TW201808314A - 改善困難梭狀桿菌感染症狀的發酵乳酸桿菌gmnl-296組合物及方法 - Google Patents
改善困難梭狀桿菌感染症狀的發酵乳酸桿菌gmnl-296組合物及方法 Download PDFInfo
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Abstract
本發明提供一種改善困難梭狀桿菌感染症狀的發酵乳酸桿菌GMNL-296組合物及方法。該發酵乳酸桿菌GMNL-296可以促進抗發炎細胞激素IL-10及調節型T細胞相關轉錄因子之表達而改善體重減輕及腸道異常的症狀。
Description
本發明係關於一種改善困難梭狀桿菌感染症狀的發酵乳酸桿菌GMNL-296組合物與改善困難梭狀桿菌感染症狀的方法,特別是關於一種可治療或預防困難梭狀桿菌感染症狀的抗發炎的發酵乳酸桿菌GMNL-296組合物與改善困難梭狀桿菌感染症狀的方法。
困難梭狀桿菌(Clostridium difficile),為造成住院病人因使用抗生素而導致腹瀉之主要病源菌,症狀從輕微腹瀉到嚴重腸道發炎如偽膜性腸炎(pseudomembranous enteritis)、毒性巨腸症(toxic megacolon),菌血症,嚴重甚至可能造成死亡。困難梭狀桿菌可藉由孢子的型式散播,過去的研究發現困難梭狀桿菌感染(C.difficile infection;CDI)在台灣的感染率有逐漸上升的趨勢(Px Zheng,Genome Announc.2013.1:e00149-12.)。根據美國疾病管制局的統計,每年有十萬名美國病患死於院內感染,其造成的死亡率正在攀升中(MF Shih.,Int.J.Immunopathol.Pharmacol.2012.25:39-48.2)。目前臨床上治療困難梭狀桿菌之方式,若因抗生素引起CDI的症狀,則建議先停止目前使用的抗生素,再依照其疾病嚴重程度使用甲硝唑 (metronidazole)及萬古黴素(vancomycin)。然而,此兩種藥物在某些病人的治療上是無效的,或者復發率高(YC Lin,2011.Antimicrob.Agents Chemother.55:1701-5.)。
目前治療的困境除了因為困難梭狀桿菌產生之抗藥性外,就是病人本身難以形成適當之保護性免疫反應,因此可能造成重複性感染問題。由於困難梭狀桿菌在醫療照護機構的感染率逐漸升高,於治療上又有復發之可能性。因此尋找非抗生素治療及改善困難梭狀桿菌感染已成為一個亟需重視之問題。
雖然過去研究發現,某些特殊乳酸菌菌種對於困難梭狀桿菌有很強的抑菌能力,藉此能改善小鼠感染困難梭狀桿菌後之症狀;但過去並沒有任何報導指出乳酸菌能經由免疫調節之方式,改善困難梭狀桿菌感染造成的腸炎症狀。
故,有必要提供一種抗發炎的發酵乳酸桿菌菌株及其組合物與改善困難梭狀桿菌感染症狀的方法,以解決習用技術中所存在的問題。
本發明之主要目的在於提供一種改善困難梭狀桿菌感染症狀的發酵乳酸桿菌GMNL-296組合物與改善困難梭狀桿菌感染症狀的方法,可藉由發酵乳酸桿菌(Lactobacillus fermentum)GMNL-296來刺激免疫反應,以改善困難梭狀桿菌造成的體重減輕及腸道不良反應。該發酵乳酸桿菌可藉由食道進入消化系統內,刺激抑制發炎的細胞激素介白質-10(Interleukin-10,IL-10)的分泌及增強調節型T細胞功能,可抑制及降低腸道發炎現象。
為達上述之目的,本發明的一實施例提供一種發酵乳酸桿菌組合物,用於改善困難梭狀桿菌感染症狀,其包含發酵乳酸桿菌(Lactobacillus fermentum)GMNL-296,該發酵乳酸桿菌GMNL-296係以寄存編號BCRC 910720寄存於食品工業發展研究所的生物資源保存及研究中心(BCRC of FIRDI)。
在本發明的一實施例中,該發酵乳酸桿菌GMNL-296為活菌菌株。
在本發明的一實施例中,該發酵乳酸桿菌組合物是一醫藥組合物、一營養補充品、一保健食品、一醫療食品或其組合。
為達上述之目的,本發明的再一實施例提供一種改善困難梭狀桿菌感染症狀的方法,其包含使用上述發酵乳酸桿菌GMNL-296以促進抗發炎細胞激素IL-10分泌。
在本發明的一實施例中,該發酵乳酸桿菌GMNL-296為活菌菌株。
在本發明的一實施例中,該困難梭狀桿菌感染症狀係體重減輕或腸道異常。
在本發明的一實施例中,該腸道異常為結腸到盲腸段長度變短。
第1圖:本發明實驗1之抑菌圈試驗後,各菌株對於困難梭狀桿菌的抑制結果比較圖。
第2圖:本發明之發酵乳酸桿菌菌株GMNL-296在實驗2之抗發炎測試中,不同劑量對NO含量影響。
第3A至3B圖:實驗3中餵食發酵乳酸桿菌菌株GMNL-296或磷酸鹽生理食鹽水(PBS)對已感染困難梭狀桿菌後的小鼠的影響。
第4圖:實驗3中餵食發酵乳酸桿菌菌株GMNL-296或磷酸鹽生理食鹽水(PBS)對腸道組織之調節型T細胞(Treg)重要轉錄因子FoxP3、GATA3以及可抑制發炎的細胞激素IL-10之mRNA的表現量。
為了讓本發明之上述及其他目的、特徵、優點能更明顯易懂,下文將特舉本發明較佳實施例,並配合所附圖式,作詳細說明如下。此外,本發明所提到的單數形式“一”、“一個”和“所述”包括複數引用,除非上下文另有明確規定。數值範圍(如10%~11%的A)若無特定說明皆包含上、下限值(即10%≦A≦11%);數值範圍若未界定下限值(如低於0.2%的B,或0.2%以下的B),則皆指其下限值可能為0(即0%≦B≦0.2%)。上述用語是用以說明及理解本發明,而非用以限制本發明。
本發明之一實施例提供一種改善困難梭狀桿菌感染症狀的發酵乳酸桿菌菌株,其中該發酵乳酸桿菌菌株是指發酵乳酸桿菌(Lactobacillus fermentum)GMNL-296,且以寄存編號BCRC 910720寄存於食品工業發展研究所的生物資源保存及研究中心(BCRC of FIRDI)。
本發明之一實施例提供一種發酵乳酸桿菌組合物,其包含如上所述之改善困難梭狀桿菌感染症狀的發酵乳酸桿菌菌株。較佳的,該發酵乳酸桿菌組合物也可以一醫藥組合物、一營養補充品、一保健食品、 一醫療食品或其組合的方式呈現。該組合物可以根據有效性或方便性來考量設計成不同的形態。此外,該組合物是以食用方式進入消化系統,可刺激免疫反應來抑制腸道發炎。
本發明之一實施例提供了一種改善困難梭狀桿菌感染症狀的方法,其包含下列步驟:使用如上述之發酵乳酸桿菌GMNL-296活菌菌株,以促進調節型T細胞(Treg)相關轉錄因子FoxP3及GATA3及可抑制發炎的細胞激素IL-10之mRNA之表現量,而改善困難梭狀桿菌感染症狀係體重減輕或腸道異常,其中該腸道異常指一般為直腸、結腸至盲腸段發炎,而且外觀長度變短變粗。
上述實施例中的該發酵乳酸桿菌菌株GMNL-296主要是從人體腸道篩選分離獲得的多個分離株的其中一株。利用表1之引子(SEQ ID NO:1及SEQ ID NO:2)進行PCR以複製多個分離株各自的16S rDNA片段,接著將其加以定序,定序完成後得到其中一株的16S rDNA基因序列如下(SEQ ID NO:3);隨後,如下表2所示,由NCBI網站比對後的結果可知,該分離株的16 S rDNA序列與發酵乳酸桿菌菌株(Lactobacillus fermentum)的16S rDNA序列相似,相似度均為99%以上,故可知此菌株GMNL-296確實為發酵乳酸桿菌屬。
該發酵乳酸桿菌菌株GMNL-296的完整16S rDNA序列(SEQ ID NO:3)如下:
對該發酵乳酸桿菌菌株GMNL-296進行醱酵試驗,可獲得如表3的結果。
為了驗證本發明所提供之該發酵乳酸桿菌GMNL-296具有抗發炎的特性,並能達到改善困難梭狀桿菌感染症狀,進行了以下實驗1-3。
實驗1:
病原菌處理:將困難梭狀桿菌病原菌(Clostridium VPI10463)畫盤後隔夜培養,將之刮下並懸浮於0.5ml BHIS broth中取病原菌液測濃度(調整為1x1010CFU/ml),取100μl塗病原菌盤培養。
乳酸菌處理:
將1x108CFU/ml的發酵乳酸桿菌(Lactobacilli fermentum)GMNL-296及下表4中所示其他乳酸菌種(對照組)培養至隔夜,並分別收集活菌上清液,並利用0.22μm過濾膜過濾(#1),並將MRS肉湯以HCl滴定至與原上清液相同pH值做為控制組(#2)。取100μl各組不同乳酸菌種 的待測物加至病原菌盤上打好的孔洞內,並放至厭氧培養箱培養隔夜,以游標卡尺測量抑菌圈內徑與外徑。
實驗結果請見第1圖,可看出菌種2之#1即L.fermentum GMNL-296之活菌菌液並無明顯抑制Clostridium VPI10463生長之情形,控制組(MRS,pH=4.0)的實驗結果也未出現抑菌圈。因此可知,發酵乳酸桿菌(Lactobacillus fermentum)GMNL-296並無直接抑制困難梭狀桿菌生長之能力。
實驗2:
菌液培養:自凍管接種發酵乳酸桿菌GMNL-296到1ml的MRS肉湯,並於37℃有氧下靜置培養20小時。次日,取15μl隔夜培養 菌液至1.5ml的MRS肉湯(1%二次活化),37℃有氧下靜置培養20小時。
細胞培養:將巨噬細胞株(RAW 264.7)之細胞數調整為8 x 105cells/ml,在24孔盤中加入0.5ml細胞液(最終細胞數為4x105cells/well),並於37℃靜置隔夜後,先以磷酸鹽生理食鹽水(以下簡稱PBS)清洗1次後,將細胞培養基更換成0.4ml/well不含血清之培養基(DMEM)進行飢餓(starvation)2小時。
菌液與細胞共培養:取出前一晚培養之菌液進行離心(13,000rpm、1分鐘),並進行兩次PBS洗菌,再次移除上清液後,取20μl的PBS懸浮菌塊混合980μl的PBS(稀釋50倍),測量OD 600,回推調整菌液濃度為1x1010CFU/ml;將調整好的菌液取0.2ml再混合0.8ml DMEM(無血清),使最終菌數成為2x109CFU/ml,並預先將此最終濃度依序調整菌量成為2 x 109、1 x 109、5 x 108、1 x 108、5 x 107CFU/ml備用。待細胞進行飢餓2小時後,再加入100μl已製好之不同稀釋倍數的菌液,處理細胞2小時。
菌液與細胞共培養2小時後,繼續在每個孔洞中加入0.5ml含200ng/ml的LPS之DMEM;控制組(mock)則加入0.5ml DMEM,再共同培養20小時後,收集細胞上清液,並測定NO含量。
將NO試劑(80μl Griess reagent A+80μl Griess reagent B)混合80μl細胞上清液,於室溫下作用5分鐘後,利用ELISA reader測定OD 550nm之吸光值。結果如第2圖所示,可發現LPS能有效的促進RAW264.7細胞之發炎物質一氧化氮(NO)的產生。此外,在不同劑量GMNL-296預先處理後,隨著GMNL-296劑量的提升,NO含量也逐漸降 低,特別是從劑量5 x 107CFU/ml到2 x 108CFU/ml,相較於不加GMNL-296而單純只加LPS的組別有非常顯著的下降,顯示發酵乳酸桿菌GMNL-296在特定劑量區間可抑制發炎反應,是具有抗發炎能力之菌株。因此,發酵乳酸桿菌GMNL-296可以有效抑制LPS刺激RAW264.7細胞所產生的發炎現象。
實驗3:
實驗材料:7-8週齡小鼠(C57BL/6)及發酵乳酸桿菌GMNL-296活菌菌粉。
實驗方法:7-8週齡小鼠(C57BL/6)每日管餵GMNL-296菌液(4*108CFU/kg),持續管餵10日,在第5日進行疾病動物模式造症,給予飲用抗生素水卡那黴素(kanamycin)0.4mg/ml、慶大霉素(gentamycin)0.057mg/ml、多粘菌素(colistin)0.057mg/ml、甲硝唑(metronidazole)0.215mg/ml、萬古黴素(vancomycin)0.045mg/ml,持續五天,並在飲用抗生素水的第4天開始每12小時管餵一次質子幫浦抑制劑(PPI)、埃索美拉唑(Esomeprazole,Nexium)40mg/kg/天。另外,以同樣模式將GMNL-296菌液替換為PBS進行管餵及造症作為對照組。
第5天抗生素水去除甲硝唑及萬古黴素。感染當日以腹腔注射克林黴素(clindamycin)4mg/kg,並餵食每隻小鼠困難梭狀桿菌(Clostridium VPI10463)菌量1x108cfu,此過程仍持續給予管餵GMNL-296。
同步觀察老鼠體重變化,並解剖分析腸子長度。將小鼠腸道組織取出並純化其RNA,利用即時定量PCR(real-time PCR)來分析調節型T細胞(Treg)相關轉錄因子FoxP3及GATA3及可抑制發炎的細胞激素 IL-10之mRNA之表現量。
由實驗3可發現,小鼠感染困難梭狀桿菌後的確會造成小鼠腸炎病癥,包含體重下降及盲腸至結腸段長度變短。請參考第3A至3B圖,餵食GMNL-296的組別,能有效保護小鼠因困難梭狀桿菌感染而引起之體重下降(第3A圖)與盲腸至結腸段長度變短(第3B圖)的症狀。從上述結果中,可以顯示發酵乳酸桿菌GMNL-296能改善因困難梭狀桿菌感染而造成的盲腸與結腸段異常現象。
此外,請參考第4圖,其顯示了轉錄因子FoxP3及GATA3及可抑制發炎的細胞激素IL-10之mRNA的表現量。從第4圖中也可以發現,發酵乳酸桿菌GMNL-296的給予能促進小鼠腸道組織中,FoxP3基因的增加;同時,也能夠促進抗發炎細胞激素IL-10之分泌,這兩個分子與Treg的活化極為相關,GMNL-296能經由這些分子之增加,進而活化調節型T細胞的產生,達到免疫調節之能力。此外,也發現GMNL-296具有增加GATA3(Trans-acting T-cell-specific transcription factor 3)基因表達之能力;GATA3為影響調節型T細胞功能之重要轉錄因子;GMNL-296也可經此分子,達到改善困難梭狀桿菌急性感染後造成的免疫紊亂。從此結果來看,發酵乳酸桿菌GMNL-296降低因困難梭狀桿菌感染而引起之體重減輕與腸道結構的異常症狀,其主要是藉由增加腸道組織之FoxP3、IL-10及GATA3基因表現調節免疫反應,而非抑制困難梭狀桿菌的生長。
綜合上述結果,可以確定本發明所提供之發酵乳酸桿菌GMNL-296組合物與改善困難梭狀桿菌感染症狀的方法,已成功建立困難梭狀桿菌感染的動物模式平台,由於受感染的小鼠在疾病表癥貼近臨床人 類的疾病病癥,包含嚴重腹瀉、體重減低、盲腸與大腸的潰瘍甚至死亡等等。從實驗結果發現發酵乳酸桿菌(Lactobacillus fermentum GMNL-296)確實具有改善困難梭狀桿菌感染所造成的動物體重與腸組織長度變短的效果,代表發酵乳酸桿菌GMNL-296具有預防及治療因困難梭狀桿菌感染所形成的惡性症狀之效果。此外,發酵乳酸桿菌GMNL-296主要係經由促進調節型T細胞相關之分子FoxP3及IL-10的表達增加,也亦有少量GATA3的表達增加,而達到改善困難梭狀桿菌感染後的症狀,與直接抑制困難梭狀桿菌生長之能力有著顯著不同,亦即,在困難梭狀桿菌感染的改善機制上是明顯不同於以往。
雖然本發明已以較佳實施例揭露,然其並非用以限制本發明,任何熟習此項技藝之人士,在不脫離本發明之精神和範圍內,當可作各種更動與修飾,因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。
國內寄存資訊【請依寄存機構、日期、號碼順序註記】
食品工業發展研究所、2016年2月26日、BCRC 910720
<110> 景岳生物科技股份有限公司
<120> 改善困難梭狀桿菌感染症狀的發酵乳酸桿菌GMNL-296組合物及方法
<130> TP160475-TW
<160> 3
<170> PatentIn version 3.5
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<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> PAF primer
<400> 1
<210> 2
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> 536R primer
<400> 2
<210> 3
<211> 516
<212> DNA
<213> Artificial Sequence
<220>
<223> Sequencing Primer
<400> 3
Claims (7)
- 一種發酵乳酸桿菌組合物,用於改善困難梭狀桿菌感染症狀,其包含發酵乳酸桿菌( Lactobacillus fermentum)GMNL-296,且該發酵乳酸桿菌GMNL-296係以寄存編號BCRC 910720寄存於食品工業發展研究所的生物資源保存及研究中心(BCRC of FIRDI)。
- 如申請專利範圍第1項所述之發酵乳酸桿菌組合物,其中該發酵乳酸桿菌GMNL-296是活菌菌株。
- 如申請專利範圍第1項所述之發酵乳酸桿菌組合物,其中該發酵乳酸桿菌組合物是一醫藥組合物、一營養補充品、一保健食品、一醫療食品或其組合。
- 一種改善困難梭狀桿菌感染症狀的方法,其包含下列步驟:使用如申請專利範圍第1項所述之發酵乳酸桿菌組合物以促進抗發炎細胞激素IL-10分泌及FoxP3及GATA3增加。
- 如申請專利範圍第4項所述之改善困難梭狀桿菌感染症狀的方法,其中該發酵乳酸桿菌菌株是活菌菌株。
- 如申請專利範圍第4項所述之改善困難梭狀桿菌感染症狀的方法,其中該困難梭狀桿菌感染症狀係體重減輕或腸道異常。
- 如申請專利範圍第4項所述之改善困難梭狀桿菌感染症狀的方法,其中該腸道異常為直腸、結腸至盲腸段發炎及/或外觀長度變短變粗。
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TW105126799A TWI598103B (zh) | 2016-08-22 | 2016-08-22 | 改善困難梭狀桿菌感染症狀的發酵乳酸桿菌gmnl-296組合物及方法 |
CN201610839865.6A CN107760615B (zh) | 2016-08-22 | 2016-09-22 | 改善困难梭状杆菌感染症状的发酵乳酸杆菌gmnl-296组合物及用途 |
US15/366,193 US10159700B2 (en) | 2016-08-22 | 2016-12-01 | Method of treating Clostridium difficile infection |
AU2017200236A AU2017200236B1 (en) | 2016-08-22 | 2017-01-13 | Composition and use of lactobacillus fermentum GMNL-296 to produce composition for improving symptoms of clostridium difficile infection |
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TW105126799A TWI598103B (zh) | 2016-08-22 | 2016-08-22 | 改善困難梭狀桿菌感染症狀的發酵乳酸桿菌gmnl-296組合物及方法 |
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CN110229769B (zh) * | 2019-06-28 | 2021-09-10 | 江南大学 | 缓解pfoa毒害作用的多功能发酵乳杆菌ccfm1051、其发酵食品及应用 |
KR102296287B1 (ko) * | 2020-12-11 | 2021-09-01 | 주식회사 바이오뱅크힐링 | 락토바실러스 퍼멘텀 균주, 및 그의 유래의 소포체 및 그의 항염증 및 항균 용도 |
WO2022124871A1 (ko) * | 2020-12-11 | 2022-06-16 | 주식회사 바이오뱅크힐링 | 락토바실러스 속 균주, 유박테리움 속 균주 또는 코프로코커스 속 균주 및 그의 유래의 소포체 및 그의 항염증 및 항균 용도 |
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PE20030274A1 (es) * | 2001-07-26 | 2003-05-08 | Alimentary Health Ltd | Cepas de lactobacillus salivarius |
PE20030283A1 (es) * | 2001-07-26 | 2003-05-01 | Alimentary Health Ltd | Cepas de lactobacillus casei |
ES2311729T5 (es) * | 2002-06-28 | 2013-02-14 | Biosearch S.A. | Cepas probióticas, un procedimiento para la selección de ellas, composiciones de las mismas y su uso |
AU2002951270A0 (en) * | 2002-09-06 | 2002-09-19 | Vri Biomedical Ltd | Probiotic Bacterium and Methods of Use |
DE102009037089A1 (de) * | 2009-08-11 | 2011-03-03 | Heller, Knut J., Prof. Dr. | Zusammensetzung mit Stämmen von Lactobazillus fermentum |
US8853269B2 (en) * | 2010-02-04 | 2014-10-07 | Copperhead Chemical Company Inc. | Composition and method for treating infections and promoting intestinal health |
CN104611275B (zh) * | 2015-02-11 | 2017-10-17 | 成都与康科技有限公司 | 植物乳杆菌ucn‑11菌株及其组合物和应用 |
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AU2017200236B1 (en) | 2018-03-01 |
TWI598103B (zh) | 2017-09-11 |
CN107760615B (zh) | 2021-04-20 |
US10159700B2 (en) | 2018-12-25 |
CN107760615A (zh) | 2018-03-06 |
US20180050072A1 (en) | 2018-02-22 |
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