KR102294456B1 - Infant and child origin lactic acid bacteria Lactobacillus rhamnosus MG4502 and composition comprising the lactic acid bacteria for enhancing intestine activity, anti-oxidant and anti-obesity - Google Patents
Infant and child origin lactic acid bacteria Lactobacillus rhamnosus MG4502 and composition comprising the lactic acid bacteria for enhancing intestine activity, anti-oxidant and anti-obesity Download PDFInfo
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- KR102294456B1 KR102294456B1 KR1020210021200A KR20210021200A KR102294456B1 KR 102294456 B1 KR102294456 B1 KR 102294456B1 KR 1020210021200 A KR1020210021200 A KR 1020210021200A KR 20210021200 A KR20210021200 A KR 20210021200A KR 102294456 B1 KR102294456 B1 KR 102294456B1
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Abstract
Description
본 발명은 영아 또는 유아의 분변으로부터 분리된 락토바실러스 람노서스 MG4502 균주 및 이의 비만 또는 비만관련 질환 예방, 개선 및 치료 용도에 관한 것이다. The present invention relates to a Lactobacillus rhamnosus MG4502 strain isolated from the feces of infants or infants and its use for preventing, improving and treating obesity or obesity-related diseases.
유산균은 특별한 생리활성능력을 가지고 있으며, 일반적으로 안전한 균주 (GRAS, generally regarded as safe bacteria)로 취급되고 있다. 유산균은 다양한 발효식품의 생산에 사용하고 있을 뿐만 아니라, 기능성과 프로바이오틱스 특성을 가지는 유제품과 발효과채 제품에 널리 사용되고 있다. 최근에는 화학보조제를 대체하는 천연 보조제에 대한 소비자의 수요가 증가함에 따라 그 대안방안으로 부각되고 있다. 프로바이오틱스는 숙주동물의 건강에 매우 유익한 효과를 주는 살아있는 미생물로, 장내 미생물의 균형을 개선하고 영양분의 흡수를 증진시킨 다. 또한, 프로바이오틱스는 장내환경에서 병원성미생물의 항균작용을 나타내는 특성을 가지고 있다. 프로바이오틱스에는 다양한 미생물이 포함되지만, 락토바실러스(Lactobacillus) 속과 비피도박테리움(Bifidobacterium) 속이 가장 많은 분포를 차지하고 있다. 특히, 락토바실러스(Lactobacillus) 속은 일반적으로 유제품, 육류, 과 채 및 시리얼 제품의 발효공정에 사용되고 있다. Lactobacillus has a special physiological activity ability, and is generally treated as a safe strain (GRAS, generally regarded as safe bacteria). Lactobacillus is not only used in the production of various fermented foods, but is also widely used in dairy and fermented vegetable products with functional and probiotic properties. Recently, as consumer demand for natural supplements that replace chemical supplements increases, it is emerging as an alternative solution. Probiotics are living microorganisms that have a very beneficial effect on the health of the host animal, improving the balance of the intestinal microflora and enhancing the absorption of nutrients. In addition, probiotics have the characteristic of showing the antibacterial action of pathogenic microorganisms in the intestinal environment. Probiotics include various microorganisms, but the genera Lactobacillus and Bifidobacterium occupy the largest distribution. In particular, the genus Lactobacillus is generally used in the fermentation process of dairy products, meat, fruits and vegetables and cereal products.
비만은 심장병, 암, 관절염, 당뇨병의 주요 원인으로 알려져 있으며, 비만을 해결하기 위한 대중의 인식은 증가 함에도 불구하고, 비만환자들은 지속적으로 증가하고 있는 추세이다. 비만은 지방분화 (adipogenesis)의 결과로 지방세포의 수가 증가하고 지방세포의 지질함량이 증가함에 따라 나타난다. 지방세포 (adipocyte)는 초과된 칼 로리를 중성지방 (triglycerides)으로 합성하고 저장하는데 주요역할을 하며, 지방분화의 결과로 지방세포의 크 기와 숫자가 증가하고 세포 내 지질축적이 가속화된다. 또한 비만은 지방 독성과 산화 스트레스를 유발하고 인슐린 저항성 상태를 유발하며, 이는 고혈당을 유발할 수 있어, 다양한 비만 관련 질환의 원인이 되고 있다. Obesity is known as a major cause of heart disease, cancer, arthritis, and diabetes, and despite the increasing public awareness for solving obesity, obese patients are continuously increasing. Obesity appears as the number of adipocytes increases as a result of adipogenesis and the lipid content of adipocytes increases. Adipocytes play a major role in synthesizing and storing excess calories as triglycerides, and as a result of adipogenesis, the size and number of adipocytes increases and intracellular lipid accumulation is accelerated. In addition, obesity causes lipotoxicity and oxidative stress, and insulin resistance, which can lead to hyperglycemia, which is the cause of various obesity-related diseases.
그러나 비만 및 비만 관련 질환을 치료하기 위한 종래의 치료제들은 심장질환, 호흡기질환, 신경계질환 등의 부작용과 함께 그 효능의 지속성도 낮아, 더욱 개선된 비만치료제의 개발이 필요하고 또한, 현재 개발되고 있는 제품도 부작용 없이 만족할 만한 치료 효과를 가지는 치료제는 거의 없어 새로운 비만치료제의 개발이 요구되고 있다. However, conventional therapeutic agents for treating obesity and obesity-related diseases have side effects such as heart disease, respiratory disease, and nervous system disease and also have low continuity of efficacy, so it is necessary to develop a more improved anti-obesity drug, and There are few products that have satisfactory therapeutic effects without side effects, so the development of new anti-obesity drugs is required.
삭제delete
본 발명자들은 식품 및 의약품 보충제에 적용 할 수 있는 항 비만, 항 당뇨 및 항산화 기능이 강화된 프로바이오틱스를 획득하고자 연구를 수행한 결과, 영유아의 분변에서 분리된 유산균이 프로바이오틱스에 적합한 성질을 나타내고, 비만 및 비만 관련 질환에 효과적으로 사용될 수 있음을 확인하고 본 발명을 완성하였다. The present inventors conducted research to obtain probiotics with enhanced anti-obesity, anti-diabetic and antioxidant functions that can be applied to food and pharmaceutical supplements. It was confirmed that it can be effectively used in obesity-related diseases, and the present invention was completed.
따라서, 본 발명의 목적은 비만 또는 비만 관련 질환의 예방, 치료, 개선 효과를 갖는 유산균을 제공하는 것이다. Accordingly, an object of the present invention is to provide a lactic acid bacterium having an effect of preventing, treating, and improving obesity or obesity-related diseases.
상기와 같은 목적을 달성하기 위하여, 본 발명은 락토바실러스 람노서스 MG4502 (기탁번호: KCTC 14095BP) 를 제공한다. In order to achieve the above object, the present invention provides Lactobacillus rhamnosus MG4502 (Accession No.: KCTC 14095BP).
또한 본 발명은 상기 균주, 이의 배양액 또는 이들의 무세포 추출물을 포함하는, 비만 또는 비만 관련 질환의 예방 또는 개선용 식품 조성물을 제공한다. In addition, the present invention provides a food composition for preventing or improving obesity or obesity-related diseases, comprising the strain, its culture medium, or a cell-free extract thereof.
또한 본 발명은 상기 균주, 이의 배양액 또는 이들의 무세포 추출물을 포함하는, 비만 또는 비만 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다. In addition, the present invention provides a health functional food composition for preventing or improving obesity or obesity-related diseases, comprising the strain, its culture medium, or a cell-free extract thereof.
또한 본 발명은 상기 균주, 이의 배양액 또는 이들의 무세포 추출물을 포함하는, 비만 또는 비만 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다. In addition, the present invention provides a pharmaceutical composition for preventing or treating obesity or obesity-related diseases, comprising the strain, its culture medium or a cell-free extract thereof.
또한 본 발명은 상기 균주, 이의 배양액 또는 이들의 무세포 추출물을 포함하는 비만 또는 비만 관련 질환의 예방 또는 개선용 의약외품 조성물을 제공한다. In addition, the present invention provides a quasi-drug composition for preventing or improving obesity or obesity-related diseases comprising the strain, its culture medium, or a cell-free extract thereof.
또한 본 발명은 상기 균주, 이의 배양액 또는 이들의 무세포 추출물을 포함하는 비만 또는 비만 관련 질환의 예방 또는 개선용 사료 조성물을 제공한다. In addition, the present invention provides a feed composition for preventing or improving obesity or obesity-related diseases comprising the strain, its culture medium, or a cell-free extract thereof.
본 발명에서 선별된 영유아의 분변으로부터 분리된 유산균주는 인체로부터 분리되어 안전할 뿐만 아니라, 프로바이오틱스에 적합한 성질을 나타내며, 우수한 지질축적 억제능, α-글루코시다아제 억제능 및 항산화능을 가져, 비만 또는 비만 관련 질환의 예방, 개선 및 치료를 위한 다양한 분야에 널리 활용될 수 있다. The lactic acid strain isolated from the feces of infants and young children selected in the present invention is not only safe as it is separated from the human body, but also exhibits properties suitable for probiotics, and has excellent lipid accumulation inhibitory ability, α-glucosidase inhibitory ability and antioxidant activity, and obesity or obesity-related It can be widely used in various fields for the prevention, improvement and treatment of diseases.
도 1은 선별된 7 개 균주가 α-글루코시다아제 활성에 미치는 영향을 조사한 결과를 나타낸 도이다.
도 2는 DPPH 자유 라티칼 소거 활성 및 ABTS 자유 라티칼 소거 활성을 통해 측정된 각 균주의 항산화 능력을 확인한 결과를 나타낸 도이다.
도 3은 각 균주의 전자 현미경 사진을 나타낸 도이다, 락토바실러스 아시도필러스 MG4558 (A), 락토바실러스 파라카제이 MG4592 (B), 락토바실러스 플란타럼 MG4553 (C), 락토바실러스 플란타럼 MG4555 (D), 락토바실러스 람노서스 MG4502 (E), 락토바실러스 람노서스 MG4505 (F), 및 락토바실러스 람노서스 MG4511 (G). 모든 균주는 10,000x 배율, 락토바실러스 람노서스 MG4505 5,000x 배율. 1 is a diagram showing the results of examining the effects of the selected seven strains on α-glucosidase activity.
2 is a diagram showing the results of confirming the antioxidant capacity of each strain measured through DPPH free radical scavenging activity and ABTS free radical scavenging activity.
3 is a diagram showing electron micrographs of each strain, Lactobacillus acidophilus MG4558 (A), Lactobacillus paracasei MG4592 (B), Lactobacillus plantarum MG4553 (C), Lactobacillus plantarum MG4555 (D), Lactobacillus rhamnosus MG4502 (E), Lactobacillus rhamnosus MG4505 (F), and Lactobacillus rhamnosus MG4511 (G). All strains were 10,000x magnification, Lactobacillus rhamnosus MG4505 5,000x magnification.
본 발명은 락토바실러스 아시도필러스 MG4558 (기탁번호 KCTC14438BP), 락토바실러스 파라카제이 MG4592(기탁번호: KCTC 14435BP), 락토바실러스 플란타럼 MG4553 (기탁번호: KCTC14097BP), 락토바실러스 플란타럼 MG4555 (기탁번호: KCTC 14437BP) 또는 락토바실러스 람노서스 MG4502 (기탁번호: KCTC 14095BP) 에 관한 것이다. The present invention is Lactobacillus acidophilus MG4558 (Accession No. KCTC14438BP), Lactobacillus paracasei MG4592 (Accession No.: KCTC 14435BP), Lactobacillus plantarum MG4553 (Accession No.: KCTC14097BP), Lactobacillus plantarum (Accession No.: KCTC14097BP), Lactobacillus plantarum ( Accession No.: KCTC 14437BP) or Lactobacillus rhamnosus MG4502 (Accession No.: KCTC 14095BP).
본 발명의 상기 균주들은 모두 영아 또는 유아의 분변으로부터 분리된 균주이며, 인체 유래 유산 균주로 체내 섭취 시 안전한 균주임을 특징으로 하고, 특히 영아 또는 유아로부터 분리되었으므로, 영유아가 안전하게 섭취할 수 있는 유산균임을 특징으로 한다. All of the above strains of the present invention are strains isolated from the feces of infants or infants, and are human-derived lactic acid strains, which are characterized as safe strains when ingested in the body. characterized.
이하, 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 발명의 락토바실러스 아시도필러스 MG4558 (기탁번호 KCTC14438BP), 락토바실러스 파라카제이 MG4592(기탁번호: KCTC 14435BP), 락토바실러스 플란타럼 MG4553 (기탁번호: KCTC14097BP), 락토바실러스 플란타럼 MG4555 (기탁번호: KCTC 14437BP) 또는 락토바실러스 람노서스 MG4502 (기탁번호: KCTC 14095BP) 균주는 비만 또는 비만 관련 질환을 예방, 치료 또는 개선할 수 있는 신규한 균주이다. 본 발명에서 용어, "락토바실러스"는 자연계에 널리 분포하는 당류를 발효하여 에너지를 획득하여 다량의 유산을 생성하는 세균으로 형태적으로는 그람 양성 무포자 간균으로 다형성을 나타낸다. Lactobacillus acidophilus MG4558 (Accession No. KCTC14438BP), Lactobacillus paracasei MG4592 (Accession No.: KCTC 14435BP), Lactobacillus plantarum MG4553 (Accession No.: KCTC14097BP), Lactobacillus plantarum of the present invention Accession No.: KCTC 14437BP) or Lactobacillus rhamnosus MG4502 (Accession No.: KCTC 14095BP) strain is a novel strain capable of preventing, treating or improving obesity or obesity-related diseases. As used herein, the term "Lactobacillus" is a bacterium that produces a large amount of lactic acid by fermenting saccharides widely distributed in nature to obtain energy.
본 발명에서는 영유아, 바람직하게는 2 ~ 15 개월의 영유아로부터 분변을 수집하고, 이를 여과, 희석하여 분변에 존재하는 균주를 수득하였고, 이들로부터 우수한 활성을 나타내는 균주를 선별하였다. In the present invention, feces are collected from infants and toddlers, preferably from 2 to 15 months of age, filtered and diluted to obtain strains present in feces, and strains exhibiting excellent activity are selected from them.
선별된 균주는 16S rRNA 유전자 시퀀싱을 결과를 기반으로 락토바실러스로 동정하였으며, 하기와 같은 기탁 번호를 부여받았다: 락토바실러스 아시도필러스 MG4558 (기탁번호 KCTC 14438BP, 수탁일 2021.01.06), 락토바실러스 파라카제이 MG4592(기탁번호: KCTC 14435BP, 수탁일 2021.01.06), 락토바실러스 플란타럼 MG4553 (기탁번호: KCTC 14097BP, 수탁일 2020.01.07), 락토바실러스 플란타럼 MG4555 (기탁번호: KCTC 14437BP, 수탁일 2021.01.06) 또는 락토바실러스 람노서스 MG4502 (기탁번호: KCTC 14095BP, 수탁일 2020.01.07). The selected strain was identified as Lactobacillus based on the results of 16S rRNA gene sequencing, and was given the following accession number: Lactobacillus acidophilus MG4558 (Accession No. KCTC 14438BP, accession date 2021.01.06), Lactobacillus Paracase J MG4592 (Accession No.: KCTC 14435BP, Accession Date 2021.01.06), Lactobacillus plantarum MG4553 (Accession No.: KCTC 14097BP, Accession Date 2020.01.07), Lactobacillus Plantarum MG4555 (Accession Number: KCTC 14437BP) , Accession Date 2021.01.06) or Lactobacillus rhamnosus MG4502 (Accession No.: KCTC 14095BP, Accession Date 2020.01.07).
본 발명의 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555 또는 락토바실러스 람노서스 MG4502 는 모두 우수한 지질 축적 억제능을 나타낼 수 있으며, 이를 통해 항 비만 활성을 나타낼 수 있다. Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555 or Lactobacillus rhamnosus MG4502 of the present invention can all exhibit excellent lipid accumulation inhibitory ability, through which It may exhibit anti-obesity activity.
또한 본 발명의 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 락토바실러스 람노서스 MG4502균주는 높은 α-글루코시다아제 억제능을 나타낸다. In addition, the Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, and Lactobacillus rhamnosus MG4502 strains of the present invention exhibit high α-glucosidase inhibitory activity.
탄수화물이 포도당으로 소화될 때 사용되는 소화효소 2가지가 α -아밀라아제와 α-글루코시다아제(αGlucosidase)인데, 상기 균주는 α -글루코시다아제 활성을 억제함으로써 α -글루코시다아제의 작용을 억제해서 장에서 다당류가 포도당으로 분해되는 속도를 늦춰주어 당분이 몸 속으로 천천히 흡수 되도록 도와준다. 이러한 활성은 상기 균주가 비만뿐만 아니라 다양한 비만 관련 질환, 대사증후군 예방 또는 개선 효능을 갖을 수 있도록 한다. Two digestive enzymes used when carbohydrates are digested into glucose are α-amylase and α-glucosidase. This strain inhibits α-glucosidase activity by inhibiting the action of α-glucosidase. It slows the rate at which polysaccharides are broken down into glucose in the intestine, helping the sugars to be absorbed into the body more slowly. This activity allows the strain to have the effect of preventing or improving not only obesity, but also various obesity-related diseases and metabolic syndrome.
또한 본 발명의 균주는 높은 수준의 자유 라디칼 소거 활성을 나타내며, 활성 산소 생성을 억제하여 높은 항산화 활성을 가짐으로써 이에 기초한 다양한 생리학적 활성을 나타낼 수 있다. In addition, the strain of the present invention exhibits a high level of free radical scavenging activity, and has high antioxidant activity by inhibiting active oxygen production, thereby exhibiting various physiological activities based thereon.
따라서, 본 발명의 균주는 지질축적 억제능, α-글루코시다아제 억제능 및 항산화능으로 이루어진 군에서 선택된 1종 이상의 활성을 갖는 것일 수 있다. Accordingly, the strain of the present invention may have at least one activity selected from the group consisting of lipid accumulation inhibitory activity, α-glucosidase inhibitory activity and antioxidant activity.
또한 본 발명의 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555 또는 락토바실러스 람노서스 MG4502 는 모두 프로바이오틱스에 적합한 내산성, 내담즙성 및 자가 응집능을 갖는 것을 특징으로 할 수 있다. In addition, Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555 or Lactobacillus rhamnosus MG4502 of the present invention are all suitable for probiotics, acid resistance and autologous bile tolerance It may be characterized as having a cohesive ability.
본 발명의 일실시예에서는 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555 또는 락토바실러스 람노서스 MG4502 균주가 강산 조건인 pH 2 내지 4에서 높은 생존율을 유지하는 것을 확인하였다. 또한 본 발명의 일실시예에서는 상기 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 가 pH 7 및 pH 8조건의 판크레아틴을 포함하는 담즙염의 환경에서도 높은 생존율을 유지하는 것을 확인하였다. In one embodiment of the present invention, the Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555 or Lactobacillus rhamnosus MG4502 strains are pH 2 to 4 under strong acid conditions. It was confirmed that the high survival rate was maintained. In addition, in one embodiment of the present invention, the Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 are pH 7 and pH 8 It was confirmed that the high survival rate was maintained even in an environment of bile salts containing pancreatin.
또한 본 발명의 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 균주는 우수한 자가응집능 (autoaggregation ability)을 가지고 있어, 장의 연축 운동에 의한 프로바이오틱스의 제거를 방지하고 장에서 효과적으로 소화관의 상피세포에 콜로니를 형성할 수 있다.In addition, the Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 strains of the present invention have excellent autoaggregation ability. It can prevent the removal of probiotics by intestinal spasm and effectively form colonies in the epithelial cells of the digestive tract in the intestine.
본 발명이 균주는 다양한 항생제에 대하여 감수성 또는 내성을 가질 수 있으며, 고유의 특성에 따라 적절히 처방 또는 섭취할 수 있다. The strain of the present invention may have sensitivity or resistance to various antibiotics, and may be appropriately prescribed or ingested according to its unique characteristics.
보다 구체적으로 본 발명의 락토바실러스 아시도필러스 MG4558 는 암피실린, 스트렙토마이신, 테트라사이클린, 에리스로마이신, 반코마이신 및 클린다마이신으로 이루어진 군에서 선택된 1종 이상의 항생제에 대하여 감수성을 갖고, 겐타마이신, 카나마이신 및 클로람페니콜로 이루어진 군에서 선택된 1종 이상의 항생제에 대하여 내성을 갖는 것일 수 있다. More specifically, Lactobacillus acidophilus MG4558 of the present invention has sensitivity to one or more antibiotics selected from the group consisting of ampicillin, streptomycin, tetracycline, erythromycin, vancomycin and clindamycin, gentamicin, kanamycin and chloramphenicol It may be one having resistance to one or more antibiotics selected from the group consisting of.
또한 본 발명의 락토바실러스 파라카제이 MG4592 균주는 암피실린, 겐타마이신, 스트렙토마이신, 테트라사이클린, 에리스로마이신 및 클린다마이신으로 이루어진 군에서 선택된 1종 이상의 항생제에 대하여 감수성을 갖고, 카나마이신 및 클로람페니콜로 이루어진 군에서 선택된 1종 이상의 항생제에 대하여 내성을 갖는 것일 수 있다. In addition, the Lactobacillus paracasei MG4592 strain of the present invention has sensitivity to at least one antibiotic selected from the group consisting of ampicillin, gentamicin, streptomycin, tetracycline, erythromycin and clindamycin, and is selected from the group consisting of kanamycin and chloramphenicol. It may be resistant to one or more antibiotics.
또한 본 발명의 락토바실러스 플란타럼 MG4553 균주는 암피실린, 겐타마이신, 카나마이신, 에리스로마이신 및 클린다마이신으로 이루어진 군에서 선택된 1종 이상의 항생제에 대하여 감수성을 갖고, 테트라사이클린 및 클로람페니콜로 이루어진 군에서 선택된 1종 이상의 항생제에 대하여 내성을 갖는 것일 수 있다.In addition, the Lactobacillus plantarum MG4553 strain of the present invention has sensitivity to one or more antibiotics selected from the group consisting of ampicillin, gentamicin, kanamycin, erythromycin and clindamycin, and at least one selected from the group consisting of tetracycline and chloramphenicol. It may be resistant to antibiotics.
또한 본 발명의 락토바실러스 플란타럼 MG4555 균주는 암피실린, 겐타마이신, 카나마이신, 에리스로마이신, 클로람페니콜 및 클린다마이신으로 이루어진 군에서 선택된 1종 이상의 항생제에 대하여 감수성을 갖고, 테트라사이클린에 대하여 내성을 갖는 것일 수 있다.In addition, the Lactobacillus plantarum MG4555 strain of the present invention has sensitivity to one or more antibiotics selected from the group consisting of ampicillin, gentamicin, kanamycin, erythromycin, chloramphenicol and clindamycin, and may have resistance to tetracycline. .
또한 본 발명의 락토바실러스 람노서스 MG4502 균주는 암피실린, 겐타마이신, 카나마이신, 스트렙토마이신, 테트라사이클린, 에리스로마이신, 클로람페니콜 및 클린다마이신으로 이루어진 군에서 선택된 1종 이상의 항생제에 대하여 감수성을 갖는 것일 수 있다. In addition, the Lactobacillus rhamnosus MG4502 strain of the present invention may have sensitivity to one or more antibiotics selected from the group consisting of ampicillin, gentamicin, kanamycin, streptomycin, tetracycline, erythromycin, chloramphenicol and clindamycin.
본 발명은 또한, 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 균주, 이의 배양액, 또는 이들의 무세포 추출물을 포함하는 조성물에 관한 것이다. The present invention also provides Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 strain, a culture medium thereof, or cell-free thereof It relates to a composition comprising the extract.
상기 조성물은 비만 또는 비만 관련 질환의 예방 또는 개선용 식품 조성물, 건강 기능식품 조성물, 식품 첨가제 조성물, 의약외품 조성물, 사료 조성물 또는 비만 또는 비만 관련 질환의 예방 또는 치료용 약학적 조성물을 포함한다. The composition includes a food composition for preventing or improving obesity or obesity-related diseases, a health functional food composition, a food additive composition, a quasi-drug composition, a feed composition, or a pharmaceutical composition for preventing or treating obesity or obesity-related diseases.
본 발명에서 있어서, 상기 배양액이란, 액체 배지에 균주를 접종하여 배양한 것을 의미하며, 무세포 추출액은 액체상의 배양액으로부터 균주를 제거한 상등액을 의미하고, 이는 "배양여액"과 상호 교환적으로 사용될 수 있다. In the present invention, the culture medium means cultured by inoculating the strain in a liquid medium, and the cell-free extract means a supernatant from which the strain is removed from the liquid culture medium, which can be used interchangeably with "culture filtrate" have.
본 발명에서 용어, "예방"이란, 본 발명에 따른 비만 관련 질환의 예방 또는 치료용 조성물을 개체에 투여하여 비만 관련 질환의 발병을 억제하거나 지연시키는 모든 행위를 의미할 수 있다. As used herein, the term "prevention" may refer to any action that inhibits or delays the onset of obesity-related diseases by administering the composition for preventing or treating obesity-related diseases according to the present invention to an individual.
본 발명에서 용어, "치료"란, 본 발명에 따른 조성물을 비만 관련 질환 발병 의심 개체에 투여하여 비만 관련 질환의 증세가 호전되도록 하거나 이롭게 되도록 하는 모든 행위를 의미할 수 있다. As used herein, the term "treatment" may refer to any action for improving or benefiting the symptoms of obesity-related disease by administering the composition according to the present invention to an individual suspected of having an obesity-related disease.
본 발명에서 용어, "개선"은 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미할 수 있다.As used herein, the term “improvement” may refer to any action that at least reduces a parameter related to a condition to be treated, for example, the degree of a symptom.
본 발명에서 용어, "개체"란, 비만 관련 질환이 발병되었거나 발병할 가능성이 있는 인간을 포함한 모든 동물을 의미할 수 있다.As used herein, the term "individual" may refer to any animal, including humans, that has or is likely to develop an obesity-related disease.
본 발명의 조성물이 식품 또는 건강기능식품 조성물인 경우 상기 식품의 종류는 특별히 제한되지 아니하며, 통상적인 의미에서의 식품을 모두 포함할 수 있다. 상기 물질을 첨가할 수 있는 식품의 비제한적인 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올 음료 및 비타민 복합제 등을 들 수 있다. 상기 조성물을 식품 첨가물로 사용할 경우, 상기 조성물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. When the composition of the present invention is a food or a health functional food composition, the type of the food is not particularly limited, and may include any food in a conventional sense. Non-limiting examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea , drinks, alcoholic beverages, and vitamin complexes. When the composition is used as a food additive, the composition may be added as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method.
본 명세서에서 식품이란 함은 영양소를 한 가지 또는 그 이상 함유하고 있는 천연물 또는 가공품을 의미하며, 바람직하게는 어느 정도의 가공 공정을 거쳐 직접 먹을 수 있는 상태가 된 것을 의미하며, 통상적인 의미이고, 상기 식품 조성물은 식품, 식품 첨가제, 건강 기능성 식품 및 음료를 모두 포함하는 의도이다. As used herein, food means a natural product or processed product containing one or more nutrients, and preferably means a state that can be eaten directly through a certain processing process, and has a conventional meaning, The food composition is intended to include all food, food additives, health functional food and beverage.
본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 각종 식품류, 음료, 껌, 캔디, 차, 비타민 복합제, 기능성 식품 등이 있다. 추가로, 본 발명에서 식품에는 특수영양식품(예, 조제유류, 영, 유아식 등), 식육가공품, 어육제품, 두부류, 묵류, 면류(예, 라면류, 국수류 등), 건강보조식품, 조미식품(예, 간장, 된장, 고추장, 혼합장 등), 소스류, 과자류(예, 스넥류), 유가공품(예, 발효유, 치즈 등), 기타 가공식품, 김치, 절임 식품(각 종 김치류, 장아찌 등), 음료(예, 과실, 채소류 음료, 두유류, 발효음료류, 아이스크림류 등), 천연조미료(예, 라면 스프 등), 비타민 복합제, 알코올 음료, 주류 및 그 밖의 건강보조식품류를 포함하나 이에 한정되지 않는다. 상기 식품, 음료 또는 식품첨가제는 통상의 제조방법으로 제조될 수 있다. Foods to which the composition of the present invention can be added include, for example, various foods, beverages, gums, candy, tea, vitamin complexes, functional foods, and the like. In addition, in the present invention, foods include special nutritional foods (eg, formula milk, infant food, etc.), processed meat products, fish meat products, tofu, jelly, noodles (eg, ramen, noodles, etc.), health supplements, seasoned foods ( Ex, soy sauce, soybean paste, gochujang, mixed soy sauce, etc.), sauces, sweets (e.g. snacks), dairy products (e.g. fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various types of kimchi, pickles, etc.), beverages (eg, fruit and vegetable beverages, soy milk, fermented beverages, ice cream, etc.), natural seasonings (eg, ramen soup, etc.), vitamin complexes, alcoholic beverages, alcoholic beverages, and other health supplements, but is not limited thereto. The food, beverage or food additive may be prepared by a conventional manufacturing method.
본 발명에서 용어, "건강기능식품"이란 건강보조의 목적으로 특정성분을 원료로 하거나 식품 원료에 들어있는 특정성분을 추출, 농축, 정제, 혼합 등의 방법으로 제조, 가공한 식품을 말하며, 상기 성분에 의해 생체 방어, 생체리듬의 조절, 질병의 방지와 회복 등 생체조절기능을 생체에 대하여 충분히 발휘할 수 있도록 설계되고 가공된 식품을 말하는 것으로서, 질병의 예방 또는 건강의 회복 등과 관련된 기능을 수행할 수 있는 것을 말한다. As used herein, the term "health functional food" refers to food manufactured and processed by methods such as extraction, concentration, purification, mixing, etc. of specific ingredients as raw materials or in food raw materials for the purpose of health supplementation, It refers to food that is designed and processed to sufficiently exert biological control functions, such as biological defense, regulation of biological rhythm, and prevention and recovery of diseases, by ingredients. say what you can
본 발명에 따른 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 균주, 이의 배양액, 또는 이들의 무세포 추출물을 건강기능식품으로 사용하는 경우, 이를 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 이는 필요에 따라 선택하여 적절하게 사용될 수 있다. 또한, 첨가되는 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 균주, 이의 배양액, 또는 이들의 무세포 추출물은 그 사용 목적에 따라 적합하게 결정할 수 있다.Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 strain according to the present invention, a culture solution thereof, or a cell-free extract thereof When used as a health functional food, it can be added as it is or used together with other foods or food ingredients, which can be appropriately selected and used as needed. In addition, the added Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 strain, a culture solution thereof, or a cell-free extract thereof may be appropriately determined according to the purpose of use.
본 발명에 따른 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 균주, 이의 배양액, 또는 이들의 무세포 추출물은 생체 안전성이 보장되며, 농도 비례하여 활성 증가 효과를 나타내므로, 특정범위로 제한하지 않고 적절한 양으로 사용할 수 있음은 자명하다. Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 strain according to the present invention, a culture solution thereof, or a cell-free extract thereof Since biosafety is guaranteed and the effect of increasing the activity is proportional to the concentration, it is obvious that it can be used in an appropriate amount without being limited to a specific range.
특히 본 발명의 균주는 영아 또는 유아의 체내에서 분리된 균주이므로, 성인 뿐만 아니라 영아 또는 유아도 안전하게 섭취할 수 있는 균주로, 영아 또는 유아가 섭취하여 비만 및 비만관련 질환의 예방 또는 개선 뿐만 아니라, 항산화, 장 건강 효과를 동시에 달성할 수 있다. In particular, since the strain of the present invention is a strain isolated from the body of an infant or infant, it is a strain that can be safely ingested not only by adults, but also by infants or toddlers. It can achieve antioxidant and intestinal health effects at the same time.
또한, 본 발명에 따른 균주가 사용될 수 있는 건강기능식품의 종류에는 특별한 제한이 없다. 예컨대, 라면, 기타 면류, 음료수, 차, 드링크제, 알콜 음료, 각종 스프, 육류, 소세지, 빵, 초코렛, 캔디류, 과자 류, 피자, 껌류, 아이스크림류를 포함한 낙농제품, 또는 비타민 복합제 등이 있다.In addition, there is no particular limitation on the type of health functional food in which the strain according to the present invention can be used. For example, ramen, other noodles, beverages, tea, drinks, alcoholic beverages, various soups, meat, sausages, bread, chocolate, candy, confectionery, pizza, gum, dairy products including ice cream, or vitamin complex.
특히, 본 발명에 따른 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 균주, 이의 배양액, 또는 이들의 무세포 추출물은 소화관 내에서의 위산 또는 담즙산에 대한 생존력, 세포내 부착력, 자가응집능 및 지질축적 억제능, α-글루코시다아제 억제능 및 항산화능을 나타내므로, 비만 또는 비만 관련 질환의 개선, 예방을 목적으로 하는 다양한 식품류에 추가되어 기능을 나타낼 수 있고, 통상의 기술자의 선택에 따라 통상적으로 건강기능식품에 함유될 수 있는 적절한 기타 보조성분과 공지의 첨가제와 혼합하여 사용할 수 있다. 상기 공지의 첨가제에는 본 발명에 따른 균주와 함께 사용할 수 있는 다른 미생물도 포함된다. In particular, Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 strain according to the present invention, a culture solution thereof, or a radish thereof Since the cell extract exhibits viability, intracellular adhesion, self-aggregation and lipid accumulation inhibitory ability, α-glucosidase inhibitory activity and antioxidant activity to gastric acid or bile acid in the digestive tract, the purpose of improvement or prevention of obesity or obesity-related diseases It can be added to a variety of food products to show a function, and according to the selection of a person skilled in the art, it can be used by mixing with other suitable auxiliary ingredients and known additives that can be normally contained in health functional foods. The known additives also include other microorganisms that can be used with the strain according to the present invention.
또한 본 발명은 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 균주, 이의 배양액, 또는 이들의 무세포 추출물을 포함하는 비만 또는 비만 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다. In addition, the present invention is Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 strain, a culture medium thereof, or a cell-free extract thereof It provides a pharmaceutical composition for the prevention or treatment of obesity or obesity-related diseases comprising a.
본 발명의 균주는 우수한 지질축적 억제능, α-글루코시다아제 억제능 및 항산화능을 나타내므로, 지질 축적 억제 및 이에 따른 비만 관련 질환, 바람직하게는 각종 대사 질환을 효과적으로 예방 또는 치료할 수 있다. Since the strain of the present invention exhibits excellent lipid accumulation inhibitory ability, α-glucosidase inhibitory activity and antioxidant activity, it is possible to effectively prevent or treat lipid accumulation inhibition and obesity-related diseases, preferably various metabolic diseases.
본 발명에 따른 비만 관련 질환은 체내 지질 축적 억제, α-글루코시다아제 억제 및 항산화에 의해 예방, 치료될 수 있는 각종 질환을 포함할 수 있으며, 바람직하게는 지방간, 제2형 당뇨, 고지혈증, 심혈관 질환, 동맥경화증 및 지질 관련 대사증후군으로 이루어진 군에서 선택된 1종 이상일 수 있다. Obesity-related diseases according to the present invention may include various diseases that can be prevented and treated by inhibition of lipid accumulation in the body, inhibition of α-glucosidase and antioxidant, preferably fatty liver, type 2 diabetes, hyperlipidemia, and cardiovascular disease. It may be at least one selected from the group consisting of diseases, arteriosclerosis, and lipid-related metabolic syndrome.
또한 본 발명의 균주는 항생제에 대하여 선택적인 내성 및 감수성을 가지고 있으므로, 내성을 가진 항생제 복용 시에 선택하여 함께 병용투여가 가능하다. In addition, since the strain of the present invention has selective resistance and sensitivity to antibiotics, it is possible to select and administer together with antibiotics with resistance.
보다 구체적으로 락토바실러스 아시도필러스 MG4558 균주는 겐타마이신, 카나마이신 및 클로람페니콜로 이루어진 군에서 선택된 1종 이상의 항생제와 병용 투여되는 병용 투여용일 수 있다. More specifically, the Lactobacillus acidophilus MG4558 strain may be for combined administration administered in combination with one or more antibiotics selected from the group consisting of gentamicin, kanamycin and chloramphenicol.
또한 락토바실러스 파라카제이 MG4592 균주는 카나마이신 및 클로람페니콜로 이루어진 군에서 선택된 1종 이상의 항생제와 병용 투여되는 병용 투여용일 수 있다. In addition, the Lactobacillus paracasei MG4592 strain may be for combined administration, which is administered in combination with one or more antibiotics selected from the group consisting of kanamycin and chloramphenicol.
또한 락토바실러스 플란타럼 MG4553 균주는 테트라사이클린 및 클로람페니콜로 이루어진 군에서 선택된 1종 이상의 항생제와 병용 투여되는 병용 투여용일 수 있다. In addition, the Lactobacillus plantarum MG4553 strain may be used in combination with one or more antibiotics selected from the group consisting of tetracycline and chloramphenicol.
또한 락토바실러스 플란타럼 MG4555 균주는 테트라사이클린과 병용 투여되는 병용 투여용일 수 있다. In addition, the Lactobacillus plantarum MG4555 strain may be for co-administration administered in combination with tetracycline.
본 발명에 따른 약학적 조성물은 약학적으로 유효한 양의 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 균주, 이의 배양액, 또는 이들의 무세포 추출물을 단독으로 포함하거나 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 포함할 수 있다.The pharmaceutical composition according to the present invention comprises a pharmaceutically effective amount of Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 strain. , a culture solution thereof, or a cell-free extract thereof, or may include one or more pharmaceutically acceptable carriers, excipients or diluents.
상기에서 "약학적으로 유효한 양"이란, 비만 또는 비만 관련 질환의 예방, 개선 또는 치료 효과를 발휘하기에 충분한 양을 말한다. 상기 "약학적으로 허용되는"이란, 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. As used herein, "pharmaceutically effective amount" refers to an amount sufficient to prevent, improve, or treat obesity or obesity-related diseases. The "pharmaceutically acceptable" refers to a composition that is physiologically acceptable and does not normally cause gastrointestinal disorders, allergic reactions such as dizziness, or similar reactions when administered to humans.
또한 본 발명에 따른 약학적 조성물은 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 당해 기술 분야에 알려진 적합한 제제는 문헌(Remington's Pharmaceutical Science, 최근, Mack Publishing Company, Easton PA)에 개시되어 있는 것을 사용하는 것이 바람직하다. 포함될 수 있는 담체, 부형제 및 희석제로는 락토 오스, 덱스트로오스, 수크로오스, 소르비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알 지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리 비닐 피롤리돈, 물, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트, 광물 유 등이 있다. 상기 약학적 조성물을 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산 제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘 카보네이트(calcium carbonate), 수크로오스, 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내 용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우 린지, 글리세로제라틴 등이 사용될 수 있다.In addition, the pharmaceutical composition according to the present invention can be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions according to conventional methods. can Suitable formulations known in the art are preferably those disclosed in Remington's Pharmaceutical Science, recently Mack Publishing Company, Easton PA. Carriers, excipients and diluents that may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose. , microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. When formulating the pharmaceutical composition, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose. , gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin oil, glycerogelatin, and the like can be used.
본 발명의 약학적 조성물은 연구자, 수의사, 의사 또는 기타 임상에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약학적 조성물의 양, 즉 치료되는 질환 또는 장애의 증상의 완화를 유도하는 양인 치료상 유효량으로 투여할 수 있다. 본 발명의 약학적 조성물에 대한 치료상 유효 투여량 및 투여횟수는 원하는 효과에 따라 변화될 것임은 당업자에게 자명하다. 그러므로, 투여될 최적의 투여 량은 당업자에 의해 쉽게 결정될 수 있으며, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 바람직한 효과를 위해서, 본 발명의 약학적 조성물은 1~10,000㎎/㎏/day, 바람직하게는 1~200㎎/㎏/day의 양으로 투여할 수 있으며, 하루에 한번 투여할 수도 있고, 수 회에 나누어 투여할 수도 있다. The pharmaceutical composition of the present invention is an amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human as considered by a researcher, veterinarian, physician or other clinician, that is, the amount of the symptom of the disease or disorder being treated. It can be administered in a therapeutically effective amount, which is an amount that induces remission. It is apparent to those skilled in the art that the therapeutically effective dosage and frequency of administration for the pharmaceutical composition of the present invention will vary depending on the desired effect. Therefore, the optimal dosage to be administered can be easily determined by those skilled in the art, and the type of disease, the severity of the disease, the content of active ingredients and other components contained in the composition, the type of formulation, and the age, weight, and general health of the patient Condition, sex and diet, administration time, administration route and secretion rate of the composition, treatment period, can be adjusted according to various factors including drugs used at the same time. For a desirable effect, the pharmaceutical composition of the present invention may be administered in an amount of 1 to 10,000 mg/kg/day, preferably 1-200 mg/kg/day, and may be administered once a day, several times It can also be administered in divided doses.
본 발명의 약학적 조성물은 개체에게 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다.The pharmaceutical composition of the present invention may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection.
또한 본 발명은 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 균주, 이의 배양액, 또는 이들의 무세포 추출물을 포함하는 비만 또는 비만 관련 질환의 예방 또는 개선용 의약외품 조성물을 제공한다. In addition, the present invention is Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 strain, a culture medium thereof, or a cell-free extract thereof It provides a quasi-drug composition for preventing or improving obesity or obesity-related diseases, including.
본 발명의 균주는 비만 관련 질환의 예방 또는 개선을 목적으로 의약외품 조성물에 첨가될 수 있다. 본 발명의 균주를 의약외품 첨가물로 사용할 경우, 상기 균주를 그대로 첨가하거나 다른 의약외품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 사용 목적 (예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. The strain of the present invention may be added to the quasi-drug composition for the purpose of preventing or improving obesity-related diseases. When the strain of the present invention is used as a quasi-drug additive, the strain may be added as it is or used together with other quasi-drug components, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment).
또한 본 발명은 인간을 제외한 가축을 치료 대상으로 하여, 락토바실러스 아시도필러스 MG4558, 락토바실러스 파라카제이 MG4592, 락토바실러스 플란타럼 MG4553, 락토바실러스 플란타럼 MG4555, 또는 락토바실러스 람노서스 MG4502 균주, 이의 배양액, 또는 이들의 무세포 추출물을 포함하는, 비만 또는 비만 관련 질환의 예방 또는 개선용 사료 조성물을 제공한다. In addition, the present invention is a treatment target for livestock other than humans, Lactobacillus acidophilus MG4558, Lactobacillus paracasei MG4592, Lactobacillus plantarum MG4553, Lactobacillus plantarum MG4555, or Lactobacillus rhamnosus MG4502 strain , It provides a feed composition for preventing or improving obesity or obesity-related diseases, comprising a culture medium thereof, or a cell-free extract thereof.
본 발명 사료 조성물은 사료 첨가제를 포함하고, 본 발명의 사료첨가제는 사료관리법상의 보조사료에 해당한다.The feed composition of the present invention includes a feed additive, and the feed additive of the present invention corresponds to an auxiliary feed under the Feed Management Act.
본 발명에서 용어 "사료"는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미할 수 있다. 상기 사료의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 사료를 사용할 수 있다. 상기 사료의 비제한적인 예로는, 곡물류, 근 과류, 식품 가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류 또는 곡물 부산물류 등과 같은 식물성 사료; 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질류, 동물성 플랑크톤류 또는 음식물 등과 같은 동물성 사료를 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.In the present invention, the term "feed" may refer to any natural or artificial diet, one-meal, etc., or a component of the one-meal, which is suitable for or suitable for the animal to eat, ingest, and digest. The type of feed is not particularly limited, and feed commonly used in the art may be used. Non-limiting examples of the feed include plant feeds such as grains, root fruits, food processing by-products, algae, fibers, pharmaceutical by-products, oils and fats, starches, gourds or grain by-products; and animal feeds such as proteins, inorganic materials, oils and fats, minerals, oils and fats, single cell proteins, zooplankton or food. These may be used alone or in mixture of two or more.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes of the present invention, and the scope of the present invention is not limited to these examples.
모든 실험은 3회 반복 수행하였으며, 결과는 평균 ± 표준 편차 (SD)로 나타내었다. R (버전 3.6.2) 및 PRIMER-E 소프트웨어 패키지를 사용하여 통계 분석을 수행하였다. All experiments were repeated three times, and the results were expressed as mean ± standard deviation (SD). Statistical analysis was performed using R (version 3.6.2) and the PRIMER-E software package.
실시예Example 1. 영유아 1. Infants 분변에서in feces 균주 분리 동정 Identification of strain isolation
유아 분변 검체에서 프로바이오틱 후보 물질을 분리하였다. 분변 샘플은 2 ~ 15 개월의 영유아로부터 수집하였다. 생분(1g)의 일부를 0.85% NaCl 9mL에 접종하고 Stomacher 샘플 믹서 (3M, Korea)를 이용하여 3 분간 잘 혼합한 후 Whatman No. 2 여과지를 통해 여과하였다. 여과된 샘플의 1mL 분취량을 연속 희석 (최대 108 개)하고 샘플을 라피노스-비피도박테리움 (raffinose-bifidobacterium, RB), 네오마이신, 파로모 마이신, 날리딕산 및 염화리튬 (NPNL) 또는 Rogosa(락토바실러스 선택 한천) 한천 배지에 도말하였다. 플레이트를 37 ℃에서 24 시간 동안 배양하였으며, 후보가 되는 젖산 박테리아 콜로니를 선택하고 동일한 배지에서 두 번 연속 정제하였다. 정제된 콜로니를 BCP(bromo cresol purple) 한천에 스트리킹하고 황색 영역 형성을 기반으로 젖산 생성 박테리아임을 확인하였다. 균주들을 MRS 한천 배지 (Difco, USA)에 유지하고 사용 전까지 -80℃에서 20 % 글리세롤에 보관하였다. 균주를 MRS 배지 또는 한천 배지에 접종하고 37 ℃에서 12-18 시간 동안 배양하였다.Probiotic candidates were isolated from infant fecal samples. Fecal samples were collected from infants between 2 and 15 months of age. A portion of raw meal (1g) was inoculated into 9mL of 0.85% NaCl, mixed well for 3 minutes using a Stomacher sample mixer (3M, Korea), and then Whatman No. 2 filtered through filter paper. Serial dilutions (up to 10 8 ) of 1 mL aliquots of the filtered samples and incubate the samples with raffinose-bifidobacterium (RB), neomycin, paromomycin, nalidic acid and lithium chloride (NPNL) or Rogosa (Lactobacillus selective agar) was plated on agar medium. The plate was incubated at 37° C. for 24 hours, and candidate lactic acid bacterial colonies were selected and purified twice in the same medium. The purified colonies were streaked on BCP (bromo cresol purple) agar, and it was confirmed that they were lactic acid-producing bacteria based on the formation of yellow areas. The strains were maintained on MRS agar medium (Difco, USA) and stored in 20% glycerol at -80°C until use. The strain was inoculated on MRS medium or agar medium and incubated at 37° C. for 12-18 hours.
균주들의 무세포 추출물 (cell free extract, CFE)을 얻기 위해, 미생물 배양액에 초음파를 처리하였고, 배양액을 용해시켰다. 먼저 3,470xg로 4℃에서 5분동안 원심분리를 수행하여 배양액을 수득하였고 PBS (pH 7.4)를 이용하여 3회 세척하여 남아있는 MRS 배지를 제거하였다. 세포 펠렛을 10mg/mL 에서 재현탁시키고, 사이클 사이에 30 초 동안 일시 정지하면서 150W에서 30 초 동안 3사이클로 초음파를 처리하여 용해시켰다. 용해된 배양액을 0.2μm 시린지 필터 (Advantech, USA)를 사용하여 여과하고, 사용할 때까지 -80 ℃에서 보관하였다.In order to obtain a cell free extract (CFE) of the strains, the microbial culture medium was sonicated, and the culture medium was dissolved. First, a culture solution was obtained by centrifugation at 3,470xg at 4°C for 5 minutes, and washed 3 times with PBS (pH 7.4) to remove the remaining MRS medium. The cell pellet was resuspended at 10 mg/mL and lysed by sonication for 3 cycles at 150 W for 30 sec, pausing for 30 sec between cycles. The lysed culture solution was filtered using a 0.2 μm syringe filter (Advantech, USA) and stored at -80°C until use.
실시예Example 2. 균주 활성 평가 2. Evaluation of strain activity
2.1 지질 축적 억제 활성 확인 2.1 Confirmation of lipid accumulation inhibitory activity
영유아 분변에서 분리된 콜로니에서 16S rRNA 유전자 시퀀싱을 수행하고, 16S rRNA 유전자 시퀀싱 결과를 기반으로 61개의 분리 균주를 동정하였다. 후보 균주는 2 속 10 종으로 구별됐으며 이를 표 1에 나타내었다: Bifidobacterium animalis subsp . lactis , B. breve , Lactobacillus acidophilus, L. casei , L. fermentum, L. gasseri , L. paracasei , L. plantarum , L. rhamnosus 및 L. salivarius. 16S rRNA gene sequencing was performed on colonies isolated from infant feces, and 61 isolated strains were identified based on the 16S rRNA gene sequencing results. Candidate strains were classified into 10 species in 2 genera and are shown in Table 1 : Bifidobacterium animalis subsp . lactis , B. breve , Lactobacillus acidophilus, L. casei , L. fermentum, L. gasseri , L. paracasei , L. plantarum , L. rhamnosus and L. salivarius.
항 비만 효과를 가질 것으로 기대되는 프로바이오틱 균주를 선별하기 위해 분화된 3T3-L1 지방 세포를 이용하여 61 개 균주 모두의 지질 축적 억제 효과를 Oil Red O 염색 강도를 측정하여 평가하였다. To select a probiotic strain expected to have an anti-obesity effect, the lipid accumulation inhibitory effect of all 61 strains using differentiated 3T3-L1 adipocytes was evaluated by measuring the Oil Red O staining intensity.
3T3-L1 세포를 10 % 우태아 혈청 (FBS) 및 1% 페니실린/스트렙토마이신이 보충된 DMEM에서 배양하였다. 적절한 수의 세포를 유지하기 위해 2 일마다 계대 배양을 수행하였으며, 지방 세포 분화를 유도하기 위해 3T3-L1 세포를 DMEM이 포함된 6 웰 플레이트에 1 x 105 세포/mL로 접종하고 최소 2 일 동안 배양하였다. 그 후 배지를 DMEM-MDI (0.5mM IBMX, 1μM DEX 및 1μg/mL 인슐린(insulin) 함유)로 교체하였다. 2 일과 4 일에 인슐린 1μg/mL 만 함유하는 배지로 배양 배지를 교체하였고, 0, 2 및 4 일에 세포를 유도 배지와 함께 0.1 mg/mL의 CFE로 처리하였다. 그 후, 분화를 유도하기 위해 배지를 2 일마다 8 일 동안 교체하였다. 3T3-L1 cells were cultured in DMEM supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin. Subcultures were performed every 2 days to maintain an appropriate number of cells, and to induce adipocyte differentiation, 3T3-L1 cells were seeded in 6-well plates with DMEM at 1 x 10 5 cells/mL and for a minimum of 2 days. incubated during Then the medium was replaced with DMEM-MDI (0.5mM IB M X , 1μM D EX and 1μg / mL insulin (i nsulin) content). On days 2 and 4, the culture medium was replaced with a medium containing only insulin 1 μg/mL, and on
분화된 3T3-L1 지방 세포의 총 지질 축적을 Oil Red O 염색을 사용하여 측정하였다. 배양된 3T3-L1 세포에서 배지를 제거하고 세포를 PBS (pH 7.4)로 2 회 세척 하였다. 그 후, 3.7 % 포름알데히드 1mL를 각 웰에 첨가하고 15 분 동안 배양하여 세포를 고정시켰다. 다음으로 포름알데히드를 제거하고 세포를 PBS로 3 회 세척하였다. Oil Red O 를 증류수와 6: 4의 비율로 혼합하고 0.2μm 필터를 통해 여과하여 제조하였다. 준비된 Oil Red O 용액 (500 μL)의 분취량을 각 웰에 첨가하고 실온에서 30 분 동안 배양한 후 PBS로 3 회 세척 하였으며, 세포를 현미경으로 관찰하였다. 마지막으로 Oil Red O 염색을 100% 이소프로판올로 염료를 추출하고 마이크로 플레이트리더를 사용하여 540 nm에서 흡광도를 측정하여 정량화하였다. MDI로 처리 된 3T3-L1 세포는 처리되지 않은 세포 (대조군)보다 더 많은 지질 방울을 형성하였다. 분화된 3T3-L1 지방 세포의 지질 축적은 다음 공식을 사용하여 계산하였다. Total lipid accumulation in differentiated 3T3-L1 adipocytes was measured using Oil Red O staining. The medium was removed from the cultured 3T3-L1 cells, and the cells were washed twice with PBS (pH 7.4). Then, 1 mL of 3.7% formaldehyde was added to each well and incubated for 15 minutes to fix the cells. Next, formaldehyde was removed and the cells were washed 3 times with PBS. Oil Red O was mixed with distilled water in a ratio of 6: 4 and filtered through a 0.2 μm filter. An aliquot of the prepared Oil Red O solution (500 μL) was added to each well, incubated at room temperature for 30 minutes, washed 3 times with PBS, and the cells were observed under a microscope. Finally, Oil Red O staining was quantified by extracting the dye with 100% isopropanol and measuring the absorbance at 540 nm using a microplate reader. 3T3-L1 cells treated with MDI formed more lipid droplets than untreated cells (control). Lipid accumulation in differentiated 3T3-L1 adipocytes was calculated using the following formula.
지질 축적 (%) = As/Ac × 100Lipid accumulation (%) = A s /A c × 100
As 는 540 nm에서의 시료 존재 하의 MDI 흡광도, Ac 는 시료 부존재 하의 MDI 흡광도 A s is the absorbance of MDI in the presence of sample at 540 nm, and A c is the absorbance of MDI in the absence of sample at 540 nm.
후보 균주들의 지질 축적 억제율을 표 1에 나타내었으며, 균주에 따라 매우 다양하게 나타났다. The lipid accumulation inhibition rates of the candidate strains are shown in Table 1, and varied greatly depending on the strains.
영유아로부터 분리 동정된 균주들 중 지질 축적 억제 능력이 > 50 %인 우수한 균주를 25종 선택하였으며, 이들 균주를 발효 생성물 수율 (> 1 x 1011 CFU/g)에 대해 평가하였다. 최종적으로 발효 생성물 수율과 지질축적 억제능이 모두 우수한 균주 5 종을 선택하였으며, 이를 한국생명공학연구원에 기탁하였다: 락토바실러스 아시도필러스 MG4558 (기탁번호 KCTC14438BP, 수탁일 2021.01.06), 락토바실러스 파라카제이 MG4592(기탁번호: KCTC 14435BP, 수탁일 2021.01.06), 락토바실러스 플란타럼 MG4553 (기탁번호: KCTC14097BP, 수탁일2020.01.07), 락토바실러스 플란타럼 MG4555 (기탁번호: KCTC 14437BP, 수탁일 2021.01.06) 또는 락토바실러스 람노서스 MG4502 (기탁번호: KCTC 14095BP, 수탁일 2020.01.07) (p <0.001). Among the isolated and identified strains from infants, 25 excellent strains having a lipid accumulation inhibition ability of >50% were selected, and these strains were evaluated for fermentation product yield (>1×10 11 CFU/g). Finally, 5 strains having excellent both yield and lipid accumulation inhibition were selected, and these were deposited at the Korea Research Institute of Bioscience and Biotechnology: Lactobacillus acidophilus MG4558 (Accession No. KCTC14438BP, access date 2021.01.06), Lactobacillus para Casei MG4592 (Accession No.: KCTC 14435BP, Accession Date 2021.01.06), Lactobacillus plantarum MG4553 (Accession No.: KCTC14097BP, Accession Date 2020.01.07), Lactobacillus Plantarum MG4555 (Accession Number: KCTC 14437BP, Accession) date 2021.01.06) or Lactobacillus rhamnosus MG4502 (Accession No.: KCTC 14095BP, Accession Date 2020.01.07) (p <0.001).
2.2 균주의 항 당뇨 활성 평가 2.2 Evaluation of anti-diabetic activity of strains
지질 축적 억제능을 가진 선별된 균주가 α- 글루코시다아제 활성에 미치는 영향을 조사하였다. 150μL의 0.01M PBS (pH 7.0)와 75 μL의 0.02 M p-니트로페닐 α-D-글루코피라노시드(PNPG) 용액을 포함하는 반응 혼합물에 25 μL의 CFS를 첨가하고 37 ℃에서 10분 동안 전 배양하였다. 50μL의 α-글루코시다아제 (0.17 unit/ mL)를 첨가하여 반응을 시작하고, 혼합물을 37℃에서 10분간 배양하였다. 반응은 0.1M Na2CO3 1mL를 첨가하여 종결하고 405nm에서 흡광도를 측정하여 방출된 ρ- 니트로페놀(PNP)의 양을 측정하였다. 억제율은 다음 식에 따라 계산하였다. The effect of the selected strains having the ability to inhibit lipid accumulation on α-glucosidase activity was investigated. To a reaction mixture containing 150 µL of 0.01 M PBS (pH 7.0) and 75 µL of 0.02 M p-nitrophenyl α-D-glucopyranoside (PNPG) solution, add 25 µL of CFS and add 25 µL of CFS at 37 °C for 10 min. pre-cultured. The reaction was started by adding 50 μL of α-glucosidase (0.17 unit/mL), and the mixture was incubated at 37° C. for 10 minutes. The reaction was terminated by adding 1 mL of 0.1M Na 2 CO 3 , and the amount of ρ-nitrophenol (PNP) released was measured by measuring the absorbance at 405 nm. The inhibition rate was calculated according to the following equation.
억제율(%) = [1 - (C - D)/(A - B)] × 100Inhibition rate (%) = [1 - (C - D)/(A - B)] × 100
A 는 α-글루코시다아제 단독 흡광도, B 는 시료 또는 α-글루코시다아제가 없는 조건의 흡광도, C 는 α- 글루코시다아제 및 시료의 흡광도, D 는 시료 단독 흡광도. A is the absorbance of α-glucosidase alone, B is the absorbance of the sample or in the absence of α-glucosidase, C is the absorbance of α-glucosidase and the sample, and D is the absorbance of the sample alone.
선별된 7 개 균주가 α- 글루코시다아제 활성에 미치는 영향을 조사한 결과를 도 1에 나타내었다. The results of examining the effects of the selected 7 strains on α-glucosidase activity are shown in FIG. 1 .
도 1에 나타낸 바와 같이, 대부분의 선별 균주는 상대적으로 높은 α-글루코시다아제 억제 활성을 나타내었으며, 가장 우수한 활성을 나타내는 균주 순으로 락토바실러스 플란타럼 MG4555 (91.6 %), 락토바실러스 아시도필러스 MG4558 (90.3 %), 락토바실러스 파라카제이 MG4592 (81.7 %), 락토바실러스 람노서스 MG4502 (63.4 %), 락토바실러스 플란타럼 MG4553 (62.1 %), 락토바실러스 람노서스 MG4505 (57.5 %) 및 락토바실러스 람노서스MG4511 (19.8 %) 활성을 나타내었다. 7 종의 균주 중 락토바실러스 람노서스 MG4511 (19.8 %)외의 모든 균주들이 지질 축적 억제 및 α-글루코시다아제 억제 활성이 50% 이상으로 나타나 우수한 효과를 나타내는 것을 확인하였다. α-글루코시다아제는 식이 전분을 소화하고 올리고당을 포도당으로 분해하여 식후 포도당을 급격히 증가시키는 역할을 하므로, α-글루코시다아제 억제제는 경구용 당뇨병 치료제로 작용하며 제 2 형 당뇨병 (T2D) 치료에 사용되고 있다. 따라서, α-글루코시다아제 억제 활성을 나타내는 본 발명의 프로바이오틱스 균주들이 지방 억제뿐만 아니라 비만 관련 질환 중 하나인 당뇨 치료제로도 활용될 수 있음을 확인하였다. As shown in FIG. 1 , most of the selected strains exhibited relatively high α-glucosidase inhibitory activity, and in order of the most excellent activity, Lactobacillus plantarum MG4555 (91.6%), Lactobacillus acidophilus S. MG4558 (90.3%), Lactobacillus paracasei MG4592 (81.7%), Lactobacillus rhamnosus MG4502 (63.4%), Lactobacillus plantarum MG4553 (62.1%), Lactobacillus rhamnosus MG4505 (57.5%) and Lactobacillus rhamnosus MG4505 (57.5%). Bacillus rhamnosus MG4511 (19.8%) showed activity. Lactobacillus rhamnosus among 7 strains It was confirmed that all strains other than MG4511 (19.8%) showed excellent effects by showing lipid accumulation inhibition and α-glucosidase inhibitory activity of 50% or more. Since α-glucosidase plays a role in digesting dietary starch and decomposing oligosaccharides into glucose to rapidly increase postprandial glucose, α-glucosidase inhibitors act as oral antidiabetic agents and may be used in the treatment of type 2 diabetes mellitus (T2D). is being used Therefore, it was confirmed that the probiotic strains of the present invention exhibiting α-glucosidase inhibitory activity can be used not only for fat suppression but also as a therapeutic agent for diabetes, which is one of obesity-related diseases.
2.3 균주의 항산화 활성 평가2.3 Evaluation of Antioxidant Activity of Strains
선택된 균주의 항산화 활성을 DPPH 및 ABTS 라디칼 소거 분석을 사용하여 평가하였다. 균주를 0.05mM DPPH 용액 (1:2)과 혼합하고 1.0의 OD600으로 조정하였다. 그 후, 혼합물을 암실에서 30분 동안 실온 배양하였다. 에탄올과 DPPH 용액을 혼합하여 대조군을 제조하였다. 상층액은 13,000rpm에서 1 분간 원심 분리하여 얻은 후 517nm에서 흡광도를 측정하였다. 각 샘플은 3회 반복 측정하였다. 결과를 대표적인 항산화 물질인 아스코르브산(100μg/mL)과 비교하고 다음 방정식을 사용하여 소거 활성을 계산하였다. The antioxidant activity of selected strains was evaluated using DPPH and ABTS radical scavenging assays. The strain was mixed with 0.05 mM DPPH solution (1:2) and adjusted to an OD600 of 1.0. The mixture was then incubated at room temperature for 30 minutes in the dark. A control was prepared by mixing ethanol and DPPH solution. The supernatant was obtained by centrifugation at 13,000 rpm for 1 minute, and then absorbance was measured at 517 nm. Each sample was measured in triplicate. The results were compared with ascorbic acid (100 μg/mL), a representative antioxidant, and the scavenging activity was calculated using the following equation.
Scavenging effect (%) = (Ac - As)/Ac × 100Scavenging effect (%) = (A c - A s )/A c × 100
As 는 517nm 에서 대상 시료의 흡광도, Ac 는 대조군의 흡광도A s is the absorbance of the target sample at 517nm, A c is the absorption of the control group
ABTS 소거 활성을 확인하기 위하여, 라디칼 양이온을 7mM ABTS와 2.45mM과 황산 칼륨 (1:1, v/v)을 혼합하여 제조하고, 24 시간 동안 암실에서 실온 배양하였다. 그 후 균주를 ABTS 용액과 혼합 (1:2)하여 1.0의 OD600으로 조정하고 암실 실온에서 10 분 동안 배양하였다. 반응 혼합물을 13,000 rpm에서 1 분 동안 원심 분리하고 상층액의 흡광도를 734 nm에서 측정하였다. 각 분석은 3회 반복 수행하였다. 결과를 대표적 항산화 물질인 아스코르브산 (100μg/mL)과 비교하고 다음 방정식을 사용하여 활성을 계산하였다. To confirm the ABTS scavenging activity, a radical cation was prepared by mixing 7 mM ABTS, 2.45 mM and potassium sulfate (1:1, v/v), and incubated at room temperature in the dark for 24 hours. Thereafter, the strain was mixed (1:2) with the ABTS solution , adjusted to an OD 600 of 1.0, and incubated at room temperature in the dark for 10 minutes. The reaction mixture was centrifuged at 13,000 rpm for 1 minute and the absorbance of the supernatant was measured at 734 nm. Each assay was performed in triplicate. The results were compared with ascorbic acid (100 μg/mL), a representative antioxidant, and the activity was calculated using the following equation.
Scavenging rate (%) = (Ac - As)/Ac × 100Scavenging rate (%) = (A c - A s )/A c × 100
As 는 734nm 에서 대상 시료의 흡광도, Ac 는 대조군의 흡광도A s is the absorbance of the target sample at 734nm, A c is the absorption of the control group
DPPH 자유 라티칼 소거 활성 및 ABTS 자유 라티칼 소거 활성을 통해 측정된 각 균주의 항산화 능력을 확인한 결과를 도 2에 나타내었다. The results of confirming the antioxidant capacity of each strain measured through DPPH free radical scavenging activity and ABTS free radical scavenging activity are shown in FIG. 2 .
도 2에 나타낸 바와 같이, 7종 균주의 DPPH 자유 라디칼 소거 활성은 21.6 %에서 27.5 % 범위였고, ABTS 라디칼 소거 활성은 40.9 %에서 44.9 % 범위로 나타나 전반적으로 유사한 O2 라디칼 소거 활성을 보였다. 모든 균주는 DPPH 분석에서보다 ABTS 분석에서 더 높은 수준의 라디칼 소거 능력을 나타내었고, 항산화 활성을 가지고 있음을 확인하였다. As shown in FIG. 2 , the DPPH free radical scavenging activity of the 7 strains ranged from 21.6% to 27.5%, and the ABTS radical scavenging activity ranged from 40.9% to 44.9%, indicating overall similar O 2 radical scavenging activity. All strains showed a higher level of radical scavenging ability in the ABTS assay than in the DPPH assay, and it was confirmed that they had antioxidant activity.
2.4. 항 비만, 항 당뇨, 항산화 활성의 2.4. Anti-obesity, anti-diabetic, antioxidant activity 상관 관계correlation 분석 analysis
본 발명 균주에서 DPPH 및 ABTS 소거 활성, α- 글루코시다아제 억제 및 지질 축적 억제 간의 상관 관계를 다중 평균 비교 및 Pearson 상관 분석에 의해 평가하였으며, 그 결과를 표 2에 나타내었다. The correlation between DPPH and ABTS scavenging activity, α-glucosidase inhibition and lipid accumulation inhibition in the strain of the present invention was evaluated by multiple means comparison and Pearson correlation analysis, and the results are shown in Table 2.
표 2에서 유의한 상관관계 결과는 볼드 및 별표 표시로 나타내었다. 표 2에 나타낸 바와 같이, ABTS 소거 활성 (p <0.01) 및 α-글루코시다아제 억제 (p <0.05)는 지질 축적 억제와 유의한 상관 관계가 있었다. 그러나 DPPH 소거 활동과 다른 특성 사이에는 통계적으로 유의한 상관 관계가 없는 것으로 나타났다(p> 0.05).Significant correlation results in Table 2 are indicated by bold and asterisk marks. As shown in Table 2, ABTS scavenging activity (p < 0.01) and α-glucosidase inhibition (p < 0.05) were significantly correlated with lipid accumulation inhibition. However, there was no statistically significant correlation between DPPH scavenging activity and other characteristics (p>0.05).
이러한 결과는 본 발명 균주의 지질 축적 억제 활성과 α-글루코시다아제 억제 활성이 유의한 상관관계가 있음을 보여주는 것이며, 본 발명의 균주가 비만과 2형 당뇨병의 상태를 동시에 개선할 수 있음을 나타내는 결과이다. These results show that there is a significant correlation between the lipid accumulation inhibitory activity of the strain of the present invention and the α-glucosidase inhibitory activity, indicating that the strain of the present invention can simultaneously improve the status of obesity and type 2 diabetes. It is the result.
실시예Example 3. 형태학적 분석 3. Morphological Analysis
FE-SEM (Hitachi, S-4300SE, Japan) 을 이용한 전자 현미경 사진으로 지질축적 억제 및 항당뇨, 항산화 활성을 갖는 선별 균주의 형태학적 분석을 수행하였고, 그 결과를 도 3에 나타내었다. Morphological analysis of the selected strain having lipid accumulation inhibition, antidiabetic and antioxidant activity was performed by electron micrograph using FE-SEM (Hitachi, S-4300SE, Japan), and the results are shown in FIG. 3 .
도 3에 나타낸 바와 같이, 모든 균주들은 막대 모양의 간균 형태였고, 대부분의 균주, 특히 락토바실러스 람노서스(Lactobacillus rhamnosus) MG4502, MG4505 및 MG4511는 엑소폴리사카라이드 (EPS) 가닥에 의해 세포가 연결되어 있음을 확인하였다. As shown in FIG. 3 , all strains were rod-shaped bacilli, and most strains, particularly Lactobacillus rhamnosus MG4502, MG4505 and MG4511, were cells connected by exopolysaccharide (EPS) strands. confirmed that there is.
실시예Example 4. 선별된 균주의 4. of the selected strain 내산성acid resistance 및 and 내담즙성biliary tolerance 확인 Confirm
프로바이오틱스로 활용되기 위해서는 산성 및 담즙엽에 대한 내성이 중요하므로, 위액 환경 (pH 3 및 4) 및 장 환경 (pH 7 및 8)에 노출시키고, 이러한 환경에서의 생존율을 확인하였다. 구체적으로 18 시간 동안 선별된 균주를 배양한 후 원심분리 (4℃, 5 분, 3,750 x g)에 의해 수확된 세포를 PBS (pH 7.4)로 2 회 세척하였다. 세척된 균주 108 CFU / mL를 SGF(simulated gastric fluid) 및 SIF (simulated intestinal fluid)을 포함하는 모의 위장 용액에 재현탁시키고 37℃ 에서 3 시간 동안 배양하였다. SGF는 3g/L의 펩신을 함유하는 MRS 배양액(1N HCl을 이용하여 pH 3 및 4로 조정됨)를 사용하여 제조하였고, SIF는 판크레아틴 (1g/L)을 멸균된 PBS (1N NaOH를 이용하여 pH 7 및 8로 조정)와 혼합하여 제조하였다. 균주의 내성은 MRS 한천 플레이트에서 생존 세포를 계수하여 CFU / mL 로 나타내었으며, 그 결과를 표 3 에 나타내었다. In order to be utilized as probiotics, resistance to acid and bile leaves is important, so it was exposed to gastric juice environment (pH 3 and 4) and intestinal environment (pH 7 and 8), and the survival rate in these environments was confirmed. Specifically, after culturing the selected strain for 18 hours, the cells harvested by centrifugation (4° C., 5 minutes, 3,750 x g) were washed twice with PBS (pH 7.4). The washed
log CFU/mL strains
log CFU/mL
표 3 에 나타낸 바와 같이, 강 산성 및 강 염기성 환경인 위액, 담즙염 조건에서 모든 균주들이 생존하였으며, 세포 생존율은 위액 조건에서 5.5 ~ 8.6 log CFU/mL, 장 조건 하에서 7.8 ~ 8.6 log CFU/mL 범위임을 확인하였다. 이는 본 발명의 균주들이 프로바이오틱스의 중요한 요소인 낮은 pH 및 담즙염에 대해 높은 저항성을 가지고 있음을 보여주는 결과이다. As shown in Table 3, all strains survived in gastric juice and bile salt conditions, which are strongly acidic and strongly basic environments, and the cell viability was 5.5 to 8.6 log CFU/mL in gastric juice conditions and 7.8 to 8.6 log CFU/mL in intestinal conditions. range was confirmed. This is a result showing that the strains of the present invention have high resistance to low pH and bile salts, which are important factors of probiotics.
실시예Example 5. 선별 균주의 자가응집 및 부착 능력 확인 5. Confirmation of self-aggregation and adhesion ability of selected strains
균주의 자가 응집 능력이 좋다면 장의 연축운동에 의한 프로바이오틱스의 제거를 방지하고 장에서 효과적으로 소화관의 상피세포에 콜로니를 형성할 수 있어 프로바이오틱스로 유용하다. 선별된 유산균주의 자가응집능을 확인하기 위하여, 37 ℃에서 18 시간 동안 MRS 배지에서 성장시켰으며, 3,750 x g에서 5 분간 원심분리하여 세포를 수확하고 PBS (pH 7.0)로 3 회 세척 한 후 PBS에 OD600 1.0이 되도록 재현탁하였다. 세포 현탁액 (4 mL)을 10 초 동안 교반 및 혼합하고 실온에서 5시간 동안 배양하였다. 그 후 EPOCH 2 Microplate 판독기 (BioTek, USA)로 600 nm에서 현탁액 0.1 mL 분취량의 흡광도를 측정하였다. 자가 응집능 (%)을 다음 방정식을 사용하여 계산하였다. If the self-aggregation ability of the strain is good, it is useful as a probiotic because it can prevent the removal of probiotics due to intestinal spasm and effectively form colonies in the epithelial cells of the digestive tract in the intestine. In order to confirm the self-aggregation ability of the selected lactic acid strains, they were grown in MRS medium at 37 ° C. for 18 hours, centrifuged at 3,750 x g for 5 minutes to harvest the cells, washed 3 times with PBS (pH 7.0), and then in PBS. It was resuspended to OD600 1.0. The cell suspension (4 mL) was stirred and mixed for 10 seconds and incubated at room temperature for 5 hours. The absorbance of 0.1 mL aliquots of the suspension was then measured at 600 nm with an EPOCH 2 Microplate reader (BioTek, USA). The self-cohesive capacity (%) was calculated using the following equation.
자가 응집능 (%) = (1 - (A5/A0)) × 100Self-cohesive capacity (%) = (1 - (A 5 /A 0 )) × 100
A5는 배양 5 시간에서의 흡광도이고, A0은 시작 직후 시간 0에서의 흡광도이다. A 5 is the absorbance at 5 hours of incubation, and A 0 is the absorbance at
자가 응집능을 측정하여 평가한 결과를 표 4에 나타내었다. Table 4 shows the results of self-aggregation and evaluation.
표 4에 나타낸 바와 같이, 락토바실러스 아시도필러스 MG4558가 가장 강력한 가자 응집능 (94.3 %)을 나타내었으며, 이들은 즉시 응집되어 침전물과 투명 용액을 형성하였다. 다른 균주는 40 내지 62 %의 자가 응집능을 나타내었고, 현탁액은 침전물을 형성했지만 일부 탁한 상태를 유지하였다. As shown in Table 4, Lactobacillus acidophilus MG4558 showed the strongest aggregation ability (94.3%), and they immediately aggregated to form precipitates and clear solutions. The other strains showed a self-aggregation capacity of 40-62%, and the suspension formed a precipitate but remained partially turbid.
실시예Example 5. 효소활성 및 탄수화물 5. Enzyme Activity and Carbohydrates 이용능availability 확인 Confirm
프로바이오틱스로서의 안전성을 확인하기 위하여 효소 활성 확인을 수행하였다. 선별 균주의 효소 활성 및 탄수화물 이용능을 측정하기 위해 박테리아를 MRS 한천 플레이트에서 37℃, 18 시간 동안 배양하였다. 제조업체의 지침 (BioMerieux, France)에 따라 API ZYM 및 API 50 CHL 키트를 사용하였으며 분석을 위해 콜로니를 선택하였다. 효소 활성을 API ZYM 색상 반응 차트를 기반으로 10nM 간격으로 0 (활성 없음)에서 5 (제품 방출량 40nM 이상)의 척도로 평가하고 그 결과를 표 5에 나타내었다. Enzyme activity was confirmed to confirm safety as a probiotic. To measure the enzyme activity and carbohydrate availability of the selected strain, the bacteria were incubated on MRS agar plates at 37° C. for 18 hours. API ZYM and API 50 CHL kits were used according to the manufacturer's instructions (BioMerieux, France) and colonies were selected for analysis. Enzyme activity was evaluated on a scale of 0 (no activity) to 5 (product release amount of 40 nM or more) at 10 nM intervals based on the API ZYM color response chart, and the results are shown in Table 5.
7개의 균주는 전반적으로 모두 높은 류신 아릴아미다아제(leucine arylamidase) 활성을 나타냈지만, β-글루쿠로니다아제(β-glucuronidase), α-만노시다아제(α-mannosidase) 또는 트립신(trypsin) 활성은 나타내지 않았다. 균주 중 락토바실러스 람노서스(Lactobacillus rhamnosus) MG4502, MG4511 및 MG4505는 다른 균주보다 상대적으로 높은 알칼리성 포스파타제, 리파아제 (C14), α-키모트립신, α-갈락토시다아제 및 α-푸코시다아제 활성을 나타냈다. All seven strains showed overall high leucine arylamidase activity, but β-glucuronidase, α-mannosidase, or trypsin No activity was shown. Among the strains, Lactobacillus rhamnosus MG4502, MG4511 and MG4505 showed relatively higher alkaline phosphatase, lipase (C14), α-chymotrypsin, α-galactosidase and α-fucosidase activities than other strains. .
각 균주의 탄수화물 대사 평가를 위하여 이용률을 API 50 CHL 시스템을 사용하여 평가했으며 결과를 표 6에 나타내었다. For carbohydrate metabolism evaluation of each strain, the utilization rate was evaluated using the API 50 CHL system, and the results are shown in Table 6.
모든 균주는 D-갈락토오스, D-글루코스, D-과당, D-만노스, N-아세틸-글루코사민, 아미그달린, 알부틴(arbutin), 에스쿨린(esculin), 살리신(salicin), D-셀로비오스(D-cellobiose), D-트레할로스, D-멜레지토스(D-melezitose) 및 겐티오비오스(gentiobiose) 를 발효하였다. 그러나 모든 균주는 글리세롤, 에리트리톨(erythritol), L-자일로스(L-xylose), D-아도니톨(D-adonitol), 메틸-β D-자일로피라노시드(methyl-βD-xylopyranoside), 메틸-α D-글루코시드(methyl-α D-glucoside), 이눌린, D-라피노스, 전분, 글리코겐, 자일리톨, D-자일로스, D-푸코스, D-아라비톨, 2-케토-글루코네이트 및 5- 케토-글루코네이트를 발효하지 못했다. All strains were D-galactose, D-glucose, D-fructose, D-mannose, N-acetyl-glucosamine, amygdalin, arbutin, esculin, salicin, D-cellobiose (D- cellobiose), D-trehalose, D-melezitose and gentiobiose were fermented. However, all strains are glycerol, erythritol, L-xylose, D-adonitol, methyl-β D-xylopyranoside (methyl-βD-xylopyranoside) , methyl-α D-glucoside, inulin, D-raffinose, starch, glycogen, xylitol, D-xylose, D-fucose, D-arabitol, 2-keto-gluconate and 5-keto-gluconate failed to ferment.
실시예Example 6. 균주의 항생제 내성 확인 6. Confirmation of antibiotic resistance of the strain
선별된 균주의 항생제 내성은 9 가지 항생제의 최소 억제 농도 (MIC)와 EFSA 가이드 라인에 의해 제안된 역학적 컷오프 값을 결정하여 평가하였다. 균주를 MRS 배지에서 37 ℃에서 18 시간 동안 성장시킨 후 3,750 x g에서 5 분 동안 원심분리하여 수확하고 PBS (pH 7.0)로 3 회 세척한 다음 PBS에 0.5 McFarland 표준으로 재현탁시켰다. 세포 현탁액을 면봉으로 Brain Heart Infusion 한천 (BHI; Difco, USA)에 접종하고 플레이트를 10-15 분 동안 건조시켰다. 그런 다음 제조업체의 권장 사항에 따라 한천 표면에 MIC 테스트 스트립 (Liofilchem, 이탈리아)을 배치하였다. 플레이트를 37℃ 에서 20시간 동안 배양한 후 각 균주의 항생제 내성을 확인한 결과를 표 7에 나타내었다. Antibiotic resistance of the selected strains was evaluated by determining the minimum inhibitory concentration (MIC) of nine antibiotics and the epidemiologic cutoff value suggested by the EFSA guidelines. The strains were grown in MRS medium at 37 °C for 18 h, then harvested by centrifugation at 3,750 x g for 5 min, washed 3 times with PBS (pH 7.0), and then resuspended in PBS with 0.5 McFarland standard. The cell suspension was inoculated on Brain Heart Infusion agar (BHI; Difco, USA) with a cotton swab and the plate was dried for 10-15 min. MIC test strips (Liofilchem, Italy) were then placed on the agar surface according to the manufacturer's recommendations. Table 7 shows the results of confirming the antibiotic resistance of each strain after incubating the plate at 37° C. for 20 hours.
표 7 에 나타낸 바와 같이, 대부분의 균주는 암피실린, 겐타마이신, 스트렙토마이신, 에리스로마이신, 및 클린다마이신(clindamycin)에 대하여 대부분 감수성이 있었고, 락토바실러스 아시도필러스 MG4558 만 겐타마이신, 카나마이신 및 클로람페니콜에 내성이 있었다. 항생제에 대한 내성은 항생제 치료 중에도 위장관에서 프로바이오틱 균주를 생존할 수 있도록 하므로, 항생제 치료 중에도 활용할 수 있다. As shown in Table 7, most strains were most susceptible to ampicillin, gentamicin, streptomycin, erythromycin, and clindamycin, and only Lactobacillus acidophilus MG4558 was resistant to gentamicin, kanamycin and chloramphenicol. there was Resistance to antibiotics allows probiotic strains to survive in the gastrointestinal tract even during antibiotic treatment, so it can be utilized during antibiotic treatment.
실시예Example 7. 선별 균주의 용혈성 평가 7. Hemolytic evaluation of selected strains
병원성 박테리아의 주요 독성 인자인 용혈을 평가하기 위한 실험을 수행하였다. 먼저 균주를 5 % 양 혈액을 포함하는 Tryptic Soy Agar (TSA) 배지에 스트리킹하고 37℃에서 48 시간 동안 배양하였다. 배양 후, 플레이트에서 콜로니 주변 투명 영역 (β-용혈), 녹색 영역 (α-용혈) 또는 no 영역 (γ-용혈, 비용혈)의 형성을 관찰하였다. 그 결과 모든 테스트된 선별 균주는 혈액 한천 플레이트 배양 48 시간에서 γ-용혈, 즉, 비용혈성을 나타내어 모두 안전한 균주임을 확인하였다. An experiment was performed to evaluate hemolysis, a major virulence factor of pathogenic bacteria. First, the strain was streaked in Tryptic Soy Agar (TSA) medium containing 5% sheep blood and incubated at 37° C. for 48 hours. After incubation, the formation of clear regions (β-hemolysis), green regions (α-hemolysis) or no regions (γ-hemolysis, non-hemolysis) around colonies was observed on the plate. As a result, all tested selection strains showed γ-hemolysis, ie, non-hemolytic properties, at 48 hours of incubation on blood agar plates, confirming that they were all safe strains.
Claims (11)
Lactobacillus rhamnosus MG4502 strain (Accession No.: KCTC 14095BP).
The Lactobacillus rhamnosus MG4502 strain according to claim 1, wherein the strain is isolated from the feces of infants or infants.
The Lactobacillus rhamnosus MG4502 strain according to claim 1, wherein the strain has lipid accumulation inhibitory ability, α-glucosidase inhibitory activity and antioxidant activity.
The Lactobacillus rhamnosus MG4502 strain according to claim 1, wherein the strain has acid resistance, bile resistance and self-aggregation ability.
According to claim 1, wherein the strain is ampicillin, gentamicin, kanamycin, streptomycin, tetracycline, erythromycin, chloramphenicol, and Lactobacillus rhamnosus MG4502 to have a sensitivity to one or more antibiotics selected from the group consisting of strain.
The food composition for preventing or improving obesity or obesity-related diseases, comprising the strain of any one of claims 1 to 5, a culture medium thereof, or a cell-free extract thereof.
The health functional food composition for preventing or improving obesity or obesity-related diseases, comprising the strain of any one of claims 1 to 5, its culture medium, or a cell-free extract thereof.
상기 비만 관련 질환은 제2형 당뇨 또는 고지혈증인, 비만 또는 비만 관련 질환의 예방 또는 치료용 약학적 조성물.
Claims 1 to 5 as a pharmaceutical composition for the prevention or treatment of obesity or obesity-related diseases, comprising the strain of any one of claims 1 to 5, its culture medium or a cell-free extract thereof,
The obesity-related disease is type 2 diabetes or hyperlipidemia, obesity or a pharmaceutical composition for the prevention or treatment of obesity-related diseases.
The quasi-drug composition for preventing or improving obesity or obesity-related diseases, comprising the strain of any one of claims 1 to 5, its culture medium or a cell-free extract thereof.
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