WO2024027401A1 - 用于改善肠道微生物群的方法及组合物 - Google Patents

用于改善肠道微生物群的方法及组合物 Download PDF

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WO2024027401A1
WO2024027401A1 PCT/CN2023/103781 CN2023103781W WO2024027401A1 WO 2024027401 A1 WO2024027401 A1 WO 2024027401A1 CN 2023103781 W CN2023103781 W CN 2023103781W WO 2024027401 A1 WO2024027401 A1 WO 2024027401A1
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tributyrin
composition
intestinal microbiota
microbiota
mammal
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PCT/CN2023/103781
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English (en)
French (fr)
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易荣华
廖琪林
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南京纽邦生物科技有限公司
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Publication of WO2024027401A1 publication Critical patent/WO2024027401A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention belongs to the technical field of health food and dietary supplements, and specifically relates to compositions and methods for improving intestinal microbiota and their related applications in medicines, nutritional supplements, health products, foods and beverages.
  • gut microbiota The community of microorganisms that live in our gastrointestinal tract is called the gut microbiota. Their active role in intestinal physiology is now widely studied, playing important roles in many host processes. Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and disruption of the intestinal barrier.
  • butyric acid has been proven to be a by-product of probiotic fermentation and has a good effect on controlling blood sugar and blood lipids, improving intestinal health, etc.
  • butyrate is also the primary source of energy for the cells lining the colon.
  • a concentrated and potent form of dietary butyrate is not easily achieved because butyrate is rapidly absorbed in the upper gastrointestinal tract before reaching the colon.
  • the odor of butyrate and butyric acid is often considered malodorous, making active consumption and sales difficult.
  • nutraceutical strategies that use prebiotics or postbiotics to target the proliferation of beneficial microbiota while suppressing the effects of harmful microbiota are increasingly attractive. Therefore, even though various prebiotic and probiotic supplements are known in the art, there remains a need to provide improved compositions and methods to enhance intestinal health through effects on certain microbiota.
  • the present invention relates to methods and compositions for increasing the level of a first intestinal microbiota in a mammal.
  • Tributyrin (Tb) is a short-chain triglyceride (SCT) in which three butyrate molecules are esterified to glycerol, a form of butyrate that is more absorbable in the intestine.
  • SCT short-chain triglyceride
  • One aspect of the present invention relates to a method of increasing the level of a first intestinal microbiota in a mammal, said method comprising: administering to a lactating lactation a dose of 20 to 2000 mg of tributyrin or a tributyrin derivative per day.
  • the animal is administered a composition containing tributyrin; wherein the composition containing tributyrin is effective to increase the level of a first intestinal microbiota in the mammal; and the first intestinal microbiota is selected from the group consisting of One or more of: Akkermansia muciniphila, Lactobacillus, T.denticola, Christensenella_uncultured, Parabacteroides , Parasutterella, Blautia, Bifidobacteria, Polymorpha Bacteroides thetaiotaomicron, Bacteroides caecimuris, Clostridia, Staphylococcus, Enterococcus, Peptostreptococcus.
  • the method further comprises reducing the level of a second intestinal microbiota in the mammal, and the second intestinal microbiota is Megamonas, Klebsiella, Gordonia Streptococcus gordonii.
  • the first intestinal microbiota is beneficial microbiota.
  • the second intestinal microbiota is deleterious microbiota.
  • the tributyrin derivative is butyric acid monoester, butyric acid diester, beta-hydroxybutyric acid, monobutyrin, dibutyrin, triacetin, tripropionic acid ester, monoacetin, diacetin or acetoacetate.
  • the mammal suffers from intestinal disease.
  • the tributyrin-containing composition is formulated as a nutritional supplement, food, beverage, animal feed, or pharmaceutical.
  • tributyrin-containing compositions are prepared as solid or liquid formulations.
  • the tributyrin-containing composition is in the form of a suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, liquor, tincture, tonic, liquid suspension in the form of potions or syrups.
  • the method comprises administering a tributyrin-containing composition to the mammal at a dose of 20 to 1000 mg of tributyrin or a tributyrin derivative per day.
  • Another aspect of the invention relates to the use of a tributyrin-containing composition in the manufacture of a nutritional supplement, food, beverage, animal feed or medicament for increasing the level of the first intestinal microbiota in a mammal , wherein the first intestinal microflora is selected from one or more of the group consisting of: Akkermansia muciniphila, Lactobacillus, Treponema denticola, Christensenella, Parabacteroidetes, Parasanthessa Terella, Blautia, Bifidobacterium, Bacteroides thetaiotaomicron, Bacteroides cecum, Clostridium, Staphylococcus, Enterococcus, Peptostreptococcus.
  • the first intestinal microflora is selected from one or more of the group consisting of: Akkermansia muciniphila, Lactobacillus, Treponema denticola, Christensenella, Parabacteroidetes,
  • the use further comprises reducing the level of a second intestinal microbiota in the mammal, wherein the second intestinal microbiota is Megamonas, Klebsiella, or Streptococcus gordonii.
  • the first intestinal microbiota is beneficial microbiota.
  • the second intestinal microbiota is deleterious microbiota.
  • the use further comprises administering to the mammal a composition containing tributyrin at a dose of 20 to 2000 mg of tributyrin or a tributyrin derivative per day; wherein the composition contains tributyrin.
  • the composition of glycerides is effective in increasing the levels of the first intestinal microbiota in mammals.
  • the tributyrin derivative is butyric acid monoester, butyric acid diester, beta-hydroxybutyric acid, monobutyrin, dibutyrin, triacetin, tripropionic acid ester, monoacetin, diacetin or acetoacetate.
  • the mammal suffers from intestinal disease.
  • tributyrin-containing compositions are prepared as solid or liquid formulations.
  • the tributyrin-containing composition is in the form of a suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, liquor, tincture, tonic, liquid suspension in the form of potions or syrups.
  • the use comprises administering a tributyrin-containing composition to a mammal at a dose of 20 to 1000 mg of tributyrin or a tributyrin derivative per day.
  • compositions containing tributyrin for increasing the level of a first intestinal microbiota in a mammal the first intestinal microbiota being selected from the group consisting of One or more of: Akkermansia muciniphila, Lactobacillus, Treponema denticola, Christensenella, Parabacteroidetes, Parasutterella, Blautia, Bifidobacteria, Polygonella Bacteroidetes, Bacteroides cecum, Clostridium, Staphylococcus, Enterococcus, Peptostreptococcus, compositions containing tributyrin at a dose of 20 to 2000 mg of tributyrin or tributyrin derivatives per day Administration to mammals.
  • the tributyrin-containing composition is further used to: reduce the level of a second intestinal microbiota in a mammal, and the second intestinal microbiota is Megamonas, Klebsiella, Streptococcus gordonii.
  • the first intestinal microbiota is beneficial microbiota.
  • the second intestinal microbiota is deleterious microbiota.
  • the tributyrin derivative is butyric acid monoester, butyric acid diester, beta-hydroxybutyric acid, monobutyrin, dibutyrin, triacetin, tripropionic acid ester, monoacetin, diacetin or acetoacetate.
  • the mammal suffers from intestinal disease.
  • the tributyrin-containing composition is formulated as a nutritional supplement, food, beverage, animal feed, or pharmaceutical.
  • tributyrin-containing compositions are prepared as solid or liquid formulations.
  • the tributyrin-containing composition is in the form of a suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, liquor, tincture, tonic, liquid suspension in the form of potions or syrups.
  • the tributyrin-containing composition is administered to the mammal at a dose of 20 to 1000 mg of tributyrin or tributyrin derivative per day.
  • compositions containing tributyrin can increase levels of Akkermansia muciniphila, a predominant bacterium in humans whose abundance is inversely related to body weight and type 1 diabetes in mice and humans.
  • Akkermansia muciniphila administration improved the intestinal microenvironment controlling inflammation, intestinal barrier, and intestinal peptide secretion.
  • Compositions containing tributyrin may also increase levels of Lactobacilli, a type of "friendly" bacteria that normally live in our digestive, urinary and reproductive systems without causing disease.
  • the tributyrin-containing composition may increase levels of one or more microorganisms selected from the group consisting of Treponema denticola, Christensenella, Parabacteroides that may enhance intestinal health.
  • Parasutterella Lactobacillus, Blautia, Bifidobacterium, Bacteroides thetaiotaomicron, Bacteroides cecum, Clostridium, Staphylococcus, Enterococcus, Peptostreptococcus.
  • compositions containing tributyrin can reduce the levels of Megamonas and Klebsiella, both of which are related to blood sugar and blood lipid metabolism. Megamonas is associated with high-density lipoprotein levels in different types of non-alcoholic fatty liver disease. Negatively related. Klebsiella is recommended as a diagnostic agent for type 1 Biomarkers of diabetes. In addition, compositions containing tributyrin may also reduce levels of Streptococcus gordonii .
  • Figure 1 is a graph of relative abundance changes of Akkermansia muciniphila.
  • Figure 2 is a graph of relative abundance changes of Lactobacilli.
  • Figure 3 is a graph of relative abundance changes of Megamonas.
  • Figure 4 is a graph of relative abundance changes of Klebsiella sp.
  • Tributyrin is a triglyceride and butyric acid ester, which can be obtained by orthoacylating the three hydroxyl groups of glycerol with butyric acid.
  • derivatives of tributyrin include beta-hydroxybutyrate, glyceryl monobutyrate, glyceryl dibutyrate, glyceryl triacetate, tripropionate, glyceryl monoacetate, glyceryl diacetate Ester, acetoacetate, butyric acid monoester and butyric acid diester.
  • aspects and embodiments of the invention relate to methods and compositions using "tributyrin-containing" compositions and/or "tributyrin-enhanced" compositions, wherein tributyrin-containing
  • the compositions include any composition having tributyrin or a tributyrin derivative.
  • subject As used herein, "subject,””mammal,” or “mammalian subject” are used interchangeably to refer to any mammal to which the methods and compositions of the present disclosure may be applied or administered.
  • the mammal may be suffering from a disease or other condition, but the mammal need not be sick to benefit from the methods and compositions of the present disclosure.
  • a mammal may need to improve its intestinal and/or overall health, but a mammal may also have a generally healthy intestine and wish to maintain or further improve its intestinal and/or overall health. Therefore, any mammal can take the disclosed compositions or be recipients of the disclosed methods. More typically, mammals as referred to herein include humans or domestic animals. For example, domestic animals include dogs, cats, or any farm animal (including horses, cattle, sheep, goats, pigs, or chickens).
  • administering refers to the direct administration of a compound or a pharmaceutically acceptable salt or composition of a compound to a subject, or the administration of a compound or a pharmaceutically acceptable salt or composition of a compound to a subject Prodrug derivatives or analogs which form equivalent amounts of the active compound in a subject.
  • compositions and administration are provided.
  • the present invention relates to a method for increasing the level of a first intestinal microbiota in a mammal and also reducing the level of a second intestinal microbiota in the mammal by administering to the mammal a composition containing tributyrin in a dose. method.
  • Contemplated methods include administration of at least 20 mg of tributyrin or tributyrin replacement per day, depending on the specific tributyrin-containing formulation and form. This amount can be administered once or multiple times per day.
  • the effective amount of tributyrin or tributyrin derivative in the tributyrin-containing composition is from 20 milligrams (mg) to 2000 mg or between 20 mg for one or more administrations per day. (mg) to 2000mg.
  • One or more doses can be administered once daily for any period of time. For example, an effective dose may be administered daily for one day, several days, multiple days, or indefinitely.
  • the amount of tributyrin or tributyrin derivative administered daily is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg , 1400mg, 1500mg, 1600, 1700mg, 1800mg, 1900mg or 2000mg. More typically, The amount of tributyrin or tributyrin derivative administered daily is 20 mg to 1000 mg. Most typically, the amount of tributyrin or tributyrin derivative administered is 200 mg per day.
  • tributyrin-containing compositions are contemplated for increasing the levels of a first intestinal microbiota in a mammal and also reducing the levels of a second intestinal microbiota in a mammal.
  • the composition will be formulated as a nutritional or dietary supplement, (medical) food, animal feed or pharmaceutical composition, in liquid or solid form, comprising a tributyrin-containing composition, and may optionally further comprise Nutritionally or pharmaceutically acceptable carrier.
  • the composition when the composition is in solid form, the composition can be formulated into snack bars, yogurt, lozenges, tablets or capsules, or can be coated on cereal products, including in baked goods.
  • the composition when the supplement is in liquid form, the composition can be formulated as a tincture, soft gel capsule, liquid capsule, syrup, carbonated beverage, brewed beverage (e.g., coffee or tea), juice, energy drink, sports drink, or Flavored water.
  • brewed beverage e.g., coffee or tea
  • juice energy drink, sports drink, or Flavored water.
  • tributyrin-containing compositions and preparations may also be used for veterinary purposes (e.g., for use in domestic companion animals (“pets”)) Feed or animal feed for farm animals.
  • the tributyrin-containing composition may also be in the form of a bulk product (e.g., in a form of 100 g or greater, 1000 g or greater, or 1000 g or greater, or tributyrin-containing compositions 10kg) are provided for the production of nutritional supplements, (medical) foods, animal feed or pharmaceuticals.
  • the tributyrin-containing composition may also be added to food products containing microbiota.
  • the present inventors contemplated a method of increasing the probiotic benefits of a food product containing a microbiota strain by combining or adding a tributyrin-containing composition to the food product. with this In this way, tributyrin or tributyrin derivatives can be processed by consumers together with microbiota strains in foods, thus enhancing the probiotic effect.
  • food includes any solid or liquid form of food or beverage that can be consumed or ingested.
  • the amount of tributyrin-containing composition to be added to a food product containing a strain of Bifidobacterium can vary depending on the type and form of the food product. Typically, the amount of tributyrin-containing composition will be determined based on the approximate amount provided per serving. More typically, the amount of tributyrin-containing composition will be from 50 mg to 2000 mg of tributyrin or tributyrin derivative per serving. Most typically, the amount of tributyrin-containing composition will be 100 mg, 200 mg, 300 mg, 400 mg or 500 mg of tributyrin or tributyrin derivative per serving.
  • yogurt or yogurt drink is a product that already contains bacterial species used for fermentation, such as Lactobacillus bulgaricus and Streptococcus thermophilus. Therefore, it is expected that yogurt could be supplemented with a composition containing tributyrin and/or a tributyrin-enhanced strain of Bifidobacterium as a synbiotic product for intestinal health.
  • tributyrin-containing compositions e.g., in liquid or solid form or as a nutritional supplement
  • tributyrin-enhanced compositions e.g., live active or inactive tributyrin-enhanced Bifidobacterium strains
  • the inventor considers containing tributyrin and/or tributyric acid.
  • the natural and unpleasant odor of tributyrin can be reduced or eliminated.
  • contemplated methods of administering a tributyrin-containing composition include administering at least one probiotic microorganism simultaneously with or subsequent to administration of the tributyrin-containing composition.
  • Any suitable probiotic or probiotics may be combined with the tributyrin-containing composition.
  • Exemplary probiotics include Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus brevis, Lactobacillus gasseri, Buckthorn Lactobacillus rhamnosus, Bifidobacterium lactis, Bifidobacterium breve or Bifidobacterium longum.
  • compositions containing tributyrin e.g., in liquid or solid form or as a nutritional supplement
  • tributyrin-enhanced compositions e.g., live active or inactive tributyrin Glyceride-enhanced Bifidobacterium strains
  • arabinoxylan AX
  • arabinoxylan oligosaccharide AXOS
  • XOS xylo-oligosaccharides
  • FOS fructooligosaccharides
  • GOS galactooligosaccharides
  • tributyrin-containing composition e.g., in liquid or solid form or as a nutritional supplement
  • tributyrin-enhanced composition e.g., live active or inactive tributyrin Glyceryl acid-enhanced Bifidobacterium strains
  • health additives may be added in any combination with the tributyrin-containing composition or the tributyrin-enhanced composition, taking into account health effects and product cost.
  • Exemplary additives that may be combined with tributyrin-containing compositions or tributyrin-enhanced compositions include superoxide dismutase (SOD), compositions containing activators of SOD, compositions containing bioavailable SOD foods or their extracts (such as sprouted wheat, wheatgrass, encapsulated (lipid and/or protein encapsulated) cantaloupe, rye, barley, barley grass, broccoli sprouts, kale, Brussels sprouts and turmeric (e.g. turmeric), copper iodide (CuI), selenium (Se), fulvic acid, foods containing fulvic acid or their extracts (e.g. potatoes, radish, beets, carrots, root vegetables, blackstrap molasses and shila Zhizhi), Coenzyme Q 10 (ubiquinone) or pyrroloquinoline quinone (PQQ).
  • SOD superoxide dismutase
  • compositions containing activators of SOD
  • control group normal mice on normal diet
  • HFD high-fat diet-induced obese mouse group
  • Tb HFD mouse treatment group
  • fecal samples were collected immediately after defecation from each mouse at baseline and during the final week and stored.
  • Fecal DNA was extracted from stool samples using the E.Z.N.A Soil DNA Kit according to the manufacturer's protocol. We then used 16s rRNA sequencing to understand the impact of tributyrin on the composition and diversity of intestinal microbiota.
  • Figure 1 is a diagram of the relative abundance changes of Akkermansia muciniphila.
  • the level of Akkermansia muciniphila in obese mice induced by high-fat diet was significantly lower than that in normal mice.
  • the level of Akkermansia muciniphila in high-fat diet-induced obese mice increased by 119%, approaching the level of normal mice.
  • Figure 2 shows the phase of Lactobacillus For the abundance change plot, the level of Lactobacilli in high-fat diet-induced obese mice was lower than that in normal mice. After tributyrin treatment, the level of Lactobacillus in high-fat diet-induced obese mice increased by 101%. Close to the level of normal mice.
  • Figure 3 is a diagram of the relative abundance changes of Megamonas. The number of Megamonas in obese mice induced by high-fat diet increased significantly. After treatment with tributyrin, the number of Megamonas in obese mice induced by high-fat diet increased. Bacteria levels were reduced by 91%.
  • Figure 4 is a diagram of the relative abundance changes of Klebsiella. The number of Klebsiella in obese mice induced by high-fat diet increased significantly. After tributyrin treatment, the number of Klebsiella in obese mice induced by high-fat diet increased significantly. Botrytis levels were reduced by 67%.
  • high-fat diet-induced obese mice had higher levels of Treponema denticola, Christensenella, Parabacteroides, Parasutterella, Lactobacillus, Blautia,
  • the levels of Bifidobacteria, Bacteroides thetaiotaiota, Bacteroides cecum, Clostridium, Staphylococcus, Enterococcus, and Peptostreptococcus increased by 80-130%, close to the levels of normal mice; the levels of obese mice induced by high-fat diet increased Streptococcus deniger levels were reduced by approximately 80%.
  • tributyrin or tributyrin derivatives may be used.
  • One or more doses can be administered once daily for any period of time.
  • One or more doses may also be administered multiple times per day for any period of time.
  • an effective dose may be administered daily for one day, several days, multiple days, or indefinitely.
  • the amount of tributyrin or tributyrin derivative administered daily is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg , 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg or 2000mg.
  • the amount of tributyrin or tributyrin derivative administered daily is from 20 mg to 1000mg.
  • the amount of tributyrin or tributyrin derivative administered is 200 mg per day.
  • the content of some of the above-mentioned bacteria increased by 80-130%, while others decreased by 67-91%, which makes the levels of these intestinal microbiota close to The level of normal mice is very beneficial to maintaining intestinal health.

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Abstract

本发明公开了一种改善肠道微生物群的方法及组合物，以及其用于制备用于调节肠道菌群的药物、营养产品、保健产品、食品及饮料的用途。本发明的三丁酸甘油酯组合物可以显著增加哺乳动物中第一肠道微生物群的水平，同时降低哺乳动物中第二肠道微生物群的水平进而来改善肠道健康。

Description

用于改善肠道微生物群的方法及组合物 技术领域
本发明属于保健食品及膳食补充剂技术领域，具体涉及用于改善肠道微生物群的组合物及方法以及其在药物、营养补充剂、保健产品、食品及饮料中的相关应用。
背景技术
居住在我们胃肠道中的微生物群落被称为肠道微生物群。它们在肠道生理学中的积极作用现在得到了广泛的研究，在许多宿主过程中发挥着重要作用。肥胖及2型糖尿病的特点是肠道微生物群改变、炎症及肠道屏障破坏。
虽然在肠道健康领域已经广泛讨论了大量益生元，但后生元(即负责益生菌微生物的许多有益作用的代谢副产物)可能会提供更直接、甚至可能更大的健康益处。例如，丁酸被证明是益生菌发酵的副产物，对控制血糖及血脂、改善肠道健康等有很好的作用。值得注意的是，丁酸也是结肠内壁细胞的主要能量来源。然而，膳食丁酸的浓缩及有效形式并不容易实现，因为丁酸在到达结肠之前会在上消化道中被迅速吸收。此外，丁酸盐及丁酸的气味通常被认为是恶臭的，这使得主动消费及销售变得困难。
因此，使用益生元或后生元来针对有益微生物群的增殖同时抑制有害微生物群的影响的营养保健策略越来越有吸引力。因此，即使本领域已知各种益生元及益生菌补充剂，仍然需要提供改进的组合物及方法以通过对一些微生物群的影响来增强肠道健康。
发明内容
本发明涉及用于增加哺乳动物中第一肠道微生物群的水平的方法及组合物。三丁酸甘油酯(Tb)是一种短链甘油三酯(SCT)，其中三个丁酸酯分子被酯化为甘油，是一种在肠道中更具吸收性的丁酸酯形式。我们发现，施用含有三丁酸甘油酯的组合物可以调节一些肠道微生物群以增强肠道健康，包括增加一些有益微生物群的水平及降低一些有害微生物群的水平。
为实现上述目的，本发明提供以下技术方案：
本发明的一个方面涉及一种增加哺乳动物中第一肠道微生物群的水平的方法，所述方法包含：以每天20至2000mg三丁酸甘油酯或三丁酸甘油酯衍生物的剂量向哺乳动物施用含三丁酸甘油酯的组合物；其中含三丁酸甘油酯的组合物有效增加哺乳动物中第一肠道微生物群的水平；并且第一肠道微生物群选自由以下组成的组中的一种或多种：嗜黏蛋白阿克曼菌(Akkermansia muciniphila)、乳杆菌(Lactobacillus)、齿垢密螺旋体(T.denticola)、克里斯滕森菌(Christensenella_uncultured)、副拟杆菌(Parabacteroides)、副萨特氏菌(Parasutterella)、布劳特氏菌(Blautia)、双歧杆菌(Bifidobacteria)、多形 拟杆菌(Bacteroides thetaiotaomicron)、盲肠拟杆菌(Bacteroides caecimuris)、梭菌(Clostridia)、葡萄球菌(Staphylococcus)、肠球菌(Enterococcus)、消化链球菌(Peptostreptococcus)。
在一些实施方案中，所述方法还包含降低哺乳动物中第二肠道微生物群的水平，并且第二肠道微生物群为巨单胞菌(Megamonas)、克雷伯菌(Klebsiella)、戈登链球菌(Streptococcus gordonii)。
在一些实施方案中，第一肠道微生物群为有益微生物群。
在一些实施方案中，第二肠道微生物群为有害微生物群。
在一些实施方案中，三丁酸甘油酯衍生物为丁酸单酯、丁酸二酯、β-羟基丁酸、单丁酸甘油酯、二丁酸甘油酯、三乙酸甘油酯、三丙酸酯、单乙酸甘油酯、二乙酸甘油酯或乙酰乙酸酯。
在一些实施方案中，哺乳动物患有肠道疾病。
在一些实施方案中，含三丁酸甘油酯的组合物配制成营养补充剂、食品、饮料、动物饲料或药物。
在一些实施方案中，含三丁酸甘油酯的组合物制备成固体制剂或液体制剂。
在一些实施方案中，含三丁酸甘油酯的组合物呈栓剂、片剂、丸剂、颗粒剂、粉剂、膜剂、胶囊、饮料、气雾剂、醑剂、酊剂、滋补剂、液体混悬剂或糖浆的形式。
在一些实施方案中，所述方法包含以每天20至1000mg三丁酸甘油酯或三丁酸甘油酯衍生物的剂量向哺乳动物施用含三丁酸甘油酯的组合物。
本发明的另一方面涉及一种含三丁酸甘油酯的组合物在制造用于增加哺乳动物中第一肠道微生物群的水平的营养补充剂、食品、饮料、动物饲料或药物中的用途，其中第一肠道微生物群选自由以下组成的组中的一种或多种：嗜黏蛋白阿克曼菌、乳杆菌、齿垢密螺旋体、克里斯滕森菌、副拟杆菌、副萨特氏菌、布劳特氏菌、双歧杆菌、多形拟杆菌、盲肠拟杆菌、梭菌、葡萄球菌、肠球菌、消化链球菌。
在一些实施方案中，所述用途还包含降低哺乳动物中第二肠道微生物群的水平，其中第二肠道微生物群为巨单胞菌、克雷伯菌、戈登链球菌。
在一些实施方案中，第一肠道微生物群为有益微生物群。
在一些实施方案中，第二肠道微生物群为有害微生物群。
在一些实施方案中，所述用途还包含以每天20至2000mg三丁酸甘油酯或三丁酸甘油酯衍生物的剂量向哺乳动物施用含三丁酸甘油酯的组合物；其中含三丁酸甘油酯的组合物有效增加哺乳动物中第一肠道微生物群的水平。
在一些实施方案中，三丁酸甘油酯衍生物为丁酸单酯、丁酸二酯、β-羟基丁酸、单丁酸甘油酯、二丁酸甘油酯、三乙酸甘油酯、三丙酸酯、单乙酸甘油酯、二乙酸甘油酯或乙酰乙酸酯。
在一些实施方案中，哺乳动物患有肠道疾病。
在一些实施方案中，含三丁酸甘油酯的组合物制备成固体制剂或液体制剂。
在一些实施方案中，含三丁酸甘油酯的组合物呈栓剂、片剂、丸剂、颗粒剂、粉剂、膜剂、胶囊、饮料、气雾剂、醑剂、酊剂、滋补剂、液体混悬剂或糖浆的形式。
在一些实施方案中，所述用途包含以每天20至1000mg三丁酸甘油酯或三丁酸甘油酯衍生物的剂量向哺乳动物施用含三丁酸甘油酯的组合物。
本发明的另一方面涉及一种含三丁酸甘油酯的组合物，该组合物用于增加哺乳动物中第一肠道微生物群的水平，第一肠道微生物群选自由以下组成的组中的一种或多种：嗜黏蛋白阿克曼菌、乳杆菌、齿垢密螺旋体、克里斯滕森菌、副拟杆菌、副萨特氏菌、布劳特氏菌、双歧杆菌、多形拟杆菌、盲肠拟杆菌、梭菌、葡萄球菌、肠球菌、消化链球菌，含三丁酸甘油酯的组合物以每天20至2000mg三丁酸甘油酯或三丁酸甘油酯衍生物的剂量向哺乳动物施用。
在一些实施方案中，含三丁酸甘油酯的组合物还用于：降低哺乳动物中第二肠道微生物群的水平，并且第二肠道微生物群为巨单胞菌、克雷伯菌、戈登链球菌。
在一些实施方案中，第一肠道微生物群为有益微生物群。
在一些实施方案中，第二肠道微生物群为有害微生物群。
在一些实施方案中，三丁酸甘油酯衍生物为丁酸单酯、丁酸二酯、β-羟基丁酸、单丁酸甘油酯、二丁酸甘油酯、三乙酸甘油酯、三丙酸酯、单乙酸甘油酯、二乙酸甘油酯或乙酰乙酸酯。
在一些实施方案中，哺乳动物患有肠道疾病。
在一些实施方案中，含三丁酸甘油酯的组合物配制成营养补充剂、食品、饮料、动物饲料或药物。
在一些实施方案中，含三丁酸甘油酯的组合物制备成固体制剂或液体制剂。
在一些实施方案中，含三丁酸甘油酯的组合物呈栓剂、片剂、丸剂、颗粒剂、粉剂、膜剂、胶囊、饮料、气雾剂、醑剂、酊剂、滋补剂、液体混悬剂或糖浆的形式。
在一些实施方案中，含三丁酸甘油酯的组合物以每天20至1000mg三丁酸甘油酯或三丁酸甘油酯衍生物的剂量向哺乳动物施用。
含三丁酸甘油酯的组合物可以增加嗜黏蛋白阿克曼菌的水平，它是人类的主要细菌，其丰度与小鼠及人类的体重及1型糖尿病成反比。嗜黏蛋白阿克曼菌施用改善了控制炎症、肠道屏障及肠道肽分泌的肠道微环境。含三丁酸甘油酯的组合物还可以增加乳杆菌的水平，这是一种“友好”的细菌，通常生活在我们的消化系统、泌尿系统及生殖系统中而不会引起疾病。此外，含三丁酸甘油酯的组合物还可以增加一种或多种可以增强肠道健康的选自由以下组成的组的微生物的水平：齿垢密螺旋体、克里斯滕森菌、副拟杆菌、副萨特氏菌、乳杆菌、布劳特氏菌、双歧杆菌、多形拟杆菌、盲肠拟杆菌、梭菌、葡萄球菌、肠球菌、消化链球菌。
含三丁酸甘油酯的组合物可以降低巨单胞菌及克雷伯菌的水平，两者均与血糖及血脂代谢有关，巨单胞菌与不同类型非酒精性脂肪肝病中高密度脂蛋白水平呈负相关。克雷伯菌被推荐作为诊断1型 糖尿病的生物标志物。此外，含三丁酸甘油酯的组合物还可以降低戈登链球菌的水平。
提供发明内容以简化的形式介绍概念的选择，这些概念将在下面的具体实施方式中进一步描述。发明内容并非旨在识别所要求保护的主题的关键特征或基本特征，也不旨在用于限制所要求保护的主题的范围。
附图说明
图1是嗜黏蛋白阿克曼菌的相对丰度变化图。
图2是乳杆菌的相对丰度变化图。
图3是巨单胞菌的相对丰度变化图。
图4是克雷伯菌的相对丰度变化图。
具体实施方式
现将详细参考本发明的优选实施方案，进一步说明其实施例。虽然将结合优选实施方案描述本发明，但应理解它们并非旨在将本发明限制于这些实施方案。相反，本发明旨在涵盖替代、修改及等同物，它们可以包括在如权利要求书所限定的本发明的精神及范围内。此外，在本发明的详细描述中，阐述了许多具体细节以提供对本发明的透彻理解。然而，对于本领域普通技术人员来说显而易见的是，可以在没有这些具体细节的情况下实施本发明。在其他情况下，没有详细描述 众所周知的方法、程序、组件及其他特征，以免不必要地混淆本发明的方面。
如本文所用，术语“或”意在包括“及”和“或”两者。换言之，术语“或”也可以替换为“及/或”。
如本文所用，除非上下文另有明确指示，否则单数形式“一(a/an)”及“所述(the)”旨在也包括复数形式。
三丁酸甘油酯是甘油三酯及丁酸酯，其可以通过丁酸将甘油的三个羟基正酰化而得。如本文所用，三丁酸甘油酯的衍生物包括β-羟基丁酸酯、单丁酸甘油酯、二丁酸甘油酯、三乙酸甘油酯、三丙酸酯、单乙酸甘油酯、二乙酸甘油酯、乙酰乙酸酯、丁酸单酯及丁酸二酯。
本发明人已经发现，施用三丁酸甘油酯可以显著增加哺乳动物中第一肠道微生物群的水平，同时降低哺乳动物中第二肠道微生物群的水平。为此，本发明的方面及实施方案涉及使用“含三丁酸甘油酯的”组合物及/或“三丁酸甘油酯增强的”组合物的方法及组合物，其中含三丁酸甘油酯的组合物包括具有三丁酸甘油酯或三丁酸甘油酯衍生物的任何组合物。
如本文所用，“受试者”、“哺乳动物”或“哺乳动物受试者”可互换使用以指代可以应用或施用本公开的方法及组合物的任何哺乳动物。哺乳动物可能患有疾病或其他疾病，但哺乳动物不需要生病才能受益于本公开的方法及组合物。哺乳动物可能需要改善其肠道及/或整体健康，但哺乳动物也可能具有总体上健康的肠道并希望维持或进一步改善其肠道及/或整体健康。因此，任何哺乳动物都可以服用所公 开的组合物或成为所公开方法的接受者。更典型地，本文所指的哺乳动物包括人或驯养动物。例如，驯养动物包括狗、猫或任何农场动物(包括马、牛、绵羊、山羊、猪或鸡)。
如本发明所用，术语“施用”是指向受试者直接施用化合物或化合物的药学上可接受的盐或组合物，或向受试者施用化合物或化合物的药学上可接受的盐或组合物的前药衍生物或类似物，其可以在受试者体内形成等量的活性化合物。
组合物及施用
本发明涉及一种通过以一定剂量向哺乳动物施用含三丁酸甘油酯的组合物来增加哺乳动物中第一肠道微生物群的水平，还降低哺乳动物中第二肠道微生物群的水平的方法。
预期的方法包括每天施用至少20mg的三丁酸甘油酯或三丁酸甘油酯替代物，这取决于具体的含三丁酸甘油酯的制剂及形式。每天的这个量可以一次或多次施用。典型地，每天一次或多次施用的含三丁酸甘油酯的组合物中的三丁酸甘油酯或三丁酸甘油酯衍生物的有效量为20毫克(mg)至2000mg或介于20毫克(mg)至2000mg之间。一个或多个剂量可以在任何时间段内每天施用一次。例如，可以每天施用有效剂量，持续一天、几天、多天或无限期地每天施用。更典型地，每天施用的三丁酸甘油酯或三丁酸甘油酯衍生物的量为50mg、100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600,1700mg、1800mg、1900mg或2000mg。更典型地， 每天施用的三丁酸甘油酯或三丁酸甘油酯衍生物的量为20mg至1000mg。最典型地，每天施用的三丁酸甘油酯或三丁酸甘油酯衍生物的量为200mg。
含三丁酸甘油酯的组合物的多种形式及制剂被考虑用于增加哺乳动物中第一肠道微生物群的水平，也降低哺乳动物中第二肠道微生物群的水平。组合物将被配制成营养补充剂或膳食补充剂、(医疗)食品、动物饲料或药物组合物，呈液体或固体形式，包含含三丁酸甘油酯的组合物，并且还可以任选地包括营养学上或药学上可接受的载体。例如，当组合物呈固体形式时，组合物可以配制成小吃棒、酸奶、锭剂、片剂或胶囊，或者可以涂覆到谷物产品上，包括在烘焙食品中。另一方面，当补充剂呈液体形式时，组合物可以配制成酊剂、软凝胶胶囊、液体胶囊、糖浆、碳酸饮料、冲泡饮料(例如咖啡或茶)、果汁、能量饮料、运动饮料或调味水。虽然特别考虑了供人类使用的营养及药物组合物，但应当理解，含三丁酸甘油酯的组合物及制剂也可以用于兽医用途(例如，用于家养伴侣动物(“宠物”)的动物饲料或用于农场动物的动物饲料。在其他考虑的方面，含三丁酸甘油酯的组合物还可以以散装产品的形式(例如，以等于或大于100g、等于或大于1000g、或等于或大于10kg的量)提供用于生产营养补充剂、(医疗)食品、动物饲料或药品。
含三丁酸甘油酯的组合物还可以添加至包含微生物群的食品中。本发明人考虑了一种通过将含三丁酸甘油酯的组合物组合或添加至食品中来增加包含微生物群菌株的食品的益生菌益处的方法。以此 方式，三丁酸甘油酯或三丁酸甘油酯衍生物可以与食品中的微生物群菌株一起被消费者加工，从而增强益生菌作用。如本文所用，食品包括可以被消耗或摄取的任何固体或液体形式的食物或饮料。如本文所公开，待添加到包含双歧杆菌菌株的食品中的含三丁酸甘油酯的组合物的量可以根据食品的种类及形式而变化。典型地，含三丁酸甘油酯的组合物的量将根据提供的每份食品的近似量来确定。更典型地，含三丁酸甘油酯的组合物的量将为每份食品中50mg至2000mg的三丁酸甘油酯或三丁酸甘油酯衍生物。最典型地，含三丁酸甘油酯的组合物的量将为每份食品中100mg、200mg、300mg、400mg或500mg三丁酸甘油酯或三丁酸甘油酯衍生物。
本发明主题的其他方面可以包括将含三丁酸甘油酯的组合物及/或三丁酸甘油酯增强的组合物添加至如本文所公开的食品中。在特定实例中，酸奶或酸奶饮料是已经含有用于发酵的细菌种，如保加利亚乳杆菌(Lactobacillus bulgaricus)和嗜热链球菌(Streptococcus thermophilus)的产品。因此，预期酸奶里可以补充含三丁酸甘油酯的组合物及/或三丁酸甘油酯增强的双歧杆菌菌株，用于肠道健康的合生元产品。
本发明人还考虑可以加工任何目前公开的含三丁酸甘油酯的组合物(例如，以液体或固体形式或作为营养补充剂)或三丁酸甘油酯增强的组合物(例如，活的活性的或非活性的三丁酸甘油酯增强的双歧杆菌菌株)从而具有较少令人不快的气味、极少的气味、没有气味或无令人不快的气味。为此，本发明人考虑含三丁酸甘油酯及/或三丁酸 甘油酯增强的组合物的形式，其可以减少或消除三丁酸甘油酯天然的及令人不快的气味。本领域已经建立了消除、减少及/或掩蔽气味的方法。
组合疗法
为了进一步增强哺乳动物的肠道健康，所考虑的施用含三丁酸甘油酯的组合物的方法包括在施用含三丁酸甘油酯的组合物的同时或之后施用至少一种益生菌微生物。任何合适的益生菌或多种益生菌可以与含三丁酸甘油酯的组合物组合。示例性的益生菌包括嗜酸乳杆菌(Lactobacillus acidophilus)、干酪乳杆菌(Lactobacillus casei)、植物乳杆菌(Lactobacillus plantarum)、短乳杆菌(Lactobacillus brevis)、加氏乳杆菌(Lactobacillus gasseri)、鼠李糖乳杆菌(Lactobacillus rhamnosus)、乳双歧杆菌(Bifidobacterium lactis)、短双歧杆菌(Bifidobacterium breve)或长双歧杆菌(Bifidobacterium longum)。
目前公开的含三丁酸甘油酯的组合物(例如，以液体或固体形式或作为营养补充剂)或三丁酸甘油酯增强的组合物(例如，活的活性的或非活性的三丁酸甘油酯增强的双歧杆菌菌株)可以与阿拉伯木聚糖(AX)、阿拉伯木聚糖寡糖(AXOS)、低聚木糖(XOS)、低聚果糖(FOS)、低聚半乳糖(GOS)、菊粉及/或果胶中的一种或两种益生元组合。
任何目前公开的含三丁酸甘油酯的组合物(例如，以液体或固体形式或作为营养补充剂)或三丁酸甘油酯增强的组合物(例如，活的活性的或非活性的三丁酸甘油酯增强的双歧杆菌菌株)可以与健康添加剂组合，以增加健康益处的广度。根据组合物的形式以及对所需健 康效果及产品成本的考虑，这些健康添加剂可以与含三丁酸甘油酯的组合物或三丁酸甘油酯增强的组合物以任何组合形式加入。可以与含三丁酸甘油酯的组合物或三丁酸甘油酯增强的组合物组合的示例性添加剂包括超氧化物歧化酶(SOD)、包含SOD的活化剂的组合物、包含可生物利用的SOD的食物或其提取物(例如发芽小麦、小麦草、包封的(脂质及/或蛋白质包封)哈密瓜、黑麦、大麦、大麦草、西兰花芽、羽衣甘蓝、抱子甘蓝及姜黄素(例如姜黄))、碘化铜(CuI)、硒(Se)、富里酸、包含富里酸的食物或其提取物(例如土豆、萝卜、甜菜、胡萝卜、根茎类蔬菜、黑带糖蜜及喜来芝)、辅酶Q10(泛醌)或吡咯并喹啉醌(PQQ)。
实施例
将小鼠随机分为三组：对照组(正常饮食的正常小鼠)、高脂饮食诱导的肥胖小鼠组(HFD)及HFD小鼠处理组(Tb)(n＝15/组)。处理8周后(每天服用200毫克(mg)三丁酸甘油酯)，在基线及最后一周在每只小鼠排便后立即收集粪便样本并储存。根据制造商的方案，使用E.Z.N.A Soil DNA Kit从粪便样本中提取粪便DNA。然后我们使用16s rRNA测序来了解三丁酸甘油酯对肠道微生物群组成及多样性的影响。
结果示于图1-4，图1是嗜黏蛋白阿克曼菌的相对丰度变化图，高脂饮食诱导的肥胖小鼠的嗜黏蛋白阿克曼菌水平显著低于正常小鼠，在三丁酸甘油酯处理后，高脂饮食诱导的肥胖小鼠的嗜黏蛋白阿克曼菌水平增加了119％，接近正常小鼠的水平。图2是乳杆菌的相 对丰度变化图，高脂饮食诱导的肥胖小鼠的乳杆菌水平低于正常小鼠，在三丁酸甘油酯处理后，高脂饮食诱导的肥胖小鼠的乳杆菌水平增加了101％，接近正常小鼠的水平。图3是巨单胞菌的相对丰度变化图，高脂饮食诱导的肥胖小鼠的巨单胞菌显著增加，在三丁酸甘油酯处理后，高脂饮食诱导的肥胖小鼠的巨单胞菌水平降低了91％。图4是克雷伯菌的相对丰度变化图，高脂饮食诱导的肥胖小鼠的克雷伯菌显著增加，在三丁酸甘油酯处理后，高脂饮食诱导的肥胖小鼠的克雷伯菌水平降低了67％。
此外，在三丁酸甘油酯处理后，高脂饮食诱导的肥胖小鼠的齿垢密螺旋体、克里斯滕森菌、副拟杆菌、副萨特氏菌、乳杆菌、布劳特氏菌、双歧杆菌、多形拟杆菌、盲肠拟杆菌、梭菌、葡萄球菌、肠球菌、消化链球菌水平增加了80-130％，接近正常小鼠的水平；高脂饮食诱导的肥胖小鼠的戈登链球菌水平降低了约80％。
在实践中，可以使用各种合适剂量的三丁酸甘油酯或三丁酸甘油酯衍生物。一个或多个剂量可以在任何时间段内每天施用一次。一个或多个剂量也可以在任何时间段内每天施用多次。例如，可以每天施用有效剂量，持续一天、几天、多天或无限期地每天施用。更典型地，每天施用的三丁酸甘油酯或三丁酸甘油酯衍生物的量为50mg、100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、1600mg、1700mg、1800mg、1900mg或2000mg。更典型地，每天施用的三丁酸甘油酯或三丁酸甘油酯衍生物的量为20mg至 1000mg。最典型地，每天施用的三丁酸甘油酯或三丁酸甘油酯衍生物的量为200mg。
在本发明中，在三丁酸甘油酯处理后，上面提到的一些细菌的含量增加了80-130％，而另一些则降低了67-91％，这使得这些肠道微生物群的水平接近正常小鼠的水平，对维持肠道健康非常有利。

Claims (21)

  1. 一种增加哺乳动物中第一肠道微生物群的水平的方法，所述方法包含：以每天20至2000mg三丁酸甘油酯或三丁酸甘油酯衍生物的剂量向所述哺乳动物施用含三丁酸甘油酯的组合物；其中所述含三丁酸甘油酯的组合物有效增加所述哺乳动物中所述第一肠道微生物群的水平；并且所述第一肠道微生物群选自由以下组成的组中的一种或多种：嗜黏蛋白阿克曼菌、乳杆菌、齿垢密螺旋体、克里斯滕森菌、副拟杆菌、副萨特氏菌、布劳特氏菌、双歧杆菌、多形拟杆菌、盲肠拟杆菌、梭菌、葡萄球菌、肠球菌、消化链球菌。
  2. 根据权利要求1所述的方法，其中所述方法还包含：降低哺乳动物中第二肠道微生物群的水平，其中所述第二肠道微生物群为巨单胞菌、克雷伯菌、戈登链球菌。
  3. 根据权利要求1或2所述的方法，其中所述第一肠道微生物群为有益微生物群。
  4. 根据权利要求2所述的方法，其中所述第二肠道微生物群为有害微生物群。
  5. 根据权利要求1-4中任一项所述的方法，其中所述含三丁酸甘油酯的组合物配制成营养补充剂、食品、饮料、动物饲料或药物。
  6. 根据权利要求1-5中任一项所述的方法，其中所述含三丁酸甘油酯的组合物制备成固体制剂或液体制剂。
  7. 根据权利要求1-6中任一项所述的方法，其中所述含三丁酸甘油酯的组合物呈栓剂、片剂、丸剂、颗粒剂、粉剂、膜剂、胶囊、饮料、气雾剂、醑剂、酊剂、滋补剂、液体混悬剂或糖浆的形式。
  8. 一种含三丁酸甘油酯的组合物在制造用于增加哺乳动物中第一肠道微生物群的水平的营养补充剂、食品、饮料、动物饲料或药物中的用途，其中所述第一肠道微生物群选自由以下组成的组中的一种或多种：嗜黏蛋白阿克曼菌、乳杆菌、齿垢密螺旋体、克里斯滕森菌、副拟杆菌、副萨特氏菌、布劳特氏菌、双歧杆菌、多形拟杆菌、盲肠拟杆菌、梭菌、葡萄球菌、肠球菌、消化链球菌。
  9. 根据权利要求8所述的用途，其进一步包含：降低哺乳动物中第二肠道微生物群的水平，其中所述第二肠道微生物群为巨单胞菌、克雷伯菌、戈登链球菌。
  10. 根据权利要求8或9所述的用途，其中所述第一肠道微生物群为有益微生物群。
  11. 根据权利要求9或10所述的用途，其中所述第二肠道微生物群为有害微生物群。
  12. 根据权利要求8-11中任一项所述的用途，其包含：以每天20至2000mg三丁酸甘油酯或三丁酸甘油酯衍生物的剂量向所述哺乳动物施用含三丁酸甘油酯的组合物；其中所述含三丁酸甘油酯的组合物有效增加所述哺乳动物中所述第一肠道微生物群的水平。
  13. 根据权利要求9-12中任一项所述的用途，其中所述含三丁酸甘油酯的组合物制备成固体制剂或液体制剂。
  14. 根据权利要求9-13中任一项所述的用途，其中所述含三丁酸甘油酯的组合物呈栓剂、片剂、丸剂、颗粒剂、粉剂、膜剂、胶囊、饮料、气雾剂、醑剂、酊剂、滋补剂、液体混悬剂或糖浆的形式。
  15. 一种含三丁酸甘油酯的组合物，所述组合物用于增加哺乳动物中第一肠道微生物群的水平，所述第一肠道微生物群选自由以下组成的组中的一种或多种：嗜黏蛋白阿克曼菌、乳杆菌、齿垢密螺旋体、克里斯滕森菌、副拟杆菌、副萨特氏菌、布劳特氏菌、双歧杆菌、多形拟杆菌、盲肠拟杆菌、梭菌、葡萄球菌、肠球菌、消化链球菌，其中所述含三丁酸甘油酯的组合物以每天20至2000mg三丁酸甘油酯或三丁酸甘油酯衍生物的剂量向所述哺乳动物施用。
  16. 根据权利要求15所述的组合物，其中所述含三丁酸甘油酯的组合物还用于：降低哺乳动物中第二肠道微生物群的水平，其中所述第二肠道微生物群为巨单胞菌、克雷伯菌、戈登链球菌。
  17. 根据权利要求15或16所述的组合物，其中所述第一肠道微生物群为有益微生物群。
  18. 根据权利要求16或17所述的组合物，其中所述第二肠道微生物群为有害微生物群。
  19. 根据权利要求15-18中任一项所述的组合物，其中所述含三丁酸甘油酯的组合物配制成营养补充剂、食品、饮料、动物饲料或药物。
  20. 根据权利要求15-19中任一项所述的组合物，其中所述含三丁酸甘油酯的组合物制备成固体制剂或液体制剂。
  21. 根据权利要求15-20中任一项所述的组合物，其中所述含三丁酸甘油酯的组合物呈栓剂、片剂、丸剂、颗粒剂、粉剂、膜剂、胶囊、饮料、气雾剂、醑剂、酊剂、滋补剂、液体混悬剂或糖浆的形式。
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