WO2021098764A1 - 副干酪乳杆菌k56在缓解肠道炎症方面的新应用 - Google Patents

副干酪乳杆菌k56在缓解肠道炎症方面的新应用 Download PDF

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WO2021098764A1
WO2021098764A1 PCT/CN2020/130032 CN2020130032W WO2021098764A1 WO 2021098764 A1 WO2021098764 A1 WO 2021098764A1 CN 2020130032 W CN2020130032 W CN 2020130032W WO 2021098764 A1 WO2021098764 A1 WO 2021098764A1
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cfu
composition
lactobacillus paracasei
mice
group
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PCT/CN2020/130032
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English (en)
French (fr)
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刘伟贤
赵雯
孙婷
洪维鍊
吴超
马国文
张海斌
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内蒙古伊利实业集团股份有限公司
内蒙古乳业技术研究院有限责任公司
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Priority to JP2022529573A priority Critical patent/JP7497433B2/ja
Priority to EP20889355.2A priority patent/EP4062763A4/en
Priority to US17/778,609 priority patent/US20230000932A1/en
Publication of WO2021098764A1 publication Critical patent/WO2021098764A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • 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
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C17/00—Buttermilk; Buttermilk preparations
    • A23C17/02—Buttermilk; Buttermilk preparations containing, or treated with, microorganisms or enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C19/00—Cheese; Cheese preparations; Making thereof
    • A23C19/02—Making cheese curd
    • A23C19/032—Making cheese curd characterised by the use of specific microorganisms, or enzymes of microbial origin
    • A23C19/0323—Making cheese curd characterised by the use of specific microorganisms, or enzymes of microbial origin using only lactic acid bacteria, e.g. Pediococcus and Leuconostoc species; Bifidobacteria; Microbial starters in general
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C19/00—Cheese; Cheese preparations; Making thereof
    • A23C19/06—Treating cheese curd after whey separation; Products obtained thereby
    • A23C19/061—Addition of, or treatment with, microorganisms
    • A23C19/062—Addition of, or treatment with, microorganisms using only lactic acid bacteria, e.g. pediococcus, leconostoc or bifidus sp., or propionic acid bacteria; Treatment with non-specified acidifying bacterial cultures
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
    • A23C9/123—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt
    • A23C9/1234—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt characterised by using a Lactobacillus sp. other than Lactobacillus Bulgaricus, including Bificlobacterium sp.
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/10—Animal feeding-stuffs obtained by microbiological or biochemical processes
    • A23K10/16—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions
    • A23K10/18—Addition of microorganisms or extracts thereof, e.g. single-cell proteins, to feeding-stuff compositions of live microorganisms
    • 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
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A23V2400/00—Lactic or propionic acid bacteria
    • A23V2400/11—Lactobacillus
    • A23V2400/165—Paracasei
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of microbial technology, in particular to a new application of Lactobacillus paracasei subsp. paracasei K56 (Deposit No. CGMCC No. 15139 or DSM27447) in alleviating intestinal inflammation.
  • enteritis With the influence of environmental factors, diet, and living habits on the microenvironment of the intestinal flora, the incidence of enteritis has also increased year by year, and enteritis has become one of the important diseases affecting human health in the world. At present, a large number of studies have shown that oxidative damage of intestinal cells, mucosal damage, intestinal epithelial cells, release of toxins and other harmful substances, resulting in intestinal epithelial cell damage and death, enhanced intestinal epithelial permeability, pathogenic bacteria, etc.
  • enteritis can be divided into modern medical treatment and traditional Chinese medicine treatment.
  • adjusting the balance of intestinal flora by supplementing probiotics in vitro has also become an important method to reduce intestinal inflammation.
  • probiotics can antagonize pathogenic bacteria, are safe, controllable, effective, and have low side effects. They are an ideal method for the treatment of enteritis.
  • the mechanism of probiotics in the treatment of enteritis has not been thoroughly studied.
  • probiotics can inhibit the colonization of pathogenic bacteria by competing for nutrients and co-receptors, or directly inhibit pathogenic bacteria by producing bacteriocins, or by producing Antitoxin proteases, etc. isolate pathogenic bacteria and their toxins.
  • Probiotics maintain the normal intestinal flora, strengthen the mucosal barrier, inhibit the exposure of inflammatory signals, the immune system adjusts the imbalanced immune response, and inhibits host mucosal damage.
  • WGO World Gastrointestinal Organization
  • An object of the present invention is to provide a new use of Lactobacillus paracasei K56.
  • Lactobacillus paracasei subsp.paracasei K56 strain was deposited in the German Collection of Microorganisms and Cell Cultures on June 27, 2013, with the deposit number DSM27447; in addition, the paracasei milk Lactobacillus (paracasei subsp.paracasei) K56 strain was also deposited in the China General Microbiological Culture Collection Center (CGMCC) on December 29, 2017, with the deposit number CGMCC No. 15139.
  • CGMCC General Microbiological Culture Collection Center
  • Lactobacillus paracasei subsp.paracasei K56 strain single bacteria has the effect of alleviating intestinal inflammation, can reduce the inflammatory factor IL-6 and/or TNF- ⁇ , promote the anti-inflammatory factor IL-10, and reduce Colitis tissue damage.
  • the present invention provides the use of Lactobacillus paracasei (subsp. paracasei) in the preparation of a composition for relieving intestinal inflammation, and the deposit number of Lactobacillus paracasei is CGMCC No. 15139 or DSM27447.
  • the present invention provides a Lactobacillus paracasei subsp. paracasei for alleviating intestinal inflammation, and the deposit number of the Lactobacillus paracasei is CGMCC No. 15139 or DSM27447.
  • the Lactobacillus paracasei may exist in the form of a composition including it.
  • the present invention also provides a method for relieving intestinal inflammation, which comprises administering to a subject an effective amount of Lactobacillus paracasei (Lactobacillus paracasei subsp. paracasei), the preservation of Lactobacillus paracasei
  • the serial number is CGMCC No.15139 or DSM27447.
  • the Lactobacillus paracasei may be administered to a subject in the form of a composition including the same.
  • the Lactobacillus paracasei is used to prepare the composition in the form of a solid or liquid bacterial preparation.
  • the composition may include a food composition, a feed composition or a pharmaceutical composition.
  • the composition can be used in animals or humans.
  • the composition may also include conventional material components in the field.
  • auxiliary materials may be included, and the auxiliary materials may be excipients, diluents, fillers, absorption enhancers, and the like.
  • the Bifidobacterium lactis of the present invention can be produced according to the food containing Bifidobacterium lactis in the prior art, and the composition can adopt different forms according to the needs of the recipient. For example, powder, lozenge, granulation, microcapsule, liquid preparation and so on.
  • the composition is used to reduce the inflammatory factors IL-6 and/or TNF- ⁇ .
  • the application amount of Lactobacillus paracasei is 1.0 ⁇ 10 6 CFU to 1.0 ⁇ 10 13 CFU/day, preferably 1.0 ⁇ 10 9 CFU to 1.0 ⁇ 10 11 CFU/day.
  • the composition is used to promote the anti-inflammatory factor IL-10.
  • the application amount of Lactobacillus paracasei is 1.0 ⁇ 10 6 CFU to 1.0 ⁇ 10 13 CFU/day, preferably 1.0 ⁇ 10 9 CFU to 1.0 ⁇ 10 12 CFU/day, more preferably 1.0 ⁇ 10 9 CFU ⁇ 1.0 ⁇ 10 11 CFU/day.
  • the Lactobacillus paracasei subsp. paracasei K56 of the present invention has significant beneficial effects far beyond the reasonable expectations of those skilled in the art in preparing the composition for promoting the anti-inflammatory factor IL-10.
  • the composition is used to reduce colitis tissue damage.
  • the application amount of Lactobacillus paracasei is 1.0 ⁇ 10 6 CFU to 1.0 ⁇ 10 13 CFU/day, preferably 1.0 ⁇ 10 9 CFU to 1.0 ⁇ 10 12 CFU/day, more preferably 1.0 ⁇ 10 9 CFU ⁇ 1.0 ⁇ 10 11 CFU/day.
  • the composition is a food composition
  • the food may be fermented dairy products (such as fermented milk, flavored fermented milk, fermented milk beverages, etc.), cheese, milk-containing beverages, solid beverages, etc. Or milk powder and so on.
  • the composition is a feed composition.
  • Other components in the feed composition can be selected with reference to conventional techniques in the field of probiotic feeds.
  • the composition is a pharmaceutical composition.
  • Other components in the pharmaceutical composition can be selected with reference to conventional techniques in the field of probiotic drugs.
  • the present invention provides a new use of Lactobacillus paracasei K56, which has a significant effect on alleviating intestinal inflammation, can reduce inflammatory factors IL-6 and/or TNF- ⁇ , and promote anti-inflammatory factor IL-10 , Reduce colitis tissue damage, can be used to prepare foods, medicines and feeds with the effect of relieving intestinal inflammation, and has a wide range of application prospects.
  • Figure 1 shows the effect of Lactobacillus paracasei K56 on IL-6 in mouse colon.
  • Figure 2 shows the effect of Lactobacillus paracasei K56 on IL-10 in mouse colon.
  • Figure 3 shows the effect of Lactobacillus paracasei K56 on mouse colon TNF- ⁇ .
  • Figure 4 shows the pathological section results of the effect of Lactobacillus paracasei K56 on mice.
  • Figure 5 shows the score results of the histological damage of Lactobacillus paracasei K56 in mice.
  • Example 1 Experiment on the efficacy of Lactobacillus paracasei K56 in relieving intestinal inflammation
  • Healthy BABL/c male mice were purchased from Beijing Huafukang Biotechnology Co., Ltd. Raised in the animal room of the Chinese Center for Disease Control and Prevention, maintained at room temperature (25 ⁇ 2°C), relative humidity (55 ⁇ 2)%, 12h/12h alternate day and night light, and free eating and drinking.
  • mice 112 healthy BABL/c male mice, 6-8 weeks old, weighing 20-22g, were divided into 8 groups using random numbers according to their body weights, each with 14 mice. Each group was reared in two cages, each with 7 animals, using picric acid numbers, and was fed adaptively with ordinary feed for 5 days. See Table 1 for specific grouping and sample size. Intervene mice by gavage, the gavage volume is 0.4ml/20g. The intervention period is 14 days.
  • mice except for the control group, the remaining 7 groups need to establish DSS-induced experimental colitis models.
  • a 5.0% DSS aqueous solution was prepared instead of drinking water, and they were free to drink for 7 days.
  • the normal group drank distilled water. Observe the changes in the physical signs of the mice daily.
  • mice were anesthetized by intraperitoneal injection of sodium pentobarbital, blood was taken from the abdominal aorta, and the serum was separated by centrifugation. Separate the mouse colon, wash it with PBS several times, measure the length, cut 2/3, store in a centrifuge tube, and store at -80°C. 1/3 is stored in 10% formalin solution and fixed for later use.
  • the Fedorak histological score standard was used for histological scoring.
  • the histological injury scoring standard is shown in Table 2.
  • cytokines IL-6, IL-10 and TNF- ⁇ in mouse colon were determined according to the instructions of the ELISA kit.
  • the experimental data is expressed as Mean ⁇ S.E.M.
  • the data is calculated using PRISM version 5.0 (GraphPad, San Diego, CA, USA). Differences between groups are counted using one-way ANOVA followed by Tukery’s multiple comparison test. There is a significant statistical difference when P ⁇ 0.05.
  • mice The weight of mice at 0, 7, and 14 days were counted, and the results are shown in Table 3.
  • the body weight of the mice in the model group and each intervention group decreased significantly, indicating that despite the sample intervention, the weight of the mice still decreased under the premise that DSS caused intestinal damage.
  • the weight of mice in each intervention group was significantly lower than that of the control group (p ⁇ 0.05), and there was no significant difference compared with the model group (p>0.05). It shows that the sample has limited intervention effect on the body weight of the mice modeled by DSS.
  • mice in each group have smooth coat color, mentally active, flexible response, normal eating, no diarrhea and bloody stools, and stools are spherical or bar-shaped; after 7 days of modeling, the mice in the model group and the intervention group have passed 5.0% The DSS induced the formation of an experimental colitis model. Observe the physical sign changes of mice in each experimental group during the modeling period, and the relevant results are shown in Table 4.
  • mice The observation results of intestinal inflammation symptoms in mice showed that the intervention effects of each sample on DSS model mice were shown in the following aspects: (1) The number of bloody stools in mice decreased after the experiment; (2) The time and time when mice appeared bloody stools The model group was delayed by 1 to 2 days. Therefore, in this model, 5% DSS was used instead of drinking water, possibly because the mice's intake and tolerance to DSS were different, and the death of mice did not change with the dose.
  • Table 5 shows the results of spleen weight of mice in each group. Compared with the control group, the spleen index of the model group was significantly higher than that of the control group (p ⁇ 0.05), indicating that 5% DSS can stimulate the proliferation of mouse splenic lymphocytes and macrophages, and stimulate the body to exert cellular immunity and humoral immunity. effect.
  • the middle-dose K56 group has a tendency to decrease in the spleen index. It can be inferred that the middle-dose K56 group may have the function of reducing the body's inflammatory response.
  • mice colon length are shown in Table 6. After modeling, the colon length of the model group was significantly lower than that of the control group (p ⁇ 0.05); after sample intervention, the colon length of each group was not significantly different from that of the model group (p>0.05), indicating that the main effect on the length of the mouse colon in this experiment is 5% DSS, and short-term intervention of the sample has no significant effect on the length of the mouse colon.
  • the pathological section results are shown in Figure 4. Histological observation of the mice in the control group can see intact colonic epithelial cells, as well as clear crypt structures and goblet cells. Histological observation of colitis mice in the model group induced by DSS showed that intact colonic epithelial cells could not be seen. At the same time, incomplete crypts and goblet cell damage appeared. The damaged area was more than 50%, and some mice were cryptic. The nest disappeared completely, and the cup shape was completely destroyed. In addition, mouse inflammatory cell infiltration can also be observed, such as neutrophils and lymphocytes.
  • mice After the intervention of K56, the mice were modeled by DSS. Inflammatory cell infiltration occurred, a small number of crypts disappeared, and goblet cells were destroyed. The low-dose group had more severe inflammation, with lesions ranging from 50 to 75%. The range of lesions in the group is relatively limited, most of which are within 25%.
  • the histological injury score results are shown in Figure 5. Compared with the model group, the colonic histological injury scores of each group have a downward trend. Among them, the histological injury scores of the K56 low and high-dose groups are significantly lower than those of the model group (p ⁇ 0.05), indicating that the above K56 has the effect of alleviating the inflammatory symptoms of the mice's colon.
  • DSS-induced colitis is the most common method for experimental animal colitis models. Usually, mice can drink freely for about 7 days to form an experimental colitis model. In this experiment, 5% DSS was used as the modeling concentration. The model group was dead, and the mice began to have blood in the stool on the third day. With time, the blood in the stool became worse and the number of blood in the stool increased, indicating that the model was established with good stability. The bloody stools of the mice in each dose group of K56 were later than the model group. The number of bloody stools in the mice was less than that of the model group, and the symptoms were lighter, which directly indicated the anti-inflammatory effect of probiotics.
  • IL-6 is a multifunctional key cytokine that can regulate the expression of other cytokines.
  • IL-6 is a pro-inflammatory factor, and its expression level is closely related to the degree of inflammation in colon studies. Mice lacking IL-10 show severe intestines. Tract inflammation, and IL-10 has a good therapeutic effect in animal colitis models.
  • TNF- ⁇ is a cytokine involved in systemic inflammation.
  • the medium dose of Lactobacillus paracasei K56 lowered the content of inflammatory factor IL-6 in the colon, lowered the content of serum TNF- ⁇ , and lowered the score of colon tissue injury; high dose increased the content of anti-inflammatory factor IL-10 in colon tissue, and reduced the colon Tissue damage score.
  • Lactobacillus paracasei K56 can significantly inhibit the inflammatory factors IL-6 and TNF- ⁇ , enhance the anti-inflammatory factor IL-10, and restore the effect of colon tissue loss. It can be used in foods such as fermented milk, cheese, and other foods. Milk beverage, milk powder or any other food containing the strain and its derivatives.

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Abstract

副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)K56在缓解肠道炎症方面的新应用，具体包括显著缓解肠道炎症的功效，能够降低炎症因子IL-6和/或TNF-α，促进抑炎因子IL-10，降低结肠炎组织损伤。

Description

副干酪乳杆菌K56在缓解肠道炎症方面的新应用 技术领域
本发明涉及微生物技术领域，尤其是涉及一种副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)K56(保藏编号CGMCC No.15139或DSM27447)在缓解肠道炎症方面的新应用。
背景技术
随着环境因素、饮食、生活习惯等对肠道菌群微环境的影响，肠炎的发病率也逐年上升，肠炎已经成为影响全球人类健康的重要疾病之一。目前已有大量研究表明，肠道细胞的氧化损伤，粘膜受损、感染肠道上皮细胞、释放毒素等有害物质、致使肠道上皮细胞损伤死亡，肠道上皮通透性增强、致病菌等透过损伤的肠道粘膜屏障、进入组织内部，引发系列的免疫应答，导致巨噬细胞产生大量的细胞因子，过度刺激T细胞，产生促炎因子，使上皮细胞发生炎症反应。
肠炎传统的治疗方法可分为现代医学治疗和中药治疗方法。随着科学技术的发展，通过体外补充益生菌的方法调节肠道菌群平衡也成为了降低肠道炎症的重要方法。益生菌作为肠道内源性和免疫性防御屏障，能够拮抗致病菌，具有安全、可控、有效、副作用小的特点，是治疗肠炎的理想方法。益生菌治疗肠炎的机制目前尚未研究透彻，目前普遍归功于益生菌可通过竞争营养性物质、竞争共同受体抑制致病菌定殖、或者通过产生细菌素直接抑制致病菌，亦或通过产生抗毒素蛋白酶等隔绝致病菌及其毒素。益生菌通过维持肠道正常菌群，加强粘膜屏障作用，抑制炎症信号的暴露免疫系统对失衡的免疫应答进行调整，抑制宿主粘膜损伤。此外，世界肠胃组织(WGO)全球指南中已指出将益生菌制剂作为炎症性肠病药物。
发明内容
本发明的一个目的在于提供副干酪乳杆菌K56的新用途。
副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)K56菌株已于2013年6月27日保存于德国微生物及细胞培养物收集中心(German Collection of Microorganisms and Cell Cultures)，保藏编号DSM27447；另外，副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)K56菌株也已于2017年12月29日保存于中 国微生物菌种保藏管理委员会普通微生物中心(China General Microbiological Culture Collection Center,CGMCC)，保藏编号CGMCC No.15139。
本发明发现副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)K56菌株单菌即具有缓解肠道炎症的功效，能够降低炎症因子IL-6和/或TNF-α，促进抑炎因子IL-10，降低结肠炎组织损伤。
从而，本发明提供了副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)在制备用于缓解肠道炎症的组合物中的应用，所述副干酪乳杆菌的保藏编号为CGMCC No.15139或DSM27447。
换而言之，本发明提供了一种用于缓解肠道炎症的副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)，所述副干酪乳杆菌的保藏编号为CGMCC No.15139或DSM27447。所述副干酪乳杆菌可以包括其的组合物的形式存在。
从另一角度而言，本发明还提供了一种缓解肠道炎症的方法，其包括给予受试者有效量的副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)，所述副干酪乳杆菌的保藏编号为CGMCC No.15139或DSM27447。所述副干酪乳杆菌可以包括其的组合物的形式施予受试者。
根据本发明的具体实施方案，所述副干酪乳杆菌以固态或液态菌制剂的形式用于制备所述组合物。
根据本发明的具体实施方案，所述组合物可以包括食品组合物、饲料组合物或药品组合物。
根据本发明的具体实施方案，所述组合物可使用于动物或是人类。所述组合物还可包括所属领域中的常规用料组分。例如，对于药物组合物，可包括适量的辅料，所述辅料可以为赋型剂、稀释剂、填充剂、吸收促进剂等。对于食品组合物，本发明的乳双歧杆菌可以按照现有技术中含乳双歧杆菌的食品进行生产，所述组合物可根据受施予者的需要，而采用不同形态。例如粉剂、锭剂、造粒、微胶囊、液体制剂等。
根据本发明的具体实施方案，所述组合物是用于降低炎症因子IL-6和/或TNF-α。具体应用时，所述副干酪乳杆菌的应用量为1.0×10 6CFU～1.0×10 13CFU/天，优选为1.0×10 9CFU～1.0×10 11CFU/天。
根据本发明的具体实施方案，所述组合物是用于促进抑炎因子IL-10。具体应用时，所述副干酪乳杆菌的应用量为1.0×10 6CFU～1.0×10 13CFU/天，优选为1.0×10 9CFU～1.0×10 12CFU/天，更优选为1.0×10 9CFU～1.0×10 11CFU/天。本发明的副干 酪乳杆菌(Lactobacillus paracasei subsp.paracasei)K56在制备用于促进抑炎因子IL-10的组合物方面，具有远远超出本领域技术人员合理预期的显著有益效果。
根据本发明的具体实施方案，所述组合物是用于降低结肠炎组织损伤。具体应用时，所述副干酪乳杆菌的应用量为1.0×10 6CFU～1.0×10 13CFU/天，优选为1.0×10 9CFU～1.0×10 12CFU/天，更优选为1.0×10 9CFU～1.0×10 11CFU/天。
在本发明的一具体实施方案中，所述组合物为食品组合物，所述食品可以为发酵乳制品(例如发酵乳、风味发酵乳、发酵乳饮料等)、乳酪、含乳饮料、固体饮料或乳粉等。
在本发明的另一具体实施方案中，所述组合物为饲料组合物。所述饲料组合物中的其他组分可以参照益生菌饲料领域的常规技术进行选择。
在本发明的另一具体实施方案中，所述组合物为药物组合物。所述药物组合物中的其他组分可以参照益生菌药物领域的常规技术进行选择。
综上所述，本发明提供了副干酪乳杆菌K56的新用途，该菌具有显著缓解肠道炎症的功效，能够降低炎症因子IL-6和/或TNF-α，促进抑炎因子IL-10，降低结肠炎组织损伤，可以用于制备具有缓解肠道炎症功效的食品、药物及饲料等，具有广泛的应用前景。
附图说明
图1显示副干酪乳杆菌K56对小鼠结肠IL-6的影响。
图2显示副干酪乳杆菌K56对小鼠结肠IL-10的影响。
图3显示副干酪乳杆菌K56对小鼠结肠TNF-α的影响。
图4显示副干酪乳杆菌K56对小鼠影响的病理学切片结果。
图5显示副干酪乳杆菌K56对小鼠组织学损伤评分结果。
具体实施方式
为了对本发明的技术特征、目的和有益效果有更加清楚的理解，现结合具体实施例及对本发明的技术方案进行以下详细说明，应理解这些实例仅用于说明本发明而不用于限制本发明的范围。
实施例中，各原始试剂材料均可商购获得，未注明具体条件的实验方法为所属领域熟知的常规方法和常规条件，或按照仪器制造商所建议的条件。
实施例1：副干酪乳杆菌K56缓解肠道炎症功效实验
1.实验材料
健康BABL/c雄性小鼠，购自北京华阜康生物科技有限责任公司。饲养于中国疾病预防控制中心动物房，维持室温(25±2℃)，相对湿度(55±2)％，12h/12h昼夜交替光照，自由进食和饮水。
2.实验方法
2.1动物分组及处理
健康BABL/c雄性小鼠112只，鼠龄6～8周，体重20～22g，依据体重，利用随机数字，分为8组，每组14只。每组分两笼饲养，每笼7只，使用苦味酸编号，普通饲料适应性喂养5天。具体分组及样品量见表1。以灌胃方式干预小鼠，灌胃体积为0.4ml/20g。干预周期为14天。
表1实验分组
Figure PCTCN2020130032-appb-000001
8组小鼠，除对照组外，其余7组需要进行DSS诱导的实验性结肠炎模型的建立。在实验过程第8天，配制5.0％的DSS水溶液替代饮水，自由饮用7天，正常组饮用蒸馏水。每日观察小鼠体征变化。
2.2结肠长度及重量测定
干预结束后，小鼠戊巴比妥钠腹腔注射麻醉，腹主动脉取血，离心分离血清。分离小鼠结肠，以PBS冲洗多次后，测量长度，剪切2/3存于离心管中，-80℃保存。1/3储存于10％福尔马林溶液中固定备用。
2.3结肠组织病理学观察及评分
结肠放入福尔马林溶液固定后，依次经过脱水、浸蜡、包埋、切片、捞片和烤片，脱蜡复水，HE染色，最后显微镜观察组织形态学。
采用Fedorak组织学积分标准进行组织学评分。组织学伤损评分标准见表2。
表2组织学损伤评分标准
评分 炎症 病变深度 隐窝破坏 病变范围
0 无 无 无 /
1 轻度 粘膜下层 基底1/3隐窝破坏 1％-25％
2 中毒 肌层 基底2/3隐窝，破坏 26％-50％
3 / 浆膜层 仅有完整表面上皮 51％-75％
4 / / 全部隐窝和上皮被破坏 76％-100％
2.4血清中细胞因子测定
按照ELISA试剂盒说明书对小鼠结肠中细胞因子IL-6、IL-10、TNF-α含量进行测定。
2.5统计分析方法
实验数据表示为Mean±S.E.M.数据采用PRISM version 5.0(GraphPad,San Diego,CA,USA)进行统计。组间差异采用one-way ANOVA跟随Tukery’s multiple comparison test的方法进行统计。P<0.05时具有显著的统计学差异。
3.实验结果与分析
3.1小鼠体重变化
对小鼠0天、7天、14天体重进行统计，结果见表3。
表3小鼠体重变化
分组 0天 7天 14天
对照组 20.92±0.56 22.25±0.88 22.68±1.02
模型组 21.36±0.99 23.18±1.21 19.19±2.28*
低剂量组 21.36±0.69 22.98±1.19 20.22±1.73*
中剂量组 21.10±0.82 23.12±0.84 19.54±2.61*
高剂量组 20.87±0.64 22.08±0.70 18.87±1.75*
注：*与对照组比较，差异具有显著性。
0天时，小鼠体重组间比较无显著性差异(p＜0.05)；表明实验开始时小鼠状态一致，可排除小鼠体重不同造成的实验差异。给予样品7天后，各组小鼠体重均增加，组间比较无显著性差异(p＜0.05)，表明短时间样品干预对小鼠的体重增长无影响。 5％DSS代替饮水7天后，模型组小鼠体重均显著降低(p＜0.05)，而对照组体重无显著性变化(p＞0.05)，同时参考小鼠状态观察结果，表示模型组造模成功。造模后，模型组和各干预组小鼠体重均显著降低，表明虽然经样品干预，但在DSS造成肠道损伤的前提下，小鼠体重依然减少。造模后，各干预组小鼠体重显著低于对照组(p＜0.05)，与模型组比较无显著性差异(p＞0.05)。表明样品对于经DSS造模小鼠体重的干预作用有限。
3.2 DSS诱导小鼠结肠炎症特征观察
0-7天，各组小鼠毛色光滑，精神活跃，反应灵活，正常进食，无腹泻及血便，大便呈球形或条形；经过7天造模，模型组与干预组小鼠均经过5.0％的DSS诱导形成了实验性结肠炎模型。分别观察个实验组小鼠在造模期的体征变化，相关结果参见表4。
表4小鼠体征观察
Figure PCTCN2020130032-appb-000002
小鼠肠道炎症症状观察结果表明，各样品对DSS造模小鼠的干预作用表现在以下几个方面：(1)实验结束小鼠血便只数减少；(2)小鼠出现血便的时间与模型组比较推迟1～2天。因此次造模以5％DSS代替饮水，可能因为小鼠对DSS的摄入量与耐受程度不同，小鼠的死亡未随着剂量而变化。
3.3各组小鼠脾脏重量
各组小鼠脾脏重量结果见表5。与对照组比较，模型组小鼠脾脏指数均显著高于对照组(p＜0.05)，表明5％DSS可刺激小鼠脾脏淋巴细胞和巨噬细胞的增殖，刺激机体发挥细胞免疫和体液免疫的作用。K56中剂量组在脾脏指数上具有降低的趋势，可以得出推测，表明K56中剂量组可能具有减少机体炎性反应的功能。
表5小鼠脾脏重量/指数
组别 脾脏重量(g) 脾脏指数
对照组 0.081±0.011 0.36±0.05
模型组 0.085±0.021 0.44±0.09*
低剂量组 0.090±0.021 0.45±0.11*
中剂量组 0.074±0.019 0.38±0.09
高剂量组 0.093±0.025 0.49±0.11*
注：*与对照组比较，差异具有显著性。
3.4检测指标
3.4.1小鼠结肠长度检测结果
小鼠结肠长度结果如表6所示，造模后，模型组小鼠结肠长度显著低于对照组(p＜0.05)；样品干预后，各组小鼠结肠长度与模型组比较无显著性差异(p＞0.05)，说明本实验中对小鼠结肠长度其主要作用的为5％DSS，样品短期干预对小鼠结肠长度无显著影响。
表6小鼠结肠长度测量结果
组别 结肠长度(cm)
对照组 12.51±0.92
模型组 7.78±1.53*
低剂量组 8.66±0.92*
中剂量组 8.43±1.10*
高剂量组 8.53±0.59*
注：*与对照组比较，差异具有显著性3.4.2IL-6检测结果
3.4.2结肠IL-6检测结果
结肠K56变化结果如图1所示，与对照组比较，模型组小鼠结肠IL-6显著高于对照组(p＜0.05)，表明小鼠DSS干预可以起小鼠肠道炎症反应的增加，表现为炎性因子IL-6的增高。与模型组比较，K56中剂量组小鼠结肠IL-6显著低于模型组(p＜0.05)；表明益生菌干预后，中、高剂量的K56可减少小鼠肠道炎症反应。
3.4.3结肠IL-10检测结果
结肠IL-10变化结果如图2所示，与对照组比较，模型组结肠IL-10虽上升，但 差距没有显著性(p＞0.05)，表明造模具有导致肠道抗炎因子IL-10分泌增加的趋势。与模型组比较，所有组别的IL-10均有上升，其中K56高剂量组(2.5×10 9cfu/mL)小鼠结肠IL-10均显著增高(p＜0.05)，表明K56干预具有促进肠道抗炎细胞产生抗炎因子IL-10的作用。
3.4.4结肠TNF-α检测结果
结肠IL-10变化结果如图3所示，与模型组比较，本发明的益生菌K56低、中、高剂量组结肠TNF-α均有下降趋势，说明K56可减少肠道炎症反应，减少结肠炎性因子TNF-α的分泌。
3.4.5病理学结果
3.4.5.1病理切片
病理学切片结果如图4所示，对照组小鼠的组织学观察可以看到完整的结肠上皮细胞，并可看到清晰的隐窝结构和杯状细胞。DSS诱导形成的模型组结肠炎小鼠的组织学观察，不能看到完整的结肠上皮细胞，同时出现隐窝不完全、杯状细胞损坏的现象，损坏面积均在50％以上，部分小鼠隐窝完全消失，杯状被完全破坏。另外还可以观察到小鼠炎性细胞浸润，如中性粒细胞和淋巴细胞等。
小鼠经K56干预后DSS造模，出现了炎性细胞浸润、少部分隐窝消失，杯状细胞被破坏，其中低剂量组炎症反应较为严重，病变范围在50～75％，中、高剂量组病变范围较为局限，大部分在25％范围内。
3.4.5.2对小鼠组织学伤损评分分析
组织学损伤评分结果如图5所示，与模型组比较，各组结肠组织学伤损评分均具有下降趋势，其中K56低、高剂量组组织学伤损评分均显著低于对模型组(p＜0.05)，说明以上K56对小鼠结肠损伤具有减轻小鼠结肠炎症症状的作用。
DSS诱导的结肠炎是实验性动物结肠炎模型最常见的方法，通常都是小鼠自由饮用7天左右即可形成实验性结肠炎模型。本试验采用5％DSS作为造模浓度，模型组为出现死亡，且小鼠在第3天开始出现便血情况，随时间延长，便血情况加重，便血只数增加，表明模型建立稳定性好。K56各剂量组小鼠出现血便的时间较模型组晚，小鼠血便只数较模型组少，症状较轻，直接表明益生菌的抗炎症反应作用。
IL-6为一种多功能的关键细胞因子，能够调节其他细胞因子的表达。在DSS诱导的实验性结肠炎的过程中，IL-6作为促炎因子，其表达水平的高低与结肠研中炎症 程度的深浅有着密切的关系,缺乏IL-10的小鼠表现出严重的肠道炎症，且IL-10在动物结肠炎模型中表现良好的治疗效果,TNF-α是一种涉及到系统性炎症的细胞因子。本研究中，副干酪乳杆菌K56中剂量降低结肠炎性因子IL-6含量，降低血清TNF-α含量，降低结肠组织伤损评分；高剂量增高结肠组织抗炎因子IL-10含量，降低结肠组织伤损评分。
以上研究结果证实：副干酪乳杆菌K56能显著抑制炎症因子IL-6和TNF-α，提升抑炎因子IL-10，恢复结肠组织损失的作用，可以用于食品，如发酵乳、乳酪、含乳饮料、乳粉或其它含有该菌株及其衍生物的任何一种食品。

Claims (10)

  1. 一种副干酪乳杆菌(Lactobacillus paracasei subsp.paracasei)在制备用于缓解肠道炎症的组合物中的应用，所述副干酪乳杆菌的保藏编号为CGMCC No.15139或DSM27447。
  2. 根据权利要求1所述的应用，其中，所述副干酪乳杆菌以固态或液态菌制剂的形式用于制备所述组合物。
  3. 根据权利要求1所述的应用，其中，所述组合物包括食品组合物、饲料组合物或药品组合物。
  4. 根据权利要求1所述的应用，其中，所述组合物是用于降低炎症因子IL-6和/或TNF-α。
  5. 根据权利要求4所述的应用，其中，所述副干酪乳杆菌的应用量为1.0×10 6CFU～1.0×10 13CFU/天，优选为1.0×10 9CFU～1.0×10 11CFU/天。
  6. 根据权利要求1所述的应用，其中，所述组合物是用于促进抑炎因子IL-10。
  7. 根据权利要求6所述的应用，其中，所述副干酪乳杆菌的应用量为1.0×10 6CFU～1.0×10 13CFU/天，优选为1.0×10 9CFU～1.0×10 11CFU/天。
  8. 根据权利要求1所述的应用，其中，所述组合物是用于降低结肠炎组织损伤。
  9. 根据权利要求8所述的应用，其中，所述副干酪乳杆菌的应用量为1.0×10 6CFU～1.0×10 13CFU/天，优选为1.0×10 9CFU～1.0×10 11CFU/天。
  10. 根据权利要求4～9任一项所述的应用，其中，所述组合物为食品组合物，优选地，所述食品为发酵乳制品、乳酪、含乳饮料、固体饮料或乳粉。
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