TWI640314B - 戈氏副擬桿菌用於降低胰島素抗性及提升葡萄糖耐受性之用途 - Google Patents
戈氏副擬桿菌用於降低胰島素抗性及提升葡萄糖耐受性之用途 Download PDFInfo
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Abstract
本發明提供一種使用戈氏副擬桿菌於降低胰島素抗性及提升葡萄糖耐受性之用途，故可用於第二型糖尿病與代謝症候群的治療。
Description
本發明係關於一種益生菌之用途。進一步而言，本發明係關於一種戈氏副擬桿菌用於降低胰島素抗性、提升葡萄糖耐受性、及治療第二型糖尿病與代謝症候群之用途。
依據世界衛生組織的報導，自1980年來全球第二型糖尿病患者的發生率已經增加一倍以上，達到全球性流行的標準。據估計2014年全球人口中約有8.5%(4.42億)罹患第二型糖尿病。糖尿病患者有較高風險發生失明、腎衰竭、高血壓、心臟病、及中風，大幅降低生活品質，並可能導致提早死亡。胰島素抗性(insulin resistance)是一種身體細胞對胰島素反應差的狀況，其可能發生於第二型糖尿病之前，並導致疲勞及多種代謝疾病(即代謝症候群)。儘管某些個體的胰島素抗性及糖尿病形成與老化及遺傳有關，糖尿病流行主要是起因於飲食不良、吸煙、及缺乏運動。因此，第二型糖尿病及其併發症可透過改變生活方式加以預防。
雖然多種用於治療第二型糖尿病的藥物已被核准，例如雙胍類(biguanides)、α-葡萄糖苷酶(α-glucosidase)抑制劑、類升糖素胜肽(glucagon-like peptides)、格列奈類(meglitinides)、鈉-葡萄糖轉運蛋白2(sodium glucose transporter 2)抑製劑、磺基尿素類(sulfonylureas)、格列酮類(thiazolidinediones)，這些藥物通常會產生副作用，因此降低治療效果和患者依從性。治療糖尿病及減輕體重的策略之一為低熱量飲食及規律運動，但這些方法難以執行，且其長期效果令人
失望。基於這些因素，開發安全而有效的第二型糖尿病替代治療方案實有其必要。
腸道菌群(gut microbiota)參與多種生理功能，例如能量調節、維生素生產、毒素中和、及養分吸收。先前研究發現糖尿病患者的腸道菌組成改變(gut dysbiosis)，但各種益生菌是否可用於治療胰島素抗性和第二型糖尿病仍不清楚。
緣此，本發明之一目的在提供一種戈氏副擬桿菌(Parabacteroides goldsteinii)用於製備降低胰島素抗性及提升葡萄糖耐受性之組合物之用途。
在本發明之一實施例中，戈氏副擬桿菌係為一活菌株，其係以口服方式施予一個體；戈氏副擬桿菌的有效劑量係為每日0.001菌落形成單位(colony-forming units，CFUs)/kg體重至5×1018CFUs/kg體重，而對一人類個體(平均體重為70公斤)而言，戈氏副擬桿菌的有效劑量係為每日給予一個體6.1×109CFUs。
前述由戈氏副擬桿菌所製備之降低胰島素抗性及提升葡萄糖耐受性之組合物可包含一其他成分，該其他成分係選自於由單醣、雙醣、寡醣、多醣、碳水化合物、胺基酸、蛋白質、脂質、維生素、及其任意組合所組成的群組。該組合物亦可包含一他種菌株。同時，該組合物具有一溶液、一明膠膠囊、一軟膠囊、或一錠劑之形式。
本發明證實戈氏副擬桿菌在哺乳類動物能有效降低胰島素抗性及提升葡萄糖耐受性，因此可提供治療或預防第二型糖尿病或代謝症候群的醫藥品、飲料、食品、或營養補充品。
以下將配合圖式進一步說明本發明的實施方式，下述所列舉的實施例係用以闡明本發明之發明特點及應用，而非以限定本發明之範圍，任何熟習此技藝者，在不脫離本發明之精神和範圍內，當可做些許更動與潤飾，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。
圖1顯示戈氏副擬桿菌(P.goldsteinii)對正常飲食(chow)及高脂飲食(high-fat diet，HFD)小鼠之胰島素抗性的影響；***表示P<0.001。
圖2顯示戈氏副擬桿菌(P.goldsteinii)對正常飲食(chow)及高脂飲食(HFD)小鼠之口服葡萄糖耐受性試驗結果的影響。
圖3顯示戈氏副擬桿菌(P.goldsteinii)對正常飲食(chow)及高脂飲食(HFD)小鼠之口服葡萄糖耐受性試驗結果的影響；縱軸之曲線下面積(area under the curve，AUC)係使用梯形法由圖2的結果計算而得，其值以任意單位(arbitrary units)表示；*表示P<0.05。
圖4顯示屎副擬桿菌(Parabacteroides merdae)對正常飲食(chow)及高脂飲食(HFD)小鼠之口服葡萄糖耐受性試驗結果的影響。
圖5顯示屎副擬桿菌(P.merdae)對正常飲食(chow)及高脂飲食(HFD)小鼠之口服葡萄糖耐受性試驗結果的影響；縱軸之曲線下面積係由圖4的結果計算而得。
本文所述之「有效劑量」係表示能降低動物及人類胰島素抗性(HOMA-IR)與提升葡萄糖耐受性之細菌量。該有效劑量可依施予生物體或個體的不同而有差異，但可運用如劑量遞增研究之多種實驗技術決定有效劑量。
本文中所使用數值為近似值，所有實驗數據皆表示在20%的範圍內，較佳為在10%的範圍內，最佳為在5%的範圍內。
本發明提供一種戈氏副擬桿菌用於製備降低胰島素抗性及提升葡萄糖耐受性之組合物之用途，故戈氏副擬桿菌可應用於治療第二型糖尿病與代謝症候群。以下實驗顯示將一有效劑量的戈氏副擬桿菌施予一表現胰島素抗性或第二型糖尿病的個體後，該個體的胰島素抗性明顯降低，且其葡萄糖耐受性增加。概括而言，每日施予哺乳動物或人類的戈氏副擬桿菌劑量可為0.001CFUs/kg體重至5×1018CFUs/kg體重。本發明之詳細說明如下。
本發明實施例中所用細菌包含購自美國典型培養物保藏中心(American Type Culture Collection，ATCC)之戈氏副擬桿菌(P.goldsteinii)ATCC BAA-1180菌株、及屎副擬桿菌(P.merdae)ATCC 43184菌株。該細菌培養於硫乙醇酸鹽(thioglycollate)液體培養基，培養條件為含10%二氧化碳、10%氫氣、及80%氮氣的無氧環境(DG250 Anaerobic Workstation，Don Whitley Scientific，英國)。
空腹血液中葡萄糖或血糖之測定係使用血糖機測試條(Johnson & Johnson Medical Devices，香港)在小鼠禁食6小時後進行。空腹血液中胰島素之測定係依據廠商說明書利用酵素連結免疫吸附分析(enzyme-linked immunosorbent assay，ELISA)試劑組(Mercodia，瑞典)。HOMA-IR指數之計算係使用下列公式：空腹血糖(mg/dl)×空腹血液中胰島素(μU/ml)/405
進行口服葡萄糖耐受性試驗時，以胃內灌食(intragastric gavage)方式給予禁食8小時的小鼠10%(w/v)葡萄糖溶液(劑量為1g/kg)，並每隔一段固定時間測定血糖。
實驗數據皆表示為平均值±標準偏差，其統計分析係使用單變量變異數分析(one-way ANOVA)及Bonferroni氏事後檢定(Bonferroni post hoc test)。
對8週齡的C57BL/6J雄性小鼠餵食標準飼料(能量來源13.5%為脂肪；參見Laboratory Rodent Diet 5001，LabDiet，美國)或高脂肪含量飼料(能量來源60%為脂肪；參見Laboratory Rodent Diet 5001，LabDiet，美國)，並且每天以胃內灌食方式給予200μL的戈氏副擬桿菌ATCC BAA-1180菌株(2×106CFUs)、屎副擬桿菌ATCC 43184菌株(2×106CFUs)、或磷酸鹽緩衝液，持續8週(n=6，代表每組各有6隻小鼠)。前述小鼠組別分為標示為正常飲食+磷酸鹽緩衝液、正常飲
食+P.goldsteini、高脂飲食+磷酸鹽緩衝液、高脂飲食+P.goldsteini、及高脂飲食+P.merdae。8週後，各組小鼠進行胰島素抗性平衡模式評估(HOMA-IR)及口服葡萄糖耐受性試驗(OGTT)。
圖1顯示戈氏副擬桿菌對正常飲食小鼠及高脂飲食小鼠之HOMA-IR指數的影響。依據圖1，高脂飲食小鼠相比正常飲食小鼠表現出較高的胰島素抗性。但相較於經高脂飲食+磷酸鹽緩衝液處理的小鼠，高脂飲食+P.goldsteini之處理明顯降低小鼠的胰島素抗性，顯示施予戈氏副擬桿菌可顯著降低個體的胰島素抗性。
圖2及圖3顯示戈氏副擬桿菌對正常飲食小鼠及高脂飲食小鼠之口服葡萄糖耐受性試驗結果的影響。依據圖2至圖3，在服用葡萄糖後，高脂飲食小鼠相比正常飲食小鼠有普遍較高的血液中葡萄糖濃度，但以戈氏副擬桿菌處理高脂飲食小鼠會顯著低其血液中葡萄糖濃度，顯示施予戈氏副擬桿菌可顯著提升個體的葡萄糖耐受性。
上述圖1至圖3的結果證實戈氏副擬桿菌對高脂飲食誘導肥胖小鼠有降低胰島素抗性及提升葡萄糖耐受性的功效。由該些結果可計算得戈氏副擬桿菌在8週間促進小鼠(平均體重為23g)胰島素敏感性或使其對抗糖尿病所需的劑量為8.7×107CFUs/kg體重。經由換算，可得戈氏副擬桿菌在8週間於人類個體(平均體重為70kg)產生相似的胰島素致敏功效的劑量為6.1×109CFUs/個人。
圖4及圖5顯示副擬桿菌屬中的屎副擬桿菌對正常飲食小鼠及高脂飲食小鼠之口服葡萄糖耐受性試驗結果的影響，該屎副擬桿菌之處理係作為負對照組。經過8週之飼料餵食及屎副擬桿菌處理，如圖4至圖5所示，相較於經高脂飲食+磷酸鹽緩衝液處理的小鼠，高脂飲食+P.merdae之處理未顯著改變小鼠的血糖濃度。此結果說明前述戈氏副擬桿菌促進胰島素敏感性的效果並非副擬桿菌屬細菌的共通特性，而是戈氏副擬桿菌的專有特性。
本實施例進一步檢測戈氏副擬桿菌之處理對小鼠血液生化指數的影響，其結果如表1所示。該血液生化指數包括用於評估肝功能的天冬胺酸轉氨酶(aspartate transaminase，AST)與丙胺酸轉氨酶(alanine transaminase，ALT)含量以及用於評估腎功能的血液中尿素氮(blood urea nitrogen)與肌酸酐(creatinine)含量，其測定係利用Hitachi 7080生化分析儀(Hitachi，日本)。依據表1，小鼠以正常飲食+磷酸鹽緩衝液處理或以正常飲食+P.goldsteini處理後，該二組小鼠的血液生化指數沒有顯著差異，顯示施予戈氏副擬桿菌不會影響肝功能及腎功能。
上述實驗結果顯示戈氏副擬桿菌在哺乳類動物中能有效降低胰島素抗性及提升葡萄糖耐受性，故其能應用於治療第二型糖尿病與代謝症候群。同時，本發明以P.merdae做為比較例，證實儘管戈氏副擬桿菌屬(Parabacteroides)之菌株眾多，非所有副擬桿菌屬之菌株皆具有降低胰島素抗性及提升葡萄糖耐受性的效果。戈氏副擬桿菌可添加於一個體的飲食，製成一醫藥品、一飲料、一食品、或一營養補充品，卻不影響個體的生活型態，亦不會引發不良健康狀況或毒性。因此，本發明提供了一種利用戈氏副擬桿菌治療胰島素抗性、第二型糖尿病、及代謝症候群的新策略。鑑於市場上對胰島素抗性、第二型糖尿病、及代謝症候群之治療或預防產品的迫切需求，本發明顯然具有產業上利用的價值。
Claims (6)
- 一種戈氏副擬桿菌(Parabacteroides goldsteinii)用於製備降低胰島素抗性及提升葡萄糖耐受性之組合物之用途。
- 如申請專利範圍第1項所述之用途，其中該戈氏副擬桿菌係以口服方式施予。
- 如申請專利範圍第1項所述之用途，其中該戈氏副擬桿菌係為一活菌株。
- 如申請專利範圍第1項所述之用途，其中該戈氏副擬桿菌的有效劑量係為每日給予0.001CFUs/kg體重至5×1018CFUs/kg體重。
- 如申請專利範圍第1項所述之用途，其中該戈氏副擬桿菌的有效劑量係為每日給予一個體6.1×109CFUs。
- 如申請專利範圍第1項所述之用途，其中該組合物具有一溶液、一明膠膠囊、一軟膠囊、或一錠劑之形式。
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