WO2019208150A1 - 脂肪蓄積抑制用組成物 - Google Patents
脂肪蓄積抑制用組成物 Download PDFInfo
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- WO2019208150A1 WO2019208150A1 PCT/JP2019/014997 JP2019014997W WO2019208150A1 WO 2019208150 A1 WO2019208150 A1 WO 2019208150A1 JP 2019014997 W JP2019014997 W JP 2019014997W WO 2019208150 A1 WO2019208150 A1 WO 2019208150A1
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- composition
- lactic acid
- polysaccharide
- composition according
- food
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Definitions
- the present invention relates to a composition for suppressing fat accumulation. More specifically, the present invention relates to a composition for inhibiting fat accumulation, comprising as an active ingredient a lactic acid bacterium belonging to Lactobacillus paracasei, a culture or fermentation product thereof, or a polysaccharide produced therefrom. About.
- Fatty liver is a condition in which neutral fat is excessively accumulated in the liver or hepatocytes, and is considered to be closely related to lifestyle-related diseases such as obesity, hyperlipidemia, and diabetes.
- the accumulation of neutral fat in the liver or hepatocytes is considered to be one of the causes, for example, when free fatty acids are taken in and accumulated as neutral fat.
- the present inventors have found that polysaccharides produced by lactic acid bacteria belonging to Lactobacillus paracasei are released from hepatocytes. It has been found that it has an action of suppressing fatty acid uptake and accumulation as neutral fat, and that lactic acid bacteria belonging to Lactobacillus paracasei have an anti-obesity action by suppressing weight gain and visceral fat accumulation. Based on this finding, the present invention was completed by further research.
- the present invention is for the purpose of inhibiting fat accumulation comprising as an active ingredient a lactic acid bacterium belonging to Lactobacillus paracasei, a culture or fermentation product thereof, or a polysaccharide produced thereby.
- the composition of the present invention can be preferably used for the prevention or improvement of obesity and for the prevention or improvement of fatty liver or liver dysfunction.
- the lactic acid bacterium is preferably a lactic acid bacterium derived from a fig, and in particular, Lactobacillus paracasei IJH-SONE68 strain (accession number NITE BP-02242) or an equivalent lactic acid bacterium is preferable.
- FIG. 1 is a photomicrograph of Lactobacillus paracasei IJH-SONE68 strain.
- 1A is a Gram-stained micrograph
- FIG. 1B is a scanning electron microscope (SEM) photo.
- FIG. 2 is a separation profile of the polysaccharide of Lactobacillus paracasei IJH-SONE68 strain by anion exchange chromatography (TOYOPEARL DEAE-650M resin (Tosoh Corporation)). The polysaccharide was eluted with NaCl (dashed line) with a gradient concentration of 0 to 500 mM mM, and the presence of the polysaccharide in each fraction was monitored at 490 nm by the phenol-sulfuric acid method (straight line).
- FIG. 1 is a photomicrograph of Lactobacillus paracasei IJH-SONE68 strain.
- 1A is a Gram-stained micrograph
- FIG. 1B is a scanning electron microscope (SEM) photo.
- FIG. 5 is a graph showing that the polysaccharide produced by Lactobacillus paracasei IJH-SONE68 strain has a fat accumulation-inhibiting action in a concentration-dependent manner.
- FIG. 6 is a graph showing a change in weight gain of an obese model mouse fed with a high fat diet fed with a pineapple juice fermented liquid fermented with Lactobacillus paracasei IJH-SONE68 strain.
- FIG. 7 is a graph showing that weight gain in obese model mice fed with a high fat diet is suppressed by ingesting a pineapple juice fermented liquid fermented with Lactobacillus paracasei IJH-SONE68 strain.
- FIG. 8 is a graph showing that the visceral fat amount in obese model mice fed with a high fat diet is suppressed by ingesting a fermented pineapple juice fermented with Lactobacillus paracasei IJH-SONE68 strain.
- a composition for inhibiting fat accumulation comprising as an active ingredient a lactic acid bacterium belonging to Lactobacillus paracasei, a culture or fermentation product thereof, or a polysaccharide produced by the lactic acid bacterium belonging to Lactobacillus paracasei provided in the present invention
- Lactic acid bacteria targeted by the present invention are lactic acid bacteria belonging to Lactobacillus paracasei, and fig-derived lactic acid bacteria are preferred.
- Lactobacillus paracasei IJH-SONE68 strain isolated and identified from the leaf of the fig according to the present invention can be mentioned.
- NITE P-02242 This strain was established on April 19, 2016 as the NITE P-02242 under the accession number NITE P-02242 at the National Institute of Technology and Evaluation Microbiology Center (Room 2-5-8 Kazusa, Kazusa, Kisarazu 292-0818, Japan) It was deposited in Japan and then transferred to an international deposit under the Budapest Treaty. On May 26, 2017, the deposit number for the international deposit was given as NITE BP-02242.
- lactic acid bacteria equivalent to Lactobacillus paracasei IJH-SONE68 strain are also targeted.
- the equivalent lactic acid bacterium is a lactic acid bacterium belonging to Lactobacillus paracasei ⁇ , which, like Lactobacillus paracasei IJH-SONE68 strain, refers to a lactic acid bacterium having an action of inhibiting fat accumulation, and is also produced by the Lactobacillus paracasei IJH-SONE68 strain.
- saccharides it refers to lactic acid bacteria that produce polysaccharides that have an action of inhibiting fat accumulation.
- lactic acid bacteria can be obtained, for example, by subjecting the Lactobacillus paracasei IJH-SONE68 strain to normal mutation treatment techniques such as mutation and gene recombination, and the Lactobacillus paracasei IJH-SONE68 strain. It may be a strain bred by selection of a mutant strain or the like.
- the obtained culture may be used as it is as an active ingredient, or the obtained culture solution may be diluted or concentrated, or cells recovered from the culture may be used.
- various additional operations such as heating and freeze-drying can be performed after culturing as long as the effects of the present invention are not impaired.
- the microbial cell of a lactic acid bacterium may be a living microbial cell or a dead microbial cell having a polysaccharide attached to its cell surface layer, or may be both a microbial cell and a dead microbial cell. Although dead cells may be crushed, it is desirable that polysaccharides are attached to the surface layer.
- fermented lactic acid bacteria usually use glucose or the like as a nutrient source, and if necessary, further add a plant lactic acid bacteria growth promoting substance such as yeast extract, pineapple fruit juice, sake lees, shochu, It can be obtained by fermentation.
- a plant lactic acid bacteria growth promoting substance such as yeast extract, pineapple fruit juice, sake lees, shochu, It can be obtained by fermentation.
- Polysaccharides produced by lactic acid bacteria can be obtained by separation and purification by a conventional method from a culture of lactic acid bacteria belonging to Lactobacillus paracasei. Specifically, for example, microbial cells are removed from a culture of lactic acid bacteria belonging to Lactobacillus paracasei by centrifugation, and polysaccharides are precipitated from the obtained culture using ethanol, acetone, or the like. Can be obtained. It can also be obtained by further separation and purification by ion exchange chromatography.
- composition of the present invention can be used in various forms such as a food and drink composition, a pharmaceutical composition, and a feed composition.
- the food / beverage product of the food / beverage product composition is not particularly limited, and beverages such as soft drinks, carbonated beverages, nutritional beverages, fruit juice beverages, lactic acid bacteria beverages, concentrated stock solutions of these beverages, powders for preparation, etc .; ice cream, sherbet, Ice confectionery such as shaved ice; sweets such as candy, gummy, cereal, chewing gum, candy, gum, chocolate, tablet confectionery, snack confectionery, biscuits, jelly, jam, cream, and baked confectionery; processed milk, milk beverage, fermented milk, drink Examples include dairy products such as yogurt and butter; bread; enteral nutrition foods, liquid foods, milk for childcare, sports drinks; foods such as puree; amazake; and other functional foods.
- the food and drink may be a supplement, for example, a granular, powder, or tablet supplement.
- Such foods and drinks can be produced by adding lactic acid bacterial cells, their cultures or fermentation products, or polysaccharides produced by them to the raw materials of food or drinks, or in the same manner as ordinary foods and drinks.
- the addition of lactic acid bacterial cells, cultures or fermented products thereof or polysaccharides produced by them may be carried out at any stage of the production process of food and drink.
- the food and drink may be manufactured through a fermentation process using the added lactic acid bacteria. Examples of such foods and drinks include fermented foods such as lactic acid bacteria beverages and fermented milk.
- the content of the lactic acid bacteria or the culture or fermented product thereof in the food or drink composition is appropriately set depending on the form of the food or drink, but usually 1 ⁇ 10 6 to 1 ⁇ 10 12 in the food or drink composition.
- the content is preferably such that the cells are contained within the range of cfu / g or 1 ⁇ 10 6 to 1 ⁇ 10 12 cfu / ml, and 1 ⁇ 10 7 to 1 ⁇ 10 11 cfu / g or 1 ⁇ 10 7 to More preferably, it is in the range of 1 ⁇ 10 11 cfu / ml.
- the pharmaceutical composition is usually used by formulating a lactic acid bacterial cell, a culture or fermentation product thereof, or a polysaccharide produced by the lactic acid bacterium into a commonly used physiologically acceptable liquid or solid pharmaceutical carrier. Is done.
- the dosage form of the pharmaceutical composition is not particularly limited. Tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, syrups, suppositories, injections, ointments, patches, eye drops And nasal drops.
- the content of lactic acid bacteria or the culture or fermented product thereof in the preparation of the pharmaceutical composition of the present invention depends on the dosage form, usage, age of subject, sex, type of disease, degree of disease, and other conditions. Usually, the content is preferably such that the cells are contained within the range of 1 ⁇ 10 6 to 1 ⁇ 10 12 cfu / g or 1 ⁇ 10 6 to 1 ⁇ 10 12 cfu / ml, More preferably, it is in the range of ⁇ 10 7 to 1 ⁇ 10 11 cfu / g or 1 ⁇ 10 7 to 1 ⁇ 10 11 cfu / ml.
- the pharmaceutical composition preferably contains 0.001% by weight or more and 0.01% by weight or more in terms of the weight of the polysaccharide.
- Examples of the feed of the feed composition include pet food, livestock feed, fish feed and the like.
- Such feeds are common feeds such as cereals, potatoes, sardines, fish meal, bone meal, fats and oils, skim milk powder, whey, bittern, mineral feeds, yeasts, etc. It can be produced by mixing the body, its culture or fermented product or the polysaccharide it produces. Further, for example, as in the case of silage, the feed may be produced through a fermentation process with added lactic acid bacteria.
- the produced feed can be orally administered to general mammals, livestock, fish farms, pets and the like.
- a method in which a lactic acid bacterium, a culture or fermentation product thereof, or a fermentation product to which a polysaccharide produced by the lactic acid bacterium is added can be used in a fish farm.
- the content of lactic acid bacteria in the feed composition, the culture or fermented product thereof is appropriately set depending on the form of the feed and the application target, but it is 1 ⁇ 10 6 to 1 ⁇ 10 12 cfu / g or 1 ⁇ 10 6.
- the content is preferably such that the microbial cells are contained within the range of ⁇ 1 ⁇ 10 12 cfu / ml, 1 ⁇ 10 7 to 1 ⁇ 10 11 cfu / g or 1 ⁇ 10 7 to 1 ⁇ 10 11 cfu / ml More preferably within the range.
- lactic acid bacteria are dead cells, cfu / g or cfu / ml can be replaced with individual cells / g or individual cells / ml.
- a polysaccharide produced by lactic acid bacteria it is preferably contained in the feed composition in an amount of usually 0.001% by weight or more, more preferably 0.01% by weight or more in terms of the weight of the polysaccharide.
- composition of the present invention Lactobacillus paracasei belonging to Lactobacillus paracasei, its culture or fermented product, or polysaccharides produced by it, hepatocytes take in free fatty acids and accumulate as neutral fat In addition, it has an anti-obesity effect by suppressing weight gain and visceral fat accumulation. Therefore, a lactic acid bacterium belonging to Lactobacillus paracasei, a culture or fermentation product thereof, or a composition containing a polysaccharide produced as an active ingredient is used for fat accumulation suppression and obesity. Can be used for suppression. Specifically, the composition of the present invention can be used for the prevention or improvement of obesity and for the prevention or improvement of fatty liver or liver dysfunction.
- composition of this invention is effective in the prevention or improvement of obesity, it can be utilized especially as a raw material of food and drink for health maintenance and health promotion. Moreover, since prevention or improvement of fatty liver or liver dysfunction leads to maintenance, enhancement, recovery, etc. of physical fitness, it can also be used as a food / beverage product for maintenance, enhancement, recovery of physical fitness.
- Example 1 Isolation and identification of lactic acid bacteria Isolation of Lactic Acid Bacteria Samples Select leaves, stems and fruits of fig (Cultivar “Toyomitsuhime”), subdivide into 2-3 mm using sterilized tweezers and scissors, then sterilized MRS liquid medium Five to six strips were placed in the test tube and statically cultured at 28 ° C. and 37 ° C. until the MRS medium, which is a standard medium for lactic acid bacteria, became cloudy (growth). Incidentally, it took 2 to 4 days before the growth of lactic acid bacteria candidate strains was visible. A part of each culture solution of the lactic acid bacterium candidate strain was line-painted on a MRS agar medium with a disposable loop, followed by stationary culture.
- a 16S rDNA portion was amplified by a PCR reaction using a 27f primer and a 1525r primer as a template, and the target fragment was recovered from an agarose gel by NucleoSpin Gel and PCR Clean-up kit (manufactured by Machalai Nagel).
- the sequencing reaction by the dye terminator method for base sequence determination is performed with Big Dye Terminator Cycle Sequencing FS Ready Reaction Kit ver.3.1 (ThermoFisher Scientific) and analyzed with ABI PRISM 3130xl Genetic Analyzer (ThermoFisher Scientific) did.
- the homologous search by the BLAST program was performed on the analyzed 16S rDNA base sequence, and the taxonomic identification of the isolate was performed by comparing with the DNA data bank (DDBJ / EMBL / GenBank) database.
- the lactic acid bacteria candidate strain isolated from the fig leaf is named IJH-SONE68 strain, and the accession number of the base sequence is the strain of “Lactobacillus paracasei R094” already registered in the DNA data bank (DDBJ / EMBL / GenBank). Since it was 100% identical with the base sequence “NR — 025880”, it was identified as Lactobacillus paracasei.
- This strain was established on April 19, 2016 as the NITE P-02242 under the accession number NITE P-02242 at the National Institute of Technology and Evaluation Microbiology Center (Room 2-5-8 Kazusa, Kazusa, Kisarazu 292-0818, Japan) The deposit was made internationally and then transferred to the international deposit under the Budapest Treaty. On May 26, 2017, the deposit number for the international deposit was given as NITE BP-02242.
- the isolated and identified lactic acid bacteria IJH-SONE68 strain is a catalase-negative gram-positive gonococci as shown in the photograph of FIG. It had the characteristics of a typical heterolactic fermentation and the ability to produce polysaccharides.
- Isolation ability of lactic acid bacteria identified and identified (1) Test method of assimilation ability The ability of IJH-SONE68 strain to assimilate 49 kinds of saccharides was examined by the following test method.
- the IJH-SONE68 strain was statically cultured in the MRS liquid medium until the stationary phase of growth. The cells obtained by centrifugation were washed with an appropriate amount of suspension medium (Biomelieu), and finally suspended in 2 mL of suspension medium. A part of this was added to 5 mL suspension medium, and the amount (n) at which the McFarland turbidity was 2 was determined.
- API 50 CHL medium Biomereu
- API 50 CHL kit Biomeryu, 49 kinds of sugar were applied to the bottom of each well.
- mineral oil was overlaid and set in a tray containing sterile water. After culturing at 37 ° C. for 48 hours, the presence or absence of assimilation ability was determined by observing changes in color tone in each well.
- Test results of assimilation ability The results of examining the assimilation ability of 49 strains of IJH-SONE68 strain are as shown in Table 1.
- Example 2 Separation and purification of polysaccharide produced by IJH-SONE68 strain
- the polysaccharide produced by IJH-SONE68 strain was separated and purified by the following method.
- the IJH-SONE68 strain was statically cultured in the MRS liquid medium until the stationary phase of growth. 5 mL of this culture solution was used as a seed culture solution, inoculated into 5 L of a polysaccharide-producing semi-synthetic medium (the composition of which will be described later), and then statically cultured at 37 ° C. for 120 hours.
- a polysaccharide-producing semi-synthetic medium the composition of which will be described later
- each added enzyme is denatured, and 8.75 mL of 100% trichloroacetic acid aqueous solution is added and mixed in order to remove it as a precipitate by subsequent centrifugation. Left to stand. The precipitate was removed by centrifugation, and 262.5 mL of 100% ethanol was added to the resulting supernatant and mixed well. Then, the polysaccharide produced by the IJH-SONE68 strain was recovered by precipitation. The precipitate was washed with 50 mL of 70% ethanol, air-dried, an appropriate amount (about 25 mL) of purified water was added, and the mixture was allowed to stand at 4 ° C. overnight to dissolve the polysaccharide. The dissolved polysaccharide sample was purified using a 10,000 MWCO ultrafiltration unit (Merck) to remove small molecules such as monosaccharides in the collected sample while replacing the solvent with purified water. A saccharide sample was obtained.
- a 10,000 MWCO ultrafiltration unit Merck
- Semi-synthetic medium for polysaccharide production is described in Kimmel SA, Roberts RF. Development of a growth medium suitable for exopolysaccharide production by Lactobacillus delbrueckii sps. Bulgaricus RR. The medium was modified as follows.
- Vitamine Soln [G / L] 4-aminobenzoic acid 0.05 Biotin 0.001 Folic acid 0.025 Lipoic acid 0.025 Nicotinic acid 0.1 Pantothenic acid 0.05 Pyridoxamin-HCl 0.25 Vitamine B12 0.05 Pyridoxine 0.025 Riboflavin 0.05 Thiamine 0.1
- Phenolic sulfate method DuBois M, Gilles KA, Hamilton JK, Rebers PA, Smith F., Colorimetric method for determination of sugars and related substances., Anal. Chem., 28, 350-356 (1956)
- the sugar composition analysis of acidic polysaccharides purified by the above-described anion exchange column chromatography was performed by measuring by high performance liquid chromatography (HPLC) method.
- HPLC high performance liquid chromatography
- Example 3 Fat Accumulation Action of Polysaccharides Produced by IJH-SONE68 Strain
- the fats of polysaccharide samples containing neutral polysaccharide fraction and acidic polysaccharide fraction, which are polysaccharides produced by IJH-SONE68 strain obtained in Example 2 The accumulation inhibitory action was examined according to the method described below.
- HuH-7 cells which are human liver cancer-derived cell lines, were used.
- HuH-7 cells are cultured in DMEM (Dulbecco's modified Eagle medium) medium (high glucose, L-glutamine, phenol) containing 10 v / v% FBS (fetal bovine serum), 100 U / mL penicillin G, and 100 ⁇ g / mL streptomycin. Red and sodium pyruvate).
- DMEM Dulbecco's modified Eagle medium
- FBS fetal bovine serum
- the confluent cells were suspended in a new DMEM medium and seeded on a 24-well plate for cell culture so as to be 8 ⁇ 10 4 cells / well.
- the liquid volume per well at this time was 500 ⁇ L.
- PA palmitic acid
- OA oleic acid
- the culture solution in each well was removed with an aspirator, and 500 ⁇ L of PBS (phosphate buffered saline) was added to wash the cells and wells. After removing PBS, 250 ⁇ L of 10% w / v% formalin solution was added to fix the cells for 10 minutes. Subsequently, the plate was washed twice with 500 ⁇ L of PBS, and after removing PBS, 150 ⁇ L of a color former solution (Triglyceride E-Test Wako) was added, and a color reaction was performed at 37 ° C. for 30 minutes.
- PBS phosphate buffered saline
- the degree of suppression was higher in the polysaccharide sample produced by the IJH-SONE68 strain than in the polysaccharide sample (EPS) (SN35N) produced by the SN35N strain. From the above results, it was revealed that the polysaccharide produced by the IJH-SONE68 strain has a fat accumulation inhibitory action.
- Example 4 Anti-obesity activity and fat accumulation inhibitory activity of IJH-SONE68 strain Using anti-obesity activity and fat accumulation inhibitory activity of IJH-SONE68 strain was evaluated using obese model mice fed with a high fat diet. As a result, it was clarified that ingestion of fermented pineapple juice fermented with IJH-SONE68 strain significantly suppressed body weight gain and visceral fat accumulation in obese model mice fed with a high fat diet.
- composition according to any one of [1] to [4] above, wherein the lactic acid bacterium is Lactobacillus paracasei IJH-SONE68 strain (Accession No. NITE BP-02242) or an equivalent lactic acid bacterium.
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Abstract
Description
本発明の組成物は、肥満の予防又は改善のために、また、脂肪肝又は肝機能不全の予防又は改善のために好ましく使用することができる。
本発明の組成物においては、乳酸菌はイチジク由来の乳酸菌であるのが好ましく、特に、Lactobacillus paracasei IJH-SONE68株(受託番号NITE BP-02242)又はそれと同等の乳酸菌が好ましい。
本発明の組成物においては、乳酸菌の培養物若しくは発酵物は、乳酸菌をパイナップル属植物の果汁の存在下で培養若しくは発酵して得られる培養物若しくは発酵物が好ましい。
本発明の組成物においては、乳酸菌が産生する多糖類としては、N-アセチルグルコサミンがα-1,6結合により連結した構造を有する中性多糖体、あるいは、主としてグルコースとマンノースから構成される酸性多糖体が挙げられる。
本発明の組成物は飲食品組成物が好ましく、飲食品としては、飲料、機能性食品、発酵食品又はサプリメントが好ましく挙げられる。
また、本発明の組成物は、医薬組成物が好ましい。
さらには、本発明の組成物は、飼料組成物が好ましい。
1.本発明で対象とする乳酸菌
本発明で対象とする乳酸菌は、ラクトバチルス・パラカゼイ(Lactobacillus paracasei)に属する乳酸菌であり、イチジク由来の乳酸菌が好ましい。具体的には、本発明により、イチジクの葉から単離同定されたLactobacillus paracasei IJH-SONE68株が挙げられる。この菌株は、2016年4月19日に独立行政法人製品評価技術基盤機構特許微生物センター(〒292-0818千葉県木更津市かずさ鎌足2-5-8 122号室)に受託番号NITE P-02242として国内寄託され、その後にブタペスト条約に基づく国際寄託に移管されて、2017年5月26日にNITE BP-02242として国際寄託の受託番号が付与されている。
本発明の組成物は、上記した乳酸菌の菌体、その培養物若しくは発酵物又はそれが産生する多糖類を有効成分として含む。
乳酸菌は、通常用いられるMRS培地やその修正培地等を用いて、液体静置培養等の通常用いられる培養方法により培養することができる。乳酸菌は、パイナップル属植物の果汁又はその抽出物の存在下で培養することにより、その増殖を促進することができ(国際公開第WO2011/046194号)、また、酒粕、酒粕抽出物又は酒粕の酵素分解物の存在下で培養することによっても、その増殖を促進することができる(特開平3-172171号公報、特開平5-15366号公報及び特許第2835548号公報)。乳酸菌を培養後、得られた培養物をそのまま有効成分として用いてもよく、得られた培養液を希釈又は濃縮して用いてもよく、培養物から回収した菌体を用いてもよい。また、本発明の効果を損なわない限り、培養後に加熱、及び凍結乾燥等の種々の追加操作を行うこともできる。また、乳酸菌の菌体は、その細胞表層に多糖類を付着している生菌体であっても死菌体であってもよく、生菌体及び死菌体の両方であってもよい。死菌体は、破砕物であってもよいが多糖類をその表層に付着していることが望ましい。また、乳酸菌の発酵物は、通常、栄養源としてグルコースなどを用い、必要に応じて、酵母エキス、パイナップル属植物の果汁、酒粕、焼酎粕等の植物乳酸菌の増殖促進物質を更に添加して、発酵させて得ることができる。
本発明の組成物は、飲食品組成物、医薬組成物、飼料組成物などの各種の形態で用いることができる。
ラクトバチルス・パラカゼイ(Lactobacillus paracasei)に属する乳酸菌の菌体、その培養物若しくは発酵物又はそれが産生する多糖類は、肝細胞が遊離脂肪酸を取り込み中性脂肪として蓄積することを抑制する作用を有し、また、体重増加と内臓脂肪の蓄積を抑制し抗肥満作用を有する。したがって、ラクトバチルス・パラカゼイ(Lactobacillus paracasei)に属する乳酸菌の菌体、その培養物若しくは発酵物又はそれが産生する多糖類を有効成分として含有する組成物は、脂肪蓄積抑制のために、また、肥満抑制のために使用することができる。具体的には、本発明の組成物は、肥満の予防又は改善のために、また、脂肪肝又は肝機能不全の予防又は改善のために使用することができる。また、本発明の組成物は、肥満の予防又は改善に有効であることから、特に、健康維持や健康増進用の飲食品の素材として利用することができる。また、脂肪肝又は肝機能不全の予防又は改善は、体力の維持、増進、回復等に繋がることから、特に、体力の維持、増進、回復用の飲食品の素材として利用することもできる。
乳酸菌の分離及び同定
1. 乳酸菌サンプルの分離
イチジク(品種「とよみつ姫」)の葉、茎、および果実を選択し、殺菌済みピンセットとハサミを用いて2~3 mmに細断片化した後、滅菌済のMRS液体培地入りの試験管に5~6個ずつの細片を入れ、28℃および37℃にて、乳酸菌の標準培地であるMRS培地が濁る (増殖する) まで静置培養した。ちなみに、乳酸菌候補株の増殖が目視できるまでに2~4日間を要した。
上記乳酸菌候補株の各培養液の一部をMRS寒天培地上にディスポーザブルループで線画塗菌後、静置培養を行った。寒天培地上に形成されたコロニーのうち、「色、つや、形状の異なるもの」を全てピックアップし、フレッシュなMRS寒天培地上に線画塗菌を行い、コロニーを純化した。
純化された各コロニーに対し、カタラーゼ酵素の産生の有無を検証するため、H2O2テストを行った。これは、10%のH2O2溶液に菌体を曝した際に起こる、カタラーゼが存在すれば生成する酸素の発生の有無を観察する試験法である。ちなみに、乳酸菌はカタラーゼを産生しない。
イチジクからの探索分離を試みた結果、イチジクの葉を分離源としたものから、カタラーゼ陰性を示す乳酸菌候補株を1株得ることができた。
上記乳酸菌候補株をMRS液体培地で改めて培養し、遠心により菌体を取得した。細胞壁溶解酵素で処理した後, DNAzol試薬を使用し、ゲノムDNAを抽出した。
Lane, D. J. (1991). 16S/23S rRNA sequencing. In Nucleic Acid Techniques in Bacterial Systematics、pp.115-175. Edited by E. Stackebrandt & M. Goodfellow. Chichester : Wileyに記載された方法に従って、ゲノムDNAを鋳型として、27fプライマーおよび1525rプライマーを用いたPCR反応により16S rDNA部分を増幅させ、NucleoSpin Gel and PCR Clean-up kit(マッハライ・ナーゲル社製)により、アガロースゲルより目的断片を回収した。塩基配列決定のためのダイターミネーター法によるシークエンス反応は, Big Dye Terminator Cycle Sequencing FS Ready Reaction Kit ver.3.1(ThermoFisher Scientific社製)にて行い、ABI PRISM 3130xl Genetic Analyzer(ThermoFisher Scientific社製)にて解析した。解析した16S rDNAの塩基配列に対してBLAST programによる相同性検索を行い、DNA data bank(DDBJ/EMBL/GenBank)のデータベースと比較することで、分離株の分類学的同定を行った。
この菌株は、2016年4月19日に独立行政法人製品評価技術基盤機構特許微生物センター(〒292-0818千葉県木更津市かずさ鎌足2-5-8 122号室)に受託番号NITE P-02242として国際寄託され、その後にブタペスト条約に基づく国際寄託に移管されて、2017年5月26日にNITE BP-02242として国際寄託の受託番号が付与されている。
分離同定された上記乳酸菌IJH-SONE68株は、図1の写真に示すように, カタラーゼ陰性のグラム陽性桿菌で、かつ、白色コロニー形成性を有し、条件的ヘテロ乳酸発酵の特性を有するとともに、多糖体を産生する能力を有していた。
(1)資化能力の試験方法
IJH-SONE68株の49種類の糖類に対する資化能力について以下の試験方法により調べた。
IJH-SONE68株をMRS液体培地で増殖の定常期まで静置培養した。遠心して得られた菌体を適量のsuspension medium (ビオメリュー社製) で洗浄した後、最終的に2 mLのsuspension mediumに懸濁した。この一部を、5 mLのsuspension mediumに加えてマクファーランド濁度が2になる量 (n) を求めた。続いて、API 50 CHL培地 (ビオメリュー社製) に2nの菌液を添加し、これをAPI 50 CHLキット (ビオメリュー社製、各ウェルの底にはそれぞれ49種類の糖が塗り付けられている) の各ウェルへ分注した。最後にミネラルオイルを重層し、滅菌水を入れたトレイにセットした。37℃で48時間培養した後に、各ウェルにおける色調の変化を観察することで、資化能の有無の判定を行った。
IJH-SONE68株の49種類の糖類に対する資化能力を調べた結果は、表1に示したとおりである。
1. IJH-SONE68株が産生する多糖体の分離精製
IJH-SONE68株が産生する多糖類を以下の方法で分離精製した。
IJH-SONE68株をMRS液体培地で増殖の定常期まで静置培養した。この培養液5 mLを種培養液とし、5 Lの多糖類産生用半合成培地 (その組成は後述する) に植菌した後、37℃で120時間静置培養した。培養液を4℃に冷却した後、培養液上清中に含まれるタンパク質を変性させて、後のステップで沈殿として除去するために、202.5 mLの100%トリクロロ酢酸水溶液を加え、混和した後に30分間静置した。遠心によって沈殿を取り除き、回収した上清に等量のアセトンを加えて混和した後、4℃で一晩静置させることによって、IJH-SONE68株が産生する多糖体を沈殿させた。沈殿物を遠心によって回収した後、250 mLの70%エタノールで沈殿物の洗浄を行った。沈殿物を風乾させた後、75 mLの50 mM Tris-HCl buffer (pH 8.0) を加えて1時間混和することで、沈殿物を溶解させた。遠心によって不溶性の夾雑物を取り除いた後、回収した上清に対し、それぞれ750 μLの1 mg/mL DNase溶液 (Worthington社) および1 mg/mL RNase溶液 (ナカライテスク社) を加え、37℃で8時間反応させた。続いて750 μLの2 mg/mL proteinase K溶液 (和光純薬工業社製) を加え、37℃で16時間反応させた。反応後の溶液を4℃に冷却した後、添加した各酵素を変性させ、次の遠心で沈殿として除去するために、8.75 mLの100%トリクロロ酢酸水溶液を加えて混和し、4℃で1時間静置した。遠心によって沈殿物を取り除き、得られた上清に対し262.5 mLの100%エタノールを加え、しっかりと混和した後、遠心によってIJH-SONE68株が産生する多糖体を沈殿物として回収した。50 mLの70%エタノールで沈殿物を洗浄した後に風乾させ、適量 (約25 mL) の精製水を加えて4℃で一晩静置することで、多糖体を溶解させた。溶解後の多糖体サンプルは、10,000 MWCOの限外濾過ユニット (メルク社) を用い、溶媒を精製水に置換しながら、回収したサンプル中の単糖類などの小分子を取り除いて、精製された多糖類サンプルを得た。
以上により、IJH-SONE68株が産生する多糖類として中性多糖画分および 酸性多糖画分が分離精製された。
Glucose 20
Tween 80 1.0
Ammonium citrate 2.0
Sodium acetate 5.0
MgSO4・7H2O 0.1
MnSO4・5H2O 0.05
K2HPO4 2.0
Bacto casitone 10.0
Vitamine Soln. 2 mL
Trace element Soln. 1 mL
4-aminobenzoic acid 0.05
Biotin 0.001
Folic acid 0.025
Lipoic acid 0.025
Nicotinic acid 0.1
Pantothenic acid 0.05
Pyridoxamin-HCl 0.25
Vitamine B12 0.05
Pyridoxine 0.025
Riboflavin 0.05
Thiamine 0.1
25% HCl 10 mL
FeCl2・4H2O 1.5
CoCl2・6H2O 0.19
MnCl2・4H2O 0.1
ZnCl2 0.07
H3BO3 0.006
Na2MoO4・2H2O 0.036
NiCl2・6H2O 0.024
CuCl2・2H2O 0.002
上記した陰イオン交換カラムクロマトグラフィー(TOYOPEARL DEAE-650M樹脂 (東ソ-株式会社))によって精製された中性多糖体を、プロトン-NMRおよびカーボン-NMRに付し、得られたそれぞれのNMRプロファイルを図3に示した。これらのNMRプロファイルからの中性多糖体の構造解析結果を図4に示した。
この構造解析結果から、IJH-SONE68株が産生する菌体外中性多糖体は、N-アセチルグルコサミンがα-1,6結合により連結した構造を有することが明らかになった。
上記した陰イオン交換カラムクロマトグラフィーによって精製された酸性多糖体の糖組成分析を高速液体クロマトグラフ(HPLC)法で測定することにより行った。
精製された酸性多糖体 (7.3 mg/mL) 10μLと水60μLを混合して7倍希釈試料溶液を調製し、試験管に調製した希釈試料溶液20μLを採取し、減圧乾固し、2 mo1/Lトリフルオロ酢酸100μLを添加して溶解し、窒素置換、減圧封管、100℃で6時間加水分解し、次いで減圧乾固した。得られた残澄に水200μLを添加して溶解し、0.22μmのフィルターでろ過して測定用試料溶液を得、測定用試料溶液を水で10倍希釈して希釈測定用試料溶液を得た。これらの測定用試料溶液および希釈測定用試料溶液50μLを分析した。分析機器として、HPLCシステム:LC-20Aシステム(株式会社島津製作所)および分光蛍光光度計M-10AxL(株式会社島津製作所)を用いた。分析条件は以下の通りであった。
カラム:TSK-gel Sugar AXG 4.6 mmI.D.×15 cm(東ソー株式会社)
カラム温度:70℃
移動相:0.5 mo1/Lホウ酸カリウム緩衝液、pH 8.7
移動相流速:0.4 mL/min
ポストカラム標識:反応試薬:l w/v %アルギニン・3 w/v% ホウ酸
反応試薬流速:0.5 mL/min
反応温度:150℃
検出波長:Ex.320 nm Em.430 nm
IJH-SONE68株が産生する多糖類の脂肪蓄積抑制作用
実施例2で得られたIJH-SONE68株が産生する多糖類である、中性多糖画分および酸性多糖画分を含む多糖類サンプルの脂肪蓄積抑制作用を、次に記載される方法にしたがって調べた。
試験対象として、ヒト肝癌由来細胞株であるHuH-7細胞を用いた。HuH-7細胞は、 10 v/v %FBS (fetal bovine serum)、100 U/mLペニシリンG、および100 μg/mLストレプトマイシンを含むDMEM (Dulbecco's modified Eagle medium) 培地 (高グルコース、L-グルタミン、フェノールレッド、ピルビン酸ナトリウム含有) で培養した。コンフルエントとなった細胞を新しいDMEM培地に懸濁させ、8×104 cells/wellとなるよう、細胞培養用24 wellプレートに播種した。この時の1 wellあたりの液量は500 μLとした。24時間培養後、各wellにパルミチン酸(PA):オレイン酸(OA) (PA/OA) 溶液 (=1:2、DMSOに溶解) を終濃度600 μM(PA:200 μM及びOA:400 μM)となるよう添加し、更に24時間培養することで、脂肪酸の取り込みを開始した。この時、各多糖類サンプル (終濃度4-400 μg/mL) についても同時に添加しておき、細胞への脂肪酸の取り込み抑制を評価した。
脂肪酸取り込み評価を2回(1st及び2nd)実施し、得られた結果を表3に示した。
以上の結果から、IJH-SONE68株が産生する多糖類が脂肪蓄積抑制作用を有することが明らかになった。
IJH-SONE68株の抗肥満作用および脂肪蓄積抑制作用
高脂肪食摂取肥満モデルマウスを用い、IJH-SONE68株の抗肥満活性および脂肪蓄積抑制活性について評価した。その結果、IJH-SONE68株で発酵させたパイナップル果汁発酵液を摂取させることにより、高脂肪食摂取肥満モデルマウスにおける体重増加と内臓脂肪の蓄積が有意に抑制されることが明らかとなった。
本試験ではC57BL/6Jcl (SPF) 雄性マウスを用いた。7週齢のマウスを搬入し、飼育ケージごとに5匹飼いとした。通常飼料 (MF、オリエンタル酵母社製) を用いた1週間の馴致飼育の後、5匹ずつの群 (A群~E群) に分け、食餌を高脂肪食 (リサーチダイエット社、#D12492) に変更し、肥満の誘導を開始した。なお、飼料を給餌する際、高脂肪食は予め木槌で粉砕して粘土状とし、ガラス製の粉末用給餌器 (KN-675-4A) を用いて1回あたり120 gとなるよう詰めて与え、1週間間隔で交換した。また、投与サンプルは給餌器に詰める前に高脂肪食と均一となるように混和しておいた。全ての群において、餌、飲用水ともに自由摂取とした。投与サンプルとしては、IJH-SONE68株を100%パイナップル果汁 (1 w/v %の焼酎蒸留残渣を含む) で48時間培養して得られた発酵液を121℃、20分の条件で滅菌処理して得たIJH-SONE68株発酵パイナップル果汁原液およびその希釈液などを用いた。マウスA群~F群の投与サンプルの詳細は、以下のとおりであった。
B群:IJH-SONE68株発酵パイナップル果汁10倍希釈液を高脂肪食と共に摂取させた群(発酵パイナップル果汁原液を滅菌蒸留水で10倍希釈した希釈液7 mLを高脂肪食120 gに添加して混和したものを摂取させた群)
C群:IJH-SONE68株発酵パイナップル果汁100倍希釈液を高脂肪食と共に摂取させた群(発酵パイナップル果汁原液を滅菌蒸留水で100倍希釈した希釈液7 mLを高脂肪食120 gに添加して混和したものを摂取させた群)
D群:発酵させていないパイナップル果汁を高脂肪食と共に摂取させた群(高脂肪食120 gに7 mLのパイナップル果汁を添加して混和したものを摂取させた群)
E群:高脂肪食のみで飼育した群 (陽性コントロール群)(高脂肪食120 gに7 mLの滅菌蒸留水を添加して混和したものを摂取させた群)
F群:通常飼料のみで飼育した群 (陰性コントロール群)
上記A群~F群の各群における1週間ごとの体重増加量 (飼育開始時点(0週)における体重からの増加量) の推移を表4および表5に示し(表4は体重増加量平均(g)、表5はその標準誤差(SE)を示す)、それらをグラフ化したものを図6に示した。また、飼育最終週 (12週) における各群の体重増加量の平均値を表6に示し、それをグラフ化したものを図7に示した。それぞれデータは平均値±標準誤差で示し、群間の有意差検定にはTukey-Kramer法を用い、危険率 (p値) が0.05未満で有意差有りと判定した (以下に記載する図6および7中には陽性コントロール群との有意差のみについて記す)。
[1] ラクトバチルス・パラカゼイ(Lactobacillus paracasei)に属する乳酸菌の菌体、その培養物若しくは発酵物又はそれが産生する多糖類を有効成分とする脂肪蓄積抑制のための組成物。
[2] 肥満の予防又は改善のための上記[1]に記載の組成物。
[3] 脂肪肝又は肝機能不全の予防又は改善のための上記[1]に記載の組成物。
[4] 乳酸菌がイチジク由来の乳酸菌である上記[1]~[3]のいずれかに記載の組成物。
[5] 乳酸菌がLactobacillus paracasei IJH-SONE68株(受託番号NITE BP-02242)又はそれと同等の乳酸菌である上記[1]~[4]のいずれかに記載の組成物。
[6] 培養物若しくは発酵物が、乳酸菌をパイナップル属植物の果汁の存在下で培養若しくは発酵して得られる培養物若しくは発酵物である、上記[1]~[5]のいずれかに記載の組成物。
[7] 多糖類がN-アセチルグルコサミンがα-1,6結合により連結した構造を有する中性多糖体である上記[1]~[5]のいずれかに記載の組成物。
[8] 多糖類が主としてグルコースとマンノースから構成される酸性多糖体である上記[1]~[5]のいずれかに記載の組成物。
[9] 組成物が飲食品組成物である上記[1]~[8]のいずれかに記載の組成物。
[10] 飲食品が、飲料、機能性食品、発酵食品又はサプリメントである上記[9]に記載の組成物。
[11] 組成物が医薬組成物である上記[1]~[8]のいずれかに記載の組成物。
[12] 組成物が飼料組成物である上記[1]~[8]のいずれかに記載の組成物。
[13] 脂肪蓄積抑制のための組成物の有効成分としてのLactobacillus paracasei IJH-SONE68株とラクトバチルス・パラカゼイ(Lactobacillus paracasei)に属する乳酸菌の菌体、その培養物若しくは発酵物又はそれが産生する多糖類の使用。
[14] 肥満の予防又は改善のための組成物である上記[13]に記載の使用。
[15] 脂肪肝又は肝機能不全の予防又は改善のための組成物である上記[13]に記載の使用。
[16] 乳酸菌がイチジク由来の乳酸菌である上記[13]~[15]のいずれかに記載の使用。
[17] 乳酸菌がLactobacillus paracasei IJH-SONE68株(受託番号NITE BP-02242)又はそれと同等の乳酸菌である上記[13]~[16]のいずれかに記載の使用。
[18] 培養物若しくは発酵物が、乳酸菌をパイナップル属植物の果汁の存在下で培養若しくは発酵して得られる培養物若しくは発酵物である、上記[13]~[17]のいずれかに記載の使用。
[19] 多糖類がN-アセチルグルコサミンがα-1,6結合により連結した構造を有する中性多糖体である上記[13]~[17]のいずれかに記載の使用。
[20] 多糖類が主としてグルコースとマンノースから構成される酸性多糖体である上記[13]~[17]のいずれかに記載の使用。
[21] 組成物が飲食品組成物である上記[13]~[20]のいずれかに記載の使用。
[22] 飲食品が、飲料、機能性食品、発酵食品又はサプリメントである上記[21]に記載の使用。
[23] 組成物が医薬組成物である上記[13]~[20]のいずれかに記載の使用。
[24] 組成物が飼料組成物である上記[13]~[20]のいずれかに記載の使用。
[25] Lactobacillus paracasei IJH-SONE68株とラクトバチルス・パラカゼイ(Lactobacillus paracasei)に属する乳酸菌の菌体、その培養物若しくは発酵物又はそれが産生する多糖類を有効成分として含む組成物を、それを必要とする対象に適用することを含む方法であって、対象において脂肪蓄積を抑制する方法。
[26] 肥満を予防又は改善する上記[25]に記載の方法。
[27] 脂肪肝又は肝機能不全を予防又は改善する上記[25]に記載の方法。
[28] 乳酸菌がイチジク由来の乳酸菌である上記[25]~[27]のいずれかに記載の方法。
[29] 乳酸菌がLactobacillus paracasei IJH-SONE68株(受託番号NITE BP-02242)又はそれと同等の乳酸菌である上記[25]~[28]のいずれかに記載の方法。
[30] 培養物若しくは発酵物が、乳酸菌をパイナップル属植物の果汁の存在下で培養若しくは発酵して得られる培養物若しくは発酵物である、上記[25]~[29]のいずれかに記載の方法。
[31] 多糖類がN-アセチルグルコサミンがα-1,6結合により連結した構造を有する中性多糖体である上記[25]~[30]のいずれかに記載の方法。
[32] 多糖類が主としてグルコースとマンノースから構成される酸性多糖体である上記[25]~[30]のいずれかに記載の方法。
[33] 組成物が飲食品組成物である上記[25]~[32]のいずれかに記載の方法。
[34] 飲食品が、飲料、機能性食品、発酵食品又はサプリメントである上記[33]に記載の方法。
[35] 組成物が医薬組成物である上記[25]~[32]のいずれかに記載の方法。
[36] 組成物が飼料組成物である上記[25]~[32]のいずれかに記載の方法。
Claims (12)
- ラクトバチルス・パラカゼイ(Lactobacillus paracasei)に属する乳酸菌の菌体、その培養物若しくは発酵物又はそれが産生する多糖類を有効成分とする脂肪蓄積抑制のための組成物。
- 肥満の予防又は改善のための請求項1に記載の組成物。
- 脂肪肝又は肝機能不全の予防又は改善のための請求項1に記載の組成物。
- 乳酸菌がイチジク由来の乳酸菌である請求項1~3のいずれかに記載の組成物。
- 乳酸菌がLactobacillus paracasei IJH-SONE68株(受託番号NITE BP-02242)又はそれと同等の乳酸菌である請求項1~4のいずれかに記載の組成物。
- 培養物若しくは発酵物が、乳酸菌をパイナップル属植物の果汁の存在下で培養若しくは発酵して得られる培養物若しくは発酵物である、請求項1~5のいずれかに記載の組成物。
- 多糖類がN-アセチルグルコサミンがα-1,6結合により連結した構造を有する中性多糖体である請求項1~6のいずれかに記載の組成物。
- 多糖類が主としてグルコースとマンノースから構成される酸性多糖体である請求項1~6のいずれかに記載の組成物。
- 組成物が飲食品組成物である請求項1~8のいずれかに記載の組成物。
- 飲食品が、飲料、機能性食品、発酵食品又はサプリメントである請求項9に記載の組成物。
- 組成物が医薬組成物である請求項1~8のいずれかに記載の組成物。
- 組成物が飼料組成物である請求項1~8のいずれかに記載の組成物。
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JP2022066881A (ja) * | 2020-10-19 | 2022-05-02 | 曽根ファーム株式会社 | 炎症性腸疾患用組成物 |
JP2023055601A (ja) * | 2021-10-06 | 2023-04-18 | 樂牧生技股▲フン▼有限公司 | ラクトバチルス・パラカセイlm-141分離株及びその使用 |
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TWI746955B (zh) * | 2018-04-25 | 2021-11-21 | 日商曾根農場股份有限公司 | 第i型過敏用組成物 |
TWI778556B (zh) * | 2021-03-25 | 2022-09-21 | 生展生物科技股份有限公司 | 一種含副乾酪乳酸桿菌s38和凝結芽孢桿菌bc198之益生菌組合物及其在改變身體組成之應用 |
CN113322216B (zh) * | 2021-07-30 | 2021-11-05 | 北京量化健康科技有限公司 | 一种副干酪乳杆菌b111h及其在代谢综合征中的应用 |
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JP2022066881A (ja) * | 2020-10-19 | 2022-05-02 | 曽根ファーム株式会社 | 炎症性腸疾患用組成物 |
JP7195714B2 (ja) | 2020-10-19 | 2022-12-26 | 曽根ファーム株式会社 | 炎症性腸疾患用組成物 |
JP2023055601A (ja) * | 2021-10-06 | 2023-04-18 | 樂牧生技股▲フン▼有限公司 | ラクトバチルス・パラカセイlm-141分離株及びその使用 |
JP7362084B2 (ja) | 2021-10-06 | 2023-10-17 | 樂牧生技股▲フン▼有限公司 | ラクトバチルス・パラカセイlm-141分離株及びその使用 |
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AU2019260952B2 (en) | 2020-11-12 |
EP3760055A4 (en) | 2021-06-30 |
US20230034847A1 (en) | 2023-02-02 |
KR102368627B1 (ko) | 2022-02-28 |
CA3086024A1 (en) | 2019-10-31 |
US20210169952A1 (en) | 2021-06-10 |
TW202002801A (zh) | 2020-01-16 |
JPWO2019208150A1 (ja) | 2020-04-30 |
JP6649539B1 (ja) | 2020-02-19 |
AU2019260952A1 (en) | 2020-05-07 |
TWI739078B (zh) | 2021-09-11 |
CA3086024C (en) | 2022-02-08 |
CN111698913A (zh) | 2020-09-22 |
EP3760055A1 (en) | 2021-01-06 |
KR20200091403A (ko) | 2020-07-30 |
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