KR102397589B1 - Novel Lactobacillus fermentum MSK 408 strain and composition for preventing or treating of epilepsy comprising Lactobacillus fermentum MSK 408 - Google Patents
Novel Lactobacillus fermentum MSK 408 strain and composition for preventing or treating of epilepsy comprising Lactobacillus fermentum MSK 408 Download PDFInfo
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A61P25/00—Drugs for disorders of the nervous system
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Abstract
Description
본 발명은 신규한 락토바실러스 퍼멘텀 MSK 408 균주 및 이를 포함하는 뇌전증의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a novel Lactobacillus fermentum MSK 408 strain and a composition for preventing, improving or treating epilepsy comprising the same.
뇌전증은 기질적 병변 또는 기능적 장애로 인하여 뇌신경 세포의 발작적인 방전으로 간헐적인 신경계의 장애를 일으키고, 신경증상, 의식상실, 경련, 감각장애 등의 증상을 나타내는 질환이다. 알츠하이머병(Alzheimer) 및 뇌졸증(Stroke)에 이어 세 번째로 흔한 신경계 질환으로, 전 세계 인구의 약 0.5~2%가 뇌전증을 앓고 있다. 또한, 전 세계적으로는 매년 10만명 당 45명 정도로 새로운 환자가 발생하고 있고, 우리나라의 경우 약 30~40만 명의 뇌전증 환자가 있는 것으로 추정되고 있다.Epilepsy is a disease that causes intermittent nervous system disorders due to episodic discharge of cranial nerve cells due to organic lesions or functional disorders, and exhibits symptoms such as neurological symptoms, loss of consciousness, convulsions, and sensory disturbances. It is the third most common neurological disease after Alzheimer's disease and stroke, and about 0.5-2% of the world's population suffers from epilepsy. In addition, it is estimated that there are about 45 new cases per 100,000 people worldwide every year, and it is estimated that there are about 300,000 to 400,000 epilepsy patients in Korea.
뇌전증 환자의 연령 분포를 살펴보면, 전체 뇌전증의 70%가 소아청소년 연령에서 시작되고, 특히, 유아기에 발병률이 높은 것으로 알려져 있고, 발병률과 유병률은 생후 1년 이내에 가장 높았다가 급격히 낮아지고, 60세 이상의 노년층에서 다시 급격히 증가하는 U자 형태를 보이며, 일생동안 발작을 경험하는 유병률은 10~15%에 이른다.Looking at the age distribution of epilepsy patients, 70% of all epilepsy begins at the age of children and adolescents, and in particular, it is known that the incidence rate is high in infancy. It shows a U-shape that rapidly increases again in the elderly aged over the age of 10, and the prevalence of experiencing seizures throughout life reaches 10 to 15%.
뇌전증은 뇌전증 발작(epileptic seizure)이 반복적으로 발생하는 만성화된 질환으로서, 아직까지 정확한 발병원인은 밝혀져 있지 않은 실정이다. 다만, 최근 신경영상검사 기술의 발달에 따라 과거에는 관찰할 수 없었던 뇌의 미세한 병리적 변화들을 관찰할 수 있게 되면서 뇌전증의 원인에 대한 규명이 점차 확대되고 있다. 일부 역학 연구에서는 환자의 1/3 이상이 뇌에 생긴 병리적 변화나 뇌손상의 과거 병력이 있는 것으로 보고된바 있고, 주요한 원인으로는 뇌졸중, 선천기형, 두부외상, 뇌염, 뇌종양, 퇴행성 뇌병증, 유전, 미숙아, 분만 전후의 손상 등으로 알려져 있다.Epilepsy is a chronic disease in which epileptic seizures occur repeatedly, and the exact cause of epilepsy is still unknown. However, with the recent development of neuroimaging technology, microscopic pathological changes in the brain that could not be observed in the past can be observed, and the investigation of the cause of epilepsy is gradually expanding. In some epidemiological studies, it has been reported that more than 1/3 of patients have a history of pathological changes or brain damage in the brain. It is known as heredity, prematurity, and damage before and after delivery.
한편, 뇌전증의 치료는 크게 약물 치료와 약물외 치료, 즉 수술, 케톤식이요법, 미주신경자극술 등으로 분류할 수 있다. 뇌전증 치료제로 사용되고 있는 종래 약물들로 페니토인(Phenytoin: Dilantin), 발프로에이트(Valproate: Orfil, Depakine, Depakote), 카바마제핀(Carbamazepine: Tegretol), 페노바비탈(Phenobarbital: Luminal), 에토숙시마이드(Ethosuximide: Zarontin) 등이 있으나, 약물에 의한 위장 자극 및 어지럼증 등과 같은 부작용이 나타내고 있다.On the other hand, the treatment of epilepsy can be largely classified into drug treatment and non-drug treatment, that is, surgery, ketogenic diet, vagus nerve stimulation, and the like. Conventional drugs used for the treatment of epilepsy include phenytoin (Dilantin), valproate (Orfil, Depakine, Depakote), carbamazepine (Tegretol), phenobarbital (Phenobarbital: Luminal), etosuccimide ( Ethosuximide: Zarontin), but it has side effects such as gastrointestinal irritation and dizziness caused by the drug.
또 다른 치료방법 중 하나인 케톤식이요법은 지방을 많이 섭취하고, 탄수화물과 단백질은 적게 섭취하여 케토시스 상태가 되게 하는 식이요법으로, 인체의 에너지원은 탄수화물, 단백질, 지방 순인데, 체내에 탄수화물 또는 단백질이 부족하면 지방을 분해해서 에너지원을 얻는다. 이때 지방이 분해되면서 케톤이라는 유기화합물이 생성되어 케토시스 상태에 이르게 되며, 구체적인 작용원리는 확실하지 않지만 케토시스 상태가 경련을 억제하는 데 효과가 있다.The ketogenic diet, which is another treatment method, is a diet that consumes a lot of fat and a small amount of carbohydrates and protein to enter a state of ketosis. When protein is insufficient, fat is broken down to obtain energy. At this time, as fat is decomposed, an organic compound called ketone is produced, which leads to a state of ketosis.
이러한 케톤식이요법은 약물로 뇌전증이 조절되지 않는 경우 또는 약물로 조절되더라도 부작용이 아주 심하거나 평생 투여해야 하는 경우, 약을 끊거나 줄이기 위해 시행할 수 있다. 그러나 케톤식이는 메스꺼움, 구역질, 설사, 변비 등 장과 관련된 부작용을 유발할 수 있는 문제점이 있다.This ketogenic diet can be administered to stop or reduce the drug if the epilepsy is not controlled with drugs or if the side effects are very severe even if controlled with drugs or if administration is required for a lifetime. However, the ketogenic diet has a problem that can cause side effects related to the intestine, such as nausea, nausea, diarrhea, and constipation.
그러므로 체내 부작용을 유발시키지 않으면서 뇌전증의 예방, 개선 또는 치료 효과가 우수한 새로운 치료제의 개발이 필요하다.Therefore, it is necessary to develop a new therapeutic agent that is excellent in preventing, improving, or treating epilepsy without causing side effects in the body.
이에 본 발명자들은 김치로부터 신규한 유산균인 락토바실러스 퍼멘텀 MSK 408 균주를 분리 및 동정하였고, 상기 락토바실러스 퍼멘텀 MSK 408 균주가 장내 균총의 변화를 조절하고, 뇌의 포도당 대사량을 감소시키며, 혈중 콜레스테롤 및 염증성 사이토카인의 생성을 억제하고, 장 길이의 증가 및 장 건강 개선효과 뿐만아니라 뇌-혈관 장벽의 투과성을 조절을 통해 뇌전증을 효과적으로 예방, 개선 또는 치료할 수 있음을 확인함으로써 본 발명을 완성하였다.Accordingly, the present inventors isolated and identified a novel lactic acid bacterium, Lactobacillus Fermentum MSK 408 strain, from kimchi, and the Lactobacillus Fermentum MSK 408 strain regulates changes in intestinal flora, reduces brain glucose metabolism, and reduces blood cholesterol The present invention was completed by confirming that epilepsy can be effectively prevented, improved, or treated by inhibiting the production of inflammatory cytokines, increasing the length of the intestine and improving intestinal health, as well as controlling the permeability of the brain-vascular barrier. .
따라서 본 발명의 목적은 뇌전증의 예방, 개선 또는 치료 효과를 갖는 신규한 락토바실러스 퍼멘텀(Lactobacillus fermentum) MSK 408 균주(기탁번호: KCTC18855P)를 제공하는 것이다.Accordingly, it is an object of the present invention to provide a novel Lactobacillus fermentum MSK 408 strain (Accession No.: KCTC18855P) having an effect of preventing, improving or treating epilepsy.
본 발명의 다른 목적은 락토바실러스 퍼멘텀(Lactobacillus fermentum) MSK 408 균주(기탁번호: KCTC18855P), 이의 배양물 또는 이의 발효물을 유효성분으로 포함하는, 뇌전증의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving epilepsy, comprising Lactobacillus fermentum MSK 408 strain (Accession No.: KCTC18855P), its culture or its fermented product as an active ingredient will be.
본 발명의 다른 목적은 락토바실러스 퍼멘텀(Lactobacillus fermentum) MSK 408 균주(기탁번호: KCTC18855P), 이의 배양물 또는 이의 발효물을 유효성분으로 포함하는, 뇌전증의 예방 또는 치료용 약학적 식품 조성물을 제공하는 것이다.Another object of the present invention is Lactobacillus fermentum (Lactobacillus fermentum) MSK 408 strain (Accession No.: KCTC18855P), its culture or its fermented product comprising as an active ingredient, a pharmaceutical food composition for the prevention or treatment of epilepsy will provide
상기와 같은 본 발명의 목적을 달성하기 위해서, 본 발명은 락토바실러스 퍼멘텀(Lactobacillus fermentum) MSK 408 균주(기탁번호: KCTC18855P)를 제공한다.In order to achieve the object of the present invention as described above, the present invention provides a Lactobacillus fermentum (Lactobacillus fermentum) MSK 408 strain (Accession No.: KCTC18855P).
또한 본 발명은 락토바실러스 퍼멘텀(Lactobacillus fermentum) MSK 408 균주(기탁번호: KCTC18855P), 이의 배양물 또는 이의 발효물을 유효성분으로 포함하는, 뇌전증의 예방 또는 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for preventing or improving epilepsy, comprising Lactobacillus fermentum MSK 408 strain (accession number: KCTC18855P), a culture thereof or a fermented product thereof as an active ingredient.
본 발명의 일실시예에 있어서, 상기 조성물은, 뇌의 포도당 대사량 감소; 혈중 콜레스테롤 감소; 염증성 사이토카인의 생성 억제; 뇌-혈관 장벽의 투과성 조절; 및 장내 균총 개선 효과를 갖는 것일 수 있다.In one embodiment of the present invention, the composition, reduction of glucose metabolism in the brain; reducing blood cholesterol; inhibition of the production of inflammatory cytokines; regulation of permeability of the brain-vascular barrier; And it may have an effect of improving intestinal flora.
본 발명의 일실시예에 있어서, 상기 조성물은 발작 증상을 개선 또는 완화할 수 있다.In one embodiment of the present invention, the composition may improve or alleviate seizure symptoms.
본 발명의 일실시예에 있어서, 상기 조성물은 GABA 수용체인 GABAA1 및 GABAB1b; 또는 글루타메이트 수용체인 GLT-1의 발현을 증진시킬 수 있다.In one embodiment of the present invention, the composition comprises GABA receptors GABAA1 and GABAB1b; Alternatively, the expression of GLT-1, a glutamate receptor, may be enhanced.
본 발명의 일실시예에 있어서, 상기 조성물은 케톤식이와 병용 섭취할 수 있다.In one embodiment of the present invention, the composition may be taken in combination with a ketogenic diet.
또한 본 발명은 락토바실러스 퍼멘텀(Lactobacillus fermentum) MSK 408 균주(기탁번호: KCTC18855P), 이의 배양물 또는 이의 발효물을 유효성분으로 포함하는, 뇌전증의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating epilepsy, comprising Lactobacillus fermentum MSK 408 strain (Accession No.: KCTC18855P), a culture thereof, or a fermented product thereof as an active ingredient.
본 발명의 일실시예에 있어서, 상기 조성물은, 뇌의 포도당 대사량 감소; 혈중 콜레스테롤 감소; 염증성 사이토카인의 생성 억제; 뇌-혈관 장벽의 투과성 조절; 및 장내 균총 개선 효과를 갖는 것일 수 있다.In one embodiment of the present invention, the composition, reduction of glucose metabolism in the brain; reducing blood cholesterol; inhibition of the production of inflammatory cytokines; regulation of permeability of the brain-vascular barrier; And it may have an effect of improving intestinal flora.
본 발명의 일실시예에 있어서, 상기 조성물은 발작 증상을 개선 또는 완화할 수 있다.In one embodiment of the present invention, the composition may improve or alleviate seizure symptoms.
본 발명의 일실시예에 있어서, 상기 조성물은 GABA 수용체인 GABAA1 및 GABAB1b; 또는 글루타메이트 수용체인 GLT-1의 발현을 증진시킬 수 있다.In one embodiment of the present invention, the composition comprises GABA receptors GABAA1 and GABAB1b; Alternatively, the expression of GLT-1, a glutamate receptor, may be enhanced.
본 발명의 일실시예에 있어서, 상기 조성물은 케톤식이와 병용 투여할 수 있다.In one embodiment of the present invention, the composition may be administered in combination with a ketogenic diet.
본 발명에 따른 신규한 락토바실러스 퍼멘텀 MSK 408 균주는 뇌의 포도당 대사량 감소, 혈중 콜레스테롤 감소, 염증성 사이토카인의 생성 억제, 뇌-혈관 장벽의 투과성 조절, 장내 균총 개선활성을 나타낼 뿐만 아니라 GABA 수용체인 GABAA1 및 GABAB1b와 글루타메이트 수용체인 GLT-1의 발현을 증진시킬 수 있으며 발작 증상을 완화시킬 수 있는 활성이 있어 뇌전증의 예방, 개선 또는 치료용 제제로 유용하게 사용할 수 있다. 나아가 본 발명의 락토바실러스 퍼멘텀 MSK 408 균주는 종래 다양한 부작용이 나타나는 케톤식이 요법을 대체할 수 있거나 케톤식이와 병용 처리하여 효과적으로 뇌전증을 예방 또는 치료할 수 있는 효과가 있다.The novel Lactobacillus Fermentum MSK 408 strain according to the present invention exhibits a decrease in brain glucose metabolism, a decrease in blood cholesterol, inhibition of the production of inflammatory cytokines, regulation of brain-vascular barrier permeability, and intestinal flora improvement activity as well as GABA receptors. It can enhance the expression of GABAA1 and GABAB1b and GLT-1, a glutamate receptor, and has an activity to alleviate seizure symptoms, so it can be usefully used as an agent for preventing, improving or treating epilepsy. Furthermore, the Lactobacillus Fermentum MSK 408 strain of the present invention has the effect of effectively preventing or treating epilepsy by replacing the conventional ketogenic diet, which has various side effects, or by treating it in combination with the ketogenic diet.
도 1은 본 발명의 일실시예에서 마우스 동물모델의 실험 스케줄을 나타낸 모식도이다.
도 2는 본 발명의 일실시예에서 각 마우스 실험군에 대한 체중의 변화를 측정한 결과를 나타낸 것이다.
도 3은 본 발명의 일실시예에서 각 마우스 실험군에 대한 혈중 내 포도당, BHB, 총 콜레스테롤(TC), 총 지질(TG) 및 염증성 사이토카인(TNF-a)의 측정결과를 나타낸 것이다.
도 4는 본 발명의 일실시예에서 각 마우스 실험군을 대상으로 한, 뇌내 투과 조절 유전자(occludin, ZO-1, claudin), GABA, GABA 수용체(GABAA1과 GABAB1b) 및 글루타메이트 수용체인 GLT-1의 유전자 발현수준을 측정한 결과를 나타낸 것이다.
도 5는 본 발명의 일실시예에서 각 마우스 실험군을 대상으로 발작 증상의 개선 및 완화 정도를 분석한 결과를 나타낸 것이다.
도 6은 본 발명의 일실시예에서 각 마우스 실험군을 대상으로 단쇄 지방산인 아세트산, 프로피온산, 이소뷰티르산, 뷰티르산의 농도를 측정한 결과를 나타낸 것이다.
도 7은 본 발명의 일실시예에서 각 마우스 실험군을 대상으로 대장 내 장내 균총의 조성을 분석한 결과를 나타낸 것이다.
도 8은 본 발명의 일실시예에서 각 마우스 실험군을 대상으로 대장 내 장내 균총의 대사변화를 분석한 결과를 나타낸 것이다.1 is a schematic diagram showing an experimental schedule of a mouse animal model in an embodiment of the present invention.
2 shows the results of measuring the change in body weight for each mouse experimental group in an embodiment of the present invention.
Figure 3 shows the measurement results of glucose, BHB, total cholesterol (TC), total lipid (TG) and inflammatory cytokines (TNF-a) in blood for each mouse experimental group in an embodiment of the present invention.
4 is a gene for intracerebral permeation control genes (occludin, ZO-1, claudin), GABA, GABA receptors (GABAA1 and GABAB1b) and glutamate receptor GLT-1 for each mouse experimental group in an embodiment of the present invention; Shows the results of measuring the expression level.
5 shows the results of analyzing the degree of improvement and alleviation of seizure symptoms for each mouse experimental group in an embodiment of the present invention.
6 shows the results of measuring the concentrations of short-chain fatty acids acetic acid, propionic acid, isobutyric acid, and butyric acid in each mouse experimental group in an embodiment of the present invention.
7 shows the results of analyzing the composition of the intestinal flora in the large intestine for each mouse experimental group in an embodiment of the present invention.
8 shows the results of analysis of metabolic changes in the colonic intestinal flora for each mouse experimental group in an embodiment of the present invention.
본 발명은 신규한 락토바실러스 퍼멘텀 MSK 408 균주 및 상기 균주의 뇌전증 예방, 개선 또는 치료 용도를 규명한 점에 특징이 있다.The present invention is characterized in that the novel Lactobacillus Fermentum MSK 408 strain and the use of the strain for preventing, improving or treating epilepsy have been identified.
본 발명자들은 뇌전증의 새로운 치료제로서 부작용이 없으며 치료, 예방 또는 개선 효과가 우수한 새로운 치료제를 발굴하기 위해 연구하던 중, 김치로부터 분리된 신규한 락토바실러스 퍼멘텀 MSK 408 균주가 뇌전증을 효과적으로 예방, 개선 또는 치료할 수 있음을 확인하였다.While the present inventors were researching to discover a new therapeutic agent that has no side effects as a new therapeutic agent for epilepsy and has excellent treatment, prevention or improvement effects, a novel Lactobacillus Fermentum MSK 408 strain isolated from kimchi effectively prevents epilepsy, It was confirmed that it can be improved or treated.
그러므로 본 발명은 락토바실러스 퍼멘텀(Lactobacillus fermentum) MSK 408 신균주(기탁번호: KCTC18855P)를 제공할 수 있다.Therefore, the present invention can provide a new strain of Lactobacillus fermentum (Lactobacillus fermentum) MSK 408 (Accession No.: KCTC18855P).
본 발명에 따른 상기 락토바실러스 퍼멘텀(Lactobacillus fermentum) MSK 408 신균주는 한국생명공학연구원에 2020년 10월 16일자로 기탁하여 기탁번호 KCTC18855P를 부여받았다.The new strain of Lactobacillus fermentum MSK 408 according to the present invention was deposited with the Korea Research Institute of Bioscience and Biotechnology on October 16, 2020 and was given an accession number KCTC18855P.
본 발명의 일실시예에서는 락토바실러스 퍼멘텀 MSK 408 균주의 뇌전증 예방, 개선 또는 치료 활성이 있는지 확인하기 위해, 일반식이 및 케톤식이(뇌전증의 알려진 치료법)를 각각 본 발명의 락토바실러스 퍼멘텀 MSK 408 균주와 함께 마우스에 섭취하도록 하고, PTZ을 투여하여 뇌전증 발작을 유도한 후, 각 마우스 실험군을 대상으로 혈중 포도당, 총 콜레스테롤, 총 지질 및 염증성 사이토카인의 수준을 측정하였는데, 그 결과, 본 발명의 락토바실러스 퍼멘텀 MSK 408 균주가 뇌의 포도당 대사량을 감소시킬 수 있고, 총 콜레스테롤 수준 및 염증성 사이토카인의 수준을 감소시킬 수 있는 것으로 확인됨에 따라, 궁극적으로 뇌전증을 예방, 개선 또는 치료할 수 있음을 알 수 있었다.In one embodiment of the present invention, in order to check whether the Lactobacillus Fermentum MSK 408 strain has epilepsy preventing, ameliorating or therapeutic activity, a general diet and a ketogenic diet (known treatment for epilepsy) of the present invention, respectively, are administered. The mice were ingested together with the MSK 408 strain, and after inducing epilepsy by administering PTZ, the levels of blood glucose, total cholesterol, total lipids and inflammatory cytokines were measured for each mouse experimental group. As a result, As it was confirmed that the Lactobacillus Fermentum MSK 408 strain of the present invention can reduce brain glucose metabolism and can reduce total cholesterol levels and levels of inflammatory cytokines, ultimately preventing, improving or treating epilepsy. knew that it could be
또 다른 일실시예에서는 뇌전증의 유발 원인으로 알려진 뇌혈관 장벽의 손상 또는 파괴를 본 발명의 신균주가 억제할 수 있는지를 확인하기 위해, 뇌내 투과를 조절하는 occludin, ZO-1, claudin 유전자 발현수준을 분석하였는데, 본 발명의 MSK 408 균주를 투여한 군에서는, occludin, ZO-1 및 claudin 유전자의 발현수준이 크게 향상된 것으로 나타났다. 이를 통해 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주가 뇌-혈관 장벽의 투과성을 조절하여 뇌전증의 증상인 발작을 개선할 수 있음을 알 수 있었다.In another embodiment, in order to confirm that the new strain of the present invention can inhibit the damage or destruction of the cerebrovascular barrier, which is known to cause epilepsy, occludin, ZO-1, and claudin gene expression that regulate intracerebral permeation The level was analyzed, and in the group administered with the MSK 408 strain of the present invention, the expression levels of occludin, ZO-1 and claudin genes were significantly improved. Through this, it was found that the new strain of Lactobacillus Fermentum MSK 408 of the present invention can improve seizures, a symptom of epilepsy, by controlling the permeability of the brain-vascular barrier.
나아가 신경계에서 주된 억제성 신경전달물질로 알려진 GABA(γ-aminobutyric acid) 및 GABA 수용체에 미치는 영향을 분석하였는데, 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주가 GABA 수용체의 발현 증진을 통해 뇌전증을 개선, 예방 또는 치료할 수 있음을 확인하였다.Furthermore, the effects on GABA (γ-aminobutyric acid) and GABA receptors, which are known as major inhibitory neurotransmitters in the nervous system, were analyzed. It was confirmed that it can be improved, prevented or treated.
또한 본 발명자들은 실제적으로 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주가 뇌전증의 증상을 개선 또는 치료할 수 있는지 확인하기 위해, 락토바실러스 퍼멘텀 MSK 408 균주를 투여한 군과 투여하지 않은 군에 대하여 PTZ 투여로 발작 증상을 유도한 후, 발작 발생률, 사망률, 경련 지속 시간, 발작횟수, 발작 발병지연 정도를 측정하였다.In addition, in order to confirm whether the new Lactobacillus Fermentum MSK 408 strain of the present invention can improve or treat the symptoms of epilepsy, the present inventors actually administered the Lactobacillus Fermentum MSK 408 strain to the group administered and the group not administered. After inducing seizure symptoms with PTZ administration, seizure incidence, mortality, seizure duration, number of seizures, and seizure onset delay were measured.
그 결과, 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주를 투여함에 따라 사망률, 경련 지속 시간 및 발작 횟수가 감소하는 것으로 나타났고, 이러한 발작 증상의 개선 정도는 종래 치료법으로 알려진 케톤식이를 섭취하게 한 군과 거의 동등한 수준으로 나타났다.As a result, the administration of the new strain of Lactobacillus Fermentum MSK 408 of the present invention showed that mortality, seizure duration, and number of seizures decreased. was found to be almost equal to that of the group.
이를 통해 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주를 케톤식이 요법을 대체할 수 있는 새로운 뇌전증의 치료제로 사용 가능함을 확인하였으며, 락토바실러스 퍼멘텀 MSK 408 신균주를 사용할 경우에는 케톤식이 대신 일반식이와 함께 투여할 수 있으며, 또한 케톤식이와도 병행하여 사용할 수 있다.Through this, it was confirmed that the new strain of Lactobacillus Fermentum MSK 408 of the present invention can be used as a new treatment for epilepsy that can replace the ketogenic diet. It can be administered with a diet, and can also be used in combination with a ketogenic diet.
한편, 최근 보고되는 연구결과들에 의하면 장내 균총의 조성 또는 변화가 뇌질환과 상관관계가 있다고 밝혀지고 있다. 이에 본 발명자들은 락토바실러스 퍼멘텀 MSK 408 신균주가 장내 균총 조성에 영향을 미치는지 확인하는 실험을 수행하였다.On the other hand, according to the research results reported recently, it is revealed that the composition or change of the intestinal flora is correlated with brain diseases. Accordingly, the present inventors performed an experiment to determine whether the Lactobacillus permentum MSK 408 new strain affects the composition of the intestinal flora.
그 결과, 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주를 투여함에 따라 장내 균총의 변화가 발생하는 것으로 나타났고, 장내 균총의 대사에도 변화를 줄 수 있는 것으로 나타났는데, 락토바실러스 퍼멘텀 MSK 408 신균주 투여에 의해 Bifidobacteria를 감소시켜 장내 유익균의 농도를 증가시킬 수 있음을 알 수 있었다.As a result, it was found that changes in the intestinal flora occurred when the new Lactobacillus Fermentum MSK 408 strain of the present invention was administered, and it was found that it was possible to change the metabolism of the intestinal flora as well. It was found that the concentration of beneficial intestinal bacteria can be increased by reducing Bifidobacteria by administering the strain.
이러한 결과를 통해 본 발명의 락토바실러스 퍼멘텀 MSK 408 균주는 장내 미생물의 균총 및 대사체의 변화를 유도하여 장내 환경을 효과적으로 개선할 수 있음을 알 수 있었고, 이러한 장 건강 개선을 통해 뇌전증도 효과적으로 예방 또는 치료할 수 있음을 알 수 있었다.Through these results, it was found that the Lactobacillus Fermentum MSK 408 strain of the present invention can effectively improve the intestinal environment by inducing changes in the intestinal microflora and metabolites, and effectively prevent epilepsy through such improvement of intestinal health Or it could be treated.
그러므로 본 발명은 락토바실러스 퍼멘텀(Lactobacillus fermentum) MSK 408 균주(기탁번호: KCTC18855P), 이의 배양물 또는 이의 발효물을 유효성분으로 포함하는, 뇌전증의 예방 또는 개선용 식품 조성물을 제공할 수 있다.Therefore, the present invention can provide a food composition for preventing or improving epilepsy, comprising Lactobacillus fermentum MSK 408 strain (Accession No.: KCTC18855P), a culture thereof or a fermented product thereof as an active ingredient. .
본 발명에서 상기 “뇌전증”은 뇌의 비정상적인 과흥분과 과동기화로 인해 신경세포 중 일부가 발작적으로 짧은 시간에 과도한 전기를 발생시켜 발작(seizure)이 반복적으로 발생하는 만성화된 질환으로서, 신경생물학적, 정신적, 인지적, 사회적 변화를 수반하는 심각한 신경 질환이다. 또한, 신경세포가 퇴행 또는 사멸하면서 인지 장애, 행동 장애 등을 나타내는 일반적인 뇌신경계 질환과 달리, 뇌전증은 신경세포가 비정상적으로 과도하게 활성화됨에 따라 발생하는 뇌신경계 질환이라는 점에 특징이 있다. 또한, 신경세포의 비정상적 과다흥분성(hyperexcitability)에 의한 흥분독성(excitotoxicity)이 유발되어 뇌전증에 의한 병리학적 손상이 잘 나타나는 대뇌 부위 중 해마(hippocampus) 내에서 해마경화증(hippocampal sclerosis), 교질화(gliosis), 비정상적 신경발생(abnormal neurogenesis)과 치아이랑 과립세포 비정상적 세포구축(cytoarchitectural abnormality of dentate granule cells) 및 이상시냅스회로 형성(aberrant synpatic circuit)등이 나타난다. 위와 같은 해마 내 병리학적 현상들이 진행됨으로서 만성 뇌전증 발작(chronic epileptic seizure)이 발생되고 인지 및 기억 장애뿐만 아니라 약물 치료에 반응하지 않는 약제불응성 난치성 뇌전증이 발생된다.In the present invention, the “epilepsy” is a chronic disease in which seizures occur repeatedly due to abnormal hyperexcitability and hypersynchronization of the brain, in which some of the nerve cells convulsively generate excessive electricity in a short time. , is a serious neurological disease that involves mental, cognitive and social changes. In addition, unlike general neurological diseases in which nerve cells degenerate or die and show cognitive impairment, behavioral disorders, etc., epilepsy is characterized in that it is a neurological disease caused by abnormally excessive activation of nerve cells. In addition, excitotoxicity due to abnormal hyperexcitability of nerve cells is induced and, in the hippocampus, among cerebral regions where pathological damage due to epilepsy is well observed, hippocampal sclerosis, collagenization ( gliosis), abnormal neurogenesis, cytoarchitectural abnormality of dentate granule cells, and aberrant synpatic circuit. As the above pathological phenomena in the hippocampus progress, chronic epileptic seizures occur, cognitive and memory impairments, and drug-refractory epilepsy that does not respond to drug treatment occurs.
본 발명에서 사용되는 용어, “예방 ”이란 본 발명에 따른 약학적 조성물의 투여에 의해 뇌전증을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term “prevention” refers to any action that suppresses or delays the onset of epilepsy by administration of the pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어, “치료”란 본 발명에 따른 약학적 조성물의 투여에 의해 뇌전증에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term “treatment” refers to any action in which the symptoms of epilepsy are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
본 발명에 따른 상기 조성물, 즉 락토바실러스 퍼멘텀(Lactobacillus fermentum) MSK 408 균주(기탁번호: KCTC18855P), 이의 배양물 또는 이의 발효물을 유효성분으로 포함하는 조성물은 뇌의 포도당 대사량 감소; 혈중 콜레스테롤 감소; 염증성 사이토카인의 생성 억제; 뇌-혈관 장벽의 투과성 조절; 및 장내 균총 개선 효과를 모두 갖는 특징이 있으며, 또한 GABA 수용체인 GABAA1 및 GABAB1b; 또는 글루타메이트 수용체인 GLT-1의 발현을 증진시켜 발작 증상을 개선 또는 완화시킬 수 있다.The composition according to the present invention, that is, Lactobacillus fermentum MSK 408 strain (Accession No.: KCTC18855P), a culture thereof, or a composition comprising a fermented product thereof as an active ingredient reduces brain glucose metabolism; reducing blood cholesterol; inhibition of the production of inflammatory cytokines; regulation of permeability of the brain-vascular barrier; And it is characterized by having both an effect of improving intestinal flora, and also GABA receptors GABAA1 and GABAB1b; Alternatively, seizure symptoms may be improved or alleviated by enhancing the expression of GLT-1, a glutamate receptor.
나아가 본 발명의 조성물은 뇌전증의 예방, 개선 또는 치료를 위해 단독으로 이를 필요로 하는 개체에 투여 또는 섭취하게 할 수 있으며, 또는 케톤식이와 병용처리할 수도 있다.Furthermore, the composition of the present invention may be administered or ingested alone to an individual in need thereof for the prevention, improvement or treatment of epilepsy, or may be treated in combination with a ketogenic diet.
본 발명의 상기 조성물에는 본 발명의 락토바실러스 퍼멘텀 MSK 408 균주 자체뿐만 아니라 이의 파쇄물, 이의 배양물 또는 이의 발효물을 유효성분으로 포함할 수 있는데, 상기 파쇄물, 배양물 또는 발효물은 본 발명의 락토바실러스 퍼멘텀 MSK 408 균주 유래의 유용 생리활성 물질이 포함되어 있을 수 있고, 이는 균주 자체를 포함하는 조성물과 동등한 효과를 나타낼 수 있다.The composition of the present invention may include not only the Lactobacillus Fermentum MSK 408 strain of the present invention itself, but also a lysate thereof, a culture thereof or a ferment thereof as an active ingredient. Useful physiologically active substances derived from the Lactobacillus fermentum MSK 408 strain may be included, which may exhibit the same effect as the composition including the strain itself.
본 발명에서 상기 식품 조성물은 기능성 식품(functional food), 영양 보조제(nutritional supplement), 건강식품(health food) 및 식품 첨가제(food additives) 등의 모든 형태를 포함한다. 상기 유형의 식품 조성물은 당 업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다. 예를 들면, 건강식품으로는 본 발명의 균주 자체, 이의 파쇄물, 이의 배양물 및 이의 발효물로 이루어진 군 중에서 하나 이상을 차, 쥬스 및 드링크의 형태로 제조하여 음용하도록 하거나, 과립화, 캡슐화 및 분말화 하여 섭취할 수 있다. 또한, 본 발명의 균주 자체, 이의 파쇄물, 이의 배양물 및 이의 발효물 중에서 하나 이상을 프로바이오틱 활성이 있는 것으로 알려진 공지의 물질 또는 활성 성분과 함께 혼합하여 조성물의 형태로 제조할 수 있다. 또한, 기능성 식품으로는 음료(알콜성 음료 포함), 과실 및 그의 가공식품(예: 과일통조림, 병조림, 잼, 마아말 레이드 등), 어류, 육류 및 그 가공식품(예: 햄, 소시지콘비이프 등), 빵류 및 면류(예: 우동, 메밀국수, 라면, 스파게티, 마카로니 등), 과즙, 각종 드링크, 쿠키, 엿, 유제품(예: 버터, 치이즈 등), 식용식물유지, 마아가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료(예: 된장, 간장, 소스 등) 등에 본 발명의 균주, 이의 파쇄물, 배양물 및 이의 발효물로 이루어진 군 중 하나 이상을 첨가하여 제조할 수 있다.In the present invention, the food composition includes all types of functional food, nutritional supplement, health food, and food additives. Food compositions of this type can be prepared in various forms according to conventional methods known in the art. For example, as a health food, at least one of the strain itself of the present invention, its lysate, its culture, and its fermented product is prepared in the form of tea, juice and drink for drinking, or granulated, encapsulated and It can be consumed in powder form. In addition, it can be prepared in the form of a composition by mixing one or more of the strain itself, its lysate, its culture, and its fermented product of the present invention with a known substance or active ingredient known to have probiotic activity. In addition, functional foods include beverages (including alcoholic beverages), fruits and their processed foods (eg, canned fruit, bottled, jam, marmalade, etc.), fish, meat and their processed foods (eg, ham, sausage corn beef) etc.), breads and noodles (eg udon noodles, soba noodles, ramen, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, syrup, dairy products (eg butter, cheese, etc.), edible vegetable oils and fats, margarine, vegetable protein , retort food, frozen food, various seasonings (eg, soybean paste, soy sauce, sauce, etc.) can be prepared by adding one or more of the group consisting of the strain of the present invention, its lysate, its culture, and its fermented product.
본 발명의 식품 조성물 중 상기 본 발명의 균주 자체, 이의 파쇄물, 이의 배양물 또는 이의 발효물 등의 바람직한 함유량으로는 이에 한정되지 않지만 바람직하게는 최종적으로 제조된 식품 중 0.01 내지 50 중량%이다. 또한, 본 발명의 본 발명의 균주 자체, 이의 파쇄물, 이의 배양물 또는 이의 발효물을 유효성분으로서 식품 첨가제의 형태로 사용하기 위해서는 분말 또는 농축액 형태로 제조하여 사용할 수 있다.The preferred content of the strain itself of the present invention, its lysate, its culture or its fermented product in the food composition of the present invention is not limited thereto, but is preferably 0.01 to 50% by weight of the finally prepared food. In addition, in order to use the strain itself of the present invention, its lysate, its culture, or its fermented product in the form of a food additive as an active ingredient, it can be prepared and used in the form of a powder or concentrate.
또한, 본 발명은 락토바실러스 퍼멘텀 MSK 408 균주, 이의 배양물 또는 이의 발효물을 유효성분으로 포함하는, 뇌전증의 예방 또는 치료용 약학적 조성물을 제공할 수 있다.In addition, the present invention may provide a pharmaceutical composition for preventing or treating epilepsy, comprising the Lactobacillus permentum MSK 408 strain, a culture thereof, or a fermented product thereof as an active ingredient.
상기 약학적 조성물에는 약학적으로 허용 가능한 염을 단독으로 함유하거나 또는 하나 이상의 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 함유할 수 있다. 약학적으로 허용되는 담체로는 예컨대, 경구 투여용 담체 또는 비경구 투여용 담체를 추가로 포함할 수 있다. 경구 투여용 담체는 락토스, 전분, 셀룰로스 유도체, 마그네슘 스테아레이트, 스테아르산 등을 포함할 수 있다. 또한, 비경구 투여용 담체는 물, 적합한 오일, 식염수, 수성 글루코스 및 글리콜 등을 포함할 수 있으며, 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안정화제로는 아황산수소나트륨, 아황산나트륨 또는 아스코르브산과 같은 항산화제가 있다. 적합한 보존제로는 벤즈알코늄 클로라이드, 메틸- 또는 프로필-파라벤 및 클로로부탄올이 있다. 그 밖의 약학적으로 허용되는 담체로는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다(Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).The pharmaceutical composition may contain a pharmaceutically acceptable salt alone or may additionally contain one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, the carrier for parenteral administration may include water, a suitable oil, saline, aqueous glucose and glycol, and the like, and may further include a stabilizing agent and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives are benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. As other pharmaceutically acceptable carriers, reference may be made to those described in the following literature (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).
본 발명의 약학적 조성물은 인간을 비롯한 포유동물에 어떠한 방법으로도 투여할 수 있다. 예를 들면, 경구 또는 비경구적으로 투여할 수 있다. 비경구적인 투여방법으로는 이에 한정되지는 않으나, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장내 투여일 수 있다. 바람직하게는 본 발명의 약학적 조성물은 경구 또는 경피 투여될 수 있다.The pharmaceutical composition of the present invention may be administered to mammals including humans by any method. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration. can be Preferably, the pharmaceutical composition of the present invention may be administered orally or transdermally.
본 발명의 약학적 조성물은 상술한 바와 같은 투여 경로에 따라 경구 투여용 또는 비경구 투여용 제제로 제형화 할 수 있다.The pharmaceutical composition of the present invention may be formulated as a formulation for oral administration or parenteral administration according to the administration route as described above.
경구 투여용 제제의 경우에 본 발명의 조성물은 분말, 과립, 정제, 환제, 당의정제, 캡슐제, 액제, 겔제, 시럽제, 슬러리제, 현탁액 등으로 당업계에 공지된 방법을 이용하여 제형화될 수 있다. 예를 들어, 경구용 제제는 활성성분을 고체 부형제와 배합한 다음 이를 분쇄하고 적합한 보조제를 첨가한 후 과립 혼합물로 가공함으로써 정제 또는 당의정제를 수득할 수 있다. 적합한 부형제의 예로는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨 및 말티톨 등을 포함하는 당류와 옥수수 전분, 밀 전분, 쌀 전분 및 감자 전분 등을 포함하는 전분류, 셀룰로즈, 메틸 셀룰로즈, 나트륨 카르복시메틸셀룰로오즈 및 하이드록시프로필메틸-셀룰로즈 등을 포함하는 셀룰로즈류, 젤라틴, 폴리비닐피롤리돈 등과 같은 충전제가 포함될 수 있다. 또한, 경우에 따라 가교결합 폴리비닐피롤리돈, 한천, 알긴산 또는 나트륨 알기네이트 등을 붕해제로 첨가할 수 있다. 나아가, 본 발명의 약학적 조성물은 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.In the case of a formulation for oral administration, the composition of the present invention may be formulated as a powder, granule, tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension, etc. using methods known in the art. can For example, oral preparations can be obtained by mixing the active ingredient with a solid excipient, grinding it, adding suitable adjuvants, and processing it into a granule mixture to obtain tablets or dragees. Examples of suitable excipients include sugars, including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches, including corn starch, wheat starch, rice starch and potato starch, cellulose, Cellulose, including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, and the like, fillers such as gelatin, polyvinylpyrrolidone, and the like may be included. In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant if necessary. Furthermore, the pharmaceutical composition of the present invention may further include an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, and an antiseptic agent.
비경구 투여용 제제의 경우에는 주사제, 크림제, 로션제, 외용연고제, 오일제, 보습제, 겔제, 에어로졸 및 비강 흡입제의 형태로 당업계에 공지된 방법으로 제형화할 수 있다. 이들 제형은 모든 제약 화학에 일반적으로 공지된 처방서인 문헌(Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour)에 기재되어 있다.Formulations for parenteral administration may be formulated in the form of injections, creams, lotions, external ointments, oils, moisturizers, gels, aerosols and nasal inhalants by methods known in the art. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a recipe commonly known to all pharmaceutical chemistry.
본 발명의 균주 자체, 이의 파쇄물, 이의 배양물 또는 이의 발효물 등의 총 유효량은 단일 투여량(single dose)으로 환자에게 투여될 수 있으며, 다중 투여량(multiple dose)으로 장기간 투여되는 분할 치료 방법(fractionated treatment protocol)에 의해 투여될 수 있다. 본 발명의 약학적 조성물은 질환의 정도에 따라 유효성분의 함량을 달리할 수 있다. 바람직하게는 본 발명의 균주, 이의 파쇄물, 이의 배양물 또는 이의 발효물의 바람직한 전체 용량은 1일당 환자 체중 1 ㎏ 당 약 0.01ug 내지 1,000 mg, 가장 바람직하게는 0.1 ug 내지 100 mg일 수 있다. 그러나 상기 본 발명의 균주 자체, 이의 파쇄물, 이의 배양물 또는 이의 발효물 등의 용량은 약학적 조성물의 투여 경로 및 치료 횟수뿐만 아니라 환자의 연령, 체중, 건강 상태, 성별, 질환의 중증도, 식이 및 배설율 등 다양한 요인들을 고려하여 환자에 대한 유효 투여량이 결정되는 것이므로, 이러한 점을 고려할 때 당 분야의 통상적인 지식을 가진 자라면 상기 본 발명의 균주, 이의 파쇄물, 이의 배양물 또는 이의 발효물을 특정한 용도에 따른 적절한 유효 투여량을 결정할 수 있을 것이다. 본 발명에 따른 약학적 조성물은 본 발명의 효과를 보이는 한 그 제형, 투여 경로 및 투여 방법에 특별히 제한되지 아니한다.The total effective amount of the strain itself, its lysate, its culture, or its fermented product of the present invention can be administered to a patient as a single dose, and a divided treatment method in which multiple doses are administered for a long period of time (fractionated treatment protocol) can be administered. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the severity of the disease. Preferably, the preferred total dose of the strain of the present invention, its lysate, its culture or its fermented product is about 0.01 ug to 1,000 mg, most preferably 0.1 ug to 100 mg per kg of patient body weight per day. However, the dose of the strain itself of the present invention, its lysate, its culture or its fermented product, etc., depends not only on the route of administration of the pharmaceutical composition and the number of treatments, but also the age, weight, health status, sex, severity of the disease, diet and Since the effective dosage for the patient is determined in consideration of various factors such as the excretion rate, those with ordinary knowledge in the art in consideration of these points may prepare the strain of the present invention, its lysate, its culture, or its fermented product. It will be possible to determine an appropriate effective dosage for a particular application. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as the effect of the present invention is exhibited.
이하, 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. These Examples are for explaining the present invention in more detail, and the scope of the present invention is not limited to these Examples.
<실시예 1><Example 1>
락토바실러스 퍼멘텀 MSK 408 신균주의 분리 및 동정Isolation and identification of new strains of Lactobacillus permentum MSK 408
본 발명자들은 뇌전증 및 신경세포에 대한 보호효과를 갖는 새로운 균주를 동정하기 위해 김치로부터 본 발명의 균주를 분리 및 동정하였다. 이를 위해 먼저, 균질화기기를 사용하여 김치를 균질화시킨 후, 0.85% 생리식염수로 현탁하였다. 이후 현탁액을 MRS 한천배지에 도말한 후 37°C에서 48시간 배양하였고, 배양 후 형성된 콜로니를 취하여 MRS 배지에 획선 배양하여 오염되지 않은 단일 콜로니를 확보하였으며, 확보된 균주들로부터 16S rDNA를 분리하여 시퀀싱 분석을 수행하였다.The present inventors isolated and identified the strain of the present invention from kimchi in order to identify a new strain having a protective effect on epilepsy and nerve cells. To this end, first, the kimchi was homogenized using a homogenizer, and then suspended in 0.85% physiological saline. Then, the suspension was smeared on MRS agar medium and incubated for 48 hours at 37 °C. After culturing, colonies formed were taken and cultured in MRS medium to obtain uncontaminated single colonies, and 16S rDNA was isolated from the secured strains. Sequencing analysis was performed.
그 결과, 종래 확인되지 않았던 새로운 신균주인 MSK 408 균주를 동정하였고, 서열상동성 분석 결과, 락토바실러스 퍼멘텀(98% 서열상동성을 가짐)에 속하는 신균주임을 확인하였다.As a result, a new strain, MSK 408, which had not been previously identified was identified, and as a result of sequence homology analysis, it was confirmed that it was a new strain belonging to Lactobacillus permentum (having 98% sequence homology).
이에 본 발명자들은 김치로부터 분리된 신균주를 “락토바실러스 퍼멘텀 MSK 408 균주”로 명명하였고, 이를 한국생명공학연구원에 2020년 10월 16일자로 기탁하여 기탁번호 KCTC18855P를 부여받았다.Accordingly, the present inventors named the new strain isolated from kimchi as “Lactobacillus permentum MSK 408 strain”, and deposited it with the Korea Research Institute of Bioscience and Biotechnology on October 16, 2020, and was given an accession number KCTC18855P.
이후 동정한 상기 신균주는 MRS 액상배지를 이용하여 배양하였으며 pH 6.5 ± 0.2, 온도 37°C, 48시간의 조건으로 정치 배양하였다. 산소 요구성은 통성혐기성이고 동결건조보존 또는 세포현탁액 동결을 통해 균주를 보존시켰다.Thereafter, the identified new strains were cultured using MRS liquid medium and stationary cultured under conditions of pH 6.5 ± 0.2, temperature 37 °C, and 48 hours. Oxygen demand was facultative anaerobic and strains were preserved through freeze-drying preservation or cell suspension freezing.
<실시예 2><Example 2>
본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주 투여에 따른 체중의 변화여부 분석Analysis of changes in body weight according to the administration of the new Lactobacillus Fermentum MSK 408 strain of the present invention
<2-1> 마우스 동물모델의 준비<2-1> Preparation of mouse animal model
본 발명자들은 뇌전증의 치료법 중 하나인 케톤식이요법에 있어서 메스꺼움, 설사, 변비, 구역질과 같은 부작용의 문제를 해결하기 위한, 즉 케톤식이요법을 대체할 수 있는 새로운 개선 또는 치료 방법으로서, 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주를 사용할 수 있는지를 확인하기 위한 실험을 수행하였다.The present inventors provide a novel improvement or treatment method that can replace the ketogenic diet to solve the problems of side effects such as nausea, diarrhea, constipation, and nausea in the ketogenic diet, which is one of the treatments for epilepsy, the present invention An experiment was performed to determine whether the new strain of Lactobacillus Fermentum MSK 408 can be used.
이를 위해 먼저 하기 실시예들의 실험에 사용할 마우스 동물모델을 다음과 같이 준비하였다. 3주령의 마우스를 1주 동안 적응시킨 후, 4주령 째에 실험에 사용하였으며, 4주간 동안 마우스 군에는 일반 사료 또는 케톤 식이를 각각 자율 배급해 섭취하도록 하였다. 또한 이때 각 실험군은 상기 사료 또는 케톤식이 공급과 함께 본 발명의 MSK 408 균주를 1일 1회 경구 투여하도록 하였다. 이때 본 발명의 MSK 408 균주는 MRS 액상배지를 이용하여 배양한 뒤 원심분리 후, PBS 완충액으로의 3회 세척한 후, PBS로 현탁시킨 MSK 408 균주를 포함하는 용액을 경구 투여하였다. To this end, first, a mouse animal model to be used in the experiments of the following Examples was prepared as follows. A 3-week-old mouse was acclimatized for 1 week, and used for the experiment at the 4th week of age. For 4 weeks, the mouse group was allowed to autonomously distribute and ingest a general feed or a ketogenic diet, respectively. In addition, at this time, each experimental group was orally administered once a day with the MSK 408 strain of the present invention together with the feed or ketogenic diet. At this time, the MSK 408 strain of the present invention was cultured using an MRS liquid medium, followed by centrifugation, washed three times with PBS buffer, and then orally administered with a solution containing the MSK 408 strain suspended in PBS.
이후 각 마우스 실험군에 PTZ(pentylenetetrazole)을 40mg/kg의 양으로 복강 투여하여 뇌전증을 유발시킨 다음, 마우스들을 희생시켜 하기 실험분석에 사용하였다. 상기 기술된 실험동물의 준비과정에 대한 모식도는 도 1에 나타내었다.Thereafter, epilepsy was induced by intraperitoneal administration of PTZ (pentylenetetrazole) in an amount of 40 mg/kg to each mouse experimental group, and then mice were sacrificed and used for the following experimental analysis. A schematic diagram of the preparation process of the experimental animals described above is shown in FIG. 1 .
<2-2> 체중변화분석<2-2> Weight change analysis
상기 <2-1>에 따른 6개 그룹의 마우스 실험군들에 대한 체중을 분석하였다. 4주간 사육기간 동안의 체중변화를 측정하였다.The body weights of the six mouse experimental groups according to <2-1> were analyzed. Changes in body weight during 4 weeks of breeding were measured.
그 결과, 도 2에 나타낸 바와 같이, 케톤식이나 본 발명의 MSK 408 신균주 섭취에 의해 실험에 사용된 대부분의 마우스 군에서 체중의 유의미한 변화가 거의 없는 것으로 나타났다. 이러한 결과를 통해 본 발명자들은 4주간의 케톤식이(저탄수 고지방 식이)가 실험군들의 대사 경로를 전환해 케톤식이의 섭취에 의한 과도한 지방축적 현상이 유발되지 않는다는 것을 알 수 있었다. 또한 2종류의 식이(케톤식이 및 일반식이)가 같은 양의 에너지를 공급해 이후 실험결과에 영향을 미치지 않는다는 것을 확인하였다.As a result, as shown in FIG. 2, it was found that there was hardly any significant change in body weight in most of the mouse groups used in the experiment by ingestion of the ketogenic diet or the new MSK 408 strain of the present invention. Through these results, the present inventors found that the ketogenic diet (low-carbohydrate, high-fat diet) for 4 weeks did not induce excessive fat accumulation by ingestion of the ketogenic diet by converting the metabolic pathways of the experimental groups. In addition, it was confirmed that the two types of diet (ketogenic diet and general diet) supplied the same amount of energy and did not affect subsequent experimental results.
<실시예 3><Example 3>
본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주 투여에 따른 혈중 포도당, BHB, 총 콜레스테롤, 총 지질 및 염증성 사이토카인 수준에 미치는 영향분석Analysis of effects on blood glucose, BHB, total cholesterol, total lipid and inflammatory cytokine levels according to the administration of the new Lactobacillus Fermentum MSK 408 strain of the present invention
본 발명의 신규 유산균인 락토바실러스 퍼멘텀 MSK 408의 섭취가 혈중 내 포도당, BHB, 총 콜레스테롤, 총 지질 및 염증성 사이토카인의 수준변화에도 영향을 미치는지를 확인하기 위한 실험을 수행하였다. 이를 위해 상기 <2-1>의 마우스 실험군들을 대상으로 혈액을 채취한 후, 혈액 내에 함유된 포도당, BHB, 총 콜레스테롤, 총 지질 및 염증성 사이토카인(TNF-a)의 함량을 측정하였다.An experiment was performed to confirm whether the intake of Lactobacillus permentum MSK 408, a novel lactic acid bacterium of the present invention, also affects changes in the level of glucose, BHB, total cholesterol, total lipid and inflammatory cytokines in blood. To this end, blood was collected from the mouse experimental groups of <2-1>, and the contents of glucose, BHB, total cholesterol, total lipid and inflammatory cytokine (TNF-a) contained in the blood were measured.
그 결과, 도 3에 나타낸 바와 같이, 케톤식이 섭취 군은 일반식이 섭취 군에 비해 혈중 포도당 농도가 유의미하게 감소하는 것을 확인할 수 있었다. 한편, 일반 식이 섭취군에 본 발명의 MSK 408 균주를 경구 투여한 군(NPL)에서는 케톤식이 섭취군과 유사한 수준으로 혈중 포도당의 농도가 감소되는 것을 확인하였다(도 3A). 이를 통해 본 발명자들은 케톤식이 요법이 대사과정의 변화를 통해 뇌의 포도당 대사량을 감소시키는 방식으로 뇌전증을 개선 또는 치료하는 활성을 나타냄을 알 수 있었고, 본 발명의 락토바실러스 퍼멘텀 MSK 408 균주 역시 케톤식이와 유사하게 뇌의 포도당 대사량을 감소시킴을 통해 뇌전증을 예방, 개선 및 치료하는 활성이 있음을 알 수 있었다.As a result, as shown in FIG. 3 , it was confirmed that the ketogenic diet group significantly decreased the blood glucose concentration compared to the general diet group. On the other hand, it was confirmed that the concentration of blood glucose was reduced to a level similar to that of the ketogenic group in the group (NPL), in which the MSK 408 strain of the present invention was orally administered to the general dietary intake group (FIG. 3A). Through this, the present inventors found that the ketogenic diet exhibits the activity of improving or treating epilepsy in a way that reduces the amount of glucose metabolism in the brain through changes in the metabolic process, and the Lactobacillus Fermentum MSK 408 strain of the present invention is also Similar to the ketogenic diet, it was found that there was an activity to prevent, improve and treat epilepsy by reducing the amount of glucose metabolism in the brain.
또한, 혈중 BHB(베타 - 하이드록시 부티레이트) 농도 분석 결과, 케톤식이에 의해 혈중 BHB 농도는 증가하는 것으로 나타났고, 일반식이 섭취 군은 MSK 408 균주와 섭취를 병행하여도 BHB 농도에는 변화가 없는 것으로 나타났다. 이를 통해 케톤식이 요법은 대사과정의 변화를 유도하여 지방산의 대사물질인 BHB를 증가시키는 작용을 한다는 것을 알 수 있었다(도 3B).In addition, as a result of analysis of blood BHB (beta-hydroxybutyrate) concentration, it was found that the blood BHB concentration increased by the ketogenic diet, and the BHB concentration did not change in the general diet group even when the MSK 408 strain and intake were concurrently taken. appear. Through this, it was found that the ketogenic diet acts to increase BHB, a metabolite of fatty acids by inducing changes in metabolic processes (FIG. 3B).
또한, 일반식이 군과 비교했을 때 케톤식이를 섭취군은 혈중 콜레스테롤 농도 및 혈중 지질 농도가 크게 증가하는 것으로 나타난 반면, 본 발명의 MSK 408 균주를 섭취한 군은 일반식이와 케톤식이를 섭취한 군에서 혈중 콜레스테롤의 농도가 유의적으로 감소되는 것으로 나타났다(도 3C).In addition, when compared with the general diet group, the group consuming the ketogenic diet showed significant increases in blood cholesterol and blood lipid concentrations, whereas the group consuming the MSK 408 strain of the present invention received the general diet and the ketogenic diet. It was found that the concentration of blood cholesterol was significantly reduced in the (FIG. 3C).
또한, 케톤식이 섭취 군의 경우, 염증성 사이토카인인 TNF-α의 농도가 증가한 것으로 나타났으며, PTZ에 의해 발작이 유도된 일반식이 섭취 군에서도 TNF-α의 농도가 증가한 것으로 나타났으나, 본 발명의 MSK 408 균주를 섭취한 군들에서 에 TNF-α의 농도가 감소되는 것으로 나타났다(도 3E).In addition, in the case of the ketogenic diet group, the concentration of TNF-α, an inflammatory cytokine, was increased, and the concentration of TNF-α was also increased in the general diet group in which seizures were induced by PTZ. It was found that the concentration of TNF-α was decreased in the group ingested with the MSK 408 strain of the present invention (FIG. 3E).
이러한 결과를 통해 본 발명자들은 본 발명의 락토바실러스 퍼멘텀 MSK 408 균주가 뇌의 포도당 대사량을 감소시킬 수 있고, 총 콜레스테롤의 수준도 감소시킬 수 있으며, 염증성 사이토카인의 수준도 감소시킬 수 있어, 궁극적으로 뇌전증을 예방, 개선 또는 치료하는 용도로 사용 가능함을 알 수 있었다.Through these results, the present inventors found that the Lactobacillus Fermentum MSK 408 strain of the present invention can reduce brain glucose metabolism, can also reduce the level of total cholesterol, and can also reduce the level of inflammatory cytokines, ultimately It was found that it can be used for the purpose of preventing, improving, or treating epilepsy.
<실시예 4><Example 4>
본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주 투여에 따른 뇌-혈관 장벽 투과성 조절능 분석Analysis of brain-vascular barrier permeability control ability following administration of Lactobacillus Fermentum MSK 408 new strain of the present invention
뇌혈관 장벽은 특정물질이 혈관으로부터 뇌신경조직에 들어가는 것을 방지하는 장막으로서, 뇌혈관 장벽이 손상되거나 파괴되면 뇌전증의 유발 원인이 된다. 이에 본 발명자들은 본 발명의 락토바실러스 퍼멘텀 MSK 균주가 뇌 투과를 조절하는 인자들로 알려진 occludin, ZO-1, claudin 유전자들의 발현 변화에 영향을 미치는지를 분석하기 위해, 상기 <2-1>의 각 마우스 실험군으로부터 뇌 조직을 수득한 후, 상기 유전자들의 발현수준을 qRT-PCR 방법을 통해 측정하였다.The cerebrovascular barrier is a barrier that prevents certain substances from entering the brain nervous system from blood vessels, and when the cerebrovascular barrier is damaged or destroyed, it causes epilepsy. Accordingly, the present inventors analyzed whether the Lactobacillus fermentum MSK strain of the present invention affects the expression change of occludin, ZO-1, and claudin genes, which are known as factors regulating brain permeation, in <2-1>. After obtaining brain tissue from each mouse experimental group, the expression level of the genes was measured by qRT-PCR method.
그 결과, 도 4에 나타낸 바와 같이, 일반식이 및 케톤식이의 식이변화에 따른 뇌내 투과를 조절하는 occludin, ZO-1, claudin 유전자 발현은 변화하지 않는 것으로 나타났다. 그러나 본 발명의 MSK 408 균주를 투여한 군은, 식이법에 관계없이 occludin, ZO-1, claudin 유전자의 발현수준이 크게 향상된 것으로 나타났다(도 4A~4C). 이러한 결과는 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주가 뇌-혈관 장벽의 투과성을 조절해 발작을 조절할 수 있음을 의미한다.As a result, as shown in FIG. 4 , it was found that the expression of occludin, ZO-1, and claudin genes, which regulate intracerebral permeation according to dietary changes in the general diet and the ketogenic diet, did not change. However, the group administered with the MSK 408 strain of the present invention showed significantly improved expression levels of occludin, ZO-1, and claudin genes regardless of the dietary method (FIGS. 4A to 4C). These results mean that the new strain of Lactobacillus Fermentum MSK 408 of the present invention can control seizures by controlling the permeability of the brain-vascular barrier.
또한, 본 발명자들은 GABA 농도와 GABA 수용체인 GABAA1 및 GABAB1b, 글루타메이트 수용체인 GLT-1의 발현수준도 측정하였는데, 그 결과, 케톤식이 섭취군은 뇌내 GABA 농도와 GABA 수용체인 GABAA1 및 GABAB1b, 글루타메이트 수용체인 GLT-1의 유전자 발현변화에는 크게 영향을 주지 않는 것으로 나타났다.In addition, the present inventors also measured the GABA concentration and the expression levels of GABA receptors GABAA1 and GABAB1b, and glutamate receptor GLT-1. It was found that there was no significant effect on the gene expression change of GLT-1.
한편, 케톤식이와 MSK 408 균주를 함께 처리한 군(KPL)에서는 GABA의 수용체인 GABAA1 및 GABAB1b의 유전자 발현이 증가되어 있는 것으로 나타났으며, 일반식이에 MSK 408 균주를 함께 처리한 군에서는 GLT-1 유전자의 발현이 증가된 것으로 나타났다(도 4E~4H).On the other hand, in the group (KPL) treated with the ketogenic diet and MSK 408 strain, gene expression of GABA receptors GABAA1 and GABAB1b was increased, and in the group treated with the MSK 408 strain in the general diet, GLT- It was found that the expression of 1 gene was increased (FIGS. 4E-4H).
이러한 결과를 통해 본 발명자들은 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주가 GABA의 직접적 생산에 영향을 미치는 대신 GABA 수용체의 발현 조절을 통해 뇌전증을 개선, 예방 또는 치료할 수 있음을 알 수 있었다.Through these results, the present inventors found that the new strain of Lactobacillus Fermentum MSK 408 of the present invention can improve, prevent or treat epilepsy by regulating the expression of GABA receptors instead of affecting the direct production of GABA.
GABA(γ-aminobutyric acid)는 신경계에서 주된 억제성 신경전달물질로서, 항우울 효과, 진정 효과, 이뇨 효과가 있는 것으로 알려져 있고, 간질, 파킨슨병, 알츠하이머병, 헌팅턴병 등의 신경학적 질환에 효과가 있는 것으로 보고된 바 있다. 또한, GABA 수용체의 활성화제는 GABA 농도증가 없이 GABA 강화작용을 발현시킴을 통해 뇌전증을 포함하는 신경학적 질환의 치료 효과를 유도할 수 있다.GABA (γ-aminobutyric acid) is a major inhibitory neurotransmitter in the nervous system and is known to have antidepressant, sedative, and diuretic effects. It has been reported that there is In addition, the GABA receptor activator can induce a therapeutic effect on neurological diseases including epilepsy by expressing GABA potentiation without increasing GABA concentration.
따라서 본 발명의 결과를 통해, 락토바실러스 퍼멘텀 MSK 408 신균주는 GABA 수용체의 발현조절, 구체적으로는 GABA 수용체의 발현 증진을 통해 뇌전증을 개선, 예방 또는 치료할 수 있다.Therefore, through the results of the present invention, the new Lactobacillus Fermentum MSK 408 strain can improve, prevent or treat epilepsy by regulating the expression of GABA receptors, specifically, enhancing the expression of GABA receptors.
<실시예 5><Example 5>
본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주 투여에 따른 뇌전증 발작 증상의 개선효과 확인Confirmation of the improvement effect of epilepsy seizure symptoms according to the administration of the new strain of Lactobacillus Fermentum MSK 408 of the present invention
본 발명은 락토바실러스 퍼멘텀 MSK 408 신균주의 투여가 실질적으로 뇌전증의 증상인 발작증상을 완화시킬 수 있는지 확인하기 위해 다음과 같은 실험을 수행하였다. 상기 <2-1>의 마우스 실험군을 대상으로, 발작 발생률, 사망률, 경련 지속 시간, 발작횟수, 발작 발병지연 정도를 측정하였다.In the present invention, the following experiment was performed to confirm that the administration of the new strain of Lactobacillus Fermentum MSK 408 can substantially alleviate seizure symptoms, which are symptoms of epilepsy. For the mouse experimental group of <2-1> above, seizure incidence, mortality, seizure duration, number of seizures, and seizure onset delay degree were measured.
그 결과, 케톤식이를 수행한 군에서는 발작의 시작 시간이 늦춰지는 것으로 나타났고, 발작 발생률과 사망률, 경련 지속시간 및 발작 횟수도 감소하는 것으로 나타났다. 또한, 일반식이와 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주를 투여한 군은 케톤식이 섭취군과 비슷한 수준으로 사망률, 경련 지속 시간 및 발작 횟수가 감소하는 것으로 나타났다(도 5A~5E).As a result, the onset time of seizures was delayed in the ketogenic diet group, and the seizure incidence and mortality, seizure duration, and number of seizures were also reduced. In addition, the group administered with the general diet and the new strain of Lactobacillus Fermentum MSK 408 of the present invention was found to have reduced mortality, duration of seizures, and number of seizures to a level similar to that of the ketogenic diet group ( FIGS. 5A to 5E ).
따라서 이러한 결과를 통해 본 발명자들은 본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주가 뇌전증의 발작을 완화 또는 개선시키는 효과가 있는 것을 알 수 있었고, 기존 뇌전증의 치료법 중 하나인 케톤식이를 대체할 수 있을 정도로 개선 효과가 우수한 것을 알 수 있었다.Therefore, through these results, the present inventors found that the new strain of Lactobacillus Fermentum MSK 408 of the present invention has the effect of alleviating or improving seizures of epilepsy, and can replace the ketogenic diet, which is one of the existing treatments for epilepsy. It was found that the improvement effect was excellent enough to be possible.
<실시예 6><Example 6>
본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주 투여에 따른 단쇄지방산 변화에 미치는 영향분석Analysis of effects on changes in short-chain fatty acids according to the administration of the new Lactobacillus Fermentum MSK 408 strain of the present invention
본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주를 섭취하였을 때, 체내 단쇄지방산의 농도에 영향을 미치는지를 확인하기 위한 실험을 수행하였다. 상기 <2-1>의 마우스 실험군의 분변 시료로부터 아세트산, 프로피온산, 이소뷰티르산 및 뷰티르산의 농도를 가스 크로마토그래피 방법을 이용하여 측정하였다.When the Lactobacillus Fermentum MSK 408 new strain of the present invention was ingested, an experiment was performed to confirm whether it affects the concentration of short-chain fatty acids in the body. Concentrations of acetic acid, propionic acid, isobutyric acid and butyric acid were measured from the fecal samples of the mouse experimental group of <2-1> by using a gas chromatography method.
그 결과, 도 6에 나타낸 바와 같이, 케톤식이를 섭취한 군은 일반식이 섭취군에 비해 프로피온산, 이소뷰티르산 및 뷰티르산의 농도가 감소한 것으로 나타났고, 단쇄 지방산의 총 함량이 감소한 것으로 나타났다. 본 발명의 MSK 408 균주를 섭취했을 때에는 일반식이 섭취군에 비해 모든 단쇄 지방산의 비율이 감소한 것으로 나타났다. As a result, as shown in FIG. 6 , the concentration of propionic acid, isobutyric acid and butyric acid was decreased in the group consuming the ketogenic diet compared to the general diet intake group, and the total content of short-chain fatty acids was decreased. When the MSK 408 strain of the present invention was ingested, it was found that the ratio of all short-chain fatty acids was reduced compared to the general dietary intake group.
또한 케톤식이와 본 발명의 MSK 408 균주를 함께 섭취시킨 군에서는 아세트산과 이소뷰티르산의 농도가 증가함에 비해 프로피온산과 뷰티르산의 농도는 감소하는 것으로 나타났다. In addition, the concentration of propionic acid and butyric acid decreased while the concentration of acetic acid and isobutyric acid increased in the group fed together with the ketogenic diet and the MSK 408 strain of the present invention.
이러한 결과를 통해 본 발명자들은 본 발명의 MSK 408 균주를 케톤식이 요법과 병행하여 투여할 경우, 아세트산에 비해 뷰티르산의 용출량을 효과적으로 감소시켜 뇌-혈관 장벽의 보호 효과를 나타낼 수 있음을 알 수 있었고, 프로피온산 및 뷰티르산을 대사 과정에서 사용하여 뇌전증을 보호하는 효과를 유도할 수 있음을 알 수 있었다. Through these results, the present inventors found that when the MSK 408 strain of the present invention is administered in parallel with a ketogenic diet, the elution amount of butyric acid is effectively reduced compared to acetic acid, thereby exhibiting a protective effect on the brain-vascular barrier. , it was found that propionic acid and butyric acid can be used in the metabolic process to induce a protective effect against epilepsy.
<실시예 7><Example 7>
본 발명의 락토바실러스 퍼멘텀 MSK 408 신균주 투여에 따른 장내 균총변화에 미치는 영향분석Analysis of the effect on changes in intestinal flora according to the administration of the new Lactobacillus Fermentum MSK 408 strain of the present invention
<7-1> 장내 균총 조성의 변화<7-1> Changes in the composition of intestinal flora
장내 미생물이 뇌질환과 상관관계가 있음이 최근 보고되고 있으며, 장내 미생물 집합체들이 병원성 감염예방, 면역과정 조절, 장내 영양흡수 등에 매우 중요한 역할을 한다는 사실이 최근 밝혀지고 있다. 이에 본 발명자들은 본 발명의 락토바실러스 퍼멘텀 MSK 408 균주 섭취에 따른 장내 미생물 균총 변화가 있는지 확인하기 위한 실험을 수행하였다.It has recently been reported that the intestinal microflora is correlated with brain diseases, and it has been recently revealed that the gut microbe aggregates play a very important role in preventing pathogenic infections, regulating immune processes, and nutrient absorption in the gut. Accordingly, the present inventors performed an experiment to confirm whether there is a change in the intestinal microbial flora according to the intake of the Lactobacillus permentum MSK 408 strain of the present invention.
이를 위해 상기 <2-1>의 각 마우스 실험군으로부터 대장을 채취하고 대장 내에 존재하는 미생물의 균총을 주성분 분석법을 통해 균총 조성을 조사하였다.To this end, the colon was collected from each mouse experimental group of <2-1>, and the colony composition of microorganisms present in the large intestine was investigated through the main component analysis method.
그 결과, 도 7에 나타낸 바와 같이, 식이 변화가 그룹 간 차이를 유발하는 가장 큰 요인이라는 것을 알 수 있었다. 한편 케톤식이 군의 경우, MSK 408 균주 처리 여부에 따라 그룹 간의 차이가 발생하는 것으로 나타났다. 구체적으로, 장내 균총의 phylum 분석 결과, 고지방 케톤식이 섭취에 의해 Proteobacteria가 증가하고 Actinobacteria가 감소하는 것으로 나타났고, 또한 케톤식이와 MSK 408 균주를 병용 처리한 군에서는 Bacteroidetes가 크게 감소한 것으로 나타났으며, Firmicutes와 Deferribacteres가 유의미하게 증가한 것으로 나타났다. 이를 통해 본 발명의 MSK 408 균주가 Bacteroidetes를 감소시켜 장내 유익균의 농도를 증가시키는 작용을 한다는 것을 알 수 있었다. As a result, as shown in FIG. 7 , it was found that the change in diet was the biggest factor causing the difference between groups. On the other hand, in the case of the ketogenic group, it was found that differences between the groups occurred depending on whether or not the MSK 408 strain was treated. Specifically, as a result of phylum analysis of the intestinal flora, Proteobacteria increased and Actinobacteria decreased by ingestion of a high-fat ketogenic diet. Also, Bacteroidetes were significantly reduced in the group treated with the ketogenic diet and MSK 408 strain. Firmicutes and Deferribacteres were significantly increased. Through this, it was found that the MSK 408 strain of the present invention acts to increase the concentration of beneficial bacteria in the intestine by reducing Bacteroidetes.
또한, 장내 균총의 genus 분석결과, 케톤식이에 의해 Alistipes의 농도가 감소하는 것으로 나타났고, 뷰티르산을 생성한다고 알려진 Butyricimonas의 농도가 케톤 식이와 MSK 408 균주 섭취 이후 크게 감소한 것으로 나타났는데 이는 MSK 408 균주에 의해 장내 뷰티르산 생성이 촉진되어 상대적으로 Butyricimonas의 농도가 감소한 것으로 볼 수 있다. 이러한 결과를 통해 본 발명의 MSK 408 균주를 케톤 식이와 병행 섭취하게 되면 장내 균총을 변화시킬 수 있음을 알 수 있었다.In addition, as a result of the genus analysis of the intestinal flora, the concentration of Alisipes was decreased by the ketogenic diet, and the concentration of Butyricimonas, which is known to produce butyric acid, was significantly decreased after the ketogenic diet and the intake of the MSK 408 strain. It can be seen that the production of butyric acid in the intestine was promoted by Through these results, it was found that when the MSK 408 strain of the present invention was consumed in parallel with a ketogenic diet, the intestinal flora could be changed.
<7-2> 장내 균총의 대사 변화<7-2> Metabolic changes in intestinal flora
PICRUSt 분석을 통해 장내 균총의 대사 변화도 분석하였다. Metabolic changes in the intestinal flora were also analyzed through PICRUSt analysis.
그 결과, 도 8에 나타낸 바와 같이, 케톤식이에 의해 포도당 함량이 낮아져 mTOR 대사 경로가 감소한 것으로 나타났고, GABA를 사용하는 시냅스 대사량은 증가한 것으로 나타났다. 또한 본 발명의 MSK 408 균주를 단독 처리한 군은 TCA 회로가 억제되고, 케톤식이 섭취군과 마찬가지로 GABA 시냅스 대사량이 증가하는 것으로 나타났다. As a result, as shown in FIG. 8, the glucose content was lowered by the ketogenic diet, which resulted in a decrease in the mTOR metabolic pathway, and an increase in synaptic metabolism using GABA. In addition, the group treated with the MSK 408 strain of the present invention alone suppressed the TCA cycle, and it was found that GABA synaptic metabolism increased as in the ketogenic group.
반면 케톤식이와 MSK 408 균주를 동시 처리한 군에서는 단쇄 지방산의 대사량이 증가하고 TCA 회로가 활성화되는데, 이와 같은 결과가 발생하는 이유로 탄수화물의 함량이 적은 케톤식이를 섭취해 MSK 408 균주가 단쇄 지방산의 재흡수를 촉진하고, 이를 TCA 대사에 사용한 것으로 볼 수 있다. 이를 통해 본 발명의 락토바실러스 퍼멘텀 MSK 408 균주는 케톤식이 요법에 있어서 대사 과정에 변화를 줄 수 있음을 알 수 있었다.On the other hand, in the group treated with the ketogenic diet and MSK 408 strain simultaneously, the metabolic rate of short-chain fatty acids increased and the TCA cycle was activated. It can be seen that it promotes reabsorption and is used for TCA metabolism. Through this, it was found that the Lactobacillus Fermentum MSK 408 strain of the present invention can change the metabolic process in the ketogenic diet.
종합적으로 상기와 같은 실험결과들을 통해 본 발명자들은 본 발명에서 동정한 신규 유산균인 락토바실러스 퍼멘텀 MSK 408 균주가 뇌의 포도당 대사량을 감소시키고, 혈중 콜레스테롤 및 염증성 사이토카인의 생성을 억제할 수 있으며, 장내 균총의 변화 조절을 통한 장 건간 개선효과를 나타낼 수 있을 뿐만 아니라 뇌-혈관 장벽의 투과성 조절 및 발작 증상의 개선을 통해 뇌전증을 예방, 개선 또는 치료할 수 있는 치료제 및 건강기능식품에 유용하게 사용할 수 있음을 알 수 있었다.Overall, through the above experimental results, the present inventors found that the Lactobacillus fermentum MSK 408 strain, a novel lactic acid bacterium identified in the present invention, can reduce brain glucose metabolism and inhibit the production of blood cholesterol and inflammatory cytokines, Not only can it exhibit the effect of improving intestinal health by controlling changes in the intestinal flora, but it can also be usefully used in therapeutics and health functional foods that can prevent, improve or treat epilepsy by controlling the permeability of the brain-vascular barrier and improving seizure symptoms. knew it could be
또한, 종래 뇌전증 치료요법으로 사용되는 케톤식이를 대체할 수 있고, 또는 케톤식이와 병행할 수 있음을 알 수 있었다.In addition, it was found that it can replace the ketogenic diet used as a conventional epilepsy therapy, or can be combined with the ketogenic diet.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, with respect to the present invention, the preferred embodiments have been looked at. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
Claims (11)
상기 조성물은,
뇌의 포도당 대사량 감소;
혈중 콜레스테롤 감소;
염증성 사이토카인인 TNF-α의 생성 억제;
뇌-혈관 장벽의 투과성 조절; 및
장내 의간균류(bacteroidetes)는 감소시키고, 후벽균류(firmicutes) 및 탈철간균류(deferribacteres)는 증진시키는 활성을 갖는 것을 특징으로 하는, 뇌전증의 예방 또는 개선용 식품 조성물.3. The method of claim 2,
The composition is
decreased glucose metabolism in the brain;
reducing blood cholesterol;
inhibition of the production of TNF-α, an inflammatory cytokine;
regulation of permeability of the brain-vascular barrier; and
A food composition for the prevention or improvement of epilepsy, characterized in that it has an activity to reduce intestinal bacteroidetes, and enhance activity of firmicutes and deferribacteres.
상기 조성물은 발작 증상을 개선 또는 완화하는 것을 특징으로 하는, 뇌전증의 예방 또는 개선용 식품 조성물.3. The method of claim 2,
The composition is characterized in that the improvement or alleviation of seizure symptoms, the prevention or improvement of epilepsy food composition.
상기 조성물은 GABA 수용체인 GABAA1 및 GABAB1b; 또는 글루타메이트 수용체인 GLT-1의 발현을 증진시키는 것을 특징으로 하는, 뇌전증의 예방 또는 개선용 식품 조성물.3. The method of claim 2,
The composition comprises GABA receptors GABAA1 and GABAB1b; Or a food composition for preventing or improving epilepsy, characterized in that it enhances the expression of GLT-1, a glutamate receptor.
상기 조성물은 케톤식이와 병용 섭취하는 것을 특징으로 하는, 뇌전증의 예방 또는 개선용 식품 조성물.3. The method of claim 2,
The composition is a food composition for the prevention or improvement of epilepsy, characterized in that it is consumed in combination with a ketogenic diet.
상기 조성물은,
뇌의 포도당 대사량 감소;
혈중 콜레스테롤 감소;
염증성 사이토카인인 TNF-α의 생성 억제;
뇌-혈관 장벽의 투과성 조절; 및
장내 의간균류(bacteroidetes)는 감소시키고, 후벽균류(firmicutes) 및 탈철간균류(deferribacteres)는 증진시키는 활성을 갖는 것을 특징으로 하는, 뇌전증의 예방 또는 치료용 약학적 조성물.8. The method of claim 7,
The composition is
decreased glucose metabolism in the brain;
reducing blood cholesterol;
inhibition of the production of TNF-α, an inflammatory cytokine;
regulation of permeability of the brain-vascular barrier; and
A pharmaceutical composition for the prevention or treatment of epilepsy, characterized in that it has an activity of reducing intestinal bacteroidetes and enhancing activity of firmicutes and deferribacteres.
상기 조성물은 발작 증상을 개선 또는 완화하는 것을 특징으로 하는, 뇌전증의 예방 또는 치료용 약학적 조성물.8. The method of claim 7,
The composition is characterized in that the improvement or alleviation of seizure symptoms, the prevention or treatment of epilepsy pharmaceutical composition.
상기 조성물은 GABA 수용체인 GABAA1 및 GABAB1b; 또는 글루타메이트 수용체인 GLT-1의 발현을 증진시키는 것을 특징으로 하는, 뇌전증의 예방 또는 치료용 약학적 조성물.8. The method of claim 7,
The composition comprises GABA receptors GABAA1 and GABAB1b; Or a pharmaceutical composition for preventing or treating epilepsy, characterized in that it enhances the expression of GLT-1, a glutamate receptor.
상기 조성물은 케톤식이와 병용 투여하는 것을 특징으로 하는, 뇌전증의 예방 또는 치료용 약학적 조성물.8. The method of claim 7,
The composition is a pharmaceutical composition for preventing or treating epilepsy, characterized in that it is administered in combination with a ketogenic diet.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20230050119A (en) * | 2021-10-07 | 2023-04-14 | 충북대학교 산학협력단 | Novel Limosilactobacillus fermentum MG7011 with probiotic activity and suitable for grain fermentation |
| CN116590175A (en) * | 2023-04-12 | 2023-08-15 | 吉林省中科特殊食品创新研究院有限公司 | Lactobacillus fermentum ELF041 and application thereof |
| KR20240023749A (en) | 2022-08-16 | 2024-02-23 | 주식회사 휴럼 | Lactiplantibacillus plantarum HMAP 12 and HEALTH FUNCTIONAL FOOD COMPOSITION FOR PREVENTING OR IMPROVING BRONCHITIS CAUSED BY FINE DUST CONTAINING THE SAME |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013190068A1 (en) * | 2012-06-22 | 2013-12-27 | Nestec S.A. | Probiotic and polyphenol against neurodegeneration |
| KR20170032845A (en) * | 2015-09-15 | 2017-03-23 | 경희대학교 산학협력단 | Novel lactic acid bacteria and composition for preventing, improving or treating neurodegenerative diseases or cognitive dysfunction |
| WO2018129722A1 (en) * | 2017-01-13 | 2018-07-19 | Bened Biomedical Co., Ltd. | A novel lactic acid bacteria and its applications |
| KR101937758B1 (en) | 2018-09-05 | 2019-01-11 | 마이크로바이오주식회사 | Lactobacillus fermentum UBC-U32, and use thereof in prevention and treatment of neurodegenerative disease |
-
2020
- 2020-11-11 KR KR1020200150539A patent/KR102397589B1/en active IP Right Grant
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013190068A1 (en) * | 2012-06-22 | 2013-12-27 | Nestec S.A. | Probiotic and polyphenol against neurodegeneration |
| KR20170032845A (en) * | 2015-09-15 | 2017-03-23 | 경희대학교 산학협력단 | Novel lactic acid bacteria and composition for preventing, improving or treating neurodegenerative diseases or cognitive dysfunction |
| WO2018129722A1 (en) * | 2017-01-13 | 2018-07-19 | Bened Biomedical Co., Ltd. | A novel lactic acid bacteria and its applications |
| KR101937758B1 (en) | 2018-09-05 | 2019-01-11 | 마이크로바이오주식회사 | Lactobacillus fermentum UBC-U32, and use thereof in prevention and treatment of neurodegenerative disease |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20230050119A (en) * | 2021-10-07 | 2023-04-14 | 충북대학교 산학협력단 | Novel Limosilactobacillus fermentum MG7011 with probiotic activity and suitable for grain fermentation |
| KR102574498B1 (en) | 2021-10-07 | 2023-09-06 | 충북대학교 산학협력단 | Novel Limosilactobacillus fermentum MG7011 with probiotic activity and suitable for grain fermentation |
| KR20240023749A (en) | 2022-08-16 | 2024-02-23 | 주식회사 휴럼 | Lactiplantibacillus plantarum HMAP 12 and HEALTH FUNCTIONAL FOOD COMPOSITION FOR PREVENTING OR IMPROVING BRONCHITIS CAUSED BY FINE DUST CONTAINING THE SAME |
| CN116590175A (en) * | 2023-04-12 | 2023-08-15 | 吉林省中科特殊食品创新研究院有限公司 | Lactobacillus fermentum ELF041 and application thereof |
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