KR102480146B1 - Lactobacillus acidophilus with cognitive function improvement - Google Patents
Lactobacillus acidophilus with cognitive function improvement Download PDFInfo
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- KR102480146B1 KR102480146B1 KR1020200174887A KR20200174887A KR102480146B1 KR 102480146 B1 KR102480146 B1 KR 102480146B1 KR 1020200174887 A KR1020200174887 A KR 1020200174887A KR 20200174887 A KR20200174887 A KR 20200174887A KR 102480146 B1 KR102480146 B1 KR 102480146B1
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- cognitive ability
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- lactic acid
- acidophilus
- memory
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Abstract
본 발명은 기억력 및/또는 인지능력 향상 기능을 가진 유산균, 이를 포함하는 기억력 및/또는 인지능력 관련 질환의 예방 또는 치료용 약학적 조성물, 이를 포함하는 기억력 및/또는 인지능력 향상용 식품 조성물, 이의 기억력 및/또는 인지능력 향상 또는 개선 용도, 및 이를 이용한 기억력 및/또는 인지능력 향상 방법에 관한 것이다.The present invention relates to a lactic acid bacteria having memory and/or cognitive ability enhancing function, a pharmaceutical composition for preventing or treating memory and/or cognitive ability-related diseases including the same, a food composition for improving memory and/or cognitive ability including the same, and a food composition thereof. It relates to a use for improving or improving memory and/or cognitive ability, and a method for improving memory and/or cognitive ability using the same.
Description
본 발명은 기억력 및/또는 인지능력 향상 기능을 가진 유산균, 이를 포함하는 기억력 및/또는 인지능력 관련 질환의 예방 또는 치료용 약학적 조성물, 이를 포함하는 기억력 및/또는 인지능력 향상용 식품 조성물, 이의 기억력 및/또는 인지능력 향상 또는 개선 용도, 및 이를 이용한 기억력 및/또는 인지능력 향상 방법에 관한 것이다. The present invention relates to a lactic acid bacteria having memory and/or cognitive ability enhancing function, a pharmaceutical composition for preventing or treating memory and/or cognitive ability-related diseases including the same, a food composition for improving memory and/or cognitive ability including the same, and a food composition thereof. It relates to a use for improving or improving memory and/or cognitive ability, and a method for improving memory and/or cognitive ability using the same.
세계보건기구 (WHO)에서는 프로바이오틱스 (Probiotics)를 '충분한 양을 섭취하였을 시 건강에 좋은 효과를 주는 살아있는 균'으로 정의하고 있다. 한국바이오 경제센터에 따르면 우리나라 전체 건강기능식품 시장 중 11% 상당을 프로바이오틱스 제품이 차지하고 있다고 한다. 이는 1조 5000억원 규모인 홍삼시장의 바로 뒤를 추격하는 규모이다. 이처럼 국내외에서 유산균에 대한 관심도가 높아지며 건강기능식품으로서의 상품성도 지속적으로 증가하고 있다.The World Health Organization (WHO) defines probiotics as 'live microorganisms that confer a beneficial effect on health when ingested in sufficient amounts'. According to the Korea Bio Economic Center, probiotics products account for 11% of the total health functional food market in Korea. This is a size that catches up just behind the red ginseng market, which is worth 1.5 trillion won. As such, interest in lactic acid bacteria is increasing at home and abroad, and the marketability as a health functional food is continuously increasing.
현재 우리나라에서 유산균 시장 1억 4700억 원 규모로 건강기능식품 중 2위를 차지하고 있다. 이는 1조 5000억원 규모인 홍삼시장의 바로 뒤를 잇는 규모이며, 최근 코로나 19등 전염병으로 인한 위험성이 생활에 밀접하게 관여하면서 면역력 강화의 중요성이 대두되며 유산균의 중요성이 더 크게 인식되고 있다.Currently, the lactobacillus market in Korea is worth 147 billion won, ranking second among health functional foods. This is a scale that follows the red ginseng market, which is worth 1.5 trillion won. Recently, as the risk of infectious diseases such as Corona 19 is closely involved in life, the importance of strengthening immunity is emerging, and the importance of lactic acid bacteria is being recognized more.
유산균 섭취 시, 장내 유익균의 비율을 늘어남으로 인해 우리 몸에 필요한 영양소 및 대사 기능을 조절하고, 장 내 점막 보호기능을 유지해 유해균으로부터 몸을 보호하는 역할을 한다고 알려져 있다. 비만, 인슐린 저항성 증후군, 제2형 당뇨병, 비알콜성 지방간, IBS 및 설사 등이 이에 해당된다. 최근 들어, 기존에 널리 알려진 기능에 더불어 암, 심장질환, 천식, 자가면역질환, 노화 등에도 유산균이 예방 및 치료 효과가 있다는 연구 결과들이 발표되며 다양한 기능성 유산균 제품이 주목 받고 있다.It is known that when lactic acid bacteria are ingested, the ratio of beneficial bacteria in the intestine increases, thereby controlling nutrients and metabolic functions necessary for our body, and protecting the body from harmful bacteria by maintaining the protective function of the intestinal mucosa. These include obesity, insulin resistance syndrome,
우리나라에서 건강기능식품으로 사용되는 균주는 주로 식약처에서 고시한 19종에 해당되는 균주이다. 이에 해당하는 균주는 락토바실러스 (Lactobacilllus) 속 11종 (L. acidophilus, L casei, L. gasseri, L. delbruekii spp. bulgaricus, L. helveticus, L. fermentum, L. paracasei, L. plantarum, L. reuteri, L. rhanosus, and L salivarius), Lactococcus 속 1 종 (Lc. lactis), 엔테로코커스 (Enterococcus) 속 1 종 (E. faecium, E. faecalis), 스트렙토코커스 (Streptococcus) 속 1 종 (S. thermophilus), 비피도박테리움 (Bifidobacterium) 속 4 종 (B. bifidum, B, breve, B. longum, B. animalis ssp. lactis)이며, 이 외에도 발효식품 등에서 추출된 유산균이 안전성 테스트를 거친 후 등록되는 경우도 있다.Strains used as health functional foods in Korea are mainly strains corresponding to 19 species notified by the Ministry of Food and Drug Safety. The corresponding strain is Lactobacillus ( Lactobacilllus ) Genus 11 species ( L. acidophilus, L casei, L. gasseri, L. delbruekii spp. bulgaricus, L. helveticus, L. fermentum, L. paracasei, L. plantarum, L. reuteri, L. rhanosus, and L salivarius ), Lactococcus genus 1 species ( Lc. lactis ), Enterococcus ( Enterococcus ) Genus 1 species ( E. faecium, E. faecalis ), Streptococcus ( Streptococcus ) 1 genus ( S. thermophilus ), 4 genus Bifidobacterium ( B. bifidum, B, breve, B. longum, B. animalis ssp. lactis ), and other lactic acid bacteria extracted from fermented foods In some cases, it is registered after passing a safety test.
유산균은 장내 미생물의 조성을 개선함으로 인해 건강에 이로운 효능을 주는 것으로 알려져 있다. 초기 유산균 건강기능식품은 섭취한 유산균으로 인해 장내 유익균의 비율을 늘려 인해 우리 몸에 필요한 영양소 및 대사 기능을 조절하거나 장 내 점막 보호기능을 유지해 유해균으로부터 몸을 보호하는 기능을 제시하였다. 구체적으로는 비만, 인슐린 저항성 증후군, 제2형 당뇨병, 비알콜성 지방간, IBS (Irritable Bowel Syndrome) 및 설사 등이 이에 해당된다. 최근 들어서 유산균 건강기능식품의 시장이 커지며 암, 심장질환, 자가면역질환, 노화 등에도 유산균이 예방 및 치료 효과가 있다는 연구 결과들이 발표되었고 이에 다양한 기능성 유산균 제품들이 주목 받고 있다. Lactic acid bacteria are known to have beneficial effects on health by improving the composition of the intestinal microflora. Early lactobacillus health functional foods suggested the function of protecting the body from harmful bacteria by increasing the ratio of beneficial bacteria in the intestine due to ingested lactic acid bacteria, regulating nutrients and metabolic functions necessary for our body, or maintaining the protective function of the intestinal mucosa. Specifically, obesity, insulin resistance syndrome,
또한, 구강을 통해 섭취해 장내 미생물의 조성을 바꾸는 형태에서 벗어나 장 외에 다른 기관에 작용하는 유산균 제품의 개발도 이어졌다. 그 중 대표적인 예가 여성 질 건강에 도움을 주는 건강기능식품으로서의 프로바이오틱스 제품이다. 유산균을 섭취 시 섭취군의 질내 균총이 변화해 생식기 감염 위험이 줄어들었다는 연구 결과와 함께 소화기관 및 회음부를 지나 질 내부에 정착하는 것이 밝혀졌다. In addition, the development of lactic acid bacteria products that act on organs other than the intestines, away from the form of changing the composition of intestinal microorganisms by ingestion through the mouth, has also been continued. Among them, a representative example is a probiotics product as a health functional food that helps women's vaginal health. When lactobacillus was consumed, the vaginal flora of the ingested group changed and the risk of genital infection was reduced, and it was found that it settled inside the vagina through the digestive tract and perineum.
한국 야쿠르트에서 개발해 특허를 받은 L. plantarum HY7714 균주는 ‘피부보습에 도움을 줄 수 있고, 자외선에 의한 피부 손상으로부터 피부 건강 유지에 도움을 줄 수 있다’는 내용으로 기능성을 인정받은바 있다. The L. plantarum HY7714 strain, which was developed and patented by Korea Yakult, has been recognized for its functionality by stating that it can help moisturize skin and maintain skin health from skin damage caused by ultraviolet rays.
또한, CJ 제일제당에서 개발한 제품으로 피부상태를 개선할 수 있는 L. plantarum CJLP133균주도 있다. 이는 면역과민반응에 의한 피부상태 개선에 도움을 줄 수 있다는 내용으로 기능성을 인정받았다.In addition, there is also L. plantarum CJLP133 strain, developed by CJ CheilJedang, that can improve skin condition. This has been recognized for its functionality as it can help improve skin conditions caused by immune hypersensitivity reactions.
최신 연구에서는 섭취한 유산균이 직접 도달한 장기 외에도 뇌 및 신경세포에 2차적인 영향을 준다는 것을 증명하였다. 미국 하버드대 의대 프란시스코 킨타나 교수팀은 지난 2018년 5월 국제학술지 '네이처'에 장내 세균이 다발성경화증을 치료할 수 있다는 내용을 발표했다. 해당 연구팀의 발표에 따르면 장내 세균이 '트립토판'을 분해할 때 발생하는 물질이 뇌로 전달되면서 뇌 속 면역세포 활동을 줄이고 염증을 억제한다는 결과를 발표했다. 같은 원리로 치매 및 파킨슨병의 치료도 가능할 것으로 전망했다. 이에 이어 알츠하이머병 치매 노인 60명에게 12주간 유산균을 꾸준히 섭취하게 했더니, 인지 기능이 유의적으로 향상됐다는 연구가 '노화신경과학 최신연구'에 실리기도 했다.Recent research has proven that ingested lactic acid bacteria have a secondary effect on the brain and nerve cells in addition to the organs they reach directly. In May 2018, a team led by Professor Francisco Quintana of Harvard Medical School published a report in the international journal Nature that gut bacteria can treat multiple sclerosis. According to the announcement of the research team, the substance generated when intestinal bacteria decompose 'tryptophan' is delivered to the brain, reducing the activity of immune cells in the brain and suppressing inflammation. The same principle is predicted to be able to treat dementia and Parkinson's disease. Following this, when 60 elderly people with Alzheimer's disease were given lactic acid bacteria steadily for 12 weeks, a study was published in 'Aging Neuroscience Latest Research' showing that cognitive function significantly improved.
일본 모리나가유업 미래세대과학연구소 요다이 고바야시 바사는 2018 국제낙농연맹 (IDF, Intertnational Dairy Ferderation) 연차총회의 학술 세션에서 ‘알츠하이머병에서 B. breve A1의 인지능력 손상 예방 가능성’에 대한 연구결과를 발표했다. 해당 연구팀에서는 인지 기능 장애를 실험동물에 일부러 유발시키기 위해 알츠하이머 병의 원인물질로 추정되는 베타 아밀로이드를 생쥐에게 주입했다. 이어 B. breve A1균주를 10일간 먹인 뒤 미로실험 및 수동회피 실험 등을 통해 생쥐의 인지기능 변화를 평가하였고, 알츠하이머 처방 약인 콜린에스테라아제 억제제를 투여한 대조그룹과 차이가 없을 만큼 회복된 것을 확인하였다. 이후 동일 균주에 대해 노인을 대상으로 섭취하게 한 후 인지기능을 평가했을 때, 기능의 향상이 있는 것을 확인했다.Yodai Kobayashi Basa, Future Generation Science Research Institute, Morinaga Milk Industry, Japan, presented research results on 'the potential of B. breve A1 to prevent cognitive impairment in Alzheimer's disease' at an academic session at the 2018 International Dairy Federation (IDF) annual meeting. did. The research team injected beta-amyloid, which is presumed to be the causative agent of Alzheimer's disease, into mice in order to intentionally induce cognitive dysfunction in experimental animals. Then, after feeding the B. breve A1 strain for 10 days, the change in cognitive function of the mice was evaluated through maze experiments and passive avoidance experiments, and it was confirmed that they recovered to the extent that there was no difference from the control group administered with a cholinesterase inhibitor, a prescription drug for Alzheimer's disease. . Later, when the cognitive function was evaluated after ingesting the same strain to the elderly, it was confirmed that there was an improvement in function.
임상실험 및 동물실험에서 유산균이 뇌에 작용한다는 연구에 이어 실제 작용 메커니즘으로 인해 장내 유산균이 신경계에 작용하는지를 밝혀내려는 연구들도 이어지고 있다.Following studies showing that lactobacilli act on the brain in clinical trials and animal experiments, studies are continuing to find out whether intestinal lactobacilli act on the nervous system due to the actual mechanism of action.
뇌에서 기분을 조절하는 호르몬으로 알려져 있는 세로토닌, 중추신경계에 작용하는 억제성 신경전달물질인 가바(GABA), 뇌 내안에서 작용하는 신경 단백질인 뇌유래신경영양인자 (brain-derived neurotrophic factor, BDNF) 등이 장내 미생물 분포에 의해 영향을 받을 수 있다는 연구들이 이어지고 있다. 그러나 아직 장내 미생물이 뇌에 어떻게 작용하는지에 대한 구체적 메커니즘을 밝혀지지 않았다.Serotonin, known as a hormone that regulates mood in the brain, GABA, an inhibitory neurotransmitter that acts on the central nervous system, and brain-derived neurotrophic factor (BDNF), a nerve protein that acts inside the brain, etc. Studies are continuing that this can be influenced by the distribution of gut microbes. However, the specific mechanism of how gut microbes act on the brain has not yet been elucidated.
이에, 본 발명의 목적은 기억력 및/또는 인지능력 향상 기능을 가진 유산균을 제공하는 것이다.Accordingly, an object of the present invention is to provide lactic acid bacteria having memory and/or cognitive ability enhancing functions.
본 발명의 다른 목적은 상기 유산균을 포함하는 기억력 및/또는 인지능력 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of memory and / or cognitive ability-related diseases containing the lactic acid bacteria.
본 발명의 또 다른 목적은 상기 유산균을 포함하는 기억력 및/또는 인지능력 향상용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for improving memory and / or cognitive ability containing the lactic acid bacteria.
본 발명의 또 다른 목적은 상기 유산균의 기억력 및/또는 인지능력 향상 또는 개선 용도를 제공하는 것이다.Another object of the present invention is to provide a use for enhancing or improving memory and/or cognitive ability of the lactic acid bacteria.
본 발명의 또 다른 목적은 상기 유산균을 이용한 기억력 및/또는 인지능력 향상 방법을 제공하는 것이다.Another object of the present invention is to provide a method for improving memory and/or cognitive ability using the lactic acid bacteria.
본 발명은 기억력 및/또는 인지능력 향상 기능을 가진 유산균, 이를 포함하는 기억력 및/또는 인지능력 관련 질환의 예방 또는 치료용 약학적 조성물, 이를 포함하는 기억력 및/또는 인지능력 향상용 식품 조성물, 이의 기억력 및/또는 인지능력 향상 또는 개선 용도, 및 이를 이용한 기억력 및/또는 인지능력 향상 방법에 관한 것이다.The present invention relates to a lactic acid bacteria having memory and/or cognitive ability enhancing function, a pharmaceutical composition for preventing or treating memory and/or cognitive ability-related diseases including the same, a food composition for improving memory and/or cognitive ability including the same, and a food composition thereof. It relates to a use for improving or improving memory and/or cognitive ability, and a method for improving memory and/or cognitive ability using the same.
이하 본 발명을 더욱 자세히 설명하고자 한다.Hereinafter, the present invention will be described in more detail.
본 발명의 일 양태는 기억력 및/또는 인지능력 향상 기능을 가진 유산균에 관한 것이다.One aspect of the present invention relates to lactic acid bacteria having memory and / or cognitive ability enhancing function.
본 발명에 있어서 상기 유산균은 락토바실러스 아시도필루스 (Lactobacillus acidophilus)인 것일 수 있다.In the present invention, the lactic acid bacteria may be Lactobacillus acidophilus .
본 발명에 있어서 락토바실러스 아시도필루스는 서열번호 1의 염기서열로 이루어진 16sRNA를 가지는 것일 수 있다.In the present invention, Lactobacillus acidophilus may have 16sRNA consisting of the nucleotide sequence of SEQ ID NO: 1.
본 발명의 락토바실러스 아시도필루스는 한국생명공학연구원 KCTC(Korean Collection for Type Cultures)에 2020년 11월 19일자 기탁번호 KCTC 14369BP로 기탁되었다.Lactobacillus acidophilus of the present invention was deposited with the Korea Research Institute of Bioscience and Biotechnology KCTC (Korean Collection for Type Cultures) on November 19, 2020 under the accession number KCTC 14369BP.
본 발명의 다른 일 예는 기억력 및/또는 인지능력 향상 기능을 가진 유산균, 이의 배양물, 이의 파쇄물 및 이의 추출물로 이루어진 군에서 선택된 1종 이상을 포함하는 기억력 또는 인지능력 관련 질환의 예방, 또는 치료용 조성물에 관한 것이다.Another example of the present invention is the prevention or treatment of memory or cognitive ability-related diseases including at least one selected from the group consisting of lactic acid bacteria having memory and/or cognitive ability enhancing function, cultures thereof, lysates thereof, and extracts thereof. It is about a composition for
본 발명에 있어서 상기 유산균은 락토바실러스 아시도필루스 (Lactobacillus acidophilus)인 것일 수 있다.In the present invention, the lactic acid bacteria may be Lactobacillus acidophilus .
본 발명에 있어서 락토바실러스 아시도필루스는 서열번호 1의 염기서열로 이루어진 16sRNA를 가지는 것일 수 있다.In the present invention, Lactobacillus acidophilus may have 16sRNA consisting of the nucleotide sequence of SEQ ID NO: 1.
본 발명의 락토바실러스 아시도필루스는 한국생명공학연구원 KCTC(Korean Collection for Type Cultures)에 2020년 11월 19일자 기탁번호 KCTC 14369BP로 기탁되었다.Lactobacillus acidophilus of the present invention was deposited with the Korea Research Institute of Bioscience and Biotechnology KCTC (Korean Collection for Type Cultures) on November 19, 2020 under the accession number KCTC 14369BP.
본 발명에 있어서 인지능력 및/또는 기억능력 관련 질환은, 해당 질환의 증상으로 인지능력 또는 기억능력이 저하 또는 감퇴가 나타날 수 있는 모든 질환을 포함하는 개념이며, 예를 들어, 퇴행성 뇌질환 또는 치매인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the cognitive ability and/or memory related disease is a concept including all diseases in which cognitive ability or memory ability may decrease or decrease as a symptom of the disease, and include, for example, degenerative brain disease or dementia It may be, but is not limited thereto.
본 발명에 있어서 퇴행성 뇌질환은 나이가 들어감에 따라 발생하는 퇴행성 질환 중 뇌에 발생하는 질환을 의미한다. 뇌경색, 뇌졸중, 알츠하이머, 전두측두엽변성증(frontotemporal lobar degeneration, FTLD), 픽병(Pick's disease), 피질기조퇴행(Corticobasal degeneration, CBD), 퇴행성 핵상마비 (progressive supranuclear palsy, PSP), 파킨슨병 또는 헌팅턴병 등 인지능력 또는 기억능력 저하 내지 감퇴를 증상으로 나타낼 수 있는 질환을 모두 포함하는 개념이다.In the present invention, degenerative brain disease refers to a disease that occurs in the brain among degenerative diseases that occur with age. Cognitive, such as cerebral infarction, stroke, Alzheimer's, frontotemporal lobar degeneration (FTLD), Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson's disease or Huntington's disease It is a concept that includes all diseases that can show a decline or decline in ability or memory ability as a symptom.
본 발명에 있어서 치매는 퇴행성 뇌질환, 뇌혈관성 치매증, 에이즈(AIDS) 유발성 치매, 뇌신경염증성 치매, 루이소체치매(Dementia with Lewy Bodies, DLB), 다발성 경색치매(Multi-Infarct Dementia, MID), 척수손상 또는 두부손상 등 다양한 원인에 의하여 발생하는 치매를 모두 포함하는 개념일 수 있다.In the present invention, dementia is degenerative brain disease, cerebrovascular dementia, AIDS-induced dementia, cranial neuroinflammatory dementia, Dementia with Lewy Bodies (DLB), Multi-Infarct Dementia (MID), It may be a concept that includes all dementia caused by various causes such as spinal cord injury or head injury.
본 발명의 약학적 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도에 따라 그 범위가 다양하다. 일일 투여량으로는, 비경구 투여 시 상기 조성물을 기준으로 하루에 체중 1 kg당 바람직하게 0.01 내지 200 mg, 더 바람직하게는 0.1 내지 120 mg의 양으로 투여되도록, 그리고 경구 투여 시는 상기 조성물을 기준으로 하루에 체중 1 kg당 바람직하게 0.01 내지 1000 mg, 더 바람직하게는 0.1 내지 500 mg의 양으로 투여되도록 1 내지 수회에 나누어 투여할 수 있다. 그러나 투여경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition of the present invention varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. The daily dosage is preferably 0.01 to 200 mg, more preferably 0.1 to 120 mg per 1 kg of body weight per day based on the composition for parenteral administration, and for oral administration, the composition It may be administered in one to several divided doses so as to be administered in an amount of preferably 0.01 to 1000 mg, more preferably 0.1 to 500 mg per 1 kg of body weight per day. However, since it may increase or decrease according to the route of administration, severity of obesity, gender, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
본 발명의 약학적 조성물은 경구 또는 비경구로 투여될 수 있으며, 비경구 투여시 피부외용; 복강내, 직장, 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사하는 주사제; 경피 투여제; 또는 비강 흡입제의 형태로 당업계에 공지된 방법에 따라 제형화할 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally, and may be administered externally for parenteral administration; Injectables for intraperitoneal, rectal, intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection; transdermal administration; Alternatively, it may be formulated according to a method known in the art in the form of nasal inhalation.
본 발명의 약학적 조성물을 제형화할 경우에는 하나 이상의 완충제 (예를 들어, 식염수 또는 PBS), 항당뇨제, 정균제, 킬레이트화제 (예를 들어, EDTA 또는 글루타치온), 충진제, 증량제, 결합제, 아쥬반트 (예를 들어, 알루미늄 하이드록사이드), 현탁제, 농후제 습윤제, 붕해제 또는 계면활성제, 희석제 또는 부형제를 사용하여 조제될 수 있다.When formulating the pharmaceutical composition of the present invention, one or more buffers (eg, saline or PBS), antidiabetic agents, bacteriostatic agents, chelating agents (eg, EDTA or glutathione), fillers, bulking agents, binders, adjuvants ( eg aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrating agents or surfactants, diluents or excipients.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분 (옥수수 전분, 밀 전분, 쌀 전분, 감자 전분 등 포함), 칼슘카보네이트 (calcium carbonate), 수크로스 (sucrose), 락토오스 (lactose), 덱스트로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨 말티톨, 셀룰로즈, 메틸 셀룰로즈, 나트륨 카르복시메틸셀룰로오즈 및 하이드록시프로필메틸-셀룰로즈 또는 젤라틴 등을 섞어 조제된다. 예컨대, 활성성분을 고체 부형제와 배합한 다음 이를 분쇄하고 적합한 보조제를 첨가한 후 과립 혼합물로 가공함으로써 정제 또는 당의정제를 수득할 수 있다. 또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in one or more compounds, such as starch (corn starch, wheat starch, rice starch, potato including starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl -It is prepared by mixing cellulose or gelatin. Tablets or dragees may be obtained, for example, by combining the active ingredient with a solid excipient which is then milled and processed into a mixture of granules after adding suitable auxiliaries. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들어, 습윤제, 감미제, 방향제 또는 보존제 등이 포함될 수 있다. 또한, 경우에 따라 가교결합 폴리비닐피롤리돈, 한천, 알긴산 또는 나트륨 알기네이트 등을 붕해제로 첨가할 수 있으며, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.Liquid formulations for oral administration include suspensions, internal solutions, emulsions, or syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, or preservatives are used. can be included In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and may further include anti-agglomerating agents, lubricants, wetting agents, flavoring agents, emulsifiers, and preservatives. .
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제 또는 좌제 등이 포함된다. 비수성용제 및 현탁용제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, freeze-dried formulations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used.
주사제의 경우에는 반드시 멸균되어야 하며 박테리아 및 진균과 같은 미생물의 오염으로부터 보호되어야 한다. 주사제의 경우 적합한 담체의 예로는 이에 한정되지는 않으나, 물, 에탄올, 폴리올 (예를 들어, 글리세롤, 프로필렌글리콜 및 액체 폴리에틸렌 글리콜 등), 이들의 혼합물 및/또는 식물유를 포함하는 용매 또는 분산매질일 수 있다. 보다 바람직하게는, 적합한 담체로는 행크스 용액, 링거 용액, 트리에탄올 아민이 함유된 PBS (phosphate buffered saline) 또는 주사용 멸균수, 10% 에탄올, 40% 프로필렌 글리콜 및 5% 덱스트로즈와 같은 등장 용액 등을 사용할 수 있다. 상기 주사제를 미생물 오염으로부터 보호하기 위해서는 파라벤, 클로로부탄올, 페놀, 소르빈산, 티메로살 등과 같은 다양한 항균제 및 항진균제를 추가로 포함할 수 있다. 또한, 상기 주사제는 대부분의 경우 당 또는 나트륨 클로라이드와 같은 등장화제를 추가로 포함할 수 있다.In the case of injections, they must be sterilized and must be protected from contamination by microorganisms such as bacteria and fungi. Examples of suitable carriers for injections include, but are not limited to, water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), mixtures thereof, and/or solvents or dispersion media containing vegetable oils. can More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) with triethanolamine or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. etc. can be used. In order to protect the injection from microbial contamination, various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, and thimerosal may be further included. Also, in most cases, the injection may further include an isotonic agent such as sugar or sodium chloride.
경피 투여제의 경우 연고제, 크림제, 로션제, 겔제, 외용액제, 파스타제, 리니멘트제, 에어롤제 등의 형태가 포함된다. 상기에서 경피 투여는 약학 조성물을 국소적으로 피부에 투여하여 약학 조성물에 함유된 유효한 양의 활성성분이 피부 내로 전달되는 것을 의미한다.Transdermal preparations include ointments, creams, lotions, gels, external solutions, pastas, liniments, air rolls, and the like. In the above, transdermal administration means that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin by topically administering the pharmaceutical composition to the skin.
흡입 투여제의 경우, 본 발명에 조성물은 적합한 추진제, 예를 들어, 디클로로플루오로메탄, 트리클로로플루오로메탄, 디클로로테트라플루오로에탄, 이산화탄소 또는 다른 적합한 기체를 사용하여, 가압 팩 또는 연무기로부터 에어로졸 스프레이 형태로 편리하게 전달 할 수 있다. 가압 에어로졸의 경우, 투약 단위는 계량된 양을 전달하는 밸브를 제공하여 결정할 수 있다. 예를 들면, 흡입기 또는 취입기에 사용되는 젤라틴 캡슐 및 카트리지는 화합물, 및 락토즈 또는 전분과 같은 적합한 분말 기제의 분말 혼합물을 함유하도록 제형화할 수 있다. 비경구 투여용 제형은 모든 제약 화학에 일반적으로 공지된 제형일 수 있다.For administration by inhalation, the compositions of the present invention may be aerosolized from pressurized packs or nebulizers using a suitable propellant such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered in the form of a spray. In the case of pressurized aerosols, dosage units may be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges for use in inhalers or insufflators may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch. Formulations for parenteral administration may be any formulation generally known in pharmaceutical chemistry.
본 발명의 약학적 조성물은 단독으로, 또는 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
본 발명의 또 다른 일 양태는 기억력 및/또는 인지능력 향상 기능을 가진 유산균, 이의 배양물, 이의 파쇄물 및 이의 추출물로 이루어진 군에서 선택된 1종 이상을 포함하는 기억력 및/또는 인지능력 향상 또는 개선용 식품 조성물에 관한 것이다.Another aspect of the present invention is for improving or improving memory and / or cognitive ability, including at least one selected from the group consisting of lactic acid bacteria, cultures thereof, lysates thereof, and extracts having memory and / or cognitive ability enhancing function It relates to food compositions.
본 발명에 있어서 유산균은 락토바실러스 아시도필루스 (Lactobacillus acidophilus)인 것일 수 있다.In the present invention, the lactic acid bacteria may be Lactobacillus acidophilus .
본 발명에 있어서 락토바실러스 아시도필루스는 서열번호 1의 염기서열로 이루어진 16sRNA를 가지는 것일 수 있다.In the present invention, Lactobacillus acidophilus may have 16sRNA consisting of the nucleotide sequence of SEQ ID NO: 1.
본 발명의 락토바실러스 아시도필루스는 한국생명공학연구원 KCTC(Korean Collection for Type Cultures)에 2020년 11월 19일자 기탁번호 KCTC 14369BP로 기탁되었다.Lactobacillus acidophilus of the present invention was deposited with the Korea Research Institute of Bioscience and Biotechnology KCTC (Korean Collection for Type Cultures) on November 19, 2020 under the accession number KCTC 14369BP.
본 발명의 식품 조성물은 유산균을 함유하는 외에 다른 성분에는 특별한 제한은 없으며, 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. The food composition of the present invention is not particularly limited in other components other than containing lactic acid bacteria, and may contain various flavoring agents or natural carbohydrates as additional components like conventional beverages.
본 발명에 있어서 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등의 디사카라이드, 예를 들어, 말토스, 슈크로스 등의 및 폴리사카라이드, 예를 들어, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜인 것일 수 있으나, 이에 한정되는 것은 아니다. Examples of natural carbohydrates in the present invention include monosaccharides such as glucose, disaccharides such as fructose, such as maltose and sucrose, and polysaccharides such as dextrins and cyclodextrins. It may be a conventional sugar and sugar alcohol such as xylitol, sorbitol, erythritol, etc., but is not limited thereto.
상술한 것 이외의 향미제로서 천연 향미제 (타우마틴, 스테비아 추출물 (예를 들어, 레바우디오시드 A, 글리시르히진등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 mL당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다. As flavoring agents other than those mentioned above, natural flavoring agents (thaumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can advantageously be used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 mL of the composition of the present invention.
상기 외에 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 식품 조성물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 식품 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and It may contain salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like. In addition, the food composition of the present invention may contain fruit flesh for preparing natural fruit juice, fruit juice beverages, and vegetable beverages. These components may be used independently or in combination. The proportion of these additives is not critical, but is generally selected from the range of 0 to about 20 parts by weight per 100 parts by weight of the food composition of the present invention.
예를 들어, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 유산균 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액, 감초 추출액 등을 추가로 포함시킬 수 있다.For example, when the food composition of the present invention is prepared as a drink, in addition to the lactic acid bacteria of the present invention, citric acid, high fructose corn syrup, sugar, glucose, acetic acid, malic acid, fruit juice, eucalyptus extract, jujube extract, licorice extract, etc. may be further included. can
본 발명의 또 다른 일 양태는 상기 유산균의 기억력 및/또는 인지능력 관련 질환의 예방 또는 치료 용도에 관한 것이다.Another aspect of the present invention relates to the prevention or treatment of diseases related to memory and / or cognitive ability of the lactic acid bacteria.
본 발명의 또 다른 일 양태는 상기 유산균의 기억력 및/또는 인지능력 향상 또는 개선 용도에 관한 것이다.Another aspect of the present invention relates to the use of improving or improving memory and / or cognitive ability of the lactic acid bacteria.
본 발명의 또 다른 일 양태는 상기 유산균을 이용한 기억력 및/또는 인지능력 향상 방법에 관한 것이다.Another aspect of the present invention relates to a method for improving memory and / or cognitive ability using the lactic acid bacteria.
본 발명은 기억력 및/또는 인지능력 향상 기능을 가진 유산균, 이를 포함하는 기억력 및/또는 인지능력 관련 질환의 예방 또는 치료용 약학적 조성물, 이를 포함하는 기억력 및/또는 인지능력 향상용 식품 조성물, 이의 기억력 및/또는 인지능력 향상 또는 개선 용도, 및 이를 이용한 기억력 및/또는 인지능력 향상 방법에 관한 것이다. 기존에 인지능력 향상에 효과가 있었던 균주는 혐기성 균주인 비피도박테리움 속으로 대량배양에도 혐기 조건을 유지하여야 했으나, 본 발명의 균주는 통상 혐기성 균주로 호기성 환경에서도 배양이 가능하여, 대량생산이 가능케 하여 상품의 단가를 낮출 수 있을 것으로 기대된다. 또한, 본 발명의 균주를 섭취하면 인지능력 및 기억력이 향상되는 효과가 있다.The present invention relates to a lactic acid bacteria having memory and/or cognitive ability enhancing function, a pharmaceutical composition for preventing or treating memory and/or cognitive ability-related diseases including the same, a food composition for improving memory and/or cognitive ability including the same, and a food composition thereof. It relates to a use for improving or improving memory and/or cognitive ability, and a method for improving memory and/or cognitive ability using the same. Previously, strains that were effective in improving cognitive ability belonged to the anaerobic strain Bifidobacterium and had to be maintained under anaerobic conditions even in mass culture, but the strains of the present invention are usually anaerobic strains and can be cultured in an aerobic environment, so mass production is possible. It is expected that this will enable the unit price of the product to be lowered. In addition, ingestion of the strain of the present invention has an effect of improving cognitive ability and memory.
도 1은 본 발명의 실시예에 따라 실험동물에 제공된 음용수의 L. acidophilus 농도 (CFU/ml)를 보여주는 그래프이다.
도 2는 본 발명에 이용된 균주의 종을 확인하기 위해 작성된 계통수이다.
도 3은 본 발명의 일 실시예에 따라 Spontaneous alternation 수행 결과에 대한 값을 boxplot을 이용해 나타낸 그래프이다.
도 4는 본 발명의 일 실시예에 따라 Novel object recognition test 수행 결과에 대한 값을 boxplot을 이용해 나타낸 그래프이다.
도 5는 본 발명의 일 실시예에 따라 Passive avoidance task 수행 결과에 대한 값을 boxplot을 이용해 나타낸 그래프이다.
도 6은 본 발명의 일 실시예에 따라 Forced alternation 수행 결과에 대한 값을 boxplot을 이용해 나타낸 결과 그래프이다.1 is a graph showing the L. acidophilus concentration (CFU/ml) of drinking water provided to experimental animals according to an embodiment of the present invention.
Figure 2 is a phylogenetic tree created to identify the species of the strain used in the present invention.
3 is a graph showing values of results of spontaneous alternation using a boxplot according to an embodiment of the present invention.
4 is a graph showing the values of the Novel object recognition test performance results using a boxplot according to an embodiment of the present invention.
5 is a graph showing values for results of performing a passive avoidance task using a boxplot according to an embodiment of the present invention.
6 is a result graph showing values for forced alternation results using a boxplot according to an embodiment of the present invention.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세히 설명한다. 그러나 이들 실시예는 본 발명을 예시하기 위한 것일 뿐이며, 본 발명의 범위가 이들 실시예에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail by the following examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.
실시예 1. 균주의 분리 및 동정Example 1. Isolation and identification of strains
발효유식품 샘플을 채취해 Man, Rogosa, Sharpe (MRS) 배지에서 균주를 분리 후 37 °C 에서 18시간 배양하였다. 분리된 균주는 16S rDNA 시퀀싱 및 계통수를 작성하였다. Fermented milk food samples were taken, strains were isolated from Man, Rogosa, and Sharpe (MRS) medium, and cultured at 37 °C for 18 hours. The isolated strains were subjected to 16S rDNA sequencing and phylogenetic trees.
1-1. 16S rRNA 시퀀싱 결과1-1. 16S rRNA sequencing results
번호order
number
표 1에서 확인할 수 있듯이, 27F 및 1492R 프라이머를 사용한 16s rRNA 시퀀싱 방법에서 Lactobacillus acidophilus와 99 % 유사성을 보였다.As can be seen in Table 1, 16s rRNA sequencing using 27F and 1492R primers showed 99% similarity to Lactobacillus acidophilus .
1-2. 계통수 작성 결과1-2. Result of creating a phylogenetic tree
계통수 작성에는 23개의 Lactobacillus 속 균주 유전체와 1개의 Bacillus 속 균주의 16s rRNA 유전자가 사용되었으며, 계통수는 Neighbor-joining method를 이용하여 작성하여, 그 결과를 도 2에 나타내었다. (Lactobacillus 속 - 9 L. acidophilus strains, L. amylovorus, L. crispatus, L. helveticus, L. delbrueckii subsp. bulgaricus, L. johnsonii, L. gasseri, L. fermentum, L. reuteri, L. brevis, L. plantarum, L. salivarius, L. rhamnosus, L. casei, L. paracasei, Bacillus속 - Bacillus subtilis) In the phylogenetic tree construction, 23 strain genomes of the genus Lactobacillus and 16s rRNA genes of one strain of the genus Bacillus were used, and the phylogenetic tree was constructed using the Neighbor-joining method, and the results are shown in FIG. 2 . (genus Lactobacillus - 9 L. acidophilus strains, L. amylovorus, L. crispatus, L. helveticus, L. delbrueckii subsp. bulgaricus, L. johnsonii, L. gasseri, L. fermentum, L. reuteri, L. brevis, L. Genus plantarum, L. salivarius, L. rhamnosus, L. casei, L. paracasei, Bacillus -Bacillus subtilis )
도 2에서 확인할 수 있듯이, 계통수에도 다른 L. acidophilus와 clustering 되는 것을 확인하였다. As can be seen in Figure 2, it was confirmed that clustering with other L. acidophilus was also confirmed in the phylogenetic tree.
실시예 2. 균주의 배양 및 희석Example 2. Cultivation and dilution of strains
2-1. 유산균 접종 및 배양하는 단계2-1. Step of inoculating and culturing lactic acid bacteria
동일한 상태의 유산균을 생산하기 위하여 매일 같은 조건하에 배양을 실시하였다. 고체 MRS 배지 (Difco, Detroit, MI) 에서 단일 균주를 배양한 후, 단일 콜로니를 10 ml 액체 MRS 배지에 접종하여 배양하였다. 37 °C에서 8시간 동안 배양된 균주는 1000 ml 액체 MRS 배지로 옮겨져 main culture가 이루어졌다. main culture는 37 °C 인큐베이터에서 쉐이킹 없이 16시간 동안 이루어졌다. In order to produce lactic acid bacteria in the same state, culture was performed under the same conditions every day. After culturing a single strain in solid MRS medium (Difco, Detroit, MI), a single colony was inoculated into 10 ml liquid MRS medium and cultured. The strain cultured at 37 °C for 8 hours was transferred to 1000 ml liquid MRS medium and the main culture was performed. The main culture was performed in a 37 °C incubator for 16 hours without shaking.
2-2. 희석하는 단계2-2. dilution step
배양된 균주는 4,000 rpm에서 세포의 변형 및 단백질 변성을 예방하기 위하여 원심분리기 내부의 온도가 4 °C로 유지되도록 10분간 원심 분리하여 상층액인 배지성분을 제거하였다. 배지성분을 완전히 제거하기 위해 1,000 ml의 0.85 % NaCl 용액으로 2차례 세척한 후, 1,000 ml의 멸균된 수돗물에 균주를 희석하였다. 이 때 최종 균수는 약 1.0E+09 CFU/ml이다.The cultured strain was centrifuged at 4,000 rpm for 10 minutes so that the temperature inside the centrifuge was maintained at 4 °C to prevent cell transformation and protein denaturation, and the supernatant, the medium component, was removed. After washing twice with 1,000 ml of a 0.85% NaCl solution to completely remove media components, the strain was diluted in 1,000 ml of sterilized tap water. At this time, the final bacterial count is about 1.0E+09 CFU/ml.
최종산물은 급여되는 유산균 수의 파악과 다른 균주의 오염 여부를 확인하기 위해 매일 생균 수 측정을 하였다. 마우스에게 급여하기 전 최종산물의 1 ml를 우선 채취하여, 0.85 %의 NaCl 용액으로 연속 희석 (serial dilution) 하였다. 희석된 용액은 고체 MRS 배지에서 spreading 후 37°C에서 쉐이킹 없이 2일간 배양되었다. 2일 후 생균수 측정을 기록하였고, 단일 균주로 확인된 플레이트는 다시 균주 접종에 사용하였다.In the final product, the number of viable cells was measured daily to determine the number of lactobacilli to be fed and to check for contamination of other strains. Before feeding the mice, 1 ml of the final product was first collected and serially diluted with a 0.85% NaCl solution. The diluted solution was incubated for 2 days at 37°C without shaking after spreading on solid MRS medium. After 2 days, the number of viable cells was recorded, and the plate identified as a single strain was used for strain inoculation again.
실시예 3. 모델 동물을 이용한 유산균의 인지능력 개선 효과 측정Example 3. Measurement of cognitive ability improvement effect of lactic acid bacteria using model animals
3-1. 유산균의 급여3-1. Salary of lactic acid bacteria
유산균 섭취 및 인지능력 평가에 사용된 동물은 쥐 (학명: Mus musculus)로 품종은 C57BL/6이다. 4주령의 수컷 쥐들은 영바이오(한국 성남시)를 통해 공급받았으며, 생체 내에 pathogen이 없는 SPF(Specific pathogen free) 동물이다. 실험 동물실에 온 후 1주일간의 적응기를 거친 후 유산균 급여를 실시하였다. 유산균 급여를 포함하여 모든 동물실험은 서울대학교 실험동물자원관리원의 관리 지침에 따라 수행되었다. 실험승인번호는 SNU-190607-4-3 이다. 실험군은 멸균된 수돗물에 L. acidophilus가 혼합된 물을 마시는 그룹 (12마리), 대조군은 멸균된 수돗물을 마시는 그룹 (12마리)으로 구성하였다. 완성된 최종산물은 매일 같은 시간에 실험동물에게 전달되었다. 1일 유산균 섭취량을 추산하기 위해 매일 급여된 음용수의 양을 ml 단위로 기록하였다. (하기 표 2 참조)The animal used for lactobacillus intake and cognitive ability evaluation was a rat (scientific name: Mus musculus ), and the breed was C57BL/6. Four-week-old male mice were supplied through Young Bio (Seongnam-si, Korea), and are SPF (Specific Pathogen Free) animals without pathogens in vivo. After coming to the laboratory animal room and going through a one-week adaptation period, lactic acid bacteria were fed. All animal experiments, including lactobacillus feeding, were performed in accordance with the management guidelines of the Laboratory Animal Resources Management Institute of Seoul National University. Experiment approval number is SNU-190607-4-3. The experimental group consisted of drinking sterilized tap water mixed with L. acidophilus (12 animals), and the control group consisted of drinking sterilized tap water (12 animals). The completed end product was delivered to the experimental animals at the same time every day. To estimate the daily lactobacillus intake, the amount of drinking water fed daily was recorded in ml units. (See Table 2 below)
모든 실험 사이에는 실험동물의 이동으로 인한 흔적을 지우기 위해 실험 틀 전체를 70% 알코올로 닦은 후 5분간 알코올 향이 증발된 이후 다음 실험을 재개하였다. NOR, PAT, FA는 실험 결과를 측정하기 위하여 마우스의 모든 이동을 촬영하였다. 각각의 실험 결과값에 대하여 independent t-test를 통해 통계적 유의성을 검정하였다.Between all experiments, the entire experiment frame was wiped with 70% alcohol to erase the traces caused by the movement of the experimental animals, and the next experiment was resumed after the alcohol scent evaporated for 5 minutes. NOR, PAT, and FA were photographed all movements of the mouse to measure the experimental results. Statistical significance was tested through an independent t-test for each experimental result.
3-2. Y-maze Spontaneous alternation test의 수행 및 측정결과3-2. Performance and measurement results of Y-maze spontaneous alternation test
유산균 급여를 시작한지 5주차에 수행하였다. 3개의 동일한 팔이 120도 각도로 이루어진 Y maze 틀을 이용하였다. Y maze 가운데에 쥐를 내려놓고 Arm entry 진입횟수와 방향 전환 횟수를 기록하여 spontaneous alternation(%)를 측정하였다. Y maze 세 개의 팔에 임의로 A, B, C의 라벨을 붙인 후 이어진 세 번의 입장이 A, B, C를 모두 포함한 경우를 spontaneous alternation이 이루어진 것으로 평가하였다. 팔의 80% 부분에 임의의 선을 긋고 네 발이 모두 넘어간 경우에만 유효하게 인정하였다. Spontaneous alternation (%)는 아래 식과 같이 계산하였다. 또한 그룹 내에서 처음 들어간 세 개의 arm이 spontaneous alternation을 보인 개체의 비율을 추가로 계산하였다. 그 결과를 표 3에 나타내었다. 또한, 두 실험군에 대하여, 통계적 유의성을 확인하기 위하여 independent t-test를 수행하여, 그 결과를 도 3에 나타내었다.It was performed at the 5th week after the start of lactobacillus feeding. A Y maze frame consisting of three identical arms at an angle of 120 degrees was used. Spontaneous alternation (%) was measured by placing the rat in the middle of the Y maze and recording the number of arm entry entries and direction changes. After randomly labeling the three arms of the Y maze with A, B, and C, spontaneous alternation was evaluated when the three subsequent entries included all of A, B, and C. Arbitrary lines were drawn on 80% of the arm, and only cases where all four feet crossed were validly recognized. Spontaneous alternation (%) was calculated according to the formula below. In addition, the proportion of subjects whose first three arms entered spontaneous alternation within the group was additionally calculated. The results are shown in Table 3. In addition, for the two experimental groups, an independent t-test was performed to confirm statistical significance, and the results are shown in FIG. 3 .
[계산식 1][Calculation 1]
표 3에서 확인할 수 있듯이, L. acidophilus를 먹인 실험군이 대조군보다 높은 Spontaneous alternation값을 보였다. 또한 처음 들어간 세 개의 entry가 spontaneous alternation을 보이는 비율도 L. acidophilus를 먹인 그룹에서 높게 나타났다. 도 3에서 확인할 수 있듯이, L. acidophilus를 먹인 그룹에서 더 높은 평균값을 나타냈으나, p value값은 0.07299로 통계적으로 유의한 차이를 보이지는 않았다.As can be seen in Table 3, the experimental group fed with L. acidophilus showed higher spontaneous alternation values than the control group. In addition, the rate of spontaneous alternation of the first three entries was also high in the L. acidophilus -fed group. As can be seen in Figure 3, the group fed L. acidophilus showed a higher average value, but the p value was 0.07299, which did not show a statistically significant difference.
3-3. Novel object recognition test의 수행 및 측정결과3-3. Performance and measurement results of Novel object recognition test
유산균 급여 후 6주차에 수행하였다. 실험은 오픈 필드 (open field)에서 수행되었다. 오픈 필드는 가로, 세로, 높이가 모두 40 cm인 아크릴 판으로 제작되었다. 두 개의 동일한 물체를 오픈 필드 대각선의 1/3, 2/3 되는 위치에 설치한 후, 쥐를 내려놓은 후, 물체에 노출시키며 각 물질을 탐색하는 시간을 측정하였다 (Sample trial). 기억 및 망각을 위해 60분간 케이지에 머물게 하였다 (interval time). 설치한 물체 중 하나를 신물질로 대체하고 실험동물의 3분간 물체와 접촉한 횟수 및 시간을 측정하였다 (Novel object trial). 전체 탐색 한 시간 중에서 각 물체에 머무르는 시간을 물체의 선호도로 나타내고 백분율로 환산하여 비교하였다. 그 결과를 표 4에 나타내었다. 또한, 두 실험군에 대하여, 통계적 유의성을 확인하기 위하여 independent t-test를 수행하여, 그 결과를 도 4에 나타내었다. It was performed at 6 weeks after lactic acid bacteria feeding. Experiments were conducted in an open field. The open field was made of an acrylic plate measuring 40 cm in width, length, and height. After installing two identical objects at 1/3 and 2/3 of the diagonal of the open field, the rat was put down, and the time to explore each substance was measured while exposing it to the object (Sample trial). For memory and forgetting, they were kept in the cage for 60 minutes (interval time). One of the installed objects was replaced with a new material, and the number and time of contact with the object for 3 minutes by the experimental animals were measured (Novel object trial). The time to stay in each object out of the total search time was expressed as the preference of the object and converted into a percentage for comparison. The results are shown in Table 4. In addition, for the two experimental groups, an independent t-test was performed to confirm statistical significance, and the results are shown in FIG. 4 .
[계산식 2][Calculation 2]
표 4에서 확인할 수 있듯이, L. acidophilus를 먹인 실험군이 대조군보다 높은 판별 비 (Discrimination ratio)를 보였다. 또한, 처음 관찰한 물체가 novel object인 마우스의 비율도 L. acidophilus를 먹인 그룹에서 약 두 배 높게 나타났다. 또한, 도 4에서 확인할 수 있듯이, L. acidophilus를 먹인 그룹에서 더 높은 평균값 및 중앙값을 나타내었다. p value값은 0.035475로 L. acidophilus를 먹인 그룹에서 새로운 물체를 잘 식별한 것으로 나타났다.As can be seen in Table 4, the experimental group fed with L. acidophilus showed a higher discrimination ratio than the control group. In addition, the ratio of mice whose first observed object was a novel object was about twice as high in the L. acidophilus -fed group. In addition, as can be seen in Figure 4, the average and median values were higher in the group fed with L. acidophilus . The p value was 0.035475, indicating that the new object was well identified in the group fed with L. acidophilus .
3-4. Passive avoidance test의 수행 및 측정결과3-4. Passive avoidance test performance and measurement results
유산균 급여 7주차에 수행된 실험이다. 점등된 칸막이와 어두운 칸막이로 나뉘고 두 칸 사이에 게이트가 있는 이동상자를 이용하였다. 실험에 사용된 이동상자는 정도바이오에서 제작 및 구입하였다. 점등된 칸막이에 마우스를 놓고 천장에 설치된 조명장치를 통해 불빛을 동물에게 비춘다. 이런 조건에서 실험 동물은 밝은 곳을 피해 어두운 상자로 들어가면서 회피반응을 보인다. 마우스가 게이트 반대 벽에 마주하는 순간 두 칸막이 사이의 문을 열고, 마우스가 어두운 칸막이로 이동하기까지의 시간을 측정하였다. 꼬리까지 완전히 어두운 칸막이로 넘어간 경우에 두 칸막이 사이의 문을 닫았다. 어두운 칸막이에서 3초의 시간을 보낸 후 0.25 mA의 전류를 바닥에 3초간 흘려주었다. 전기 충격을 기억할 수 있도록 어두운 칸막이에 30초간 머무르게 하였다. 그 후, 사육 케이지로 돌려보내고 24시간 후 전기충격 없이 같은 시행을 반복하였을 때 어두운 칸막이로 들어가기까지의 시간을 측정하였다. 2일간의 시행을 비교하였을 때, 칸막이로 들어가기까지의 시간(latency time)의 증가를 비교하여 인지능력을 평가하였다. 그 결과를 표 5에 나타내었다. 또한, 통계적 유의성을 확인하기 위하여 independent t-test를 수행하여, 그 결과를 도 5에 나타내었다.This is an experiment conducted on the 7th week of lactic acid bacteria feeding. It is divided into a lighted partition and a dark partition, and a moving box with a gate between the two partitions was used. The mobile box used in the experiment was manufactured and purchased from Jeongdo Bio. Place the mouse in the lighted cubicle and shine light on the animal through a lighting device installed on the ceiling. Under these conditions, the experimental animals show an avoidance reaction by entering a dark box to avoid a bright place. The moment the mouse faced the opposite wall of the gate, the door between the two partitions was opened, and the time until the mouse moved to the dark partition was measured. The door between the two partitions was closed when it passed into a completely dark partition up to its tail. After spending 3 seconds in a dark cubicle, a current of 0.25 mA was applied to the floor for 3 seconds. They were kept in a dark cubicle for 30 seconds to remember the electric shock. Thereafter, when returned to the breeding cage and repeated the same trial without electric shock after 24 hours, the time to enter the dark cubicle was measured. When the 2-day trials were compared, the cognitive ability was evaluated by comparing the increase in latency time until entering the cubicle. The results are shown in Table 5. In addition, an independent t-test was performed to confirm statistical significance, and the results are shown in FIG. 5 .
표 5에에서 확인할 수 있듯이, L. acidophilus를 먹인 실험군이 대조군보다 높은 Step-through latency 값을 나타냈다. 또한, 도 5에서 확인할 수 있듯이, L. acidophilus를 먹인 그룹에서 더 높은 평균값 및 중앙값을 나타내었다. p value 값은 0.039885로 L. acidophilus를 먹인 그룹에서 전 날 가해진 전기 충격을 더 잘 기억하는 것으로 나타났다.As can be seen in Table 5, the experimental group fed with L. acidophilus showed a higher step-through latency value than the control group. In addition, as can be seen in Figure 5, the average and median values were higher in the group fed with L. acidophilus . The p value was 0.039885, indicating that the group fed L. acidophilus better remembered the electric shock applied the previous day.
3-5. Y maze 2 (Forced alternation; FA)의 수행 및 측정결과3-5. Performance and measurement results of Y maze 2 (Forced alternation; FA)
유산균 급여 8주가 되었을 때 수행되었다. SA에서 이용한 Y maze와 동일한 틀을 사용하였다. 하얀 판을 이용해서 하나의 팔에 진입이 불가능하도록 입구를 막아놓고, 마우스를 나머지 두 팔 중 한쪽에 벽을 마주보게 하여 놓는다. 마우스는 5분간 두 팔을 자유롭게 돌아다녔다 (Sample trial). 그 후, 케이지에서 1시간의 안정시간을 취하였다. 하나의 팔을 막아놓았던 블록을 제거한 후 마우스를 같은 위치에 내려놓았다. 5분간 세 개의 팔을 자유롭게 탐구하게 두고, sample trial에서 막혀있던 팔에 진입하는 횟수와 시간을 측정하였다 (Alternation trial). 그 결과를 표 6에 나타내었다. 또한, 통계적 유의성을 확인하기 위하여 independent t-test를 수행하여, 그 결과를 도 6에 나타내었다.It was performed when lactobacillus feeding was 8 weeks. The same frame as the Y maze used in SA was used. Block the entrance to one arm using a white plate, and place the mouse on one of the other arms facing the wall. Mice were allowed to move freely on both arms for 5 minutes (Sample trial). After that, a rest period of 1 hour was taken in the cage. After removing the block blocking one arm, the mouse was put down in the same position. The three arms were freely explored for 5 minutes, and the number and time of entering the blocked arm were measured in the sample trial (Alternation trial). The results are shown in Table 6. In addition, an independent t-test was performed to confirm statistical significance, and the results are shown in FIG. 6 .
표 6에에서 확인할 수 있듯이, L. acidophilus를 먹인 실험군이 대조군보다 높은 Forced alternation값을 보였다. 또한, 처음 arm이 novel arm인 마우스의 비율도 L. acidophilus를 먹인 그룹에서 높게 나타났다. 또한, 도 6에서 확인할 수 있듯이, L. acidophilus를 먹인 그룹에서 더 높은 평균값을 나타냄을 확인하였다.As can be seen in Table 6, the experimental group fed with L. acidophilus showed higher forced alternation values than the control group. Also, the proportion of mice whose first arm was a novel arm was higher in the L. acidophilus -fed group. In addition, as can be seen in Figure 6, it was confirmed that the group fed L. acidophilus showed a higher average value.
실시예 4. 장내미생물 변화 양상 분석Example 4. Analysis of changes in intestinal microbes
실제 투여한 미생물이 장에 안착하여 미생물 조성이 변화되었는지를 확인하기 위하여 분변의 메타게놈 (metagenome) 분석을 수행하였다. 분석에 이용된 쥐 분변은 유산균 투여 8주 후 채취하였으며, 채취 후 sequencing 전까지 -80 °C에서 냉동보관 하였다. 메타게놈 시퀀싱은 Oxford사의 nanopore (flongle)을 이용해 미생물의 16s rRNA에 대해 전장 유전체 (whole genome) 시퀀싱을 수행하였다.Metagenome analysis of the feces was performed to confirm whether the actually administered microorganisms settled in the intestine and changed the microbial composition. Rat feces used for analysis were collected 8 weeks after administration of lactic acid bacteria and stored frozen at -80 °C until sequencing. For metagenome sequencing, whole genome sequencing was performed on the 16s rRNA of microorganisms using Oxford's nanopore (flongle).
MiniON으로 생성된 로두 데이터 (raw data) (fast5 file)는 Guppy 프로그램을 통해 basecalling이 이루어졌다. basecalling하여 생성된 fastq 데이터는 porechop (version 3) 프로그램을 사용하여 adaptor trimming 과정을 거친 후, minimap2 프로그램을 사용하여 GTDB와 alignment하여 assembly를 완성하였다. 대조군과 실험군의 장내 L. acidophilus 비율 차이를 하기 표 7에 나타내었다. Basecalling was performed on raw data (fast5 file) generated by MiniON using the Guppy program. The fastq data generated by basecalling went through adapter trimming using the porechop (version 3) program, and then aligned with GTDB using the minimap2 program to complete assembly. The difference between the intestinal L. acidophilus ratio between the control group and the experimental group is shown in Table 7 below.
표 7에서 확인할 수 있듯이, 생성된 데이터는 각 생물학적 분류 계급에 따라 전체 장 내에서 가지는 비율로 나타내었다. 두 그룹의 평균차이는 independence t test를 통해 유의한 차이가 있는지 확인하였다. p value 값은 0.00069로 두 그룹간 매우 유의미한 차이가 있는 것을 확인하였다.As can be seen in Table 7, the generated data is expressed as a percentage within the entire field according to each biological classification class. The average difference between the two groups was confirmed through independence t test to see if there was a significant difference. The p value was 0.00069, confirming that there was a very significant difference between the two groups.
<110> C&K genomics Inc. Seoul National University R&DB Foundation <120> Lactobacillus acidophilus with cognitive function improvement <130> PN200327 <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 1502 <212> RNA <213> Artificial Sequence <220> <223> Lactobacillus acidophilus_16s rRNA <400> 1 ggacgaacgc tggcggcgtg cctaatacat gcaagtcgag cgagctgaac caacagattc 60 acttcggtga tgacgttggg aacgcgagcg gcggatgggt gagtaacacg tggggaacct 120 gcccccatag tctgggatac cacttggaaa caggtgctaa taccggataa gaaagcagat 180 cgcatgatca gcttataaaa ggcggcgtaa gctgtcgcta tgggatggcc ccgcggtgca 240 ttagctagtt ggtagggtaa cggcctacca aggcaatgat gcatagccga gttgagagac 300 tgatcggcca cattgggact gagacacggc ccaaactcct acgggaggca gcagtaggga 360 atcttccaca atggacgaaa gtctgatgga gcaacgccgc gtgagtgaag aaggttttcg 420 gatcgtaaag ctctgttgtt ggtgaagaag gatagaggta gtaactggcc tttatttgac 480 ggtaatcaac cagaaagtca cggctaacta cgtgccagca gccgcggtaa tacgtaggtg 540 gcaagcgttg tccggattta ttgggcgtaa agcgagcgca ggcggaagaa taagtctgat 600 gtgaaagccc tcggcttaac cgaggaactg catcggaaac tgtttttctt gagtgcagaa 660 gaggagagtg gaactccatg tgtagcggtg gaatgcgtag atatatggaa gaacaccagt 720 ggcgaaggcg gctctctggt ctgcaactga cgctgaggct cgaaagcatg ggtagcgaac 780 aggattagat accctggtag tccatgccgt aaacgatgag tgctaagtgt tgggaggttt 840 ccgcctctca gtgctgcagc taacgcatta agcactccgc ctggggagta cgaccgcaag 900 gttgaaactc aaaggaattg acgggggccc gcacaagcgg tggagcatgt ggtttaattc 960 gaagcaacgc gaagaacctt accaggtctt gacatctagt gcaatccgta gagatacgga 1020 gttcccttcg gggacactaa gacaggtggt gcatggctgt cgtcagctcg tgtcgtgaga 1080 tgttgggtta agtcccgcaa cgagcgcaac ccttgtcatt agttgccagc attaagttgg 1140 gcactctaat gagactgccg gtgacaaacc ggaggaaggt ggggatgacg tcaagtcatc 1200 atgcccctta tgacctgggc tacacacgtg ctacaatgga cagtacaacg aggagcaagc 1260 ctgcgaaggc aagcgaatct cttaaagctg ttctcagttc ggactgcagt ctgcaactcg 1320 actgcacgaa gctggaatcg ctagtaatcg cggatcagca cgccgcggtg aatacgttcc 1380 cgggccttgt acacaccgcc cgtcacacca tgggagtctg caatgcccaa agccggtggc 1440 ctaaccttcg ggaaggagcc gtctaaggca gggcagatga ctggggtgaa tctaaaaggg 1500 gg 1502 <110> C&K genomics Inc. Seoul National University R&DB Foundation <120> Lactobacillus acidophilus with cognitive function improvement <130> PN200327 <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 1502 <212> RNA <213> artificial sequence <220> <223> Lactobacillus acidophilus_16s rRNA <400> 1 ggacgaacgc tggcggcgtg cctaatacat gcaagtcgag cgagctgaac caacagattc 60 acttcggtga tgacgttggg aacgcgagcg gcggatgggt gagtaacacg tggggaacct 120 gcccccatag tctgggatac cacttggaaa caggtgctaa taccggataa gaaagcagat 180 cgcatgatca gcttataaaa ggcggcgtaa gctgtcgcta tgggatggcc ccgcggtgca 240 ttagctagtt ggtagggtaa cggcctacca aggcaatgat gcatagccga gttgagagac 300 tgatcggcca cattgggact gagacacggc ccaaactcct acgggaggca gcagtaggga 360 atcttccaca atggacgaaa gtctgatgga gcaacgccgc gtgagtgaag aaggttttcg 420 gatcgtaaag ctctgttgtt ggtgaagaag gatagaggta gtaactggcc tttattgac 480 ggtaatcaac cagaaagtca cggctaacta cgtgccagca gccgcggtaa tacgtaggtg 540 gcaagcgttg tccggattta ttgggcgtaa agcgagcgca ggcggaagaa taagtctgat 600 gtgaaagccc tcggcttaac cgaggaactg catcggaaac tgtttttctt gagtgcagaa 660 gaggagagtg gaactccatg tgtagcggtg gaatgcgtag atatatggaa gaacaccagt 720 ggcgaaggcg gctctctggt ctgcaactga cgctgaggct cgaaagcatg ggtagcgaac 780 aggattagat accctggtag tccatgccgt aaacgatgag tgctaagtgt tgggaggttt 840 ccgcctctca gtgctgcagc taacgcatta agcactccgc ctggggagta cgaccgcaag 900 gttgaaactc aaaggaattg acgggggccc gcacaagcgg tggagcatgt ggtttaattc 960 gaagcaacgc gaagaacctt accaggtctt gacatctagt gcaatccgta gagatacgga 1020 gttcccttcg gggacactaa gacaggtggt gcatggctgt cgtcagctcg tgtcgtgaga 1080 tgttgggtta agtcccgcaa cgagcgcaac ccttgtcatt agttgccagc attaagttgg 1140 gcactctaat gagactgccg gtgacaaacc ggaggaaggt ggggatgacg tcaagtcatc 1200 atgcccctta tgacctgggc tacacacgtg ctacaatgga cagtacaacg aggagcaagc 1260 ctgcgaaggc aagcgaatct cttaaagctg ttctcagttc ggactgcagt ctgcaactcg 1320 actgcacgaa gctggaatcg ctagtaatcg cggatcagca cgccgcggtg aatacgttcc 1380 cgggccttgt acacaccgcc cgtcacacca tgggagtctg caatgcccaa agccggtggc 1440 ctaaccttcg ggaaggagcc gtctaaggca gggcagatga ctggggtgaa tctaaaaggg 1500 gg 1502
Claims (10)
A pharmaceutical composition for preventing or treating degenerative brain disease or dementia, comprising at least one selected from the group consisting of live bacteria of Lactobacillus acidophilus of accession number KCTC 14369BP, lysates thereof, and extracts thereof.
The pharmaceutical composition according to claim 4, wherein the Lactobacillus acidophilus has 16sRNA consisting of the nucleotide sequence of SEQ ID NO: 1.
Accession No. KCTC 14369BP Lactobacillus acidophilus ( Lactobacillus acidophilus ) Live cells, their lysates and their extracts containing at least one member selected from the group consisting of memory or cognitive ability improvement, or food composition for improvement.
The food composition according to claim 8, wherein the Lactobacillus acidophilus has 16sRNA consisting of the nucleotide sequence of SEQ ID NO: 1.
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