KR20230112549A - Compositions for preventing, alleviating, or treating inflammatory diseases, comprising extracellular vesicles derived from Roseburia spp. or Bifidobacterium spp. - Google Patents
Compositions for preventing, alleviating, or treating inflammatory diseases, comprising extracellular vesicles derived from Roseburia spp. or Bifidobacterium spp. Download PDFInfo
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- KR20230112549A KR20230112549A KR1020230006807A KR20230006807A KR20230112549A KR 20230112549 A KR20230112549 A KR 20230112549A KR 1020230006807 A KR1020230006807 A KR 1020230006807A KR 20230006807 A KR20230006807 A KR 20230006807A KR 20230112549 A KR20230112549 A KR 20230112549A
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- roseburia
- bifidobacterium
- extracellular vesicles
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- disease
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Abstract
본 발명은 로세부리아 속 균주(Roseburia spp.) 및/또는 비피도박테리움 속 균주(Bifidobacterium spp.) 유래한 세포외소포체(extracellular vesicles, EV)를 포함하는 염증성 질환(inflammatory disease)의 예방, 개선 또는 치료용 조성물에 관한 것이다. 본 발명의 세포외소포체는 IBD 환자에서 장 상피세포 장벽 및 면역세포의 침윤을 감소시키고, 배상세포의 수를 유지하고, 장 염증과 관련된 맹장 무게와 장 길이 감소를 억제하고, 장내 균총 변화를 통해 염증성 사이토카인의 분비를 억제하고, 배상세포의 점액 분비와 장 상피세포의 치밀결합 능력을 회복시킴에 따라 IBD를 개선하는 효과를 나타낸다. 뿐만 아니라, 로세부리아 속 균주 또는 비피도박테리움 속 균주에 해당하는 동속이종 균주들로부터 유래한 EV들의 항염 효과를 확인한 결과, 상기 EV 모두 강력한 염증 억제 효과를 발휘하는 것으로 확인됐다. 따라서, 본 발명의 균주 및 이로부터 유래한 EV는 다양한 염증성 질환의 예방, 개선, 또는 치료용 조성물로 제공될 수 있다.The present invention relates to a composition for preventing, improving or treating inflammatory diseases, including extracellular vesicles (EV) derived from Roseburia spp. and/or Bifidobacterium spp. The extracellular vesicles of the present invention reduce the intestinal epithelial cell barrier and infiltration of immune cells in IBD patients, maintain the number of goblet cells, suppress the decrease in caecal weight and intestinal length associated with intestinal inflammation, suppress the secretion of inflammatory cytokines through changes in the intestinal flora, and restore the mucous secretion of goblet cells and the tight coupling ability of intestinal epithelial cells, thereby improving IBD. In addition, as a result of confirming the anti-inflammatory effect of EVs derived from homologous and heterogeneous strains corresponding to Roseburia genus strains or Bifidobacterium genus strains, it was confirmed that all of the EVs exerted a strong anti-inflammatory effect. Therefore, the strain of the present invention and the EV derived therefrom can be provided as a composition for preventing, improving, or treating various inflammatory diseases.
Description
본 발명은 로세부리아 속(Roseburia spp.) 균주, 비피도박테리움 속(Bifidobacterium spp.) 균주, 또는 이들로부터 유래한 세포외소포체(extracellular vesicles, EV)를 포함하는, 염증성 질환(inflammatory disease)의 예방, 개선 또는 치료용 조성물 등에 관한 것이다.The present invention relates to a composition for preventing, improving or treating inflammatory diseases, including Roseburia spp. strains, Bifidobacterium spp. strains, or extracellular vesicles (EVs) derived therefrom.
염증(inflammation)이란 외부 감염원(박테리아, 곰팡이, 바이러스, 다양한 종류의 알레르기 유발물질)의 침입에 의하여 형성되는 농양의 병리적 상태를 뜻한다. 구체적으로, 외부 세균이 특정 조직에 침입하여 증식을 하게 되면 생체의 백혈구가 이를 인지하여 증식된 외부 세균을 활발히 공격하게 되는데, 이 과정 중 발생되는 백혈구의 사해가 균에 의하여 침입받은 조직에 축적됨과 동시에 백혈구에 의하여 사멸된 침입균의 세포 파괴물이 침입 받은 조직 내로 융해되어 농양이 형성된다. 염증에 의한 농양의 치료는 소염작용을 통하여 촉진될 수 있는데, 소염작용이란 항균제를 이용하여 침입균의 증식을 억제하거나 농양 중에 축적된 이물질들을 탐식하는 대식세포(macrophage)를 활성화하여 상기 이물질들을 소화 및 배설하는 대식세포의 기능을 항진시키는 등의 염증치료 촉진작용이다.Inflammation refers to the pathological condition of an abscess formed by the invasion of external infectious agents (bacteria, fungi, viruses, various types of allergens). Specifically, when external bacteria invade and proliferate in a specific tissue, the leukocytes of the body recognize this and actively attack the proliferated external bacteria. During this process, the dead cells of the white blood cells generated are accumulated in the tissue invaded by the bacteria, and at the same time, the cell destruction of the invaded bacteria killed by the white blood cells dissolves into the invaded tissue to form an abscess. The treatment of abscesses due to inflammation can be promoted through anti-inflammatory action, which is an inflammatory treatment promoting action, such as inhibiting the proliferation of invading bacteria using antibacterial agents or activating macrophages that phagocytize foreign substances accumulated in abscesses to enhance the function of macrophages to digest and excrete the foreign substances.
일반적으로 염증반응은 생체의 세포나 조직에 기질적 변화를 가져오는 침습으로 인한 손상을 수복 및 재생하기 위한 생체방어 반응과정이고, 이 반응과정에는 국소의 혈관, 체액의 각종 조직세포 및 면역세포 등이 작용한다. 정상적으로 외부 침입균에 의하여 유도되는 염증반응은 생체를 보호하기 위한 방어 시스템인 반면, 비정상적으로 과도한 염증반응이 유도되면 다양한 질환들이 나타나는데, 이러한 질환들을 염증질환이라 칭한다. 염증질환은 외부자극에 의하여 활성화된 표적세포로부터 분비되는 다양한 염증 매개물질이 염증을 증폭 및 지속시켜 인체의 생명을 위협할 수 있다. 염증성 질환은 급성 기관지염, 만성 기관지염, 급성 세기관지염, 만성 세기관지염, 패혈증, 패혈성 쇼크, 급성 호흡곤란 증후군, 다발성 장기부전 및 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease) 등을 포함한다. 대표적인 염증성 질환 중 하나인 염증성 장질환(inflammatory bowel disease, IBD)은 위장관 내에 만성적인 염증을 일으키는 질환으로, 만성적인 경과를 보이며 점진적으로 병이 진행되고, 합병증을 일으키며 신체적 기능을 감소시킨다(SY Na and W Moon, Korean J Gastroenterol Vol. 71 No. 2, 61-68). 염증성 장질환은 주로 궤양성 대장염(Ulcerative colitis, UC)과 크론병(Cron's disease, CD)의 2가지 형태로 분류된다. 염증성 장질환은 명확한 발병 기전이 알려져 있지 않으며, 유전적 요인이나 스트레스, 약물 사용 등과 같은 환경적 요인들이 복합적으로 작용하여 생기는 것으로 추정된다. 따라서, 환자마다 다른 병인을 갖고 있으며, 경과 및 예후도 상이하기 때문에, 완치가 어려운 질환이다.In general, the inflammatory response is a biological defense reaction process for repairing and regenerating damage caused by invasion that causes organic changes in cells or tissues of a living body, and local blood vessels, various tissue cells of body fluids, and immune cells act in this reaction process. Normally, the inflammatory response induced by external invading bacteria is a defense system to protect the living body, but when an abnormally excessive inflammatory response is induced, various diseases appear, and these diseases are called inflammatory diseases. In inflammatory diseases, various inflammatory mediators secreted from target cells activated by external stimuli amplify and sustain inflammation, which can threaten the life of the human body. Inflammatory diseases include acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, sepsis, septic shock, acute respiratory distress syndrome, multiple organ failure, and chronic obstructive pulmonary disease. Inflammatory bowel disease (IBD), one of the representative inflammatory diseases, is a disease that causes chronic inflammation in the gastrointestinal tract, shows a chronic course, gradually progresses, causes complications, and reduces physical function (SY Na and W Moon, Korean J Gastroenterol Vol. 71 No. 2, 61-68). Inflammatory bowel disease is mainly classified into two forms: ulcerative colitis (UC) and Crohn's disease (CD). Inflammatory bowel disease has no clear pathogenesis, and is presumed to be caused by a combination of genetic factors and environmental factors such as stress and drug use. Therefore, since each patient has a different etiology and a different course and prognosis, it is a disease that is difficult to cure.
많은 염증 관련 질환의 발병에는 대식세포의 활성화와 이에 따른 염증관련 인자들의 과도한 생성이 연관되어 있는데, 대표적인 염증관련 인자들로는 IL-1β, TNF-α 등이 있다. 또한, 염증반응의 유도물질들 중에서 LPS(lipopolysaccharide)는 그람음성세균의 세포 표면을 구성하는 물질로서 백혈구와 같은 면역세포와 상호 작용을 하며, 염증관련 사이토카인의 조절에 관여한다. 특히, IL-1βTNF-α 및 IL-6과 같은 염증성 사이토카인은 다양한 전염성 또는 염증성 질환의 병리학적 진행을 매개하는데 있어 중대한 역할을 한다. 이러한 염증성 사이토카인들은 여러 면역 세포와 염증 세포에 의해 생성되며, 조직과 장기 손상을 유발하는 손상 부위로 추가적인 염증 세포를 모집하는데 기여한다.The onset of many inflammation-related diseases is associated with the activation of macrophages and the consequent excessive production of inflammation-related factors, such as IL-1β and TNF-α. In addition, among the inducers of the inflammatory response, LPS (lipopolysaccharide) is a substance constituting the cell surface of Gram-negative bacteria, interacts with immune cells such as leukocytes, and is involved in the regulation of inflammatory-related cytokines. In particular, inflammatory cytokines such as IL-1βTNF-α and IL-6 play an important role in mediating the pathological progression of various infectious or inflammatory diseases. These inflammatory cytokines are produced by various immune and inflammatory cells and contribute to the recruitment of additional inflammatory cells to the site of injury resulting in tissue and organ damage.
본 발명자들은 종래 염증성 질환의 치료제보다 우수한 효과를 갖는 약물을 찾기 위해 예의 노력한 결과, 로세부리아 속(Roseburia spp.) 균주 및 비피도박테리움 속(Bifidobacterium spp.) 균주 유래 세포외소포체(extracellular vesicles, EV)가 염증성 질환에 대해 우수한 예방, 개선, 및 치료 효과를 발휘하는 것을 확인하여 본 발명을 완성하였다.As a result of diligent efforts to find a drug having a superior effect than conventional therapeutic agents for inflammatory diseases, the inventors of the present invention have completed the present invention by confirming that extracellular vesicles (EVs) derived from Roseburia spp. strains and Bifidobacterium spp.
따라서, 본 발명의 목적은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는, 염증성 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases, comprising at least one selected from the group consisting of extracellular vesicles derived from strains of the genus Roseburia and extracellular vesicles derived from strains of the genus Bifidobacterium as an active ingredient.
본 발명의 다른 목적은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는, 염증성 질환의 예방 또는 치료용 키트를 제공하는 것이다.Another object of the present invention is to provide a kit for preventing or treating inflammatory diseases, comprising at least one selected from the group consisting of extracellular vesicles derived from strains of the genus Roseburia and extracellular vesicles derived from strains of the genus Bifidobacterium as an active ingredient.
본 발명의 또 다른 목적은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 염증성 질환의 예방 또는 치료방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating inflammatory diseases, comprising administering at least one selected from the group consisting of extracellular vesicles derived from strains of the genus Roseburia and extracellular vesicles derived from strains of the genus Bifidobacterium to a subject in need thereof.
본 발명의 또 다른 목적은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 포함하는, 염증성 질환의 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving inflammatory diseases, comprising at least one selected from the group consisting of extracellular vesicles derived from strains of the genus Roseburia and extracellular vesicles derived from strains of the genus Bifidobacterium.
본 발명의 또 다른 목적은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 포함하는, 염증성 질환의 예방 또는 개선용 사료 조성물을 제공하는 것이다.Another object of the present invention is to provide a feed composition for preventing or improving inflammatory diseases, comprising at least one selected from the group consisting of extracellular vesicles derived from strains of the genus Roseburia and extracellular vesicles derived from strains of the genus Bifidobacterium.
그러나, 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 본 발명이 속하는 기술 분야의 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.
본 발명은 로세부리아 속(Roseburia spp.) 균주 유래 세포외소포체 및 비피도박테리움 속(Bifidobacterium spp.) 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는, 염증성 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases comprising, as an active ingredient, at least one selected from the group consisting of extracellular vesicles derived from Roseburia spp. strains and extracellular vesicles derived from Bifidobacterium spp. strains.
또한, 본 발명은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는, 염증성 질환의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving inflammatory diseases, comprising at least one selected from the group consisting of extracellular vesicles derived from strains of the genus Roseburia and extracellular vesicles derived from strains of the genus Bifidobacterium as an active ingredient.
또한, 본 발명은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는, 염증성 질환의 예방 또는 개선용 사료 조성물을 제공한다.In addition, the present invention provides a feed composition for preventing or improving inflammatory diseases, comprising at least one selected from the group consisting of extracellular vesicles derived from a strain of the genus Roseburia and extracellular vesicles derived from a strain of the genus Bifidobacterium as an active ingredient.
또한, 본 발명은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 포함하는, 염증성 질환의 예방, 개선, 또는 치료용 키트를 제공한다.In addition, the present invention provides a kit for preventing, improving, or treating inflammatory diseases, including at least one selected from the group consisting of extracellular vesicles derived from a strain of the genus Roseburia and extracellular vesicles derived from a strain of the genus Bifidobacterium.
뿐만 아니라, 본 발명은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 이를 필요로 하는 개체에 투여하는 단계를 포함하는, 염증성 질환의 예방 또는 치료방법을 제공한다.In addition, the present invention provides a method for preventing or treating inflammatory diseases, comprising administering at least one selected from the group consisting of extracellular vesicles derived from strains of the genus Roseburia and extracellular vesicles derived from strains of the genus Bifidobacterium to a subject in need thereof.
뿐만 아니라, 본 발명은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상의 염증성 질환 예방 또는 치료 용도를 제공한다.In addition, the present invention provides a use for preventing or treating one or more inflammatory diseases selected from the group consisting of extracellular vesicles derived from strains of the genus Roseburia and extracellular vesicles derived from strains of the genus Bifidobacterium.
뿐만 아니라, 본 발명은 염증성 질환의 치료제의 제조를 위한 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상의 용도를 제공한다.In addition, the present invention provides one or more uses selected from the group consisting of extracellular vesicles derived from a strain of the genus Roseburia and extracellular vesicles derived from a strain of the genus Bifidobacterium for the preparation of a therapeutic agent for inflammatory diseases.
본 발명의 일 구현예에서, 상기 세포외소포체는 평균 직경이 30 nm 내지 200 nm일 수 있으나, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the extracellular vesicles may have an average diameter of 30 nm to 200 nm, but is not limited thereto.
본 발명의 다른 구현예에서, 상기 로세부리아 속 균주 유래 세포외소포체는 로세부리아 속 균주로부터 자연적으로 또는 인공적으로 분비되는 것이고;In another embodiment of the present invention, the extracellular vesicles derived from the strain of the genus Roseburia are naturally or artificially secreted from the strain of the genus Roseburia;
본 발명의 또 다른 구현예에서, 상기 비피도박테리움 속 균주 유래 세포외소포체는 비피도박테리움 속 균주로부터 자연적으로 또는 인공적으로 분비될 수 있으나, 이에 한정되지 않는다.In another embodiment of the present invention, the extracellular vesicles derived from the strain of the genus Bifidobacterium may be naturally or artificially secreted from the strain of the genus Bifidobacterium, but are not limited thereto.
본 발명의 또 다른 구현예에서, 상기 로세부리아 속 균주는 로세부리아 인테스티날리스(Roseburia intestinalis), 로세부리아 파에시스(Roseburia faecies), 로세부리아 호미니스(Roseburia hominis), 및 로세부리아 이눌리니보란스(Roseburia inulinivorans)로 이루어진 군에서 선택된 하나 이상일 수 있으나, 이에 한정되는 것은 아니다. In another embodiment of the present invention, the strain of the genus Roseburia may be one or more selected from the group consisting of Roseburia intestinalis , Roseburia faecies , Roseburia hominis , and Roseburia inulinivorans , but is not limited thereto.
본 발명의 또 다른 구현예에서, 상기 비피도박테리움 속 균주는 비피도박테리움 롱검(Bifidobacterium longum), 비피도박테리움 비피덤(Bifidobacterium bifidum), 비피도박테리움 브레이브(Bifidobacterium breve), 비피도박테리움 락티스(Bifidobacterium lactis), 및 비피도박테리움 어돌레스켄티스(Bifidobacterium adolescentis)로 이루어진 군에서 선택된 하나 이상일 수 있으나, 이에 한정되지 않는다.In another embodiment of the present invention, the strain of the genus Bifidobacterium is Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium breve , Bifidobacterium lactis , and Bifidobacterium adolescentis . It may be one or more selected from the group consisting of, but is not limited thereto.
본 발명의 또 다른 구현예에서, 상기 염증성 질환은 위염, 위궤양, 십이지장궤양, 염증성 피부질환, 알레르기성 질환, 과민성 대장 증후군, 궤양성 대장염, 염증성 장질환, 복막염, 골수염, 봉소염, 뇌막염, 뇌염, 췌장염, 외상 유발 쇼크, 기관지 천식, 낭포성 섬유증, 뇌졸중, 급성 기관지염, 만성 기관지염, 급성 세기관지염, 만성 세기관지염, 골관절염, 통풍, 척추관절병증, 강직성 척추염, 라이터 증후군, 건선성 관절병증, 장질환 척추염, 연소자성 관절병증, 연소자성 강직성 척추염, 반응성 관절병증, 감염성 관절염, 후-감염성 관절염, 임균성 관절염, 결핵성 관절염, 바이러스성 관절염, 진균성 관절염, 매독성 관절염, 라임병, 혈관염 증후군과 관련된 관절염, 결절성 다발동맥염, 과민성 혈관염, 루게릭 육아종증, 류마티스성 다발성근육통, 관절 세포 동맥염, 칼슘 결정 침착 관절병증, 가성 통풍, 비-관절 류마티즘, 점액낭염, 건초염, 상과염, 신경병증성 관절 질환(charco and joint), 출혈성 관절증(hemarthrosic), 헤노흐-쉔라인 자반병, 비후성 골관절병증, 다중심성 세망조직구종, 수르코일로시스(surcoilosis), 혈색소증, 겸상 적혈구증, 혈색소병증, 고지단백혈증, 저감마글로불린혈증, 가족성 지중해열, 베하트 병, 전신성 홍반성 루푸스, 재귀열, 건선, 다발성 경화증, 패혈증, 패혈성 쇼크, 다장기 기능장애 증후군, 급성 호흡곤란 증후군, 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease), 급성 폐손상(acute lung injury), 및 기관지 폐 형성장애(broncho-pulmonary dysplasia)로 이루어진 군에서 선택된 하나 이상일 수 있으나, 이에 한정되지 않는다.In another embodiment of the present invention, the inflammatory disease is gastritis, gastric ulcer, duodenal ulcer, inflammatory skin disease, allergic disease, irritable bowel syndrome, ulcerative colitis, inflammatory bowel disease, peritonitis, osteomyelitis, cellulitis, meningitis, encephalitis, pancreatitis, trauma-induced shock, bronchial asthma, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis arthritis, chronic bronchiolitis, osteoarthritis, gout, spondyloarthropathy, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enteropathic spondylitis, juvenile arthropathy, juvenile ankylosing spondylitis, reactive arthropathy, infectious arthritis, post-infectious arthritis, gonococcal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with vasculitic syndrome, polyarteritis nodosa, hypersensitivity vasculitis, Lou Gehrig Granulomatosis, polymyalgia rheumatica, joint cell arteritis, calcium crystal deposition arthropathy, pseudogout, non-articular rheumatism, bursitis, tenosynovitis, epicondylitis, neuropathic joint disease (charco and joint), hemorrhagic arthrosis (hemarthrosic), Henoch-Schönlein purpura, hypertrophic osteoarthropathy, multicentric reticulocytoma, surcoilosis, blood Pigmentosis, sickle cell disease, hemochromatosis, hyperlipoproteinemia, hypogammaglobulinemia, familial thalassemia fever, Behatt's disease, systemic lupus erythematosus, relapsing fever, psoriasis, multiple sclerosis, sepsis, septic shock, multiorgan dysfunction syndrome, acute respiratory distress syndrome, chronic obstructive pulmonary disease, acute lung injury, and broncho-pulmonary dysplasia dysplasia), but may be one or more selected from the group consisting of, but is not limited thereto.
본 발명의 또 다른 구현예에서, 상기 염증성 장질환은 궤양성 대장염, 크론병, 베체트병, 교원성 대장염, 림프성 대장염, 허혈성 대장염, 출혈성 직장 궤양, 회장 낭염, 및 전환성 대장염으로 이루어진 군에서 선택된 하나 이상일 수 있으나, 이에 한정되지 않는다.In another embodiment of the present invention, the inflammatory bowel disease may be at least one selected from the group consisting of ulcerative colitis, Crohn's disease, Behcet's disease, collagenous colitis, lymphocytic colitis, ischemic colitis, hemorrhagic rectal ulcer, ileal pouchitis, and converting colitis, but is not limited thereto.
본 발명의 또 다른 구현예에서, 본 발명에 따른 조성물은 하기로 이루어진 군에서 선택된 하나 이상의 효과를 가질 수 있으나, 이에 한정되지 않는다:In another embodiment of the present invention, the composition according to the present invention may have one or more effects selected from the group consisting of, but not limited to:
i) 장 상피세포 장벽 손상 감소;i) reducing intestinal epithelial barrier damage;
ii) 면역세포의 장 조직 침윤 감소;ii) reduction of intestinal tissue infiltration of immune cells;
iii) 배상세포(goblet cells)의 수 감소 억제;iii) inhibition of reduction in the number of goblet cells;
iv) 맹장 무게 감소 억제;iv) inhibition of cecal weight loss;
v) 장 길이 감소 억제;v) inhibition of intestinal length reduction;
vi) 염증성 사이토카인 생성 억제;vi) inhibition of inflammatory cytokine production;
vii) 항염증성 사이토카인 생성 촉진;vii) promoting anti-inflammatory cytokine production;
viii) 배상세포의 점액 분비 증진;viii) enhancement of mucus secretion by goblet cells;
ix) 장 상피세포의 치밀결합 증진; 및ix) enhancing the compactness of intestinal epithelial cells; and
x) 장내 비피도박테리움(Bifidobacterium) 수 증가.x) Increased number of Bifidobacterium in the intestine.
본 발명의 또 다른 구현예에서, 상기 식품 조성물은 건강기능식품 조성물일 수 있으나, 이에 한정되지 않는다.In another embodiment of the present invention, the food composition may be a health functional food composition, but is not limited thereto.
본 발명은 로세부리아 속 균주(Roseburia spp.) 및/또는 비피도박테리움 속 균주(Bifidobacterium spp.) 유래한 세포외소포체(extracellular vesicles, EV)를 포함하는 염증성 질환(inflammatory disease)의 예방, 개선 또는 치료용 조성물에 관한 것이다. 본 발명의 세포외소포체는 염증성 장질환 동물모델에서 장 상피세포 장벽 손상 및 면역 세포의 침윤을 감소시키고, 배상세포의 수를 유지하며, 장염으로 인한 맹장 무게 및 장 길이의 감소를 억제하고, 장내 균총 변화를 통해 염증성 사이토카인의 분비를 억제할 뿐만 아니라, 배상세포의 점액 분비와 장 상피세포의 치밀결합 능력을 회복시키는 것으로 나타났다. 특히, 뿐만 아니라, 로세부리아 속 균주 또는 비피도박테리움 속 균주에 해당하는 동속이종 균주들로부터 유래한 EV들은 모두 강력한 항염 효과를 발휘하는 것이 확인되었다. 즉, 본 발명에 따른 로세부리아 속 균주 또는 비피도박테리움 속 균주 유래 세포외소포체는 염증을 효과적으로 억제하고 염증으로 인한 조직의 손상이나 기능 이상을 개선할 수 있는 바, 다양한 염증성 질환의 예방, 개선, 및/또는 치료용 조성물로 제공될 수 있다.The present invention relates to a composition for preventing, improving or treating inflammatory diseases, including extracellular vesicles (EV) derived from Roseburia spp. and/or Bifidobacterium spp. The extracellular vesicles of the present invention have been shown to reduce intestinal epithelial cell barrier damage and immune cell infiltration in inflammatory bowel disease animal models, maintain the number of goblet cells, suppress a decrease in caecal weight and intestinal length due to enteritis, and inhibit secretion of inflammatory cytokines through changes in intestinal flora, as well as restore mucous secretion of goblet cells and the ability of intestinal epithelial cells to bind tightly. In particular, it was confirmed that all EVs derived from homologous and heterologous strains corresponding to Roseburia genus strains or Bifidobacterium genus strains exert strong anti-inflammatory effects. That is, the extracellular vesicles derived from the strain of the genus Roseburia or the genus Bifidobacterium according to the present invention can effectively inhibit inflammation and improve tissue damage or functional abnormality due to inflammation, and thus prevent, improve, and / or treat various inflammatory diseases. It can be provided as a composition for treatment.
도 1은 로세부리아 인테스티날리스(Roseburia intestinalis) 유래 세포외소포체(extracellular vesicles, EV) (Ri-EV)의 Ultrathin-section TEM(좌) 및 Cryo-TEM(우) 사진이다.
도 2는 Ri-EV의 크기 및 표면전하를 측정한 결과이다.
도 3a는 R. intestinalis로부터 추출된 Ri-EV의 입자 농도를 나타낸 결과이다.
도 3b는 로세부리아 인테스티날리스 유래 세포외소포체(Ri-EV) 및 비피도박테리움 롱검(Bifidobacterium longum) 유래 EV(Bl-EV)의 입자 크기 측정 결과이다.
도 4는 DSS(dextran sulfate sodium salt colitis grade) 유도 염증성 장질환(inflammatory bowel disease, IBD) 동물모델의 실험 모식도이다.
도 5는 대조군(control), DSS 유도 IBD 동물모델(DSS), R. intestinalis 투여군(Ri-Cell), Ri-EV 투여군(Ri-EV)의 장 상피세포 장벽을 관찰하기 위해, 각각의 장 조직을 H&E(Hematoxilin-Eosin) 염색 및 AB(Alcian blue)으로 염색한 도이다.
도 6a 내지 6d는 대조군, DSS 유도 IBD 동물모델, R. intestinalis 투여군, Ri-EV 투여군의 장 조직의 병리학적 분석을 위해, 조직학적 점수 및 배상세포(goblet cells)의 수(도 6a), 맹장(cecum)의 무게(도 6b), 장 길이(도 6c), 및 질병활성도(disease activity index) (도 6d)를 측정한 결과를 나타낸 도이다.
도 7a 내지 7b는 R. intestinalis 또는 Ri-EV 투여에 따른 장내 염증 수준, 점액 단백질 수준, 및 치밀결합의 변화를 확인하기 위해, 대조군, DSS 유도 IBD 동물모델, R. intestinalis 투여군, Ri-EV 투여군의 장 조직 내 IL(Interleukin)-1β도 7a), Muc-2(Mucin 2), ZO-1(Zonula occludens-1)의 발현량(도 7b)을 측정한 결과를 나타낸 도이다.
도 8a 및 8b는 R. intestinalis 또는 Ri-EV 투여에 따른 장내 미생물 군집의 변화를 확인하기 위해, 대조군, DSS 유도 IBD 동물모델, R. intestinalis 투여군, Ri-EV 투여군의 장내 미생물 군집(도 8a) 및 샤논 다양성(Shannon diversity)(도 8b)을 측정한 결과를 나타낸 도이다.
도 9는 대조군, DSS 유도 IBD 동물모델, R. intestinalis 투여군, Ri-EV 투여군의 비피도박테리움(Bifidobacterium)의 풍부도를 나타낸 도이다.
도 10은 마우스 대식세포에 LPS를 처리하여 염증환경을 유도한 후, 동속이종의 로세부리아 속 균주들(R. intestinalis (Ri), R. hominis (Rho), R. faecies (Rfa), 및 R. inulinivorans (Rin)) 유래 EV 처리에 따른 산화질소(NO) 생성량, 염증성 사이토카인(TNF-α, IL-6) 발현량, 및 항염증성 사이토카인(IL-10) 발현량을 측정하여 나타낸 도이다.
도 11은 Kuffer cell 모사 in vitro 환경에 LPS를 처리하여 염증환경을 유도한 후, 로세부리아 속 균주들(R. intestinalis, R. faecies, R. hominis, 및 R. inulinivorans) 유래 EV 또는 비피도박테리움 속 균주들(B. bifidum, B. breve, B. lactis, B. adolescentis, 및 B. longum) 유래 EV의 처리에 따른 염증 억제 효과를 산화질소의 생성량 측정을 통해 확인한 결과이다.1 is Roseburia intestinalis ) derived extracellular vesicles (extracellular vesicles, EV) (Ri-EV) Ultrathin-section TEM (left) and Cryo-TEM (right) photographs.
2 is a result of measuring the size and surface charge of Ri-EV.
Figure 3a is a result showing the particle concentration of Ri-EV extracted from R. intestinalis .
Figure 3b is Roseburia interiorlis derived extracellular vesicles (Ri-EV) and Bifidobacterium longum ( Bifidobacterium longum ) derived This is the result of measuring the particle size of EV (Bl-EV).
4 is a schematic diagram of an experiment of a dextran sulfate sodium salt colitis grade (DSS) induced inflammatory bowel disease (IBD) animal model.
5 is a diagram of H&E (Hematoxilin-Eosin) staining and AB (Alcian blue) staining of each intestinal tissue to observe the intestinal epithelial cell barrier of the control group, DSS-induced IBD animal model (DSS), R. intestinalis administration group (Ri-Cell), and Ri-EV administration group (Ri-EV).
6A to 6D are diagrams showing the results of measuring histological scores, the number of goblet cells (FIG. 6A), the weight of the cecum (FIG. 6B), the length of the intestine (FIG. 6C), and the disease activity index (FIG. 6D) for pathological analysis of the intestinal tissues of the control group, the DSS-induced IBD animal model, the R. intestinalis -administered group, and the Ri-EV-administered group.
7a to 7b show the results of measuring the expression levels (FIG. 7b) of IL (Interleukin)-1β in the intestinal tissue of the control group, the DSS-induced IBD animal model, the R. intestinalis- administered group, and the Ri-EV-administered group (Fig. 7a), Muc-2 (Mucin 2), ZO-1 (Zonula occludens-1) in order to confirm changes in intestinal inflammation level, mucous protein level, and tight junctions according to R. intestinalis or Ri-EV administration. is a diagram showing
8a and 8b are diagrams showing the results of measuring the intestinal microbial communities (FIG. 8a) and Shannon diversity (FIG. 8b) of a control group, a DSS-induced IBD animal model, an R. intestinalis- administered group, and a Ri-EV-administered group in order to confirm changes in the intestinal microbial community according to R. intestinalis or Ri-EV administration.
9 is a diagram showing the abundance of Bifidobacterium in the control group, the DSS-induced IBD animal model, the R. intestinalis administration group, and the Ri-EV administration group.
Figure 10 shows the amount of nitric oxide ( NO ) production, the amount of inflammatory cytokines (TNF-α, IL -6), and the anti-inflammatory cytokines ( IL-10) is a diagram showing the expression level measured.
Figure 11 is a Kuffer cell-simulated in vitro environment after inducing an inflammatory environment by treating LPS, Roseburia genus strains ( R. intestinalis, R. faecies, R. hominis, and R. inulinivorans ) derived EVs or Bifidobacterium genus strains (B. bifidum, B. breve, B. lactis, B. adolescentis, and B. longum ) The inflammation inhibitory effect according to the treatment of EVs produced by nitric oxide This is the result confirmed through measurement.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, but the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
본 발명은 로세부리아 속(Roseburia spp.) 균주 유래 세포외소포체 및 비피도박테리움 속(Bifidobacterium spp.) 균주 유래 세포외소포체를 유효성분으로 포함하는, 염증성 질환의 예방 또는 치료용 약학적 조성물 등에 관한 것으로서, 다양한 로세부리아 속 균주, 비피도박테리움 속 균주, 및/또는 이들로부터 유래한 세포외소포체가 강력한 항염 효과를 발휘할 뿐만 아니라 염증으로 인한 조직의 손상 및 기능 이상을 개선할 수 있음을 확인하여 완성된 것이다. 따라서, 본 발명의 세포외소포체들은 다양한 염증성 질환의 예방, 개선, 및/또는 치료용 조성물로 사용될 수 있다.The present invention relates to a pharmaceutical composition for the prevention or treatment of inflammatory diseases, including extracellular vesicles derived from Roseburia spp. and extracellular vesicles derived from Bifidobacterium spp. It was completed by confirming that it could be improved. Therefore, the extracellular vesicles of the present invention can be used as a composition for preventing, improving, and/or treating various inflammatory diseases.
본 발명에 따른 조성물은 로세부리아 속(Roseburia spp.) 균주, 이의 파쇄물, 이의 배양액, 이의 세포외소포체, 및 이들의 혼합물; 및 비피도박테리움 속(Bifidobacterium spp.), 이의 파쇄물, 이의 배양액, 이의 세포외소포체, 및 이들의 혼합물로 이루어진 군에서 선택된 하나 이상을 포함할 수 있다. 본 발명의 일 구현에에서, 본 발명에 따른 조성물은 균주를 포함하지 않는 것일 수 있다.The composition according to the present invention is Roseburia spp. strain, its lysate, its culture medium, its extracellular vesicles, and mixtures thereof; And it may include at least one selected from the group consisting of Bifidobacterium spp., a lysate thereof, a culture solution thereof, an extracellular vesicle thereof, and a mixture thereof. In one embodiment of the present invention, the composition according to the present invention may not contain a strain.
본 발명에 있어서, “로세부리아 속(Roseburia spp. 또는 the Roseburia genus) 균주”는 로세부리아 속에 속하는 균주로서 당업계에 이미 알려져 있거나 미래에 새로 알려지는 균주를 포함한다. 로세부리아는 인간의 결장내에 서식하는 그람-양성 세균으로, 당분해 및 부티레이트 생성능을 갖는 것으로 알려져 있다. 본 발명에 따른 로세부리아 속 균주는 로세부리아 속에 해당하는 것이라면 제한 없이 포함되고 구체적인 종류로 한정되지 않으나, 바람직하게는 로세부리아 인테스티날리스(Roseburia intestinalis), 로세부리아 파에시스(Roseburia faecies), 로세부리아 호미니스(Roseburia hominis), 로세부리아 이눌리니보란스(Roseburia inulinivorans), 로세부리아 세시콜라(Roseburia cecicola)로 이루어진 군에서 선택된 하나 이상일 수 있다. 이중 “로세부리아 인테스티날리스(Roseburia intestinalis)”는 인간의 대변에서 처음으로 분리된 미생물로서, 장내에서 대사산물을 생성하여 에너지 항상성을 유지하는 것으로 알려져 있다. In the present invention, " Roseburia spp. or the Roseburia genus strain" includes strains already known in the art or newly known in the future as strains belonging to the Roseburia genus. Roseburia is a Gram-positive bacterium that inhabits the human colon and is known to have glycolytic and butyrate-producing abilities. Roseburia genus strains according to the present invention are included without limitation as long as they correspond to the Roseburia genus and are not limited to specific types, but are preferably Roseburia intestinalis , Roseburia faecies , Roseburia hominis, Roseburia inulinivorans , and the like. It may be one or more selected from the group consisting of Ceburia cecicola . Among them, " Roseburia intestinalis " is a microorganism first isolated from human feces, and is known to maintain energy homeostasis by producing metabolites in the intestine.
본 발명에 있어서, “비피도박테리움 속(Bifidobacterium spp. 또는 the genus Bifidobacterium) 균주”는 비피도박테리움 속에 속하는 균주로서 당업계에 이미 알려져 있거나 미래에 새로 알려지는 균주를 포함한다. 비피도박테리움은 그람-양성의 혐기성 세균으로서, 포유동물의 위장관 미생물군을 구성하는 박테리아의 주요 종류 중 하나이다. 일부 비피도박테리움은 유산균으로도 이용된다. 본 발명에 따른 비피도박테리움 속 균주는 비피도박테리움 속에 해당하는 것이라면 제한 없이 포함되고 구체적인 종류로 한정되지 않으나, 바람직하게는 비피도박테리움 롱검(Bifidobacterium longum), 비피도박테리움 비피덤(Bifidobacterium bifidum), 비피도박테리움 브레이브(Bifidobacterium breve), 비피도박테리움 락티스(Bifidobacterium lactis), 및 비피도박테리움 어돌레스켄티스(Bifidobacterium adolescentis)로 이루어진 군에서 선택된 하나 이상일 수 있다. 이중 “비피도박테리움 롱검(Bifidobacterium longum)”은 비피더스 균으로도 명명되며, 대장균 증식 억제, 장 운동 및 배변 활동 강화 등에 효능이 있는 것으로 알려져 있다.In the present invention, " Bifidobacterium spp. or the genus Bifidobacterium strain" includes strains already known in the art or newly known in the future as strains belonging to the genus Bifidobacterium. Bifidobacterium is a Gram-positive anaerobic bacterium, and is one of the main types of bacteria constituting the gastrointestinal tract microflora of mammals. Some Bifidobacterium are also used as lactobacilli. Bifidobacterium strains according to the present invention are included without limitation as long as they correspond to the genus Bifidobacterium and are not limited to specific types, but are preferably Bifidobacterium longum , Bifidobacterium bifidum, Bifidobacterium breve , Bifidobacterium lactis , and Bifidobacterium. It may be at least one selected from the group consisting of Bifidobacterium adolescentis . Among them, “ Bifidobacterium longum” is also named as Bifidobacteria, and is known to be effective in inhibiting the growth of Escherichia coli and enhancing intestinal motility and defecation activity.
본 발명에서 용어, “균주”는 배양 배지 등 배양물로부터 수득된 생균 그 자체뿐만 아니라, 당업자에게 알려진 균주에 대한 임의의 가공형태를 포함하는 것으로서, 예를 들어 균체 파쇄물, 건조물, 동결물 등을 포함하지만, 이에 제한되지 않는다. 본 명세서에서 용어 “균주”는 “세균”, “세포” 등과 혼용될 수 있다.In the present invention, the term "strain" includes not only live cells obtained from cultures such as culture media, but also any processed forms of strains known to those skilled in the art, for example, cell lysates, dried products, frozen products, etc., but is not limited thereto. In the present specification, the term “strain” may be used interchangeably with “bacteria” and “cells”.
본 발명에서 용어, "파쇄물"은 균주에 화학적 처리 또는 물리적 힘을 가하여 균주의 세포벽을 파쇄하여 얻은 산물을 의미할 수 있다.As used herein, the term "lysate" may refer to a product obtained by crushing the cell wall of a strain by applying chemical treatment or physical force to the strain.
본 발명에서 용어, "배양액"은 균주가 시험관 내에서 성장 및 생존할 수 있도록 영양분을 공급할 수 있는 배지에 상기 균주를 일정기간 배양하여 얻어지는, 상기 균주, 이의 대사물, 여분의 영양분 등을 포함하는 전체 배지를 의미할 수 있다. 또한, 상기 배양액은 균주를 배양하여 얻은 균체 배양액에서 균체를 제거한 배양액을 의미할 수도 있다. 한편, 상기 배양액 중 균체를 제거한 액체를 "상등액"이라고도 하며, 배양액을 일정시간 가만히 두어 하층에 가라앉은 부분을 제외한 상층의 액체만을 취하거나, 여과를 통해 균체를 제거하거나, 배양액을 원심분리하여 하부의 침전을 제거하고 상부의 액체만을 취하여 획득할 수 있다. 상기 "균체"는 본 발명의 균주 자체를 의미하는 것으로 생물학적 샘플 등으로부터 분리하여 선별한 균주 자체 또는 상기 균주가 배양된 배양액으로부터 분리한 균주를 포함한다. 상기 균체는 배양액을 원심분리하여 하층에 가라앉은 부분을 취하여 획득할 수 있고, 또는 중력에 의해 배양액의 하층으로 가라앉으므로 일정 시간 동안 가만히 두었다가 상부의 액체를 제거함으로써 획득할 수 있다. 상기 배양액은 "배양 상층액", "조건 배양액" 또는 "조정 배지"와 혼용될 수 있다. In the present invention, the term "culture medium" is obtained by culturing the strain for a certain period of time in a medium capable of supplying nutrients so that the strain can grow and survive in vitro. In addition, the culture solution may mean a culture solution obtained by removing the cells from the cell culture solution obtained by culturing the strain. On the other hand, the liquid from which the cells are removed from the culture solution is also called "supernatant", and the culture solution is left for a certain period of time to take only the liquid of the upper layer except for the part sunk in the lower layer, or the cells are removed through filtration. The "cell" refers to the "strain" itself of the present invention, and includes the "strain" itself separated and selected from biological samples, etc., or the "strain" separated from the culture medium in which the "strain" is cultured. The cells can be obtained by centrifuging the culture solution and taking the part that has sunk in the lower layer, or it can be obtained by leaving it for a certain period of time and then removing the upper liquid as it sinks to the lower layer of the culture medium by gravity. The culture medium may be used interchangeably with "culture supernatant", "conditioned medium" or "conditioned medium".
상기 배양액은 균주를 배양하여 수득된 배양액 자체, 이의 추출물, 이의 농축물, 또는 이의 동결건조물; 또는 배양액로부터 균주를 제거하여 수득된 배양 상층액, 이의 추출물, 이의 농축물 또는 이의 동결건조물;을 포함할 수 있으나, 이에 제한되지 않는다.The culture medium itself obtained by culturing the strain, its extract, its concentrate, or its lyophilized product; Or a culture supernatant obtained by removing the strain from the culture medium, an extract thereof, a concentrate thereof, or a lyophilisate thereof; may include, but is not limited thereto.
상기 배양액은 본 발명의 균주를 적절한 배지(예를 들면, RCM(reinforced clostridial medium) 배지) 에서 10℃ 내지 50℃, 10℃ 내지 40℃, 20℃ 내지 50℃, 20℃ 내지 40℃, 또는 30℃ 내지 40℃ 중 어느 온도에서 일정 시간, 예를 들면, 4 내지 50시간, 4 내지 40시간, 4 내지 30시간, 4 내지 20시간, 또는 10 내지 20시간 동안 배양하여 수득된 것일 수 있으나, 이에 제한되지 않는다. 본 발명의 균주를 배양하기 위한 배양용 배지 및 배양 조건은 통상의 지식을 가진 자가 적절하게 선택하거나 변형하여 이용할 수 있다.The culture medium is prepared by cultivating the strain of the present invention in an appropriate medium (eg, reinforced clostridial medium (RCM) medium) at any temperature of 10 ° C to 50 ° C, 10 ° C to 40 ° C, 20 ° C to 50 ° C, 20 ° C to 40 ° C, or 30 ° C to 40 ° C for a certain period of time, for example, 4 to 50 hours, 4 to 40 hours, 4 to 30 hours, 4 to 40 hours. It may be obtained by culturing for 20 hours, or 10 to 20 hours, but is not limited thereto. Culture medium and culture conditions for culturing the strain of the present invention can be appropriately selected or modified by those skilled in the art.
일 구체예에서, 본 발명의 배양 상층액은 전술한 균주 배양액을 원심분리, 여과 등의 방법으로 균주를 제거하는 단계에 의해 수득될 수 있다.In one embodiment, the culture supernatant of the present invention can be obtained by removing the strain from the strain culture medium described above by centrifugation, filtration, or the like.
본 발명에서 용어, “농축물”은 전술한 배양액 자체, 또는 상기 배양액을 원심분리, 여과 등의 방법으로 수득된 상층액을 농축하는 단계에 의해 수득될 수 있다.In the present invention, the term "concentrate" may be obtained by concentrating the above-described culture medium itself or the supernatant obtained by centrifugation, filtration, or the like.
본 발명에서, 용어 "추출물"은 전술한 배양액 또는 이의 농축물로부터 추출한 것을 의미하며, 추출액, 추출액의 희석액 또는 농축물, 추출액을 건조하여 얻어지는 건조물 또는 동결건조물, 또는 이들 조정제물 또는 정제물, 이를 분획한 분획물을 포함할 수 있다.In the present invention, the term "extract" means an extract from the aforementioned culture medium or a concentrate thereof, and may include an extract, a diluent or concentrate of the extract, a dried or lyophilized product obtained by drying the extract, or a crude or purified product thereof, or a fraction obtained by fractionating them.
본 발명에서 용어 "소포체(vesicle)"는 세포에서 분비되어 세포 외 공간으로 방출된 입자를 의미하는 것으로서, 엑소좀(exosome), 엑토좀(ectosome), 마이크로소낭(microvesicle), 마이크로입자(microparticle), 엑소좀 유사 소포체(exosome like vesicle) 등의 다수의 상이한 종을 포함할 수 있다. 세포외소포체(extracellular vesicles, EV)는 분비하는 기원 세포(공여 세포)의 상태를 반영할 수 있으며, 어떤 세포에서 분비되었는가에 따라 다양한 생물학적 활성을 나타내고, 세포들 사이에 유전 물질과 단백질을 옮기면서 세포 간 상호작용에 중요한 역할을 할 수 있다. 또한, 상기 소포체를 포함하는 세포 유래 물질들은 질병을 일으키거나 또는 면역세포를 자극하여 질병에 대항하게 하며, 미생물의 대사과정을 통해 사람이 소화시키지 못하는 물질들을 분해하여 흡수할 수 있도록 도와주는 효과가 있다. 상기 소포체는 막 구조 소포체로 내부와 외부가 구분되며, 세포의 세포막 지질(plasma membrane lipid), 세포막 단백질(plasma membrane protein), 핵산(nucleic acid), 및 세포질 성분 등을 가지고 있고, 원래 세포보다 크기가 작은 것일 수 있다. 상기 용어 “세포외소포체”는 “세포밖소포체”와 혼용될 수 있으며, 간략히 “소포체” 혹은 “소포” 등으로 지칭될 수 있다.In the present invention, the term "vesicle" refers to particles secreted from cells and released into the extracellular space, and may include a number of different species such as exosomes, ectosomes, microvesicles, microparticles, and exosome-like vesicles. Extracellular vesicles (EVs) can reflect the state of the secreting cell of origin (donor cell), exhibit various biological activities depending on which cell they are secreted from, and play an important role in cell-to-cell interactions by transferring genetic material and proteins between cells. In addition, cell-derived substances including the endoplasmic reticulum cause diseases or stimulate immune cells to fight against diseases, and have an effect of helping to decompose and absorb substances that humans cannot digest through the metabolic process of microorganisms. The endoplasmic reticulum is a membrane-structured endoplasmic reticulum, which is divided into an inside and an outside, has a plasma membrane lipid, a plasma membrane protein, a nucleic acid, and a cytoplasmic component of the cell, and may be smaller in size than the original cell. The term "extracellular endoplasmic reticulum" may be used interchangeably with "extracellular endoplasmic reticulum", and may be briefly referred to as "endosicles" or "vesicles".
특히, 본 발명의 로세부리아 속 균주나 비피도박테리움 속 균주와 같은 그람-양성 세균 유래 소포는 단백질과 핵산 외에도 세균의 세포벽 구성성분인 펩티도글리칸(peptidoglycan)과 리포테이코산(lipoteichoic acid) 등을 포함할 수 있다. In particular, the vesicles derived from Gram-positive bacteria, such as the strains of the genus Roseburia or the genus Bifidobacterium of the present invention, may contain peptidoglycan and lipoteichoic acid, which are components of the bacterial cell wall, in addition to proteins and nucleic acids.
본 발명의 일 구현예에서, 상기 로세부리아 속 균주 유래 세포외소포체는 단일의 지질막 구조를 가질 수 있으나, 이에 한정되지 않는다.In one embodiment of the present invention, the Roseburia genus strain-derived extracellular vesicles may have a single lipid membrane structure, but is not limited thereto.
본 발명에 따른 소포는 균주의 in vitro 배양 동안 생산될 수 있다. 구체적으로, 본 발명에 따른 소포는 로세부리아 속 균주 및/또는 비피도박테리움 속 균주로부터 자연적으로 분비되거나 또는 세균에 열처리, 가압처리 등을 통해 인공적으로 생산(분리)될 수 있으며, 30 내지 200 nm, 30 내지 150 nm, 30 내지 100 nm, 30 내지 80 nm, 40 내지 200 nm, 50 내지 200 nm, 50 내지 100 nm, 또는 50 내지 80 nm의 직경을 가질 수 있다. 본 발명의 일 실시예에서, R. intestinalis 유래 EV 및 B. longum 유래 EV의 크기를 zeta-sizer를 이용하여 측정한 결과, 각각 약 76 nm의 평균 입자 크기를 가지는 것을 확인하였다(도 1).Vesicles according to the present invention can be produced during in vitro cultivation of strains. Specifically, the vesicles according to the present invention may be naturally secreted from strains of the genus Roseburia and / or strains of the genus Bifidobacterium or artificially produced (separated) through heat treatment, pressure treatment, etc. to bacteria, 30 to 200 nm, 30 to 150 nm, 30 to 100 nm, 30 to 80 nm, 40 to 200 nm, 50 to 200 nm, 50 to 100 nm, or may have a diameter of 50 to 80 nm. In one embodiment of the present invention, as a result of measuring the sizes of R. intestinalis- derived EV and B. longum- derived EV using a zeta-sizer, it was confirmed that each had an average particle size of about 76 nm (FIG. 1).
또한, 본 발명에 따른 세포외소포체는 표면전하가 -20 내지 5 mV, -20 내지 0 mV, -10 내지 0 mV, -5 내지 0 mV, -10 내지 -1 mV, 또는 -5 내지 -1 mV 일 수 있으나, 이에 한정되지 않는다. In addition, the extracellular vesicles according to the present invention may have a surface charge of -20 to 5 mV, -20 to 0 mV, -10 to 0 mV, -5 to 0 mV, -10 to -1 mV, or -5 to -1 mV, but is not limited thereto.
상기 소포는 로세부리아 속 균주 및/또는 비피도박테리움 속 균주를 포함하는 배양액에 원심분리, 초고속 원심분리, 압출, 초음파분해, 세포 용해, 균질화, 냉동-해동, 전기천공, 기계적 분해, 화학물질 처리, 필터에 의한 여과, 겔 여과 크로마토그래피, 프리-플로우 전기영동, 및 모세관 전기영동으로 이루어진 군에서 선택된 하나 이상의 방법을 적용하여 분리될 수 있다. 또한, 불순물의 제거를 위한 세척, 수득된 소포의 농축 등의 과정을 추가로 포함할 수 있다.The vesicles may be separated by applying one or more methods selected from the group consisting of centrifugation, ultra-high-speed centrifugation, extrusion, sonication, cell lysis, homogenization, freeze-thaw, electroporation, mechanical disassembly, chemical treatment, filtration with a filter, gel filtration chromatography, free-flow electrophoresis, and capillary electrophoresis to a culture solution containing a Roseburia genus strain and/or a Bifidobacterium genus strain. In addition, processes such as washing to remove impurities and concentration of the obtained vesicles may be further included.
본 발명에 따른 조성물은 염증성 질환에 대해 예방, 개선, 및/또는 치료 효과를 가질 수 있다. The composition according to the present invention may have preventive, ameliorative, and/or therapeutic effects on inflammatory diseases.
일예로, 본 발명에 따른 조성물은 다음 중 선택되는 어느 하나 이상의 효과를 가질 수 있다:For example, the composition according to the present invention may have one or more effects selected from among the following:
i) 장 상피세포 장벽 손상 감소;i) reducing intestinal epithelial barrier damage;
ii) 면역세포의 장 조직 침윤 감소;ii) reduced intestinal tissue infiltration of immune cells;
iii) 배상세포(goblet cells)의 수 감소 억제;iii) inhibition of reduction in the number of goblet cells;
iv) 맹장 무게 감소 억제;iv) inhibition of cecal weight loss;
v) 장 길이 감소 억제;v) inhibition of intestinal length reduction;
vi) 염증성 사이토카인 생성 억제;vi) inhibition of inflammatory cytokine production;
vii) 항염증성 사이토카인 생성 촉진;vii) promoting anti-inflammatory cytokine production;
viii) 배상세포의 점액 분비 증진;viii) enhancement of mucus secretion by goblet cells;
ix) 장 상피세포의 치밀결합 증진; 및ix) promoting the compaction of intestinal epithelial cells; and
x) 장내 비피도박테리움(Bifidobacterium) 수 증가.x) Increased number of Bifidobacterium in the intestine.
즉, 본 발명에 따른 조성물의 염증성 질환의 예방, 개선, 및/또는 치료 효과는 상기 i) 내지 x)의 효과에 의해 발휘되는 것일 수 있다.That is, the effects of preventing, improving, and/or treating inflammatory diseases of the composition according to the present invention may be exerted by the effects of i) to x).
본 발명 조성물의 i) 장 상피세포 장벽 손상 감소; ii) 면역 세포 침윤 감소; iii) 배상세포의 수 감소 억제 효과와 관련하여, 본 발명의 일 실시예에서 염증성 장질환(IBD) 동물모델을 이용한 실험 수행 결과, IBD 동물모델은 정상 대조군 대비 장 상피세포 장벽이 손상되고, 면역세포들이 침윤되었으며, 점액 생산을 담당하는 배상세포의 수가 감소한 반면, 본 발명의 Ri-EV 투여군은 장 상피세포 장벽의 손상이 개선되고 면역세포의 침윤이 감소하였으며, 배상세포의 수가 정상 대조군과 비슷한 수준으로 유지되었다. 특히, Ri-EV 투여시 IBD 발병으로 인한 조직학적 점수가 현저히 감소한 바, IBD로 인한 장 손상 및 기능적 이상이 개선되는 것을 확인하였다(도 5 및 도 6a).i) reduction of intestinal epithelial barrier damage; ii) reduced immune cell infiltration; iii) Regarding the effect of inhibiting the decrease in the number of goblet cells, in one embodiment of the present invention, as a result of experiments using an inflammatory bowel disease (IBD) animal model, the IBD animal model had intestinal epithelial cell barrier damage, immune cells were infiltrated, and the number of goblet cells responsible for mucus production was reduced, whereas in the Ri-EV-administered group of the present invention, intestinal epithelial cell barrier damage was improved, immune cell infiltration was reduced, and the number of goblet cells was maintained at a level similar to that of the normal control group. In particular, when Ri-EV was administered, the histological score due to IBD significantly decreased, and it was confirmed that intestinal damage and functional abnormality due to IBD were improved (FIGS. 5 and 6a).
본 발명 조성물의 iv) 맹장 무게 감소 억제; v) 장 길이 감소 억제 효과와 관련하여, 본 발명의 다른 일 실시예에서는 정상 대조군 대비 IBD 동물모델에서 장 염증으로 인해 맹장 무게 및 장 길이가 현저히 감소한 반면, R. intestinalis 또는 Ri-EV 투여군은 맹장 무게 및 장 길이의 감소가 억제되었으며, 특히 균주 자체와 비교하여 세포외소포체의 맹장 및 장 회복/개선 효과가 더욱 우수한 것으로 나타났다(도 6b, 6c). 질병활성도(disease activity index) 역시, R. intestinalis 또는 Ri-EV 투여시 감소하였으며, Ri-EV 투여군에서 질병활성도가 가장 낮은 것으로 확인되었다(도 6d). 상기 결과들은 본 발명에 따른 세포외소포체가 장 염증으로 인한 맹장이나 장의 조직학적 변화를 개선할 수 있음을 보여준다. iv) inhibition of caecal weight loss; v) Regarding the intestinal length reduction inhibitory effect, in another embodiment of the present invention, the caecal weight and intestinal length were significantly reduced due to intestinal inflammation in the IBD animal model compared to the normal control group, whereas the R. intestinalis or Ri-EV administered group suppressed the reduction in caecal weight and intestinal length, and in particular, the effect of the caecum and intestinal recovery / improvement of the extracellular endoplasmic reticulum was more excellent than that of the strain itself (Figs. 6b, 6c). The disease activity index also decreased when R. intestinalis or Ri-EV was administered, and it was confirmed that the disease activity was the lowest in the Ri-EV-administered group (FIG. 6d). The above results show that the extracellular vesicles according to the present invention can improve histological changes in the cecum or intestine caused by intestinal inflammation.
본 발명 조성물의 vi) 염증성 사이토카인 분비 억제; vii) 항염증성 사이토카인 생성 촉진; viii) 배상세포의 점액 분비 증진; ix) 장 상피세포의 치밀결합 증진 효과와 관련하여, 본 발명의 또 다른 일 실시예에서는 정상 대조군 대비 IBD 동물모델에서 염증 유발성 사이토카인인 IL-1β의 발현이 증가하고, 점액 단백질 및 치밀결합과 관련된 Muc-2 및 ZO-1의 발현이 감소함에 따라 장내 염증이 증가하고 점액 분비와 치밀결합이 약해짐을 확인하였다. 반면, R. intestinalis 또는 Ri-EV 투여군은 IL-1β의 발현이 감소되고, Muc-2 및 ZO-1의 발현이 증가하였다. 특히, 이와 같은 장내 항염 효과와 점액 분비능 및 치밀결합의 회복능은 균주 대비 세포외소포체가 더욱 우수한 것으로 나타났다. 뿐만 아니라, 다양한 동속이종의 로세부리아 속 균주들 및 비피도박테리움 속 균주들로부터 세포외소포체를 분리하여 이들의 항염 효과를 확인한 결과, 상기 세포외소포체 모두 염증성 인자들의 생성은 억제하고, 항염 사이토카인의 생성은 촉진하여 우수한 항염 효과를 발휘하는 것을 확인하였다(도 10 및 도 11).vi) inhibition of inflammatory cytokine secretion by the composition of the present invention; vii) promoting anti-inflammatory cytokine production; viii) enhancement of mucus secretion by goblet cells; ix) Regarding the effect of enhancing the tight junction of intestinal epithelial cells, in another embodiment of the present invention, the expression of the inflammatory cytokine IL-1β increased in the IBD animal model compared to the normal control group, and mucous proteins and tight junction. As the expression of Muc-2 and ZO-1 decreased, it was confirmed that intestinal inflammation increased and mucus secretion and tight junction were weakened. On the other hand, in the R. intestinalis or Ri-EV-administered group, the expression of IL-1β was decreased, and the expression of Muc-2 and ZO-1 was increased. In particular, such intestinal anti-inflammatory effect and mucus secretion ability and recovery ability of dense bonding were found to be more excellent than the extracellular vesicles compared to strains. In addition, as a result of confirming their anti-inflammatory effect by isolating extracellular vesicles from various homologous and heterogeneous strains of the genus Roseburia and strains of the genus Bifidobacterium, it was confirmed that both of the extracellular vesicles suppressed the production of inflammatory factors and promoted the production of anti-inflammatory cytokines to exert excellent anti-inflammatory effects (FIGS. 10 and 11).
본 발명 조성물의 x) 장내 비피도박테리움 수 증가 효과와 관련하여, 본 발명의 또 다른 일 실시예에서 대조군 대비 IBD 동물모델에서는 프로테오박테리아(Proteobacteria)와 데페리박테레스(Deferribacteres) 문(phylum)의 증가와 같은 장내 미생물 군집의 변화가 눈에 띄게 관찰된 반면(도 8a, 8b), R. intestinalis 또는 Ri-EV 투여군은 IBD의 완화에 기여하는 박테리아로 알려진 비피도박테리움의 수가 증가하였으며, 특히 R. intestinalis 투여군보다 Ri-EV 투여군에서 비피도박테리움 수가 유의성 있게 증가하였다(도 9). 이를 통해, 본 발명에 따른 로세부리아 균주 유래 세포외소포체의 투여가 IBD의 장내 환경에서 비피도박테리움의 성장 유도에 따른 장내 균총 변화를 유도함으로써 염증성 사이토카인의 분비를 억제하고, 배상세포의 점액 분비와 장 상피세포의 치밀결합 능력을 회복시킴에 따라 IBD를 개선함을 알 수 있다.In relation to x) the effect of increasing the number of bifidobacterium in the intestine, in another embodiment of the present invention, in the IBD animal model compared to the control group, changes in the intestinal microbial community, such as an increase in the phylum of Proteobacteria and Deferribacteres , were conspicuously observed (Figs. The number of Pidobacterium was increased, and in particular, the number of Bifidobacterium was significantly increased in the Ri-EV-administered group than in the R. intestinalis -administered group (FIG. 9). From this, it can be seen that the administration of the roseburia strain-derived extracellular vesicles according to the present invention induces changes in the intestinal microflora according to the growth induction of Bifidobacterium in the intestinal environment of IBD, thereby inhibiting the secretion of inflammatory cytokines, and recovering mucus secretion of goblet cells and the ability of intestinal epithelial cells to bind tightly, thereby improving IBD.
종합하면, 본 발명에 따른 조성물은 염증으로 인한 장 상피세포 장벽 손상 및 면역세포의 장내 침윤을 감소시키고, 배상세포의 수를 정상 수준으로 유지하며, 장 염증으로 인한 맹장 무게와 장 길이 감소를 억제하고, 장내 균총 변화를 통해 염증성 사이토카인의 분비를 억제하고, 배상세포의 점액 분비와 장 상피세포의 치밀결합 능력을 회복시킬 수 있는 바, 염증성 질환의 예방, 개선, 및/또는 치료 용도로 사용될 수 있다.In summary, the composition according to the present invention can reduce intestinal epithelial cell barrier damage due to inflammation and infiltration of immune cells into the intestine, maintain the number of goblet cells at a normal level, suppress the decrease in caecal weight and intestinal length due to intestinal inflammation, suppress the secretion of inflammatory cytokines through changes in intestinal flora, and restore mucus secretion of goblet cells and the ability of intestinal epithelial cells to bind tightly, and thus can be used for the prevention, improvement, and/or treatment of inflammatory diseases.
한편, 본 발명에 따른 조성물은 “염증성 질환(inflammatory dieseases)”의 예방, 개선, 및/또는 치료 용도로 사용될 수 있다. 본 발명에 있어서, 염증성 질환은 염증과 관련된 질환 내지 염증을 억제함으로써 개선/치료될 수 있는 질환이라면 제한 없이 포함하고, 구체적인 종류로 한정되는 것은 아니나, 바람직하게는 위염, 위궤양, 십이지장궤양, 염증성 피부질환, 알레르기성 질환, 크론병(Crohn's desease), 과민성 대장 증후군, 궤양성 대장염, 염증성 장질환, 복막염, 골수염, 봉소염, 뇌막염, 뇌염, 췌장염, 외상 유발 쇼크, 기관지 천식, 낭포성 섬유증, 뇌졸중, 급성 기관지염, 만성 기관지염, 급성 세기관지염, 만성 세기관지염, 골관절염, 통풍, 척추관절병증, 강직성 척추염, 라이터 증후군, 건선성 관절병증, 장질환 척추염, 연소자성 관절병증, 연소자성 강직성 척추염, 반응성 관절병증, 감염성 관절염, 후-감염성 관절염, 임균성 관절염, 결핵성 관절염, 바이러스성 관절염, 진균성 관절염, 매독성 관절염, 라임병, 혈관염 증후군과 관련된 관절염, 결절성 다발동맥염, 과민성 혈관염, 루게릭 육아종증, 류마티스성 다발성근육통, 관절 세포 동맥염, 칼슘 결정 침착 관절병증, 가성 통풍, 비-관절 류마티즘, 점액낭염, 건초염, 상과염(테니스 엘보), 신경병증성 관절 질환(charco and joint), 출혈성 관절증(hemarthrosic), 헤노흐-쉔라인 자반병, 비후성 골관절병증, 다중심성 세망조직구종, 수르코일로시스(surcoilosis), 혈색소증, 겸상 적혈구증 및 기타 혈색소병증, 고지단백혈증, 저감마글로불린혈증, 가족성 지중해열, 베하트 병, 전신성 홍반성 루푸스, 재귀열, 건선, 다발성 경화증, 패혈증, 패혈성 쇼크, 다장기 기능장애 증후군, 급성 호흡곤란 증후군, 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease), 급성 폐손상(acute lung injury), 및 기관지 폐 형성장애(broncho-pulmonary dysplasia) 등으로부터 선택될 수 있다. Meanwhile, the composition according to the present invention may be used for preventing, improving, and/or treating “inflammatory diseases”. In the present invention, inflammatory diseases include without limitation any disease related to inflammation or a disease that can be improved/treated by suppressing inflammation, and is not limited to specific types, but is preferably gastritis, gastric ulcer, duodenal ulcer, inflammatory skin disease, allergic disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, inflammatory bowel disease, peritonitis, osteomyelitis, cellulitis, Meningitis, encephalitis, pancreatitis, trauma-induced shock, bronchial asthma, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondyloarthropathy, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enteropathic spondylitis, juvenile arthropathy, juvenile ankylosing spondylitis, reactive arthropathy, infectious arthritis, post-infectious arthritis, gonococcal arthritis, tuberculosis Arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with vasculitic syndrome, polyarteritis nodosa, hypersensitivity vasculitis, amyotrophic granulomatosis, polymyalgia rheumatica, articular cell arteritis, calcium crystal deposition arthropathy, pseudogout, non-articular rheumatism, bursitis, tenosynovitis, epicondylitis (tennis elbow), neuropathic joint disease (charco and joint), hemar throsic), Henoch-Schenlein purpura, hypertrophic osteoarthropathy, multicentric reticuloid histiocytoma, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathy, hyperlipoproteinemia, hypogammaglobulinemia, familial thalassemia fever, Behart's disease, systemic lupus erythematosus, relapsing fever, psoriasis, multiple sclerosis, sepsis, septic shock, multiple bowel It may be selected from respiratory dysfunction syndrome, acute respiratory distress syndrome, chronic obstructive pulmonary disease, acute lung injury, broncho-pulmonary dysplasia, and the like.
본 발명에서 용어, “염증성 장질환(inflammatory bowel disease, IBD)”은 위장관 내에 만성적인 염증을 원인으로 하는 질환을 의미한다. 염증성 장질환은 장에 만성적인 염증이 발생하는 질환을 의미하며, 재발성 복통, 설사, 혈변, 체중 감소 등을 주요 증상으로 한다. 구체적으로는, 장에 생긴 염증이 6개월 이상 지속되어 만성화되는 만성 소화기 질환을 통칭한다. 따라서, 세균성, 바이러스성, 아메바성, 결핵성 장염 등의 감염성 장염, 허혈성 장질환, 및 방사선성 장염 등이 이에 포함될 수 있다. 본 발명에 있어서, 염증성 장질환은 장내 염증과 관련된 질환 내지 염증을 억제함으로써 개선/치료될 수 있는 질환이라면 제한 없이 포함하고, 구체적인 종류로 한정되는 것은 아니나, 바람직하게는 궤양성 대장염, 크론병, 베체트병, 교원성 대장염, 림프성 대장염, 허혈성 대장염, 출혈성 직장 궤양, 회장 낭염, 및 전환성 대장염으로 이루어진 군에서 선택된 하나 이상일 수 있다.In the present invention, the term "inflammatory bowel disease (IBD)" means a disease caused by chronic inflammation in the gastrointestinal tract. Inflammatory bowel disease refers to a disease in which chronic inflammation occurs in the intestine, and has recurrent abdominal pain, diarrhea, bloody stools, weight loss, and the like as major symptoms. Specifically, it collectively refers to chronic digestive diseases in which inflammation in the intestines lasts for 6 months or more and becomes chronic. Accordingly, infectious enteritis such as bacterial, viral, amebic, and tuberculosis enteritis, ischemic bowel disease, and radiation-induced enteritis may be included therein. In the present invention, inflammatory bowel disease includes without limitation any disease related to intestinal inflammation or a disease that can be improved/treated by suppressing inflammation, and is not limited to specific types, but is preferably one or more selected from the group consisting of ulcerative colitis, Crohn's disease, Behçet's disease, collagenous colitis, lymphocytic colitis, ischemic colitis, hemorrhagic rectal ulcer, ileal pouchitis, and converting colitis.
바람직하게는, 본 발명에 따른 염증성 장질환은 궤양성 대장염(ulcerative colitis, UC), 크론병(Crohn's disease, CD), 및 베체트병(Behcet's disease)으로부터 선택될 수 있다. “궤양성 대장염”은 대장에서의 만성 염증성 질환을 의미하며, 그 범위에 따라 직장염, 좌측대장염, 광범위대장염으로 더 나뉠 수 있다. “크론병”은 입에서 항문에 이르는 소화관 전체에서 염증이 발생한 질환을 의미한다. 다만, 염증 부위가 항상 연속된 것은 아니며, 여러 곳에서 분리되어 존재할 수 있다. 크론병 환자 중 약 1/3은 소장에서만 염증이 있으며, 1/3은 대장에서만 염증이 있고, 나머지 1/3은 대장 및 소장 양쪽에서 만성 염증이 발생한다. 특히, 소장의 끝과 대장이 만나는 부위에 염증이 발생한 경우가 가장 흔하다. 궤양성 대장염은 장의 점막층에만 염증이 생기는데 반하여 크론병에서는 점막층, 점막하층, 근육층 및 장막층 등 장벽의 전층을 침범하는 염증 반응을 특징으로 한다. “베체트병”은 만성적이고 반복적인 전신질환으로 염증이 피부, 점막, 눈, 장, 관절, 비뇨생식기, 미 신경계 등 여러 장기로 침범한 질환을 의미한다. 베체트병 환자의 3 내지 5%는 소장 또는 대장에서 염증이 발생하며, 소장의 끝부분과 대장이 연결되는 부위에서 염증이 가장 흔하게 발생한다. Preferably, the inflammatory bowel disease according to the present invention may be selected from ulcerative colitis (UC), Crohn's disease (CD), and Behcet's disease. "Ulcerative colitis" means a chronic inflammatory disease in the large intestine, and according to its scope, it can be further divided into proctitis, left colitis, and extensive colitis. "Crohn's disease" refers to a disease in which inflammation occurs throughout the digestive tract, from the mouth to the anus. However, the inflammatory site is not always continuous, and may exist separately in several places. About 1/3 of patients with Crohn's disease have inflammation only in the small intestine, 1/3 have inflammation only in the large intestine, and 1/3 have chronic inflammation in both the large intestine and small intestine. In particular, the most common case where inflammation occurs in the area where the end of the small intestine and the large intestine meet. Ulcerative colitis is inflamed only in the mucosal layer of the intestine, whereas Crohn's disease is characterized by an inflammatory reaction that invades all layers of the intestinal wall, including the mucosal, submucosal, muscular and serosal layers. “Behçet’s disease” is a chronic and repetitive systemic disease in which inflammation invades various organs such as the skin, mucous membranes, eyes, intestines, joints, genitourinary system, and the causal system. In 3 to 5% of patients with Behcet's disease, inflammation occurs in the small or large intestine, and inflammation most commonly occurs at the site where the end of the small intestine and the large intestine are connected.
본 발명의 조성물 내의 상기 균주, 파쇄물, 배양액, 및/또는 세포외소포체의 함량은 질환의 증상, 증상의 진행 정도, 환자의 상태 등에 따라서 적절히 조절 가능하며, 예컨대, 전체 조성물 중량을 기준으로 0.0001 내지 99.9중량%, 또는 0.001 내지 50중량%일 수 있으나, 이에 한정되는 것은 아니다. 상기 함량비는 용매를 제거한 건조량을 기준으로 한 값이다.The strain, lysate, culture medium, and / or the content of the extracellular vesicles in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the progress of the symptoms, the condition of the patient, etc., for example, 0.0001 to 99.9% by weight, or 0.001 to 50% by weight, but is not limited thereto. The content ratio is a value based on the dry amount after removing the solvent.
본 발명에 따른 약학적 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 상기 부형제는 예를 들어, 희석제, 결합제, 붕해제, 활택제, 흡착제, 보습제, 필름-코팅 물질, 및 제어방출첨가제로 이루어진 군으로부터 선택된 하나 이상일 수 있다. The pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. The excipient may be, for example, one or more selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a moisturizer, a film-coating material, and a controlled release additive.
본 발명에 따른 약학적 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 서방형 과립제, 장용과립제, 액제, 점안제, 엘실릭제, 유제, 현탁액제, 주정제, 트로키제, 방향수제, 리모나아데제, 정제, 서방형정제, 장용정제, 설하정, 경질캅셀제, 연질캅셀제, 서방캅셀제, 장용캅셀제, 환제, 틴크제, 연조엑스제, 건조엑스제, 유동엑스제, 주사제, 캡슐제, 관류액, 경고제, 로션제, 파스타제, 분무제, 흡입제, 패취제, 멸균주사용액, 또는에어로졸 등의 외용제 등의 형태로 제형화하여 사용될 수 있으며, 상기 외용제는 크림, 젤, 패치, 분무제, 연고제, 경고제, 로션제, 리니멘트제, 파스타제 또는 카타플라스마제 등의 제형을 가질 수 있다. The pharmaceutical compositions according to the present invention are powders, granules, sustained-release granules, enteric granules, solutions, eye drops, elsilic agents, emulsions, suspensions, spirits, troches, perfumes, limonadese, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, and soft drinks, respectively, according to conventional methods. It can be formulated and used in the form of external preparations such as extracts, dry extracts, fluid extracts, injections, capsules, irrigation solutions, warning agents, lotions, pastes, sprays, inhalants, patches, sterilized injection solutions, or aerosols.
본 발명에 따른 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 올리고당, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, and propylhydroxy. hydroxybenzoate, talc, magnesium stearate and mineral oil.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
본 발명에 따른 정제, 산제, 과립제, 캡슐제, 환제, 트로키제의 첨가제로 옥수수전분, 감자전분, 밀전분, 유당, 백당, 포도당, 과당, 디-만니톨, 침강탄산칼슘, 합성규산알루미늄, 인산일수소칼슘, 황산칼슘, 염화나트륨, 탄산수소나트륨, 정제 라놀린, 미결정셀룰로오스, 덱스트린, 알긴산나트륨, 메칠셀룰로오스, 카르복시메칠셀룰로오스나트륨, 카올린, 요소, 콜로이드성실리카겔, 히드록시프로필스타치, 히드록시프로필메칠셀룰로오스(HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, 프로필렌글리콜, 카제인, 젖산칼슘, 프리모젤 등 부형제; 젤라틴, 아라비아고무, 에탄올, 한천가루, 초산프탈산셀룰로오스, 카르복시메칠셀룰로오스, 카르복시메칠셀룰로오스칼슘, 포도당, 정제수, 카제인나트륨, 글리세린, 스테아린산, 카르복시메칠셀룰로오스나트륨, 메칠셀룰로오스나트륨, 메칠셀룰로오스, 미결정셀룰로오스, 덱스트린, 히드록시셀룰로오스, 히드록시프로필스타치, 히드록시메칠셀룰로오스, 정제쉘락, 전분호, 히드록시프로필셀룰로오스, 히드록시프로필메칠셀룰로오스, 폴리비닐알코올, 폴리비닐피롤리돈 등의 결합제가 사용될 수 있으며, 히드록시프로필메칠셀룰로오스, 옥수수전분, 한천가루, 메칠셀룰로오스, 벤토나이트, 히드록시프로필스타치, 카르복시메칠셀룰로오스나트륨, 알긴산나트륨, 카르복시메칠셀룰로오스칼슘, 구연산칼슘, 라우릴황산나트륨, 무수규산, 1-히드록시프로필셀룰로오스, 덱스트란, 이온교환수지, 초산폴리비닐, 포름알데히드처리 카제인 및 젤라틴, 알긴산, 아밀로오스, 구아르고무(Guar gum), 중조, 폴리비닐피롤리돈, 인산칼슘, 겔화전분, 아라비아고무, 아밀로펙틴, 펙틴, 폴리인산나트륨, 에칠셀룰로오스, 백당, 규산마그네슘알루미늄, 디-소르비톨액, 경질무수규산 등 붕해제; 스테아린산칼슘, 스테아린산마그네슘, 스테아린산, 수소화식물유(Hydrogenated vegetable oil), 탈크, 석송자, 카올린, 바셀린, 스테아린산나트륨, 카카오지, 살리실산나트륨, 살리실산마그네슘, 폴리에칠렌글리콜(PEG) 4000, PEG 6000, 유동파라핀, 수소첨가대두유(Lubri wax), 스테아린산알루미늄, 스테아린산아연, 라우릴황산나트륨, 산화마그네슘, 마크로골(Macrogol), 합성규산알루미늄, 무수규산, 고급지방산, 고급알코올, 실리콘유, 파라핀유, 폴리에칠렌글리콜지방산에테르, 전분, 염화나트륨, 초산나트륨, 올레인산나트륨, dl-로이신, 경질무수규산 등의 활택제;가 사용될 수 있다.Corn starch, potato starch, wheat starch, lactose, white sugar, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, calcium monohydrogen phosphate, calcium sulfate, sodium chloride, sodium hydrogen carbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methyl cellulose, carboxymethyl cellulose sodium, kaol excipients such as phosphorus, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropylmethylcellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose phthalate acetate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, purified shellac, starch starch, hydroxypropylcellulose, hydroxypropylmethyl Binders such as cellulose, polyvinyl alcohol, and polyvinylpyrrolidone may be used, and hydroxypropyl methyl cellulose, corn starch, agar powder, methyl cellulose, bentonite, hydroxypropyl starch, sodium carboxymethyl cellulose, sodium alginate, calcium carboxymethyl cellulose, calcium citrate, sodium lauryl sulfate, silicic anhydride, 1-hydroxypropyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde disintegrants such as hydrotreated casein and gelatin, alginic acid, amylose, guar gum, sodium bicarbonate, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethyl cellulose, sucrose, magnesium aluminum silicate, di-sorbitol liquid, light anhydrous silicic acid; Calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopod, kaolin, petrolatum, sodium stearate, cacao butter, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogenated soybean oil (Lubri wax), aluminum stearate, Lubricants such as zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, silicic anhydride, higher fatty acid, higher alcohol, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, light anhydrous silicic acid; can be used.
본 발명에 따른 액제의 첨가제로는 물, 묽은 염산, 묽은 황산, 구연산나트륨, 모노스테아린산슈크로스류, 폴리옥시에칠렌소르비톨지방산에스텔류(트윈에스텔), 폴리옥시에칠렌모노알킬에텔류, 라놀린에텔류, 라놀린에스텔류, 초산, 염산, 암모니아수, 탄산암모늄, 수산화칼륨, 수산화나트륨, 프롤아민, 폴리비닐피롤리돈, 에칠셀룰로오스, 카르복시메칠셀룰로오스나트륨 등이 사용될 수 있다.As the additives for the liquid formulation according to the present invention, water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, carr boxymethylcellulose sodium and the like can be used.
본 발명에 따른 시럽제에는 백당의 용액, 다른 당류 혹은 감미제 등이 사용될 수 있으며, 필요에 따라 방향제, 착색제, 보존제, 안정제, 현탁화제, 유화제, 점조제 등이 사용될 수 있다.In the syrup according to the present invention, a solution of white sugar, other sugars, or a sweetener may be used, and aromatics, coloring agents, preservatives, stabilizers, suspending agents, emulsifiers, thickeners, etc. may be used as necessary.
본 발명에 따른 유제에는 정제수가 사용될 수 있으며, 필요에 따라 유화제, 보존제, 안정제, 방향제 등이 사용될 수 있다.Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.
본 발명에 따른 현탁제에는 아카시아, 트라가칸타, 메칠셀룰로오스, 카르복시메칠셀룰로오스, 카르복시메칠셀룰로오스나트륨, 미결정셀룰로오스, 알긴산나트륨, 히드록시프로필메칠셀룰로오스(HPMC), HPMC 1828, HPMC 2906, HPMC 2910 등 현탁화제가 사용될 수 있으며, 필요에 따라 계면활성제, 보존제, 안정제, 착색제, 방향제가 사용될 수 있다.Acacia, tragacantha, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, microcrystalline cellulose, sodium alginate, hydroxypropylmethyl cellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, etc. suspending agents may be used in the suspension agent according to the present invention, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used if necessary.
본 발명에 따른 주사제에는 주사용 증류수, 0.9% 염화나트륨주사액, 링겔주사액, 덱스트로스주사액, 덱스트로스+염화나트륨주사액, 피이지(PEG), 락테이티드 링겔주사액, 에탄올, 프로필렌글리콜, 비휘발성유-참기름, 면실유, 낙화생유, 콩기름, 옥수수기름, 올레인산에칠, 미리스트산 이소프로필, 안식향산벤젠과 같은 용제; 안식향산나트륨, 살리실산나트륨, 초산나트륨, 요소, 우레탄, 모노에칠아세트아마이드, 부타졸리딘, 프로필렌글리콜, 트윈류, 니정틴산아미드, 헥사민, 디메칠아세트아마이드와 같은 용해보조제; 약산 및 그 염(초산과 초산나트륨), 약염기 및 그 염(암모니아 및 초산암모니움), 유기화합물, 단백질, 알부민, 펩톤, 검류와 같은 완충제; 염화나트륨과 같은 등장화제; 중아황산나트륨(NaHSO3) 이산화탄소가스, 메타중아황산나트륨(Na2S2O5), 아황산나트륨(Na2SO3), 질소가스(N2), 에칠렌디아민테트라초산과 같은 안정제; 소디움비설파이드 0.1%, 소디움포름알데히드 설폭실레이트, 치오우레아, 에칠렌디아민테트라초산디나트륨, 아세톤소디움비설파이트와 같은 황산화제; 벤질알코올, 클로로부탄올, 염산프로카인, 포도당, 글루콘산칼슘과 같은 무통화제; 시엠시나트륨, 알긴산나트륨, 트윈 80, 모노스테아린산알루미늄과 같은 현탁화제를 포함할 수 있다.Injections according to the present invention include distilled water for injection, 0.9% sodium chloride injection, IV injection, dextrose injection, dextrose + sodium chloride injection, PEG (PEG), lactated IV injection, ethanol, propylene glycol, solvents such as non-volatile oil-sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, benzene benzoate; solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, twins, nijuntinamide, hexamine, and dimethylacetamide; buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; tonicity agents such as sodium chloride; Stabilizers such as sodium bisulfite (NaHSO 3 ) carbon dioxide gas, sodium metabisulfite (Na 2 S 2 O 5 ), sodium sulfite (Na 2 SO 3 ), nitrogen gas (N 2 ), ethylenediaminetetraacetic acid; Sulfating agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, ethylenediamine disodium tetraacetate, acetone sodium bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; Suspending agents such as Siemesis sodium, sodium alginate, Tween 80, aluminum monostearate may be included.
본 발명에 따른 좌제에는 카카오지, 라놀린, 위텝솔, 폴리에틸렌글리콜, 글리세로젤라틴, 메칠셀룰로오스, 카르복시메칠셀룰로오스, 스테아린산과 올레인산의 혼합물, 수바날(Subanal), 면실유, 낙화생유, 야자유, 카카오버터+콜레스테롤, 레시틴, 라네트왁스, 모노스테아린산글리세롤, 트윈 또는 스판, 임하우젠(Imhausen), 모놀렌(모노스테아린산프로필렌글리콜), 글리세린, 아뎁스솔리두스(Adeps solidus), 부티룸 태고-G(Buytyrum Tego-G), 세베스파마 16(Cebes Pharma 16), 헥사라이드베이스 95, 코토마(Cotomar), 히드록코테 SP, S-70-XXA, S-70-XX75(S-70-XX95), 히드록코테(Hydrokote) 25, 히드록코테 711, 이드로포스탈(Idropostal), 마사에스트라리움(Massa estrarium, A, AS, B, C, D, E, I, T), 마사-MF, 마수폴, 마수폴-15, 네오수포스탈-엔, 파라마운드-B, 수포시로(OSI, OSIX, A, B, C, D, H, L), 좌제기제 IV 타입(AB, B, A, BC, BBG, E, BGF, C, D, 299), 수포스탈(N, Es), 웨코비(W, R, S, M ,Fs), 테제스터 트리글리세라이드 기제(TG-95, MA, 57)와 같은 기제가 사용될 수 있다.The suppository according to the present invention includes cacao butter, lanolin, witapsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cacao butter + cholesterol, lecithin, lanet wax, glycerol monostearate, twin or span, Imhausen, monolen (monosteol) Propylene Glycol Phosphate), Glycerin, Adeps Solidus, Buytyrum Tego-G, Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydrocote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Hydrocote (Hydr okote) 25, Hydrocote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), suppository type IV (AB, B , A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecobi (W, R, S, M, Fs), testosterone triglyceride bases (TG-95, MA, 57).
경구 투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing the extract with at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
경구 투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. 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.
본 발명에 따른 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, drug activity, sensitivity to the drug, administration time, administration route and discharge rate, treatment period, factors including concurrently used drugs, and other factors well known in the medical field.
본 발명에 따른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 본 발명이 속하는 기술분야에 통상의 기술자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention belongs.
본 발명의 약학적 조성물은 개체에게 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구 복용, 피하 주사, 복강 투여, 정맥 주사, 근육 주사, 척수 주위 공간(경막내) 주사, 설하 투여, 볼점막 투여, 직장내 삽입, 질 내 삽입, 안구 투여, 귀 투여, 비강 투여, 흡입, 입 또는 코를 통한 분무, 피부 투여, 경피 투여 등에 따라 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be envisaged, for example, oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, ear administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, and the like.
본 발명의 약학적 조성물은 치료할 질환, 투여 경로, 환자의 연령, 성별, 체중 및 질환의 중등도 등의 여러 관련 인자와 함께 활성성분인 약물의 종류에 따라 결정된다. 구체적으로, 본 발명에 따른 조성물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 1 kg 당 0.001 내지 150 mg, 바람직하게는 0.01 내지 100 mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 질환의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient together with various related factors such as the disease to be treated, the route of administration, the age, sex, weight and severity of the disease of the patient. Specifically, the effective amount of the composition according to the present invention may vary depending on the patient's age, sex, and weight, and is generally 0.001 to 150 mg, preferably 0.01 to 100 mg per 1 kg of body weight, administered daily or every other day, or 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity of disease, sex, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
본 발명에서 “개체”란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는 인간 또는 비-인간인 영장류, 생쥐(mouse), 쥐(rat), 개, 고양이, 말, 및 소 등의 포유류를 의미한다.In the present invention, "individual" means a subject in need of treatment of a disease, and more specifically, a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, and cow. It means.
본 발명에서 “투여”란 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.In the present invention, "administration" means providing a given composition of the present invention to a subject by any suitable method.
본 발명에서 “예방”이란 목적하는 질환의 발병을 억제하거나 지연시키는 모든 행위를 의미하고, “치료”란 본 발명에 따른 약학적 조성물의 투여에 의해 목적하는 질환과 그에 따른 대사 이상 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미하며, “개선”이란 본 발명에 따른 조성물의 투여에 의해 목적하는 질환과 관련된 파라미터, 예를 들면 증상의 정도를 감소시키는 모든 행위를 의미한다.In the present invention, "prevention" means any action that inhibits or delays the onset of a desired disease, and "treatment" means any action that improves or beneficially changes a desired disease and its associated metabolic abnormalities by administration of the pharmaceutical composition according to the present invention, and "improvement" means any action that reduces a parameter related to a desired disease, for example, the severity of symptoms, by administration of the composition according to the present invention.
또한, 본 발명은 본 발명에 따른 조성물을 포함하는, 염증성 질환의 예방, 개선, 또는 치료용 키트를 제공한다.In addition, the present invention provides a kit for preventing, improving, or treating inflammatory diseases, including the composition according to the present invention.
본 발명에 따른 키트는 염증성 질환의 예방, 개선, 또는 치료의 목적을 수행할 수 있는 것이라면 구체적인 형태에 제한이 없으며, 본 발명에 따른 조성물의 제조(예컨대, 균주의 배양, 세포외소포체의 분리 등), 보관, 투여 등을 위한 임의의 성분 및 기기를 제한 없이 포함할 수 있다. 또한, 상기 키트는 본 발명의 조성물의 특징, 사용방법, 보관방법, 투여용량 등 전반적인 설명이 기재된 설명서를 포함할 수 있다.The kit according to the present invention is not limited in specific form as long as it can perform the purpose of prevention, improvement, or treatment of inflammatory diseases, and preparation of the composition according to the present invention (eg, culturing of strains, isolation of extracellular vesicles, etc.), It may include arbitrary components and devices for storage, administration, etc. without limitation. In addition, the kit may include a description describing the general description of the composition of the present invention, such as how to use it, how to store it, and how to administer it.
또한, 본 발명은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는, 염증성 질환의 예방 또는 개선용 식품 조성물을 제공한다. 상기 식품 조성물은 건강기능식품 조성물을 포함한다.In addition, the present invention provides a food composition for preventing or improving inflammatory diseases, comprising at least one selected from the group consisting of extracellular vesicles derived from strains of the genus Roseburia and extracellular vesicles derived from strains of the genus Bifidobacterium as an active ingredient. The food composition includes a health functional food composition.
본 발명의 균주, 파쇄물, 배양액, 및/또는 세포외소포체를 식품 첨가물로 사용할 경우, 상기 균주, 세포외소포체 등을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 상기 식품 조성물에서 유효성분의 함량은 사용 목적(예방, 개선 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 유효성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조시 본 발명의 균주, 세포외소포체 등은 원료에 대하여 15 중량% 이하, 또는 10 중량% 이하의 양으로 첨가될 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.When using the strain, lysate, culture medium, and / or extracellular vesicles of the present invention as a food additive, the strain, extracellular vesicles, etc. may be added as is or used together with other foods or food ingredients, and may be appropriately used according to conventional methods. The content of the active ingredient in the food composition may be appropriately determined depending on the purpose of use (prevention, improvement or therapeutic treatment). The mixing amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment). In general, when preparing food or beverage, the strain, extracellular vesicles, etc. of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the above range.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There is no particular limitation on the type of food. Examples of foods to which the substance can be added include meat, sausages, bread, chocolates, candies, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and vitamin complexes, and includes all health functional foods in the usual sense.
본 발명에 따른 건강음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당 및 과당과 같은 모노사카라이드, 말토오스 및 수크로오스와 같은 디사카라이드, 덱스트린 및 시클로덱스트린과 같은 폴리사카라이드, 및 자일리톨, 소르비톨 및 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 mL당 일반적으로 약 0.01-0.20g, 또는 약 0.04-0.10g 이다.The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional components, like conventional beverages. The aforementioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrins and cyclodextrins, and sugar alcohols such as xylitol, sorbitol and erythritol. As the sweetener, natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used. The proportion of the natural carbohydrate is generally about 0.01-0.20 g, or about 0.04-0.10 g per 100 mL of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 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 조성물은 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01-0.20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the composition of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like. In addition, the 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 ratio of these additives is not critical, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.
본 명세서에 있어서, “건강기능식품”이란 특정보건용 식품(food for special health use, FoSHU)와 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미하는데, 상기 식품은 염증성 질환의 예방 또는 개선에 유용한 효과를 얻기 위하여 정제, 캡슐, 분말, 과립, 액상, 환 등의 다양한 형태로 제조될 수 있다.In the present specification, "health functional food" is the same term as food for special health use (FoSHU), and refers to medical and medically effective foods that are processed to efficiently display bioregulatory functions in addition to nutritional supply. In order to obtain useful effects for preventing or improving inflammatory diseases, the food can be prepared in various forms such as tablets, capsules, powders, granules, liquids, and pills.
본 발명의 건강기능식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어날 수 있다.The health functional food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and components commonly added in the art during the preparation. In addition, unlike general drugs, there is an advantage in that there is no side effect that may occur when taking a drug for a long time by using food as a raw material, and it can be excellent in portability.
또한, 본 발명은 로세부리아 속 균주 유래 세포외소포체 및 비피도박테리움 속 균주 유래 세포외소포체로 이루어진 군에서 선택된 하나 이상을 유효성분으로 포함하는, 염증성 질환의 예방 또는 개선용 사료 조성물을 제공한다.In addition, the present invention provides a feed composition for preventing or improving inflammatory diseases, comprising at least one selected from the group consisting of extracellular vesicles derived from a strain of the genus Roseburia and extracellular vesicles derived from a strain of the genus Bifidobacterium as an active ingredient.
본 발명의 용어 "사료"는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분으로, 본 발명의 그래핀 나노입자를 유효성분으로 포함하는 사료는 당업계의 공지된 다양한 형태의 사료로 제조가능하며, 구체적으로 농후사료, 조사료 및/또는 특수사료가 포함될 수 있다.The term "feed" of the present invention refers to any natural or artificial diet, one-meal meal, etc., or a component of the one-meal meal for animals to eat, ingest, and digest.
본 발명의 사료 조성물에 포함되는 본 발명의 균주, 파쇄물, 배양액, 및/또는 세포외소포체는 사료의 사용목적 및 사용조건에 따라 달라질 수 있으며, 일 예로 가축 사료 조성물의 총 중량에 대하여 0.01 내지 100 중량%, 보다 구체적으로는 1 내지 80 중량%로 포함될 수 있으나, 이에 제한되지 않는다.The strain, lysate, culture medium, and/or extracellular vesicles of the present invention included in the feed composition of the present invention may vary depending on the purpose and conditions of use of the feed, for example, 0.01 to 100% by weight, more specifically, 1 to 80% by weight relative to the total weight of the livestock feed composition, but is not limited thereto.
상기 조성물이 사료 첨가제로서 제조될 경우, 상기 조성물은 20 내지 90% 고농축물이거나 분말 또는 과립 형태로 제조될 수 있다. 상기 사료 첨가제는 구연산, 후말산, 아디픽산, 젖산, 사과산등의 유기산이나 인산 나트륨, 인산 칼륨, 산성 피로인산염, 폴리인산염(중합인산염) 등의 인산염이나, 폴리페놀, 카테킨, 알파-토코페롤, 로즈마리 추출물, 비타민 C, 녹차 추출물, 감초 추출물, 키토산, 탄닌산, 피틴산 등의 천연 항산화제 중 어느 하나 또는 하나 이상을 추가로 포함할 수 있다. 사료로서 제조될 경우, 상기 조성물은 통상의 사료 형태로 제제화될 수 있으며, 통상의 사료 성분을 함께 포함할 수 있다.When the composition is prepared as a feed additive, the composition may be in a high concentration of 20 to 90% or in powder or granular form. The feed additive may further include organic acids such as citric acid, fumaric acid, adipic acid, lactic acid, and malic acid, phosphates such as sodium phosphate, potassium phosphate, acid pyrophosphate, and polyphosphate (polymeric phosphate), and natural antioxidants such as polyphenol, catechin, alpha-tocopherol, rosemary extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, and phytic acid. When prepared as a feed, the composition may be formulated in a conventional feed form, and may include common feed ingredients together.
상기 사료 및 사료 첨가제는 곡물, 예를 들면 분쇄 또는 파쇄된 밀, 귀리, 보리, 옥수수 및 쌀; 식물성 단백질 사료, 예를 들면 평지, 콩, 및 해바라기를 주성분으로 하는 사료; 동물성 단백질 사료, 예를 들면 혈분, 육분, 골분 및 생선분; 당분 및 유제품, 예를 들면 각종 분유 및 유장 분말로 이루어지는 건조성분 등을 더 포함할 수 있으며, 이외에도 영양보충제, 소화 및 흡수향상제, 성장촉진제 등을 더 포함할 수 있다.The feed and feed additives include grains such as milled or ground wheat, oats, barley, corn and rice; vegetable protein feeds such as those based on rape, soybean, and sunflower; animal protein feed such as blood meal, meat meal, bone meal and fish meal; It may further include sugar and dairy products, for example, dry ingredients composed of various powdered milk and whey powder, etc., and may further include nutritional supplements, digestion and absorption enhancers, growth promoters, and the like.
상기 사료 첨가제는 동물에게 단독으로 투여하거나 식용 담체 중에서 다른 사료 첨가제와 조합하여 투여할 수도 있다. 또한, 상기 사료 첨가제는 탑드레싱으로서 또는 이들을 동물사료에 직접 혼합하거나 또는 사료와 별도의 경구제형으로 용이하게 동물에게 투여할 수 있다. 상기 사료 첨가제를 동물사료와 별도로 투여할 경우, 당해 기술분야에 잘 알려진 바와 같이 약제학적으로 허용 가능한 식용 담체와 조합하여, 즉시 방출 또는 서방성 제형으로 제조할 수 있다. 이러한 식용 담체는 고체 또는 액체, 예를 들어 옥수수전분, 락토오스, 수크로오스, 콩플레이크, 땅콩유, 올리브유, 참깨유 및 프로필렌글리콜일 수 있다. 고체 담체가 사용될 경우, 사료 첨가제는 정제, 캡슐제, 산제, 트로키제 또는 함당정제 또는 미분산성 형태의 탑 드레싱일 수 있다. 액체 담체가 사용될 경우, 사료 첨가제는 젤라틴 연질 캡슐제, 또는 시럽제나 현탁액, 에멀젼제, 또는 용액제의 제형일 수 있다.The feed additive may be administered to animals alone or in combination with other feed additives in an edible carrier. In addition, the feed additives can be easily administered to animals as a top dressing, directly mixed with animal feed, or in an oral formulation separate from feed. When the feed additive is administered separately from animal feed, it can be prepared as an immediate release or sustained release formulation by combining it with a pharmaceutically acceptable edible carrier, as is well known in the art. Such edible carriers can be solid or liquid, for example corn starch, lactose, sucrose, soybean flakes, peanut oil, olive oil, sesame oil and propylene glycol. When a solid carrier is used, the feed additive may be a tablet, capsule, powder, troche or sugar-containing tablet or top dressing in a microdispersible form. When a liquid carrier is used, the feed additive may be in the form of a gelatin soft capsule, or a syrup, suspension, emulsion, or solution formulation.
또한, 상기 사료 및 사료 첨가제는 보조제, 예를 들어 보존제, 안정화제, 습윤제 또는 유화제, 용액 촉진제 등을 함유할 수 있다. 상기 사료 첨가제는 침주, 분무 또는 혼합하여 동물의 사료에 첨가하여 이용될 수 있다.In addition, the feed and feed additives may contain auxiliary agents, such as preservatives, stabilizers, wetting agents or emulsifying agents, solution accelerators, and the like. The feed additive may be used by adding it to an animal's feed by steeping, spraying or mixing.
본 발명의 사료 또는 사료 첨가제는 포유류, 가금 및 어류를 포함하는 다수의 동물 식이에 적용할 수 있다.The feed or feed additive of the present invention can be applied to a number of animal diets including mammals, poultry and fish.
상기 포유류로서 돼지, 소, 말, 양, 토끼, 염소, 설치동물 및 실험용 설치동물인 쥐, 햄스터, 기니피그 뿐만 아니라, 반려동물(예: 개, 고양이) 등에게 사용할 수 있으며, 상기 가금류로서 닭, 칠면조, 오리, 거위, 꿩, 및 메추라기 등에도 사용할 수 있고, 상기 어류로서 잉어, 붕어 및 송어 등에 이용될 수 있으나, 이에 한정되는 것은 아니다.As the mammal, it can be used not only for pigs, cows, horses, sheep, rabbits, goats, rodents and laboratory rodents such as rats, hamsters, and guinea pigs, but also for companion animals (eg, dogs and cats). It can also be used for chickens, turkeys, ducks, geese, pheasants, and quail as the poultry, and it can be used for carp, crucian carp, and trout as the fish, but is not limited thereto.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, but the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
[실시예] [Example]
실시예 1. 로세부리아 인테스티날리스(Example 1. Roseburia internalis ( Roseburia intestinalisRoseburia intestinalis ) 또는 비피도박테리움 롱검() or Bifidobacterium longum ( Bifidobacterium longumBifidobacterium longum ) 유래 세포외소포체(extracellular vesicles, EV) (Ri-EV, Bl-EV)의 추출 및 크기 분석) extraction and size analysis of extracellular vesicles (EV) (Ri-EV, Bl-EV)
R. intestinalis 및 B. longum에서 각각 EV를 추출하기 위해, R. intestinalis KCTC 15746 및 B. longum KCTC 3249을 RCM(reinforced clostridial medium) 배지(MB cell, MB-R1602)를 이용하여 37℃의 혐기성 챔버에서 18시간 동안 배양하였다. 배양액을 2000 × g조건에서 20분 동안 원심분리한 후, 상층액을 회수하고, 0.22 μm 필터를 이용하여 배양배지 내 세포 잔해물 및 노폐물을 제거하였다. 상기 배양액으로부터 EV를 300kDa 분자량의 TFF(Tangential Flow Filtration) 막 필터 기반 TFF 시스템을 통해 추출하고, 인산완충용액(phosphate-buffered saline, PBS)에 희석하여 정제하여, 최종적으로 PBS에 분산된 R. intestinalis 유래 EV(Ri-EV) 및 B. longum유래 EV(Bl-EV)를 추출하였다.To extract EVs from R. intestinalis and B. longum , respectively, R. intestinalis KCTC 15746 and B. longum KCTC 3249 were cultured for 18 hours in an anaerobic chamber at 37°C using reinforced clostridial medium (RCM) medium (MB cell, MB-R1602). After centrifuging the culture medium at 2000 × g for 20 minutes, the supernatant was collected, and cell debris and waste products in the culture medium were removed using a 0.22 μm filter. EVs were extracted from the culture medium through a 300 kDa molecular weight Tangential Flow Filtration (TFF) membrane filter-based TFF system, diluted in phosphate-buffered saline (PBS) and purified, and finally R. intestinalis- derived EV (Ri-EV) and B. longum- derived EV (Bl-EV) dispersed in PBS were extracted.
다음으로, Ri-EV의 물리화학적 특성을 전자현미경(Ultrathin-section TEM, Cryo-TEM) 및 나노입자추적분석기를 통해 확인하였다. 그 결과, Ultrathin-section TEM을 통해 R. intestinalis가 in vitro 배양 동안 EV를 생산하는 것을 확인하고, Cryo-TEM을 통해 상기 EV가 단일의 지질막 구조를 가지는 것을 확인하였다(도 1). 추출된 Ri-EV는 76±10 nm 의 크기와 -4±1 mV의 표면전하를 나타내며(도 2), 4.8 × 1010±5.9 × 107 particles/ml의 농도로 추출되었다(도 3a). Next, the physicochemical properties of Ri-EV were confirmed through electron microscopy (ultrathin-section TEM, cryo-TEM) and nanoparticle tracking analyzer. As a result, it was confirmed through ultrathin-section TEM that R. intestinalis produced EVs during in vitro culture, and through cryo-TEM it was confirmed that the EVs had a single lipid membrane structure (FIG. 1). The extracted Ri-EV exhibited a size of 76±10 nm and a surface charge of -4±1 mV (Fig. 2), and was extracted at a concentration of 4.8 × 10 10 ± 5.9 × 10 7 particles/ml (Fig. 3a).
추가로 Ri-EV 및 Bl-EV의 크기를 zeta-sizer를 이용하여 측정한 결과, 각각 75 nm와 58 nm의 평균 입자 크기를 갖는 것으로 확인되었다(도 3b). In addition, as a result of measuring the sizes of Ri-EV and Bl-EV using a zeta-sizer, it was confirmed that they had average particle sizes of 75 nm and 58 nm, respectively (FIG. 3b).
실시예 2. DSS(dextran sulfate sodium salt colitis grade) 유도 염증성 장질환(inflammatory bowel disease, IBD) 동물모델에서 Ri-EV 투여에 따른 항염증 효과 평가Example 2. Anti-inflammatory effect evaluation of Ri-EV administration in DSS (dextran sulfate sodium salt colitis grade) induced inflammatory bowel disease (IBD) animal model
IBD를 유발하는 것으로 알려진 DSS를 2.5%[v/v]의 농도로 포함하는 식수를 정상 C57BL/6 마우스에 일주일 동안 제공하여 IBD 동물모델을 제작하였다(도 4). 실험군에는 DSS를 주입하는 일주일 동안 1일, 3일, 5일, 7일차에 R. intestinalis 균주 또는 상기 실시예 1에서 추출된 Ri-EV를 총 단백질 200 μg/mouse/day 기준으로 경구투여하였다. 실험 시작 10일차에 마우스를 희생시켜 상기 EV 투여에 따른 항염증 효과를 확인하였다. DSS를 투여하지 않은 정상 마우스를 대조군으로 하였다.An IBD animal model was constructed by providing normal C57BL/6 mice with drinking water containing DSS, which is known to cause IBD, at a concentration of 2.5% [v/v] for one week (FIG. 4). To the experimental group, R. intestinalis strain or Ri-EV extracted in Example 1 was orally administered on the basis of total protein of 200 μg/mouse/day on days 1, 3, 5, and 7 during a week of DSS injection. On the 10th day of the experiment, the mice were sacrificed to confirm the anti-inflammatory effect of the EV administration. Normal mice not administered with DSS were used as a control group.
먼저, 장 조직의 병리학적 분석을 위해, 마우스의 장을 적출하여 4% 중성 완충 포르말린으로 고정시키고 파라핀으로 포매한 후 4μm 두께의 조직절편을 제작하였다. 조직절편에 대해 H&E(Hematoxilin-Eosin) 염색 및 AB(Alcian blue) 염색을 수행한 후 광학현미경으로 관찰하였다. First, for pathological analysis of intestinal tissue, the intestines of mice were excised, fixed in 4% neutral buffered formalin, embedded in paraffin, and tissue sections having a thickness of 4 μm were prepared. After performing H&E (Hematoxilin-Eosin) staining and AB (Alcian blue) staining on the tissue sections, they were observed under an optical microscope.
다음으로, 장 염증과 관련된 맹장(cecum) 무게와 장 길이를 측정하였다.Next, cecum weight and intestinal length related to intestinal inflammation were measured.
다음으로, Ri-EV의 장내 환경에서 염증, 점액 단백질 및 치밀결합에 관한 조절능력을 확인하기 위하여 앞서 확보한 장 조직 내 IL(Interleukin)-1β, Muc-2(Mucin 2), ZO-1(Zonula occludens-1)의 발현량을 qRT-PCR로 확인하였다. 장 조직을 Trizol 용액(Life Technologies, CA, USA)으로 용해한 후, 제조사의 분석방법에 따라 클로로포름-이소프로판올 방법을 이용하여 전체 RNA를 조직으로부터 분리하였다. 분리된 샘플의 cDNA는 고용량 cDNA 합성 키트(high-capacity cDNA synthesis kit, Invitrogen, CA, USA)를 이용하여 합성하였으며, 7500 Real-Time PCR System(Applied Biosystems, CA, USA)으로 TaqMan 유전자 특이적 프로브(Thermo Fisher Scientific)를 이용하여 증폭되었다.Next, in order to confirm the ability of Ri-EV to regulate inflammation, mucous proteins, and tight junctions in the intestinal environment, the expression levels of IL (Interleukin) -1β, Muc-2 (Mucin 2), and ZO-1 (Zonula occludens-1) in the previously obtained intestinal tissue were confirmed by qRT-PCR. After dissolving the intestinal tissue in Trizol solution (Life Technologies, CA, USA), total RNA was isolated from the tissue using the chloroform-isopropanol method according to the manufacturer's analysis method. The cDNA of the isolated sample was synthesized using a high-capacity cDNA synthesis kit (Invitrogen, CA, USA) and amplified using a TaqMan gene-specific probe (Thermo Fisher Scientific) with a 7500 Real-Time PCR System (Applied Biosystems, CA, USA).
그 결과, 도 5와 같이, DSS를 투여하지 않은 대조군 대비 DSS 유도 IBD 동물모델에서는 장 상피세포 장벽이 손상되고, 면역세포들이 침윤되었으며, 점액 생산을 담당하는 배상세포(goblet cells)의 수가 감소하였다. 반면, Ri-EV 투여군에서는 장 상피세포 장벽 손상 및 면역 세포의 침윤이 감소하고 배상세포의 수가 정상 그룹과 비슷하게 유지되었다. 특히, Ri-EV 투여군은 IBD 발병으로 인한 조직학적 점수가 현저히 감소하여 IBD가 개선되는 것을 확인하였다(도 6a). As a result, as shown in FIG. 5, the intestinal epithelial cell barrier was damaged, immune cells were infiltrated, and the number of goblet cells responsible for mucus production was reduced in the DSS-induced IBD animal model compared to the control group not administered with DSS. On the other hand, in the Ri-EV-administered group, intestinal epithelial cell barrier damage and immune cell infiltration were reduced, and the number of goblet cells was maintained similar to that of the normal group. In particular, in the Ri-EV-administered group, it was confirmed that the histological score due to the onset of IBD was significantly reduced, and IBD was improved (FIG. 6a).
또한, 대조군 대비 DSS 유도 IBD 동물모델에서는 장 염증과 관련된 맹장 무게와 장 길이가 현저히 줄어드는 반면, R. intestinalis 또는 Ri-EV 투여군은 맹장 무게와 장 길이 감소가 억제되었으며, 특히 Ri-EV 투여군은 R. intestinalis 투여군과 비교하여서도 맹장 무게와 장 길이 감소가 현저히 억제되었다(도 6b 및 6c). 질병활성도(disase activity index) 역시, Ri-EV 투여군에서의 수준이 가장 낮은 것으로 확인하였다(도 6d).In addition, in the DSS-induced IBD animal model compared to the control group, the caecal weight and intestinal length related to intestinal inflammation were significantly reduced, whereas the R. intestinalis or Ri-EV-administered group suppressed the caecal weight and intestinal length reduction. In particular, the Ri-EV-administered group significantly suppressed the caecal weight and intestinal length reduction compared to the R. intestinalis- administered group (Figs. 6b and 6c). The disease activity index was also confirmed to be the lowest in the Ri-EV administration group (FIG. 6d).
또한, 대조군 대비 DSS유도 IBD 동물모델에서는 염증을 유발하는 염증성 사이토카인인 IL-1β의 발현이 증가하고, 점액 단백질 및 치밀결합과 관련된 Muc-2 및 ZO-1의 발현이 감소함에 따라 장내 염증이 증가하고 점액 분비와 치밀결합이 약해짐을 확인하였다. 반면, R. intestinalis 또는 Ri-EV 투여군은 IBD 동물모델 대비 IL-1β의 발현이 감소되고(도 7a), Muc-2 및 ZO-1의 발현이 증가한 것으로 나타났다(도 7b). 특히, Ri-EV 투여군은 R. intestinalis 투여군보다 유의성 있게 IL-1β의 발현이 감소되고, Muc-2 및 ZO-1의 발현이 증가한 것으로 나타났다. 상기 결과는 Ri-EV 투여가 효과적으로 장내 염증을 감소시킬 뿐만 아니라 점액 분비능 및 치밀결합을 회복시킬 수 있으며, 이와 같은 효과는 균주 자체를 투여하는 것보다도 더욱 우수하다는 것을 보여준다.In addition, in the DSS-induced IBD animal model compared to the control group, the expression of IL-1β, an inflammatory cytokine that induces inflammation, increased, and the expression of Muc-2 and ZO-1 related to mucus protein and tight junction decreased. It was confirmed that inflammation increased and mucus secretion and tight junction were weakened. On the other hand, the R. intestinalis or Ri-EV administration group showed a decrease in the expression of IL-1β compared to the IBD animal model (FIG. 7a) and an increase in the expression of Muc-2 and ZO-1 (FIG. 7b). In particular, the Ri-EV-administered group showed a significant decrease in the expression of IL-1β and an increase in the expression of Muc-2 and ZO-1, compared to the R. intestinalis- administered group. The above results show that administration of Ri-EV can effectively reduce intestinal inflammation as well as restore mucus secretion ability and tight coupling, and that this effect is superior to administration of the strain itself.
실시예 3. DSS 유도 IBD 동물모델에서 Ri-EV 투여에 따른 장내 균총 변화 평가Example 3. Evaluation of intestinal microbiota change according to Ri-EV administration in DSS-induced IBD animal model
IBD 동물모델에서 Ri-EV 투여에 따른 장내균총 변화 및 이에 따른 항염증 효과를 확인하기 위해, 상기 실시예 2의 DSS 유도 IBD 동물모델에서 확보한 분변 시료에 대해 QIAamp Power Fecal Pro DNA Kit(QIAGEN, Germany)를 활용한 16S 리보솜 RNA 유전자 시퀀싱 분석을 수행하였다.In order to confirm the changes in the intestinal flora and the anti-inflammatory effect according to Ri-EV administration in the IBD animal model, the DSS induction of Example 2 16S ribosomal RNA gene sequencing analysis was performed using the QIAamp Power Fecal Pro DNA Kit (QIAGEN, Germany) for fecal samples obtained from IBD animal models.
그 결과, 도 8a와 같이, DSS를 투여하지 않은 대조군 대비 DSS 유도 IBD 동물모델에서는 프로테오박테리아(Proteobacteria)와 데페리박테레스(Deferribacteres) 문(phylum)의 증가와 같은 장내 미생물 군집의 변화가 눈에 띄게 관찰되었다. 또한, Ri-EV 투여군에서 샤논 다양성(Shannon diversity) 수치가 다른 그룹들보다 상당히 증가하는 것을 통해 샘플 내에 다양한 균총 변화가 일어났음을 확인하였다(도 8b). 특히, 도 9와 같이, 장내 박테리아의 변화에서 IBD의 완화에 기여하는 박테리아로 알려진 비피도박테리움(Bifidobacterium)의 수가 R. intestinalis 또는 Ri-EV 투여군에서 증가하였으며, R. intestinalis 투여군보다 Ri-EV 투여군에서 유의성 있게 증가하였다. 이를 통해, Ri-EV 투여가 IBD의 장내 환경에서 비피도박테리움의 성장 유도에 따른 장내 균총 변화를 통해 염증성 사이토카인의 분비를 억제하고, 배상세포의 점액 분비와 장 상피세포의 치밀결합 능력을 회복시킴에 따라 IBD를 개선함을 알 수 있다.As a result, as shown in FIG. 8a, in the DSS-induced IBD animal model compared to the control group not administered with DSS, changes in the intestinal microbial community, such as an increase in the phylum of Proteobacteria and Deferribacteres , were conspicuously observed. In addition, it was confirmed that the Shannon diversity value in the Ri-EV-administered group increased significantly compared to the other groups, indicating that various changes in the flora occurred in the sample (FIG. 8b). In particular, as shown in FIG. 9, the number of Bifidobacterium known as bacteria contributing to the alleviation of IBD in the change of intestinal bacteria increased in the R. intestinalis or Ri-EV-administered group, and the Ri-EV-administered group significantly increased than the R. intestinalis -administered group. From this, it can be seen that Ri-EV administration improves IBD by suppressing the secretion of inflammatory cytokines through changes in the intestinal microflora caused by the induction of growth of Bifidobacterium in the intestinal environment of IBD, and restoring mucus secretion of goblet cells and the ability of intestinal epithelial cells to bind tightly.
실시예 4. 로세부리아 속(Roseburia spp.) 균주 유래 세포외소포체에 대한 항염증 활성 분석Example 4. Roseburia spp. Anti-inflammatory activity assay for strain-derived extracellular vesicles
본 실시예에서는 실시예 1의 과정을 통해 추출된 R. intestinalis의 EV 외에 기타 로세부리아 속 균주의 EV도 IBD에 대한 치료 효과를 발휘할 수 있는지 확인하였다.In this Example, it was confirmed whether EVs of other strains of the genus Roseburia, in addition to EVs of R. intestinalis extracted through the process of Example 1, could exert a therapeutic effect on IBD.
구체적으로, 로세부리아 인테스티날리스(Ri)에 더하여 3종의 로세부리아 속 균주(로세부리아 파에시스(Roseburia faecies; Rfa, KCTC 15739), 로세부리아 호미니스(Roseburia hominis; Rho, KCTC 5845), 로세부리아 이눌리니보란스(Roseburia inulinivorans; Rin, DSM 16841))로부터 각각 세포외소포체를 추출한 후 이들의 항염증 활성을 분석하였다. EV는 실시예 1과 동일한 과정으로 추출하였다. Specifically, in addition to Roseburia interioris (Ri), three strains of the genus Roseburia (Roseburia faecies (Rfa, KCTC 15739), Roseburia hominis (Rho, KCTC 5845), Roseburia inulinivorans (Rin, DSM 1) 6841)), respectively, after extracting extracellular vesicles, their anti-inflammatory activity was analyzed. EVs were extracted in the same manner as in Example 1.
각 EV들의 항염증 활성을 평가하기 위해, 염증 지표인 산화질소(NO) 생성량을 측정하였으며, 염증성 사이토카인 및 항염증 사이토카인의 발현량도 측정하여 그 결과를 도 10에 나타내었다. In order to evaluate the anti-inflammatory activity of each EV, the amount of nitric oxide (NO) production, which is an inflammatory indicator, was measured, and the expression levels of inflammatory cytokines and anti-inflammatory cytokines were also measured, and the results are shown in FIG. 10 .
구체적으로, 산화질소 생성량은 마우스 대식세포를 이용하여 측정하였다. 마우스 대식세포 Raw 264.7 세포를 10% 소태아혈청(FBS: fetal bovine serum), 1% 항생제(100U/ml 페니실린 및 100μg/ml 스트렙토마이신)을 포함하는 RPMI1640 배양액으로 5% CO2 존재 하에서 37℃로 배양하였다. 이후 12웰 플레이트에 5×105 세포/웰의 농도로 1ml씩 분주하고, CO2 배양기에서 37℃ 및 24시간 배양하였다. 염증 유발을 위해, lipopolysaccharide(LPS) 10μg/ml가 첨가된 배지를 웰에 처리한 후, 4시간 동안 추가 배양하고, 상기 소포체들을 총 단백질양 기준 2mg을 배지에 첨가하여 처리한 다음 37℃에서 16시간 배양하였다. 이후에 웰 상층액 50μl와 Griess 시약 50μl를 섞어서 실온에서 10분간 반응시킨 후 플레이드 리더기로 540nm에서 흡광도 측정하여 산화질소의 생성량을 확인하였다. Specifically, the amount of nitric oxide production was measured using mouse macrophages. Mouse macrophage Raw 264.7 cells were cultured at 37°C in the presence of 5% CO 2 in RPMI1640 culture medium containing 10% fetal bovine serum (FBS) and 1% antibiotics (100 U/ml penicillin and 100 μg/ml streptomycin). Thereafter, 1ml was dispensed into a 12-well plate at a concentration of 5×10 5 cells/well, and incubated at 37° C. for 24 hours in a CO2 incubator. To induce inflammation, the wells were treated with a medium supplemented with 10 μg/ml of lipopolysaccharide (LPS), followed by further incubation for 4 hours, and the vesicles were treated by adding 2 mg based on the total protein amount to the medium, and then cultured at 37° C. for 16 hours. Thereafter, 50 μl of the well supernatant and 50 μl of Griess reagent were mixed and reacted at room temperature for 10 minutes, and then the absorbance was measured at 540 nm using a plaid reader to confirm the production of nitric oxide.
염증성 사이토카인과 항염증성 사이토카인의 발현량도 LPS 처리된 Raw264.7 세포를 이용하여 측정하였다. 상기와 동일한 방법으로 LPS 처리된 Raw264.7 세포에 상기 소포체를 총 단백질양 기준으로 2mg을 처리한 다음 37℃에서 16시간 배양하였다. 이후에 상기 세포의 TNF-α, IL-6, 및 IL-10의 단백질 발현량을 ELISA kit(R&D Systems, US)를 이용하여 제조사의 프로토콜에 따라 450nm에서 흡광도를 측정하였다. Expression levels of inflammatory cytokines and anti-inflammatory cytokines were also measured using LPS-treated Raw264.7 cells. Raw264.7 cells treated with LPS in the same manner as above were treated with 2 mg of the endoplasmic reticulum based on the total protein amount, and then cultured at 37° C. for 16 hours. Thereafter, the protein expression levels of TNF-α, IL-6, and IL-10 in the cells were measured for absorbance at 450 nm using an ELISA kit (R&D Systems, US) according to the manufacturer's protocol.
그 결과, 도 10과 같이, 동속이종의 로세부리아 속 균주 유래 세포외소포체를 염증이 유도된 마우스 대식세포에 처리했을 때, Rin 유래 EV(Rin-EV)를 제외한 나머지 로세부리아 속 균주 유래 세포외소포체에서 산화질소 생성량을 유의적으로 감소시킴을 확인하였다. 또한, 염증성 사이토카인과 항염증성 사이토카인의 발현량의 경우, 실험군으로 사용된 로세부리아 속 균주 유래 세포외소포체 전부(이하, Ri-EV, Rho-EV, Rfa-EV, 및 Rin-EV) 대조군과 비교하여 유의적으로 TNF-α와 IL-6를 효과적으로 감소시킬 뿐만 아니라 IL-10을 증가시킴을 확인하였다. As a result, as shown in FIG. 10, when the inflammation-induced mouse macrophages were treated with the homologous and heterogeneous Roseburia genus strain-derived extracellular vesicles, the rest of the Roseburia genus strain-derived extracellular vesicles except for Rin-derived EV (Rin-EV) It was confirmed that the production of nitric oxide was significantly reduced. In addition, in the case of the expression level of inflammatory cytokines and anti-inflammatory cytokines, all of the extracellular vesicles derived from Roseburia genus strains used as experimental groups (hereinafter, Ri-EV, Rho-EV, Rfa-EV, and Rin-EV) were significantly compared to the control group. It was confirmed that TNF-α and IL-6 were effectively reduced as well as IL-10 was increased.
상기 로세부리아 균주의 동속이종간의 항염증 활성 분석을 통해, 실험에 사용된 모든 로세부리아 속 균주들에서 유래된 세포외소포체들이 모두 우수한 항염 효과를 발휘하며, 따라서 염증성 장질환의 예방, 개선 또는 치료용 조성물로서 활용될 수 있음을 확인하였다.Through analysis of the anti-inflammatory activity of the Roseburia strains among all species, it was confirmed that all the extracellular vesicles derived from all Roseburia genus strains used in the experiment exhibited excellent anti-inflammatory effects, and therefore could be used as a composition for preventing, improving or treating inflammatory bowel disease.
실시예 5. 로세부리아 속(Roseburia spp.) 균주와 비피도박테리움 속(Bifidobacterium spp.) 균주 유래 세포외소포체의 항염증 활성 분석Example 5. Analysis of anti-inflammatory activity of extracellular vesicles derived from Roseburia spp. and Bifidobacterium spp.
실시예 4에 이어서, R. intestinalis 또는 B. longum 속에 해당하는 균주들로부터 유래한 EV들이 항염 효과를 발휘할 수 있는지 확인하였다.Following Example 4, it was confirmed whether EVs derived from strains corresponding to the genus R. intestinalis or B. longum could exert an anti-inflammatory effect.
구체적으로, 4종의 로세부리아 속 균주(로세부리아 파에시스(Roseburia faecies, KCTC 15739), 로세부리아 호미니스(Roseburia hominis, KCTC 5845), 로세부리아 이눌리니보란스(Roseburia inulinivorans, DSM 16841)), 및 5종의 비피도박테리움 속 균주(비피도박테리움 비피덤(Bifidobacterium bifidum, KCTC 3281), 비피도박테리움 브레이브(Bifidobacterium breve, KCTC 3220), 비피도박테리움 락티스(Bifidobacterium lactis, KCTC 5854), 비피도박테리움 어돌레스켄티스(Bifidobacterium adolescentis, KCTC 3216))에서 각각 세포외소포체를 추출한 후 이들의 항염증 활성을 분석하였다. EV는 실시예 1과 동일한 과정으로 추출하였다. Specifically, four strains of the genus Roseburia (Roseburia faecies, KCTC 15739), Roseburia hominis (KCTC 5845), Roseburia inulinivorans (DSM 16841)), and five strains of the genus Bifidobacterium (Bifidobacterium Extracellular vesicles were extracted from Bifidobacterium bifidum (KCTC 3281), Bifidobacterium breve (KCTC 3220), Bifidobacterium lactis (KCTC 5854), and Bifidobacterium adolescentis (KCTC 3216), respectively. Anti-inflammatory activity was assayed. EVs were extracted in the same manner as in Example 1.
각 EV들의 항염증 활성을 평가하기 위해, 간 조직 구성 세포중 하나인 Kupffer cell을 모사한 in vitro 환경을 마우스 대식세포인 Raw264.7 세포를 이용해 제작하였으며, 이들의 산화질소(NO) 생성량을 측정한 결과를 도 11에 나타냈다. 구체적으로, 마우스 대식세포 Raw 264.7 세포를 10% 소태아혈청(FBS: fetal bovine serum), 1% 항생제(100U/ml 페니실린 및 100 μg/ml 스트렙토마이신)을 포함하는 RPMI1640 배양액으로 5% CO2 존재 하에서 37℃로 배양하였다. 이후 12웰 플레이트에 5×105 세포/웰의 농도로 1ml씩 분주하고, CO2 배양기에서 37℃ 및 24시간 배양하였다. 염증 유발을 위해, lipopolysaccharide(LPS) 10μg/ml가 첨가된 배지를 웰에 처리한 후, 4시간 동안 추가 배양하고, 상기 소포체들을 총 단백질양 기준 200μg 농도로 배지에 첨가한 다음 37℃에서 16시간 배양하였다. 이후에 웰 상층액 50μl 및 Griess 시약 50μl를 혼합하여 실온에서 10분간 반응시킨 후 플레이드 리더기로 540nm에서 흡광도 측정하여 산화질소의 생성량을 확인하였다. In order to evaluate the anti-inflammatory activity of each EV, an in vitro environment mimicking Kupffer cells, one of the cells constituting liver tissue, was prepared using Raw264.7 cells, which are mouse macrophages, and the results of measuring the amount of nitric oxide (NO) produced by them are shown in FIG. 11. Specifically, mouse macrophage Raw 264.7 cells were cultured at 37° C. in the presence of 5% CO 2 in RPMI1640 culture medium containing 10% fetal bovine serum (FBS) and 1% antibiotics (100 U/ml penicillin and 100 μg/ml streptomycin). Thereafter, 1ml was dispensed into a 12-well plate at a concentration of 5×10 5 cells/well, and incubated at 37° C. for 24 hours in a CO 2 incubator. To induce inflammation, the wells were treated with a medium supplemented with 10 μg/ml of lipopolysaccharide (LPS), followed by further incubation for 4 hours, and the endoplasmic reticulum was added to the medium at a concentration of 200 μg based on the total protein amount, followed by incubation at 37° C. for 16 hours. Thereafter, 50 μl of the well supernatant and 50 μl of Griess reagent were mixed and reacted at room temperature for 10 minutes, and then the absorbance was measured at 540 nm using a plaid reader to confirm the production of nitric oxide.
그 결과, 도 11과 같이 실험군으로 사용된 로세부리아 속 균주 유래 세포외소포체 투여군 전부에서 유의성 있게 LPS에 의한 산화질소의 생성을 효과적으로 감소시킴을 확인하였다. 비피도박테리움 속 균주 유래 세포외소포체가 투여된 군에서도 산화질소의 생성이 효과적으로 감소한 것을 확인하였으며, 이 중 Bbr-EV와 Bla-EV의 산화질소 생성량 억제능은 총 단백질량 200μg 또는 50μg에서 조절됨을 확인하였다. As a result, it was confirmed that production of nitric oxide by LPS was effectively reduced significantly in all groups administered with the extracellular vesicles derived from the strain of Roseburia used as the experimental group, as shown in FIG. 11 . It was confirmed that the production of nitric oxide was effectively reduced even in the group administered with extracellular vesicles derived from a strain of the genus Bifidobacterium, and among them, the ability to inhibit the production of nitric oxide of Bbr-EV and Bla-EV was controlled at 200 μg or 50 μg of total protein.
상기 결과들은 로세부리아 속 또는 비피도박테리움 속에 해당하는 동속이종 균주들의 EV가 우수한 항염증 효과를 발휘한다는 것을 보여준다. 즉, 상기 결과로부터 로세부리아 속 균주 및 비피도박테리움 속 균주 유래 세포외소포체들은 강력한 항염 효과를 통해 다양한 염증성 질환의 예방, 개선, 또는 치료용도로 활용될 수 있음을 확인하였다. The above results show that EVs of homogeneous strains corresponding to the genus Roseburia or the genus Bifidobacterium exert excellent anti-inflammatory effects. That is, from the above results, it was confirmed that extracellular vesicles derived from strains of the genus Roseburia and strains of the genus Bifidobacterium can be used for prevention, improvement, or treatment of various inflammatory diseases through strong anti-inflammatory effects.
상기 실시예들에서 살펴본 바와 같이, 본 발명의 로세부리아 속 균주 유래 및 비피도박테리움 속 균주 유래 세포외소포체는 염증으로 인한 장 상피세포 장벽 손상 및 면역 세포의 침윤을 감소시키고, 배상세포의 수를 유지하며, 장염으로 인한 맹장 무게 및 장 길이의 감소를 억제하고, 장내 균총 변화를 통해 염증성 사이토카인의 분비를 억제하며, 배상세포의 점액 분비와 장 상피세포의 치밀결합 능력을 회복시키는 것으로 나타났다. 특히, 로세부리아 속 또는 비피도박테리움 속의 다양한 동속이종 균주에서 유래한 세포외소포체들은 모두 우수한 항염 효과를 발휘하는 것이 확인되었다. 따라서, 본 발명의 로세부리아 속 및 비피도박테리움 속 균주 유래 세포외소포체는 강력한 항암효과를 발휘할 뿐만 아니라 염증으로 인한 조직학적 손상이나 기능 상실을 개선할 수 있는 바, 다양한 염증성 질환의 강력한 예방, 개선, 및/또는 치료용 조성물로 제공될 수 있다. As mentioned in the above embodiments, the derived from the roseburia strain in the present invention and the bifidobacterium -derived cell -derived cell -derived cell -derived cells, reducing the intestinal epithelial barrier damage due to inflammation, reducing the infiltration of immune cells, maintaining the number of compensation cells, suppressing the reduction of the cecum and intestinal length due to enteritis, and changing the intestinal bacteria through the change in the intestinal bacteria. It was found to inhibit the secretion of Cain and to restore the mucus secretion of compensation cells and the dense binding ability of the intestinal epithelial cells. In particular, it was confirmed that all extracellular vesicles derived from various homologous and heterogeneous strains of the genus Roseburia or the genus Bifidobacterium exhibit excellent anti-inflammatory effects. Therefore, the extracellular vesicles derived from strains of the genus Roseburia and the genus Bifidobacterium of the present invention not only exert a strong anticancer effect, but also improve histological damage or loss of function due to inflammation, and thus can be provided as a composition for the prevention, improvement, and/or treatment of various inflammatory diseases.
이상의 설명으로부터, 본 발명이 속하는 기술 분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will be able to understand that the present invention may be embodied in other specific forms without changing its technical spirit or essential features. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not limiting. The scope of the present invention should be construed as including all changes or modifications derived from the meaning and scope of the claims to be described later and equivalent concepts rather than the detailed description above are included in the scope of the present invention.
Claims (13)
A pharmaceutical composition for preventing or treating inflammatory diseases, comprising at least one selected from the group consisting of strain-derived extracellular vesicles derived from Roseburia spp. and extracellular vesicles derived from Bifidobacterium spp.
상기 세포외소포체는 평균 직경이 30 nm 내지 200 nm인 것을 특징으로 하는, 약학적 조성물.
According to claim 1,
The extracellular vesicles are characterized in that the average diameter of 30 nm to 200 nm, the pharmaceutical composition.
상기 로세부리아 속 균주 유래 세포외소포체는 로세부리아 속 균주로부터 자연적으로 또는 인공적으로 분비되는 것이고;
상기 비피도박테리움 속 균주 유래 세포외소포체는 비피도박테리움 속 균주로부터 자연적으로 또는 인공적으로 분비되는 것을 특징으로 하는, 약학적 조성물.
According to claim 1,
The extracellular vesicles derived from the strain of the genus Roseburia are naturally or artificially secreted from the strain of the genus Roseburia;
The extracellular vesicles derived from the strain of the genus Bifidobacterium are naturally or artificially secreted from the strain of the genus Bifidobacterium, a pharmaceutical composition.
상기 로세부리아 속 균주는 로세부리아 인테스티날리스(Roseburia intestinalis), 로세부리아 파에시스(Roseburia faecies), 로세부리아 호미니스(Roseburia hominis), 및 로세부리아 이눌리니보란스(Roseburia inulinivorans)로 이루어진 군에서 선택된 하나 이상인, 약학적 조성물.
According to claim 1,
The Roseburia genus strain is at least one selected from the group consisting of Roseburia intestinalis , Roseburia faecies , Roseburia hominis , and Roseburia inulinivorans . Pharmaceutical composition.
상기 비피도박테리움 속 균주는 비피도박테리움 롱검(Bifidobacterium longum), 비피도박테리움 비피덤(Bifidobacterium bifidum), 비피도박테리움 브레이브(Bifidobacterium breve), 비피도박테리움 락티스(Bifidobacterium lactis), 및 비피도박테리움 어돌레스켄티스(Bifidobacterium adolescentis)로 이루어진 군에서 선택된 하나 이상인, 약학적 조성물.
According to claim 1,
The strain of the Bifidobacterium genus is at least one selected from the group consisting of Bifidobacterium longum , Bifidobacterium bifidum, Bifidobacterium breve , Bifidobacterium lactis , and Bifidobacterium adolescentis , about academic composition.
상기 염증성 질환은 위염, 위궤양, 십이지장궤양, 염증성 피부질환, 알레르기성 질환, 과민성 대장 증후군, 궤양성 대장염, 염증성 장질환, 복막염, 골수염, 봉소염, 뇌막염, 뇌염, 췌장염, 외상 유발 쇼크, 기관지 천식, 낭포성 섬유증, 뇌졸중, 급성 기관지염, 만성 기관지염, 급성 세기관지염, 만성 세기관지염, 골관절염, 통풍, 척추관절병증, 강직성 척추염, 라이터 증후군, 건선성 관절병증, 장질환 척추염, 연소자성 관절병증, 연소자성 강직성 척추염, 반응성 관절병증, 감염성 관절염, 후-감염성 관절염, 임균성 관절염, 결핵성 관절염, 바이러스성 관절염, 진균성 관절염, 매독성 관절염, 라임병, 혈관염 증후군과 관련된 관절염, 결절성 다발동맥염, 과민성 혈관염, 루게릭 육아종증, 류마티스성 다발성근육통, 관절 세포 동맥염, 칼슘 결정 침착 관절병증, 가성 통풍, 비-관절 류마티즘, 점액낭염, 건초염, 상과염, 신경병증성 관절 질환(charco and joint), 출혈성 관절증(hemarthrosic), 헤노흐-쉔라인 자반병, 비후성 골관절병증, 다중심성 세망조직구종, 수르코일로시스(surcoilosis), 혈색소증, 겸상 적혈구증, 혈색소병증, 고지단백혈증, 저감마글로불린혈증, 가족성 지중해열, 베하트 병, 전신성 홍반성 루푸스, 재귀열, 건선, 다발성 경화증, 패혈증, 패혈성 쇼크, 다장기 기능장애 증후군, 급성 호흡곤란 증후군, 만성 폐쇄성 폐질환(chronic obstructive pulmonary disease), 급성 폐손상(acute lung injury), 및 기관지 폐 형성장애(broncho-pulmonary dysplasia)로 이루어진 군에서 선택된 하나 이상인, 약학적 조성물.
According to claim 1,
The inflammatory diseases include gastritis, gastric ulcer, duodenal ulcer, inflammatory skin disease, allergic disease, irritable bowel syndrome, ulcerative colitis, inflammatory bowel disease, peritonitis, osteomyelitis, cellulitis, meningitis, encephalitis, pancreatitis, trauma-induced shock, bronchial asthma, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondyloarthropathy, ankylosing spine Inflammation, Reiter's syndrome, psoriatic arthropathy, enteropathic spondylitis, juvenile arthropathy, juvenile ankylosing spondylitis, reactive arthropathy, infectious arthritis, post-infectious arthritis, gonococcal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with vasculitis syndrome, polyarteritis nodosa, hypersensitivity vasculitis, Lou Gehrig's granulomatosis, polymyalgia rheumatica, articular cell arteritis, calcium Crystal deposition arthropathy, pseudogout, non-articular rheumatism, bursitis, tenosynovitis, epicondylitis, neuropathic joint disease (charco and joint), hemorrhagic joint disease (hemarthrosic), Henoch-Schenlein purpura, hypertrophic osteoarthropathy, multicentric reticulocytoma, surcoilosis, hemochromatosis, sickle cell disease, hemochromatosis, hyperlipoproteinemia, reduction Maglobulinemia, familial Mediterranean fever, Behart's disease, systemic lupus erythematosus, relapsing fever, psoriasis, multiple sclerosis, sepsis, septic shock, multiple organ dysfunction syndrome, acute respiratory distress syndrome, chronic obstructive pulmonary disease (chronic obstructive pulmonary disease), acute lung injury, and at least one selected from the group consisting of broncho-pulmonary dysplasia, a pharmaceutical composition.
상기 염증성 장질환은 궤양성 대장염, 크론병, 베체트병, 교원성 대장염, 림프성 대장염, 허혈성 대장염, 출혈성 직장 궤양, 회장 낭염, 및 전환성 대장염으로 이루어진 군에서 선택된 하나 이상인, 약학적 조성물.
According to claim 6,
The inflammatory bowel disease is at least one selected from the group consisting of ulcerative colitis, Crohn's disease, Behçet's disease, collagenous colitis, lymphocytic colitis, ischemic colitis, hemorrhagic rectal ulcer, ileal pouchitis, and convertible colitis, a pharmaceutical composition.
상기 약학적 조성물은 하기로 이루어진 군에서 선택된 하나 이상의 효과를 갖는 것을 특징으로 하는, 약학적 조성물:
i) 장 상피세포 장벽 손상 감소;
ii) 면역세포의 장 조직 침윤 감소;
iii) 배상세포(goblet cells)의 수 감소 억제;
iv) 맹장 무게 감소 억제;
v) 장 길이 감소 억제;
vi) 염증성 사이토카인 생성 억제;
vii) 항염증성 사이토카인 생성 촉진;
viii) 배상세포의 점액 분비 증진;
ix) 장 상피세포의 치밀결합 증진; 및
x) 장내 비피도박테리움(Bifidobacterium) 수 증가.
According to claim 1,
Characterized in that the pharmaceutical composition has one or more effects selected from the group consisting of:
i) reducing intestinal epithelial barrier damage;
ii) reduction of intestinal tissue infiltration of immune cells;
iii) inhibition of reduction in the number of goblet cells;
iv) inhibition of cecal weight loss;
v) inhibition of intestinal length reduction;
vi) inhibition of inflammatory cytokine production;
vii) promoting anti-inflammatory cytokine production;
viii) enhancement of mucus secretion by goblet cells;
ix) promoting the compaction of intestinal epithelial cells; and
x) Increased number of Bifidobacterium in the intestine.
A kit for preventing or treating inflammatory diseases, comprising the pharmaceutical composition of any one of claims 1 to 8.
A method for preventing or treating inflammatory diseases, comprising administering at least one selected from the group consisting of extracellular vesicles derived from strains of the genus Roseburia and extracellular vesicles derived from strains of the genus Bifidobacterium to a subject in need thereof, wherein the subject is a non-human subject.
A food composition for preventing or improving inflammatory diseases, comprising at least one selected from the group consisting of extracellular vesicles derived from a strain of the genus Roseburia and extracellular vesicles derived from a strain of the genus Bifidobacterium as an active ingredient.
상기 식품 조성물은 건강기능식품 조성물인, 식품 조성물.
According to claim 11,
The food composition is a health functional food composition, food composition.
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CN113728088A (en) * | 2018-09-13 | 2021-11-30 | 组装生物科学公司 | Methods and compositions for treating gastrointestinal and inflammatory disorders |
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KR20170033372A (en) | 2014-07-17 | 2017-03-24 | 프로타고니스트 테라퓨틱스, 인코포레이티드 | Oral peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory bowel diseases |
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KR20170033372A (en) | 2014-07-17 | 2017-03-24 | 프로타고니스트 테라퓨틱스, 인코포레이티드 | Oral peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory bowel diseases |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113728088A (en) * | 2018-09-13 | 2021-11-30 | 组装生物科学公司 | Methods and compositions for treating gastrointestinal and inflammatory disorders |
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