KR102579159B1 - 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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- KR102579159B1 KR102579159B1 KR1020210050798A KR20210050798A KR102579159B1 KR 102579159 B1 KR102579159 B1 KR 102579159B1 KR 1020210050798 A KR1020210050798 A KR 1020210050798A KR 20210050798 A KR20210050798 A KR 20210050798A KR 102579159 B1 KR102579159 B1 KR 102579159B1
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- saccharomyces boulardii
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Abstract
본 발명은 신규한 사카로마이세스 보울라디 28-7 균주 및 이의 용도에 관한 것으로 기탁번호 KFCC11825P로 수탁된 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주는 장내 염증성 사이토카인의 발현수준을 감소시키고 장관벽누수가 발생하지 않고, 갈락토오스(galactose) 발효능이 없으며, 내산성, 내담즙 및 장부착성이 우수하다.The present invention relates to a novel Saccharomyces boulardii 28-7 strain and its use. The Saccharomyces boulardii 28-7 strain, deposited with accession number KFCC11825P, is a strain that determines the expression level of intestinal inflammatory cytokines. It reduces intestinal wall leakage, does not have galactose fermentation ability, and has excellent acid resistance, bile resistance, and intestinal adhesion.
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 boulardii 28-7 strain that reduces the expression level of inflammatory cytokines in the intestine, does not cause intestinal wall leakage, and has excellent acid resistance, bile resistance, and intestinal adhesion, and its use.
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 undesirable eating habits and unhealthy lifestyle habits, such as meat-centered eating habits, eating habits centered on instant and processed foods, excessive intake of irritating foods, and hasty changes in food intake patterns due to busy living environments, and as we age. As harmful bacteria become more dominant than beneficial bacteria, the balance of intestinal bacteria is disrupted, which can have many negative effects on intestinal health, causing indigestion, constipation, and colon 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 robust microbial environment. This microbial environment changes depending on 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. This effect is related to the tendency of microorganisms in the gastrointestinal tract, and the balance of these microorganisms in the gastrointestinal tract may lower the risk of gastrointestinal diseases. The benefits of probiotics include the prevention and improvement of lactose intolerance, nutrient bioavailability, and allergy, and anti-mutagenic, anti-cancer, anti-high cholesterol, anti-hypertension, anti-osteoporosis, and immune function modulation effects have been reported.
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, liver, 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 health-promoting benefits of probiotic foods are widely accepted worldwide. According to FAO/WHO, health-promoting probiotics are viable, active microorganisms that have a positive effect on the health of the host when consumed in sufficient quantities (at least 10 6 -10 7 cfu/g). Recent studies have reported the immunological properties of dead microorganisms. Most probiotic microorganisms are bacteria that produce lactic acid bacteria, and among them, Lactobacillus is one of the most basic bacteria that improve human health. Accordingly, the genome sequences of several Lactobacillus species have been identified and have been used in a wide range of fermented foods. Additionally, the metabolic pathways, gene regulation, and functions associated with these probiotic microorganisms have been reported, and most researchers have believed that the best way to deliver probiotics is through 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.Nowadays, researchers are more interested in producing new biotics, and it is believed that non-dairy probiotics can be a good basis for the development of probiotic functional foods for humans. Several of the well-characterized probiotic microorganisms are commercially available worldwide, and 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.The purpose of the present invention is to reduce the expression level of inflammatory cytokines in the intestine, to develop a novel Saccharomyces boulardii 28 that does not cause intestinal wall leakage, has no galactose fermentation ability, and has 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 boulardii 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 boulardii 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 boulardii 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 boulardii 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 new strain of the present invention for achieving the above purpose is the 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 to achieve the above-mentioned other purposes is deposited under the accession 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 includes health functional food for preventing or improving inflammatory bowel disease; Alternatively, it may be a health functional food for improving intestinal adhesion of strains.
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 to achieve the above-described other purposes 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 to achieve the above-described other purposes is deposited under the accession 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 includes a feed composition for preventing or improving inflammatory bowel disease; Alternatively, it may be a feed composition for improving intestinal adhesion of strains.
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 preventing or treating inflammatory bowel disease of the present invention for achieving the above-described other purposes is deposited under the accession number KFCC11825P and contains Saccharomyces boulardii 28-7 strain as an active ingredient. You 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. The Saccharomyces boulardii 28-7 strain of the present invention is a new 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 preparations, health functional foods, feed compositions, etc.
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.Figure 1 is a molecular diagram showing the ITS gene sequence analysis of the Saccharomyces boulardii 28-7 strain of the present invention.
Figure 2 is a graph measuring the survival rate in bile acid using the novel 28-7 strain isolated according to Example 1 of the present invention, the s288c strain of control group 1, and the biopolymer of control group 2.
Figure 3 is a graph measuring the survival rate in acid using the novel 28-7 strain isolated according to Example 1 of the present invention, the s288c strain of control group 1, and the biopolymer of control group 2.
Figure 4 is a graph measuring the attachment ability using Biopoly of the new 28-7 strain isolated according to Example 1 of the invention and the control group 2.
Figure 5 is a diagram schematically showing the process of raising laboratory animals according to an embodiment of the present invention.
Figure 6a is a graph showing the DAI values of the DSS group, Example 1 group, non-Ople group, and s288c group, and Figure 6b is a graph showing the AUC of the normal group, DSS group, Example 1 group, non-Ople group, and s288c group. It's a graph.
Figure 7a is a graph showing the colon length of the normal group, DSS group, Example 1 group, BIOPL group, and s288c group; Figure 7b is a graph showing the weight/length of the large intestine in the normal group, DSS group, Example 1 group, BIOPL group, and s288c group.
Figure 8a is a graph showing the mRNA levels of IL-1β in the normal group, DSS group, Example 1 group, and BIOPL group; Figure 8b is a graph showing the mRNA level of ZO1 in the normal group, DSS group, Example 1 group, and BIOPL group.
Figure 9 shows the measurement of inflammatory cytokine levels in the blood of the normal group, DSS group, Example 1 group, and BIOPL group.
Figure 10a is a graph measuring the number of viable strains in the cecum of the normal group, DSS group, Example 1 group, and BIOPL group using Saccharomyces primers; Figure 10b is a graph measuring the number of viable strains in the cecum of the normal group, DSS group, Example 1 group, and Biople group using Saccharomyces cerevisiae primers.
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 is a novel Saccharomyces boulardii 28-7 that reduces the expression level of inflammatory cytokines in the intestine, does not cause intestinal wall leakage, has no galactose fermentation ability, and has excellent acid resistance, bile resistance, and intestinal adhesion. It relates to 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.The Saccharomyces boulardii 28-7 strain of the present invention 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).In the following examples, strain 28-7, a novel strain derived from yeast and having probiotic activity, was subjected to ITS sequencing for identification and classification of microorganisms, and 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 found to be a strain belonging to Saccharomyces boulardii , and as a result of confirming the homology to the nucleic acid sequence, Saccharomyces boulardii ( Saccharomyces boulardii ) was confirmed to be 98% identical to the standard strain (Figure 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 base 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 (deposit) Number: 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 boulardii 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 foods, and food additives, and can be manufactured in various forms according to conventional methods known in the art. For example, it can be prepared and consumed in the form of tea, juice, and drinks, or it can be consumed by granulating, encapsulating, and powdering. 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.Additionally, the present invention provides a probiotic preparation containing the Saccharomyces boulardii 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 preparation can be manufactured and administered in various formulations and methods according to methods known in the art. For example, the 28-7 strain of the present invention can be mixed with carriers commonly used in the pharmaceutical field to produce powders, liquids and solutions, tablets, capsules, and syrups. , it can be manufactured and administered in the form of a suspension or granule. The carrier may include, for example, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a coloring agent, and a flavoring agent, but is not limited thereto. In addition, the administered dose can be appropriately selected depending on the absorption rate of the active ingredient in the body, the inactivation rate, the excretion rate, the age, gender, species, condition, and severity of the disease of the recipient.
또한, 본 발명은 상기 사카로마이세스 보울라디 28-7 균주를 유효성분으로 함유하는 동물 사료 조성물을 제공한다. Additionally, the present invention provides an animal feed composition containing the Saccharomyces boulardii 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 can be added to basic feed at a certain ratio. The basic feed may include, but is not limited to, corn, soybean meal, whey, fish meal, molasses, salt, vitamin premix, and mineral premix. The vitamin premix may consist of vitamin A, vitamin D, vitamin E, riboflavin, and niacin, and the mineral premix may consist of, but are not limited to, manganese, iron zinc, calcium, copper, cobalt, and selenium. no.
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 boulardii 28-7 strain in the feed composition may be appropriately selected depending on the species, age, body weight, and rearing conditions of the fed animals. In the animal feed composition of the present invention, the animal may be a mammal such as a rat, mouse, or livestock, but is not limited thereto. The feed composition of the present invention can be manufactured according to a feed manufacturing method known in the technical field, for example, after mixing various feed raw materials or compound feed with the strain of the present invention, an additional processing process is performed, for example, into pellets. It can be manufactured by further performing steps such as molding into a shape 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 technical field.
또한, 본 발명은 포유동물에게 유효량의 28-7 균주를 투여하는 것을 포함하는 염증성 장질환의 개선, 예방 또는 치료 방법을 제공한다.Additionally, 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, preferably a human, that is the subject of treatment, observation or experiment.
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” means the amount of an active ingredient or pharmaceutical composition that is believed by a researcher, veterinarian, physician, or other clinician to induce a biological or medical response in a tissue system, animal, or human, which means that It includes amounts that induce relief of symptoms of a disease or disorder. The effective amount and frequency of administration of 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 a person skilled in the art, and can be determined based on the type of disease, the severity of the disease, the content of the active ingredient and other ingredients contained in the composition, the type of dosage form, and the patient's age, weight, and general health. It can be adjusted according to various factors, including condition, gender 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 heat-treated salt once or several times a day at a dose of 0.001 g/kg to 10 g/kg.
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 embodiments are presented to aid understanding of the present invention. However, the following examples are merely illustrative of the present invention, and it is clear to those skilled in the art that various changes and modifications are possible within the scope and spirit of the present invention. It is natural that such variations and modifications fall within the scope of the attached patent claims.
실시예 1. 사카로마이세스 보울라디 28-7 균주의 분리 및 동정Example 1. Isolation and identification of Saccharomyces boulardii 28-7 strain
1-1. 균주의 분리방법1-1. Isolation method of strains
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 yeast showing probiotic activity from over 60 types of traditional yeast listed in old literature. Approximately 200 yeast colonies of the genus Saccharomyces were isolated from 60 types of traditional yeast, and from these, 12 new types of Saccharomyces with the high temperature growth ability of 37 ℃ and galactose specific ability, which are characteristics of Boulardi yeast, were identified. A cerevisiae (or Boulardi) yeast strain was selected. Afterwards, the Saccharomyces boulardii 28-7 strain, which is expected to have probiotic function, was finally selected through growth tests in a high temperature/low acid environment at 37°C and pH 2.0.
1-2. 균주의 동정방법 1-2. Strain identification method
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 base sequence analysis was performed using the chromosomal DNA of the 28-7 strain, and as a result of the base sequence analysis, the 28-7 strain of the present invention was found to be a strain belonging to Saccharomyces boulardii , and the sequence It was found to have the base sequence number 1 (see Figure 1). In addition, as a result of analyzing the base sequence through BLAST Search, it showed approximately 98% homology with Saccharomyces boulardii strains previously listed in the database, SEQ ID NO: 1 It was confirmed that no strain with 100% homology exists.
따라서 본 발명자들은 사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주를 2019년 4월 1일자로 한국미생물보존센터에 기탁하여 수탁번호 KFCC11825P를 부여받았다.Therefore, the present inventors deposited Saccharomyces boulardii 28-7 strain at the Korea Microorganism Conservation Center on April 1, 2019, and received 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 ‘live microorganisms that are beneficial to the health of the host when administered in sufficient amounts.’ Most probiotics reported so far are known to be lactic acid bacteria, and there is a recent trend of gradually trying the use of probiotics in the area of colonic diseases such as irritable bowel syndrome, antibiotic-related diarrhea, inflammatory bowel disease, and constipation. The biggest disadvantage that may arise when using lactic acid bacteria as probiotics is lack of resistance to antibiotics. Therefore, yeast bacteria that are not inhibited by antibiotics and show probiotic function in the intestines have recently been used as a colonizer.
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. The Saccharomyces boulardii 28-7 strain of the present invention is a strain with excellent probiotic activity comparable to Bioflor ( Saccharomyces boulardii , Saccharomyces boulardii strain) currently sold 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. The Saccharomyces boulardii strain, known as a strain with existing probiotic efficacy, 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 boulardii 28-7 strain of the present invention also does not have the ability to ferment galactose, 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 control group 1, the standard strain S. cerevisiae s288c strain was used, and as control group 2, Bioflor ( Saccharomyces boulardii , Saccharomyces boulardii strain), which is currently sold as a pharmaceutical, was used. used.
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 bile acid resistance: The strains of Example 1, Control Group 1, and Control Group 2 were treated with bile acid at a concentration of 0.3% by weight, and the survival rate was measured.
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: To analyze the acid resistance of each strain, yeast strains cultured in YPD medium for 24 hours were subcultured in YPD medium adjusted to pH 2 and pH 3. For the yeast subcultured in this way, the number of viable bacteria was measured after 2.5 hours, compared with the initial number of bacteria, and the survival rate was expressed as a percentage.
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 ability: To analyze the intestinal adhesion ability of yeast, HT-29 cells, a human colon adenocarcinoma cell line, were mixed with 10% bovine serum, 100 U/ml penicillin, and 100 mg/ml. HT-29 cells were cultured in DMEM medium containing streptomycin at 37°C and 5% CO 2 conditions, and a monolayer was formed with 90% occupancy. The cultured yeast was corrected to a cell number of about 10 8 and then treated with HT-29. The treated yeast sample was cultured at 37°C and 5% CO 2 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, then the number of viable cells was measured, and the adhesive ability 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.Figure 2 is a graph measuring the survival rate in bile acid using the novel 28-7 strain isolated according to Example 1 of the present invention, the s288c strain of control group 1, and the biopolymer of control group 2; Figure 3 is a graph measuring the survival rate in acid using the novel 28-7 strain isolated according to Example 1 of the present invention, the s288c strain of control group 1, and the biopolymer of control group 2; Figure 4 is a graph measuring the attachment ability using Biopoly of the new 28-7 strain isolated according to Example 1 of the invention and the control group 2.
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 Figures 2 to 4, it was confirmed that the 28-7 strain of Example 1 showed a high survival rate of about 90% at a bile acid concentration of 0.3%, which was also superior to that of Biople of the control group 2.
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 showed high survival rates of about 103% and 109%, respectively, at pH 2 and pH 3, which was compared to the s288c strain of Control 1, which had a survival rate of 0 at both pH 2 and pH 3. It was confirmed that it was superior and similar to Biopl of Control Group 2.
또한, 장부착능에 있어서 실시예 1의 28-7 균주는 대조군 2의 비오플에 비하여 약 2배 높은 장부착능을 보이는 것을 확인하였다.In addition, it was confirmed that the 28-7 strain of Example 1 showed a tenon attachment ability that was about twice as high as that of Biople of Control Group 2.
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 be suitable for survival in the intestinal environment and to have better intestinal adhesion ability than strains of the same species, confirming that it has excellent probiotic function.
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. An animal test was conducted to determine whether the Saccharomyces boulardii 28-7 strain, a novel strain identified from yeast, is effective as a probiotic that helps the host's health when actually ingested. The efficacy of probiotics was examined using a mouse model of colitis induced by dextran sodium sulfate (DSS), which shows intestinal inflammation related to inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS). It is widely used as a model to induce inflammation. In particular, this is an animal model used to verify the efficacy of Bioflor, 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 in drinking water at a level of 1 to 3% by weight and fed to mice, and within a week, intestinal inflammation occurs, showing signs such as diarrhea, bloody stool, and weight loss. At this time, a disease score (disease activity index, DAI) is assigned according to the standard index, and finally, the mouse is sacrificed, and the shortening of the colon (colon) length and the increase in weight within the colon due to excessive inflammation are measured and expressed as indicators of weight/length. 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 approximately 20 g were used in the experiment, and the mice underwent an acclimatization process for 1 week before the experiment. Mice were raised on free diet in a breeding room with a temperature of 22ㅁ1℃ and 55%ㅁ10% humidity throughout the experiment, and the light/dark cycle was adjusted to a 12-hour cycle. All animal experiments were conducted in accordance with the Korea Food Research Institute's animal experiment operation regulations.
사카로마이세스 보울라디(Saccharomyces boulardii) 28-7 균주의 효능 평가를 위하여 마우스들을 랜덤으로 다섯 그룹으로 나누어 진행하였다. To evaluate the efficacy of Saccharomyces boulardii 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 was a group that did not administer DSS or strains, and the DSS group was a group in which intestinal inflammation was induced by feeding DSS (36-50kDA, MPBio) at a concentration of 3% by weight in drinking water. In addition, strains 28-7 (Example 1 group), Biople (Biople group), and s288c (s288c group) strains were orally administered at 10 8 CFU/day for 2 weeks before feeding 3% by weight DSS. After administration of the strain for 2 weeks, DSS was mixed with drinking water at a concentration of 3% by weight for 1 week, and during this period, daily weight, stool type, and bleeding pattern were scored according to the standards in Table 1 and DAI was recorded, and on the 7th day. On the next day, the DSS was replaced with a normal negative number and stabilized for two days. Blood and colonic tissue were obtained after fasting for 15 hours and then collected under anesthesia, 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 mean values between groups, and a p value lower than 0.05 was considered 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 intestinal inflammation improvement efficacy
시험예 2. 대장 내 염증 억제 효과 확인Test Example 2. Confirmation of the effect of suppressing inflammation in the large intestine
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 values of the DSS group, Example 1 group, non-Ople group, and s288c group, and Figure 6b is a graph showing the AUC of the normal group, DSS group, Example 1 group, non-Ople group, and s288c group. It's a graph.
DAI(disease activity index) 점수는 7일 동안 측정한 값의 area under curve (AUC)를 측정하여 개선 효능을 통계적으로 분석하였다. The DAI (disease activity index) score was statistically analyzed for improvement efficacy by measuring the area under curve (AUC) of values measured over 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 Figures 6a and 6b, it was confirmed that the AUC value of DAI was significantly reduced in the Example 1 group and the BIOPL group compared to the DSS group, and these results confirmed that intestinal inflammation was improved. .
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 any statistical difference from the DSS group, it was confirmed that not all intestinal inflammation was improved by simple administration of the strain alone, and that the effect of improving enteritis was only shown when treating specific strains.
특히, 본 발명의 실시예 1군은 수치상으로는 비오플군보다 우수한 수준의 장내 염증 개선효능을 가지는 것을 확인하였다.In particular, it was confirmed that the Example 1 group of the present invention had a numerically superior level of efficacy in improving intestinal inflammation than the Biople group.
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, BIOPL group, and s288c group; Figure 7b is a graph showing the weight/length of the large intestine in the normal group, DSS group, Example 1 group, BIOPL 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.When DSS is administered mixed with drinking water, inflammation is induced in the intestines, inflammatory cytokines are secreted in the intestines, polyps are formed in the intestinal wall, the colon wall thickens and its length decreases, and the weight per length of the colon increases accordingly, causing colitis. It can be used as a measurement indicator.
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. As shown in Figures 7a and 7b, the length and weight of the large intestine were measured after mouse sacrifice, and the length-to-weight ratio was significantly increased in the DSS group compared to the normal group, but this change was observed in the Example 1 group and the non-OPL group. The results were confirmed to be 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 length of the Example 1 group significantly increased compared to the DSS group, which had a reduced intestinal length. On the other hand, this effect was minimal 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 BIOPL group; Figure 8b is a graph showing the mRNA level of ZO1 in the normal group, DSS group, Example 1 group, and BIOPL 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 an intestinal inflammatory response is induced by DSS treatment, the secretion of various inflammatory cytokines increases and the homeostasis of the intestinal wall is broken, causing adverse effects such as increased gut permeability.
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 the indicators related to inflammatory cytokine secretion and intestinal leakage are actually improved by administration of the 28-7 strain of the present invention, interleukin-1β (IL-1β), a representative inflammatory cytokine, and intestinal wall-related The mRNA level of ZO1 (zonula occludens 1), an indicator, was examined. For this purpose, mRNA was extracted from colon tissue and synthesized into cDNA. RNA extraction was performed using the RNeasy PowerMicrobiome Kit (Qiagen), and RNA concentration measurement was performed with 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 of IL-1β, an inflammatory cytokine, in the colon was significantly increased by DSS treatment (DSS group), and this increase was observed in the 28-7 strain of the present invention and Biople. It was confirmed that the dose decreased by approximately 70%.
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 compared to the normal group by DSS treatment, which means that the permeability of the intestinal wall increased and intestinal wall leakage occurred. It was confirmed that this also recovered by administering the 28-7 strain and Biople. In particular, the 28-7 strain was confirmed to have a superior protective effect compared to Biople and induce recovery to the normal group level.
시험예 5. 혈중 염증성 사이토카인 측정Test Example 5. Measurement of inflammatory cytokines in the blood
도 9는 정상군, DSS군, 실시예 1군 및 비오플군의 혈액 내의 염증성 사이토카인 수준을 측정한 것이다.Figure 9 shows the measurement of inflammatory cytokine levels in the blood of the normal group, DSS group, Example 1 group, and BIOPL 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. To further confirm the effectiveness of improving inflammation, a cytokine antibody array was performed using blood (serum) samples to explore the level of inflammatory cytokines in the blood. This experiment was conducted using the Mouse cytokine array kit (R&D systems, ARY006) according to the protocol provided by the manufacturer. In this experiment, the protein in the blood reacts with the antibody attached to the membrane and appears in the form of a spot. By detecting this, the degree of cytokine secretion/expression can be detected 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 Figure 9, Example 1 group was confirmed to show an expression pattern similar to that of the normal group, which is believed to be superior to the expression pattern of the non-OPL 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 mean that Saccharomyces boulardii 28-7 strain, a new strain identified from yeast, is effective in alleviating inflammation in the large intestine induced by DSS.
균주의 장내 생존 측정Measurement of intestinal survival of strains
시험예 6. 균주의 장내 생존여부 확인Test Example 6. Confirmation of intestinal survival of strains
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 measuring the number of viable strains in the cecum of the normal group, DSS group, Example 1 group, and BIOPL group using Saccharomyces primers; Figure 10b is a graph measuring the number of viable strains in the cecum of the normal group, DSS group, Example 1 group, and Biople group using Saccharomyces cerevisiae primers.
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 in improving inflammation at a level similar to or higher than that of the commercially available Biople. Therefore, in order to confirm whether these strains can survive to the actual intestine during in vivo oral administration, RNA in the cecum was extracted and the log number of living strains (yeast) was confirmed. For this purpose, experimental mice were administered the strain (10 8 CFU) the day before sacrifice, fasted for 15 hours, anesthetized, and cecal contents were obtained. The cecal contents were weighed and transferred to a clean RNase- and DNase-free tube to extract total RNA. RNA extraction was performed using the RNeasy PowerMicrobiome Kit (Qiagen), and RNA concentration measurement was performed with a spectrophotometer (Varioskan, Thermo Electron Co.). It is impossible to produce a strain specific primer for the 28-7 strain of the present invention, and in fact, the genetic homology between S. cerevisiae and Saccharomyces boulardii is very high. Confirmation of S. boulardii is possible using S. cerevisiae specific primers.
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, to quantify live yeast in the cecum, two types of primers , S. cerevisiae specific primer and Saccharomyces primer, were used to identify S. boulardii . 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, which measured the number of viable bacteria, and compared to this, 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 Figures 10A and 10B, the log value per cecal content (g) is Since it was significantly increased by the administration of the 28-7 strain of the present invention, it was confirmed that the 28-7 strain, a novel strain, has an excellent survival rate in the intestine even when the strain itself is ingested orally. In particular, when detected using S. cerevisiae- specific primers, it was confirmed that the concentration of live S. cerevisiae when administered with strain 28-7 was more than 10 2 times higher than when administered with Biopl. This is a result of indirectly confirming that strain 28-7 can survive in the intestine more stably 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. Considering the above results 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 Biople, a commercially available drug. It was confirmed to be excellent.
하기에 본 발명의 분말을 함유하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Below, a formulation example of a composition containing the powder of the present invention is described, but the present invention is not intended to be limited, but merely explained in detail.
제제예 1. 산제의 제조Formulation Example 1. Preparation of powder
실시예 1에서 얻은 28-7 균주 500 mg500 mg of strain 28-7 obtained in Example 1
유당 100 mg100 mg lactose
탈크 10 mgTalc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled into an airtight bubble to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2. Preparation of tablets
실시예 1에서 얻은 28-7 균주 300 mg300 mg of strain 28-7 obtained in Example 1
옥수수전분 100 mgCorn starch 100 mg
유당 100 mg100 mg lactose
스테아린산 마그네슘 2 mgMagnesium stearate 2 mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above ingredients, tablets are manufactured by compressing them according to a typical tablet manufacturing method.
제제예 3. 캅셀제의 제조Formulation Example 3. Preparation of capsules
실시예 1에서 얻은 28-7 균주 200 mg200 mg of strain 28-7 obtained in Example 1
결정성 셀룰로오스 3 mg3 mg crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.Capsules are prepared by mixing the above ingredients and filling them into gelatin capsules according to a typical capsule manufacturing method.
제제예 4. 주사제의 제조Formulation Example 4. Preparation of injections
실시예 1에서 얻은 28-7 균주 600 mg600 mg of strain 28-7 obtained in Example 1
만니톨 180 mgMannitol 180 mg
주사용 멸균 증류수 2974 mgSterile distilled water for injection 2974 mg
Na2HPO4,12H2O 26 mgNa 2 HPO 4, 12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플 당 상기의 성분 함량으로 제조한다.It is prepared with the above ingredients per ampoule according to the usual manufacturing method for injections.
제제예 5. 액제의 제조Formulation Example 5. Preparation of liquid formulation
실시예 1에서 얻은 28-7 균주 4 g4 g of strain 28-7 obtained in Example 1
이성화당 10 g10 g isomerized sugar
만니톨 5 g5 g mannitol
정제수 적량Proper amount of purified water
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 the usual liquid preparation method, add and dissolve each ingredient in purified water, add an appropriate amount of lemon flavor, mix the above ingredients, add purified water, adjust the total to 100g by adding purified water, and then fill it in a brown bottle and sterilize it. to produce a liquid.
제제예 6. 과립제의 제조Formulation Example 6. Preparation of granules
실시예 1에서 얻은 28-7 균주 1,000 mg1,000 mg of strain 28-7 obtained in Example 1
비타민 혼합물 적량Vitamin mixture dosage
비타민 A 아세테이트 70 ㎍Vitamin A acetate 70 μg
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 mgVitamin B6 0.5 mg
비타민 B12 0.2 ㎍Vitamin B12 0.2 ㎍
비타민 C 10 mgVitamin C 10 mg
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 mgNicotinamide 1.7 mg
엽산 50 ㎍Folic acid 50 μg
판토텐산 칼슘 0.5 mgCalcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture appropriate amount
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 mgMonobasic Potassium Phosphate 15 mg
제2인산칼슘 55 mgDibasic calcium phosphate 55 mg
구연산칼륨 90 mgPotassium citrate 90 mg
탄산칼슘 100 mgCalcium carbonate 100 mg
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 above vitamin and mineral mixture is a mixture of components relatively suitable for granules in a preferred embodiment, but the mixing ratio may be modified arbitrarily. The above components are mixed according to a typical granule manufacturing method, and then the granules are mixed. It can be prepared and used to manufacture 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 strain 28-7 obtained in Example 1
구연산 1,000 mg1,000 mg citric acid
올리고당 100 g100 g oligosaccharides
매실농축액 2 g2 g plum concentrate
타우린 1 g1 g taurine
정제수를 가하여 전체 900 mLAdd purified water to make a total of 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 a typical health drink manufacturing method, stirring and heating at 85°C for about 1 hour, the resulting solution was filtered, placed in a sterilized 2 L container, sealed, sterilized, stored in the refrigerator, and then refrigerated. Used for manufacturing the functional beverage composition of the 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.The composition ratio is a preferred embodiment of mixing ingredients relatively suitable for beverages of preference, but the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as demand class, country of demand, and intended 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. 0.1 kg of strain 28-7 obtained in Example 1, 25.5 kg of corn, 15.04 kg of wheat, 8.15 kg of wheat flour, 7.4 kg of rice bran, 18 kg of soybean meal, 1 kg of octopus, 14 kg of chicken by-products, 9 kg of animal fat, 0.3 kg of processed salt. , 0.3 kg of tricalcium phosphate, 1 kg of limestone, 0.01 kg of choline chloride, 0.05 kg of vitamins, 0.05 kg of minerals, and 0.1 kg of digestive enzymes were mixed to prepare an animal (dog, pet) feed composition.
<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 it <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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| KR101893735B1 (en) | 2018-05-04 | 2018-08-31 | 주식회사이-글벳 | Pharmaceutical copositions for animal of previntion of intestinal disorder the same method |
| 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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| Title |
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| Korean J. Gastroenterol.,제76권,6호,314-321면(2020.12.) 1부.* |
| 메디컬투데이, 전통누룩서 프로바이오틱스 효모 기능 확인(2021.04.07.) 1부.* |
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