KR102089836B1 - The pharmaceutical composition for treating or preventing for inflammation disease using Tryptophanase-negative bacteria and bacteria inducing Interferon gamma and method using thereof - Google Patents
The pharmaceutical composition for treating or preventing for inflammation disease using Tryptophanase-negative bacteria and bacteria inducing Interferon gamma and method using thereof Download PDFInfo
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- KR102089836B1 KR102089836B1 KR1020170032383A KR20170032383A KR102089836B1 KR 102089836 B1 KR102089836 B1 KR 102089836B1 KR 1020170032383 A KR1020170032383 A KR 1020170032383A KR 20170032383 A KR20170032383 A KR 20170032383A KR 102089836 B1 KR102089836 B1 KR 102089836B1
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- tryptophan
- bacteria
- streptococcus
- bifidobacterium
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Abstract
본 발명은 유산균, 비피도박테리아, 스트렙토코커스 및 이의 혼합물에서 선택된 IFN 감마를 유도하는 미생물과 조합하여, 유산균, 비피도박테리아, 스트렙토코커스 및 이의 혼합물에서 선택된 트립토판 분해 효소-음성 미생물을 포함하는 식품, 기능성 식품, 약학 및 식품 보조 조성물에 관한 것이다.The present invention, in combination with a microorganism that induces IFN gamma selected from lactic acid bacteria, Bifidobacteria, Streptococcus and mixtures thereof, food comprising tryptophan degrading enzyme-negative microorganisms selected from Lactic acid bacteria, Bifidobacteria, Streptococcus and mixtures thereof, Functional food, pharmaceutical and food supplement composition.
Description
본 발명은 인터페론 감마(IFN 감마)를 유도하는 유산균과 함께, 트립토판을 대사할 수 없는 유산균(lactic bacteria)(트립토판분해효소-음성 박테리아)을 포함하는 조성물에 관한 것이다. 본 발명에 관한 조성물은 키뉴레닌 대사 경로의 활성화에 의해 이익을 얻는 모든 질환들에서, 예컨대 예를 들어 임신중 내성, 만성 염증의 제어, 자가 면역의 보호, 자가면역 질환 증상의 경감을 위한 예방 및 치료, 장기 거부 예방의 보조, 및 에너지(아데노신 트리포스페이트, ATP), 니코틴아미드 및 관련 화합물(니코틴아미드 아데닌 뉴클레오타이드 및 니코틴아미드 아데닌 뉴클레오타이드 포스페이트; NAD 및 NADP)의 생성에서, 식이, 건강기능성 식품 및 약학 분야에서 그리고 식품첨가제로서, 사용될 수 있다. The present invention relates to a composition comprising lactic bacteria (tryptophanase-negative bacteria) that cannot metabolize tryptophan, together with lactic acid bacteria that induce interferon gamma (IFN gamma). The composition according to the present invention prevents for all diseases that benefit from activation of the kynurenine metabolic pathway, such as, for example, resistance during pregnancy, control of chronic inflammation, protection of autoimmunity, reduction of symptoms of autoimmune diseases, and In the treatment, aid in the prevention of long-term rejection, and in the production of energy (adenosine triphosphate, ATP), nicotinamide and related compounds (nicotinamide adenine nucleotide and nicotinamide adenine nucleotide phosphate; NAD and NADP), diet, health functional food and pharmaceutical It can be used in the field and as a food additive.
트립토판은 필수 아미노산이고, 따라서 척추동물 유기체가 생산할 수 없는 아미노산군의 하나이므로 음식을 통해 섭취해야 한다. 단백질 생산을 위해 신체가 사용하는 것이외에도, 트립토판은 포유동물의 생리적 기능에 필수적이고, 상이한 대사 경로를 통해 처리되어 생물기원 아민 예컨대 세로토닌, 멜라토닌, 트립타민 등, 집합적으로 키뉴레닌으로 알려진 수많은 분해 생성물의 생성을 초래하며, 최종적으로 에너지 대사에 중요한 보효소인, 니코틴아미드 아데닌 디뉴클레오타이드(NAD+)의 합성에 기여한다. 따라서, 전신 및 세포 트립토판 수준은 음식 섭취에 의해서 뿐만 아니라, 무엇보다도 그를 전환시키거나 또는 분해시키는 대사 경로의 활성에 의해 결정된다. Tryptophan is an essential amino acid and is therefore one of the groups of amino acids that vertebrate organisms cannot produce, so it should be consumed through food. In addition to being used by the body for protein production, tryptophan is essential for the physiological function of mammals, and is processed through different metabolic pathways, resulting in a number of degradations collectively known as kynurenine, such as bio-origin amines such as serotonin, melatonin, and tryptamine. It leads to the production of the product and finally contributes to the synthesis of nicotinamide adenine dinucleotide (NAD +), a coenzyme important for energy metabolism. Thus, systemic and cellular tryptophan levels are determined not only by food intake, but above all by the activity of metabolic pathways that convert or degrade them.
체내에서, 트립토판은 인돌 고리를 개방시켜 대사되어 포밀키뉴레닌 및 키뉴레닌이 형성된다. 이 과정은 니코틴산 및 니코틴아미드, 비타민 B 복합체의 생합성, 및 ATP 생성의 초기 단계를 나타낸다(도 1). In the body, tryptophan is metabolized by opening the indole ring, forming formylkynurenine and kynurenine. This process represents the biosynthesis of nicotinic acid and nicotinamide, vitamin B complex, and the initial stages of ATP production (Figure 1).
트립토판의 키뉴레닌 화합물, 또는 키뉴레닌으로의 전환을 촉매하는 것을 담당하는 효소는 인돌아민 2,3-디옥시게나제(이하 본원에서 IDO라고 함)이다. 이 특성은 IDO에 면역 반응을 억제하는 능력을 제공하는데, 트립토판 프로세싱이 T 림프구의 성장 및 증식에 필수적인, 이 아미노산을 미세환경에서 고갈되게 야기하고, 또한 T 림프구의 아폽토시스를 야기할 수 있는 대사산물을 생성시킬 수 있기 때문이다. IDO의 면역조절 효과를 설명하는데 가장 인정받는 가설 중 하나는 단백질 발현 시 결과에 따른 트립토판 고갈이 T 세포를 세포 주기의 G1기에 억류시켜, 그들 클로날 확장을 방해하고 그들을 프로아폽토시스 신호에 더 감응성이게 만든다는 것이다(Munn et al., 1999). 대안적인 가설은 IDO가 항원-제시 세포(APC)의 생물학적 특성에 부정적인 영향을 미쳐서, 항원을 제시하는 그 능력을 감소시키거나 또는 억제성 리간드(예를 들어, CD95 리간드)의 발현을 증가시키거나 또는 면역조절성 사이토카인 예컨대 IL-10 또는 TGF-β의 방출을 촉진시킬 수 있다는 것이다(Mellor and Munn, 2004).The enzyme responsible for catalyzing the conversion of tryptophan to a kynurenine compound or kynurenine is
사실 IDO는 숙주 자신에 손상을 줄 수 있는 과도한 면역 활성화를 제한하도록 염증성 상태에 대응하는 역조절 기전으로서 중요한 역할을 한다. 체내 IDO는 면역성 및 내성의 효과를 균형잡아, 수지상 세포를 통한 T 세포의 반응을 제어한다. 강력한 보조제로서 알려진, 탈메틸화된 CpG 서열을 함유하는 올리고데옥시뉴클레오타이드(CpG ODN)가 인터페론-감마(IFN-γ), 인터페론-알파(IFN-α) 및 다른 프로염증성 사이토카인의 유도를 통해 매우 다양한 조직에서 IDO의 작용인자로서 작용한다는 것이 또한 밝혀졌다(Mellor et al., 2005). 이러한 증거는 CpG ODN이 특히 강력한 면역자극제라는 사실에도 불구하고, 일부 조건에서, IDO에 의해 매개되는 역조절 효과를 유도할 수 있다는 실질적인 관점에서 중요할 수 있다. In fact, IDO plays an important role as a counterregulatory mechanism in response to inflammatory conditions to limit excessive immune activation that can damage the host itself. IDO in the body balances the effects of immunity and tolerance, controlling the response of T cells through dendritic cells. Oligodeoxynucleotides (CpG ODN) containing demethylated CpG sequences, known as potent adjuvants, are highly mediated through induction of interferon-gamma (IFN-γ), interferon-alpha (IFN-α) and other pro-inflammatory cytokines. It has also been found to act as an agonist of IDO in various tissues (Mellor et al., 2005). This evidence may be important from the practical point of view that despite the fact that CpG ODN is a particularly potent immunostimulant, in some conditions it can induce an IDO-mediated adverse regulatory effect.
본 발명은 유산균(lactic bacteria), 비피도박테리아(bifidobacteria), 스트렙토코커스(streptococci) 및 이의 혼합물에서 선택된 IFN 감마를 유도하는 미생물과 조합하여, 유산균, 비피도박테리아, 스트렙토코커스 및 이의 혼합에서 선택된 트립토판분해효소-음성 미생물을 포함하는, 식이, 건강기능성 식품, 약학 및 식품 첨가제 조성물에 관한 것이다. The present invention, in combination with microorganisms inducing IFN gamma selected from lactic bacteria, bifidobacteria, streptococci, and mixtures thereof, tryptophan selected from lactic acid bacteria, bifidobacteria, streptococcus, and mixtures thereof It relates to a dietary, dietary supplement, pharmaceutical and food additive composition comprising a degrading enzyme-negative microorganism.
조성물에서 함께 작용하는 IFN 감마를 유도시키는 그들 능력에 대해 선택되는 유산균, 비피도박테리아, 스트렙토코커스 및 이의 혼합물에서 선택된 미생물과 조합한, 트립토판 분해효소 활성이 없어 선택되는 유산균, 비피도박테리아, 스트렙토코커스 및 이의 혼합물에서 선택된 미생물은, 예를 들어, 경구, 장 또는 직장으로 투여시, 장내 균총을 변경시켜, 트립토판 분해효소-음성 박테리아의 비율을 증가시켜 결과적으로 숙주 세포에 대한 트립토판의 이용률이 더 커지고, 도 2에 예시한 바와 같이, 본 발명과 관련된 조합으로 투여된 IFN 감마 유도 박테리아에 의해서 그 생산이 유도된, IFN 감마에 의해 IDO의 활성화가 더욱 자극된다는 것을 이제 발견하였다. Lactic acid bacteria selected for lack of tryptophan degrading enzyme activity in combination with microorganisms selected from lactic acid bacteria, Bifidobacteria, Streptococcus and mixtures thereof selected for their ability to induce IFN gamma acting in the composition, Bifidobacteria, Streptococcus And microbes selected from mixtures thereof, for example, when administered orally, intestinal or rectal, alter the intestinal flora, thereby increasing the ratio of tryptophan degrading enzyme-negative bacteria, resulting in greater utilization of tryptophan for host cells , As illustrated in FIG. 2, it has now been found that the activation of IDO is further stimulated by IFN gamma, whose production is induced by IFN gamma-inducing bacteria administered in combination with the present invention.
키뉴레닌 경로는 염증의 제어 및 에너지(ATP,NAD, NADH, 니코틴아미드)의 생성에 필수적이다. 따라서, 본 발명의 조성물은 특히 국소, 전신 및 뇌 수준에서의 만성 염증의 예방 및 치료, 예를 들어 장의 염증성 질환, 만성 간 질환(지방 간염, 만성 간염), 항바이러스 치료, 중추 및 말초 신경계의 만성 염증성 질환, 자가면역 질환, 대변 이식, 이식 후 항거부 치료, 임신 중 태아의 내성 증가, 트립토판 대사 안정화 및 조절 및 초기 유아기의 미세아교세포의 염증, 예를 들어 자폐증, 트립토판 이상대사 상황의 다양한 이유로 발생되는, 노년층의 편도체, 해마 및/또는 전두엽의 변화, 심혈관 질환 및 당뇨병에서 효과적이다. 본 발명이 관련된 조성물은 또한 에너지가 부족한 개체에서 또는 신체에 보다 높은 에너지 생산이 요구되는 경우 에너지(아데노신 트리포스페이트, ATP), 니코틴아미드 및 관련 화합물(니코틴아미드 아데닌 뉴클레오타이드 및 니코틴아미드 아데닌 뉴클레오타이드 포스페이트; NAD 및 NADP)를 생산하는데도 효과적이다. The kynurenine pathway is essential for the control of inflammation and the production of energy (ATP, NAD, NADH, nicotinamide). Thus, the compositions of the invention are particularly useful for the prevention and treatment of chronic inflammation at the local, systemic and brain levels, for example inflammatory diseases of the intestine, chronic liver disease (fatty hepatitis, chronic hepatitis), antiviral treatment, central and peripheral nervous system. Chronic inflammatory disease, autoimmune disease, stool transplantation, anti-rejection treatment after transplantation, increased fetal resistance during pregnancy, stabilization and regulation of tryptophan metabolism and inflammation of microglia in early childhood, e.g. autism, tryptophan metabolism It is effective in changes in the amygdala, hippocampus and / or frontal lobe, cardiovascular disease and diabetes in older people, which are caused by reasons. Compositions related to the present invention also provide energy (adenosine triphosphate, ATP), nicotinamide and related compounds (nicotinamide adenine nucleotides and nicotinamide adenine nucleotide phosphates) in NAD, or in individuals with insufficient energy And NADP).
본 발명에 따른 바람직한 미생물은 트립토판 분해효소가 부재하고 IFN-γ의 생성을 유도하는 능력에 대해 선택된, 유산균, 비피도박테리아 및 스트렙토코커스, 및 이의 혼합물에서 선택된다. 이들은 실활 박테리아 형태, 예를 들어 열, 방사선 또는 이 목적에 유용한 임의의 다른 방법에 의해 사멸된 박테리아, 또는 생활 박테리아로서, 또는 동시에 두 형태로서 사용될 수 있다. Preferred microorganisms according to the present invention are selected from lactic acid bacteria, Bifidobacteria and Streptococcus, and mixtures thereof, which are free of tryptophan degrading enzyme and selected for their ability to induce the production of IFN-γ. They can be used as deactivating bacterial forms, for example bacteria killed by heat, radiation or any other method useful for this purpose, or living bacteria, or both simultaneously.
본 발명의 다른 목적은 식품, 상기 박테리아 균주를 함유하는 식품, 식이, 약학, 및 기능성 식품 용도 및 식품 보충제로서의 조성물이다. 언급된 모든 박테리아 균주는 상업적으로 입수할 수 있다. Other objects of the present invention are foods, foods containing the bacterial strain, dietary, pharmaceutical, and functional food uses and compositions as food supplements. All bacterial strains mentioned are commercially available.
다른 목적은 본 발명의 하기 구체적인 설명을 통해 분명해 진다. Other objects become apparent through the following detailed description of the invention.
본 발명자들은 만성 염증성 병태를 예방, 치료 및 완화시키고 이를 필요로 하는 모든 경우에서 신체 에너지 생성을 향상시키도록, 투여된 포유동물, 인간 또는 동물에서 IDO 효소와 그에 따라 키뉴레닌 대사 경로를 활성화시키고 상승시키기 위해, IFN 감마를 유도시키는 능력에 대해 선택된 유산균과 함께 트랍토판 분해 효소가 없는 균주를 선택함으로써, 상승적 방식으로, 식품 산업에서 사용되고 이미 알려져 있는 유산균, 비피도박테리아 및 스트렙토코커스를 사용하는 것이 가능함을 발견하였다. The present inventors activate and elevate IDO enzymes and thus kynurenine metabolic pathways in administered mammals, humans or animals to prevent, treat and alleviate chronic inflammatory conditions and improve body energy production in all cases where it is needed. In order to do so, it is possible to use lactic acid bacteria, Bifidobacteria and Streptococcus already known and used in the food industry, in a synergistic manner, by selecting strains without a trapptophan degrading enzyme together with lactic acid bacteria selected for their ability to induce IFN gamma. Found.
도 1: TOx 경로. 간외부 인간 TOx 경로를 IDO 억제인자 및 유도인자와 함께 도시하였다. IDO1, 인돌아민 2,3-디옥시게나제 1; IDO2, 인돌아민 2,3-디옥시게나제 2; AFMID, 아릴포름아미다제; KMO, 키뉴레닌 3-모노옥시게나제; KAT, 키뉴레닌 아미노트랜스퍼라제; KYNU, 키뉴레니나제; HAAO, 3-하이드록시안트라닐레이트 3,4-디옥시게나제; ACMSD, 아미노카르복시뮤코네이트 세미알데하이드 디카르복실라제; QPRT, 퀴놀레이트 포스포리보실트랜스퍼라제(문헌 [F. Murray. Science Translational Medicine vol 2, issue 32, 19 May 2010] 참조)
도 2: IFN 감마를 유도하는 그들 능력에 대해 선택된 유산균 프로바이오틱스와 조합한, 트립토판 분해효소 활성이 없어 선택된 유산균, 비피도박테리아 및 스트렙토코커스는 함께 협동적으로 작용함으로써, 숙주 세포에 대해 트립토판 이용률이 더욱 높아지고 여기서 본 발명과 관련된 조합으로 투여된 IFN 감마-유도 박테리아에 의해 그 생성이 유도된, IFN 감마에 의해 IDO 활성이 더욱 자극된다.
도 3: 엘. 파라카세이(L. paracasei)를 사용한 인돌 검사의 결과. Figure 1: TOx path. The extrahepatic human TOx pathway is shown with IDO inhibitors and inducers. IDO1,
Figure 2: Lactobacillus, Bifidobacteria and Streptococcus selected without tryptophan degrading enzyme activity, in combination with lactic acid bacteria probiotics selected for their ability to induce IFN gamma, cooperatively work together, resulting in more tryptophan utilization against host cells. IDO activity is further stimulated by IFN gamma, which is elevated and its production is induced here by IFN gamma-derived bacteria administered in combination with the present invention.
Figure 3: L. Results of indole test using L. paracasei .
본 발명의 목적을 위해서, "식품 조성물"은 본 발명에 따른 박테리아가 부가되거나 또는 본 발명에 따른 박테리아로 제제화되는 적어도 하나의 식품을 포함하는 조성물을 의미한다. For the purposes of the present invention, "food composition" means a composition comprising at least one food product to which the bacteria according to the invention are added or formulated into bacteria according to the invention.
본 발명자는 만성 염증성 병태를 예방, 치료 및 완화시키고 필요한 모든 경우에서 신체의 에너지 생성을 향상시키도록, 투여되는 포유동물, 인간 또는 동물에서 IDO 효소와 그에 따라 키뉴레닌 대사 경로를 활성화 및 상승시키기 위해, IFN 감마를 유도하는 능력에 대해 선택된 유산균과 함께, 트립토판 분해효소가 없는 균주를 선택함으로써, 상승적 방식으로, 식품 산업에서 사용되고 이미 알려져 있는 유산균, 비피토박테리아 및 스트렙토코커스를 사용하는 것이 가능하다는 것을 발견하였다. The present inventors for the purpose of activating and elevating the IDO enzyme and thus the kynurenine metabolic pathway in mammals, humans or animals administered, to prevent, treat and alleviate chronic inflammatory conditions and improve the body's energy production in all cases where necessary. , By selecting strains without tryptophan degrading enzymes, with lactic acid bacteria selected for their ability to induce IFN gamma, in a synergistic manner, it is possible to use lactic acid bacteria, biphytobacteria and streptococcus already known and used in the food industry Found.
본 발명에 따른 조성물은 사실 장내 미생물균총을 변화시켜 트립토판 대사에 영향을 미칠 수 있어서, 골수 이식 및 대변 이식을 포함한, 장기 거부의 예방, 임신 중 태아의 내성, 국소, 전신 및 뇌 염증의 예방 및 치료, 및 바이러스 질환을 포함한 자가면역 질환의 예방 및 치료를 보조하여, 염증성 병태에 긍정적인 영향을 준다. The composition according to the present invention can actually affect the tryptophan metabolism by changing the intestinal microflora, thus preventing long-term rejection, including bone marrow transplantation and fecal transplantation, prevention of fetal resistance during pregnancy, local, systemic and brain inflammation, and It assists treatment and prevention and treatment of autoimmune diseases, including viral diseases, which positively affects inflammatory conditions.
본 발명에 따른 조성물은 초기 유아기에 트립토판 대사의 안정화 및 조절 및 예를 들어 자폐증의 미세아교세포의 염증에 특히 유리하다. 다른 바람직한 응용 분야는 트립토판 이상대사 상황에서의 다양한 이유(병원 또는 호스피스에 체류, 항생제 치료 또는 장내 균총을 변화시키는 약물, 예컨대 항바이러스 및 항종양 약물에 의한 치료)로 발생하는, 노년층에서의 편도체, 해마 및/또는 전두엽 변화의 치료를 위한 용도이다. The composition according to the invention is particularly advantageous for the stabilization and regulation of tryptophan metabolism in early infancy and for the inflammation of microglia, for example of autism. Other preferred applications include amygdala in older people, caused by various reasons in a tryptophan metabolic situation (residence in a hospital or hospice, treatment with antibiotics, or treatment with drugs that change the intestinal flora, such as antiviral and antitumor drugs), It is used for the treatment of hippocampus and / or frontal lobe changes.
본 발명에 따른 조성물의 다른 중요한 효과는 에너지 부족 상태에서 그리고 스포츠 수행능을 향상시키기 위해, 포유동물, 인간, 및 동물에서 ATP, NAD 및 NADP의 생성의 상승이다. Another important effect of the composition according to the present invention is an increase in the production of ATP, NAD and NADP in mammals, humans, and animals, in an energy deficient state and to improve sports performance.
본 발명에 따른 조성물은 만성 염증 및 다른 상기 표시한 병적 상태를 특징으로 하는 질환의 예방 및 치료에서 사용하기 위해 인간 또는 동물에 투여될 수 있다. 상기 조성물은 증상을 보이거나(예를 들어, 염증성 장질환을 앓는 환자), 또는 증상은 없지만 염증의 검출 가능한 위험성(반복적인 자연 유산 경험이 있는 임신 개체)이 있는 개체, 인간 또는 동물을 비롯하여, 무증상 개체에게, 예방 목적(예를 들어, 아테롬성 동맥경화증 및 노인성 치매의 예방)으로, 또는 단지 신체 기능 향상을 위해 투여될 수 있다. The composition according to the present invention can be administered to humans or animals for use in the prevention and treatment of diseases characterized by chronic inflammation and other conditions indicated above. Such compositions include individuals, humans or animals that have symptoms (eg, patients with inflammatory bowel disease), or who have no symptoms but have a detectable risk of inflammation (pregnant individuals with repetitive natural abortion experiences), It may be administered to asymptomatic individuals, for prophylactic purposes (eg, prevention of atherosclerosis and senile dementia), or just to improve body function.
본 발명에 따른 조성물의 섭취는 숙주의 장내에서 트립토판을 이용할 수 없는 박테리아인, 트립토판 분해효소-음성 박테리아의 수를 증가시키게 된다. 이는 IDO 효소(인돌아민 2-3 디옥시게나제)가 이용할 수 있는 트립토판의 비율을 증가시키며, 그 다음으로 IDO는 IFN-γ 활성을 상승시키는데, IFN-γ은 IFN-γ의 생성을 유도하는 박테리아에 의해, 본 발명과 관련된 조성물의 제2 성분에 의한 자극 후에 숙주의 면역적격 세포에 의해 상당한 양으로 생산된다. 따라서, 상기 조성물은 기질(트립토판)을 더욱 이용할 수 있게 하며 또한 IFN-γ의 생산을 강력화시켜서 IDO를 상승시킨다. 그러므로, 키뉴레닌 경로는 치료되는 개체에서 상승된다. 키뉴레닌 경로는 염증의 제어 및 에너지(ATP,NAD, NADH, 니코틴아미드)의 생성에 핵심적이다.Ingestion of the composition according to the present invention increases the number of tryptophan degrading enzyme-negative bacteria, bacteria that cannot use tryptophan in the intestine of the host. This increases the proportion of tryptophan available to IDO enzymes (indoleamine 2-3 deoxygenase), and then IDO increases IFN-γ activity, where IFN-γ is a bacteria that induces the production of IFN-γ By stimulation by the second component of the composition related to the present invention, it is produced in a significant amount by the host's immunocompetent cells. Thus, the composition makes the substrate (tryptophan) more available and also enhances the production of IFN-γ, thereby increasing IDO. Therefore, the kynurenine pathway is elevated in the individual being treated. The kynurenine pathway is key to the control of inflammation and the production of energy (ATP, NAD, NADH, nicotinamide).
본 발명자들은 먼저 트립토판 분해효소 활성이 없는 유산균, 비피도박테리아 및 스트렙토코커스를 선택하였다. 박테리아의 트립토판 분해효소 활성 부재는 인돌에 대해 코백스(Kovacs) 시약(산성 용액 중 p-디메틸-아미노-벤즈알데하이드)을 사용해 검정하였다. 인돌은 트립토판의 대사 분해 부산물 중 하나이다. 트립토판 분해효소를 함유하는 박테리아는 트립토판을 가수분해하고 탈아민화할 수 있어, 인돌, 피루브산 및 암모니아가 생성된다. 이들 검정을 위해, 박테리아 에스케리치아 콜라이(Escherichia coli)가 트립토판 분해효소 활성 존재에 대한 양성 표준으로 사용되었다. 이 시험예는 실시예에 예시한다. The inventors first selected lactic acid bacteria, Bifidobacteria and Streptococcus without tryptophan degrading enzyme activity. The absence of bacterial tryptophan degrading enzyme activity was assayed for indole using Kovacs reagent (p-dimethyl-amino-benzaldehyde in acidic solution). Indole is one of the by-products of tryptophan metabolism. Bacteria containing tryptophan degrading enzymes can hydrolyze and deaminize tryptophan, producing indole, pyruvic acid and ammonia. For these assays, bacterial Escherichia coli was used as a positive standard for the presence of tryptophan degrading enzyme activity. This test example is illustrated in the Examples.
인돌 시험을 사용하여 검정시, 하기의 박테리아들이 트립토판 분해효소 활성이 없는 것으로 확인되었고, 구체적으로 에스. 써모필러스(S. Thermophilus), 엘. 플란타럼(L. plantarum), 엘. 파라플란타럼(L. paraplantarum), 엘. 액시도필러스(L. acidophilus), 엘. 카세이(L. casei), 엘. 파라카세이(L. paracasei), 엘. 헬베티커스(L. helveticus), 비. 락티스(B. lactis), 비. 브레베(B. breve), 비. 인판티스(B. infantis), 비. 롱검(B. longum), 엘. 락티스(L. lactis), 엘. 브레비스(L. brevis), 피. 플로이덴레이치(P. Freudenreichii)이다.When assayed using the indole test, the following bacteria were found to have no tryptophan degrading enzyme activity, specifically S. Thermophilus , L. Plantarum , L. L. paraplantarum , L. L. acidophilus , L. L. casei , L. L. paracasei , L. Helvetica ( L. helveticus ), B. B. lactis , B. B. breve , B. B. infantis , B. Long gum ( B. longum ), L. L. lactis , L. L. brevis , p. P. Freudenreichii .
다음으로, 발명자들은 IFN-γ의 생성을 유도시키는 그들 능력에 대해 유산균을 선택하였다. IFN-γ 생성은 건강한 개체의 림프구를 1:1 비율로 배양 중에 시험 하에 박테리아로 자극시킨 후 IFN-γ를 측정하는 ELISA 키트를 사용해 측정하였다. 시험예는 실시예에 예시하였다. Next, the inventors selected lactic acid bacteria for their ability to induce the production of IFN-γ. IFN-γ production was measured using ELISA kits that measure IFN-γ after stimulating lymphocytes in healthy individuals with bacteria under test during incubation in a 1: 1 ratio. The test examples are exemplified in Examples.
본 발명의 목적을 위해서, 0.2 ng/mL 이상으로 IFN-γ 생성을 유도할 수 있는 균주만을 선택 가치가 있다고 간주하였다: IFN-γ의 생성을 유도하는 최고의 3가지 균주는 에스. 써모필러스(S. Thermophilus)(1.8 ng/mL), 엘. 액시도필러스(L. acidophilus)(1.5 ng/mL), 비. 락티스(B. lactis)(1.3 ng/mL), 비. 비피덤(B. bifidum)(1.3 ng/mL) 및 엘. 헬베티커스(L. helveticus)(1.2 ng/mL)인 것으로 입증되었다. For the purposes of the present invention, only those strains capable of inducing IFN-γ production above 0.2 ng / mL were considered to be of value for selection: the top three strains inducing the production of IFN-γ were S. Thermophilus (1.8 ng / mL), L. L. acidophilus (1.5 ng / mL), B. B. lactis (1.3 ng / mL), B. B. bifidum (1.3 ng / mL) and L. It was proven to be L. helveticus (1.2 ng / mL).
따라서, 본 발명의 목적을 위해서, 에스. 써모필러스, 엘. 플란타럼, 엘. 파라플란타럼, 엘. 액시도필러스, 엘. 카세이, 엘. 파라카세이, 엘. 헬베티커스, 비. 락티스, 비. 브레베, 비. 인판티스, 비. 롱검, 엘. 락티스, 엘. 브레비스, 및 피. 플로이덴레이치에서 선택된, 트립토판 분해효소 활성이 없는 박테리아의 적어도 하나의 균주, 및 바람직하게 에스. 써모필러스, 엘. 액시도필러스, 엘. 헬베티커스, 비. 락티스 및 비. 비피덤에서 선택된, IFN-γ의 생성을 유도하는 박테리아의 적어도 하나의 균주를 포함하는 조성물이 개발되었다. Therefore, for the purposes of the present invention, S. Thermophilus, L. Plantarum, L. Paraplantarum, L. Axidophilus, L. Kasei, L. Paracasey, L. Helvetica, B. Lactis, B. Breve, B. Infantis, B. Long Sword, L. Lactis, L. Brevis, and P. At least one strain of bacteria without tryptophan degrading activity selected from Plauden Leach, and preferably S. Thermophilus, L. Axidophilus, L. Helvetica, B. Lactis and rain. A composition has been developed that comprises at least one strain of bacteria that induces the production of IFN-γ, selected from non-dermal.
단독으로 또는 혼합물로 사용되는 특히 바람직한 균주를 하기 표 1에 열거하였다. Particularly preferred strains used alone or in mixtures are listed in Table 1 below.
L. Helvetica Rafty L10
엘. 헬베티커스 HA-128L. Helvetica R0052
L. Helvetica HA-128
비. 비피덤 MB109ratio. B-derm BB01
ratio. BEIDUM MB109
ratio. Vipidum R0071
비. 롱검 ATCC SD5588ratio. Longsword Rossel-175
ratio. Long Gum ATCC SD5588
ratio. Infantis R0033
비. 인판티스 BI02 ratio. Infantis HA-116
ratio. Infantis BI02
ratio. Breve Rosell-70
비. 브레베 ATCC SD5206ratio. Breve HA-129
ratio. Breve ATCC SD5206
엘. 액시도필러스 ATCC SD5212
L. Axidophilus HA-122
L. Axidophilus ATCC SD5212
엘. 액시도필러스 로셀-418
엘. 액시도필러스 LBA091L. Axidophilus R0052
L. Axidophilus Rossel-418
L. Axidophilus LBA091
L. Kasei ATCC SD5213
엘. 카세이 HA-108L. Casey Rossel-215
L. Kasei HA-108
엘. 파라카세이 ATCC SD5275L. Paracasei HA-196
L. Paracasei ATCC SD5275
엘. 파라카세이 LP01L. Paracasey Rafty L26 ND
L. Paracasey LP01
엘. 플란타럼 P94
엘. 플란타럼 D747L. Plantarum P83
L. Plantarum P94
L. Plantarum D747
엘. 플란타럼 HA-119
엘. 플란타럼 ATCC SD5209L. Plantarum Rosel-1012
L. Plantarum HA-119
L. Plantarum ATCC SD5209
엘. 브레비스 ATCC SD5214L. Brevis LBR01
L. Brevis ATCC SD5214
엘. 살리바리우스 LS01L. Salivarius HA-11
L. Salivarius LS01
Lactobacillus delbruekki ssp. Bulgaricus SP96
비. 락티스 HA-194
ratio. Lactis ATCC SD5219
ratio. Lactis HA-194
비. 락티스 ATCC SD5220
비. 락티스 ATCC SD5219
비. 락티스 BL086ratio. Lactis Rafty B94
ratio. Lactis ATCC SD5220
ratio. Lactis ATCC SD5219
ratio. Lactis BL086
피. 플로이덴레이치 ssp 플로이덴레이치 HA-273blood. Ployden Leach ssp shermany HA-182
blood. Floiden Litch ssp Floiden Litch HA-273
스트렙토코커스 써모필러스 SP4 MDX
스트렙토코커스 써모필러스 (TH-4®)Streptococcus thermophilus SP4 CS
Streptococcus thermophilus SP4 MDX
Streptococcus thermophilus (TH-4®)
스트렙토코커스 써모필러스 SP4Streptococcus thermophilus ATCC SD5207
Streptococcus thermophilus SP4
바람직하게, 본 발명에 따른 조성물에서 그들 농도는 그램 당 1.109 내지 5.1012 박테리아로 가변적이다. 트립토판 분해효소 활성이 없는 박테리아와 IFN-γ의 생성을 유도하는 박테리아간 비율은 1:1 내지 1000:1 또는 심지어 1:1000 범위이고, 치료하려는 개체에 의한 염증 반응 정도 또는 1일 식이 트립토판 투입량을 기반으로 당업자가 선택할 수 있다. 본 발명에 따른 조성물은 단일 용량으로 또는 수회 용량으로 투여되며, 유산균 또는 유산균에서 유래된 성분의 1일 섭취량이 바람직하게 1일 체중 기준으로 0.01 내지 200 mg/kg, 보다 바람직하게 1일 체중 기준으로 0.1 내지 100 mg/kg이다. Preferably, their concentration in the composition according to the invention is variable from 1.10 9 to 5.10 12 bacteria per gram. The ratio between bacteria without tryptophan degrading enzyme activity and bacteria inducing the production of IFN-γ ranges from 1: 1 to 1000: 1 or even 1: 1000, and the degree of inflammatory response by the individual to be treated or daily dietary tryptophan dose Based on this, a person skilled in the art can select. The composition according to the present invention is administered in a single dose or in multiple doses, and the daily intake of a component derived from lactic acid bacteria or lactic acid bacteria is preferably from 0.01 to 200 mg / kg, more preferably from a daily weight basis. 0.1 to 100 mg / kg.
본 발명에 따라서, IFN-γ의 생성을 유도하는 박테리아는 실활될 수 있고, 따라서 방사선 또는 포유동물에서 IFN-γ의 생성을 유도하는 그들 능력에 영향을 미치지 않는 당업자에게 공지된 임의의 다른 수단에 의해 불활성화된다. According to the present invention, bacteria that induce the production of IFN-γ can be deactivated, and thus any other means known to those skilled in the art that do not affect radiation or their ability to induce the production of IFN-γ in mammals. It is inactivated by.
본 발명에 따른 조성물은 건조되거나 또는 동결건조되거나 또는 조성물의 액상 성분에 영향을 주는 임의의 공정을 겪을 수 있다. 액체부, 대체로 물을 제거하는 단계는 동결건조 또는 건조 또는 분무 건조, 또는 진공 하 건조 및 공기 건조를 포함한, 박테리아의 건조에 적합한 임의의 건조 공정을 통해 편리하게 수행할 수 있다. The composition according to the invention can be dried or lyophilized or subjected to any process that affects the liquid component of the composition. The step of removing the liquid portion, usually water, can be conveniently carried out through any drying process suitable for drying the bacteria, including lyophilization or drying or spray drying, or vacuum drying and air drying.
본 발명에 관한 조성물은 트립토판, 5-하이드록시트립타민 또는 멜라토닌, 및 식품, 식이, 기능성식품 및 약학 조성물의 제조에서 현재 사용되는 보통의 부형제에서 선택된 1 이상의 성분을 더 함유할 수 있다. The composition according to the present invention may further contain tryptophan, 5-hydroxytryptamine or melatonin, and one or more ingredients selected from common excipients currently used in the manufacture of food, dietary, functional food and pharmaceutical compositions.
약학적으로 허용되는 작용제 예컨대 부형제, 분해제, 윤활제, 결합제, 산화 억제제, 착색제, 응집 억제제, 흡수 촉진제, 용해 보조제 및 안정화제가 또한 적합하게 조성물에 부가될 수 있다. 상기 조성물은 또한 식품 보충제(예를 들어, 캡슐, 정제, 과립, 스프레더블 크림), 건강 암시 식품(예를 들어, 건강을 위한 특정 용도의 음식 제품, 기능성 표시의 식품) 또는 기능성 식품(예를 들어, 다이어트 제품, 식품 보충제)의 형태로 제조된다. Pharmaceutically acceptable agents such as excipients, degradants, lubricants, binders, antioxidants, colorants, aggregation inhibitors, absorption promoters, dissolution aids and stabilizers can also be suitably added to the composition. The composition may also include food supplements (e.g. capsules, tablets, granules, spreadable creams), health suggestive foods (e.g. food products for specific use for health, foods with functional indications) or functional foods (e.g. For diet products, food supplements) are manufactured in the form.
본 발명에 따른 조성물은 문헌에 공지된 일반적인 기능석 식품 및 약학 형태, 예를 들어 정제, 과자류, 캡슐, 과립, 음료, 동결건조물, 용액, 현탁물, 에멀션, 펠렛, 시럽, 좌제 또는 질좌약으로 생산될 수 있고, 활성 성분이 부형제 및/또는 비히클과 혼합되어 통상 제조되며, 경우에 따라 공보조제 및/또는 분산제가 부가되고, 예를 들어 물이 희석제로 사용되고 다른 유기 용매가 또한 보조제의 형태로 사용될 수 있다. The composition according to the present invention can be used in general functional stone food and pharmaceutical forms known in the literature, for example tablets, confectionery, capsules, granules, beverages, lyophilisates, solutions, suspensions, emulsions, pellets, syrups, suppositories or suppositories. Can be produced, the active ingredient is usually prepared by mixing with excipients and / or vehicles, if desired co-adjuvants and / or dispersants are added, e.g. water is used as a diluent and other organic solvents are also in the form of auxiliaries. Can be used.
보조제는 예를 들어, 물, 무독성 유기 용매 예컨대 파라핀, 식물성 기름(땅콩유 또는 깨유), 알콜(예를 들어, 에탄올, 글리세린), 글리콜(프로필렌 글리콜, 폴리에틸렌 글리콜), 고형 기질 예컨대 천연 미네랄 가루(카올린, 탈크), 합성 미네랄 가루(예를 들어, 실리케이트), 당류(예를 들어, 사탕수수당), 유화제(알킬 설포네이트 또는 아릴 설포네이트 등), 분산제(예를 들어, 말토스, 리그닌, 메틸셀룰로스, 전분 및 폴리비닐피롤리돈) 및 윤활제(예를 들어, 마그네슘 스테아레이트, 탈크, 스테아르산, 나트륨 라우릴 설포네이트) 및 유사 물질일 수 있다. Adjuvants are, for example, water, non-toxic organic solvents such as paraffins, vegetable oils (peanut oil or sesame oil), alcohols (e.g. ethanol, glycerin), glycols (propylene glycol, polyethylene glycol), solid substrates such as natural mineral powders ( Kaolin, talc), synthetic mineral powders (e.g. silicates), sugars (e.g. sugarcane), emulsifiers (such as alkyl sulfonates or aryl sulfonates), dispersants (e.g. maltose, lignin, Methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg, magnesium stearate, talc, stearic acid, sodium lauryl sulfonate) and similar materials.
활성 성분과 부형제 간 비율은 바람직하게 1:10 내지 100:1로 다양할 수 있다.The ratio between the active ingredient and excipients may preferably vary from 1:10 to 100: 1.
조성물은 단독으로 또는 식품 또는 식이 성질(예컨대, 콩에서 단리된 단백질, 분말 알부민, 건조 스피룰리나 조류, 건조 계란, 호박씨, 맥주 효모) 또는 기능성식품 및 약학 성질의 다른 활성 성분과 조합하여 투여될 수 있고 사전용량화되어 포장된 유닛으로 제조된 성분의 키트 형태로 포장될 수 있다. The composition may be administered alone or in combination with food or dietary properties (e.g., protein isolated from soybeans, powdered albumin, dried spirulina algae, dried eggs, pumpkin seeds, beer yeast) or functional foods and other active ingredients of pharmaceutical nature, It can be packaged in the form of kits of ingredients made in pre-dose packaged units.
투여는 정상 방식으로, 바람직하게는 경구로 수행된다. 이러한 경우, 이 목적에 적합한 약학 형태는 또한 나트륨 시트레이트, 칼슘 카보네이트 또는 포스페이트를 포함하는 다른 첨가제를 다양한 첨가제 예컨대 전분, 젤라틴, 및 일반적인 부형제 이외에도 유사한 생성물 예컨대 락툴로스, 덱스트로스, 락토스, 말토스와 함께 함유할 수 있다. 상용성 착색제 또는 향미제가 액상 형태의 경우에 부가될 수 있다. Administration is carried out in a normal manner, preferably orally. In this case, pharmaceutical forms suitable for this purpose also include other additives including sodium citrate, calcium carbonate or phosphate, with various additives such as starch, gelatin, and similar products such as lactulose, dextrose, lactose, maltose in addition to common excipients. It can contain together. A compatible colorant or flavoring agent can be added in the case of a liquid form.
본 발명과 관련된 조성물은 본원에 제시된 활성 성분의 활성을 상승시킬 수 있는 사용된 박테리아와 상용성인 약물을 포함하여, 아미노산 및 비타민에서 선택된 1 이상의 성분을 더 포함할 수 있다. 이들 약물 중에서, 예를 들어 항염증제, 해열제, 방부제, 진통제, 항류마티스제, 항박테리아제, 간보호제, 항고지혈제, 항바이러스제 및 화학요법제 및 항종양 약물이 사용될 수 있다. Compositions related to the present invention may further comprise one or more components selected from amino acids and vitamins, including drugs compatible with the bacteria used to enhance the activity of the active ingredients presented herein. Among these drugs, anti-inflammatory agents, antipyretics, antiseptics, analgesics, antirheumatic agents, antibacterial agents, hepatoprotectants, antihyperlipidemic agents, antiviral and chemotherapeutic agents and antitumor drugs can be used, for example.
본 발명에 따라서, 액상 형태의 식품 예컨대 과일 주스, 및 제한없이 우유, 요거트, 아이스크림, 치즈, 버터, 크림을 포함한, 우유 및 치즈 제품, 또는 우유를 사용한 모든 음식 제품을 포함한, 유제품에 선택된 박테리아를 부가하여 제제화된 식품 조성물이 특히 유리한 조성물로 간주되고, 트립토판이 풍부한 식품, 예를 들어, 아몬드, 견과류, 콩에서 단리된 단백질, 분말 알부민, 분말 계란, 맥주 효모, 건조 스피룰리나 조류 및 파르메산을 포함하는 식품 조성물이 또한 특이 유리한 것으로 고려된다. According to the present invention, the bacteria selected for dairy products, including liquid and food products such as fruit juices, and milk and cheese products, including without limitation milk, yogurt, ice cream, cheese, butter, cream, or any food product using milk, Food compositions formulated in addition are considered particularly advantageous and include foods rich in tryptophan, such as proteins isolated from almonds, nuts, soybeans, powdered albumin, powdered eggs, beer yeast, dried spirulina algae and parmesan. The food composition to be considered is also considered to be particularly advantageous.
본 발명과 관련된 조성물은 인간 또는 동물용 식품, 기능성 식품, 식품 보충제, 동물 또는 사람 용도의 약물, 또는 약학 제품으로서 사용될 수 있다. The composition related to the present invention can be used as food for human or animal, functional food, food supplement, drug for animal or human use, or pharmaceutical product.
유산균의 양은 본 발명에 따른 조성물이 식품으로서 사용되는 상황에서는 특별히 제한되지 않는다. 그 양은 예를 들어, 식품의 0.00001 내지 100 중량%, 바람직하게 0.001 내지 50 중량%, 보다 바람직하게 0.1 내지 10 중량%이다. The amount of lactic acid bacteria is not particularly limited in a situation in which the composition according to the present invention is used as food. The amount is, for example, 0.00001 to 100% by weight of the food, preferably 0.001 to 50% by weight, more preferably 0.1 to 10% by weight.
본 발명에 따른 약학, 기능성식품 및 영양 조성물은 최종 생성물을 얻기 위해 박테리아 균주 및/또는 적합한 보조제(들)와 그들의 효소 생성물을 혼합하여 제조될 수 있다. Pharmaceutical, functional food and nutritional compositions according to the present invention can be prepared by mixing bacterial strains and / or suitable adjuvant (s) with their enzyme products to obtain the final product.
본 발명의 제1 바람직한 실시형태에서, 식품 및/또는 식이 및/또는 기능성식품 및/또는 약학 조성물은In a first preferred embodiment of the invention, the food and / or dietary and / or functional food and / or pharmaceutical composition is
제제 1
스트렙토코커스 써모필러스(Streptococcus thermophilus)(40 - 60%) Streptococcus thermophilus (40-60%)
비피도박테리움 브레베(Bifidobacterium breve)(10 - 15%) Bifidobacterium breve (10-15%)
비피도박테리움 인판티스(Bifidobacterium infantis)(10 -15%) Bifidobacterium infantis (10 -15%)
비피도박테리움 롱검(Bifidobacterium longum)(10 - 15%) Bifidobacterium longum (10-15%)
엘. 액시도필러스(2 - 5%)L. Axidophilus (2-5%)
엘. 플란타럼(3 - 5%)L. Plantarum (3-5%)
엘. 파라카세이(4 - 4.9%)L. Paracasei (4-4.9%)
엘. 델브루엑키 하위종 불가리커스(L. delbrueckii subsp bulgaricus)(0.1 - 1%)(중량% 기준), L. L. delbrueckii subsp bulgaricus (0.1-1%) (by weight percent),
경우에 따라 경우에 따라 0 내지 80 중량%의 부형제 또는 0 내지 20 중량%의 상용성 약물Occasionally 0 to 80% by weight of excipients or 0 to 20% by weight of compatible drug
을 포함한다. It includes.
제2의 바람직한 실시형태에서, 본 발명에 따른 조성물은 제1의 바람직한 실시형태에서와 동일한 %로, In a second preferred embodiment, the composition according to the invention is in the same% as in the first preferred embodiment,
제제 2
스트렙토코커스 써모필러스 (40 - 60%) Streptococcus thermophilus (40-60%)
비피도박테리움 브레베(10 - 15%)Bifidobacterium brevet (10-15%)
비피도박테리움 락티스(10 - 15%)Bifidobacterium lactis (10-15%)
비피도박테리움 락티스(10 - 15%)Bifidobacterium lactis (10-15%)
엘. 액시도필러스(2 - 5%)L. Axidophilus (2-5%)
엘. 카세이(3 - 5%)L. Kasei (3-5%)
엘. 헬베티커스(4 - 4.9%).L. Helvetica (4-4.9%).
에서 선택된 동결건조된 유산균 균주(중량% 기준), Freeze-dried lactic acid bacteria strain selected from (based on weight%),
경우에 따라 0 내지 80 중량%의 부형제 및 0 내지 20 중량%의 상용성 약물Optionally, 0 to 80% by weight of excipients and 0 to 20% by weight of compatible drug
을 포함한다.It includes.
제3의 바람직한 실시형태에서, 본 발명에 따른 조성물은 In a third preferred embodiment, the composition according to the invention is
제제 3
스트렙토코커스 써모필러스(34 - 57%)Streptococcus thermophilus (34-57%)
비피도박테리움 락티스(3 - 10%)Bifidobacterium lactis (3-10%)
비피도박테리움 락티스(3 - 10%)Bifidobacterium lactis (3-10%)
엘. 액시도필러스(3 - 5%)L. Axidophilus (3-5%)
엘. 플란타럼(3 - 8%)L. Plantarum (3-8%)
엘. 카세이(3 - 4.9%)L. Kasei (3-4.9%)
엘. 헬베티커스(0.1 - 1%)L. Helvetica (0.1-1%)
엘. 브레비스(5 - 50%)L. Brevis (5-50%)
에서 선택된 동결건조된 유산균 균주(중량% 기준),Freeze-dried lactic acid bacteria strain selected from (based on weight%),
경우에 따라 0 내지 80 중량%의 부형제 및 0 내지 20 중량%의 상용성 약물Optionally, 0 to 80% by weight of excipients and 0 to 20% by weight of compatible drug
을 포함한다.It includes.
제4의 바람직한 실시형태에서, 본 발명에 따른 조성물은 In a fourth preferred embodiment, the composition according to the invention is
제제 4Formulation 4
스트렙토코커스 써모필러스(34 - 57%)Streptococcus thermophilus (34-57%)
비피도박테리움 롱검(3 - 10%)Bifidobacterium long sword (3-10%)
비피도박테리움 롱검(3 - 10%)Bifidobacterium long sword (3-10%)
비피도박테리움 인판티스(3 - 5%)Bifidobacterium infantis (3-5%)
엘. 액시도필러스(3 - 8%)L. Axidophilus (3-8%)
엘. 플란타럼(3 - 4.9%)L. Plantarum (3-4.9%)
엘. 파라카세이(0.1 - 1%)L. Paracasei (0.1-1%)
엘. 헬베티커스(0.1 - 1%)L. Helvetica (0.1-1%)
엘. 브레비스(5 - 50%)L. Brevis (5-50%)
에서 선택된 동결건조된 유산균 균주(제3의 바람직한 실시형태와 동일한 %),A lyophilized lactic acid bacteria strain selected from (% the same as the third preferred embodiment),
경우에 따라 0 내지 80 중량%의 부형제 및 0 내지 20 중량%의 상용성 약물Optionally, 0 to 80% by weight of excipients and 0 to 20% by weight of compatible drug
을 포함한다.It includes.
제5의 바람직한 실시형태에서, 본 발명에 따른 조성물은 In a fifth preferred embodiment, the composition according to the invention is
제제 5Formulation 5
엘. 브레비스(15 -20%)L. Brevis (15 -20%)
피. 세르마니(P. shermanii)(5 -20%)blood. P. shermanii ( 5-20 %)
에서 선택된 동결건조된 유산균 균주(중량% 기준), Freeze-dried lactic acid bacteria strain selected from (based on weight%),
0 내지 80 중량%의 부형제 및 0 내지 20 중량%의 상용성 약물0 to 80% by weight of excipients and 0 to 20% by weight of compatible drug
을 포함한다.It includes.
제6의 바람직한 실시형태에서, 본 발명에 따른 조성물은 In a sixth preferred embodiment, the composition according to the invention is
제제 6
엘. 브레비스(25 -30%)L. Brevis (25 -30%)
피. 세르마니(5 - 30%)blood. Sermany (5-30%)
에서 선택된 동결건조된 유산균 균주(중량% 기준),Freeze-dried lactic acid bacteria strain selected from (by weight%),
0 내지 80 중량%의 부형제 및 0 내지 20 중량%의 상용성 약물0 to 80% by weight of excipients and 0 to 20% by weight of compatible drug
을 포함한다.It includes.
본 발명에 따른 조성물의 제7의 바람직한 실시형태에서, In a seventh preferred embodiment of the composition according to the invention,
제제 7Formulation 7
엘. 브레비스 (10 - 40%) L. Brevis (10-40%)
에서 선택된 동결건조된 유산균 균주(중량% 기준), Freeze-dried lactic acid bacteria strain selected from (by weight%),
0 내지 80 중량%의 부형제 및 0 내지 20 중량%의 상용성 약물0 to 80% by weight of excipients and 0 to 20% by weight of compatible drug
을 포함한다.It includes.
본 발명은 이하의 실시예를 참조하여 이제 설명하지만, 그 범주를 한정하는 것으로 간주하지 않는다. The present invention is now described with reference to the following examples, but is not to be considered as limiting its scope.
실시예Example
실시예 1 내지 7에서 제조된 유산균 혼합물을 본 발명의 조성물을 제조하기 위해 사용하였다. The lactic acid bacteria mixtures prepared in Examples 1 to 7 were used to prepare the composition of the present invention.
실시예 1Example 1
* 각 균주는 단독으로 또는 혼합물로 취하였다. * Each strain was taken alone or as a mixture.
실시예 2Example 2
* 각 균주는 단독으로 또는 혼합물로 취하였다. * Each strain was taken alone or as a mixture.
실시예 3Example 3
* 각 균주는 단독으로 또는 혼합물로 취하였다. * Each strain was taken alone or as a mixture.
실시예 4Example 4
* 각 균주는 단독으로 또는 혼합물로 취하였다. * Each strain was taken alone or as a mixture.
실시예 5Example 5
* 각 혼합물은 단독으로 또는 혼합물로 취하였다. * Each mixture was taken alone or as a mixture.
실시예 6Example 6
* 각 균주는 단독으로 또는 혼합물로 취하였다. * Each strain was taken alone or as a mixture.
실시예 7Example 7
* 엘. 브레비스 HA-112와 엘. 브레비스 LBR01 및/또는 엘. 브레비스 ATCC SD5214의 혼합물* L. Brevis HA-112 and L. Brevis LBR01 and / or L. Mixture of Brevis ATCC SD5214
실시예 1-7에서 제조된 혼합물에 전분 및/또는 당류 및/또는 약물 예컨대 항바이러스제를 100%가 되게 부가하였다. Starch and / or saccharides and / or drugs such as antiviral agents were added at 100% to the mixture prepared in Examples 1-7.
락토바실러스 및 비피도박테리아 혼합물의 동결건조Lyophilization of Lactobacillus and Bifidobacteria mixtures
이하 표시한 락토바실러스, 비피토박테리아 및 스트렙토코커스의 혼합물을 다음과 같이 제조하였다. A mixture of Lactobacillus, Bifitobacteria, and Streptococcus, shown below, was prepared as follows.
자석 교반기가 장착된 1,000 mL 비이커에서, 21 g의 D-말토스를 5℃로 적합하게 냉각된 350 mL의 탈염수에 용해시켰다. 완벽하게 투명한 노란빛 용액이 수 분의 교반 후 얻어졌다. 이 용액을 2℃∼5℃의 온도로 냉각하여 유지하면서, 45 g의 락토바실러스 혼합물을 교반 하에 부가하였다. 온도를 2℃∼5℃로 유지하면서 대략 5분 동안 상기 현탁물을 교반하였다. 다음으로 현탁물을 냉장고에서 -20℃로 사전냉각시킨 AISI 316 스테인레스강에 부었다. In a 1,000 mL beaker equipped with a magnetic stirrer, 21 g of D-maltose was dissolved in 350 mL of demineralized water suitably cooled to 5 ° C. A perfectly transparent yellowish solution was obtained after a few minutes of stirring. While maintaining the solution cooled to a temperature of 2 ° C to 5 ° C, 45 g of a Lactobacillus mixture was added under stirring. The suspension was stirred for approximately 5 minutes while maintaining the temperature at 2 ° C to 5 ° C. Next, the suspension was poured into AISI 316 stainless steel pre-cooled to -20 ° C in a refrigerator.
상기 현탁물은 실제로 순간적으로 얼어버리는 경향이 있다. 박테리아 혼합물의 양호하고, 지속적인 미생물 안정성을 확보하는데 필요한 조건인 5% 이하의 분말 습도로 동결건조된 생성물을 얻기 위한 목적으로 동결건조 주기를 시작하였다. 동결건조 조건은 하기와 같다. The suspension actually tends to freeze instantaneously. A lyophilization cycle was started with the aim of obtaining a lyophilized product with a powder humidity of 5% or less, which is a condition necessary to ensure good, continuous microbial stability of the bacterial mixture. Lyophilization conditions are as follows.
에드워드 미니패스트(Edward Minifast) 2000 동결건조기Edward Minifast 2000 freeze dryer
냉각기 온도: -47℃Cooler temperature: -47 ℃
플레이트 온도: -45℃Plate temperature: -45 ℃
진공 주기 시작전 생성물 온도: -40℃Product temperature before the start of the vacuum cycle: -40 ℃
동결건조 가열 램프: -5℃의 생성물 온도까지 2시간 마다 5℃. 생성물은 온도 회복 램프가 25℃의 생성물 온도까지 2시간 마다 5℃의 속도로 재개된 후 이 온도에서 12시간 방치된다. Lyophilized heating lamp: 5 ° C every 2 hours to a product temperature of -5 ° C. The product is allowed to stand for 12 hours at this temperature after the temperature recovery lamp is resumed at a rate of 5 ° C every 2 hours to a product temperature of 25 ° C.
생성물 미적재. Product unloaded.
실시예 4Example 4
상기 기술된 균주들의 혼합물을 사용해, 하기의 제제를 제조하였다:Using the mixture of strains described above, the following formulation was prepared:
150 bln CFU/사셰 용량의 8종/9종 균주의 혼합물을 함유하는 어린이 사셰Children's sachets containing a mixture of 8/9 strains at 150 bln CFU / sachet dose
균주 혼합물 0.5 g0.5 g of strain mixture
락토스 0.352 gLactose 0.352 g
수크로스 1.5 gSucrose 1.5 g
아세설팜 K 및/또는 아스파탐 0.035 gAcesulfame K and / or aspartame 0.035 g
향미제 0.100 gFlavoring agent 0.100 g
실리카 0.013 gSilica 0.013 g
총 사셰 중량 2.5 gTotal sachet weight 2.5 g
450 bln CFU/사셰 용량의 8종/9종 균주의 혼합물을 함유하는 성인 사셰Adult sachets containing a mixture of 8/9 strains at 450 bln CFU / sachet dose
균주 혼합물 1.5 g1.5 g of strain mixture
말토스 4.38 gMaltose 4.38 g
아스파탐 0.04 gAspartame 0.04 g
향미제 0.07 gFlavoring agent 0.07 g
실리카 0.01 gSilica 0.01 g
총 사셰 중량 6.0 gTotal sachet weight 6.0 g
사용할 수 있는 향미제는 매우 다양하다. 최고 결과는 레몬향 및 딸기향으로 얻었다. There are a wide variety of flavors that can be used. The best results were obtained with lemon and strawberry flavors.
트립토판 분해효소-음성 박테리아 균주의 선택 - 인돌 시험Tryptophan degrading enzyme-selection of negative bacterial strains-indole test
엘. 파라카세이를 사용해 수행한 실험 결과를 예로서 보고한다. L. Report the results of experiments performed using paracasey as an example.
엘. 파라카세이 및 이. 콜라이(도 3)를 MRS 액체배지(de Man, Rogosa and Sharp)에서 배양하였고(+37℃에서 18시간) 1% 트립토판 액체배지로 옮겼다. +37℃에서 24시간 및 48시간 동안 항온배양 후, 시험관에 직접 코백스 시약 5액적을 부가하여 인돌 시험을 수행하였다. L. Paracasey and E. E. coli (FIG. 3) was cultured in MRS liquid medium (de Man, Rogosa and Sharp) (18 hours at + 37 ° C) and transferred to a 1% tryptophan liquid medium. After incubation for 24 hours and 48 hours at + 37 ° C., an indole test was performed by adding 5 drops of Covacs reagent directly to the test tube.
인돌 시험(Manual of Clinical Microbiology - ASM, 1985, page 1094)은 p-디메틸아미노벤즈알데하이드의 알데하이드 기와 인돌 간 반응에 기인한 자주색 복합체의 형성을 기반으로 한다. The indole test (Manual of Clinical Microbiology-ASM, 1985, page 1094) is based on the formation of a purple complex due to the reaction between indole and the aldehyde group of p-dimethylaminobenzaldehyde.
24시간 및 48시간 시험은 도 3(좌: 이콜라이; 우: 엘파라카세이)에 예시한 바와 같이 이.콜라이에 대해서만 양성이었다. The 24-hour and 48-hour tests were only positive for E. coli, as illustrated in Figure 3 (left: E. coli; right: El Paracasey).
인돌 시험으로 검정한 하기 박테리아는 트립토판 분해효소 활성을 갖지 않는 것으로 확인되어서 본 발명에 유용한 것으로 간주하였다: 에스. 써모필러스, 엘. 플란타럼, 엘. 액시도필러스, 엘. 파라카세이, 엘. 헬베티커스, 비. 락티스, 비. 브레베, 비. 인판티스, 비. 롱검, 엘. 락티스, 엘. 브레비스, 피. 플로이덴레이치. 인돌 시험에 음성인 다른 박테리아 예컨대 보르데텔라(Bordetella), 해모필러스(Haemophilus), 프로테우스 미라빌리스(Proteus mirabilis), 슈노모나스(Pseudomonas)는 본 발명의 목적에 사용할 수 없는데, 무엇보다도 이들이 병원성이거나 또는 잠재적으로 병원성이기 때문이다. The following bacteria assayed by the indole test were found to have no tryptophan degrading enzyme activity and were considered useful for the present invention: S. Thermophilus, L. Plantarum, L. Axidophilus, L. Paracasey, L. Helvetica, B. Lactis, B. Breve, B. Infantis, B. Long Sword, L. Lactis, L. Brevis, P. Ployden Litch. Other bacteria that are negative for indole testing such as Bordetella , Haemophilus , Proteus mirabilis , Pseudomonas cannot be used for the purposes of the present invention, among other things, they are pathogenic. Or is potentially pathogenic.
IFN-γ의 생성을 유도할 수 있는 박테리아 균주의 선택Selection of bacterial strains that can induce the production of IFN-γ
건강한 도너의 말초 혈액을 헤파린 첨가 튜브에 수집하고 인산염 완충 염수(PBS)로 1:2로 희석하였다. 단핵 세포를 밀도 구배 원심분리를 통해 단리하고 글루타민, HEPES 완충액, 페니실린, 스트렙토마이신 및 10%의 태아 소 혈청(Flow Laboratories)이 보충된 RPMI-1640 중에 1 × 106/mL로 희석하였다. 시험을 위해 박테리아로 자극시, 박테리아를 웰의 세포 현탁물에 1:1의 비율로 부가하였고 항온반응시간은 37℃, 5% CO2에서 24시간이었다.Peripheral blood from healthy donors was collected in a heparin addition tube and diluted 1: 2 with phosphate buffered saline (PBS). Mononuclear cells were isolated via density gradient centrifugation and diluted 1 × 10 6 / mL in RPMI-1640 supplemented with glutamine, HEPES buffer, penicillin, streptomycin and 10% fetal bovine serum (Flow Laboratories). Upon stimulation with bacteria for testing, bacteria were added to the cell suspension of the wells in a ratio of 1: 1 and the incubation time was 24 hours at 37 ° C., 5% CO 2 .
인터페론-γ 측정Interferon-γ measurement
Abcam의 인터페론 감마(IFNG) 인간 ELISA(Enzyme-Linked Immunosorbent Assay) 키트는 세포 용해물 및 조직 용해물에서 인간 인터페론 감마의 정량 측정을 위한 시험관내 효소-연결 면역흡착 검정법이다. Abcam's Interferon Gamma (IFNG) Human Enzyme-Linked Immunosorbent Assay (ELISA) kit is an in vitro enzyme-linked immunosorbent assay for quantitative determination of human interferon gamma in cell lysates and tissue lysates.
이 검정법은 96웰 플레이트 상에 코팅된 인간 인터페론 감마에 특이적인 항체를 적용한다. 표준물 및 샘플을 웰에 파이펫팅해 넣어 샘플에 존재하는 인터페론 감마가 고정된 항체에 의해 웰에 결합된다. 웰을 세척하고 바이오틴화된 항-인간 인터페론 감마 항체를 부가하였다. 미결합된 바이오틴화된 항체를 세척해 내고, HRP-접합된 스트렙타비딘을 웰에 파이펫팅해 넣었다. 웰을 다시 세척하고, TMB 기질 용액을 웰에 부가하여 색상이 결합된 인터페론 감마의 양에 비례하여 발색되었다. 정지 용액이 색상을 파란색에서 노란색으로 변화시켰고, 그 색상 강도를 450 nm에서 측정하였다.This assay applies antibodies specific to human interferon gamma coated on 96-well plates. The standard and sample are pipetted into the wells and the interferon gamma present in the sample is bound to the wells by the immobilized antibody. Wells were washed and biotinylated anti-human interferon gamma antibody was added. The unbound biotinylated antibody was washed off and HRP-conjugated streptavidin was pipetted into the wells. The wells were washed again and TMB substrate solution was added to the wells to develop color in proportion to the amount of color-coupled interferon gamma. The stop solution changed color from blue to yellow, and the color intensity was measured at 450 nm.
본 발명의 목적을 위해, 시험관 내에서 0.2 ng/mL이 넘게 IFN-γ 수준을 유도할 수 있는 균주를 본 발명의 목적을 위해 사용할 수 있다. 바람직하게 에스. 써모필러스(1.8 ng/mL), 엘. 액시도필러스(1.5 ng/mL), 비. 락티스(1.3 ng/mL), 비. 비피덤(1.3 ng/mL) 및 엘. 헬베티커스(1.2 ng/mL)이다.For the purposes of the present invention, strains capable of inducing IFN-γ levels in excess of 0.2 ng / mL in vitro can be used for the purposes of the present invention. Preferably S. Thermophilus (1.8 ng / mL), L. Axidophilus (1.5 ng / mL), B. Lactis (1.3 ng / mL), b. Non-dermal (1.3 ng / mL) and L. Helvetica (1.2 ng / mL).
AIDS를 앓는 환자에서 항염증성 활성Anti-inflammatory activity in patients with AIDS
항레트로바이러스 요법(ART)은 HIV-감염된 사람의 생명을 극적으로 호전시켰다. 그러나, ART에도 불구하고 지속되는, 잔여 면역 활성화 및 염증은 관련 비-AIDS 질환의 높은 위험성과 연관되었다(Ishizaka A. et al, 2016). 다양한 증거들이 HIV-1 감염이 장 면역 항상성, 점막 구조 및 미생물 조성 변화를 유도함을 보여주었다. 우리는 ART 하의 만성 HIV-1 감염 환자의 말초 혈액 및 장세포 면역 활성화에 대한 6개월간 조성물(조성물 N°1) 보충의 영향을 분석하였다. Antiretroviral therapy (ART) has dramatically improved the lives of HIV-infected people. However, persisting immune activation and inflammation despite ART has been associated with a high risk of related non-AIDS disease (Ishizaka A. et al, 2016). Various evidence has shown that HIV-1 infection induces intestinal immune homeostasis, mucosal structure and microbial composition changes. We analyzed the effect of supplementing the composition (composition N ° 1) for 6 months on peripheral blood and intestinal cell immune activation in patients with chronic HIV-1 infection under ART.
장상피의 손상, 변경된 장내 미생물총 조성, 신경인지 손상 및 트립토판 경로의 변경 간에 강력한 상관성이 HIV 환자에서 관찰되었음을 고려해 볼때, 우리는 식이 프로바이오틱 보충 전과 후에 다음을 평가하였다: Given that a strong correlation was observed in HIV patients with damage to the intestinal epithelium, altered intestinal microflora composition, neurocognitive damage, and alteration of the tryptophan pathway, we evaluated the following before and after dietary probiotic supplementation:
a) 장 생검에서 상피 무결성에 대한 염증성 침윤 및 손상; a) inflammatory infiltration and damage to epithelial integrity in the intestinal biopsy;
b) 장에 의한 IDO의 생성; b) generation of IDO by intestine;
c) 뇌척수액(CSF)의 네옵테린의 수준;c) the level of neoopterin in CSF;
d) 말초 혈액의 세로토닌 수준;d) Serotonin levels in peripheral blood;
e) 말초 혈액의 트립토판 양.e) The amount of tryptophan in peripheral blood.
프로바이오틱 보충 전 및 후에 환자에서 말초 혈액을 샘플링하고 대장내시경을 하였다. 검사 전 24시에 PEG 투여를 통해 결장 세척을 수행하였다. 큰컵 포셉(Radial Jaw 4, Boston Scientific, Natick,Massachusetts, USA)을 사용해 의식하 진정(미다졸람 5 mg/iv)시켜 내시경 시술을 수행하였다. 모든 HIV-1 양성 환자들은 말단 회장의 적어도 10 cm에 대해 통상의 또는 가는 스코프(모델 CF 또는 PCF-160 AI, Olympus Medical Europe GmbH, Hamburg, Germany)를 사용한 전체 대장내시경 및 역행 일리오스코피(Ileoscopy)를 받았다. 우리는 말단 회장, 맹장, 상행, 횡행 및 하행 결장에서 표본(각 부위에서 2생검)을 얻었다. Peripheral blood was sampled and colonoscopy was performed in patients before and after probiotic supplementation. Colon cleansing was performed via PEG administration at 24 hours prior to testing. Endoscopic procedures were performed with conscious sedation (midazolam 5 mg / iv) using a large cup forceps (Radial Jaw 4, Boston Scientific, Natick, Massachusetts, USA). All HIV-1 positive patients had a full colonoscopy and retrograde Ilioscopy using a conventional or fine scope (model CF or PCF-160 AI, Olympus Medical Europe GmbH, Hamburg, Germany) for at least 10 cm of the terminal ileum. ). We obtained specimens (2 biopsies at each site) from the terminal ileum, appendix, ascending, transverse and descending colons.
각 현미경 시야에서 평가된 모든 수를 5개의 무작위로 선별한 조직학적 섹션 시야에서 계산하고, 40XHPFS에서 평가하였다. 각 항원에 대해 면역조직화학적으로 양성인 모든 세포를 계측하였다. All numbers evaluated in each microscope field of view were counted in 5 randomly selected histological section fields of view and evaluated at 40XHPFS. All cells that were immunohistochemically positive for each antigen were counted.
조직학적 검사는 주로 상피내 림프구(I.E.L)(단핵 세포, 예컨대 마크로파지, 림프구, 혈장 세포, 및 호중구)의 양을 400X 배율에서 점수매겨 세포 침윤 및 응집의 평가를 포함하였다. Histological examination mainly included the evaluation of cell infiltration and aggregation by scoring the amount of intraepithelial lymphocytes (I.E.L) (monocytes such as macrophages, lymphocytes, plasma cells, and neutrophils) at 400X magnification.
염증 세포의 수는 이전에 기술된 바와 같은, 반정량적 방법을 사용해 평가하였고(ref. IBD Working Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition), 결과는 전체 표본에 대한 평균으로 보고하였다. The number of inflammatory cells was assessed using a semiquantitative method, as previously described (ref. IBD Working Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition), and the results reported as the mean for the entire sample.
아폽토시스 세포의 상피 및 림프구 수준의 동소발생 검출을 위해, 말단 데옥 시뉴클레오티딜 트랜스퍼라제-매개 디그옥시게닌데옥시우리딘 트리포스페이트 닉-말단 표지화(TUNEL)를 문헌 [Gavrieli et al., (Gavrieli Y et al.,)]에서 수행된 별법에 따라 모든 HIV-1 양성 환자에서 얻은 내시경 회장 및 결장 생검 표본의 조직학적 섹션에 적용하였다. 그 섹션을 20 ㎍/mL의 프로테이나제 K(Sigma Chemical, St Louis, MO)로 15분간 실온에서 분해시킨 후 수돗물로 세척하였다. 내생성 퍼옥시다제를 20분간 3% 수소 퍼옥시다제를 사용해 켄칭한 후 인산염-완충 염수(PBS)로 세척하였다. 평형화 후, 섹션을 습윤 챔버에서 말단 데옥시뉴클레오티딜 트랜스퍼라제 효소와 1시간 동안 37℃에서 항온반응시켰다. 이후, 섹션을 30분간 정지-세척 완충액에 함침시키고 PBS로 세정한 후, 항디그옥시게닌 퍼옥시다제와 습윤 챔버에서 30분간 항온반응시켰으며, 이어서 디아미노벤지딘 및 과산화수소를 1 내지 3분간 부가하여 아폽토시스 핵이 발색되도록 하였다. 마지막으로, 섹션을 해리스 헤마톡실린으로 대비염색하였다. For the detection of apoptosis of apoptotic cells at the epithelial and lymphocyte level, terminal deoxynucleotidyl transferase-mediated dioxygenindeoxyuridine triphosphate nick-terminal labeling (TUNEL) is described in Gavrieli et al., (Gavrieli Y. et al.,)] was applied to the histological sections of endoscopic ileal and colon biopsy specimens obtained from all HIV-1 positive patients. The section was digested with 20 μg / mL proteinase K (Sigma Chemical, St Louis, MO) at room temperature for 15 minutes and then washed with tap water. The endogenous peroxidase was quenched with 3% hydrogen peroxidase for 20 minutes and then washed with phosphate-buffered saline (PBS). After equilibration, sections were incubated with terminal deoxynucleotidyl transferase enzyme in a wetting chamber for 1 hour at 37 ° C. Thereafter, the sections were immersed in a stop-wash buffer for 30 minutes, washed with PBS, and then incubated with an anti-dioxygenin peroxidase for 30 minutes in a wet chamber, followed by addition of diaminobenzidine and hydrogen peroxide for 1 to 3 minutes. The apoptotic nuclei were allowed to develop. Finally, sections were counterstained with Harris Hematoxylin.
CSF를 요추 천자로 수집하여, 원심분리하고 세포 무함유 상등액 샘플을 분취액으로 -80℃에 저장하였다. 전체 혈액의 20 밀리리터를 각 실험 방문시 에틸렌디아민테트라아세트산(BD Biosciences, San Jose, CA)을 함유하는 진공 채혈관에 정맥 천자로 수집하였다. 혈장을 원심분리로 즉시 분리하여 -80℃에 저장하였다.CSF was collected by lumbar puncture, centrifuged and a cell-free supernatant sample was stored at -80 ° C as an aliquot. 20 milliliters of total blood was collected by venipuncture in vacuum blood vessels containing ethylenediaminetetraacetic acid (BD Biosciences, San Jose, CA) at each experimental visit. Plasma was immediately separated by centrifugation and stored at -80 ° C.
트립토판의 양과 관련하여 크로마토그래피 용리를 80:20(v/v) 비율의 나트륨 아세테이트(30 mM, pH 6.5) 및 아세토니트릴(용매 A) 및 50:50(v/v)의 프로판-2-올과 아세토니트릴(용매 B)의 2원 구배 시스템을 사용해 수행하였다. 데이터 분석은 전용 소프트웨어(Millennium32)를 사용해 수행하였다. Chromatographic elution with respect to the amount of tryptophan was 80:20 (v / v) in sodium acetate (30 mM, pH 6.5) and acetonitrile (solvent A) and 50:50 (v / v) propan-2-ol And acetonitrile (solvent B) using a binary gradient system. Data analysis was performed using dedicated software (Millennium 32 ).
결과: result:
무엇보다 우리는 HIV-1 감염된 환자의 LPL에서 그 양을 측정하여, GALT에서, 트립토판 대사에 관여하는, IDO의 수준을 평가하였다. 우리는 우리가 실험한 개체 군에서, 프로바이오틱 보충 후 IDO의 수준이 더 높음을 발견하였다(변동 계수 > 100%). 대조적으로 트립토판의 양은 프로바이오틱 식이 통합 6개월 후 모든 환자에서 감소하였다. Above all, we measured the amount in the LPL of HIV-1 infected patients and evaluated the level of IDO, which is involved in tryptophan metabolism in GALT. We found that in the population we tested, the level of IDO was higher after probiotic supplementation (variation coefficient> 100%). In contrast, the amount of tryptophan decreased in all
또한, 장 및 CNS 둘 모두에서 염증률을 평가하기 위해, 우리는 상피내 림프구(IEL) 밀도 및 아폽토시스를 겪는 장세포의 속도에 집중하여, 프로바이오틱 보충 전 및 후에 수집한 장 생검에서 염증성 침윤을 평가하였다. 우리는 프로바이오틱 보충 후 장 상피를 침윤하는 IEL의 감소가 상피 및 장 크립트 둘 모두에서 장세포 아폽토시스 지수 수준의 통계적으로 유의한 감소와 절대적으로 연관되었음을 발견하였다(p=0.04).In addition, to assess the inflammatory rate in both the intestine and the CNS, we focused on the concentration of lymphocytes (IEL) in the epithelium and the rate of intestinal cells undergoing apoptosis, resulting in inflammatory infiltration in intestinal biopsies collected before and after probiotic supplementation. Evaluated. We found that the decrease in IEL infiltrating the intestinal epithelium after probiotic supplementation was absolutely correlated with a statistically significant decrease in the level of intestinal apoptosis in both epithelial and intestinal crypts (p = 0.04).
유사하게, 모든 실험한 개체군에서, 우리는 프로바이오틱 보충 전(TO) 및 후(T6)에 CSF에서 네옵테린 수준의 유의한 감소 및 세로토닌 수준의 유의한 증가를 발견하였다. Similarly, in all tested populations, we found a significant decrease in the level of neoopterin and a significant increase in serotonin level in CSF before (TO) and after (T6) probiotic supplementation.
결론적으로 조합 항레트로바이러스 요법(cART) 하의 6명의 HIV-1+에서 6개월 동안 프로바이오틱 보충은 변경된 트립토판 대사와 관련된 IDO를 높은 수준으로 유도하였다. In conclusion, probiotic supplementation for 6 months in 6 HIV-1 + under combination antiretroviral therapy (cART) induced high levels of IDO associated with altered tryptophan metabolism.
또한 모든 환자에서 프로바이오틱 보충 6개월 후에 장과 CSF 모두에서 일반 염증이 유의하게 감소되는 것으로 관찰되었다. It was also observed that general inflammation was significantly reduced in both intestinal and CSF after 6 months of probiotic supplementation in all patients.
상기 결과 데이터는 다음과 같다.The result data are as follows.
Claims (34)
유산균, 비피도박테리아, 스트렙토코커스 및 이의 혼합물에서 선택된 트립토판 분해효소-음성 미생물을 포함하되;
상기 IFN 감마를 유도하는 미생물은 0.2ng/ml 이상으로 IFN 감마 생성을 유도할 수 있고, 이를 통해 IDO(인돌아민 2,3-디옥시게나제) 상승 및 키뉴레닌 대사활성화를 통해 염증 감소를 나타내는, 면역조절성 항염증 조성물.Microorganisms that induce IFN gamma selected from lactic acid bacteria, Bifidobacteria, Streptococcus, and mixtures thereof; And
Lactobacillus, Bifidobacteria, Streptococcus and tryptophan lysase-negative microorganisms selected from mixtures thereof;
The microorganism that induces IFN gamma can induce IFN gamma production at 0.2 ng / ml or more, thereby increasing IDO (indolamine 2,3-dioxygenase) and reducing inflammation through kynurenine metabolic activation. Immunomodulatory anti-inflammatory composition.
유산균, 비피도박테리아, 스트렙토코커스 및 이의 혼합물에서 선택된 트립토판 분해효소-음성 미생물을 포함하고;
상기 IFN 감마를 유도하는 미생물은 0.2ng/ml 이상으로 IFN 감마 생성을 유도할 수 있고, 이를 통해 IDO(인돌아민 2,3-디옥시게나제)의 상승 및 키뉴레닌 대사 활성화를 통해 에너지 대사 활성화 성분의 생산 상승에 효과가 있는, 에너지 보충용 조성물.Microorganisms that induce IFN gamma selected from lactic acid bacteria, Bifidobacteria, Streptococcus, and mixtures thereof; And
Tryptophan degrading enzyme-negative microorganisms selected from lactic acid bacteria, Bifidobacteria, Streptococcus and mixtures thereof;
The microorganism that induces IFN gamma can induce IFN gamma production at 0.2 ng / ml or more, and through this, an energy metabolism activation component through elevation of IDO (indolamine 2,3-dioxygenase) and activation of kynurenine metabolism The composition for energy supplementation, which is effective in increasing production.
10. The composition of claim 1 or 9, wherein the bacteria are selected from the following list alone or a mixture thereof.
스트렙토코커스 써모필러스(40 - 60%)
비피도박테리움 브레베(10 - 15%)
비피도박테리움 인판티스(10 - 15%)
비피도박테리움 롱검(10 - 15%)
엘. 액시도필러스(2 - 5%)
엘. 플랜타럼(3 - 5%)
엘. 파라카세이(4 - 4.9%)
엘. 델브루엑키 하위종 불가리커스(0.1 - 1%)
을 포함하는 조성물.The method according to claim 1 or 9, on a weight basis,
Streptococcus thermophilus (40-60%)
Bifidobacterium brevet (10-15%)
Bifidobacterium infantis (10-15%)
Bifidobacterium long sword (10-15%)
L. Axidophilus (2-5%)
L. Plan tarum (3-5%)
L. Paracasei (4-4.9%)
L. Delbruekki subspecies Bulgaricus (0.1-1%)
Composition comprising a.
스트렙토코커스 써모필러스 (40 - 60%)
비피도박테리움 브레베(10 - 15%)
비피도박테리움 락티스(10 - 15%)
비피도박테리움 락티스(10 - 15%)
엘. 액시도필러스(2 - 5%)
엘. 카세이(3 - 5%)
엘. 헬베티커스(4 - 4.9%)
을 포함하는 조성물.The method according to claim 1 or 9,
Streptococcus thermophilus (40-60%)
Bifidobacterium brevet (10-15%)
Bifidobacterium lactis (10-15%)
Bifidobacterium lactis (10-15%)
L. Axidophilus (2-5%)
L. Kasei (3-5%)
L. Helvetica (4-4.9%)
Composition comprising a.
스트렙토코커스 써모필러스(34 - 57%)
비피도박테리움 락티스(3 - 10%)
비피도박테리움 락티스(3 - 10%)
엘. 액시도필러스(3 - 5%)
엘. 플란타럼(3 - 8%)
엘. 카세이(3 - 4.9%)
엘. 헬베티커스(0.1 - 1%)
엘. 브레비스(5 - 50%)
을 포함하는 조성물.The method according to claim 1 or 9,
Streptococcus thermophilus (34-57%)
Bifidobacterium lactis (3-10%)
Bifidobacterium lactis (3-10%)
L. Axidophilus (3-5%)
L. Plantarum (3-8%)
L. Kasei (3-4.9%)
L. Helvetica (0.1-1%)
L. Brevis (5-50%)
Composition comprising a.
스트렙토코커스 써모필러스(34 - 57%)
비피도박테리움 롱검(3 - 10%)
비피도박테리움 롱검(3 - 10%)
비피도박테리움 인판티스(3 - 5%)
엘. 액시도필러스(3 - 8%)
엘. 플란타럼(3 - 4.9%)
엘. 파라카세이(0.1 - 1%)
엘. 헬베티커스(0.1 - 1%)
엘. 브레비스(5 - 50%)
을 포함하는 조성물.The method according to claim 1 or 9, on a weight basis,
Streptococcus thermophilus (34-57%)
Bifidobacterium long sword (3-10%)
Bifidobacterium long sword (3-10%)
Bifidobacterium infantis (3-5%)
L. Axidophilus (3-8%)
L. Plantarum (3-4.9%)
L. Paracasei (0.1-1%)
L. Helvetica (0.1-1%)
L. Brevis (5-50%)
Composition comprising a.
엘. 브레비스(15 - 20%)
피. 세르마니(5 - 20%),
0 내지 80 중량%의 부형제 및 0 내지 20 중량%의 상용성 약물
을 포함하는 조성물.The method according to claim 1 or 9, on a weight basis,
L. Brevis (15-20%)
blood. Sermani (5-20%),
0 to 80% by weight of excipients and 0 to 20% by weight of compatible drug
Composition comprising a.
엘. 브레비스(25 - 30%)
피. 세르마니(5 - 30%),
을 포함하는 조성물.The method according to claim 1 or 9, on a weight basis,
L. Brevis (25-30%)
blood. Sermany (5-30%),
Composition comprising a.
스트렙토코커스 써모필러스(34wt% 내지 60wt%)
를 포함하는 조성물.The method according to claim 1 or 9,
Streptococcus thermophilus (34 wt% to 60 wt%)
Composition comprising a.
엘. 브레비스(10 - 40%),
0 내지 80 중량%의 부형제 및 0 내지 20 중량%의 상용성 약물
을 포함하는 조성물.The method according to claim 1 or 9,
L. Brevis (10-40%),
0 to 80% by weight of excipients and 0 to 20% by weight of compatible drug
Composition comprising a.
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CN201880018611.5A CN110446497A (en) | 2017-03-15 | 2018-03-14 | Tryptophanase feminine gender lactic acid bacteria, correspondent composition and purposes |
JP2019572333A JP2020512014A (en) | 2017-03-15 | 2018-03-14 | Tryptophan-degrading enzyme-negative lactic acid bacterium, corresponding composition and use |
PCT/KR2018/002969 WO2018169297A1 (en) | 2017-03-15 | 2018-03-14 | Tryptophanase-negative lactic bacteria, corresponding compositions and uses |
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MY180910A (en) | 2010-12-31 | 2020-12-11 | Abbott Lab | Methods for reducing the incidence of oxidative stress using human milk oligosaccharides, vitamin c and anti-inflammatory agents |
WO2013016111A1 (en) | 2011-07-22 | 2013-01-31 | Abbott Laboratories | Galactooligosaccharides for preventing injury and/or promoting healing of the gastrointestinal tract |
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