopolysaccharide-binding protein (LBP) (LPS), monocyte-1 chemotactic protein (MCP-1), leptin and adiponectin were measured, and the results are shown in Figure 6. The experiments demonstrate that HFD significantly increased the level of LBP in the serum; but the administration of berberine at 100 mg / kg significantly abolished the increase in serum LBP (P <0.05, Figure 6A).
    [0047] [0047] MCP-1 is a pro-inflammatory cytokine that works in chemotaxis and monocyte / macrophage activation. The occurrence and development of several inflammation-related diseases are closely related to MCP-1, including atherosclerosis, obesity, type 2 diabetes, arthritis, sepsis, and chronic bacterial infection. The results from the experiment demonstrated that, in the process of the gradual appearance of obesity and insulin resistance in rats induced by HFD, the level of MCP-1 is gradually elevated; however, after the intervention with the administration of berberine, the level of MCP-1 was significantly reduced, and, surprisingly, it was even lower than the level of the NCD group (Figure 6B).
    [0048] [0048] Leptin is a hormone secreted by adipose tissue, and participates widely in the metabolism of lipids, glucose, and energy metabolism. The results from the experiment demonstrated that the level of leptin in the HFD group is significantly higher than the level of the NCD group (P <0.01); however, berberine significantly reduced the level of leptin in the rats' serum, especially in rats fed with HFD (P <0.05, Figure 6C).
    [0049] [0049] Adiponectin levels were analyzed in all four groups. The results show that the level of adiponectin normalized by the weight of body fat was significantly lower in the HFD group when compared to that of the NCD group (P <0.001); however, administration of berberine significantly increased the level of adiponectin in rats fed with HFD (P <0.01, Figure 6D). Therefore, berberine improves the population of the intestinal microbiota, reduces the levels of LPB, MCP-1, and leptin, and increases the secretion of adiponectin. TABLE 1 SEQUENCE OF THE V3 REGION OF THE GENE 16S RRNA OF BERRIES ENRICHED BY BERBERINA.
    [0050] [0050] In the detailed description above, reference is made to the attached drawings, which form part of the present. In the drawings, similar symbols usually identify similar components, unless the context indicates otherwise. The illustrative embodiments described in the detailed description, drawings and claims are not intended to limit the scope of the invention. Other examples of realization can be used, and other changes can be made without departing from the spirit or scope of the material disclosed here. It will be easily understood that aspects of the present disclosure, as described in general and illustrated in the figures, can be arranged, replaced, combined, separated, and designed in a wide variety of different configurations, all of which are expressly contemplated in the present invention.
    [0051] [0051] The present disclosure should not be limited to the specific embodiments described in the present patent application, which are intended only to illustrate the different aspects. Many modifications and variations can be made without departing from the spirit and scope of the invention, as will be evident to those skilled in the art. Functionally equivalent methods and devices within the scope of the disclosure, in addition to those cited here, will be evident to those skilled in the art from the descriptions above. Such modifications and variations are also intended to fall within the scope of the appended claims. This description is to be limited only by the provisions of the appended claims, together with the full scope of equivalents to which such claims are entitled. It should be understood that the present disclosure is not limited to specific biological methods, reagents, compounds, compositions or systems which, of course, may vary. It is also necessary to understand that the terminology used in this document is only intended to describe examples of specific achievements, without the intention of being a limiting factor.
    [0052] [0052] With respect to the use of substantially any plural and / or singular term described in the present disclosure, those skilled in the subject may translate from the plural to the singular and / or from the singular to the plural, as appropriate for a given context and / or application. The various permutations in the singular / plural can be expressly provided for in this document for the sake of clarity.
    [0053] [0053] It will be understood by those skilled in the art that, in general, the terms used in the present, and especially in the appended claims (for example, body of the appended claims) in general are intended to be "open" (broad) terms (for example, the term "including" should be interpreted as "including, but not limited to", the term "having" should be interpreted as "having, at least," the term "includes" should be interpreted as "includes, but is not limited to ", etc.). It will also be understood by those skilled in the art that if a specific number is introduced in a claimed recitation, that intention will be explicitly recited in the claim, and in the absence of such a recitation such an intention will be present. as an aid to understanding, the following appended claims may contain the use of the introductory phrases "at least one" and "one or more" to introduce claim claims. However, the use of such phrases should not be interpreted taken to imply that the introduction of a claim recitation by the indefinite articles "one" or "one" limits any particular claim containing such recitation to contain only such recitation; even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles, such as "one" or "one" (for example, "one" and / or "one" are to be interpreted in the sense of "at least one” or "one or more”); the same goes for the use of defined articles used to enter claim claims. In addition, even if a specific number of an entered claim recitation is expressly recited, those skilled in the art will recognize that the recitation should be interpreted as at least that recited number (for example, the recitation of "two recitations", without other modifiers) , means "at least two recitations", or "two or more recitations"). In addition, in cases where a convention analogous to "at least one of A, B, and C, etc." is used, in general, as construction is intended to say, in the sense that a person skilled in the art will understand, that such a convention (for example, "a system that has at least one of A, B and C") can include, but not be limited to, systems that have only A, only B, only C, A and B together, A and C together, as well as B and C together, and / or A, B and C together, etc.). In cases where a convention analogous to " at least one of A, B, or C, etc. ”is used, in general, this construction is meant to say, in the sense that a specialist you will understand that such a convention (for example, "a system that has at least one of A, B or C") can include, but not be limited to, systems that have only A, only B, only C, A and B together, A and C together, B and C together and / or A, B and C together, etc.). It will also be understood by technicians skilled in the subject that virtually any disjunctive word and / or phrase that presents two or more alternative terms, whether in the specification, claims or drawings, it must be understood that the said word or phrase includes the possibilities of including one of the terms, either term, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B."
    [0054] [0054] Furthermore, when characteristics or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the invention is also described in terms of any individual member or subgroup of members of the Markush group.
    [0055] [0055] As will be understood by a person skilled in the art, for any and all purposes, such as with the aim of providing a written description, all intervals disclosed in the present also cover any and all possible subintervals and combinations of subintervals . Any range listed can easily be recognized as one that sufficiently describes and allows the same range to be divided into at least equal halves, thirds, quarters, fifths or tenths, etc. As a non-limiting example, each interval disclosed here can be readily divided into a lower third, middle third and upper third, and so on. Thus, it will also be understood by an expert on the subject that expressions such as "until", "at least", and the like include the quoted number and refer to intervals that can subsequently be divided into subintervals as discussed above. Finally, as will be understood by a person skilled in the art, an interval includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1.2, or 3 cells. Likewise, a group with 1-5 cells refers to groups having 1,2, 3, 4 or 5 cells, and so on.
    [0056] [0056] From the above, it is understood that the various examples of realization of the present invention have been described for illustrative purposes, and that various modifications can be made without departing from the scope and spirit of the present disclosure. Consequently, the various examples of realization described herein are not intended to be limiting, the true scope and spirit of the invention being indicated by the following claims.
    权利要求:
    Claims (4)
    [0001]
    USE OF BERBERINE or a derivative of berberine, characterized by being in the manufacture of a medicine to improve the population of the intestinal microbiota in a subject who has obesity or insulin resistance, where the improvement of the intestinal microbiota population is defined by the increase of a first intestinal microbiota population while decreasing a second intestinal microbiota population in a subject who has obesity or insulin resistance to increase the level of chain fatty acids short in a subject or reduce insulin sensitivity, and wherein the first population of the intestinal microbiota comprises Blautia, Allobaculum, Bacterioides Butyricicoccus, Dorea, Holdemania, Lawsonia, Parabacteroides, Phascolarctobacterium, Sedimentibacter, or a combination thereof; and the second population of the intestinal microbiota comprises Alistipes, Anaeroplasma, Barnesiella, Bifidobacterium, Butyricimonas, Butyrivibrio, Coprococcus, Fastidiosipila, Helicobacter, Hespellia, Marvinbryantia, Oribacterium, Oscillibacter, Prevotella, Roseburia, Ruminococera, TM.
    [0002]
    USE according to claim 1, characterized in that berberine is prepared as a food, drink, supplement, or pharmaceutical formulation.
    [0003]
    USE according to claim 1, characterized in that the first population of the intestinal microbiota comprises a bacterium whose V3 region of the 16S rRNA gene sequence has a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1 to 93.
    [0004]
    USE according to claim 1, characterized in that the second population of the intestinal microbiota comprises a bacterium whose V3 region of the 16S rRNA gene sequence has a nucleic acid sequence selected from the group consisting of SEQ ID NO: 94 to 268.
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