WO2019205942A1 - 一种提高肠道中scfa产生菌的复合制剂及制备方法与应用 - Google Patents

一种提高肠道中scfa产生菌的复合制剂及制备方法与应用 Download PDF

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WO2019205942A1
WO2019205942A1 PCT/CN2019/082118 CN2019082118W WO2019205942A1 WO 2019205942 A1 WO2019205942 A1 WO 2019205942A1 CN 2019082118 W CN2019082118 W CN 2019082118W WO 2019205942 A1 WO2019205942 A1 WO 2019205942A1
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Prior art keywords
extract
scfa
intestinal tract
producing bacteria
improving
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PCT/CN2019/082118
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English (en)
French (fr)
Inventor
沈鹤霄
李国龙
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美益添生物医药(武汉)有限公司
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Priority claimed from CN201810394911.5A external-priority patent/CN108576821A/zh
Priority claimed from CN201810395759.2A external-priority patent/CN108403930B/zh
Priority claimed from CN201810393624.2A external-priority patent/CN108478633B/zh
Priority claimed from CN201810395768.1A external-priority patent/CN108567901B/zh
Application filed by 美益添生物医药(武汉)有限公司 filed Critical 美益添生物医药(武汉)有限公司
Publication of WO2019205942A1 publication Critical patent/WO2019205942A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/733—Fructosans, e.g. inulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/64—Orobanchaceae (Broom-rape family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8969—Polygonatum (Solomon's seal)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the application number of this application is 201810395768.1 (the application date is April 27, 2018, the invention name is “a compound preparation for improving SCFA-producing bacteria in the intestinal tract and its preparation method and application"), 201810394911.5 (application date is April 2018)
  • the invention was titled “a composite preparation for regulating the expression of fat metabolism genes and its preparation method and application”), 201810393624.2 (the application date is April 27, 2018, the invention name is “a composite preparation for improving insulin resistance and Preparation method and application”) and 201810395759.2 (application date is April 27, 2018, the invention name is "a compound preparation for improving the ratio of AKK bacteria/pathogenic bacteria in the intestinal tract and preparation method and application thereof")
  • Priority is hereby incorporated by reference in its entirety.
  • the present disclosure relates to the field of oral preparations, and in particular to a composite preparation for improving SCFA-producing bacteria in the intestinal tract, a preparation method and application thereof.
  • SCFA-producing bacteria in the intestine such as: Butyrivibrio butyric acid; Bifidobacterium bifidum; Bifidobacterium pseudocatenulatum; B. bisporus; Megasphaera
  • the ratio of the thick-walled bacteria/Bacteroides in the intestinal tract is significantly increased
  • beneficial bacteria such as: Akkermansia muciniphila, Akk bacteria; Bifidobacterium Bifidobacterium) specific gravity is significantly reduced;
  • conditional pathogens such as: Enterobacter cloacae Enterobacter cloacae
  • specific gravity increased significantly, induced inflammation
  • Intestinal flora can inhibit the expression of fasting induced adipocytokines (Fiaf), increase the activity of lipoprotein lipase (LPL) in fat cells, and induce fat deposition.
  • Fiaf fasting induced adipocytokines
  • LPL lipoprotein lipase
  • intestinal flora as an important part of symbiosis with the human body affects the nutrition, energy metabolism and immune status of the host.
  • the current validated conclusions are: intestinal flora imbalance is involved in the pathogenesis of metabolic diseases such as obesity and type 2 diabetes, and the mechanisms involved include excessive energy storage and chronic low-grade inflammation caused by metabolic endotoxemia.
  • the object of the present disclosure includes, for example, providing a composite preparation for improving SCFA-producing bacteria in the intestinal tract which is safe and can effectively regulate intestinal flora.
  • Another object of the present disclosure includes, for example, a method for preparing a composite preparation for improving SCFA-producing bacteria in the intestinal tract, which is simple in process and easy to industrialize.
  • Another object of the present disclosure includes, for example, the use of a composite preparation for improving SCFA-producing bacteria in the intestinal tract, the composite preparation for reducing the ratio of the thick-walled phylum/Bacteroides in the intestinal tract, and increasing the SCFA-producing bacterium Oral preparation of specific gravity.
  • the present disclosure provides a composite preparation for improving SCFA-producing bacteria in the intestine, which is prepared from the following raw materials, and the raw materials include:
  • the present disclosure also provides a composite preparation for improving SCFA-producing bacteria in the intestine, which is prepared from the following raw materials, and the raw materials include:
  • the oligosaccharide is selected from the group consisting of inulin, oligofructose, xylooligosaccharide, galactooligosaccharide, oligoisomaltose, polydextrose, resistant dextrin, L-ara At least one of a combination of a sugar and a konjac glucomannan composition.
  • the present disclosure provides a composite preparation for improving SCFA-producing bacteria in the intestinal tract.
  • the raw materials include: 1%-10% inulin, 1%-5% oligomerization by mass percentage. Xylose, 2%-10% galactooligosaccharide, 2%-5% oligo-isomaltose, 5%-10% polydextrose, 5%-10% resistant dextrin, 5%-10% L arabinose and 1%-3% konjac glucomannan.
  • the main component of the plant extract is a plant polysaccharide.
  • the plant extract is selected from the group consisting of seaweed extract, kelp extract, huangjing extract, medlar extract, medlar extract, pueraria flavonoids and ginseng extract, and psyllium chinensis At least one of a combination of shell compositions.
  • the present invention provides a composite preparation for improving SCFA-producing bacteria in the intestinal tract.
  • the raw materials include: 5%-10% seaweed extract, 3%-5% kelp. Extract, 2%-4% Polygonatum extract, 3%-5% alfalfa extract, 5%-10% alfalfa extract, 1%-3% Pueraria flavonoids, 3%-6% round psyllium husk.
  • the main component of the bacterial extract is a fungal polysaccharide.
  • the fungal extract is at least one selected from the group consisting of a mushroom extract, a cordyceps extract, a ganoderma lucidum extract, a Hericium erinaceus extract, and a yeast extract.
  • the present invention provides a composite preparation for improving SCFA-producing bacteria in the intestinal tract.
  • the raw materials include: 4%-10% shiitake mushroom extract, 0.5-5% Cordyceps extract according to mass percentage. 1.5-5% Hericium erinaceus extract and 4%-10% yeast extract.
  • the raw material further comprises a white fungus extract, and the white fungus extract is used in an amount of 1% to 5% by mass of the fungal extract.
  • the raw material further comprises an extract of Dendrobium candidum, and the extract of Dendrobium candidum is 1% to 5% of the mass of the plant extract.
  • the raw material further comprises a flower extract
  • the flower extract is used in an amount of 2% to 10% by mass of the plant extract.
  • the flower extract is selected from at least one of the group consisting of peony flower extract, honeysuckle extract, and dandelion extract.
  • the flower extract is prepared according to the following preparation method: adding the raw material of the flower to the yeast for fermentation, filtering, ripening, and clarifying to obtain a flower and fruit fermentation liquid; filtering and concentrating the fermentation liquid; A powdery flower extract was obtained.
  • the present disclosure provides a method for preparing a composite preparation for improving SCFA-producing bacteria in the intestinal tract, which comprises the following steps:
  • the oligosaccharide, the plant extract, the fungal extract, the sodium taurate and the xanthine extract are mixed and ground.
  • the method for preparing the plant extract is as follows:
  • the selected plant raw materials are washed, pulverized and mixed, and added with 4-6 times weight and 60 ° C-80 ° C hot water extraction for 3-4 hours, and filtered to obtain an extract; after the extract is concentrated, ethanol precipitation is carried out to obtain a crude polysaccharide.
  • the crude polysaccharide is separated by chromatography and eluted with distilled water to obtain a polysaccharide liquid; after the polysaccharide liquid is concentrated, it is precipitated with ethanol and dried to obtain a powdery plant extract.
  • the fungal extract is prepared as follows:
  • the fungal raw material is dried and fully ground, and then added with 10-20 volumes of pure water, extracted at 70-80 ° C for 3-4 hours, and filtered to obtain an extract; the extract is centrifuged at 3000-5000 r/min for 10-15 minutes. The supernatant was taken; the supernatant was concentrated, and precipitated with ethanol; the precipitate was taken and dried to obtain a powdery fungal extract.
  • the preparation method of the astragalus extract is as follows:
  • microwave extraction device of the Huangqi set microwave power 500W-900W, temperature 70 °C, a total of 3 extractions, the first addition of 50%-90% ethanol, extraction 10min-30min; the second addition 50%-90% Ethanol, extracting for 10min-30min; adding distilled water for the third time, extracting for 20min-40min;
  • the first and second ethanol extracts were concentrated to remove ethanol, and the third aqueous extract was added thereto, mixed, and concentrated to obtain a powdery xanthine extract.
  • the present disclosure proposes an application of the above-mentioned composite preparation for improving SCFA-producing bacteria in the intestinal tract.
  • the composite preparation is used for preparing an oral preparation for reducing the ratio of the thick-walled mycelium/Bacteroides in the intestinal tract and increasing the specific gravity of the SCFA-producing bacteria.
  • Advantageous effects of the composite preparation for improving SCFA-producing bacteria in the intestinal tract and the preparation method and application thereof of the embodiments of the present disclosure include, for example, a composite preparation for improving SCFA-producing bacteria in the intestinal tract, which is the following by mass percentage Raw materials prepared: 22%-63% oligosaccharides; 22%-43% plant extracts; 10%-30% fungal extracts; 0.5%-5% sodium taurate; and 0.5%-5% scutellaria extract
  • the composite preparation has good safety and can effectively regulate intestinal flora.
  • the preparation method of the composite preparation is that the oligosaccharide, the plant extract, the fungal extract, the sodium taurine and the xanthine extract are mixed and ground, and the process is simple and easy to industrialize.
  • the use of the composite preparation for improving SCFA-producing bacteria in the intestinal tract of the embodiments of the present disclosure is an oral preparation for preparing a composite preparation for reducing the ratio of the thick-walled bacteria/Bacteroides in the intestinal tract and increasing the specific gravity of the SCFA-producing bacteria.
  • the embodiments of the present disclosure provide a composite preparation for improving SCFA-producing bacteria in the intestinal tract, which is prepared from the following raw materials, and the raw materials include: 22%-63% oligosaccharides; 22%-43% plant extracts by mass percentage 10%-30% fungal extract; 0.5%-5% sodium taurate; and 0.5%-5% xanthine extract.
  • the raw material comprises: 35%-50% oligosaccharide; 30%-35% plant extract; 15%-25% fungal extract; 2%-5% sodium taurate; and 1%-4% jaundice Extract.
  • the oligosaccharide is selected from the group consisting of inulin, oligofructose, xylooligosaccharide, galacto-oligosaccharide, oligo-isomaltose, polydextrose, resistant dextrin, L-arabinose and konjac glucomannan. At least one of them.
  • the raw materials include 1%-10% inulin, 1%-5% xylooligosaccharide, 2%-10% galacto-oligosaccharide, 2%-5% oligomeric isomaltose, 5%-by mass percent. 10% polydextrose, 5%-10% resistant dextrin, 5%-10% L arabinose and 1%-3% konjac glucomannan.
  • plant extracts are obtained by plant extraction, mostly plant polysaccharides.
  • the plant extract is selected from the group consisting of seaweed extract, kelp extract, extract of Rhizoma Polygonati, extract of alfalfa, extract of alfalfa, extract of Pueraria lobata (ie, Pueraria lobata extract), ginseng extract, and composition of psyllium psyllium. At least one of the combinations.
  • the front hull of the round shovel is the outer shell of the seed of the planted psyllium (Llant name: Plantago ovata), which can be directly ground.
  • the raw materials include 5%-10% seaweed extract, 3%-5% kelp extract, 2%-4% huangjing extract, 3%-5% quince extract, 5%-10% by mass percentage.
  • the fungal extract is obtained by fungal extraction, mostly fungal polysaccharides.
  • the fungal extract is at least one selected from the group consisting of a mushroom extract, a cordyceps extract, a ganoderma lucidum extract, a Hericium erinaceus extract, and a yeast extract.
  • the raw materials include 4% to 10% of mushroom extract, 0.5-5% of Cordyceps extract, 1.5-5% of Hericium erinaceus extract, and 4% to 10% of yeast extract by mass percentage.
  • the raw material may further comprise Tremella extract, and the Tremella extract is used in an amount of from 1% to 5% by mass of the fungal extract.
  • the raw material further comprises Dendrobium candidum extract, and the Dendrobium candidum extract is 1% to 5% by mass of the plant extract.
  • the raw material further comprises a flower extract
  • the flower extract is used in an amount of from 2% to 10% by mass of the plant extract.
  • the flower extract is selected from at least one of a combination of a peony flower extract, a honeysuckle extract, and a dandelion extract.
  • the composite preparation of the present embodiment is prepared by using oligosaccharides, plant extracts, fungal extracts, sodium taurate and astragalus extract, wherein oligosaccharides, plant extracts, fungal extracts, sodium taurate synergistically, It can effectively reduce the ratio of thick-walled bacteria/Bacteroides in the intestine and increase the specific gravity of SCFA-producing bacteria.
  • Embodiments of the present disclosure provide a method for preparing a composite preparation for improving SCFA-producing bacteria in the intestinal tract, which comprises the following steps:
  • the oligosaccharide, the plant extract, the fungal extract, the sodium taurate and the xanthine extract are mixed and ground.
  • the plant extract can be purchased as a high-purity extract, or can be prepared according to the following preparation method:
  • the selected plant raw materials are washed, pulverized and mixed, and added with 4-6 times weight and 60 ° C-80 ° C hot water extraction for 3-4 hours, and filtered to obtain an extract; after the extract is concentrated, ethanol precipitation is carried out to obtain a crude polysaccharide.
  • the crude polysaccharide is separated by chromatography and eluted with distilled water to obtain a polysaccharide liquid; after the polysaccharide liquid is concentrated, it is precipitated with ethanol and dried to obtain a powdery plant extract.
  • the fungal extract can be purchased as a high-purity extract, or can be prepared according to the following preparation method:
  • the fungal raw material is dried and fully ground, and then added with 10-20 volumes of pure water, extracted at 70-80 ° C for 3-4 hours, and filtered to obtain an extract; the extract is centrifuged at 3000-5000 r/min for 10-15 minutes. The supernatant was taken; the supernatant was concentrated, and precipitated with ethanol; the precipitate was taken and dried to obtain a powdery fungal extract.
  • the flower extract can be purchased or prepared according to the following preparation methods:
  • the flower raw material is added to the yeast for fermentation, filtered, matured, and clarified to obtain a flower and fruit fermentation liquid; the fermentation liquid is filtered and concentrated to obtain a powdery flower extract.
  • the extract of Astragalus membranaceus can be purchased or prepared according to the following preparation method: the microwave extraction device of the radix scutellariae is weighed, the microwave power is 500W-900W, the temperature is 70 ° C, and the total extraction is 3 times, and the first time is 50%-90. % ethanol, extract 10min-30min; add 25% 50%-90% ethanol, extract 10min-30min; add distilled water for the third time, extract 20min-40min.
  • the first and second ethanol extracts were concentrated to remove ethanol, and the third aqueous extract was added thereto, mixed, and concentrated to obtain a powdery xanthine extract.
  • Embodiments of the present disclosure provide the above-described use of a composite preparation for improving SCFA-producing bacteria in the intestinal tract.
  • the composite preparation has the function of significantly reducing the ratio of the thick-walled bacteria/Bacteroides in the intestinal tract, and significantly increasing the specific gravity of various SCFA-producing bacteria in the intestinal tract, thereby making the imbalanced intestinal flora normalization.
  • the composite preparation can be used for the preparation of an oral preparation for reducing the ratio of the thick-walled bacteria/Bacteroides in the intestinal tract and increasing the specific gravity of the SCFA-producing bacteria. More specifically, the composite preparation is used for the preparation of an oral preparation for improving the symptoms of obesity in obese people.
  • One of the key factors of intestinal flora imbalance is the ratio of the thick-walled bacteria/Bacteroides gate, and one of the functions of the composite preparation is to significantly reduce the ratio of the thick-walled bacteria/Bacteroides in the intestinal tract, thereby improving the obese Obesity symptoms:
  • the ratio of the thick-walled bacteria/Bacteroides gate is positively correlated with obesity. In the intestinal tract of obese people, there are relatively few Bacteroides and relatively thick-walled bacteria.
  • the composite preparation can significantly reduce the abundance of the fertilized bacteria in the thick-walled bacteria: the abundance of the 14a/4 clusters of the bacterium, the genus Clostridium, and induce the rapid transformation of the intestinal flora.
  • the abundance of the 25 genus changes significantly, and the folic acid production Streptococcus and Lactococcus are rapidly increasing, accompanied by elevated serum folate levels, improving the quality of life of obese people.
  • Another key factor in intestinal flora imbalance is the proportion of SCFA-producing bacteria in the intestine, and one of the functions of the composite preparation is to significantly increase the specific gravity of various SCFA-producing bacteria in the intestine, thereby improving the obesity symptoms of obese people:
  • SCFA-producing bacteria produce a large amount of SCFA to regulate the production, transportation and function of innate immune and adaptive immune cells;
  • SCFA inhibits liver cholesterol synthesis or redistributes cholesterol in plasma and liver, and lowers plasma cholesterol concentration
  • Acetic acid in SCFA is a molecular source of energy for liver and peripheral tissues and molecular signals of gluconeogenesis to promote fat burning;
  • Propionate inhibits lipogenic enzymes and lowers blood lipid levels
  • Butyric acid in SCFA not only provides energy for intestinal epithelium, but also helps to maintain intestinal mucosal integrity. It can also directly act on immune cells in intestinal mucosa, increasing the number and activity of Treg to maintain normal immune function;
  • butyric acid can also inhibit the inflammatory response, plays an important role in apoptosis and cell proliferation;
  • SCFA can regulate the expression of glucagon in the precursors of GLP-1 and PYY peptides, and stimulate the release of satiety factors such as CCK and GLP-1, as well as reduce the secretion of gastric growth hormone, resulting in satiety and thus reducing food. Ingestion, reducing body weight and accumulation of fat.
  • oligosaccharide 100 g inulin, 100 g oligofructose, 100 g xylooligosaccharide, 90 g galactooligosaccharide, 50 g oligo-isomaltose, 50 g polydextrose, 50 g resistant dextrin, 50 g L arabinose and 40 g Konjac glucomannan
  • 230 g plant extract 50 g kelp extract, 80 g scutellaria extract, 50 g sorghum extract, 50 g sorghum extract
  • 120 g fungal extract 60 g mushroom extract, 40 g cordyceps extract, 20 g yeast) Extract
  • 10 g of sodium taurate 60 g mushroom extract, 40 g cordyceps extract, 20 g yeast
  • 220 g oligosaccharide 50 g galactooligosaccharide, 50 g oligo isomaltose, 50 g polydextrose, 50 g L arabinose and 20 g konjac glucomannan
  • 430 g plant extract 100 g kelp extract, 80 g huangjing extract
  • 300 g of fungal extract 100 g of mushroom extract, 50 g of cordyceps extract, 100 g of extract of Hericium erinaceus and 50 g of yeast extract
  • 25 g of astragalus extract 10 g of Dendrobium candidum extract.
  • the oligosaccharide, the plant extract, the fungal extract, the sodium taurine and the xanthine extract, and the Dendrobium candidum extract are mixed and ground.
  • oligosaccharide 100 g inulin, 100 g oligofructose, 100 g xylooligosaccharide, 100 g galactooligosaccharide, 100 g oligo-isomalt
  • 300 g plant extract 100 g seaweed extract, 100 g yellow essence extract
  • 50g of alfalfa extract, 50g of alfalfa extract 50g of alfalfa extract
  • 150g of fungal extract 50g of mushroom extract, 50g of cordyceps extract, 50g of extract of Hericium erinaceus
  • 25g of sodium taurate and 25g of astragalus extract
  • 8g of white fungus extract Things 50g of white fungus extract Things.
  • the oligosaccharide, the plant extract, the fungal extract, the sodium taurine and the xanthine extract, and the white fungus extract are mixed and ground.
  • oligosaccharide 50g inulin, 50g oligofructose, 50g xylooligosaccharide, 50g galactooligosaccharide, 50g oligo-isomaltose, 50g polydextrose, 50g resistant dextrin
  • 350g plant extract 50 g seaweed extract, 50 g kelp extract, 100 g scutellaria extract, 50 g sorghum extract, 50 g sorghum extract and 50 g ginseng extract
  • 250 g fungal extract 100 g mushroom extract, 50 g cordyceps extract, 50 g monkey head
  • Mushroom extract and 50 g of yeast extract
  • 25 g of sodium taurate and 25 g of astragalus extract.
  • oligosaccharide 50g inulin, 50g xylooligosaccharide, 50g galacto-oligosaccharide, 30g oligo-isomaltose, 50g polydextrose, 50g resistant dextrin, 100gL arabinose and 40g konjac glucomannan
  • 320g plant extract 50g seaweed extract, 50g kelp extract, 50g scutellaria extract, 30g sorghum extract, 60g sorghum extract and 30g puerarin, 50g psyllium husk
  • 200g fungal extract 40 g of mushroom extract, 40 g of Cordyceps extract, 40 g of Hericium erinaceus extract and 40 g of yeast extract
  • 20 g of sodium taurate and 40 g of astragalus extract.
  • oligosaccharide 50g inulin, 50g xylooligosaccharide, 50g galacto-oligosaccharide, 30g oligo-isomaltose, 50g polydextrose, 50g resistant dextrin, 100gL arabinose and 40g konjac glucomannan
  • 320g plant extract 50g seaweed extract, 50g kelp extract, 50g scutellaria extract, 30g sorghum extract, 60g sorghum extract and 30g puerarin, 50g psyllium husk
  • 200g fungal extract 40 g of shiitake mushroom extract, 40 g of Cordyceps extract, 40 g of extract of Hericium erinaceus and 40 g of yeast extract
  • 40 g of xanthine extract 30 g of peony flower extract.
  • the oligosaccharide, the plant extract, the fungal extract, the sodium taurine and the xanthine extract, and the peony flower extract are mixed and ground.
  • mice Female BALb/c mice, 4 weeks old (body weight 20 ⁇ 1g), SPF grade, were purchased from Hubei Experimental Animal Research Center. Raised in the SPF animal room. Oral feed (fat calorie 10%) and high-fat high-protein feed (fat calories 40% or more) fed to mice were purchased from the Hubei Animal Research Center, and mice were given free access to water during feeding.
  • mice After adaptive feeding for 1 week, the mice were randomly divided into 3 groups, 12 in each group:
  • Blank control group continuous feeding of common feed
  • Conditional control group After feeding high-fat feed for 6 weeks, the feed was changed to normal feed for 1 week;
  • Example 5 The compound preparation of Example 5 was changed to 6 weeks after continuous feeding of the high fat diet, and each mouse was perfused for 1 week at a dose of 1 g/kg.
  • mice were dissected, fresh intestinal feces were collected to the corresponding labeled cryotubes and stored at -80 °C until use.
  • mice obesity model The results of induction of mouse obesity model can be seen from the table.
  • the changes in body weight of the high-fat diet (P ⁇ 0.05) in the control group and the experimental group were significantly higher than those in the control group.
  • the weight gain of the comparison group was ⁇ 20%.
  • Mouse obesity model The changes in body weight of the high-fat diet (P ⁇ 0.05) in the control group and the experimental group were significantly higher than those in the control group.
  • the weight gain of the comparison group was ⁇ 20%.
  • mice After the fresh feces of the mice were pretreated, the samples were filtered and the supernatant was subjected to internal standard GC to detect the content of SCFA (acetic acid, propionic acid, n-butyric acid).
  • SCFA acetic acid, propionic acid, n-butyric acid
  • the intestinal SCFA acetic acid, propionic acid, n-butyric acid
  • the intestinal SCFA of the control group was significantly lower than that in the blank group (P ⁇ 0.01); the acetic acid content in the experimental group was still lower than that in the blank group.
  • the intestinal SCFA of the control group was significantly increased (P ⁇ 0.05). It indicated that the intestinal flora disorder caused by high-fat feeding had obvious recovery and close to normal state after 1 week of compound preparation intervention.
  • the 454 GS FLX sequencing technology was used to sequence the 16S rRNA gene V1-V3 hypervariable region of the intestinal flora of different groups of mice (3 samples in each group). The results showed that there were mainly 5 bacteria (>95%). ), respectively, thick-walled bacteria, Bacteroidetes, Proteobacteria, Ferribacter, and actinomycetes; the statistical results are as follows:
  • the conditional control group fed with high-fat and high-protein feed was significantly reduced in the production of butyric acid-producing bacteria (H. genus), the Bacteroides was significantly reduced, but the number of Bacteroides monocytogenes increased, and the Escherichia coli had a certain abundance.
  • Akkermansia muciniphila was significantly reduced; in general, the conditional pathogens in the control group increased, and the intestinal barrier state decreased in the intestinal disorder.
  • the abundance of Akkermansia muciniphila was significantly enriched in the experimental group after 1 week of compound preparation intervention.
  • the SCFA-producing bacteria increased significantly, and the number of conditional pathogens decreased. It is considered that the intestinal immune function is significantly enhanced.
  • the composite microbial agent of the examples of the present disclosure has the effect of down-regulating the ratio of the phylum of the phylum of the phylum of the genus Bacteroides and the Bacteroides. Therefore, the composite bacterium of the embodiment of the present disclosure It can effectively regulate the intestinal flora, thereby improving the obesity symptoms of obese people.
  • the composite preparation for improving SCFA-producing bacteria in the intestinal tract of the embodiment of the present invention has the functions of increasing the abundance of SCFA-producing bacteria and quantifying SCFA, and has good safety and can effectively regulate intestinal flora;
  • the preparation method has the advantages of simple process, easy industrial production and industrial applicability.
  • the application of the composite preparation for improving SCFA-producing bacteria in the intestinal tract of the embodiments of the present disclosure is a composite preparation for preparing an oral preparation for reducing the ratio of the thick-walled bacteria/Bacteroides in the intestinal tract and increasing the specific gravity of the SCFA-producing bacteria, thereby making the imbalance
  • the intestinal flora normalizes and improves obesity in obese people.

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Abstract

一种提高肠道中SCFA产生菌的复合制剂及其制备方法与应用，该复合制剂是由按质量百分数计的以下原料制备而成：22％-63％低聚糖，22％-43％植物提取物，10％-30％真菌提取物，0.5％-5％牛磺酸钠以及0.5％-5％黄芪提取物。制备方法是将低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物混合、研磨即得。该复合制剂用于制备减少肠道中厚壁菌门/拟杆菌门的比值，增大SCFA产生菌的比重的口服制剂。

Description

一种提高肠道中SCFA产生菌的复合制剂及制备方法与应用
相关申请的交叉引用
本申请要求申请号为201810395768.1(申请日为2018年04月27日，发明名称为“一种提高肠道中SCFA产生菌的复合制剂及制备方法与应用”)、201810394911.5(申请日为2018年04月27日，发明名称为“一种调控脂肪代谢基因表达的复合制剂及制备方法与应用”)、201810393624.2(申请日为2018年04月27日，发明名称为“一种改善胰岛素抵抗的复合制剂及制备方法与应用”)和201810395759.2(申请日为2018年04月27日，发明名称为“一种提高肠道中AKK菌/致病菌比值的复合制剂及制备方法与应用”)的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本公开涉及口服制剂领域，且特别涉及一种提高肠道中SCFA产生菌的复合制剂及制备方法与应用。
背景技术
经研究表明，人体内的肠道菌群变化会导致肥胖，其产生机制为：高热量食物经过牙齿的咀嚼和胃的初步降解之后进入肠道，寄居在肠道里的微生物负责完成剩下的消化工作；在微生物的发酵过程中，会有大量的乙酸盐产生，这些乙酸盐被肠道吸收，随血液循环穿过血脑屏障，进入大脑；进入大脑的乙酸盐会激活副交感神经系统。被乙酸盐激活的副交感神经会给胰岛发出分泌胰岛素(insulin)的指令，于是β细胞开始大量分泌胰岛素，细胞启动储存能量的程序；于此同时，副交感神经又给胃发出了释放饥饿激素(ghrelin)和胃泌素(gastrin)的指令，饥饿激素大量产生，饥饿感随之而来。
另外，长期摄入高脂肪食物会导致肠道菌群失调，使肠道中存在更高水平的乙酸，这种正向的调节机制使食量越来越大，从而促进肥胖，和产生胰岛素抵抗。肥胖发展过程中肠道优势菌群变化会促使肠道微生物环境进一步失调：
1、肠道中SCFA产生菌(比如：Butyrivibrio丁酸弧菌属；Bifidobacterium bifidum双歧杆菌；Bifidobacterium pseudocatenulatum假链状双歧杆菌；Megasphaera巨球型菌属)的比重显著降低；
2、肠道中厚壁菌门/拟杆菌门的比值显著增加；
3、有益菌群(比如：Akkermansia muciniphila，Akk菌；Bifidobacterium双歧杆菌属) 比重显著降低；
4、条件致病菌(比如：Enterobacter cloacae阴沟肠杆菌)比重显著增加，诱发炎症反应；
5、肠道菌群能够抑制禁食诱导脂肪细胞因子(Fiaf)的表达，增加脂肪细胞脂蛋白酯酶(LPL)活性，诱导脂肪的沉积。
总之，肠道菌群作为与人体共生的一个重要部分，影响着宿主的营养、能量代谢和免疫状况。目前已验证的结论有：肠道菌群失调参与了肥胖和2型糖尿病等代谢性疾病的发病，涉及的机制包括过度能量存储以及代谢性内毒素血症导致的慢性低度炎症等。
因此，需要一种能有效调节肠道菌群、且安全性高的口服制剂。
发明内容
本公开的目的包括，例如，提供一种提高肠道中SCFA产生菌的复合制剂，其安全性好，能有效调节肠道菌群。
本公开的另一目的包括，例如，提供一种提高肠道中SCFA产生菌的复合制剂的制备方法，该工艺简单，易产业化生产。
本公开的另一目的包括，例如，提供一种提高肠道中SCFA产生菌的复合制剂的应用，复合制剂用于制备减少肠道中厚壁菌门/拟杆菌门的比值，增大SCFA产生菌的比重的口服制剂。
本公开解决其技术问题是采用以下技术方案来实现的。
本公开提出一种提高肠道中SCFA产生菌的复合制剂，其是由以下原料制备而成，按质量百分数计，原料包括：
Figure PCTCN2019082118-appb-000001
本公开还提出一种提高肠道中SCFA产生菌的复合制剂，其是由以下原料制备而成，按质量百分数计，原料包括：
Figure PCTCN2019082118-appb-000002
Figure PCTCN2019082118-appb-000003
可选地，在本公开较佳实施例中，低聚糖选自菊粉、低聚果糖、低聚木糖、低聚半乳糖、低聚异麦芽糖、聚葡萄糖、抗性糊精、L阿拉伯糖和魔芋葡甘聚糖组成的组合中的至少一种。
可选地，在本公开较佳实施例中，本公开提供的提高肠道中SCFA产生菌的复合制剂，按质量百分数计，原料包括：1％-10％菊粉、1％-5％低聚木糖、2％-10％低聚半乳糖、2％-5％低聚异麦芽糖、5％-10％聚葡萄糖、5％-10％抗性糊精、5％-10％L阿拉伯糖和1％-3％魔芋葡甘聚糖。
可选地，在本公开较佳实施例中，植物提取物的主要成分为植物多糖。
可选地，在本公开较佳实施例中，植物提取物选自海藻提取物、昆布提取物、黄精提取物、茯苓提取物、枸杞提取物、葛根黄酮和人参提取物、圆苞车前子壳组成的组合中的至少一种。
可选地，在本公开较佳实施例中，本公开提供的提高肠道中SCFA产生菌的复合制剂，按质量百分数计，原料包括：5％-10％海藻提取物、3％-5％昆布提取物、2％-4％黄精提取物、3％-5％茯苓提取物、5％-10％枸杞提取物、1％-3％葛根黄酮、3％-6％圆苞车前子壳。
可选地，在本公开较佳实施例中，菌提取物的主要成分为真菌多糖。
可选地，在本公开较佳实施例中，真菌提取物选自香菇提取物、虫草提取物、灵芝提取物、猴头菇提取物和酵母提取物组成的组合中的至少一种。
可选地，在本公开较佳实施例中，本公开提供的提高肠道中SCFA产生菌的复合制剂，按质量百分数计，原料包括：4％-10％香菇提取物、0.5-5％虫草提取物、1.5-5％猴头菇提取物和4％-10％酵母提取物。
可选地，在本公开较佳实施例中，原料还包括银耳提取物，银耳提取物的使用量为真菌提取物质量的1％-5％。
可选地，在本公开较佳实施例中，原料还包括铁皮石斛提取物，铁皮石斛提取物为植物提取物质量的1％-5％。
可选地，在本公开较佳实施例中，原料还包括鲜花提取物，鲜花提取物的使用量为植物提取物质量的2％-10％。
可选地，在本公开较佳实施例中，鲜花提取物选自牡丹花提取物、金银花提取物和蒲公英提取物组成的组合中的至少一种。
可选地，在本公开较佳实施例中，鲜花提取物按照以下制备方法制备得到：将鲜花原料加入酵母进行发酵，过滤、后熟、澄清得到花果发酵液；将发酵液过滤、浓缩， 得到粉状的鲜花提取物。
本公开提出一种上述的提高肠道中SCFA产生菌的复合制剂的制备方法，其包括以下步骤：
将低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物混合、研磨即得。
可选地，在本公开较佳实施例中，植物提取物的制备方法如下：
将选取的植物原料清洗、粉碎后混合，添加4-6倍重量、60℃-80℃的热水提取3-4小时，过滤得到提取液；将提取液浓缩后，再用乙醇沉淀得到粗品多糖；将粗品多糖经层析分离、蒸馏水洗脱，得到多糖液；将多糖液浓缩后，再用乙醇沉淀，干燥得到粉状的植物提取物。可选地，在本公开较佳实施例中，真菌提取物的制备方法如下：
将真菌原料干燥后充分研磨，再加10-20倍体积纯水，于70-80℃下提取3-4小时，过滤得到提取液；将提取液经3000-5000r/min离心10-15分钟后取上清液；将上清液浓缩后，用乙醇沉淀；取沉淀，干燥后得到粉状的真菌提取物。
可选地，在本公开较佳实施例中，黄芪提取物的制备方法如下：
称取黄芪置微波提取装置中，微波功率500W-900W，温度70℃，共提取3次，第1次加50％-90％的乙醇，提取10min-30min；第2次加50％-90％乙醇，提取10min-30min；第3次加蒸馏水，提取20min-40min；以及
再将第1、2次的乙醇提取液浓缩，除去乙醇，再加入第3次的水提取液，混合，浓缩，得到粉状的黄芪提取物。
本公开提出一种上述的提高肠道中SCFA产生菌的复合制剂的应用，复合制剂用于制备减少肠道中厚壁菌门/拟杆菌门的比值，增大SCFA产生菌的比重的口服制剂。
本公开实施例的提高肠道中SCFA产生菌的复合制剂及制备方法与应用的有益效果包括，例如，本公开实施例的提高肠道中SCFA产生菌的复合制剂，其是由按质量百分数计的以下原料制备而成：22％-63％低聚糖；22％-43％植物提取物；10％-30％真菌提取物；0.5％-5％牛磺酸钠；以及0.5％-5％黄芪提取物，该复合制剂的安全性好，能有效调节肠道菌群。复合制剂的制备方法是将低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物混合、研磨即得，该工艺简单，易产业化生产。本公开实施例的提高肠道中SCFA产生菌的复合制剂的应用是复合制剂用于制备减少肠道中厚壁菌门/拟杆菌门的比值，增大SCFA产生菌的比重的口服制剂。
具体实施方式
为使本公开实施例的目的、技术方案和优点更加清楚，下面将对本公开实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者，按照常规条件或制造商建议 的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
下面对本公开实施例的提高肠道中SCFA产生菌的复合制剂及制备方法与应用进行具体说明。
本公开实施例提供一种提高肠道中SCFA产生菌的复合制剂，其是由以下原料制备而成，按质量百分数计，原料包括：22％-63％低聚糖；22％-43％植物提取物；10％-30％真菌提取物；0.5％-5％牛磺酸钠；以及0.5％-5％黄芪提取物。优选的，原料包括：35％-50％低聚糖；30％-35％植物提取物；15％-25％真菌提取物；2％-5％牛磺酸钠；以及1％-4％黄芪提取物。
其中，低聚糖选自菊粉、低聚果糖、低聚木糖、低聚半乳糖、低聚异麦芽糖、聚葡萄糖、抗性糊精、L阿拉伯糖和魔芋葡甘聚糖组成的组合中的至少一种。例如，按质量百分数计，原料包括1％-10％菊粉、1％-5％低聚木糖、2％-10％低聚半乳糖、2％-5％低聚异麦芽糖、5％-10％聚葡萄糖、5％-10％抗性糊精、5％-10％L阿拉伯糖和1％-3％魔芋葡甘聚糖。
其中，植物提取物是采用植物提取得到的，多为植物多糖。本实施例中，植物提取物选自海藻提取物、昆布提取物、黄精提取物、茯苓提取物、枸杞提取物、葛根黄酮(即葛根提取物)和人参提取物、圆苞车前子壳组成的组合中的至少一种。圆苞车前子壳是人工种植的车前科车前属圆苞车前(拉丁学名：Plantago ovata)种子的外壳，可以直接磨粉使用。例如，按质量百分数计，原料包括5％-10％海藻提取物、3％-5％昆布提取物、2％-4％黄精提取物、3％-5％茯苓提取物、5％-10％枸杞提取物、1％-3％葛根黄酮、3％-6％圆苞车前子壳。
其中，真菌提取物是采用真菌提取得到的，多为真菌多糖。本实施例中，真菌提取物选自香菇提取物、虫草提取物、灵芝提取物、猴头菇提取物和酵母提取物组成的组合中的至少一种。例如，按质量百分数计，原料包括4％-10％香菇提取物、0.5-5％虫草提取物、1.5-5％猴头菇提取物和4％-10％酵母提取物。
在其他实施例中，原料还可以包括银耳提取物，银耳提取物的使用量为真菌提取物质量的1％-5％。
在其他实施例中，原料还包括铁皮石斛提取物，铁皮石斛提取物为植物提取物质量的1％-5％。
在其他实施例中，原料还包括鲜花提取物，鲜花提取物的使用量为植物提取物质量的2％-10％。鲜花提取物选自牡丹花提取物、金银花提取物和蒲公英提取物组成的组合中的至少一种。
本实施例的复合制剂采用低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物制成，其中低聚糖、植物提取物、真菌提取物、牛磺酸钠协同作用，能够有效减少肠道中 厚壁菌门/拟杆菌门的比值，增大SCFA产生菌的比重。
本公开实施例提供一种上述的提高肠道中SCFA产生菌的复合制剂的制备方法，其包括以下步骤：
将低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物混合、研磨即得。
其中，植物提取物可以购买得到的高纯度提取物，也可以按照以下制备方法制备得到：
将选取的植物原料清洗、粉碎后混合，添加4-6倍重量、60℃-80℃的热水提取3-4小时，过滤得到提取液；将提取液浓缩后，再用乙醇沉淀得到粗品多糖；将粗品多糖经层析分离、蒸馏水洗脱，得到多糖液；将多糖液浓缩后，再用乙醇沉淀，干燥得到粉状的植物提取物。其中，真菌提取物可以购买得到的高纯度提取物，也可以按照以下制备方法制备得到：
将真菌原料干燥后充分研磨，再加10-20倍体积纯水，于70-80℃下提取3-4小时，过滤得到提取液；将提取液经3000-5000r/min离心10-15分钟后取上清液；将上清液浓缩后，用乙醇沉淀；取沉淀，干燥后得到粉状的真菌提取物。
其中，鲜花提取物可以购买得到，也可以按照以下制备方法制备得到：
将鲜花原料加入酵母进行发酵，过滤、后熟、澄清得到花果发酵液；将发酵液过滤、浓缩，得到粉状的鲜花提取物。
其中，黄芪提取物可以购买得到，也可以按照以下制备方法制备得到：称取黄芪置微波提取装置中，微波功率500W-900W，温度70℃，共提取3次，第1次加50％-90％的乙醇，提取10min-30min；第2次加50％-90％乙醇，提取10min-30min；第3次加蒸馏水，提取20min-40min。
再将第1、2次的乙醇提取液浓缩，除去乙醇，再加入第3次的水提取液，混合，浓缩，得到粉状的黄芪提取物。
本公开实施例提供一种上述的提高肠道中SCFA产生菌的复合制剂的应用。针对肠道菌群失调的关键因素，复合制剂具有显著降低肠道中厚壁菌门/拟杆菌门的比值，显著提高肠道中多种SCFA产生菌的比重的功能，从而使失衡的肠道菌相正常化。相应的，复合制剂可用于制备减少肠道中厚壁菌门/拟杆菌门的比值，增大SCFA产生菌的比重的口服制剂。更具体的，复合制剂用于制备改善肥胖者肥胖症状的口服制剂。
肠道菌群失调的关键因素之一是厚壁菌门/拟杆菌门的比值，而复合制剂的功能之一是可显著降低肠道中厚壁菌门/拟杆菌门的比值，从而改善肥胖者的肥胖症状：
1、厚壁菌门/拟杆菌门的比值与肥胖呈正相关，肥胖者肠道中拟杆菌门的相对较少、厚壁菌门相对较多；
2、拟杆菌门的增加与减重百分比存在正相关，降低肠道中厚壁菌门/拟杆菌门的比值可 改善患者脂肪酸代谢，下调脂肪酸代谢、β-丙氨酸代谢和色氨酸代谢；
3、降低肠道中厚壁菌门/拟杆菌门的比值，可增加SCFA、促进瘦素分泌，增大能量消耗，显著减少脂肪生成、增强β-氧化(血清β-羟基丁酸浓度大幅上升)，抑制脂肪在脂肪组织的积累，使肝脏脂肪含量急剧下降；
4、复合制剂可显著降低厚壁菌门中的肥菌：颤杆菌、梭菌属14a/4簇的丰度，诱导肠道菌群快速转变，25个菌属丰度显著变化，产叶酸的链球菌属和乳球菌属迅速增多，伴随着血清叶酸水平上升，改善肥胖者生活质量。
肠道菌群失调的另一关键因素是肠道中SCFA产生菌的比重，而复合制剂的功能之一是可显著提高肠道中多种SCFA产生菌的比重，从而改善肥胖者的肥胖症状：
1、多种SCFA产生菌发酵产生多量SCFA可以调节先天免疫和适应性免疫细胞的产生、运输和功能；
2、SCFA抑制肝脏胆固醇合成或使胆固醇在血浆和肝脏中再分配，而降低血浆胆固醇浓度；
3、SCFA中的乙酸是肝脏和外周组织的能量来源和葡萄糖异生作用的分子信号，促进脂肪燃烧；
4、丙酸盐则抑制了脂肪生成酶，降低血脂水平；
5、SCFA中的丁酸不仅为肠上皮提供了能量，利于保持肠道粘膜完整性，也可直接作用于肠道粘膜处的免疫细胞，增加Treg的数量及活性维持正常免疫功能；
6、丁酸还可以抑制炎症反应，在细胞凋亡和细胞增生起重要作用；
7、SCFA可以调节GLP-1和PYY肽的前体胰高血糖素表达，通过刺激CCK，GLP-1等饱腹因子的释放，以及减少胃促生长激素的分泌，产生饱腹感从而减少食物摄入，降低体重和脂肪的蓄积。
以下结合实施例对本公开的特征和性能作进一步的详细描述。
实施例1
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：630g低聚糖(100g菊粉、100g低聚果糖、100g低聚木糖、90g低聚半乳糖、50g低聚异麦芽糖、50g聚葡萄糖、50g抗性糊精、50gL阿拉伯糖和40g魔芋葡甘聚糖)；230g植物提取物(50g昆布提取物、80g黄精提取物、50g茯苓提取物、50g枸杞提取物)；120g真菌提取物(60g香菇提取物、40g虫草提取物、20g酵母提取物)；10g牛磺酸钠；以及10g黄芪提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物混合、研磨即得。
实施例2
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：220g低聚糖(50g低聚半乳糖、50g低聚异麦芽糖、50g聚葡萄糖、50gL阿拉伯糖和20g魔芋葡甘聚糖)；430g植物提取物(100g昆布提取物、80g黄精提取物、100g茯苓提取物、100g枸杞提取物、20g葛根黄酮和30g人参提取物)；300g真菌提取物(100g香菇提取物、50g虫草提取物、100g猴头菇提取物和50g酵母提取物)；25g牛磺酸钠；以及25g黄芪提取物、10g铁皮石斛提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物、铁皮石斛提取物混合、研磨即得。
实施例3
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：500g低聚糖(100g菊粉、100g低聚果糖、100g低聚木糖、100g低聚半乳糖、100g低聚异麦芽糖)；300g植物提取物(100g海藻提取物、100g黄精提取物、50g茯苓提取物、50g枸杞提取物)；150g真菌提取物(50g香菇提取物、50g虫草提取物、50g猴头菇提取物)；25g牛磺酸钠；以及25g黄芪提取物；8g银耳提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物、银耳提取物混合、研磨即得。
实施例4
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：350g低聚糖(50g菊粉、50g低聚果糖、50g低聚木糖、50g低聚半乳糖、50g低聚异麦芽糖、50g聚葡萄糖、50g抗性糊精)；350g植物提取物(50g海藻提取物、50g昆布提取物、100g黄精提取物、50g茯苓提取物、50g枸杞提取物和50g人参提取物)；250g真菌提取物(100g香菇提取物、50g虫草提取物、50g猴头菇提取物和50g酵母提取物)；25g牛磺酸钠；以及25g黄芪提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物混合、研磨即得。
实施例5
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：420g低聚糖(50g菊粉、50g低聚木糖、50g低聚半乳糖、30g低聚异麦芽糖、50g聚葡萄糖、50g抗性糊精、100gL阿拉伯糖和40g魔芋葡甘聚糖)；320g植物提取物(50g海藻提取物、50g昆布提取物、50g黄精提取物、30g茯苓提取物、60g枸杞提取物和30g葛根黄酮、50g圆苞车前子壳)；200g真菌提取物(40g香菇提取物、40g虫草提取物、40g猴头菇提取物和40g酵母提取物)；20g牛磺酸钠；以及40g黄芪提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物混合、研磨即得。
实施例6
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：420g低聚糖(50g菊粉、50g低聚木糖、50g低聚半乳糖、30g低聚异麦芽糖、50g聚葡萄糖、50g抗性糊精、100gL阿拉伯糖和40g魔芋葡甘聚糖)；320g植物提取物(50g海藻提取物、50g昆布提取物、50g黄精提取物、30g茯苓提取物、60g枸杞提取物和30g葛根黄酮、50g圆苞车前子壳)；200g真菌提取物(40g香菇提取物、40g虫草提取物、40g猴头菇提取物和40g酵母提取物)；20g牛磺酸钠；以及40g黄芪提取物；30g牡丹花提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物、牡丹花提取物混合、研磨即得。
以下通过动物实验对本公开实施例的复合制剂的功效进行验证。
(1)实验动物：
雌性BALb/c小鼠，4周龄(体重20±1g)，SPF级，购于湖北省实验动物研究中心。饲养在SPF级动物房。喂养小鼠的普通饲料(脂肪热量10％)和高脂高蛋白饲料(脂肪热量40％以上)均购于湖北省动物研究中心，小鼠在喂养期间自由饮水。
(2)分组与干预：
小鼠适应性喂养1周后进行随机分组共分为3组，每组12只：
1、空白对照组：连续喂饲普通饲料；
2、条件对照组：连续喂饲高脂饲料6周后改为喂饲普通饲料1周；
3、实验组：连续喂饲高脂饲料6周后改为喂实施例5的复合制剂，每只小鼠每天以1g/kg的剂量灌喂1周。
小鼠样品收集：小鼠解剖后，采集肠道新鲜粪便至相应标记的冻存管，-80℃保存备用。
(3)肥胖小鼠模型的建立：
表1肥胖小鼠模型
Figure PCTCN2019082118-appb-000004
*P<0.05
小鼠肥胖模型诱导结果从表中可以看出条件对照组和实验组饲喂6周高脂饲料体重变化(P<0.05)显著大于对照组；对比空白组体重增加≥20％可视为典型的小鼠肥胖模型。
(4)结果分析：
①粪便短链脂肪酸SCFA的含量检测
小鼠新鲜粪便经预处理后，取样品过滤后上清液内标法GC检测SCFA(乙酸、丙酸、正丁酸)含量。
表2不同分组小鼠SCFA的含量变化
Figure PCTCN2019082118-appb-000005
对比空白组**P<0.01，对比条件对照组#P<0.05
实验至第8周结束时，条件对照组的小鼠肠道SCFA(乙酸、丙酸、正丁酸)显著低于空白组(P<0.01)；实验组的乙酸的含量仍低于空白组，丙酸与正丁酸对比空白组无显著差异(P＞0.05)；实验组对比条件对照组的小鼠肠道SCFA有明显上升(P<0.05)。说明高脂饲养导致的肠道菌群紊乱经过1周的复合制剂干预作用中有明显恢复并接近与正常状态。
②不同分组小鼠肠道菌群的门水平分析
运用454 GS FLX测序技术对不同分组小鼠(每组选取3个样本)肠道菌群的16S rRNA基因V1-V3高变区序列进行测序，结果检测出主要有5个菌门(>95％)，分别是厚壁菌门、拟杆菌门、变形菌门、脱铁杆菌门、放线菌门；统计结果如下：
表3小鼠肠道菌群的门水平
Figure PCTCN2019082118-appb-000006
从结果中可以看出，厚壁菌门和拟杆菌门是肠道菌群中的最主要优势菌门，厚壁菌门/拟杆菌门的比值各有差异，高脂高蛋白饲料喂养的条件对照组的厚壁菌门/拟杆菌门的比值显著高于普通饲料喂养的空白组(P<0.05)，而经过1周复合制剂干预下实验组厚壁菌门/拟杆菌门的比值发生了极显著的降低(P<0.05)，显示复合制剂可有效调节因肥胖引起的肠道菌群紊乱从而改变肠道菌群的代谢。
③不同分组小鼠肠道菌群的属、种水平分析
表4小鼠肠道菌群的属、种水平
Figure PCTCN2019082118-appb-000007
Figure PCTCN2019082118-appb-000008
对比空白组*P<0.05，对比条件对照组#P<0.05，##P<0.01
从结果看，高脂高蛋白饲料喂养的条件对照组在产丁酸菌(毛螺菌属)显著减少，拟杆菌属显著减少但单形拟杆菌增加，大肠埃希菌有一定丰度增加，Akkermansia muciniphila显著减少；总之对照组条件致病菌增加，肠屏障菌减少的肠道紊乱状态。对比对照组经过1周复合制剂干预的实验组Akkermansia muciniphila丰度显著富集，产SCFA菌明显增加，条件致病菌数量减少，认为肠道免疫功能显著加强。
按照上述相同的动物实验方法对本公开其他实施例的复合制剂的功效进行验证，结果显示本公开其他实施例的复合制剂具有相同或类似的功效。由上述不同分组小鼠SCFA的含量变化、不同分组小鼠肠道菌群的门水平分析，不同分组小鼠肠道菌群的属、种水平分析可知，本公开实施例的复合菌剂具有增加SCFA产生菌丰度以及SCFA定量的作用。由上述不同分组小鼠肠道菌群的门水平分析可知，本公开实施例的复合菌剂具有使厚壁菌门/拟杆菌门的比值下调的作用，因此，本公开实施例的复合菌剂能有效调节肠道菌群，从而改善肥胖者的肥胖症状。
以下通过临床实验对本公开实施例的复合制剂的功效进行验证。
(1)实验对象：
研究对象的总体特征：有430名受试者参与，其中男性202名，平均年龄为34.5±11.2岁；女性228名，平均年龄为36.9±12.1岁。本次项目的所有受试者随机选自国内10个不同省份地区。
已有研究表明，男性体脂率(PBF％)平均值为22.7％，低于女性的28.9％，标准体脂率(PBF％))如下：
表5标准体脂率
Figure PCTCN2019082118-appb-000009
表6成年人超重与肥胖评判标准
Figure PCTCN2019082118-appb-000010
Figure PCTCN2019082118-appb-000011
表7受试者体型分布
Figure PCTCN2019082118-appb-000012
(2)干预治疗
不同体型分组的受试者统一剂量服用实施例6的复合制剂；服用复合制剂期间(7天)禁食；禁食前，3天预先调整饮食，清淡素食为主。禁食期：本产品完全代替一日三餐，早中晚各服用15g/袋，粉剂使用37℃温水冲服，每日饮水3-5L。禁食期之后经7天复食期恢复正常饮食。
(3)数据统计：
本实验所涉及的数据结果均为计量资料，全部数据以均数和标准差
Figure PCTCN2019082118-appb-000013
表示。
表8不同分组体脂率变化
Figure PCTCN2019082118-appb-000014
对比干预前*P＜0.05
结果显示，连续7天使用复合制剂代替正常饮食的干预治疗的减脂效果具有统计学显著意义(P＜0.05)。
综上所述，本公开实施例的提高肠道中SCFA产生菌的复合制剂，即具有增加SCFA产生菌丰度以及SCFA定量的作用，其安全性好，能有效调节肠道菌群；该复合制剂的制备方法的工艺简单，易产业化生产，具备工业实用性。本公开实施例的提高肠道中SCFA产生菌的复合制剂的应用是复合制剂用于制备减少肠道中厚壁菌门/拟杆菌门的比值，增大SCFA产生菌的比重的口服制剂，从而使失衡的肠道菌相正常化并改善肥胖者的肥胖症状。
以上所描述的实施例是本公开一部分实施例，而不是全部的实施例。本公开的实施例的详细描述并非旨在限制要求保护的本公开的范围，而是仅仅表示本公开的选定实施例。基于本公开中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本公开保护的范围。

Claims (20)

  1. 一种提高肠道中SCFA产生菌的复合制剂，其特征在于，其是由以下原料制备而成，按质量百分数计，所述原料包括：
    Figure PCTCN2019082118-appb-100001
  2. 一种提高肠道中SCFA产生菌的复合制剂，其特征在于，其是由以下原料制备而成，按质量百分数计，所述原料包括：
    Figure PCTCN2019082118-appb-100002
  3. 根据权利要求1或2所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述低聚糖选自菊粉、低聚果糖、低聚木糖、低聚半乳糖、低聚异麦芽糖、聚葡萄糖、抗性糊精、L阿拉伯糖和魔芋葡甘聚糖组成的组合中的至少一种。
  4. 根据权利要求3所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，按质量百分数计，所述原料包括：1％-10％菊粉、1％-5％低聚木糖、2％-10％低聚半乳糖、2％-5％低聚异麦芽糖、5％-10％聚葡萄糖、5％-10％抗性糊精、5％-10％L阿拉伯糖和1％-3％魔芋葡甘聚糖。
  5. 根据权利要求1或2所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述植物提取物为植物多糖。
  6. 根据权利要求5所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述植物提取物选自海藻提取物、昆布提取物、黄精提取物、茯苓提取物、枸杞提取物、葛根黄酮和人参提取物、圆苞车前子壳组成的组合中的至少一种。
  7. 根据权利要求6所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，按质量百分数计，所述原料包括：5％-10％海藻提取物、3％-5％昆布提取物、2％-4％黄精提取物、3％-5％茯苓提取物、5％-10％枸杞提取物、1％-3％葛根黄酮、3％-6％圆苞车前子壳。
  8. 根据权利要求1或2所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述真菌提取物为真菌多糖。
  9. 根据权利要求8所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述真菌提取物选自香菇提取物、虫草提取物、灵芝提取物、猴头菇提取物和酵母提取物组成的组合中的至少一种。
  10. 根据权利要求9所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，按质量百分数计，所述原料包括：4％-10％香菇提取物、0.5-5％虫草提取物、1.5-5％猴头菇提取物和4％-10％酵母提取物。
  11. 根据权利要求1或2所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述原料还包括银耳提取物，所述银耳提取物的使用量为所述真菌提取物质量的1％-5％。
  12. 根据权利要求1或2所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述原料还包括铁皮石斛提取物，所述铁皮石斛提取物为所述植物提取物质量的1％-5％。
  13. 根据权利要求1或2所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述原料还包括鲜花提取物，鲜花提取物的使用量为植物提取物质量的2％-10％。
  14. 根据权利要求13所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述鲜花提取物选自牡丹花提取物、金银花提取物和蒲公英提取物组成的组合中的至少一种。
  15. 根据权利要求13所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述鲜花提取物按照以下制备方法制备得到：
    将鲜花原料加入酵母进行发酵，过滤、后熟、澄清得到花果发酵液；将发酵液过滤并浓缩，得到粉状的鲜花提取物。
  16. 一种如权利要求1至15中任一项所述的提高肠道中SCFA产生菌的复合制剂的制备方法，其特征在于，其包括以下步骤：
    将低聚糖、植物提取物、真菌提取物、牛磺酸钠和黄芪提取物混合、研磨即得。
  17. 根据权利要求16所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述植物提取物的制备方法如下：
    将选取的植物原料清洗、粉碎后混合，添加4-6倍重量、60℃-80℃的热水提取3-4小时，过滤得到提取液；将提取液浓缩后，再用乙醇沉淀得到粗品多糖；将粗品多糖经层析分离、蒸馏水洗脱，得到多糖液；将多糖液浓缩后，再用乙醇沉淀，干燥得到粉状的植物提取物。
  18. 根据权利要求16所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述真菌提取物的制备方法如下：
    将真菌原料干燥后充分研磨，再加10-20倍体积纯水，于70-80℃下提取3-4小时，过滤得到提取液；将提取液经3000-5000r/min离心10-15分钟后取上清液；将上清液浓缩后，用乙醇沉淀；取沉淀，干燥后得到粉状的真菌提取物。
  19. 根据权利要求16所述的提高肠道中SCFA产生菌的复合制剂，其特征在于，所述黄芪提取物的制备方法如下：
    称取黄芪置微波提取装置中，微波功率500W-900W，温度70℃，共提取3次，第1次加50％-90％的乙醇，提取10min-30min；第2次加50％-90％乙醇，提取10min-30min；第3次加蒸馏水，提取20min-40min；以及
    再将第1、2次的乙醇提取液浓缩，除去乙醇，再加入第3次的水提取液，混合，浓缩，得到粉状的黄芪提取物。
  20. 一种如权利要求1至15中任一项所述的提高肠道中SCFA产生菌的复合制剂的应用，其特征在于，所述复合制剂用于制备减少肠道中厚壁菌门/拟杆菌门的比值，增大SCFA产生菌的比重的口服制剂。
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