KR20220144468A - A novel strain of Saccharomyces boulardii 28-7 and uses thereof - Google Patents
A novel strain of Saccharomyces boulardii 28-7 and uses thereof Download PDFInfo
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- KR20220144468A KR20220144468A KR1020210050798A KR20210050798A KR20220144468A KR 20220144468 A KR20220144468 A KR 20220144468A KR 1020210050798 A KR1020210050798 A KR 1020210050798A KR 20210050798 A KR20210050798 A KR 20210050798A KR 20220144468 A KR20220144468 A KR 20220144468A
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Abstract
Description
본 발명은 장내 염증성 사이토카인의 발현수준을 감소시키고 장관벽누수가 발생되지 않고, 내산성, 내담즙 및 장부착성이 우수한 신규 사카로마이세스 보울라디 28-7 균주 및 이의 용도에 관한 것이다.The present invention relates to a novel Saccharomyces bouladi 28-7 strain that reduces the expression level of intestinal inflammatory cytokines, does not cause intestinal wall leakage, and has excellent acid resistance, bile resistance and intestinal adhesion, and uses thereof.
현대인의 육류 위주의 식생활, 인스턴트 및 가공식품위주의 식습관, 자극성 있는 식품의 지나친 섭취, 바쁜 생활환경으로 성급해진 음식물 섭취 패턴의 변화 등 바람직하지 못한 식생활과 건전하지 못한 생활습관 그리고 나이가 들어감에 따라서 유익한 균들보다 유해한 균들이 우세하게 되어 장내 세균의 균형이 깨어져 장의 건강에 많은 악영향을 미치게 되어 소화불량, 변비, 대장암을 유발시킬 수 있다. Modern people's meat-centered diet, instant and processed food-oriented eating habits, excessive consumption of stimulant foods, changes in food intake patterns hastily due to busy living environment, etc. Harmful bacteria prevail over beneficial bacteria, and the balance of intestinal bacteria is disrupted, which can adversely affect intestinal health, causing indigestion, constipation, and colorectal cancer.
사람의 위장관은 복잡하고 강력한 미생물 환경을 갖고 있다. 이러한 미생물 환경은 나이, 건강 및 생활양식에 따라 변화하며, 병원체와 유해음식물질의 작용을 저해하고 숙주에게 유익한 효과를 촉진하는 중요한 역할을 한다. 이러한 효과는 위장관 내 미생물의 경향과 관련이 있으며, 위장관의 이러한 미생물의 균형은 위장병의 위험을 낮출 수 있다. 프로바이오틱스의 이점으로는 락토오스 불내성, 영양분의 생체이용률 및 알레르기 예방과 개선이 포함되며, 항-돌연변이, 항암, 항-고콜레스테롤, 항-고혈압, 항-골다공증 및 면역기능조절 효과가 보고된 바 있다. The human gastrointestinal tract has a complex and powerful microbial environment. The microbial environment changes according to age, health and lifestyle, and plays an important role in inhibiting the action of pathogens and harmful food substances and promoting beneficial effects on the host. These effects are related to the propensity of microbes in the gastrointestinal tract, and the balance of these microbes in the gastrointestinal tract may lower the risk of gastrointestinal diseases. Advantages of probiotics include prevention and improvement of lactose intolerance, nutrient bioavailability, and allergy.
또한, 프로바이오틱스는 염증성 장 질환, 과민성 장증후군, 간경변, 변비를 없애고 결장암, 간암 및 유방암의 위험을 줄일 수 있는 것으로도 보고된 바 있다.It has also been reported that probiotics can eliminate inflammatory bowel disease, irritable bowel syndrome, cirrhosis, constipation, and reduce the risk of colon cancer, liver cancer and breast cancer.
현재, 건강 증진 프로바이오틱 식품의 장점은 전세계적으로 널리 받아들여지고 있다. FAO/WHO에 따르면, 건강증진용 프로바이오틱스는 충분한 양(적어도 106~107 cfu/g)으로 섭취하면 숙주의 건강에 긍정적인 영향을 미치는 생존 가능한 활성 미생물이다. 최근 연구에서 죽은 미생물의 면역학적 특성이 보고된 바 있다. 대부분의 프로바이오틱 미생물은 유산균을 생산하는 박테리아이며 그중 락토바실러스(Lactobacillus)는 인간의 건강을 향상시키는 가장 기본적인 속균 중 하나이다. 따라서 여러 락토바실러스 종들의 게놈 서열이 규명되었으며 광범위한 발효식품에 사용되어 왔다. 또한 이러한 프로바이오틱 미생물과 관련된 대사경로, 유전자의 조절 및 기능이 보고되었으며, 대부분의 연구자들은 프로바이오틱스를 전달하기 위한 가장 좋은 방법이 특히 발효유와 요구르트를 통한 발효유제품이라고 생각해왔다.Currently, the benefits of health-promoting probiotic foods are widely accepted worldwide. According to FAO/WHO, health-promoting probiotics are viable, active microorganisms that, when consumed in sufficient amounts (at least 10 6 to 10 7 cfu/g), have a positive effect on the health of the host. Recent studies have reported the immunological properties of dead microorganisms. Most probiotic microorganisms are bacteria that produce lactic acid bacteria, among which Lactobacillus is one of the most basic genus bacteria that improve human health. Therefore, the genome sequence of several Lactobacillus species has been identified and has been used in a wide range of fermented foods. In addition, metabolic pathways, gene regulation and function related to these probiotic microorganisms have been reported, and most researchers have thought that the best way to deliver probiotics is fermented milk products, especially fermented milk and yogurt.
오늘날 연구자들은 새로운 바이오틱스를 생산하는 것에 더 많은 관심을 가지고 있으며, 비유제품 프로바이오틱스는 사람을 위한 프로바이오틱 기능성 식품의 개발을 위한 좋은 기반이 될 수 있을 것으로 생각한다. 잘 특성화된 프로바이오틱 미생물 중 몇몇은 전세계에서 상업적으로 이용가능하며, 신규한 미생물의 스크리닝은 여전히 프로바이오틱스 산업으로부터 큰 관심을 받고 있다.Today, researchers are more interested in producing novel probiotics, and non-dairy probiotics believe that it could be a good basis for the development of probiotic functional foods for humans. Some of the well-characterized probiotic microorganisms are commercially available worldwide, and the screening of novel microorganisms is still of great interest from the probiotic industry.
본 발명의 목적은 장내 염증성 사이토카인의 발현수준을 감소시키고 장관벽누수가 발생되지 않고, 갈락토오스(galactose) 발효능이 없으며, 내산성, 내담즙 및 장부착성이 우수한 신규 사카로마이세스 보울라디 28-7 균주를 제공하는데 있다.An object of the present invention is to reduce the expression level of intestinal inflammatory cytokines, do not cause intestinal wall leakage, do not have galactose fermentation ability, and have excellent acid resistance, bile resistance and intestinal adhesion. -7 strains are provided.
또한, 본 발명의 다른 목적은 상기 사카로마이세스 보울라디 28-7 균주를 유효성분으로 함유하는 장내 환경 개선용 건강기능식품을 제공하는데 있다.In addition, another object of the present invention is to provide a health functional food for improving the intestinal environment containing the Saccharomyces bouladi 28-7 strain as an active ingredient.
또한, 본 발명의 또 다른 목적은 상기 사카로마이세스 보울라디 28-7 균주를 유효성분으로 함유하는 프로바이오틱스 제제를 제공하는데 있다.In addition, another object of the present invention is to provide a probiotic preparation containing the Saccharomyces bouladi 28-7 strain as an active ingredient.
또한, 본 발명의 또 다른 목적은 상기 사카로마이세스 보울라디 28-7 균주를 유효성분으로 함유하는 장내 환경 개선용 사료 조성물을 제공하는데 있다.In addition, another object of the present invention is to provide a feed composition for improving the intestinal environment containing the Saccharomyces bouladi 28-7 strain as an active ingredient.
또한, 본 발명의 또 다른 목적은 상기 사카로마이세스 보울라디 28-7 균주를 유효성분으로 함유하는 염증성 장질환의 예방 또는 치료용 약학 조성물을 제공하는데 있다.In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory bowel disease containing the Saccharomyces bouladi 28-7 strain as an active ingredient.
상기한 목적을 달성하기 위한 본 발명의 신규한 균주는 기탁번호 KFCC11825P로 수탁된 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주이다. The novel strain of the present invention for achieving the above object is a Saccharomyces boulardii 28-7 strain deposited under the accession number KFCC11825P.
상기 균주는 누룩으로 분리된 것일 수 있다.The strain may be isolated from yeast.
또한, 상기한 다른 목적을 달성하기 위한 본 발명의 장내 환경 개선용 건강기능식품은 기탁번호 KFCC11825P로 수탁되고 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주를 유효성분으로 함유할 수 있다.In addition, the health functional food for improving the intestinal environment of the present invention for achieving the above-described other object is deposited with the deposit number KFCC11825P and may contain Saccharomyces boulardii 28-7 strain as an active ingredient.
상기 장내 환경 개선용 건강기능식품은 염증성 장질환의 예방 또는 개선용 건강기능식품; 또는 균주의 장부착 향상용 건강기능식품일 수 있다.The health functional food for improving the intestinal environment is a health functional food for the prevention or improvement of inflammatory bowel disease; Or it may be a health functional food for improving intestinal adhesion of the strain.
또한, 상기한 다른 목적을 달성하기 위한 본 발명의 프로바이오틱스 제제는 기탁번호 KFCC11825P로 수탁되고 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주를 유효성분으로 함유할 수 있다.In addition, the probiotic preparation of the present invention for achieving the above other object is deposited under the accession number KFCC11825P and may contain Saccharomyces boulardii 28-7 strain as an active ingredient.
또한, 상기한 다른 목적을 달성하기 위한 본 발명의 장내 환경 개선용 사료 조성물은 기탁번호 KFCC11825P로 수탁되고 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주를 유효성분으로 함유할 수 있다.In addition, the feed composition for improving the intestinal environment of the present invention for achieving the above-mentioned other object is deposited with the deposit number KFCC11825P and may contain Saccharomyces boulardii 28-7 strain as an active ingredient.
상기 장내 환경 개선용 사료 조성물은 염증성 장질환의 예방 또는 개선용 사료 조성물; 또는 균주의 장부착 향상용 사료 조성물일 수 있다.The feed composition for improving the intestinal environment is a feed composition for preventing or improving inflammatory bowel disease; Or it may be a feed composition for improving intestinal adhesion of the strain.
또한, 상기한 다른 목적을 달성하기 위한 본 발명의 염증성 장질환의 예방 또는 치료용 약학 조성물은 기탁번호 KFCC11825P로 수탁되고 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주를 유효성분으로 함유할 수 있다.In addition, the pharmaceutical composition for the prevention or treatment of inflammatory bowel disease of the present invention for achieving the above other object is deposited with accession number KFCC11825P and contains Saccharomyces boulardii 28-7 strain as an active ingredient. can
상기 염증성 장질환은 궤양성 대장염 또는 크론병일 수 있다.The inflammatory bowel disease may be ulcerative colitis or Crohn's disease.
본 발명의 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주는 장내 염증성 사이토카인의 발현수준을 감소시키고 장관벽누수를 발생시키지 않고, 내산성, 내담즙 및 장부착성이 우수한 신규 균주로서, 프로바이오틱스 제제, 건강기능식품, 사료 조성물 등에 이용될 수 있다. Saccharomyces boulardii 28-7 strain of the present invention is a novel strain that reduces the expression level of intestinal inflammatory cytokines, does not cause intestinal wall leakage, and has excellent acid resistance, bile resistance and intestinal adhesion, It can be used in probiotic formulations, health functional foods, feed compositions, and the like.
도 1은 본 발명의 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주의 ITS 유전자 서열을 분석하여 나타낸 분자계통도이다.
도 2는 본 발명의 실시예 1에 따라 분리된 신규한 28-7 균주, 대조군 1의 s288c 균주 및 대조군 2의 비오플을 이용하여 담즙산에서의 생존율을 측정한 그래프이다.
도 3은 본 발명의 실시예 1에 따라 분리된 신규한 28-7 균주, 대조군 1의 s288c 균주 및 대조군 2의 비오플을 이용하여 산성에서의 생존율을 측정한 그래프이다.
도 4는 발명의 실시예 1에 따라 분리된 신규한 28-7 균주 및 대조군 2의 비오플을 이용하여 장부착능을 측정한 그래프이다.
도 5는 본 발명의 일 실시예에 따라 실험동물을 사육하는 과정을 대략적으로 나타낸 도면이다.
도 6a는 DSS군, 실시예 1군, 비오플군 및 s288c군의 DAI 값을 나타낸 그래프이며, 도 6b는 정상군, DSS군, 실시예 1군, 비오플군 및 s288c군의 AUC를 측정한 그래프이다.
도 7a는 정상군, DSS군, 실시예 1군, 비오플군 및 s288c군의 대장길이를 나타낸 그래프이며; 도 7b는 정상군, DSS군, 실시예 1군, 비오플군 및 s288c군의 대장의 무게/길이를 나타낸 그래프이다.
도 8a는 정상군, DSS군, 실시예 1군 및 비오플군의 IL-1β의 mRNA 수준을 나타낸 그래프이며; 도 8b는 정상군, DSS군, 실시예 1군 및 비오플군의 ZO1의 mRNA 수준을 나타낸 그래프이다.
도 9는 정상군, DSS군, 실시예 1군 및 비오플군의 혈액 내의 염증성 사이토카인 수준을 측정한 것이다.
도 10a는 정상군, DSS군, 실시예 1군 및 비오플군의 맹장 내 살아있는 균주의 수를 사카로마이세스 프라이머를 이용하여 측정한 그래프이며; 도 10b는 정상군, DSS군, 실시예 1군 및 비오플군의 맹장 내 살아있는 균주의 수를 사카로마이세스 세레비지에 프라이머를 이용하여 측정한 그래프이다.1 is a molecular system diagram showing the ITS gene sequence analysis of the Saccharomyces boulardii 28-7 strain of the present invention.
2 is a graph measuring the survival rate in bile acids using the novel 28-7 strain isolated according to Example 1 of the present invention, the s288c strain of the
3 is a graph measuring the survival rate in acidity using the novel 28-7 strain isolated according to Example 1 of the present invention, the s288c strain of the
Figure 4 is a graph measuring the intestinal adhesion capacity using the novel 28-7 strain isolated according to Example 1 of the present invention and Biople of
5 is a diagram schematically illustrating a process of breeding experimental animals according to an embodiment of the present invention.
Figure 6a is a graph showing the DAI value of the DSS group, Example 1 group, non-opul group and s288c group, Figure 6b is a normal group, DSS group, Example 1 group, non-opul group and s288c group AUC measurements It is a graph.
Figure 7a is a graph showing the colon length of the normal group, DSS group, Example 1 group, non-opul group and s288c group; Figure 7b is a graph showing the weight / length of the colon in the normal group, DSS group, Example 1 group, non-opul group and s288c group.
Figure 8a is a graph showing the mRNA level of IL-1β in the normal group, DSS group, Example 1 group, and non-opul group; Figure 8b is a graph showing the mRNA level of ZO1 in the normal group, DSS group, Example 1 group, and non-opul group.
9 is a measurement of the level of inflammatory cytokines in the blood of the normal group, the DSS group, the Example 1 group, and the non-opul group.
Figure 10a is a graph in which the number of viable strains in the cecum of the normal group, DSS group, Example 1 group and Biople group was measured using Saccharomyces primers; Figure 10b is a graph in which the number of living strains in the cecum of the normal group, DSS group, Example 1 group and Biople group was measured using a Saccharomyces cerevisiae primer.
본 발명은 장내 염증성 사이토카인의 발현수준을 감소시키고 장관벽누수가 발생되지 않고, 갈락토오스(galactose) 발효능이 없으며, 내산성, 내담즙 및 장부착성이 우수한 신규 사카로마이세스 보울라디 28-7 균주 및 이의 용도에 관한 것이다.The present invention reduces the expression level of intestinal inflammatory cytokines, does not cause intestinal wall leakage, does not have galactose fermentation ability, and has excellent acid resistance, bile resistance and intestinal adhesion properties Novel Saccharomyces bouladi 28-7 strains and their uses.
이하, 본 발명을 상세하게 설명한다. Hereinafter, the present invention will be described in detail.
본 발명의 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주는 누룩으로부터 분리된 것이 바람직하나, 이에 한정하지는 않는다.Saccharomyces boulardii of the present invention ( Saccharomyces boulardii ) 28-7 strain is preferably isolated from yeast, but is not limited thereto.
하기 실시예를 통해 누룩으로부터 유래되어 프로바이오틱스 활성을 갖는 신규한 균주인 28-7 균주를 미생물 동정 및 분류를 위한 ITS sequencing을 수행한 결과, 서열번호 1의 핵산서열을 갖는 것으로 나타났다. 상기 균주의 핵산서열을 분석한 결과, 사카로마이세스 보울라디(Saccharomyces boulardii)에 속하는 균주인 것으로 조사되었고, 상기 핵산서열에 대한 상동성(homology)을 확인해본 결과, 사카로마이세스 보울라디(Saccharomyces boulardii) 표준균주와 98% 동일함을 확인할 수 있었다(도 1).As a result of performing ITS sequencing for microbial identification and classification of 28-7 strains, which are novel strains derived from yeast and having probiotic activity through the following examples, it was found to have the nucleic acid sequence of SEQ ID NO: 1. As a result of analyzing the nucleic acid sequence of the strain, it was investigated to be a strain belonging to Saccharomyces boulardii , and as a result of confirming homology to the nucleic acid sequence, Saccharomyces boulardii ( Saccharomyces boulardii ) was confirmed to be 98% identical to the standard strain (FIG. 1).
따라서, 서열번호 1의 ITS 염기서열을 갖는 본 발명의 미생물을 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주로 명명하였으며, 한국미생물보존센터에 2019년 4월 1일자로 기탁하였다(기탁번호: KFCC11825P).Therefore, the microorganism of the present invention having the ITS sequence of SEQ ID NO: 1 was named Saccharomyces boulardii 28-7 strain, and was deposited at the Korea Microorganism Conservation Center on April 1, 2019 (deposited) No.: KFCC11825P).
또한, 본 발명은 상기 사카로마이세스 보울라디 28-7 균주를 유효성분으로 함유하는 장내 환경 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for improving the intestinal environment containing the Saccharomyces bouladi 28-7 strain as an active ingredient.
본 발명의 건강기능식품은 영양보조제, 건강식품 및 식품 첨가제 등의 모든 형태를 포함하고, 당업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다. 예를 들면, 차, 쥬스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화하여 섭취할 수 있다. 또한, 본 발명의 28-7 균주의 바람직한 함유량으로는 식품의 전체 중량에 대해 약 1 내지 100 중량%를 포함할 수 있다.The health functional food of the present invention includes all forms such as nutritional supplements, health food and food additives, and can be prepared in various forms according to conventional methods known in the art. For example, it can be prepared in the form of tea, juice, and drink for drinking, or it can be ingested by granulation, encapsulation, and powder. In addition, the preferred content of the 28-7 strain of the present invention may include about 1 to 100% by weight based on the total weight of the food.
또한, 본 발명은 상기 사카로마이세스 보울라디 28-7 균주를 유효성분으로 함유하는 프로바이오틱스 제제를 제공한다.In addition, the present invention provides a probiotic preparation containing the Saccharomyces bouladi 28-7 strain as an active ingredient.
상기 프로바이오틱스 제제는 당업계에 공지된 방법에 따라 다양한 제형과 방법으로 제조 및 투여될 수 있다. 예를 들어, 본 발명의 28-7 균주는 약제학적 분야에서 통상적으로 사용되는 담체와 혼합하여 산제(powder), 액제(liquids and solutions), 정제(tablet), 캡슐(capsule), 시럽(syrup), 현탁제(suspension) 또는 과립제(granule) 등의 형태로 제조되어 투여될 수 있다. 상기 담체로는 예를 들어, 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소 및 향료 등일 수 있으나, 이에 제한되지 않는다. 또한, 투여 용량은 체내에서의 활성 성분의 흡수도, 불활성률, 배설속도, 피투여자의 연령, 성별, 축종, 상태 및 질병의 중증 정도 등에 따라 적절히 선택할 수 있다.The probiotic formulation may be prepared and administered in various formulations and methods according to methods known in the art. For example, the 28-7 strain of the present invention is mixed with a carrier commonly used in the pharmaceutical field to form powders, liquids and solutions, tablets, capsules, and syrups. , may be prepared and administered in the form of a suspension or granule. The carrier may be, for example, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a fragrance, and the like, but is not limited thereto. In addition, the administration dose can be appropriately selected according to the absorption of the active ingredient in the body, the inactivation rate, the excretion rate, the age, sex, breed, condition and severity of the disease of the recipient.
또한, 본 발명은 상기 사카로마이세스 보울라디 28-7 균주를 유효성분으로 함유하는 동물 사료 조성물을 제공한다. In addition, the present invention provides an animal feed composition containing the Saccharomyces bouladi 28-7 strain as an active ingredient.
본 발명의 동물 사료 조성물은 기초사료에 일정 비율로 첨가할 수 있다. 상기 기초사료는 주성분이 옥수수, 대두박, 유청, 어분, 당밀, 소금, 비타민 프리믹스 및 미네랄 프리믹스 등으로 이루어질 수 있으나, 이에 제한되지 않는다. 비타민 프리믹스는 비타민 A, 비타민 D, 비타민 E, 리보프라빈 및 나이아신으로 구성될 수 있으며, 미네랄 프리믹스는 망간, 철아연, 칼슘, 구리, 코발트 및 셀레니늄 등으로 구성될 수 있으나, 이에 제한되는 것은 아니다.The animal feed composition of the present invention may be added to the basic feed in a certain ratio. The basic feed may consist of a main component of corn, soybean meal, whey, fish meal, molasses, salt, vitamin premix and mineral premix, and the like, but is not limited thereto. The vitamin premix may be composed of vitamin A, vitamin D, vitamin E, ribopravine and niacin, and the mineral premix may be composed of manganese, zinc iron, calcium, copper, cobalt and selenium, but is not limited thereto. not.
사료 조성물 중의 상기 사카로마이세스 보울라디 28-7 균주의 함량은 급여 동물의 종, 주령, 체중, 및 사육 조건 등에 따라 적절히 선택될 수 있다. 본 발명의 동물 사료 조성물에 있어서, 상기 동물은 쥐, 생쥐 또는 가축 등의 포유동물 등 일 수 있으나, 이에 제한되지 않는다. 본 발명의 사료 조성물은 기술분야에 공지된 사료 제조방법에 따라 제조될 수 있으며, 예를 들어, 각종 사료 원료 또는 배합사료와 본 발명의 상기 균주를 혼합한 후, 추가적인 가공 공정, 예를 들어 펠렛 형태로의 성형 또는 과립 등의 형태로의 절단 단계 등을 더 수행함으로써 제조될 수 있다. 본 발명의 사료 조성물의 구성성분, 조성, 제조방법, 급여방법 등은 기술분야에 공지된 통상의 기술로부터 적절히 선택될 수 있음이 통상의 기술자에게 명백하다.The content of the Saccharomyces bouladi 28-7 strain in the feed composition may be appropriately selected according to the species, week age, weight, and breeding conditions of the feed animal. In the animal feed composition of the present invention, the animal may be a mammal such as a rat, a mouse, or a livestock, but is not limited thereto. The feed composition of the present invention may be prepared according to a feed manufacturing method known in the art, for example, after mixing the strain of the present invention with various feed raw materials or compound feed, an additional processing process, for example, pellets It can be prepared by further performing a step of forming into a form or cutting into a form such as granules. It is clear to those skilled in the art that the components, composition, manufacturing method, feeding method, etc. of the feed composition of the present invention can be appropriately selected from conventional techniques known in the art.
또한, 본 발명은 포유동물에게 유효량의 28-7 균주를 투여하는 것을 포함하는 염증성 장질환의 개선, 예방 또는 치료 방법을 제공한다.In addition, the present invention provides a method for improving, preventing or treating inflammatory bowel disease, comprising administering an effective amount of strain 28-7 to a mammal.
여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다.As used herein, the term "mammal" refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
여기에서 사용된 용어 "유효량"은 연구자, 수의사, 의사 또는 기타 임상의에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약학적 조성물의 양을 의미하는 것으로, 이는 해당 질환 또는 장애의 증상의 완화를 유도하는 양을 포함한다. 본 발명의 유효 성분에 대한 유효량 및 투여횟수는 원하는 효과에 따라 변화될 수 있다. 그러므로, 투여될 최적의 투여량은 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, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 본 발명의 예방, 치료 또는 개선 방법에 있어서, 성인의 경우, 열처리 가공염을 1일 1회 내지 수회 투여시, 0.001 g/kg 내지 10 g/kg의 용량으로 투여하는 것이 바람직하다.As used herein, the term "effective amount" refers to the amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human as conceived by a researcher, veterinarian, physician or other clinician, which an amount that induces amelioration of the symptoms of a disease or disorder. The effective amount and frequency of administration for the active ingredient of the present invention may 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 It can be adjusted according to various factors including condition, sex and diet, administration time, administration route and secretion rate of the composition, treatment period, and concurrently used drugs. In the prevention, treatment or improvement method of the present invention, for adults, it is preferable to administer the heat-treated processed salt at a dose of 0.001 g/kg to 10 g/kg when administered once to several times a day.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시하나, 하기 실시예는 본 발명을 예시하는 것일 뿐 본 발명의 범주 및 기술사상 범위 내에서 다양한 변경 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속하는 것도 당연한 것이다.Hereinafter, preferred examples are presented to help the understanding of the present invention, but the following examples are merely illustrative of the present invention, and it will be apparent to those skilled in the art that various changes and modifications are possible within the scope and spirit of the present invention, It goes without saying that such variations and modifications fall within the scope of the appended claims.
실시예 1. 사카로마이세스 보울라디 28-7 균주의 분리 및 동정Example 1. Isolation and identification of Saccharomyces bouladi 28-7 strain
1-1. 균주의 분리방법1-1. Isolation method of strain
고문헌에 수록된 60여종의 전통누룩으로부터 프로바이오틱 (probiotic) 활성을 보이는 효모를 분리 및 선발하기 위해 다음과 같은 실험을 수행하였다. 전통누룩 60종으로부터 약 200여개의 사카로마이세스 속 효모 콜로니를 분리하였고, 이들로부터 보울라디 효모의 특성인 37 ℃의 고온 생육능과 갈락토오즈 비분해능을 가진 12종의 신규 사카로마이세스 세레비지애(또는 보울라디) 효모 균주를 선발하였다. 이후 37 ℃ 및 pH 2.0의 고온/저산성 환경에서의 생육테스트를 통해 프로바이오틱스 기능을 가질 것으로 예상되는 사카로마이세스 보울라디 28-7 균주를 최종 선발하였다. The following experiment was performed to isolate and select yeasts showing probiotic activity from about 60 types of traditional yeast listed in the old literature. About 200 yeast colonies of the genus Saccharomyces were isolated from 60 kinds of traditional yeast, and 12 new Saccharomyces with high temperature growth capability of 37 ℃ and non-galactose non-degrading ability, which are characteristics of Bouladi yeast, from them. cerevisiae (or bouladi) yeast strains were selected. After that, the Saccharomyces bouladi 28-7 strain, which is expected to have a probiotic function, was finally selected through a growth test in a high temperature/low acid environment at 37° C. and pH 2.0.
1-2. 균주의 동정방법 1-2. Identification method of strain
28-7 균주의 염색체 DNA를 이용하여 ITS 염기서열 분석을 수행하였고, 상기 염기서열 분석 결과 본 발명의 28-7 균주는 사카로마이세스 보울라디(Saccharomyces boulardii)에 속하는 균주인 것으로 조사되었으며, 서열번호 1의 염기서열을 갖는 것으로 나타났다(도 1 참조). 또한, 상기 염기서열을 BLAST Search를 통하여 분석한 결과 기존에 데이터베이스(Data Base)에 올려져 있는 사카로마이세스 보울라디(Saccharomyces boulardii) 균주들과 약 98%의 상동성을 나타내었으며, 서열번호 1과 100% 상동성을 갖는 균주는 기존에 존재하지 않는 것을 확인하였다.ITS sequencing was performed using the chromosomal DNA of the 28-7 strain, and as a result of the nucleotide sequence analysis, the 28-7 strain of the present invention was investigated as a strain belonging to Saccharomyces boulardii , and the sequence It was found to have the nucleotide sequence of No. 1 (see FIG. 1). In addition, as a result of analyzing the base sequence through BLAST Search, it showed about 98% homology with Saccharomyces boulardii strains previously uploaded to the database (Data Base), and SEQ ID NO: 1 It was confirmed that the strain with 100% homology to and does not exist in the past.
따라서 본 발명자들은 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주를 2019년 4월 1일자로 한국미생물보존센터에 기탁하여 수탁번호 KFCC11825P를 부여받았다.Therefore, the present inventors deposited the Saccharomyces boulardii 28-7 strain with the Korea Microorganism Conservation Center on April 1, 2019 and were given an accession number KFCC11825P.
<시험예><Test Example>
프로바이오틱스(probiotics)란 '충분한 양을 투여할 때 숙주의 건강에 유익한, 살아있는 미생물'을 의미한다. 지금까지 보고된 대부분의 프로바이오틱스는 유산균으로 알려져 있으며, 최근 과민성 대장 증후군이나 항생제 연관 설사, 염증성 장질환, 변비 등과 같은 대장 질환의 영역에서 최근 점차 프로바이오틱스의 사용을 시도해보는 추세이다. 프로바이오틱스로 유산균을 사용하였을 때 야기될 수 있는 가장 큰 단점은 항생제에 대한 내성이 부족하다는 점을 들 수 있다. 따라서 항생제에 저해받지 않으면서 장내에서 프로바이오틱스 기능을 보이는 효모균이 최근 정장제로 활용되고 있다. Probiotics refer to 'living microorganisms that are beneficial to the health of the host when administered in sufficient amounts'. Most of the probiotics reported so far are known as lactic acid bacteria, and recently, there is a trend to gradually try the use of probiotics in the area of colon diseases such as irritable bowel syndrome, antibiotic-associated diarrhea, inflammatory bowel disease, and constipation. The biggest disadvantage that can be caused when lactic acid bacteria is used as a probiotic is the lack of resistance to antibiotics. Therefore, yeast bacteria that show a probiotic function in the intestine without being inhibited by antibiotics are recently used as intestinal agents.
본 발명의 사카로마이세스 보울라디 28-7 균주는 현재 의약품으로 판매중에 있는 비오플(Bioflor, Saccharomyces boulardii, 사카로마이세스 보울라디 균주)에 비견될 수준의 우수한 프로바이오틱 활성을 갖는 균주이며, 그 효능을 하기에 나타내었다. Saccharomyces boulardi 28-7 strain of the present invention is a strain having excellent probiotic activity at a level comparable to that of Bioflor (Bioflor, Saccharomyces boulardii , Saccharomyces boulardii strain) currently on sale as a pharmaceutical. , its efficacy is shown below.
기존의 프로바이오틱스 효능을 가지는 균주로 알려진 사카로마이세스 보울라디 균주는 사카로마이세스 세레비지에(S. cerevisiae) 균주와 유전적 상동성이 매우 높으며 갈락토오스(galactose) 발효능이 떨어지고 내산성을 가진다. Saccharomyces bouladi strain, known as a strain having an existing probiotic effect, has very high genetic homology with the S. cerevisiae strain, and has poor galactose fermentation ability and acid resistance.
본 발명의 사카로마이세스 보울라디 28-7 균주 역시 갈락토오스(galactose) 발효능이 없으며 내산성 및 내담즙산염에 내성이 있을 뿐만 아니라 장부착성이 우수하다.The Saccharomyces bouladi 28-7 strain of the present invention also has no galactose fermenting ability, is resistant to acid and bile salts, and has excellent intestinal adhesion.
대조군 1로는 표준균주인 사카로마이세스 세레비지에(S. cerevisiae) s288c 균주를 사용하였으며, 대조군 2로는 현재 의약품으로 판매중에 있는 비오플(Bioflor, Saccharomyces boulardii, 사카로마이세스 보울라디 균주)을 사용하였다.As the
시험예 1. 내담즙산, 내산성 및 장부착능 측정Test Example 1. Measurement of bile acid resistance, acid resistance and intestinal adhesion ability
1-1. 내담즙산 측정: 실시예 1, 대조군 1 및 대조군 2의 균주에 0.3 중량% 농도의 담즙산을 처리하여 생존율을 측정하였다.1-1. Measurement of endothelial bile acid: Viability was measured by treating the strains of Example 1,
1-2. 내산성 측정: 각 균주의 내산성 분석을 위해 YPD 배지에 24시간 배양된 효모 균주를 pH 2와 pH 3으로 조절된 YPD 배지에 계대 배양하였다. 이렇게 계대 배양된 효모는 2.5시간 후 생균수를 측정하여 초기균수와 비교, 생존율을 백분율로 나타내었다. 1-2. Acid resistance measurement: For acid resistance analysis of each strain, yeast strains cultured in YPD medium for 24 hours were subcultured in YPD medium adjusted to
1-3. 장부착능 측정: 효모의 장부착능 분석을 위해 인간 결장암(human colon adenocarcinoma) 세포주인 HT-29세포를 10% 소혈청(fetal bovine serum), 100 U/ml 페니실린(penicillin) 및 100 mg/ml 스트렙토마이신(streptomycin)이 포함된 DMEM 배지에서 37 ℃, 5% CO2조건으로 HT-29 세포를 배양하고, 90 %의 occupancy 정도로 단층을 형성하게 하였다. 배양한 효모를 108정도의 세포수로 보정한 뒤 HT-29에 처리하였다. 처리한 효모 샘플은 37 ℃, 5% CO2조건에서 2시간 동안 배양 후 PBS로 2회 세척한 다음 Trypsin-EDTA를 처리하였다. 처리한 샘플을 단계별로 희석하여 플레이트에 도말한 후 생균수를 측정하여, 각 효모의 장부착능을 상대적인 접착율로 표현하였다.1-3. Measurement of intestinal adhesion capacity: For analysis of intestinal adhesion capacity of yeast, HT-29 cells, a human colon adenocarcinoma cell line, were treated with 10% fetal bovine serum, 100 U/ml penicillin, and 100 mg/ml HT-29 cells were cultured in DMEM medium containing streptomycin under conditions of 37 °C and 5% CO 2 , and a monolayer was formed with an occupancy of 90%. The cultured yeast was corrected to a cell number of about 10 8 and treated with HT-29. The treated yeast sample was incubated at 37 ° C., 5% CO 2 condition for 2 hours, washed twice with PBS, and then treated with Trypsin-EDTA. The treated samples were diluted step-by-step and spread on a plate, and the number of viable cells was measured, and the intestinal adhesion capacity of each yeast was expressed as a relative adhesion rate.
도 2는 본 발명의 실시예 1에 따라 분리된 신규한 28-7 균주, 대조군 1의 s288c 균주 및 대조군 2의 비오플을 이용하여 담즙산에서의 생존율을 측정한 그래프이며; 도 3은 본 발명의 실시예 1에 따라 분리된 신규한 28-7 균주, 대조군 1의 s288c 균주 및 대조군 2의 비오플을 이용하여 산성에서의 생존율을 측정한 그래프이고; 도 4는 발명의 실시예 1에 따라 분리된 신규한 28-7 균주 및 대조군 2의 비오플을 이용하여 장부착능을 측정한 그래프이다.2 is a graph measuring the viability in bile acids using the novel 28-7 strain isolated according to Example 1 of the present invention, the s288c strain of the
도 2 내지 4에 도시된 바와 같이, 0.3% 담즙산 농도에서 실시예 1의 28-7 균주는 약 90%의 높은 생존율을 보이는 것을 확인하였고, 이는 대조군 2의 비오플에 비해서도 우수한 것을 확인하였다.As shown in FIGS. 2 to 4 , it was confirmed that the 28-7 strain of Example 1 at a concentration of 0.3% bile acid showed a high survival rate of about 90%, which was also superior to that of Biople in
또한, pH 2와 pH 3에서 실시예 1의 28-7 균주는 각각 약 103%, 109%의 높은 생존율을 보이는 것을 확인하였고, 이는 pH 2와 pH 3 모두에서 생존율이 0인 대조군 1의 s288c 균주보다 우수하고 대조군 2의 비오플과 유사한 것을 확인하였다.In addition, it was confirmed that the 28-7 strain of Example 1 at
또한, 장부착능에 있어서 실시예 1의 28-7 균주는 대조군 2의 비오플에 비하여 약 2배 높은 장부착능을 보이는 것을 확인하였다.In addition, in terms of intestinal adhesion, it was confirmed that the 28-7 strain of Example 1 exhibited about two times higher intestinal adhesion compared to Biople of
따라서 실시예 1의 28-7 균주는 장내 환경에 생존하기 적합하고 같은 종의 균주보다 더 우수한 장내 부착능을 가지는 것으로 확인된 바, 우수한 프로바이오틱스 기능을 갖는 것을 확인하였다.Therefore, the 28-7 strain of Example 1 was confirmed to have an excellent probiotic function as it was confirmed that it was suitable for surviving in the intestinal environment and had better intestinal adhesion than the strain of the same species.
동물실험animal testing
누룩으로부터 동정한 신균한 균주인 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주를 실제로 섭취 시 host의 건강에 도움을 주는 프로바이오틱스로서 효능이 있는지 확인하기 위하여 동물실험을 진행하였다. 프로바이오틱스 효능은 DSS(dextran sodium sulfate)로 유도된 대장염(colitis) 마우스 모델을 사용하였으며, 이 모델은 염증성 장질환(inflammatory bowel disease, IBD)이나 과민성 대장 증후군 (Irritable bowel syndrome, IBS)과 관련된 장내의 염증을 유발하는 모델로 널리 사용되고 있다. 특히, 현재 프로바이오틱 효모로 시판중인 비오플(Bioflor)의 효능 검증에도 활용된 동물모델이다. In order to confirm whether the Saccharomyces boulardii 28-7 strain, which is a novel strain identified from yeast, is effective as a probiotic to help the health of the host when actually ingested, an animal experiment was conducted. For the efficacy of probiotics, a mouse model of dextran sodium sulfate (DSS)-induced colitis was used, and this model was used for intestinal disorders related to inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS). It is widely used as a model for inducing inflammation. In particular, it is an animal model used to verify the efficacy of Bioflor, which is currently commercially available as a probiotic yeast.
DSS는 음수에 1 내지 3 중량% 수준으로 섞어 마우스에 급여하고 일주일 이내로 장내의 염증이 발생하여 설사 및 혈변, 체중 감소 등의 징후를 보이게 된다. 이때 기준지표에 따라 질병점수(disease activity index, DAI)를 매기고 최종적으로 마우스를 희생시킨 후 대장(colon)의 길이 단축, 과도한 염증으로 인한 대장 내 무게 증가 등을 측정하여 무게/길이의 지표로 나타냄으로서 장염증 정도를 확인하였다. DSS is mixed with negative water at a level of 1 to 3% by weight and fed to mice, and intestinal inflammation occurs within a week, resulting in signs of diarrhea, bloody stools, and weight loss. At this time, the disease activity index (DAI) is assigned according to the standard index, and after the mouse is finally sacrificed, the length of the colon is shortened and the weight increase in the colon due to excessive inflammation is measured and expressed as an index of weight/length. As a result, the degree of intestinal inflammation was confirmed.
해당 균주의 프로바이오틱스 효능을 확인하기 위하여 20 g 내외의 6주령 C57BL/6 수컷 마우스(Orient Bio)를 실험에 사용하였으며, 실험 전 마우스는 1주간 순화과정을 거쳤다. 마우스는 실험 내내 22ㅁ1 ℃ 온도 및 55%ㅁ10% 습도가 조절된 사육실에서 자유식이로 사육되었으며 명암 주기는 12시간 주기로 조절하였다. 모든 동물실험은 한국식품연구원 동물실험운영규정에 준하여 수행하였다.To confirm the probiotic efficacy of the strain, 6-week-old C57BL/6 male mice (Orient Bio) weighing about 20 g were used for the experiment, and the mice were acclimatized for 1 week before the experiment. Mice were bred ad libitum in a breeding room controlled at 22°C temperature and 55%·10% humidity throughout the experiment, and the light-dark cycle was controlled at a 12-hour cycle. All animal experiments were conducted in accordance with the Animal Experiment Operation Regulations of the Korea Food Research Institute.
사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주의 효능 평가를 위하여 마우스들을 랜덤으로 다섯 그룹으로 나누어 진행하였다. Saccharomyces boulardii ( Saccharomyces boulardii ) In order to evaluate the efficacy of the 28-7 strain, mice were randomly divided into five groups.
정상군은 DSS 및 균주를 투여하지 않은 군이며, DSS군은 음수에 DSS(36-50kDA, MPBio)를 3 중량%의 농도로 급여하여 장내 염증이 유도된 군이다. 또한, 3 중량% DSS 급여 전에 2주간 108 CFU/day로 각각 28-7 균주(실시예 1군), 비오플(비오플군), s288c(s288c군) 균주를 경구투여하였다. 2주간의 균주 투여 후, 1주일 동안 3 중량%의 농도로 DSS를 음수에 섞어 급여하였고 이 기간 동안에는 매일 무게, 분변 형태, 출혈패턴을 표 1의 기준에 따라 점수를 매겨 DAI를 기록하였으며 7일째 되는 날 DSS를 다시 일반 음수로 교체 후 이틀간 안정화시켰다. 혈액과 대장조직은 15시간 공복 후 마취하여 채혈한 후 획득하였고, 대장조직의 길이는 캘리퍼스로 측정하여 기록하였다. 실험의 통계분석을 위하여 one-way ANOVA (Dunnett's test vs. DSS)를 사용하여 그룹 간 평균수치 유의차를 확인하였으며, 0.05 보다 낮은 p 값을 가질 경우에 유의미한 결과로 고려하였다 (*, p<0.05; **, p<0.01; ***, p<0.001). The normal group is a group not administered with DSS and strain, and the DSS group is a group in which intestinal inflammation is induced by feeding DSS (36-50kDA, MPBio) in negative water at a concentration of 3% by weight. In addition, 28-7 strains (Example 1 group), Biople (Biople group), and s288c (s288c group) strains were orally administered at 10 8 CFU/day for 2 weeks before 3 wt% DSS feeding. After administration of the strain for 2 weeks, DSS was mixed with negative water at a concentration of 3% by weight for 1 week. During this period, the daily weight, fecal shape, and bleeding pattern were scored according to the criteria in Table 1 to score the DAI, and the DAI was recorded on the 7th day. On the same day, the DSS was replaced with a normal negative water and stabilized for two days. Blood and colonic tissue were obtained after anesthesia and blood collection after fasting for 15 hours, and the length of colonic tissue was measured and recorded with a caliper. For statistical analysis of the experiment, one-way ANOVA (Dunnett's test vs. DSS) was used to confirm the significant difference in the mean value between groups, and when it had a p value lower than 0.05, it was considered as a significant result (*, p<0.05) ; **, p<0.01; ***, p<0.001).
(% of initial wt.)weight loss
(% of initial wt.)
장염증 개선 효능 측정Measurement of the efficacy of improving intestinal inflammation
시험예 2. 대장 내 염증 억제 효과 확인Test Example 2. Confirmation of the effect of inhibiting inflammation in the colon
도 6a는 DSS군, 실시예 1군, 비오플군 및 s288c군의 DAI 값을 나타낸 그래프이며, 도 6b는 정상군, DSS군, 실시예 1군, 비오플군 및 s288c군의 AUC를 측정한 그래프이다.Figure 6a is a graph showing the DAI value of the DSS group, Example 1 group, non-opul group and s288c group, Figure 6b is a normal group, DSS group, Example 1 group, the non-opul group and s288c group AUC measurements It is a graph.
DAI(disease activity index) 점수는 7일 동안 측정한 값의 area under curve (AUC)를 측정하여 개선 효능을 통계적으로 분석하였다. For the DAI (disease activity index) score, the improvement efficacy was statistically analyzed by measuring the area under curve (AUC) of the values measured for 7 days.
그 결과 도 6a 및 도 6b에 도시된 바와 같이, 실시예 1군 및 비오플군은 DSS군에 비하여 유의적으로 DAI의 AUC 값이 감소하는 것을 확인하였으며 이러한 결과를 통해 장내 염증이 개선되었음을 확인하였다.As a result, as shown in FIGS. 6A and 6B , it was confirmed that the AUC value of DAI was significantly decreased in the Example 1 group and the non-opul group compared to the DSS group, and intestinal inflammation was improved through these results. .
반면, s288c군은 DSS군과 통계적 차이가 나타나지 않았으므로 단순 균주의 투여만으로 장내 염증이 모두 개선되는 것은 아니며, 특정 균주 처리 시에만 장염 개선 효과를 보임을 확인하였다. On the other hand, since the s288c group did not show a statistical difference from the DSS group, it was confirmed that not all intestinal inflammation was improved only by administration of a simple strain, and only the treatment of a specific strain showed an effect of improving enteritis.
특히, 본 발명의 실시예 1군은 수치상으로는 비오플군보다 우수한 수준의 장내 염증 개선효능을 가지는 것을 확인하였다.In particular, it was confirmed that the group of Example 1 of the present invention had an effect of improving intestinal inflammation at a level superior to that of the BIOFL group in numerical terms.
시험예 3. 대장길이 측정Test Example 3. Measurement of colon length
도 7a는 정상군, DSS군, 실시예 1군, 비오플군 및 s288c군의 대장길이를 나타낸 그래프이며; 도 7b는 정상군, DSS군, 실시예 1군, 비오플군 및 s288c군의 대장의 무게/길이를 나타낸 그래프이다.Figure 7a is a graph showing the colon length of the normal group, DSS group, Example 1 group, non-opul group and s288c group; Figure 7b is a graph showing the weight / length of the colon in the normal group, DSS group, Example 1 group, non-opul group and s288c group.
DSS를 음수에 섞어 투여함으로써, 장내에 염증이 유발되면 장내의 염증성 사이토카인이 분비되고 장벽에 폴립이 형성되는 등 대장벽이 두꺼워지고 길이가 감소하며, 이에 따라 대장 길이 당 무게가 증가하므로 이를 대장염의 측정 지표로 사용될 수 있다.By administering DSS by mixing it with negative water, when inflammation is induced in the intestine, the intestinal wall thickens and decreases in length, such as the secretion of inflammatory cytokines and the formation of polyps in the intestinal wall. can be used as a measure of
도 7a 및 도 7b에 도시된 바와 같이, 마우스 희생 후 대장의 길이와 무게를 측정한 결과 정상군 대비 DSS군은 길이 대 무게 비율이 유의적으로 증가하였으나 실시예 1군 및 비오플군에서는 이러한 변화가 유의적으로 개선되는 결과를 확인하였다. 7a and 7b, as a result of measuring the length and weight of the large intestine after mouse sacrifice, the length-to-weight ratio of the DSS group compared to the normal group was significantly increased, but this change in the Example 1 group and the non-opul group It was confirmed that the results were significantly improved.
즉, 실시예 1군은 장길이가 감소된 DSS군에 비하여 유의적으로 증가하는 것을 확인하였다. 반면, s288c군에서는 이러한 효과가 미비하였다.That is, it was confirmed that the Example 1 group significantly increased compared to the DSS group in which the length was decreased. On the other hand, this effect was insignificant in the s288c group.
시험예 4. 대장 내 염증성 사이토카인 및 장관벽 지표 확인Test Example 4. Confirmation of inflammatory cytokines and intestinal wall indicators in the colon
도 8a는 정상군, DSS군, 실시예 1군 및 비오플군의 IL-1β의 mRNA 수준을 나타낸 그래프이며; 도 8b는 정상군, DSS군, 실시예 1군 및 비오플군의 ZO1의 mRNA 수준을 나타낸 그래프이다. Figure 8a is a graph showing the mRNA level of IL-1β in the normal group, DSS group, Example 1 group, and non-opul group; Figure 8b is a graph showing the mRNA level of ZO1 in the normal group, DSS group, Example 1 group, and non-opul group.
DSS 처리에 의하여 장내 염증반응이 유도되면 다양한 염증성 사이토카인의 분비가 증가하고 이에 따라 장관벽의 항상성이 깨지게 되면서 장투과성(gut permeability)이 증가하는 등의 악영향을 유발하게 된다. When the intestinal inflammatory response is induced by DSS treatment, the secretion of various inflammatory cytokines is increased, and thus the homeostasis of the intestinal wall is broken and adverse effects such as increased gut permeability are induced.
본 발명 28-7 균주의 투여에 의하여 실제로 이러한 염증성 사이토카인 분비와 장누수와 관련된 지표들이 개선되는지를 확인하기 위하여 대표적인 염증성 사이토카인인 인터루킨-1β(Interleukin-1β, IL-1β)와 장관벽 관련 지표인 ZO1(zonula occludens 1)의 mRNA 수준을 탐식하였다. 이를 위하여 대장 조직으로부터 mRNA를 추출하고 이를 cDNA로 합성하였다. RNA 추출은 RNeasy PowerMicrobiome Kit(Qiagen)를 사용하였으며 RNA 농도 측정은 spectrophotometer(Varioskan, Thermo Electron Co.)로 수행하였다. cDNA로 합성 후 IL-1β와 ZO1 두 종류의 프라이머를 사용하여 quantitative RT-PCR (StepOnePlus, Applied Biosystems)을 활용하여 측정하였다. In order to confirm whether such indicators related to secretion of inflammatory cytokines and intestinal leakage are actually improved by administration of the strain 28-7 of the present invention, interleukin-1β (Interleukin-1β, IL-1β), a representative inflammatory cytokine, and intestinal wall-related The mRNA level of the indicator ZO1 (zonula occludens 1) was phagocytosed. To this end, mRNA was extracted from colon tissue and synthesized as cDNA. RNA extraction was performed using RNeasy Power Microbiome Kit (Qiagen), and RNA concentration was measured using a spectrophotometer (Varioskan, Thermo Electron Co.). After synthesizing cDNA, it was measured using quantitative RT-PCR (StepOnePlus, Applied Biosystems) using two types of primers, IL-1β and ZO1.
도 8a 및 도 8b에 도시된 바와 같이, DSS 처리에 의하여 염증성 사이토카인인 IL-1β의 대장 내 mRNA 발현 수준은 크게 증가하였고(DSS군), 이러한 증가는 본 발명의 28-7 균주와 비오플 투여에 의하여 70% 가량 감소한 것을 확인하였다. As shown in Figures 8a and 8b, the mRNA expression level in the colon of IL-1β, an inflammatory cytokine, was greatly increased by DSS treatment (DSS group), and this increase was confirmed with the 28-7 strain of the present invention and Biople It was confirmed that it was reduced by about 70% by administration.
ZO1은 DSS 처리에 의하여 정상군 대비 1/12 수준으로 감소하였는데, 이는 장관벽의 투과성이 높아져 장관벽누수가 일어났음을 의미한다. 28-7 균주와 비오플 투여에 의하여 이 역시 회복되는 것을 확인하였으며 특히 28-7 균주는 비오플 대비 더 뛰어난 보호 효능과 더불어 정상군 수준으로의 회복을 유도하는 것을 확인하였다. ZO1 was reduced to 1/12 level compared to the normal group by DSS treatment, which means that intestinal wall leakage occurred due to increased intestinal wall permeability. It was confirmed that this was also recovered by administration of the 28-7 strain and Biople, and in particular, it was confirmed that the 28-7 strain induces recovery to the level of the normal group with superior protective efficacy compared to Biople.
시험예 5. 혈중 염증성 사이토카인 측정Test Example 5. Measurement of inflammatory cytokines in blood
도 9는 정상군, DSS군, 실시예 1군 및 비오플군의 혈액 내의 염증성 사이토카인 수준을 측정한 것이다.9 is a measurement of the level of inflammatory cytokines in the blood of the normal group, the DSS group, the Example 1 group, and the non-opul group.
염증의 개선효능을 추가적으로 확인하기 위하여 혈액(serum) 시료를 활용하여 혈중 염증성 사이토카인 수준을 탐색하는 cytokine antibody array를 수행하였다. 이는 Mouse cytokine array kit(R&D systems, ARY006)을 사용하여 제조사가 제공하는 프로토콜에 맞추어 실험하였다. 해당 실험은 혈액 내의 단백질이 멤브레인에 부착된 안티바디와 반응하여 스팟형태로 나타나게 되는데 이를 검출하여 사이토카인 분비/발현 정도를 상대적 정도로 검출할 수 있도록 한다. In order to further confirm the efficacy of improving inflammation, a cytokine antibody array was performed to detect the level of inflammatory cytokines in the blood using a serum sample. This was tested according to the protocol provided by the manufacturer using the Mouse cytokine array kit (R&D systems, ARY006). In this experiment, the protein in the blood reacts with the antibody attached to the membrane and appears in the form of a spot, which detects the cytokine secretion/expression level to a relative degree.
도 9에 도시된 바와 같이, 실시예 1군은 정상군과 유사한 발현 패턴을 보이는 것을 확인하였으며, 이는 비오플군에 의한 발현 패턴보다 더 우수한 것으로 사료된다.As shown in FIG. 9 , it was confirmed that the Example 1 group showed an expression pattern similar to that of the normal group, which is considered to be superior to that of the non-opul group.
이러한 결과들은 누룩으로부터 동정한 신규한 균주인 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주가 DSS로 유도되는 대장내 염증을 완화시키는 등의 효능이 있음을 의미한다. These results suggest that a novel strain identified from yeast, Saccharomyces boulardii 28-7 strain, has an effect such as alleviating DSS-induced colonic inflammation.
균주의 장내 생존 측정Determination of intestinal viability of strains
시험예 6. 균주의 장내 생존여부 확인Test Example 6. Confirmation of intestinal viability of the strain
도 10a는 정상군, DSS군, 실시예 1군 및 비오플군의 맹장 내 살아있는 균주의 수를 사카로마이세스 프라이머를 이용하여 측정한 그래프이며; 도 10b는 정상군, DSS군, 실시예 1군 및 비오플군의 맹장 내 살아있는 균주의 수를 사카로마이세스 세레비지에 프라이머를 이용하여 측정한 그래프이다.Figure 10a is a graph in which the number of viable strains in the cecum of the normal group, DSS group, Example 1 group and Biople group was measured using Saccharomyces primers; Figure 10b is a graph in which the number of living strains in the cecum of the normal group, DSS group, Example 1 group and Biople group was measured using a Saccharomyces cerevisiae primer.
DSS로 유도되는 대장염에 있어서 본 발명의 28-7 균주가 시판 중인 비오플과 유사하거나 높은 수준으로 염증을 개선하는 효능이 있음을 동물실험을 통하여 확인하였다. 따라서 in vivo 경구투여 시에 실제 장까지 이들 균주가 생존할 수 있는지를 확인하기 위하여 맹장 내의 RNA를 추축하여 살아있는 균주(효모)의 log수를 확인하였다. 이를 위하여 실험 마우스는 희생 전날 균주(108 CFU)를 투여하고 15시간의 절식 후 마취하여 맹장 내용물을 획득하였다. 맹장 내용물은 무게를 측정한 후 RNase, DNase free의 깨끗한 튜브에 옮겨 담아 total RNA를 추출하였다. RNA 추출은 RNeasy PowerMicrobiome Kit(Qiagen)를 사용하였으며, RNA 농도 측정은 spectrophotometer (Varioskan, Thermo Electron Co.)로 수행하였다. 본 발명의 28-7 균주의 strain specific primer의 제작은 불가능하며, 실제로 사카로마이세스 세레비지에(S. cerevisiae)와 사카로마이세스 보울라디(Saccharomyces boulardii) 사이의 유전적 상동성이 매우 높아 S. cerevisiae specific primer로 S. boulardii의 확인이 가능한 수준이다. In DSS-induced colitis, it was confirmed through animal experiments that the 28-7 strain of the present invention has an effect of improving inflammation at a level similar to or higher than that of commercially available Biople. Therefore, in order to confirm whether these strains can survive to the actual intestine during oral administration in vivo , RNA in the cecum was extracted and the log number of the living strain (yeast) was confirmed. To this end, the experimental mice were administered the strain (10 8 CFU) the day before sacrifice, and were anesthetized after 15 hours of fasting to obtain cecal contents. The cecal contents were weighed and transferred to a clean tube free of RNase and DNase to extract total RNA. RNA extraction was performed using RNeasy PowerMicrobiome Kit (Qiagen), and RNA concentration was measured using a spectrophotometer (Varioskan, Thermo Electron Co.). The production of the strain specific primer of the 28-7 strain of the present invention is impossible, and the genetic homology between S. cerevisiae and Saccharomyces boulardii is very high. S. cerevisiae specific primer is at a level that can confirm S. boulardii .
따라서 맹장 내 살아있는 효모의 정량을 위해 S. cerevisiae specific primer와 Saccharomyces primer 두 종류의 primer를 사용하여 S. boulardii를 확인하였다. RNA를 cDNA로 합성 후 두 종류의 프라이머를 사용하여 quantitative RT-PCR(StepOnePlus, Applied Biosystems)을 활용하여 측정하였다. Standard curve는 생균수를 측정한 표준효모균주 S. cereviseae strain s288c의 RNA를 활용하였으며, 이에 대비하여 맹장 내 균주의 RNA를 정량하였다. Therefore, S. boulardii was identified using two types of primers: S. cerevisiae specific primer and Saccharomyces primer for quantification of live yeast in the cecum. After synthesizing RNA into cDNA, it was measured using quantitative RT-PCR (StepOnePlus, Applied Biosystems) using two types of primers. The standard curve used the RNA of the standard yeast strain S. cereviseae strain s288c for which the number of viable cells was measured. In contrast, the RNA of the strain in the cecum was quantified.
도 10a 및 도 10b에 도시된 바와 같이, 맹장 내용물(g) 당 log 값이 본 발명 28-7 균주의 투여에 의하여 유의적으로 증가하였기 때문에 신규한 균주인 28-7 균주는 균주 자체를 경구로 섭취하여도 장내에서 우수한 생존율을 가진다는 것을 확인하였다. 특히, S. cerevisiae 특이적인 primer를 사용하여 검출하였을 때 비오플 투여 시 보다 28-7 균주 투여시의 살아있는 S. cerevisiae의 농도가 102배 이상 높은 것으로 확인하였다. 이는 비오플보다 28-7 균주가 더 안정적으로 장내에 생존할 수 있음을 간접적으로 확인한 결과이다. As shown in FIGS. 10A and 10B , the log value per cecal content (g) was Since it was significantly increased by the administration of the 28-7 strain of the present invention, it was confirmed that the novel strain 28-7 strain had an excellent survival rate in the intestine even when the strain itself was orally ingested. In particular, when it was detected using a S. cerevisiae -specific primer, it was confirmed that the concentration of live S. cerevisiae was 10 to 2 times higher when 28-7 strains were administered than when bioflu was administered. This is the result of indirectly confirming that the 28-7 strain can more stably survive in the intestine than Biople.
위의 결과들을 종합적으로 보았을 때, 본 발명의 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주는 프로바이오틱 효모로서의 가능성이 충분하며 특히 일부 효능에 대해서는 시판중인 의약품인 비오플보다 효능이 뛰어난 것을 확인하였다. When the above results are taken comprehensively, the Saccharomyces boulardii 28-7 strain of the present invention has sufficient potential as a probiotic yeast, and in particular, for some efficacy, it is more effective than the commercially available drug Biople. was confirmed to be excellent.
하기에 본 발명의 분말을 함유하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, formulation examples of the composition containing the powder of the present invention will be described, but the present invention is not intended to limit the present invention, but merely to describe it in detail.
제제예 1. 산제의 제조Formulation Example 1. Preparation of powder
실시예 1에서 얻은 28-7 균주 500 mg500 mg of the 28-7 strain obtained in Example 1
유당 100 mg
탈크 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight bag to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2. Preparation of tablets
실시예 1에서 얻은 28-7 균주 300 mg300 mg of the 28-7 strain obtained in Example 1
옥수수전분 100 mg100 mg cornstarch
유당 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above ingredients, tablets are prepared by tableting according to a conventional manufacturing method of tablets.
제제예 3. 캅셀제의 제조Formulation Example 3. Preparation of capsules
실시예 1에서 얻은 28-7 균주 200 mg200 mg of the 28-7 strain obtained in Example 1
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mg0.2 mg magnesium stearate
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled in a gelatin capsule to prepare a capsule.
제제예 4. 주사제의 제조Formulation Example 4. Preparation of injection
실시예 1에서 얻은 28-7 균주 600 mg600 mg of 28-7 strains obtained in Example 1
만니톨 180 mgmannitol 180 mg
주사용 멸균 증류수 2974 mg2974 mg of sterile distilled water for injection
Na2HPO4,12H2O 26 mgNa 2 HPO 4, 12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플 당 상기의 성분 함량으로 제조한다.According to a conventional method for preparing injections, the content of the above ingredients per 1 ampoule is prepared.
제제예 5. 액제의 제조Formulation Example 5. Preparation of liquid formulation
실시예 1에서 얻은 28-7 균주 4 g4 g of 28-7 strains obtained in Example 1
이성화당 10 g10 g isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water appropriate amount
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100g으로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.According to a conventional liquid preparation method, each component is added to purified water to dissolve, an appropriate amount of lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 g by adding purified water, and then filled in a brown bottle to sterilize to prepare a liquid.
제제예 6. 과립제의 제조Formulation Example 6. Preparation of granules
실시예 1에서 얻은 28-7 균주 1,000 mg1,000 mg of the 28-7 strain obtained in Example 1
비타민 혼합물 적량appropriate amount of vitamin mixture
비타민 A 아세테이트 70 ㎍70 μg vitamin A acetate
비타민 E 1.0 mgVitamin E 1.0 mg
비타민 B1 0.13 mgVitamin B1 0.13 mg
비타민 B2 0.15 mgVitamin B2 0.15 mg
비타민 B6 0.5 mg0.5 mg of vitamin B6
비타민 B12 0.2 ㎍0.2 μg of vitamin B12
비타민 C 10 mg
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 mgNicotinamide 1.7 mg
엽산 50 ㎍50 μg folic acid
판토텐산 칼슘 0.5 mgCalcium pantothenate 0.5 mg
무기질 혼합물 적량Appropriate amount of inorganic mixture
황산제1철 1.75 mgferrous sulfate 1.75 mg
산화아연 0.82 mgZinc Oxide 0.82 mg
탄산마그네슘 25.3 mgMagnesium carbonate 25.3 mg
제1인산칼륨 15 mgPotassium monophosphate 15 mg
제2인산칼슘 55 mgDibasic calcium phosphate 55 mg
구연산칼륨 90 mgPotassium citrate 90 mg
탄산칼슘 100 mg100 mg calcium carbonate
염화마그네슘 24.8 mgMagnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 과립제에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 과립제 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강기능식품 조성물 제조에 사용할 수 있다.The composition ratio of the vitamin and mineral mixture is relatively suitable for granules in a preferred embodiment, but the mixing ratio may be arbitrarily modified. It can be prepared and used in the preparation of a health functional food composition according to a conventional method.
제제예 7. 기능성 음료의 제조Formulation Example 7. Preparation of functional beverage
실시예 1에서 얻은 28-7 균주 1,000 mg1,000 mg of the 28-7 strain obtained in Example 1
구연산 1,000 mg1,000 mg citric acid
올리고당 100 g100 g of oligosaccharides
매실농축액 2 g2 g of plum concentrate
타우린 1 g1 g taurine
정제수를 가하여 전체 900 mLAdd purified water to total 900 mL
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1 시간 동안 85 ℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 기능성 음료 조성물 제조에 사용한다. After mixing the above ingredients according to the usual health drink manufacturing method, after stirring and heating at 85 ° C for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed and sterilized, then refrigerated. It is used to prepare the functional beverage composition of the present invention.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 수요계층, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is prepared by mixing ingredients suitable for relatively favorite beverages in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as demand class, demanding country, and use.
제제예 8: 사료 조성물의 제조Formulation Example 8: Preparation of feed composition
실시예 1에서 얻은 28-7 균주 0.1 kg, 옥수수 25.5 kg, 소맥 15.04 kg, 소맥분 8.15 kg, 미강 7.4 kg, 대두박 18 kg, 옥구르텐 1kg, 닭부산물 14 kg, 동물성유지 9 kg, 가공염 0.3 kg, 인산제삼칼슘 0.3 kg, 석회석 1 kg, 염화콜린 0.01 kg, 비타민 0.05 kg, 미네랄 0.05 kg 및 소화효소제 0.1 kg을 혼합하여 동물(개, 애완견) 사료 조성물을 제조하였다. 28-7 strain obtained in Example 1 0.1 kg, corn 25.5 kg, wheat 15.04 kg, wheat flour 8.15 kg, rice bran 7.4 kg, soybean meal 18 kg, okgurten 1 kg, chicken by-product 14 kg, animal fat 9 kg, processed salt 0.3 kg , tricalcium phosphate 0.3 kg,
<110> Korea Food Research Institute <120> A novel strain of Saccharomyces boulardii 28-7 and uses thereof <130> HPC9875 <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 791 <212> DNA <213> Unknown <220> <223> Saccharomyces boulardii <400> 1 tcaactttaa gaacattgtt cgcctagacg ctctcttctt atcgataacg ttccaatacg 60 ctcagtataa aaaaaaataa cccgcatttg gtaaaaccta aaacaacggt acttgcatta 120 tacctcaggc acgcaaagaa ccctctcttt gaaaaaaaaa catccaatga aaaggccagc 180 aatttcaagt taactccaaa gagtatcact cactaccaaa cagaaggttt gagaaggaaa 240 tgacgctcaa acaggcatgc cccctggaat accaaggggc gcaatgtgcg ttcaaagatt 300 cgatgattca cggaattctg caattcacat tacgtatcgc atttcgctgc gttcttcatc 360 gatgcgagaa ccaagagatc cgttgttgaa agtttttaat attttaaaat ttccagttac 420 gaaaattctt gtttttgaca aaaatttaat gaataaataa aattgtttgt gtttgttacc 480 tctgggcccc gattgctcga atgcccaaag aaaaagttgc aaagatatga aaactccaca 540 gtgtgttgta ttgaaacggt tttaattgtc ctataacaaa agcacagaaa tctctcaccg 600 tttggaatag caagaaagaa acttacaagc ctagcaagac cgcgcactta agcgcaggcc 660 cggctggact ctccatctct tgtcttcttg cccagtaaaa gctctcatgc tcttgccaaa 720 acaaaaaaat ctattttttc aataataaaa tttctctaaa gagacttctc cacgtgctcc 780 tccagagacc t 791 <110> Korea Food Research Institute <120> A novel strain of Saccharomyces boulardii 28-7 and uses thereof <130> HPC9875 <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 791 <212> DNA <213> Unknown <220> <223> Saccharomyces boulardii <400> 1 tcaactttaa gaacattgtt cgcctagacg ctctcttctt atcgataacg ttccaatacg 60 ctcagtataa aaaaaaataa cccgcatttg gtaaaaccta aaacaacggt acttgcatta 120 tacctcaggc acgcaaagaa ccctctcttt gaaaaaaaaa catccaatga aaaggccagc 180 aatttcaagt taactccaaa gagtatcact cactaccaaa cagaaggttt gagaaggaaa 240 tgacgctcaa acaggcatgc cccctggaat accaaggggc gcaatgtgcg ttcaaagatt 300 cgatgattca cggaattctg caattcacat tacgtatcgc atttcgctgc gttcttcatc 360 gatgcgagaa ccaagagatc cgttgttgaa agtttttaat attttaaaat ttccagttac 420 gaaaattctt gtttttgaca aaaatttaat gaataaataa aattgtttgt gtttgttacc 480 tctgggcccc gattgctcga atgcccaaag aaaaagttgc aaagatatga aaactccaca 540 gtgtgttgta ttgaaacggt tttaattgtc ctataacaaa agcacagaaa tctctcaccg 600 tttggaatag caagaaagaa acttacaagc ctagcaagac cgcgcactta agcgcaggcc 660 cggctggact ctccatctct tgtcttcttg cccagtaaaa gctctcatgc tcttgccaaa 720 acaaaaaaat ctattttttc aataataaaa tttctctaaa gagacttctc cacgtgctcc 780 tccagagacc t 791
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| KR102110956B1 (en) | 2018-12-11 | 2020-05-14 | (주)카보엑스퍼트 | Saccharomyces boulardii CEY2 mutant strain having high productivity of glycogen and uses thereof |
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| KR102110956B1 (en) | 2018-12-11 | 2020-05-14 | (주)카보엑스퍼트 | Saccharomyces boulardii CEY2 mutant strain having high productivity of glycogen and uses thereof |
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