KR20230104518A - Composition for improving intestinal health, intestinal function or intestinal immunity comprising mother's milk oligosaccharide mixture - Google Patents
Composition for improving intestinal health, intestinal function or intestinal immunity comprising mother's milk oligosaccharide mixture Download PDFInfo
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- KR20230104518A KR20230104518A KR1020220170405A KR20220170405A KR20230104518A KR 20230104518 A KR20230104518 A KR 20230104518A KR 1020220170405 A KR1020220170405 A KR 1020220170405A KR 20220170405 A KR20220170405 A KR 20220170405A KR 20230104518 A KR20230104518 A KR 20230104518A
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- South Korea
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- intestinal
- composition
- food composition
- fucosyllactose
- improving
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Abstract
본 발명은 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 유효성분으로 포함하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물, 장 염증 예방 또는 개선용 식품 조성물, 염증성 장질환 치료 또는 예방용 약학 조성물, 영유아용 식품 조성물, 또는 모유 보충제 조성물에 관한 것이다. 본 발명의 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 유효성분으로 포함하는 조성물은 장내 단쇄 지방산의 함량을 증가시키고 장내 염증성 사이토카인 TNF-α의 분비를 억제함으로써 장 건강, 장 기능 또는 장관 면역을 개선하고, 장내 균총을 개선하며, 배변기능을 개선고, 장 염증을 개선하고 나아가 염증성 장질환을 치료 또는 개선할 수 있다. The present invention relates to a food composition for improving intestinal health, intestinal function or intestinal immunity, a food composition for preventing or improving intestinal inflammation, and inflammatory bowel disease, comprising a human milk oligosaccharide mixture containing galactooligosaccharide and 2'-fucosyllactose as an active ingredient. It relates to a pharmaceutical composition for treatment or prevention, a food composition for infants and young children, or a breast milk supplement composition. The composition comprising the human milk oligosaccharide mixture including galactooligosaccharide and 2'-fucosyllactose of the present invention as an active ingredient increases the content of short-chain fatty acids in the intestine and inhibits the secretion of TNF-α, an inflammatory cytokine in the intestine, thereby improving intestinal health, It can improve intestinal function or intestinal immunity, improve intestinal flora, improve bowel function, improve intestinal inflammation, and further treat or improve inflammatory bowel disease.
Description
본 발명은 모유 올리고당 혼합물을 유효성분으로 포함하는 장 건강, 장 기능 또는 장관 면역 개선용 조성물에 관한 것이다. The present invention relates to a composition for improving intestinal health, intestinal function or intestinal immunity comprising a human milk oligosaccharide mixture as an active ingredient.
최근 장내미생물이 감염병 예방, 면역과정 조절, 장내 영양흡수 등에 결정적인 역할을 한다는 사실이 새롭게 규명되어진 후, 장내미생물에 관한 연구가 전 세계적으로 폭발적으로 증가하고 있다. Recently, the fact that intestinal microbes play a decisive role in preventing infectious diseases, regulating the immune process, and nutrient absorption in the intestine has been newly identified.
특히, 장내미생물은 체내에서 인간(숙주)의 정상적인 생리적 기능을 유지하는데 중요한 역할을 하며, 이러한 장내미생물의 분포 변화는 비만이나 당뇨병, 고지혈증 등과 같은 대사증후군 이외에도 장염, 아토피와 같은 면역관련 질병 등의 유발과 밀접한 관련성을 갖는다는 사실이 밝혀지면서 장내미생물은 체내 대사를 조절하는데 매우 중요한 역할을 한다는 연구결과가 지속적으로 발표되고 있다. In particular, intestinal microbes play an important role in maintaining normal physiological functions of humans (hosts) in the body, and changes in the distribution of these intestinal microbes can lead to immune-related diseases such as enteritis and atopy, as well as metabolic syndromes such as obesity, diabetes, and hyperlipidemia. As the fact that it has a close relationship with induction is revealed, research results are continuously being published that the intestinal microbes play a very important role in regulating the body's metabolism.
이러한 장내미생물은 노화, 염증반응, 항생제, 프로바이오틱스, 식이, 식이패턴 그리고 스트레스 등의 다양한 인자들에 의해서 변화되는 것으로 알려져 있으며, 그 중 특히 식품의 섭취와 식습관이 장내미생물 변화에 미치는 영향이 가장 큰 것으로 다수의 논문에서 보고되어지고 있다. It is known that these intestinal microbes are changed by various factors such as aging, inflammatory response, antibiotics, probiotics, diet, dietary pattern, and stress. It has been reported in a number of papers.
장내미생물의 균형을 위해 가장 많이 섭취하는 것은 유산균 등의 프로바이오틱스로 이들 유익균을 섭취하여 장내미생물 균형을 개선함으로써 인체 좋은 영향을 준다고 알려져 있으나, 실제로 대장까지 도달하는데 어려움이 많은 것으로 알려져 있다. Probiotics such as lactic acid bacteria are the most consumed for the balance of intestinal microorganisms. It is known that these beneficial bacteria improve the intestinal microbial balance and have a good effect on the human body, but it is known that it is difficult to actually reach the large intestine.
이에 프리바이오틱스(prebiotics)는 이미 장 속에 존재하는 미생물들의 성장과 증식에 도움을 주는 비소화성 식품 성분들을 이르는 것으로 이를 섭취하였을 때에 더욱 효과적으로 장내미생물의 변화를 양질화 할 수 있다고 보고되고 있다. Accordingly, it has been reported that prebiotics refer to non-digestible food components that help the growth and proliferation of microorganisms already present in the intestine, and can improve the quality of intestinal microorganisms more effectively when ingested.
한편 인간의 모유에는 200~300여 종류에 이르는 모유 올리고당 (Human Milk Oligosaccharides, HMOs)이 고농도 10~20 g/L로 존재하며, 모유 올리고당 중에서도 푸코실올리고당, 그 중에서도 2'-푸코실락토오스가 높은 함량으로 존재하는 것으로 알려져 있고, 2'푸코실락토오스는 프리바이오틱스 효과, 병원균 및 이들이 분비하는 장내독소가 장내상피에 달라붙는 것을 막아줌으로써 감염을 방지하는 효과가 알려졌으며, 인간의 건강에 도움을 주는 장내 미생물총의 형성에 기여하는 역할을 하는 것으로 알려져 있다. On the other hand, human milk contains about 200 to 300 human milk oligosaccharides (HMOs) at a high concentration of 10 to 20 g/L, and among human milk oligosaccharides, fucosyl oligosaccharides, especially 2'-fucosyllactose, are high. It is known that 2' fucosyllactose has a prebiotics effect, an effect of preventing infection by preventing pathogens and intestinal toxins secreted by them from adhering to the intestinal epithelium, and is useful for human health. It is known to play a role in contributing to the formation of the intestinal microflora.
2'-푸코실락토오스를 생산할 수 있는 방법은 크게 화학적 합성법, 효소반응을 이용한 합성법, 미생물 발효를 이용하여 생산하는 방법 등이 있으나, 2'-푸코실락토오스 단독으로는 장내 유익균 증식효과가 크지 않고, 가격이 높아 기능성을 발휘할 정도로 높은 함량이나 비율로 식품에 적용하는 데에는 한계가 있었다. Methods that can produce 2'-fucosyllactose include chemical synthesis, synthesis using enzymatic reaction, and production using microbial fermentation. However, due to its high price, there were limitations in applying it to food in a content or ratio high enough to demonstrate functionality.
한편 갈락토올리고당, 특히 4'-갈락토실락토오스 또한 모유 올리고당의 하나로 장내 유익균 증식 효과가 큰 올리고당으로 알려져 있으나, 2'-푸코실락토오스와 갈락토올리고당을 특정 비율로 조합했을 때의 장내 단쇄 지방산의 생성 증가 또는 장 염증성 사이토카인의 분비 억제 효과에 대해서는 지금까지 알려진 바가 없었다. On the other hand, galacto-oligosaccharide, especially 4'-galactosyllactose, is also known as one of the human milk oligosaccharides and has a great effect on the growth of beneficial bacteria in the intestine. Up to now, nothing has been known about the effect of increasing the production or inhibiting the secretion of intestinal inflammatory cytokines.
본 발명의 목적은 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 유효성분으로 포함하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물, 장 염증 예방 또는 개선용 식품 조성물, 염증성 장질환 치료 또는 예방용 약학 조성물, 영유아용 식품 조성물, 또는 모유 보충제 조성물을 제공하는 데 있다. An object of the present invention is a food composition for improving intestinal health, intestinal function or intestinal immunity, a food composition for preventing or improving intestinal inflammation, comprising a human milk oligosaccharide mixture containing galactooligosaccharide and 2'-fucosyllactose as an active ingredient, To provide a pharmaceutical composition for treating or preventing intestinal disorders, a food composition for infants and young children, or a breast milk supplement composition.
본 발명은 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 유효성분으로 포함하는 장 건강, 장 기능 또는 장관 면역 개선용 조성물을 제공한다. The present invention provides a composition for improving intestinal health, intestinal function or intestinal immunity, comprising a human milk oligosaccharide mixture containing galactooligosaccharide and 2'-fucosyllactose as an active ingredient.
또한, 본 발명은 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 유효성분으로 포함하는 장 염증 예방 또는 개선용 식품 조성물을 제공한다. In addition, the present invention provides a food composition for preventing or improving intestinal inflammation comprising a human milk oligosaccharide mixture containing galactooligosaccharide and 2'-fucosyllactose as an active ingredient.
또한, 본 발명은 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 유효성분으로 포함하는 염증성 장질환 치료 또는 예방용 약학 조성물을 제공한다. In addition, the present invention provides a pharmaceutical composition for treating or preventing inflammatory bowel disease comprising a mixture of human milk oligosaccharides including galactooligosaccharide and 2'-fucosyllactose as an active ingredient.
상기 갈락토올리고당 및 2'-푸코실락토오스는 60:40 내지 85:15 중량비일 수 있다. The galacto-oligosaccharide and 2'-fucosyllactose may have a weight ratio of 60:40 to 85:15.
상기 갈락토올리고당은 총 갈락토올리고당 중에서 4'-갈락토실락토오스 10-20 중량% 및 6'-갈락토실락토오스 0.05-0.5 중량%를 포함할 수 있다. The galactooligosaccharide may include 10-20% by weight of 4'-galactosyllactose and 0.05-0.5% by weight of 6'-galactosyllactose out of the total galactooligosaccharide.
상기 모유 올리고당 혼합물은 시알릴락토오스를 추가로 포함할 수 있다. The human milk oligosaccharide mixture may further include sialyllactose.
상기 시알릴락토오스는 상기 갈락토올리고당 및 2'-푸코실락토오스의 합 100 중량부에 대하여 1-10 중량부 포함할 수 있다. The sialyllactose may be included in an amount of 1 to 10 parts by weight based on 100 parts by weight of the sum of the galactooligosaccharide and 2'-fucosyllactose.
상기 조성물은 장내 단쇄 지방산(short chain fatty acid)의 함량을 증가시킬 수 있다. The composition can increase the content of short chain fatty acids in the intestine.
상기 단쇄 지방산은 아세트산, 부티르산 및 프로피온산 중에서 선택되는 어느 하나 이상일 수 있다. The short-chain fatty acid may be any one or more selected from acetic acid, butyric acid, and propionic acid.
상기 조성물은 장내 유익균의 증식 또는 생장을 촉진하거나, 장내 유해균의 증식 또는 생장을 억제하는 것일 수 있다. The composition may promote the proliferation or growth of beneficial bacteria in the intestine or inhibit the proliferation or growth of harmful bacteria in the intestine.
상기 조성물은 배변 기능을 개선하는 것일 수 있다. The composition may improve bowel function.
상기 조성물은 TNF-α의 분비를 억제하는 것일 수 있다. The composition may inhibit the secretion of TNF-α.
또한, 본 발명은 상기 장 건강, 장 기능 또는 장관 면역 개선용 조성물 또는 상기 장 염증 예방 또는 개선용 식품 조성물을 포함하는 영유아용 식품 조성물을 제공한다. In addition, the present invention provides a food composition for infants and young children comprising the composition for improving intestinal health, intestinal function or intestinal immunity, or the food composition for preventing or improving intestinal inflammation.
상기 영유아용 식품 조성물은 조제유, 영아용 조제식, 성장기용 조제식 또는 영유아용이유식일 수 있다. The food composition for infants and young children may be formula milk, formula for infants, formula for growth or weaning formula for infants and young children.
또한, 본 발명은 상기 장 건강, 장 기능 또는 장관 면역 개선용 조성물 또는 상기 장 염증 예방 또는 개선용 식품 조성물을 포함하는 모유 보충제 조성물을 제공한다. In addition, the present invention provides a breast milk supplement composition comprising the composition for improving intestinal health, intestinal function or intestinal immunity, or the food composition for preventing or improving intestinal inflammation.
본 발명의 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 유효성분으로 포함하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물, 장 염증 예방 또는 개선용 식품 조성물, 염증성 장질환 치료 또는 예방용 약학 조성물, 영유아용 식품 조성물, 또는 모유 보충제 조성물은, 장내 유익균의 증식을 촉진하고, 유해균의 증식을 억제하며, 장내 단쇄 지방산의 함량을 증가시키고, 장내 균총을 개선할 수 있다. 또한, 본 발명의 조성물을 이용하면, 장 건강, 장 기능 또는 장관 면역을 개선할 수 있으며, 배변 기능을 개선할 수 있다. Food composition for improving intestinal health, intestinal function or intestinal immunity, food composition for preventing or improving intestinal inflammation, inflammatory bowel disease comprising the human milk oligosaccharide mixture containing galactooligosaccharide and 2'-fucosyllactose of the present invention as an active ingredient A pharmaceutical composition for treatment or prevention, a food composition for infants, or a breast milk supplement composition can promote the growth of beneficial bacteria in the intestine, inhibit the growth of harmful bacteria, increase the content of short-chain fatty acids in the intestine, and improve the intestinal flora. In addition, using the composition of the present invention, intestinal health, intestinal function or intestinal immunity can be improved, and bowel function can be improved.
도 1은 실험예 1에서 인간 분변시스템에서 혼합비율을 달리한 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 처리했을 때의 아세트산 생성량을 나타낸 그래프이다.
도 2는 실험예 1에서 인간 분변시스템에서 혼합비율을 달리한 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 처리했을 때의 프로피온산 생성량을 나타낸 그래프이다.
도 3은 실험예 1에서 인간 분변시스템에서 혼합비율을 달리한 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 처리했을 때의 부티르산 생성량을 나타낸 그래프이다.
도 4는 실험예 2에서 리포폴리사카라이드(LPS)를 이용하여 염증을 유도시킨 인간 유래 장관상피세포(caco-2)에서 항염증 효과를 확인하기 위해 TNF-α의 분비 억제 정도를 비교한 그래프이다.
도 5는 실험예 2에서 리포폴리사카라이드(LPS)를 이용하여 염증을 유도시킨 인간 유래 장관상피세포(caco-2)에서 항염증 효과를 확인하기 위해 염증 인자인 COX-2 mRNA 발현 수준을 비교한 그래프이다.
도 6은 실험예 2에서 리포폴리사카라이드(LPS)를 이용하여 염증을 유도시킨 인간 유래 장관상피세포(caco-2)에서 항염증 효과를 확인하기 위해 염증 인자인 iNOS mRNA 발현 수준을 비교한 그래프이다.
도 7은 실험예 2에서 리포폴리사카라이드(LPS)를 이용하여 염증을 유도시킨 마우스 유래 대식세포(RAW 264.7)에서 산화질소 생성능을 비교한 그래프이다.
도 8은 실험예 3에서 DSS 투여로 장 상피세포 손상을 유도한 염증성 장질환 동물모델 마우스를 희생시킨 후 장 길이를 확인하기 위한 사진이다.
도 9는 실험예 3에서 장 조직내 염증 인자 발현 확인을 위한 웨스턴블랏 밴드 사진이다. 1 is a graph showing the amount of acetic acid produced when treating a human milk oligosaccharide mixture containing galactooligosaccharide and 2'-fucosyllactose at different mixing ratios in the human fecal system in Experimental Example 1.
Figure 2 is a graph showing the amount of propionic acid produced when treating human milk oligosaccharide mixtures containing galactooligosaccharides and 2'-fucosyllactose at different mixing ratios in the human fecal system in Experimental Example 1.
Figure 3 is a graph showing the amount of butyric acid produced when treating human milk oligosaccharide mixtures containing galactooligosaccharide and 2'-fucosyllactose at different mixing ratios in the human fecal system in Experimental Example 1.
Figure 4 is a graph comparing the degree of inhibition of TNF-α secretion in order to confirm the anti-inflammatory effect in human-derived intestinal epithelial cells (caco-2) in which inflammation was induced using lipopolysaccharide (LPS) in Experimental Example 2 am.
Figure 5 compares the expression level of COX-2 mRNA, an inflammatory factor, to confirm the anti-inflammatory effect in human-derived intestinal epithelial cells (caco-2) in which inflammation was induced using lipopolysaccharide (LPS) in Experimental Example 2. it is a graph
Figure 6 is a graph comparing the expression level of iNOS mRNA, an inflammatory factor, to confirm the anti-inflammatory effect in human-derived intestinal epithelial cells (caco-2) in which inflammation was induced using lipopolysaccharide (LPS) in Experimental Example 2 am.
7 is a graph comparing the nitric oxide generating ability in mouse-derived macrophages (RAW 264.7) in which inflammation was induced using lipopolysaccharide (LPS) in Experimental Example 2.
8 is a photograph for confirming the intestinal length after sacrificing the inflammatory bowel disease animal model mouse in which intestinal epithelial cell damage was induced by DSS administration in Experimental Example 3.
9 is a photograph of a western blot band for confirming the expression of inflammatory factors in intestinal tissue in Experimental Example 3.
본 발명은 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 유효성분으로 포함하는 장 건강, 장 기능 또는 장관 면역 개선용 조성물에 관한 것이다. The present invention relates to a composition for improving intestinal health, intestinal function or intestinal immunity, comprising a human milk oligosaccharide mixture including galactooligosaccharide and 2'-fucosyllactose as an active ingredient.
또한, 본 발명은 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 유효성분으로 포함하는 장 염증 예방 또는 개선용 식품 조성물에 관한 것이다. In addition, the present invention relates to a food composition for preventing or improving intestinal inflammation comprising a human milk oligosaccharide mixture including galactooligosaccharide and 2'-fucosyllactose as an active ingredient.
또한, 본 발명은 갈락토올리고당 및 2'-푸코실락토오스를 포함하는 모유 올리고당 혼합물을 유효성분으로 포함하는 염증성 장질환 치료 또는 예방용 약학 조성물에 관한 것이다. In addition, the present invention relates to a pharmaceutical composition for treating or preventing inflammatory bowel disease comprising a mixture of human milk oligosaccharide containing galactooligosaccharide and 2'-fucosyllactose as an active ingredient.
상기 염증성 장질환은 크론병, 궤양성 대장염, 장형 베체트병, 감염성 장염, 허혈성 장질환, 방사선 장염 및 장누수증후군으로 이루어진 군에서 선택되는 질환일 수 있다. The inflammatory bowel disease may be a disease selected from the group consisting of Crohn's disease, ulcerative colitis, intestinal Behçet's disease, infectious enteritis, ischemic bowel disease, radiation enteritis, and leaky gut syndrome.
상기 장누수증후군(leaky gut syndrome; LGS)이란, 장점막세포는 일정한 세포 사이의 간극을 유지하다가 소화 흡수 과정이 일어나는 동안 어떠한 자극이나 손상이 가해지면서 세포 사이의 틈으로 고분자 물질이 왕복할 수 있는 장점막 투과성이 증가되는 현상을 나타내는 것으로, 장벽의 기능을 제대로 하지 못하여 혈액 내 고분자 물질이 장관내 관강으로 누수되거나 관강 내의 고분자 물질이 직접 혈액으로 들어가는 현상으로 인해 유발되는 증상을 총괄하여 의미한다. 상기 증상들은 노화, 알레르기, 다발성 외상, 류마티스 관절염, 염증성 대장질환, 만성피로 증후군, 과민성 증후군 등의 다양한 임상적 상태로 나타난다. 또한 장점막 투과성의 증가나 장점막의 손상으로 인해 병원체, 항원, 부패물질 등이 장점막 내로 유입되어 염증반응이 일어나고 내독소가 혈류로 유입되어 장내세균 전위(bacterial translocation), 장관내독소혈증(intestinal endotoxemia) 등을 야기하여 각종 염증반응 및 면역 반응이 나타나게 된다. 이러한, 장누수증후군은, 특이한 증상 없이 다양하고 광범위하며 모호한 증상을 호소하게 된다. 구체적으로 여러 가지 질환에서 공통적으로 호소하는 증상을 갖고 있다는 점에서 특이점이 있다. The leaky gut syndrome (LGS) refers to the intestinal mucosa in which the intestinal mucosal cells maintain a constant intercellular gap, and when any stimulus or damage is applied during the digestion and absorption process, the intestinal mucosa in which a polymer material can shuttle back and forth through the gap between the cells It indicates a phenomenon in which permeability is increased, and refers collectively to symptoms caused by a phenomenon in which polymeric substances in the blood leak into the lumen of the intestinal tract or polymeric substances in the lumen enter the blood directly due to a failure of the barrier function properly. The above symptoms appear in various clinical conditions such as aging, allergy, multiple trauma, rheumatoid arthritis, inflammatory bowel disease, chronic fatigue syndrome, and hypersensitivity syndrome. In addition, pathogens, antigens, decaying substances, etc. are introduced into the intestinal mucosa due to increased permeability of the intestinal mucosa or damage to the intestinal mucosa, causing an inflammatory reaction, and endotoxins are introduced into the bloodstream, resulting in bacterial translocation and intestinal endotoxemia. etc., resulting in various inflammatory and immune responses. Such leaky gut syndrome complains of various, extensive, and ambiguous symptoms without specific symptoms. Specifically, it is unique in that it has symptoms commonly complained of in various diseases.
상기 장관 면역 개선 또는 장관 면역 증강이란 장관에 존재하는 면역세포의 초기활성화 과정에서 비특이적으로 항원에 대해 면역반응을 촉진하는 기능 또는 면역계의 세포의 활성을 증대시킴으로써 장관의 면역을 강화하는 기능을 의미한다. 장관 면역 기능저하로 인한 질환은 병원성 미생물에 의한 감염성 질환, 암으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있다. 상기 장관 면역 개선 또는 증강용 조성물은 사람의 환절기 독감 개선 또는 예방, 세균성 설사 개선 또는 예방, 세균성 감염 개선 또는 예방, 상처 후 치료 효과 강화의 응용효과를 갖는다. The improvement of intestinal immunity or enhancement of intestinal immunity refers to a function of promoting an immune response to an antigen in a non-specific manner during the initial activation of immune cells present in the intestinal tract or a function of enhancing the immunity of the intestinal tract by increasing the activity of cells of the immune system. . Diseases caused by reduced intestinal immune function may be any one or more selected from the group consisting of infectious diseases caused by pathogenic microorganisms and cancer. The composition for improving or enhancing intestinal immunity has an application effect of improving or preventing seasonal flu in humans, improving or preventing bacterial diarrhea, improving or preventing bacterial infections, and enhancing post-wound treatment effects.
상기 갈락토올리고당 및 2'-푸코실락토오스는 60:40 내지 85:15 중량비, 바람직하게는 65:35 내지 80:20 중량비, 더욱 바람직하게는 70:30 내지 75:25 중량비일 수 있다. 갈락토올리고당의 비율이 상기 하한치 미만이거나 2'-푸코실락토오스의 비율이 상기 상한치 초과하는 경우 염증성 사이토카인 TNF-α의 분비 억제 효과가 충분치 않고, 갈락토올리고당의 비율이 상기 상한치 초과하거나 2'-푸코실락토오스의 비율이 상기 하한치 미만인 경우 장내 단쇄 지방산, 특히 프로피온산 및 부티르산 생성량 증대 효과가 충분치 않다. The galactooligosaccharide and 2'-fucosyllactose may be in a weight ratio of 60:40 to 85:15, preferably 65:35 to 80:20, and more preferably 70:30 to 75:25. When the ratio of galactooligosaccharide is less than the lower limit or the ratio of 2'-fucosyllactose exceeds the upper limit, the effect of inhibiting the secretion of the inflammatory cytokine TNF-α is not sufficient, and the ratio of galactooligosaccharide exceeds the upper limit or 2' - When the ratio of fucosyllactose is less than the above lower limit, the effect of increasing the production of short-chain fatty acids in the intestine, particularly propionic acid and butyric acid, is not sufficient.
상기 갈락토올리고당은 총 갈락토올리고당 중에서 4'-갈락토실락토오스 10-20 중량%, 바람직하게는 12-18 중량% 및 6'-갈락토실락토오스 0.05-0.5 중량%, 바람직하게는 0.1-0.3 중량%를 포함할 수 있다. The galactooligosaccharide contains 10-20% by weight of 4'-galactosyllactose, preferably 12-18% by weight and 0.05-0.5% by weight of 6'-galactosyllactose, preferably 0.1-20% by weight of the total galactooligosaccharide. 0.3% by weight.
상기 모유 올리고당 혼합물은 시알릴락토오스를 추가로 포함할 수 있다. 시알릴락토오스는 3'-시알릴락토오스, 6'-시알릴락토오스 또는 이들의 혼합물일 수 있고, 시알릴락토오스를 추가로 포함할 경우 모유 올리고당 혼합물의 장내 단쇄 지방산 생성 효과 또는 염증성 사이토카인의 분비 억제 효과가 증대된다. The human milk oligosaccharide mixture may further include sialyllactose. Sialyllactose may be 3'-sialyllactose, 6'-sialyllactose, or a mixture thereof, and when sialyllactose is further included, the human milk oligosaccharide mixture inhibits the production of short-chain fatty acids in the intestine or the secretion of inflammatory cytokines. effect is increased.
상기 시알릴락토오스는 상기 갈락토올리고당 및 2'-푸코실락토오스의 합 100 중량부에 대하여 1-10 중량부 포함할 수 있다. The sialyllactose may be included in an amount of 1 to 10 parts by weight based on 100 parts by weight of the sum of the galactooligosaccharide and 2'-fucosyllactose.
상기 조성물은 장내 단쇄 지방산(short chain fatty acid)의 함량을 증가시킬 수 있고, 상기 단쇄 지방산은 아세트산, 부티르산 및 프로피온산 중에서 선택되는 어느 하나 이상일 수 있고, 바람직하게는 부티르산의 생성을 증대시킨다. The composition may increase the content of short chain fatty acids in the intestine, and the short chain fatty acids may be any one or more selected from acetic acid, butyric acid and propionic acid, and preferably increases the production of butyric acid.
상기 조성물은 장내 단쇄 지방산 함량을 증가시키는 것으로서, 장내 단쇄 지방산 함량을 증가시키는 장내 유익균의 증식 또는 생장을 촉진할 수 있고, 장내 유해균의 증식 또는 생장을 억제하는 것일 수 있다. The composition increases the content of short-chain fatty acids in the intestine, can promote the proliferation or growth of beneficial bacteria in the intestine that increases the content of short-chain fatty acids in the intestine, and may inhibit the proliferation or growth of harmful bacteria in the intestine.
상기 조성물은 장내 단쇄 지방산 함량을 증가시키고, 장내 유익균의 증식 및 생장을 촉진함으로써, 배변 기능을 개선하는 것일 수 있다. The composition may improve bowel function by increasing the content of short-chain fatty acids in the intestine and promoting the proliferation and growth of beneficial bacteria in the intestine.
상기 조성물은 장내 단쇄 지방산 함량을 증가시키고, 장내 유익균의 증식 및 생장을 촉진함으로써, 장내 염증성 사이토카인, 특히 TNF-α의 분비를 억제하는 것일 수 있다. The composition may inhibit the secretion of intestinal inflammatory cytokines, particularly TNF-α, by increasing the content of short-chain fatty acids in the intestine and promoting the proliferation and growth of beneficial bacteria in the intestine.
또한, 본 발명은 상기 장 건강 개선용 또는 장 기능 개선용 조성물 또는 상기 장 염증 예방 또는 개선용 식품 조성물을 포함하는 영유아용 식품 조성물을 제공한다. In addition, the present invention provides a food composition for infants and young children comprising the composition for improving intestinal health or improving intestinal function or the food composition for preventing or improving intestinal inflammation.
상기 영유아용 식품 조성물은 조제유, 영아용 조제식, 성장기용 조제식 또는 영유아용이유식일 수 있다. The food composition for infants and young children may be formula milk, formula for infants, formula for growth or weaning formula for infants and young children.
또한, 본 발명은 상기 장 건강 개선용 또는 장 기능 개선용 조성물 또는 상기 장 염증 예방 또는 개선용 식품 조성물을 포함하는 모유 보충제 조성물을 제공한다. In addition, the present invention provides a breast milk supplement composition comprising the composition for improving intestinal health or improving intestinal function or the food composition for preventing or improving intestinal inflammation.
본 발명의 조성물은 식품 조성물로, 본 발명의 모유 올리고당 혼합물을 유효성분으로 포함하는 각종 식품류 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 영유아용 식품 조성물, 모유보충제 등의 형태로 사용할 수 있다. 상기 영유아용 식품 조성물은 조제유, 영아용 조제식, 성장기용 조제식 또는 영유아용이유식일 수 있다. The composition of the present invention is a food composition, and various foods containing the human milk oligosaccharide mixture of the present invention as an active ingredient, for example, beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, food compositions for infants and young children, breast milk It can be used in supplement form. The food composition for infants and young children may be formula milk, formula for infants, formula for growth or weaning formula for infants and young children.
본 발명에 따른 식품 조성물은 후술하는 상기 약학 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 알코올 음료류, 과자류, 다이어트바, 유제품, 육류, 초코렛, 피자, 라면, 기타 면류, 껌류, 아이스크림류, 비타민 복합제, 건강보조식품류 등이 있다. The food composition according to the present invention may be formulated in the same way as the pharmaceutical composition described later and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, alcoholic beverages, confectionery, diet bars, dairy products, meat, chocolate, pizza, ramen, other noodles, chewing gum, ice cream, vitamin complexes, and health supplements. etc.
본 발명의 식품 조성물은 유효성분으로서 모유 올리고당 혼합물뿐만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있으며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등]) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다. 예컨대, 본 발명의 식품 조성물이 드링크제와 음료류로 제조되는 경우에는 본 발명의 모유 올리고당 혼합물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 및 각종 식물 추출액 등을 추가로 포함시킬 수 있다. The food composition of the present invention may include not only the human milk oligosaccharide mixture as an active ingredient, but also ingredients commonly added during food preparation, such as proteins, carbohydrates, fats, nutrients, seasonings and flavors. . Examples of the aforementioned carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides such as conventional sugars such as dextrins and cyclodextrins and sugar alcohols such as xylitol, sorbitol and erythritol. As flavoring agents, natural flavoring agents [thaumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.]) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used. For example, when the food composition of the present invention is made into drinks and beverages, in addition to the human milk oligosaccharide mixture of the present invention, citric acid, high fructose corn syrup, sugar, glucose, acetic acid, malic acid, fruit juice, and various plant extracts may be further included. .
본 발명은 상기 모유 올리고당 혼합물을 유효성분으로 포함하는 염증성 장질환 또는 장누수증후군 개선, 억제 또는 예방용 식품 조성물을 포함하는 건강기능식품을 제공한다. 건강기능식품이란, 모유 올리고당 혼합물을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용시 발생할 수 있는 부작용 등이 없는 장점이 있다. 이와 같이 하여 얻어지는 본 발명의 건강기능식품은, 일상적으로 섭취하는 것이 가능하기 때문에 매우 유용하다. 이와 같은 건강기능식품에 있어서의 모유 올리고당 혼합물의 첨가량은, 대상인 건강기능식품의 종류에 따라 달라 일률적으로 규정할 수 없지만, 식품 본래의 맛을 손상시키지 않는 범위에서 첨가하면 되며, 대상 식품에 대하여 통상 0.01 내지 50 중량%, 바람직하기로는 0.1 내지 20 중량%의 범위이다. 또한, 환제, 과립제, 정제 또는 캡슐제 형태의 건강기능식품의 경우에는 통상 0.1 내지 100 중량% 바람직하기로는 0.5 내지 80 중량%의 범위에서 첨가하면 된다. 한 구체예에서, 본 발명의 건강기능식품은 환제, 정제, 캡슐제 또는 음료의 형태일 수 있다. The present invention provides a health functional food comprising a food composition for improving, suppressing, or preventing inflammatory bowel disease or leaky gut syndrome containing the human milk oligosaccharide mixture as an active ingredient. Health functional food refers to food produced by adding human milk oligosaccharide mixture to food materials such as beverages, teas, spices, chewing gum, confectionery, etc., or by encapsulation, powdering, suspension, etc. However, unlike general drugs, it has the advantage of not having side effects that may occur when taking drugs for a long time using food as a raw material. The health functional food of the present invention obtained in this way is very useful because it can be consumed on a daily basis. The addition amount of the human milk oligosaccharide mixture in such a health functional food cannot be determined uniformly depending on the type of target health functional food, but it can be added within a range that does not impair the original taste of the food. It ranges from 0.01 to 50% by weight, preferably from 0.1 to 20% by weight. In addition, in the case of health functional foods in the form of pills, granules, tablets or capsules, it is usually added in the range of 0.1 to 100% by weight, preferably 0.5 to 80% by weight. In one embodiment, the health functional food of the present invention may be in the form of pills, tablets, capsules or beverages.
또 다른 예에서 상기한 바와 같은 상기 모유 올리고당 혼합물을 유효성분으로 하는 염증성 장질환 또는 장누수증후군 예방 또는 치료용 약학 조성물로 다양하게 이용될 수 있다. 유효성분인 모유 올리고당 혼합물 외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다. In another example, a pharmaceutical composition for preventing or treating inflammatory bowel disease or leaky gut syndrome comprising the above-described human milk oligosaccharide mixture as an active ingredient may be variously used. In addition to the human milk oligosaccharide mixture as an active ingredient, it can be prepared using pharmaceutically suitable and physiologically acceptable adjuvants, such as excipients, disintegrants, sweeteners, binders, coating agents, expanding agents, lubricants, lubricants, or flavoring agents. You can use my back.
상기 약학 조성물은 투여를 위해서 상기 기재한 유효 성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 약학 조성물로 바람직하게 제제화할 수 있다. The pharmaceutical composition may be preferably formulated as a pharmaceutical composition by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration.
상기 약학 조성물의 제제 형태는 과립제, 산제, 정제, 피복정, 캡슐제, 좌제, 액제, 시럽, 즙, 현탁제, 유제, 점적제 또는 주사 가능한 액제 등이 될 수 있다. 예를 들어, 정제 또는 캡슐제의 형태로의 제제화를 위해, 유효 성분은 에탄올, 글리세롤, 물 등과 같은 경구, 무독성의 약제학적으로 허용 가능한 불활성 담체와 결합될 수 있다. 또한, 원하거나 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은 아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연 당, 옥수수 감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성 검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐 아세테이트, 소듐 클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸 셀룰로스, 아가, 벤토니트, 잔탄 검 등을 포함한다. Formulations of the pharmaceutical composition may be granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops, or injectable solutions. For example, for formulation in the form of tablets or capsules, the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. In addition, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
액상 용액으로 제제화되는 조성물에 있어서 허용 가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. In compositions formulated as liquid solutions, acceptable pharmaceutical carriers are sterile and biocompatible, and include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added if necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to prepare formulations for injections such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.
더 나아가 해당분야의 적절한 방법으로 Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다. Furthermore, using a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA as an appropriate method in the field, it can be preferably formulated according to each disease or component.
본 발명의 약학 조성물은 경구 투여할 수 있다. 본 발명의 약학 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료 또는 예방에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. 본 발명의 바람직한 구현예에 따르면, 본 발명의 약학 조성물의 1일 투여량은 0.001-10 g/㎏이다.The pharmaceutical composition of the present invention can be administered orally. The suitable dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration method, patient's age, weight, sex, medical condition, food, administration time, administration route, excretion rate and reaction sensitivity, usually This allows the skilled physician to readily determine and prescribe dosages effective for the desired treatment or prophylaxis. According to a preferred embodiment of the present invention, the daily dose of the pharmaceutical composition of the present invention is 0.001-10 g/kg.
본 발명의 약학 조성물은 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention may be prepared in a unit dose form by formulation using a pharmaceutically acceptable carrier and/or excipient, or prepared by putting it into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally contain a dispersing agent or stabilizer.
또한, 본 발명은 포유동물에게 유효량의 모유 올리고당 혼합물을 투여하는 것을 포함하는 염증성 장질환 또는 장누수증후군의 개선, 예방 또는 치료 방법을 제공한다.In addition, the present invention provides a method for improving, preventing or treating inflammatory bowel disease or leaky gut syndrome comprising administering an effective amount of a human milk oligosaccharide mixture to a mammal.
여기에서 사용된 용어 "포유동물"은 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다.As used herein, the term "mammal" refers to a mammal that is a subject of treatment, observation or experimentation, and preferably refers to a human.
여기에서 사용된 용어 "유효량"은 연구자, 수의사, 의사 또는 기타 임상의에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약학적 조성물의 양을 의미하는 것으로, 이는 해당 증상의 완화를 유도하는 양을 포함한다. 본 발명의 유효성분에 대한 유효량 및 투여횟수는 원하는 효과에 따라 변화될 수 있다. 그러므로, 투여될 최적의 투여량은 당업자에 의해 쉽게 결정될 수 있으며, 염증성 장질환의 증상 정도, 장누수증후군에 대한 장투과성 정도, 면역세포 활성화 정도, 항원에 대한 면역반응 정도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 본 발명의 예방, 치료 또는 개선 방법에 있어서, 성인의 경우, 모유 올리고당 혼합물을 1일 1회 내지 수회 투여시, 0.001 g/㎏ 내지 10 g/㎏의 용량으로 투여하는 것이 바람직하다.As used herein, the term "effective amount" means an amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human, which is considered by a researcher, veterinarian, physician or other clinician, which is Includes an amount that induces relief of symptoms. The effective amount and frequency of administration of the active ingredient of the present invention may vary depending on the desired effect. Therefore, the optimal dose to be administered can be easily determined by a person skilled in the art, and the degree of symptoms of inflammatory bowel disease, the degree of intestinal permeability for leaky gut syndrome, the degree of immune cell activation, the degree of immune response to antigens, and the effective amount contained in the composition Depending on various factors, including the content of ingredients and other ingredients, the type of dosage form, and the patient's age, middle, general health condition, sex and diet, administration time, administration route and secretion rate of the composition, treatment period, and concurrently used drugs can be regulated. In the prevention, treatment or improvement method of the present invention, in the case of adults, it is preferable to administer the human milk oligosaccharide mixture at a dose of 0.001 g/kg to 10 g/kg when administered once to several times a day.
이하 본 발명을 실시예를 통해 더욱 상세하게 설명하나, 본 발명이 이에 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail through examples, but the present invention is not limited thereto.
[제조예 1][Production Example 1]
갈락토올리고당 및 2'-푸코실락토오스의 혼합비율에 따른 장내 단쇄 지방산 생성량 및 인간유래 장관상피세포 및 마우스유래 대식세포에서의 항염증 효과를 확인하기 위하여 갈락토올리고당 및 2'-푸코실락토오스를 아래 표 1과 같이 혼합하였다. 상기 갈락토올리고당은 갈락토올리고당 75 중량%, 유당, 포도당 및 갈락토오스 20 중량% 및 수분 5 중량%인 분말로서, 총 갈락토올리고당 중에서 4'-갈락토실락토오스는 13.5 중량%, 6'-갈락토실락토오스는 0.15 중량%를 포함하는 것이고, 상기 2'-푸코실락토오스는 2'-푸코실락토오스를 95 중량% 포함하는 수분 5 중량%의 분말을 사용하였다. 표 1의 혼합 중량비는 각각 갈락토올리고당 및 2'-푸코실락토오스의 고형분의 혼합비율이다. Galactooligosaccharide and 2'-fucosyllactose were tested to determine the amount of short-chain fatty acids produced in the intestine and the anti-inflammatory effect in human-derived intestinal epithelial cells and mouse-derived macrophages according to the mixing ratio of galactooligosaccharide and 2'-fucosyllactose. They were mixed as shown in Table 1 below. The galactooligosaccharide is a powder comprising 75% by weight of galactooligosaccharide, 20% by weight of lactose, glucose and galactose, and 5% by weight of water, and 13.5% by weight of 4'-galactosyllactose and 6'-gal Lactosyllactose contains 0.15% by weight, and the 2'-fucosyllactose was used as a powder containing 95% by weight of 2'-fucosyllactose and 5% by weight of moisture. The mixing weight ratios in Table 1 are the mixing ratios of the solids of galacto-oligosaccharide and 2'-fucosyllactose, respectively.
[실험예 1: 인간분변시스템에서의 장내 단쇄 지방산 생성량 확인][Experimental Example 1: Confirmation of short-chain fatty acid production in the intestine in human feces system]
평균 3 개월령의 유아 5명으로부터 얻은 분변 각 1 g씩을 혼합한 혼합 분변 5g을 pH7.7의 PBS 완충액 50 mL과 혼합하여 분변 슬러리를 제조하였다. 상기 분변 슬러리에 표 1의 모유 올리고당 혼합물을 1 mg/mL 농도로 혼합하고, 모유 올리고당 혼합물이 처리된 분변 슬러리 1 mL을 BHI broth 배지(Brain Heart Infusion, 조성(g/L); Brain Heart Infusion 37 g, Hemin solution (1%) 0.5 mL, L-Cysteine.HCL 0.5 g, Resazurin (0.1%) 0.5 mL, Distilled water 1 L) 9 mL에 접종한 후 혼합한 후, 37℃, 혐기적 조건에서 48 시간 배양하였다. Fecal slurry was prepared by mixing 5 g of mixed feces obtained by mixing 1 g each of feces obtained from 5 infants of an average age of 3 months with 50 mL of pH 7.7 PBS buffer. The fecal slurry was mixed with the human milk oligosaccharide mixture of Table 1 at a concentration of 1 mg/mL, and 1 mL of the fecal slurry treated with the human milk oligosaccharide mixture was mixed with BHI broth medium (Brain Heart Infusion, composition (g/L); Brain Heart Infusion 37 g, Hemin solution (1%) 0.5 mL, L-Cysteine.HCL 0.5 g, Resazurin (0.1%) 0.5 mL, Distilled water 1 L) 9 mL and then mixed, 37 ℃, 48 ℃ under anaerobic conditions time incubated.
상기 배양액을 12,100 x g, 4 ℃에서 20분간 원심분리하고, 원심분리 된 상등액 900 μL를 2 mL EP튜브에 옮긴 후, 내부 표준품으로 농도 400 mM의 아세트산을 첨가하고, 0.5 mL 헥산을 첨가하고 상온에서 10분간 혼합한 후, 1,932 x g, 4 ℃에서 10분간 원심분리하여 헥산층을 수집한는 과정을 2회 반복하여 얻은 헥산층을 180 μL를 인서트 바이알에 넣어준 후 유도체시약인 MTBSTFA(+1% t-BDMCS)를 각 바이알에 6 μL씩 첨가하고, 각 vial을 볼텍싱 해주고 건조 오븐에서 70 ℃, 45분간 인큐베이션 후 GC-MS로 단쇄 지방산 3종, 즉 아세트산, 프로피온산 및 부티르산을 분석하였다. The culture solution was centrifuged at 12,100 x g and 4 ° C for 20 minutes, and 900 μL of the centrifuged supernatant was transferred to a 2 mL EP tube, and then 400 mM acetic acid was added as an internal standard, 0.5 mL hexane was added, and at room temperature After mixing for 10 minutes, 180 μL of the hexane layer obtained by repeating the process of collecting the hexane layer by centrifugation at 1,932 x g and 4 ° C for 10 minutes was added twice to an insert vial, and then the derivative reagent MTBSTFA (+1% t -BDMCS) was added to each vial by 6 μL, each vial was vortexed, and after incubation at 70 ° C. for 45 minutes in a drying oven, three types of short-chain fatty acids, namely acetic acid, propionic acid and butyric acid, were analyzed by GC-MS.
표 1의 모유 올리고당 혼합물을 처리하지 않고 분변 슬러리만 배양한 음성대조군은 "fecal"로 표시하고, 표 1의 모유 올리고당 단독 및 그 혼합물을 처리한 분변 슬러리의 아세트산, 프로피온산 및 부티르산 함량(mM)을 각각 도 1, 도 2 및 도 3에 나타내었다. The negative control group in which only the fecal slurry was cultured without treatment with the human milk oligosaccharide mixture of Table 1 was indicated as "fecal", and the acetic acid, propionic acid and butyric acid contents (mM) of the fecal slurry treated with the human milk oligosaccharide alone and the mixture in Table 1 1, 2 and 3, respectively.
도 1에서 아세트산은 음성대조군(fecal) 대비 GF1, GF2, GF3 및 GF5 그룹에서 유의적으로 증가하였다. 즉 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)에서는 아세트산 생성에 유의적인 증가가 없었고, 모유 올리고당 혼합물 중에서는 갈락토올리고당 및 2'푸코실락토오스를 0.7:0.3 내지 0.88:0.12로 혼합한 GF1, GF2 및 GF3 그룹에서 유의적 증가폭이 더 컸다. In FIG. 1, acetic acid was significantly increased in the GF1, GF2, GF3, and GF5 groups compared to the negative control group (fecal). That is, there was no significant increase in acetic acid production in the galactooligosaccharide-only group (GL) and 2'-fucosyllactose-only group (FL), and among the human milk oligosaccharide mixtures, galactooligosaccharide and 2'fucosyllactose were administered at a concentration of 0.7:0.3 to 0.7:0.3. A significant increase was greater in the GF1, GF2, and GF3 groups mixed at 0.88:0.12.
도 2에서 프로피온산은 음성대조군(fecal) 대비 GF3, GF4, GF5 및 GL 그룹에서 유의적으로 증가하였다. 특히 fecal 그룹의 부티르산 농도는 4.84±0.02 mM인데 비해서 GF3 그룹은 5.68±0.27 mM로서 부티르산 생성량이 가장 높게 증가하였다. In FIG. 2, propionic acid was significantly increased in the GF3, GF4, GF5, and GL groups compared to the negative control group (fecal). In particular, the concentration of butyric acid in the fecal group was 4.84±0.02 mM, whereas the concentration of butyric acid in the GF3 group was 5.68±0.27 mM, showing the highest increase in butyric acid production.
도 3에서 부티르산은 음성대조군(fecal) 대비 모든 모유 올리고당 단독 및 혼합 그룹에서 유의적으로 증가하였다. 특히 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)은 물론 다른 비율로 갈락토올리고당 및 2'-푸코실락토오스를 혼합한 GF1, GF2, GF4 및 GF5 그룹에 비해 갈락토올리고당 및 2'-푸코실락토오스를 0.7:0.3 중량비로 혼합한 GF3 그룹은 부티르산 생성량이 2 배 정도 현저히 증가하였다. In Figure 3, butyric acid was significantly increased in all human milk oligosaccharide alone and mixed groups compared to the negative control group (fecal). In particular, compared to the galactooligosaccharide alone group (GL) and 2'-fucosyllactose alone group (FL) as well as the GF1, GF2, GF4, and GF5 groups mixed with galactooligosaccharide and 2'-fucosyllactose at different ratios, In the GF3 group in which lacto-oligosaccharide and 2'-fucosyllactose were mixed at a weight ratio of 0.7:0.3, the production of butyric acid was significantly increased by about two times.
상기 인간분변시스템에서 장내 단쇄 지방산 생성 효과를 확인한 결과 fecal 그룹이나 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)에 비해 갈락토올리고당 및 2'-푸코실락토오스를 0.7:0.3 중량비로 혼합한 GF3 그룹은 아세트산, 프로피온산 및 부티르산 생성량이 현저하게 유의적으로 증가하였다. As a result of confirming the effect of short-chain fatty acid production in the intestine in the human fecal system, galactooligosaccharide and 2'-fucosyllactose were reduced to 0.7 compared to the fecal group, the galactooligosaccharide alone group (GL), and the 2'-fucosyllactose alone group (FL). : The GF3 group mixed at a weight ratio of 0.3 significantly increased the production of acetic acid, propionic acid and butyric acid.
특히 GF3 그룹은 산업적 용도로 사용함에 있어서 가격이 높은 2'-푸코실락토오스의 함량을 낮추었음에도 2'-푸코실락토오스 단독 그룹(FL)에 비해 현저히 높은 장내 단쇄 지방산 생성 효과를 나타낸다는 점에서 활용 가능성이 높다. In particular, the GF3 group is used for industrial purposes in that it shows a significantly higher intestinal short-chain fatty acid production effect than the 2'-fucosyllactose alone group (FL), even though the content of 2'-fucosyllactose, which is expensive, is lowered. Most likely.
[실험예 2: 장관상피세포 및 대식세포에서의 염증 억제 효과 확인][Experimental Example 2: Confirmation of Inhibitory Effect of Inflammation in Intestinal Epithelial Cells and Macrophages]
1. 장관상피세포에서의 염증성 사이토카인 TNF-α의 분비 억제 효과 확인1. Confirmation of the secretion inhibitory effect of TNF-α, an inflammatory cytokine in intestinal epithelial cells
인간유래 장관상피세포(caco-2)에 1 μg/mL의 리포폴리사카라이드(LPS, 시그마알드리치사)로 염증을 유도하고, 제조예 1의 모유 올리고당 혼합물을 1 mg/mL를 처리한 후 TNF-α 농도를 고마바이오텍스에서 구입한 ELISA kit를 이용하여 kit 내 측정방법에 따라 측정하여 도 4에 나타내었다. Inflammation was induced in human-derived intestinal epithelial cells (caco-2) with 1 μg/mL of lipopolysaccharide (LPS, Sigma-Aldrich), and the human milk oligosaccharide mixture of Preparation Example 1 was treated with 1 mg/mL of TNF. -α concentration was measured according to the measurement method in the kit using an ELISA kit purchased from Goma Biotex and shown in FIG.
정상대조군(Con)은 LPS 및 모유 올리고당 혼합물을 처리하지 않은 군이고, 음성대조군(LPS)은 LPS만 처리한 군이며, 나머지 제조예 1의 모유 올리고당 혼합물 실험군은 LPS와 모유 올리고당 혼합물을 동시처리하였을 때의 450 nm에서의 OD값, 즉 TNF-α 함량(pg/mL)을 측정한 것이다. The normal control group (Con) is a group not treated with LPS and human milk oligosaccharide mixture, the negative control group (LPS) is a group treated only with LPS, and the remaining experimental group of human milk oligosaccharide mixture of Preparation Example 1 is treated with LPS and human milk oligosaccharide mixture at the same time. The OD value at 450 nm, that is, the TNF-α content (pg/mL) was measured.
LPS만 처리한 음성대조군(LPS)에서 정상대조군(Con) 대비 유의적으로 증가하였고, GF4 그룹에서는 음성대조군(LPS)에 비하여 오히려 TNF-α 분비량이 유의적으로 증가하였고, GL, GF4 및 GF5 그룹에서는 음성대조군(LPS)과 유의적인 차이가 없었으며, GF2, GF3 및 FL 그룹에서 음성대조군(LPS) 대비 유의적으로 감소하였다. In the negative control group (LPS) treated only with LPS, there was a significant increase compared to the normal control group (Con), and in the GF4 group, the amount of TNF-α secretion increased significantly compared to the negative control group (LPS), and in the GL, GF4 and GF5 groups There was no significant difference from the negative control group (LPS), and there was a significant decrease compared to the negative control group (LPS) in the GF2, GF3 and FL groups.
염증성 사이토카인 TNF-α 분비량은 갈락토올리고당 단독 그룹(GL)에서는 나타나지 않았고, 2'-푸코실락토오스 단독 그룹(FL)에서는 나타내었으나, 갈락토올리고당 및 2'-푸코실락토오스를 0.3:0.7 내지 0.83:0.17 중량비로 혼합했을 때 2'-푸코실락토오스 단독 그룹(FL)과 유사한 활성을 나타내었다. The amount of inflammatory cytokine TNF-α secretion was not observed in the galactooligosaccharide-only group (GL) and was found in the 2'-fucosyllactose-only group (FL), but galactooligosaccharide and 2'-fucosyllactose were mixed at 0.3:0.7 to 0.3:0.7 When mixed at a weight ratio of 0.83:0.17, activity similar to that of the 2'-fucosyllactose alone group (FL) was exhibited.
2. 장관상피세포에서의 염증 인자 발현 억제 효과 확인2. Confirmation of inhibitory effect on inflammatory factor expression in intestinal epithelial cells
인간유래 장관상피세포(Caco-2)에 제조예 1의 모유 올리고당 혼합물 각각 1 mg/mL, LPS 1 μg/mL을 24시간 공동처리 후 배양한 후, 염증 인자인 COX-2 및 iNOS의 mRNA 발현 수준을 확인하였다. Human-derived intestinal epithelial cells (Caco-2) were co-treated with 1 mg/mL of the human milk oligosaccharide mixture of Preparation Example 1 and 1 μg/mL of LPS, respectively, for 24 hours and then cultured, followed by mRNA expression of the inflammatory factors COX-2 and iNOS. level was confirmed.
상기 mRNA 발현 수준 확인은 트리졸(trizol)을 이용하여 세포막을 용해 후 mRNA를 추출함. 이후 추출된 mRNA양을 nanodrop을 이용해 동량으로 정량한 후 LeGene premium express first-strand cDNA synthesis system을 이용해 cDNA를 합성하고, cDNA를 HiPi real-time PCR 2x master mix SYBR green mix와 섞어 PCR reaction solution을 만든 후 iQ5 thermal cycler를 이용해 상기 염증 인자의 발현 수준을 확인하여 도 5 및 도 6에 각각 나타내었다. The mRNA expression level is confirmed by dissolving the cell membrane using trizol and then extracting the mRNA. Afterwards, the amount of extracted mRNA was quantified in the same amount using nanodrop, and cDNA was synthesized using the LeGene premium express first-strand cDNA synthesis system, and the cDNA was mixed with HiPi real-time PCR 2x master mix SYBR green mix to make a PCR reaction solution. After confirming the expression levels of the inflammatory factors using an iQ5 thermal cycler, they are shown in FIGS. 5 and 6 , respectively.
COX-2의 mRNA 발현 수준은 정상대조군(Con) 대비 LPS만 처리한 음성대조군(LPS)에서 군에 유의적으로 증가하였고, 갈락토올리고당 단독 그룹(GL)은 음성대조군(LPS)과 유의차가 없었고, 2'-푸코실락토오스 단독 그룹(FL)과 GF2, GF3, GF4 및 GF5 그룹은 음성대조군(LPS) 대비 유의적으로 감소하였다. The mRNA expression level of COX-2 significantly increased in the negative control group (LPS) treated only with LPS compared to the normal control group (Con), and the galacto-oligosaccharide alone group (GL) showed no significant difference from the negative control group (LPS). , The 2'-fucosyllactose alone group (FL) and the GF2, GF3, GF4 and GF5 groups were significantly reduced compared to the negative control group (LPS).
iNOS의 mRNA 발현 수준은 정상대조군(Con) 대비 LPS만 처리한 음성대조군(LPS)에서 군에 유의적으로 증가하였고, 갈락토올리고당 단독 그룹(GL)은 음성대조군(LPS)과 유의차가 없으나 그 발현량이 매우 증가하였고, 2'-푸코실락토오스 단독 그룹(FL)과 GF2 및 GF3 그룹은 음성대조군(LPS) 대비 유의적으로 감소하였다. The mRNA expression level of iNOS increased significantly in the negative control group (LPS) treated only with LPS compared to the normal control group (Con), and the galacto-oligosaccharide alone group (GL) showed no significant difference from the negative control group (LPS), but its expression The amount was greatly increased, and the 2'-fucosyllactose alone group (FL) and the GF2 and GF3 groups were significantly decreased compared to the negative control group (LPS).
염증 인자인 COX-2 및 iNOS의 mRNA 발현 수준을 억제하는 활성은 갈락토올리고당 단독 그룹(GL)에서는 나타나지 않았고, 2'-푸코실락토오스 단독 그룹(FL)에서는 나타내었으나, 갈락토올리고당 및 2'-푸코실락토오스를 0.21:0.79 내지 0.83:0.17 중량비, 바람직하게는 0.44:0.56 내지 0.7:0.3 중량비로 혼합했을 때 2'-푸코실락토오스 단독 그룹(FL)과 유사하거나 오히려 뛰어난 활성을 나타내었다. The activity of suppressing the mRNA expression levels of COX-2 and iNOS, which are inflammatory factors, was not shown in the galactooligosaccharide alone group (GL) and was shown in the 2'-fucosyllactose alone group (FL), but galactooligosaccharide and 2' - When fucosyllactose was mixed in a weight ratio of 0.21:0.79 to 0.83:0.17, preferably 0.44:0.56 to 0.7:0.3, it exhibited similar or superior activity to that of the 2'-fucosyllactose alone group (FL).
3. 대식세포에서의 산화질소 생성 억제 효과 확인3. Confirmation of the inhibitory effect on nitric oxide production in macrophages
리포폴리사카라이드(LPS)를 이용하여 염증을 유도시킨 마우스유래 대식세포(RAW 264.7) 모델에서 제조예 1의 모유 올리고당 혼합물의 산화질소(nitric oxide, NO) 생성능을 확인하여 항염증 효능을 확인하였다. In a mouse-derived macrophage (RAW 264.7) model in which inflammation was induced using lipopolysaccharide (LPS), the nitric oxide (NO) production ability of the human milk oligosaccharide mixture of Preparation Example 1 was confirmed to confirm anti-inflammatory efficacy. .
제조에 1의 모유 올리고당 혼합물 각각을 0.25 mg/mL의 농도로 12시간 100 ng/mL LPS와 동시 처리한 후 상등액 50 μL를 취하여 1% Sulfanilamide/5% phosphoric acid 용액을 50 μL를 넣고, 0.1% NEAD 50 μL를 넣어 준 후, 540 nm에서 흡광도를 측정하여 상등액 내의 산화질소 농도를 측정하여 도 7에 나타내었다. In the preparation, each of the human milk oligosaccharide mixtures in 1 was simultaneously treated with 100 ng/mL LPS at a concentration of 0.25 mg/mL for 12 hours, then 50 μL of the supernatant was taken, 50 μL of 1% Sulfanilamide/5% phosphoric acid solution was added, and 0.1% After adding 50 μL of NEAD, the absorbance was measured at 540 nm to measure the nitric oxide concentration in the supernatant, which is shown in FIG. 7 .
정상대조군(Con)은 LPS 및 모유 올리고당 혼합물을 처리하지 않은 군이고, 음성대조군은 LPS만 처리한 군이며, 나머지 제조예 1의 모유 올리고당 혼합물 실험군은 LPS와 모유 올리고당 혼합물을 동시처리하였을 때의 540 nm에서의 OD값, 즉 산화질소 함량 (μM)을 측정한 것이다. The normal control group (Con) is a group not treated with LPS and human milk oligosaccharide mixture, the negative control group is a group treated only with LPS, and the other experimental group of human milk oligosaccharide mixture of Preparation Example 1 is 540 when LPS and human milk oligosaccharide mixture are simultaneously treated. OD values in nm, i.e., nitric oxide content (μM) were measured.
LPS만 처리한 음성대조군(LPS)에서 정상대조군(Con) 대비 유의적으로 증가하였고, GL 및 FL 그룹에서는 음성대조군(LPS)에 비하여 오히려 산화질소 농도를 유의적으로 증가시켰으나, GF1, GF2, GF3 및 GF4 그룹에서는 산화질소 생성을 억제하였다. In the negative control group (LPS) treated only with LPS, there was a significant increase compared to the normal control group (Con), and in the GL and FL groups, the concentration of nitric oxide was significantly increased compared to the negative control group (LPS), but GF1, GF2, and GF3 and in the GF4 group, nitric oxide production was suppressed.
산화 질소 생성 억제를 통한 항염증 효과는 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)에서는 나타나지 않았고, 갈락토올리고당 및 2'-푸코실락토오스를 0.44:0.56 내지 0.88:0.12 중량비로 혼합했을 때 음성대조군(LPS) 대비 산화질소 생성을 억제하여 뛰어난 항염증 효과를 나타내었다. The anti-inflammatory effect through inhibition of nitric oxide production was not shown in the galactooligosaccharide-only group (GL) and 2'-fucosyllactose-only group (FL), and galactooligosaccharide and 2'-fucosyllactose were administered at 0.44:0.56 to 0.88 : When mixed at a weight ratio of 0.12, it suppressed the production of nitric oxide compared to the negative control group (LPS) and showed an excellent anti-inflammatory effect.
[실험예 3: 염증성 장질환 동물모델에서의 장 염증 개선 효과 확인][Experimental Example 3: Confirmation of Intestinal Inflammation Improvement Effect in Inflammatory Bowel Disease Animal Model]
1. 장 투과도 억제 효과, 장 내 염증 및 장 길이 확인1. Confirmation of intestinal permeability inhibition effect, intestinal inflammation and intestinal length
실험예 1 및 2에서 단쇄지방산 생성 효과가 뛰어나고, 항염증 효과가 뛰어난 GF2 및 GF3 그룹을 선택하고, 양성대조군으로 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)을 선택하여 염증성 장질환 동물모델에서 장염증 개선 효과를 비교하였다. In Experimental Examples 1 and 2, the GF2 and GF3 groups with excellent short-chain fatty acid production and anti-inflammatory effects were selected, and galactooligosaccharide alone group (GL) and 2'-fucosyllactose alone group (FL) were selected as positive control groups. Selected and compared the effect of improving intestinal inflammation in inflammatory bowel disease animal models.
마우스에 Dextran Sulfate Sodium(DSS)을 투여할 경우 장 상피세포에 손상을 유도하여 장 염증을 유도하고 장 누수를 유발한다. 250~300 g의 수컷 C57BL/6 마우스(6주령)을 충분한 사료와 물이 공급되며 적절한 인공조도로 12시간의 낮, 밤을 조절하였다(am 8:00부터 낮). 그리고 일정한 온도(20~24℃) 및 습도(45~65%)를 유지시켜 주었다. 바뀐 환경에 적응하도록 일주일간 살펴보며 수면주기를 유지하고, 이상행동을 확인하였다. When dextran sulfate sodium (DSS) is administered to mice, it induces damage to intestinal epithelial cells, induces intestinal inflammation, and induces intestinal leakage. Male C57BL/6 mice (6 weeks old) weighing 250-300 g were supplied with sufficient food and water and controlled for 12 hours of daytime and nighttime (daytime from 8:00 am) with appropriate artificial lighting. And a constant temperature (20 ~ 24 ℃) and humidity (45 ~ 65%) were maintained. The sleep cycle was maintained for a week to adapt to the changed environment, and abnormal behavior was checked.
상기와 같이 2주일간 적응 기간을 거친 후, 5일 동안 2% DSS를 음수로 투여하여 장염을 유도하였다. 실험동물은 체중변화가 일정하고 건강한 동물만을 선별하여 임의 배치법에 의해 생리식염수를 투여한 정상대조군(CON), DSS를 투여한 음성대조군(DSS), DSS를 투여한 후 제조예 1의 GF2 또는 GF3 투여 그룹, 양성대조군으로 GL 또는 FL 투여 그룹으로 구분하였다. 상기 그룹 중 제조예 1의 모유 올리고당 혼합물 투여 그룹들은 각각의 모유 올리고당 혼합물을 1 g/kg 농도로 0.1M PBS(pH 7.4)에 녹여 각 200 μL씩 1일 1회 경구투여하였다. 4주의 투여 기간 동안 사료 및 식수의 공급은 자율적으로 이뤄지며(희생전날 저녁까지 공급), 희생 12시간 전 사료 공급을 중단하고, 희생 4시간 전에는 FITC-dextran을 200 μg/g 경구투여하였다. 희생 시에는 CO2를 이용해 마취하며, 이후 복대정맥에서 혈액을 채취하였다. After undergoing an adaptation period for 2 weeks as described above, enteritis was induced by administering 2% DSS in negative water for 5 days. For the experimental animals, only healthy animals with constant weight change were selected, and a normal control group (CON) administered with physiological saline by a random batch method, a negative control group (DSS) administered with DSS, and GF2 or GF3 of Preparation Example 1 after administration of DSS The administration group and the positive control group were divided into GL or FL administration groups. Among the above groups, the groups administered with the human milk oligosaccharide mixture of Preparation Example 1 dissolved each of the human milk oligosaccharide mixtures in 0.1M PBS (pH 7.4) at a concentration of 1 g/kg and orally administered 200 μL each once a day. Feed and drinking water were supplied autonomously during the 4-week administration period (supplied until the evening before sacrifice), feed was stopped 12 hours before sacrifice, and FITC-dextran was orally administered at 200 μg/g 4 hours before sacrifice. At the time of sacrifice, anesthesia was performed using CO 2 , and blood was then collected from the abdominal vena cava.
희생 4시간 전 경구투여한 FITC의 장 투과성을 확인하기 위하여 상기 채취한 혈액을 15℃, 2000 rpm 조건에서 15분간 원심분리하여 얻은 혈청 내 FITC 농도를 측정하기 위하여 96 black well에 옮겨 excitation 490 nm, emission 520 nm으로 형광도를 측정하여 아래 표 2에 나타내었다. In order to confirm the intestinal permeability of FITC orally administered 4 hours before sacrifice, the collected blood was centrifuged at 15 ° C and 2000 rpm for 15 minutes, and transferred to a 96 black well to measure the concentration of FITC in serum obtained by excitation 490 nm, Fluorescence was measured at emission 520 nm and shown in Table 2 below.
또한 상기 마우스의 대장조직에서 MPO 활성을 측정하여 장 내 염증을 수치화하여 아래 표 2에 함께 나타내었다. MPO 활성은 25 mg의 대장조직을 덜어 HTAB buffer(6.8 g/L monobasic potassium phosphate에 8.7 g/L dibasic potassium phosphate를 넣어 pH 6.0을 맞춘 후, 5 g의 hexadecyltrimethylammonium bromide(HTAB)를 1 L의 potassium phosphate buffer (50 mM, pH 6.0)에 녹여 준비한 반응용액)를 25 mg/mL이 되도록 하고, 대장조직을 균질화한 후 4℃, 13400 xg, 6 min외 조건으로 원심분리하여 상등액을 채취하고, 채취한 상등액을 96 well plate에 7 μL씩 3반복으로 분주하고 O-dinisidine solution을 200 μL 혼합하여 450 nm에서 흡광도를 측정하였다. In addition, by measuring MPO activity in the colon tissue of the mouse, intestinal inflammation was quantified and shown in Table 2 below. For MPO activity, take 25 mg of colon tissue, add 8.7 g/L dibasic potassium phosphate to HTAB buffer (6.8 g/L monobasic potassium phosphate, adjust the pH to 6.0, and then add 5 g of hexadecyltrimethylammonium bromide (HTAB) to 1 L of potassium phosphate). Reaction solution prepared by dissolving in buffer (50 mM, pH 6.0)) to 25 mg / mL, homogenize the colon tissue, and centrifuge at 4 ° C, 13400 xg, 6 min and other conditions to collect the supernatant. The supernatant was dispensed in 3 repetitions of 7 μL in a 96 well plate, and 200 μL of O-dinisidine solution was mixed and the absorbance was measured at 450 nm.
또한 각 실험군의 장 길이 사진을 도 8에 나타내었고, 장 무게/길이 비율을 표 2에 함께 나타내었다. In addition, the intestinal length photograph of each experimental group is shown in FIG. 8, and the intestinal weight/length ratio is shown in Table 2 together.
표 2에서 혈장 내 FITC 농도는 DSS 투여로 인한 장누수에 의해 음성대조군(DSS)에서 정상대조군(con)에 비해 2 배 이상 유의적으로 증가하였다. 또한 갈락토올리고당 단독 그룹(GL), 2'-푸코실락토오스 단독 그룹(FL), 그리고 갈락토올리고당과 2'-푸코실락토오스를 혼합하여 항염증 효과가 뛰어났던 GF2 및 GF3 그룹에서는 음성대조군(DSS)에 비해 FITC 농도를 유의적으로 감소시켰고, 특히 GF2 및 GF3 그룹에서는 정상대조군(Con)과 유의차가 없는 수준까지 현저히 감소시켰다. In Table 2, the concentration of FITC in plasma was significantly increased by more than 2 times compared to the normal control group (con) in the negative control group (DSS) due to intestinal leakage due to DSS administration. In addition, the galactooligosaccharide alone group (GL), the 2'-fucosyllactose alone group (FL), and the GF2 and GF3 groups, which had excellent anti-inflammatory effects by mixing galactooligosaccharide and 2'-fucosyllactose, were negative control groups ( DSS), the FITC concentration was significantly reduced, and in particular, in the GF2 and GF3 groups, it was significantly reduced to a level with no significant difference from the normal control group (Con).
한편 표 2에서 MPO 활성은 DSS 투여로 인한 장누수에 의해 음성대조군(DSS)에서 정상대조군(con)에 비해 유의적으로 증가하였다. 또한 갈락토올리고당 단독 그룹(GL), 2'-푸코실락토오스 단독 그룹(FL), 그리고 갈락토올리고당과 2'-푸코실락토오스를 혼합한 GF2 및 GF3 그룹에서는 음성대조군(DSS)에 비해 MPO 활성을 유의적으로 감소하였고, 특히 GF2 및 GF3 그룹에서는 정상대조군(Con)과 유의차가 없는 수준까지 현저히 감소하였다. Meanwhile, in Table 2, MPO activity was significantly increased in the negative control group (DSS) compared to the normal control group (con) due to intestinal leakage due to DSS administration. In addition, in the galactooligosaccharide alone group (GL), the 2'-fucosyllactose alone group (FL), and the GF2 and GF3 groups mixed with galactooligosaccharide and 2'-fucosyllactose, MPO activity was higher than that of the negative control group (DSS). was significantly reduced, especially in the GF2 and GF3 groups, to a level that was not significantly different from that of the normal control group (Con).
한편 도 8에서 DSS 투여로 인해 음성대조군(DSS)의 장 길이는 정상대조군(Con)에 비해 현저히 감소하였고, 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)에서는 음성대조군(DSS)에 비해 장 길이가 어느 정도 증가하였으며, 갈락토올리고당과 2'-푸코실락토오스를 혼합한 GF2 및 GF3 그룹에서는 GL 그룹 및 FL 그룹에 비해서도 장 길이가 현저히 증가하였다. Meanwhile, in FIG. 8, due to DSS administration, the intestinal length of the negative control group (DSS) was significantly reduced compared to the normal control group (Con), and the galacto-oligosaccharide alone group (GL) and 2'-fucosyllactose alone group (FL) were negative. Compared to the control group (DSS), the intestinal length increased to some extent, and in the GF2 and GF3 groups in which galacto-oligosaccharide and 2'-fucosyllactose were mixed, the intestinal length significantly increased compared to the GL and FL groups.
한편 표 2에서 장 무게/길이 비율은 DSS 투여로 인한 장누수에 의해 음성대조군(DSS)에서 정상대조군(con)에 비해 유의적으로 증가하였다. 또한 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)에서는 장 무게/길이 비율에 있어서 음성대조군(DSS)와 유의적인 차이가 없었으나, 갈락토올리고당과 2'-푸코실락토오스를 혼합한 GF2 및 GF3 그룹에서는 음성대조군(DSS)에 비해 장 무게/길이 비율이 정상대조군(Con)과 유의차가 없는 수준까지 현저히 감소되었다. Meanwhile, in Table 2, the intestinal weight/length ratio was significantly increased in the negative control group (DSS) compared to the normal control group (con) due to intestinal leakage due to DSS administration. In addition, there was no significant difference from the negative control group (DSS) in the intestinal weight/length ratio in the galactooligosaccharide-only group (GL) and 2'-fucosyllactose-only group (FL), but galacto-oligosaccharide and 2'-fucose In the GF2 and GF3 groups mixed with room lactose, compared to the negative control group (DSS), the intestinal weight/length ratio was significantly reduced to a level that was not significantly different from that of the normal control group (Con).
2. 분변 내 단쇄지방산 생성량 확인2. Check the amount of short-chain fatty acids produced in feces
상기 각 실험군의 맹장분변을 10 mg 채취한 후 internal standard(Acetic acid-d4), hydrochloric acid, ether를 2:1:4 비율로 넣은 extraction solution을 350 μL씩 분주한 후 균질화하여 준비하고, 이후 4℃, 1000 g, 10 min의 조건으로 원심분리하여 얻은 상등액 80 μL을 insert vial에 넣고 유도체 시약 - 인 MTBSTFA(+1% t-BDMCS)를 각 vial에 16 μL을 첨가하였다. 상기 상등액과 유도체시약을 첨가한 vial을 80℃에서 20분간 반응 후 48 시간 동안 room temperature에서 incubation하여 GC-MS로 아세트산, 프로피온산 및 부티르산 농도를 분석하여 표 3에 나타내었다. After collecting 10 mg of caecal feces from each experimental group, 350 μL of extraction solution containing internal standard (Acetic acid-d4), hydrochloric acid, and ether at a ratio of 2:1:4 was dispensed, homogenized, and prepared. 80 μL of the supernatant obtained by centrifugation at °C, 1000 g, 10 min was placed in an insert vial, and 16 μL of the derivative reagent - MTBSTFA (+1% t-BDMCS) was added to each vial. The vial to which the supernatant and the derivative reagent was added was reacted at 80 ° C. for 20 minutes and then incubated at room temperature for 48 hours. The concentrations of acetic acid, propionic acid and butyric acid were analyzed by GC-MS and are shown in Table 3.
아세트산은 정상대조군(con)에서 1556 mM이었으나, 음성대조군(DSS)에서 1340 mM로 유의적으로 감소하였고, 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)에서는 음성대조군(DSS)과 동등하거나 오히려 감소하는 경향을 나타내었다. 그러나 갈락토올리고당과 2'-푸코실락토오스를 혼합하여 항염증 효과가 뛰어났던 GF2 및 GF3 그룹에서는 음성대조군(DSS)에 비해 유의적으로 아세트산 농도가 증가하였고, 정상대조군(con)보다도 높은 농도를 나타내었다. Acetic acid was 1556 mM in the normal control group (con), but significantly decreased to 1340 mM in the negative control group (DSS), and in the galactooligosaccharide alone group (GL) and 2'-fucosyllactose alone group (FL), the negative control group (DSS) showed a tendency equal to or rather decreasing. However, in the GF2 and GF3 groups, which had excellent anti-inflammatory effects by mixing galacto-oligosaccharide and 2'-fucosyllactose, the concentration of acetic acid increased significantly compared to the negative control group (DSS), and the concentration was higher than that of the normal control group (con). showed up
프로피온산은 정상대조군(con)에서 34.7 mM이었으나, 음성대조군(DSS)에서 22.5 mM로 유의적으로 감소하였고, 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)에서는 음성대조군(DSS)에 비해 프로피온산 함량을 증가시키지 않았다. 그러나 GF2 및 GF3 그룹에서는 음성대조군(DSS)에 비해 유의적으로 프로피온산 농도가 증가하였고, 정상대조군(con)보다도 높은 농도를 나타내었다. Propionic acid was 34.7 mM in the normal control group (con), but significantly decreased to 22.5 mM in the negative control group (DSS), and in the galactooligosaccharide alone group (GL) and 2'-fucosyllactose alone group (FL), the negative control (DSS) did not increase the propionic acid content. However, in the GF2 and GF3 groups, the concentration of propionic acid increased significantly compared to the negative control group (DSS), and showed a higher concentration than that of the normal control group (con).
부티르산은 정상대조군(con)이 음성대조군(DSS)보다 높았으나 유의적인 차이를 나타내지은 않았다. 다만 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)에서는 정상대조군(con)에 비해 유의적으로 낮은 농도를 나타내었고, GF2 및 GF3 그룹에서는 정상대조군(con)과 유의적인 차이가 없었다. 그러나 GF3 그룹은 음성대조군(DSS)보다 유의적으로 높은 부티르산 농도를 나타내었다. Butyric acid was higher in the normal control group (con) than in the negative control group (DSS), but did not show a significant difference. However, in the galacto-oligosaccharide alone group (GL) and 2'-fucosyllactose alone group (FL), the concentration was significantly lower than that of the normal control group (con), and in the GF2 and GF3 groups, the concentration was significantly lower than that of the normal control group (con). there was no significant difference However, the GF3 group showed a significantly higher concentration of butyric acid than the negative control group (DSS).
따라서 장 누수를 나타내는 염증성 장질환 동물모델의 분변 내 단쇄지방산 함량 분석을 통해 갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)은 음성대조군(DSS)에 비해 유의적인 단쇄지방산 생성 증대 효과를 확인하기 어려웠으나, 갈락토올리고당과 2'-푸코실락토오스를 혼합하여 항염증 효과가 뛰어났던 GF2 및 GF3 그룹에서는 음성대조군(DSS)에 비해 유의적으로 단쇄지방산 생성 증대 효과를 나타내고, 정상대조군(con)과 동등하거나 오히려 더 높은 단쇄지방산 생성을 확인할 수 있었다. Therefore, through the analysis of short-chain fatty acid content in the feces of inflammatory bowel disease animal models showing leaky gut, the galacto-oligosaccharide-only group (GL) and the 2'-fucosyllactose-only group (FL) showed significant short-chain compared to the negative control group (DSS). Although it was difficult to confirm the effect of increasing fatty acid production, the GF2 and GF3 groups, which had excellent anti-inflammatory effects by mixing galacto-oligosaccharide and 2'-fucosyllactose, showed a significant increase in short-chain fatty acid production compared to the negative control group (DSS). It was confirmed that the production of short-chain fatty acids was equal to or rather higher than that of the normal control group (con).
3. 장 조직 내 염증인자의 발현량 확인3. Check the expression level of inflammatory factors in intestinal tissue
상기 각 실험군의 장 조직을 이용한 Western blotting을 통해 NF-κB pathway 관련 인자 INF-α, iNOS, COX-2 및 p-NF-κB/NF-κB의 발현을 확인하여 도 9 및 표 4에 나타내었다. 이를 위해 2 mm가량으로 자른 장 조직을 protein extraction buffer인 RIPA buffer를 이용하여 protein을 추출하고 단백질 정량 후, 10% SDS-PAGE로 분리하여 PVDF membrane을 transfer하고, Tris-buffered saline Tween 20 (TBST)에 용해된 5% skim milk로 blocking 후 TNF-α, iNOS, COX-2, p-NF-κB/NF-κB를 확인하였다. TNF-α, iNOS, COX-2의 발현량은 GAPDH에 대한 상대 발현 배수로 나타내었다. The expression of NF-κB pathway related factors INF-α, iNOS, COX-2, and p-NF-κB/NF-κB was confirmed through Western blotting using the intestinal tissue of each experimental group, and shown in FIG. 9 and Table 4. . To this end, protein was extracted from intestinal tissue cut into pieces of about 2 mm using RIPA buffer, a protein extraction buffer, and after protein quantification, separated by 10% SDS-PAGE, PVDF membrane transfer, and Tris-buffered saline Tween 20 (TBST) After blocking with 5% skim milk dissolved in , TNF-α, iNOS, COX-2, and p-NF-κB/NF-κB were confirmed. Expression levels of TNF-α, iNOS, and COX-2 were expressed as relative expression folds for GAPDH.
(배수)p-NF-κB/NF-κB
(Drainage)
음성대조군(LPS)은 정상대조군(Con) 대비 TNF-α, iNOS, COX-2 및 p-NF-κB/NF-κB 염증 인자의 발현이 유의적으로 증가하였다. Expressions of TNF-α, iNOS, COX-2, and p-NF-κB/NF-κB inflammatory factors were significantly increased in the negative control group (LPS) compared to the normal control group (Con).
갈락토올리고당 단독 그룹(GL) 및 2'-푸코실락토오스 단독 그룹(FL)은 TNF-α, iNOS, COX-2 및 p-NF-κB/NF-κB 모든 염증 인자에서 음성대조군(DSS)과 유의적 차이를 나타내지 않았다. 다만 GL그룹은 FL그룹에 비해 다소 낮은 염증 인자 발현을 나타내었다. 한편 갈락토올리고당과 2'-푸코실락토오스를 혼합한 GF2 및 GF3 그룹에서는 음성대조군(DSS)에 비해 유의적으로 모든 염증 인자의 발현이 억제되었고, 정상대조군(Con)과 동일한 수준을 나타내었다. The galacto-oligosaccharide alone group (GL) and 2'-fucosyllactose alone group (FL) were compared to the negative control group (DSS) in TNF-α, iNOS, COX-2 and p-NF-κB/NF-κB all inflammatory factors. No significant difference was shown. However, the GL group showed slightly lower expression of inflammatory factors than the FL group. On the other hand, in the GF2 and GF3 groups in which galacto-oligosaccharide and 2'-fucosyllactose were mixed, the expression of all inflammatory factors was significantly suppressed compared to the negative control group (DSS), and showed the same level as the normal control group (Con).
[제조예 2][Production Example 2]
제조예 1의 모유 올리고당 혼합물 중에서 항염증 효과가 뛰어난 GF2 및 GF3 그룹에 시알릴락토오스를 추가했을 때의 단쇄지방산 생성 증가 및 항염증 효과의 상승 효과를 확인하기 위해 아래 표 5의 비율로 모유 올리고당 혼합물을 제조하였다. 상기 시알릴락토오스는 3'-시알릴락토오스 및 6'-시알릴락토오스가 1:1 중량비로 혼합된 것을 사용하였다. In order to confirm the synergistic effect of increased short-chain fatty acid production and anti-inflammatory effect when sialyllactose was added to the GF2 and GF3 groups, which had excellent anti-inflammatory effects in the human milk oligosaccharide mixture of Preparation Example 1, the human milk oligosaccharide mixture was prepared in the ratio shown in Table 5 below. was manufactured. As the sialyllactose, a mixture of 3'-sialyllactose and 6'-sialyllactose in a weight ratio of 1:1 was used.
[실험예 4: 시알릴락토오스 함유 모유 올리고당 혼합물의 인간분변시스템에서의 장내 단쇄 지방산 생성량 확인][Experimental Example 4: Confirmation of Short-Chain Fatty Acid Production in Human Fecal System of Sialyllactose-Containing Human Milk Oligosaccharide Mixture]
SL1 그룹을 제외한 모든 모유 올리고당 또는 그 혼합물 그룹은 1 mg/mL로 혼합하여 실험예 1과 동일한 방법으로 실험하여 그 결과를 표 6에 나타내었다. SL1 그룹은 저농도 시알릴락토오스를 투여한 것으로 SL2의 1/10인 50 ㎍/mL로 혼합한 것만 차이가 있었다. 상기 SL1의 투여 농도는 GF2S 및 GF3S 그룹에 포함된 시알릴락토오스의 농도와 동일하다. All human milk oligosaccharides or mixtures thereof except for the SL1 group were mixed at 1 mg/mL and tested in the same manner as in Experimental Example 1, and the results are shown in Table 6. The SL1 group was administered low-concentration sialyllactose, with a difference only in that it was mixed at 50 μg/mL, 1/10 of SL2. The dose of SL1 was the same as that of sialyllactose in the GF2S and GF3S groups.
표 4의 모유 올리고당 혼합물을 처리하지 않고 분변 슬러리만 배양한 음성대조군은 "fecal"로 표시하고, 표 4의 모유 올리고당 혼합물을 처리한 분변 슬러리의 아세트산, 프로피온산 및 부티르산 함량(mM)을 각각 표 6에 나타내었다. The negative control group in which only the fecal slurry was cultured without treatment with the human milk oligosaccharide mixture of Table 4 was indicated as "fecal", and the acetic acid, propionic acid and butyric acid contents (mM) of the fecal slurry treated with the human milk oligosaccharide mixture of Table 4 were respectively shown in Table 6 shown in
표 6에서 아세트산은 음성대조군(fecal) 대비 SL2, GF2, GF3, GF2S 및 GF3S 그룹에서 유의적으로 증가하였다. 즉 갈락토올리고당 단독 그룹(GL), 2'-푸코실락토오스 단독 그룹(FL), 시알릴락토오스 저농도 그룹(SL1)에서는 아세트산 생성에 유의적인 증가가 없었다. In Table 6, acetic acid was significantly increased in the SL2, GF2, GF3, GF2S and GF3S groups compared to the negative control group (fecal). That is, there was no significant increase in acetic acid production in the galacto-oligosaccharide alone group (GL), the 2'-fucosyllactose alone group (FL), and the low sialyllactose concentration group (SL1).
시알릴락토오스를 20배 높여 고농도로 투여한 시알릴락토오스 고농도 그룹(SL2) 및 모유 올리고당 혼합물 중에서 갈락토올리고당 및 2'푸코실락토오스를 혼합한 GF2 및 GF3 그룹에서 음성대조군(fecal) 대비 아세트산 생성이 유의적으로 증가하였다. Acetic acid production was higher in the sialyllactose high concentration group (SL2), in which sialyllactose was increased 20 times and administered at a high concentration, and in the GF2 and GF3 groups in which galactooligosaccharide and 2'fucosyllactose were mixed in the human milk oligosaccharide mixture, compared to the negative control group (fecal). increased significantly.
GF2 그룹 및 GF3 그룹에 각각 시알릴락토오스를 저농도로 추가한 GF2S 및 GF3S 그룹은 GF2 그룹 및 GF3 그룹에 비해 아세트산 생성량이 유의적으로 증가하였고, 시알릴락토오스 고농도 그룹(SL2)에 비해서도 높은 생성량을 나타내었다. The GF2S and GF3S groups, in which low concentrations of sialyllactose were added to the GF2 and GF3 groups, respectively, showed a significant increase in acetic acid production compared to the GF2 and GF3 groups, and higher production than the high-concentration sialyllactose group (SL2). was
표 6에서 프로피온산은 음성대조군(fecal) 대비 GL, SL2, GF3, GF2S 및 GF3S그룹에서 유의적으로 증가하였다. 2'-푸코실락토오스 단독 그룹(FL), 시알릴락토오스 저농도 그룹(SL1)에서는 아세트산 생성에 유의적인 증가가 없었다. In Table 6, propionic acid was significantly increased in the GL, SL2, GF3, GF2S and GF3S groups compared to the negative control group (fecal). There was no significant increase in acetic acid production in the 2'-fucosyllactose alone group (FL) and the sialyllactose low concentration group (SL1).
시알릴락토오스를 20배 높여 고농도로 투여한 시알릴락토오스 고농도 그룹(SL2), 모유 올리고당 혼합물 중에서 갈락토올리고당 및 2'푸코실락토오스를 혼합한 GF3 그룹, 그리고 GF2 그룹 및 GF3 그룹에 각각 시알릴락토오스를 저농도로 추가한 GF2S 및 GF3S 그룹은 음성대조군(fecal) 대비 아세트산 생성이 유의적으로 증가하였다. Sialyllactose high concentration group (SL2) in which sialyllactose was increased 20 times and administered at high concentration, GF3 group in which galactooligosaccharide and 2'fucosyllactose were mixed in human milk oligosaccharide mixture, and sialyllactose in GF2 and GF3 groups, respectively The GF2S and GF3S groups added with a low concentration showed a significant increase in acetic acid production compared to the negative control group (fecal).
표 6에서 부티르산은 음성대조군(fecal) 대비 모든 모유 올리고당 단독 및 혼합 그룹에서 유의적으로 증가하였다. 특히 시알릴락토오스 고농도 그룹(SL2), 갈락토올리고당 및 2'-푸코실락토오스를 혼합한 GF2 및 GF3 그룹, 그리고 갈락토올리고당, 2'-푸코실락토오스 및 시알릴락토오스를 혼합한, GF2S 및 GF3S 그룹은 갈락토올리고당 단독 그룹(GL) 및 시알릴락토오스 저농도 그룹(SL1)에 비해서 부티르산 생성 농도를 유의적으로 증가시켰다. In Table 6, butyric acid was significantly increased in all human milk oligosaccharide alone and mixed groups compared to the negative control group (fecal). In particular, sialyllactose high concentration group (SL2), GF2 and GF3 groups mixed with galactooligosaccharide and 2'-fucosyllactose, and GF2S and GF3S mixed with galactooligosaccharide, 2'-fucosyllactose and sialyllactose The group significantly increased the concentration of butyric acid production compared to the galacto-oligosaccharide alone group (GL) and the low-sialyllactose group (SL1).
특히 GF2S 및 GF3S 그룹은 산업적 용도로 사용함에 있어서 가격이 높은 2'-푸코실락토오스의 함량을 낮추고, 시알릴락토오스를 저농도로 투여했음에도 2'-푸코실락토오스 단독 그룹(FL) 또는 시알릴락토오스 고농도 그룹(SL2)에 비해 현저히 높은 장내 단쇄 지방산 생성 효과를 나타낸다는 점에서 활용 가능성이 높다. In particular, the GF2S and GF3S groups lower the content of expensive 2'-fucosyllactose in industrial use, and even though sialyllactose is administered at a low concentration, the 2'-fucosyllactose alone group (FL) or high concentration of sialyllactose Compared to the group (SL2), it has a high possibility of utilization in that it shows a significantly higher effect on short-chain fatty acids production in the intestine.
[제조예 3][Production Example 3]
제조예 1의 모유 올리고당 혼합물 중에서 항염증 효과가 뛰어난 GF2 및 GF3 그룹을 각각 모유 올리고당을 함유하지 않은 기존 조제분유 100 중량부에 0.5 중량비로 혼합하였다. 모유 올리고당을 함유하지 않은 기존 조제분유는 IF1 그룹, GF2를 혼합한 조제분유는 IF2 그룹, GF3를 혼합한 조제분유는 IF3 그룹으로 나타내었다. 상기 조제분유를 첨가하지 않고 LPS만 투여한 음성대조군은 LPS로, 상기 조제분유 및 LPS를 모두 투여하지 않은 정상대조군은 Con으로 나타내었다. Among the human milk oligosaccharide mixtures of Preparation Example 1, the GF2 and GF3 groups, which had excellent anti-inflammatory effects, were each mixed with 100 parts by weight of conventional milk powder containing no human milk oligosaccharides at a weight ratio of 0.5. Conventional milk powder containing no human milk oligosaccharides was represented as the IF1 group, formula mixed with GF2 as the IF2 group, and formula mixed with GF3 as the IF3 group. The negative control group in which only LPS was administered without adding the formula was denoted as LPS, and the normal control group in which both the formula and LPS were not administered was denoted as Con.
[실험예 5: 모유올리고당 혼합물 함유 조제분유의 장 내 염증 억제 및 장관 장벽 보호 효과 확인][Experimental Example 5: Confirmation of Inhibition of Intestinal Inflammation and Intestinal Barrier Protection Effect of Formulated Milk Containing Human Milk Oligosaccharide Mixture]
1. 손상된 장점막 장벽의 TEER(rans epithelial electrical resistance) 증대 효과 확인1. Check the effect of increasing the TEER (rans epithelial electrical resistance) of the damaged intestinal barrier
공동배양 모델을 조성하기 위해 transwell plate를 이용하며, insert 윗부분인 apical side에는 Caco-2를 1×105 cell/mL의 밀도로 분주하여 10% FBS를 포함한 DMEM low glucose media에서 배양하고 아랫부분인 basolateral side는 세포 없이 FBS가 포함되지 않은 DMEM low glucose 배지를 분주하여 monolayer를 형성할 수 있도록 21일간 배양하여 분화를 유도하였다. 배양한 Caco-2의 안정적인 monolayer 형성 여부를 확인하기 위하여 trans-epithelial electrical resistance (TEER)값을 3일 간격으로 21일간 측정하였다. THP-1 배양은 RPMI media에 10% inactivated FBS와 40 nM의 phorbol 12-myristate 13-actate(PMA)를 포함하여 1×105 cell/mL로 12 well plate에 1 mL씩 분주한 후 72시간 37℃, 5% CO2 조건에서 배양하였다. Caco-2 배양 21일 차에 분화된 THP-1 macrophage가 있는 12 well plate에 Caco-2가 배양된 insert well을 삽입하여 공동 배양을 시작하였다. 9~12일 차 사이에 최고점을 찍은 TEER값이 21일 차에 평균 600 Ω㎠를 유지하는 것을 확인하고, 배양 21일 차에 제조예 3의 IF1, IF2 및 IF3 그룹을 1 mg/mL의 농도로 처리하였으며 정상대조군 (Con)과 음성대조군 (LPS)에는 DMEM low glucose 배지를 분주하였다. Basolateral side에 위치한 인간유래 면역세포인 THP-1에는 정상대조군 (Con)을 제외한 모든 실험군에 1 μg/mL LPS를 처리하여 24시간 배양하였다. A transwell plate is used to create a co-culture model, and Caco-2 is dispensed at a density of 1×10 5 cells/mL on the apical side, which is the upper part of the insert, and cultured in DMEM low glucose media containing 10% FBS. The basolateral side was cultured for 21 days to form a monolayer by dispensing DMEM low glucose medium without FBS without cells to induce differentiation. In order to confirm whether the cultured Caco-2 formed a stable monolayer, trans-epithelial electrical resistance (TEER) values were measured every 3 days for 21 days. THP-1 culture was carried out in RPMI media containing 10% inactivated FBS and 40 nM of phorbol 12-myristate 13-actate (PMA) at a concentration of 1×10 5 cells/mL by dispensing 1 mL each into a 12-well plate for 72
정상대조군(Con) 대비 각 실험군의 TEER 값의 변화를 %로 아래 표 7에 나타내었다. The change in TEER value of each experimental group compared to the normal control group (Con) is shown in Table 7 below in %.
음성대조군(LPS)은 염증 유발로 인해 monolayer가 붕괴되어 TEER 값이 낮아지기 때문에 정상대조군(Con)에 비해 TEER가 유의적으로 감소하였다. 기존 조제분유(IF1)은 음성대조군(LPS)에 비해서 TEER가 증가하는 경향을 나타내었으나 유의적인 차이는 없었고, 모유 올리고당을 혼합한 IF2 및 IF3그룹에서는 음성대조군(LPS)에 비해서 TEER가 유의적으로 증가함을 확인하였다. In the negative control group (LPS), TEER was significantly reduced compared to the normal control group (Con) because the monolayer was collapsed due to inflammation and the TEER value was lowered. Compared to the negative control group (LPS), the existing formula (IF1) showed a tendency to increase TEER, but there was no significant difference. confirmed to increase.
2. 염증 인자 발현 억제 효과 확인2. Confirmation of inhibitory effect on inflammatory factor expression
LPS로 유도한 염증을 각 분유 제품이 억제하는지 확인하기 위해 공동배양한 Caco-2를 qPCR을 이용해 염증 인자 TNF-α, IL-6, iNOS, COX-2 및 IL-8의 발현 억제 효과를 확인하여 아래 표 8에 나타내었다. qPCR을 이용하기 위해 트리졸(trizol)을 이용하여 세포막을 깬 후 mRNA를 추출하였다. 이후 추출된 mRNA양을 nanodrop을 이용해 동량으로 정량한 후 LeGene premium express first-strand cDNA synthesis system을 이용해 cDNA를 합성하였다. cDNA를 HiPi real-time PCR 2x master mix SYBR green mix와 섞어 PCR reaction solution을 만들어 이를 qPCR에 사용하였다. 상기 발현 억제 효과는 정상대조군(Con)의 발현량을 1로 했을 때의 상대 발현량을 배수로 나타내었다. In order to determine whether each milk powder product suppresses LPS-induced inflammation, co-cultured Caco-2 is used to confirm the suppression of the expression of inflammatory factors TNF-α, IL-6, iNOS, COX-2, and IL-8 using qPCR. and are shown in Table 8 below. In order to use qPCR, mRNA was extracted after breaking the cell membrane using trizol. Afterwards, the amount of extracted mRNA was quantified in the same amount using nanodrop, and cDNA was synthesized using LeGene premium express first-strand cDNA synthesis system. cDNA was mixed with HiPi real-time PCR 2x master mix SYBR green mix to create a PCR reaction solution, which was used for qPCR. The expression suppression effect was expressed as a multiple of the relative expression level when the expression level of the normal control group (Con) was set to 1.
음성대조군(LPS)은 정상대조군(Con) 대비 TNF-α, IL-6, COX-2 및 IL-8 염증 인자의 발현이 유의적으로 증가하였고, iNOS의 경우는 유의차는 없으나 증가하는 경향을 나타내었다. In the negative control group (LPS), the expression of TNF-α, IL-6, COX-2, and IL-8 inflammatory factors increased significantly compared to the normal control group (Con), and in the case of iNOS, there was no significant difference, but there was a tendency to increase. was
모유 올리고당 혼합물을 함유하지 않은 기존 조제분유 그룹(IF1)은 음성대조군(LPS) 대비 TNF-α, IL-6, iNOS, COX-2 및 IL-8 모든 염증 인자의 발현을 유의적으로 감소시켰고, 모유 올리고당 혼합물을 함유한 IF2 및 IF3 그룹은 IF1 그룹에 비해 NF-α, IL-6, COX-2 및 IL-8 염증 인자의 발현을 더욱 더 유의적으로 감소시켰다. Compared to the negative control group (LPS), the conventional formula group (IF1), which did not contain the human milk oligosaccharide mixture, significantly reduced the expression of all inflammatory factors such as TNF-α, IL-6, iNOS, COX-2, and IL-8, The IF2 and IF3 groups containing the human milk oligosaccharide mixture significantly reduced the expression of inflammatory factors NF-α, IL-6, COX-2 and IL-8 compared to the IF1 group.
3. 장관 장벽 보호 효과 확인3. Confirm intestinal barrier protection effect
장관 장벽 보호 효과를 확인하기 위하여 공동배양한 Caco-2에서의 Tight junction 인자인 Claudin-1, Occludin 및 ZO-1) 발현을 qPCR로 확인하여 아래 표 9에 나타내었다. 상기 발현 억제 효과는 정상대조군(Con)의 발현량을 1로 했을 때의 상대 발현량을 배수로 나타내었다. In order to confirm the intestinal barrier protective effect, the expression of tight junction factors Claudin-1, Occludin and ZO-1) in the co-cultured Caco-2 was confirmed by qPCR and is shown in Table 9 below. The expression suppression effect was expressed as a multiple of the relative expression level when the expression level of the normal control group (Con) was set to 1.
음성대조군(LPS)는 정상대조군(Con) 대비 Occludin 발현이 유의적으로 증가하였고, Claudin-1 및 ZO-1에서는 유의차는 없으나 증가하는 경향을 나타내었다. The negative control group (LPS) showed a significant increase in Occludin expression compared to the normal control group (Con), and there was no significant difference in Claudin-1 and ZO-1, but showed an increasing tendency.
모유 올리고당 혼합물을 함유하지 않은 기존 조제분유 그룹(IF1)은 음성대조군(LPS) 대비 Claudin-1을 유의적으로 증가시키고, Occludin은 유의적으로 감소시키며, ZO-1에는 영향을 주지 않았다. 그러나 모유 올리고당 혼합물을 함유한 IF2 및 IF3 그룹은 음성대조군(LPS)는 물론 정상대조군(Con)에 비해 Claudin-1, Occludin 및 ZO-1 모두 유의적으로 증가시켜서, 장관 장벽 보호 효과가 뛰어남을 확인하였다. Compared to the negative control group (LPS), the conventional formula group (IF1) without human milk oligosaccharide mixture significantly increased Claudin-1, significantly decreased Occludin, and had no effect on ZO-1. However, the IF2 and IF3 groups containing the human milk oligosaccharide mixture significantly increased Claudin-1, Occludin, and ZO-1 compared to the negative control group (LPS) as well as the normal control group (Con), confirming that the intestinal barrier protective effect was excellent. did
상기 실험예들의 통계처리는 students t-test (p<0.05) 방법으로 수행하였고, 실험결과에서 a, b, c, d, e는 각각 p value < 0.05에서 유의적 차이가 있음을 의미한다.Statistical treatment of the above experiments was performed by the students t-test ( p <0.05) method, and in the experimental results, a, b, c, d, and e each indicate a significant difference at p value < 0.05.
아래 본 발명의 모유 올리고당 혼합물을 함유하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Examples of formulation of a composition containing the human milk oligosaccharide mixture of the present invention are described below, but the present invention is not intended to be limited thereto, but only specifically described.
제제예 1. 산제의 제조Formulation Example 1. Preparation of powder
제조예 1의 GF2, GF3, 또는 제조예 2의 GF2S, GF3S 500 ㎎GF2, GF3 of Preparation Example 1, or GF2S, GF3S of Preparation Example 2 500 mg
유당 100 ㎎
탈크 10 ㎎
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.A powder is prepared by mixing the above ingredients and filling them in an airtight bag.
제제예 2. 정제의 제조Formulation Example 2. Preparation of tablets
제조예 1의 GF2, GF3, 또는 제조예 2의 GF2S, GF3S 300 ㎎GF2, GF3 of Preparation Example 1, or GF2S, GF3S of Preparation Example 2 300 mg
옥수수전분 100 ㎎
유당 100 ㎎
스테아린산 마그네슘 2 ㎎
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above ingredients, tablets are prepared by tableting according to a conventional tablet manufacturing method.
제제예 3. 캅셀제의 제조Formulation Example 3. Preparation of capsule formulation
제조예 1의 GF2, GF3, 또는 제조예 2의 GF2S, GF3S 200 ㎎200 mg of GF2, GF3 of Preparation Example 1, or GF2S and GF3S of Preparation Example 2
결정성 셀룰로오스 3 ㎎3 mg of crystalline cellulose
락토오스 14.8 ㎎Lactose 14.8 mg
마그네슘 스테아레이트 0.2 ㎎Magnesium stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.Capsules are prepared by mixing the above ingredients and filling them into gelatin capsules according to a conventional capsule preparation method.
제제예 4. 액제의 제조Formulation Example 4. Preparation of liquid formulation
제조예 1의 GF2, GF3, 또는 제조예 2의 GF2S, GF3S 4 g4 g of GF2, GF3 of Preparation Example 1, or GF2S and GF3S of Preparation Example 2
이성화당 10 gIsomerized sugar 10 g
만니톨 5 g5 g mannitol
정제수 적량Appropriate amount of purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100g으로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.According to the conventional liquid formulation manufacturing method, each component is dissolved in purified water, lemon flavor is added in an appropriate amount, the above components are mixed, and then purified water is added to adjust the total amount to 100g, and then filled into a brown bottle to be sterilized. to prepare a liquid.
제제예 5. 과립제의 제조Formulation Example 5. Preparation of granules
제조예 1의 GF2, GF3, 또는 제조예 2의 GF2S, GF3S 1,000 ㎎GF2, GF3 of Preparation Example 1, or GF2S, GF3S of Preparation Example 2 1,000 mg
비타민 혼합물 적량Appropriate amount of vitamin mixture
비타민 A 아세테이트 70 ㎍Vitamin A
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎Vitamin B1 0.13 mg
비타민 B2 0.15 ㎎Vitamin B2 0.15 mg
비타민 B6 0.5 ㎎Vitamin B6 0.5 mg
비타민 B12 0.2 ㎍Vitamin B12 0.2 μg
비타민 C 10 ㎎
비오틴 10 ㎍10 μg of biotin
니코틴산아미드 1.7 ㎎Nicotinamide 1.7 mg
엽산 50 ㎍Folic acid 50 μg
판토텐산 칼슘 0.5 ㎎Calcium Pantothenate 0.5 mg
무기질 혼합물 적량Appropriate amount of mineral mixture
황산제1철 1.75 ㎎Ferrous sulfate 1.75 mg
산화아연 0.82 ㎎Zinc Oxide 0.82 mg
탄산마그네슘 25.3 ㎎Magnesium Carbonate 25.3 mg
제1인산칼륨 15 ㎎Potassium Phosphate Monobasic 15 mg
제2인산칼슘 55 ㎎Dibasic Calcium Phosphate 55 mg
구연산칼륨 90 ㎎
탄산칼슘 100 ㎎
염화마그네슘 24.8 ㎎Magnesium Chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 과립제에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 과립제 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강기능식품 조성물 제조에 사용할 수 있다.Although the composition ratio of the above vitamin and mineral mixture was prepared by mixing ingredients suitable for granules in a preferred embodiment, the mixing ratio may be arbitrarily modified, and after mixing the above ingredients according to a conventional granule manufacturing method, It can be prepared and used for preparing a health functional food composition according to a conventional method.
제제예 6. 기능성 음료의 제조Formulation Example 6. Preparation of functional beverage
제조예 1의 GF2, GF3, 또는 제조예 2의 GF2S, GF3S 1,000 ㎎GF2, GF3 of Preparation Example 1, or GF2S, GF3S of Preparation Example 2 1,000 mg
구연산 1,000 ㎎Citric Acid 1,000 mg
올리고당 100 g100 g of oligosaccharides
매실농축액 2 g2 g plum concentrate
타우린 1 g1 g of taurine
정제수를 가하여 전체 900 ㎖Add purified water to make a total of 900 ml
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1 시간 동안 85 ℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 기능성 음료 조성물 제조에 사용한다. After mixing the above ingredients according to the normal health drink manufacturing method, stirring and heating at 85 ° C. for about 1 hour, the resulting solution is filtered and collected in a sterilized 2 L container, sealed and sterilized, and then refrigerated. It is used for preparing the functional beverage composition of the present invention.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 수요계층, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is a mixture of ingredients suitable for a relatively favorite beverage in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the class of demand, the country of demand, and the purpose of use.
Claims (33)
상기 갈락토올리고당 및 2'-푸코실락토오스는 60:40 내지 85:15 중량비인 것을 특징으로 하는 장 건강, 장 기능 또는 장관 면역 개선용 조성물.According to claim 1,
The composition for improving intestinal health, intestinal function or intestinal immunity, characterized in that the galacto-oligosaccharide and 2'-fucosyllactose have a weight ratio of 60:40 to 85:15.
상기 갈락토올리고당은 총 갈락토올리고당 중에서 4'-갈락토실락토오스 10-20 중량% 및 6'-갈락토실락토오스 0.05-0.5 중량%를 포함하는 것을 특징으로 하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물.According to claim 2,
The galacto-oligosaccharide comprises 10-20% by weight of 4'-galactosyllactose and 0.05-0.5% by weight of 6'-galactosyllactose out of the total galacto-oligosaccharide. Food composition for improvement.
상기 모유 올리고당 혼합물은 시알릴락토오스를 추가로 포함하는 것을 특징으로 하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물.According to claim 1,
The human milk oligosaccharide mixture is a food composition for improving intestinal health, intestinal function or intestinal immunity, characterized in that it further comprises sialyllactose.
상기 시알릴락토오스는 상기 갈락토올리고당 및 2'-푸코실락토오스의 합 100 중량부에 대하여 1-10 중량부 포함하는 것을 특징으로 하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물.According to claim 4,
The sialyllactose is a food composition for improving intestinal health, intestinal function or intestinal immunity, characterized in that it comprises 1-10 parts by weight based on 100 parts by weight of the sum of the galactooligosaccharide and 2'-fucosyllactose.
상기 조성물은 장내 단쇄 지방산(short chain fatty acid)의 함량을 증가시키는 것을 특징으로 하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물.According to any one of claims 1 to 5,
The composition is a food composition for improving intestinal health, intestinal function or intestinal immunity, characterized in that it increases the content of short chain fatty acids in the intestine.
상기 단쇄 지방산은 아세트산, 부티르산 및 프로피온산 중에서 선택되는 어느 하나 이상인 것을 특징으로 하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물.According to claim 6,
The short-chain fatty acid is a food composition for improving intestinal health, intestinal function or intestinal immunity, characterized in that at least one selected from acetic acid, butyric acid and propionic acid.
상기 조성물은 장내 유익균의 증식 또는 생장을 촉진하거나, 장내 유해균의 증식 또는 생장을 억제하는 것을 특징으로 하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물.According to any one of claims 1 to 5,
The composition is a food composition for improving intestinal health, intestinal function or intestinal immunity, characterized in that it promotes the proliferation or growth of beneficial bacteria in the intestine or inhibits the proliferation or growth of harmful bacteria in the intestine.
상기 조성물은 배변 기능을 개선하는 것을 특징으로 하는 것을 특징으로 하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물.According to any one of claims 1 to 5,
The composition is a food composition for improving intestinal health, intestinal function or intestinal immunity, characterized in that to improve bowel function.
상기 조성물은 TNF-α의 분비를 억제하는 것을 특징으로 하는 특징으로 하는을 특징으로 하는 장 건강, 장 기능 또는 장관 면역 개선용 식품 조성물.According to any one of claims 1 to 5,
The composition is a food composition for improving intestinal health, intestinal function or intestinal immunity, characterized in that for inhibiting the secretion of TNF-α.
상기 갈락토올리고당 및 2'-푸코실락토오스는 60:40 내지 85:15 중량비인 것을 특징으로 하는 장 염증 예방 또는 개선용 식품 조성물.According to claim 11,
The galacto-oligosaccharide and 2'-fucosyllactose are a food composition for preventing or improving intestinal inflammation, characterized in that the weight ratio of 60:40 to 85:15.
상기 갈락토올리고당은 총 갈락토올리고당 중에서 4'-갈락토실락토오스 10-20 중량% 및 6'-갈락토실락토오스 0.05-0.5 중량%를 포함하는 것을 특징으로 하는 장 염증 예방 또는 개선용 식품 조성물.According to claim 12,
The galactooligosaccharide is a food composition for preventing or improving intestinal inflammation, characterized in that it comprises 10-20% by weight of 4'-galactosyllactose and 0.05-0.5% by weight of 6'-galactosyllactose out of the total galacto-oligosaccharide. .
상기 모유 올리고당 혼합물은 시알릴락토오스를 추가로 포함하는 것을 특징으로 하는 장 건강 개선용 또는 장 기능 개선용 식품 조성물.According to claim 11,
The human milk oligosaccharide mixture is a food composition for improving intestinal health or improving intestinal function, characterized in that it further comprises sialyllactose.
상기 시알릴락토오스는 상기 갈락토올리고당 및 2'-푸코실락토오스의 합 100 중량부에 대하여 1-10 중량부 포함하는 것을 특징으로 하는 장 염증 예방 또는 개선용 식품 조성물.According to claim 14,
The sialyllactose is a food composition for preventing or improving intestinal inflammation, characterized in that it comprises 1-10 parts by weight based on 100 parts by weight of the sum of the galactooligosaccharide and 2'-fucosyllactose.
상기 조성물은 장내 단쇄 지방산(short chain fatty acid)의 함량을 증가시키는 것을 특징으로 하는 장 염증 예방 또는 개선용 식품 조성물.According to any one of claims 11 to 15,
The composition is a food composition for preventing or improving intestinal inflammation, characterized in that to increase the content of short chain fatty acids (short chain fatty acid) in the intestine.
상기 단쇄 지방산은 아세트산, 부티르산 및 프로피온산 중에서 선택되는 어느 하나 이상인 것을 특징으로 하는 장 염증 예방 또는 개선용 식품 조성물.According to claim 16,
The short-chain fatty acid is a food composition for preventing or improving intestinal inflammation, characterized in that at least one selected from acetic acid, butyric acid and propionic acid.
상기 조성물은 장내 유익균의 증식 또는 생장을 촉진하거나, 장내 유해균의 증식 또는 생장을 억제하는 것을 특징으로 하는 장 염증 예방 또는 개선용 식품 조성물.According to any one of claims 11 to 15,
The composition is a food composition for preventing or improving intestinal inflammation, characterized in that it promotes the proliferation or growth of beneficial bacteria in the intestine or inhibits the proliferation or growth of harmful bacteria in the intestine.
상기 조성물은 배변 기능을 개선하는 것을 특징으로 하는 것을 특징으로 하는 장 염증 예방 또는 개선용 식품 조성물.According to any one of claims 11 to 15,
The composition is a food composition for preventing or improving intestinal inflammation, characterized in that to improve bowel function.
상기 조성물은 TNF-α의 분비를 억제하는 것을 특징으로 하는 특징으로 하는을 특징으로 하는 장 염증 예방 또는 개선용 식품 조성물.According to any one of claims 11 to 15,
The composition is a food composition for preventing or improving intestinal inflammation, characterized in that for inhibiting the secretion of TNF-α.
상기 갈락토올리고당 및 2'-푸코실락토오스는 60:40 내지 85:15 중량비인 것을 특징으로 하는 염증성 장질환 치료 또는 예방용 약학 조성물.According to claim 21,
The galacto-oligosaccharide and 2'-fucosyllactose is a pharmaceutical composition for treating or preventing inflammatory bowel disease, characterized in that the weight ratio of 60:40 to 85:15.
상기 갈락토올리고당은 총 갈락토올리고당 중에서 4'-갈락토실락토오스 10-20 중량% 및 6'-갈락토실락토오스 0.05-0.5 중량%를 포함하는 것을 특징으로 하는 염증성 장질환 치료 또는 예방용 약학 조성물.The method of claim 22,
The galactooligosaccharide comprises 10-20% by weight of 4'-galactosyllactose and 0.05-0.5% by weight of 6'-galactosyllactose out of the total galacto-oligosaccharide. composition.
상기 모유 올리고당 혼합물은 시알릴락토오스를 추가로 포함하는 것을 특징으로 하는 염증성 장질환 치료 또는 예방용 약학 조성물.According to claim 21,
The human milk oligosaccharide mixture is a pharmaceutical composition for treating or preventing inflammatory bowel disease, characterized in that it further comprises sialyllactose.
상기 시알릴락토오스는 상기 갈락토올리고당 및 2'-푸코실락토오스의 합 100 중량부에 대하여 1-10 중량부 포함하는 것을 특징으로 하는 염증성 장질환 치료 또는 예방용 약학 조성물.According to claim 24,
The pharmaceutical composition for treating or preventing inflammatory bowel disease, characterized in that the sialyllactose comprises 1-10 parts by weight based on 100 parts by weight of the sum of the galactooligosaccharide and 2'-fucosyllactose.
상기 조성물은 장내 단쇄 지방산(short chain fatty acid)의 함량을 증가시키는 것을 특징으로 하는 염증성 장질환 치료 또는 예방용 약학 조성물.The method of any one of claims 21 to 25,
The composition is a pharmaceutical composition for treating or preventing inflammatory bowel disease, characterized in that to increase the content of short chain fatty acids (short chain fatty acid) in the intestine.
상기 단쇄 지방산은 아세트산, 부티르산 및 프로피온산 중에서 선택되는 어느 하나 이상인 것을 특징으로 하는 염증성 장질환 치료 또는 예방용 약학 조성물.The method of claim 26,
The short-chain fatty acid is a pharmaceutical composition for treating or preventing inflammatory bowel disease, characterized in that any one or more selected from acetic acid, butyric acid and propionic acid.
상기 조성물은 장내 유익균의 증식 또는 생장을 촉진하거나, 장내 유해균의 증식 또는 생장을 억제하는 것을 특징으로 하는 염증성 장질환 치료 또는 예방용 약학 조성물.The method of any one of claims 21 to 25,
The pharmaceutical composition for treating or preventing inflammatory bowel disease, characterized in that the composition promotes the proliferation or growth of beneficial bacteria in the intestine or inhibits the proliferation or growth of harmful bacteria in the intestine.
상기 조성물은 배변 기능을 개선하는 것을 특징으로 하는 것을 특징으로 하는 염증성 장질환 치료 또는 예방용 약학 조성물.The method of any one of claims 21 to 25,
The composition is a pharmaceutical composition for treating or preventing inflammatory bowel disease, characterized in that to improve bowel function.
상기 조성물은 TNF-α의 분비를 억제하는 것을 특징으로 하는 특징으로 하는을 특징으로 하는 염증성 장질환 치료 또는 예방용 약학 조성물.The method of any one of claims 21 to 25,
The composition is a pharmaceutical composition for treating or preventing inflammatory bowel disease, characterized in that for inhibiting the secretion of TNF-α.
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EP1332759A1 (en) * | 2002-02-04 | 2003-08-06 | Kyowa Hakko Kogyo Co., Ltd. | Pharmaceutical and nutritional compositions containing a di- or oligosaccharide as insulin secretion promoter |
KR102335067B1 (en) | 2013-09-10 | 2021-12-03 | 젠와인 바이오테크놀로지 게엠바하 | Production of oligosaccharides |
KR101477693B1 (en) | 2013-11-22 | 2014-12-31 | (주)네오크레마 | A preparation method of galactooligosaccharides with enhanced galactosyllactose which is a ingredient of mother's milk |
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