⭐️前言
腸道中各種類型的微生物稱為腸道菌群。據研究指出，人類結腸中每克有10^10–10^12個微生物[1]。胃、小腸和大腸中的微生物群對人類健康相當重要。這些微生物大多數（大多數是厭氧菌）生活在大腸中[2]。
儘管某些內源性因素（例如粘蛋白分泌）會影響微生物的平衡，但人類飲食卻是其生長的主要能量來源。特別是，不可消化的碳水化合物可以高度改變腸道菌群的組成和功能[3]。有益的腸道微生物會發酵這些被稱為益生元的不可消化的飲食物質，並透過降解益生元而獲得其生存能量[4,5]。
益生元可以選擇性地影響腸道菌群[6,7]，而腸道菌群會影響腸道功能，例如腸道的新陳代謝和完整性。益生元可以透過誘導雙歧桿菌和乳桿菌屬產生的乳酸來對病原體產生拮抗作用，進而抑制健康個體中的病原體[8,9,10,11]。
截至目前已有許多研究測試了各種化合物以確定其作為益生元的功能。果寡醣（FOS）、半乳寡醣（GOS）和反式半乳寡醣（TOS）是最常見的益生元。腸道菌群對益生元進行發酵後會產生短鏈脂肪酸（SCFA），包括乳酸、丁酸和丙酸。這些產品可能對身體產生多種影響。例如，丙酸鹽會影響呼吸道中的T helper 2和巨噬細胞以及骨髓中的樹突細胞[12,13]。 SCFAs降低結腸的pH值[14,15]。肽聚醣是另一種益生元發酵產品，可刺激針對病原微生物的先天免疫系統[12,16]。益生元的結構和腸道細菌組成決定了發酵產物[14,15]。益生元對人類健康的影響是透過微生物降解產物來作用的。例如，丁酸鹽影響腸上皮的發育[17]。由於SCFA可透過腸細胞擴散至血液循環，因此益生元不僅具有影響胃腸道的能力還會影響遠處的器官[18]。
在這篇文章中，我們將闡述益生元的定義、類型、來源，機制和臨床應用。
⭐️定義
益生元的概念於1995年由Glenn Gibson和Marcel Roberfroid首次提出[4]。益生元被描述為「一種不可消化的食品成分，透過選擇性刺激結腸中一種或有限數量細菌的生長或活性來有益地影響宿主，從而改善宿主健康」。這個定義在15年多的時間內幾乎沒有改變。
根據該定義，僅碳水化合物基團的幾種化合物，例如短鏈和長鏈β-聚果糖[FOS和菊糖]，乳果糖和GOS，可以歸類為益生元。在2008年，國際益生菌和益生元科學協會（ISAPP）的第六次會議將「飲食益生元」定義為「可使胃腸道微生物群的組成或活性發生特定變化，進而為宿主帶來健康的選擇性發酵成份」[19]。
以下標準用於將化合物歸類為益生元：（i）它應該對胃的酸性pH值有抵抗力，不能被哺乳動物的酶水解，也不能在胃腸道中吸收，（ii）它可以被腸道菌群發酵，以及（iii）該化合物可以選擇性地刺激腸道細菌的生長或活性，並且該過程可改善宿主的健康[19]。
儘管並非所有的益生元都是碳水化合物，但是可以利用以下兩個標準來區分纖維和衍生碳水化合物的益生元：（i）纖維是聚合度（DP）等於或高於3的碳水化合物，並且（ii）小腸內源性酶不能將之水解。
科學文獻中還發布了一些有關益生元的修訂定義[22]。但是，上述定義是在2008年給出的，近年來已被接受。儘管沒有共識定義，但原始定義和其他定義的重要部分是益生元的攝入與人類福祉相關。
⭐️益生元的種類
益生元有很多類型。它們大多數是碳水化合物的分子，並且主要是寡醣碳水化合物（OSC）。相關文章主要是針對OSC，但也有一些研究已指出益生元不全是碳水化合物。
▪️聚果糖
該類別包括菊糖和果寡醣。它們的結構是具有線性鏈的β（2→1）鍵結的果糖。它們末端通常具有帶有β（2→1）鍵的葡萄糖單元。菊糖的DP高達60，而FOS的DP小於10 [2]。過去的一些研究指出聚果糖可以選擇性刺激乳酸菌。然而近年來，一些研究表明聚果糖的長度是確定哪些細菌可以發酵它們的重要標準[26]。因此，聚果糖也可以直接或間接地促進其他的細菌種類。
▪️半乳寡糖
乳糖延伸的產物半乳寡醣（GOS）分為兩組：（i）在C3，C4或C6處有過量半乳糖的GOS，以及（ii）乳糖透過enzymatic trans-glycosylation製得的GOS。該反應的最終產物主要是三碳糖至五碳糖與半乳糖的混合物。這種類型的GOS也稱為反式半乳寡醣（TOS） [19,27]。GOS可以刺激雙歧桿菌 和乳酸桿菌。嬰兒的雙歧桿菌已顯示出與GOS有高度結合。腸內菌, 厚壁菌門細菌和擬桿菌門細菌也受GOS刺激，但程度低於雙歧桿菌[2]。有一些源自乳果糖的GOS-乳糖異構體。這種乳果糖衍生的GOS也被視為益生元[19]。除了這些類型的GOS外，其他類型都基於蔗糖延伸而名為棉子糖家族寡醣（raffinose family oligosaccharides；RFO）。 RFO對腸道菌群的影響尚未闡明[28,29]。
▪️澱粉和葡萄糖衍生的寡糖
一種抵抗上消化道消化的澱粉被稱為抗性澱粉（RS）。 RS可以透過產生大量的丁酸來促進健康。因此有人建議將其歸類為益生元[30]。不同類別的厚壁菌門細菌和RS有高度的作用[3]。一項體外研究指出布氏瘤胃球菌和 青春雙歧桿菌也可以降解RS，直腸真桿菌 和 擬桿菌屬細菌也可以少量降解RS。然而，在細菌和糞便的混合培養中，在布氏瘤胃球菌不存在的情況下，RS降解是不太可能發生的[31]。聚葡萄糖是葡萄糖衍生的寡醣。它由具有許多分支和糖苷鍵的葡聚糖組成。有研究指出它可以刺激雙歧桿菌，但尚未得到證實[32]。
▪️其他寡醣
一些寡糖源自被稱為果膠的多醣。這種類型的寡醣稱為果膠寡醣（POS）。它們是半乳糖醛酸或鼠李糖的延伸。羧基可以被甲基酯化取代，並且結構可以在C2或C3處被
乙醯化。側鏈連接著各種類型的糖（例如阿拉伯糖，半乳糖和木糖)或阿魏酸 [33]。它們的結構根據POS的來源而有很大差異[34]。
▪️非碳水化合物寡醣
儘管碳水化合物更可能符合益生元定義的標準，但是有些化合物未歸類為碳水化合物，但建議將其歸類為益生元，例如可可來源的黃烷醇。已有體內和體外的實驗證明黃烷醇可以刺激乳酸菌[35]。
⭐️益生元預防疾病的機制
1.益生元和腸胃疾病
1)腸躁症和克隆氏症
關於益生元對腸躁症（IBS）和克隆氏症的影響已有一些研究。 IBS是一種胃腸道綜合症，其特徵是在沒有任何器質性原因的情況下出現慢性腹痛和排便習慣改變。克隆氏症是一種慢性反覆性腸道發炎的疾病（IBD），可能涉及從口腔到肛門的胃腸道的任何部位。據研究指出，在IBS和克隆氏症中，雙歧桿菌和普拉梭菌的數量，以及擬桿菌門/厚壁菌門的比率降低了[29,98]。
一項雙盲交叉研究指出，FOS的劑量為6 g /天，持續4週，對IBS患者沒有治療效果[99]。同樣，2000年發表的另一項隨機，雙盲、安慰劑對照試驗指出，每天補充20克的FOS不能改善IBS [100]。相比之下，另外兩項最近的隨機、雙盲、臨床試驗指出，在6週[101]每天服用5 gFOS或在12週[102]每天服用3.5 g的GOS後，IBS症狀得到了改善。2006年的一項小組研究報告指出，連續3週每天補充15 g 的FOS可以增加糞便中雙歧桿菌的數量並改善克隆氏症[103]。然而，其他隨機、雙盲和安慰劑對照試驗則顯示，對於活動性克隆氏症患者，每天可以給予15 g的FOS劑量；而對於非活動性或輕度至中度活躍的克隆氏症患者，每天可以給予富含FOS的菊糖20g[104,105]，持續4週。
2) 大腸癌
大腸癌是全球第三大最常見的惡性腫瘤，是一種從遺傳突變到腺瘤性息肉的多步驟疾病，繼而導致浸潤性和轉移性癌症[106]。已有研究指出益生元的發酵產物，例如丁酸鹽，可以透過誘導細胞凋亡而對結腸直腸癌的風險及其進展具有保護作用[106,107,108]。此外，一項臨床試驗指出，共生療法（鼠李糖乳桿菌和乳酸雙岐桿菌加菊粉）可以透過降低結直腸癌的增殖率，誘導結腸細胞壞死來降低結直腸癌的風險，從而改善上皮屏障的完整性和功能[106,109,110]。
3) 壞死性小腸結腸炎
壞死性小腸結腸炎（NEC）是一種多發於早產嬰兒的疾病，可能會導致小腸壞死，嚴重時會危及生命。由於益生元，例如FOS和GOS，可以刺激腸道菌群的生長（例如雙歧桿菌）並減少早產兒腸內的病原菌[112,113,114]，據稱它們可以預防NEC [111]。此外，短鏈脂肪酸可透過增強胃排空和腸蠕動來改善攝食耐受性[115,116,117]。四項隨機對照試驗的分析結果顯示，FOS、GOS或其混合物可以提高糞便雙歧桿菌的濃度，但對降低NEC的風險和進展沒有顯著影響[118]。因此，需要做更多的臨床試驗來闡明益生元對NEC的確切作用。
2.益生元和免疫系統
食用益生元可以透過增加保護性微生物的數量來提高免疫功能。動物和人體研究表明，益生元可以透過乳桿菌和雙歧桿菌來減少有害細菌的數量[12,121,122,123,124]。例如，甘露糖可以透過促進甘露糖對沙門氏菌的粘附來減少病原體的生長。甘露糖透過type 1 fimbriae （手指狀突起）與沙門氏菌結合[125]。此外，在OSC的存在下，病原體無法與上皮結合。益生元還可以誘導免疫分子，特別是細胞因子的表達。
有趣的是，母親的益生元代謝產物能夠穿過胎盤，進而影響胎兒免疫系統的發育[12,126]。 2010年，Fugiwara等人[127]報導在懷孕小鼠模型中給予FOS可以改變後代的微生物群，而使得後代的皮膚炎症得到緩解。相反地，Shadid等人 [128]在一項安慰劑對照、隨機和雙盲研究中指出，益生元補充劑對人的雙歧作用不能轉移到下一代。益生元對免疫系統的已知作用如下：
▪️I-FOS和菊糖混合物：FOS和菊糖的混合物可以改善對病毒疫苗（例如流感和麻疹）的抗體反應[129]。
▪️II- FOS：研究指出食用FOS後除了對流感疫苗的抗體反應有所改善，還減少了流感疫苗的副作用[130,131]。此類益生元還可以減少嬰兒腹瀉相關的發燒。除此之外，它還可以減少嬰兒的抗生素使用、疾病持續時間以及熱痙攣的發生率[132,133]。β（2→1）聚果糖可以向上調節血清中細胞介素4（IL-4）的濃度以及健康人的CD282+/TLR2+ 骨髓幹細胞的樹突細胞, 和 a toll-like receptor 2-mediated 的免疫反應[134]。相比之下，另一項研究指出，食用β（2→1）聚果糖後，唾液免疫球蛋白A（IgA）、血清中的免疫細胞以及T細胞和自然殺手（NK）細胞的激活和增殖都沒有改變[135]。另外研究也指出，FOS降低了嬰兒發生某些免疫性疾病（如異位性皮膚炎）的風險[136,137]。這種類型的益生元會降低單核細胞和顆粒球中IL-6的表達以及吞噬作用[138]。
▪️III- GOS：研究表明，GOS可增加成人血液中的白介素8（IL-8）、白介素10（IL-10）和C反應蛋白的濃度，但會降低IL-1β的濃度。目前也已發現，透過食用GOS可以改善NK細胞的功能[139,140]。在嬰兒中，GOS降低了異位性皮膚炎和濕疹的風險[136,137,141]。
▪️IV- AOS（酸性寡醣）：在低危嬰兒中，AOS減少了異位性皮膚炎的可能性[136]。
3. 益生元和神經系統
胃腸道透過“腸腦軸”連接到中樞神經系統[142]。例如，給予小豬益生元可以減少灰質進而改善神經修剪[143]。但是，益生元對人腦的調節作用尚未確定。腸道菌群透過三種途徑影響大腦，包括神經、內分泌和免疫途徑[142,144,145]。
▪️I-神經通路：益生元發酵產物可以透過迷走神經影響大腦[146]。一些益生元，例如FOS和GOS，對腦源性神經營養因子、神經傳遞物質（例如d-絲胺酸）和突觸蛋白（例如突觸素和N-甲基-D-天門冬胺酸或NMDA受體）具有調節作用[147,148 ]。
▪️II-內分泌途徑：下視丘-腦垂腺-腎上腺軸是神經內分泌途徑。小鼠中微生物叢的生長可以透過適當的方式誘導皮質酮和促腎上腺皮質激素[149]。此外，益生元還可充當其他激素的調節劑，例如胜肽YY [147]。
▪️III-免疫途徑：如前所述，益生元可以影響免疫系統的不同方面。除神經功能外，益生元還能夠透過改變腸道菌群的活性或組成來影響情緒、記憶、學習和某些精神疾病[145]。
▪️IV-情緒：壓力荷爾蒙能夠影響與焦慮相關的行為[150,151]。研究結果指出，在暴露於壓力下的無菌小鼠中，壓力激素（促腎上腺皮質激素（ACTH）和皮質酮）的濃度會增加。但在給予雙歧桿菌後，皮質酮和ACTH則可以回到正常濃度[149]。
▪️V-記憶力、注意力和學習能力：近期許多研究指出，動物和人類的記憶力與可發酵化合物的攝取有關聯[152]。研究指出不同種類的益生元能讓中年人的記憶力得到改善[153,154]。一些益生元，如阿拉伯木聚醣和阿拉伯糖，可以增強小鼠的認知能力，並減輕癡呆相關的膠質纖維酸性蛋白的累積過程[155]。益生元可能在保存回憶和學習方面比在發展過程中更有效。在2015年進行了一項隨機、雙盲和安慰劑的對照研究，研究給予成年人攝取三週的FOS和GOS並觀察其對唾液皮質醇和情緒賀爾蒙濃度的影響。結果顯示，在成年人中FOS沒有顯著作用，但是攝入5.5 g GOS可以增加唾液中皮質醇的濃度[156]。另一項隨機、雙盲、安慰劑對照試驗結果指出，攝取非澱粉多醣（每天3.6 g）十二周可增強中年人的記憶能力[153,154]。相反地，在24個月後，FOS、GOS和AOS的混合物不能促進早產兒神經系統的發育[157]。在另外兩個臨床研究中，Smith等人觀察到富含菊糖的FOS的攝取可能會增強情緒、識別、立即記憶和回憶（4小時後）。但是，這種益生元未能恢復長期記憶（43天後）[158,159]。在另一項研究中，給予聚葡萄糖和GOS混合物可減少公豬的焦慮行為，並促進大鼠的積極社交互動[143,160]。此外，攝取這種混合物增強了他們的認知記憶[160,161]。
▪️VI-自閉症：70％的自閉症患者患有伴隨的胃腸道疾病，而健康個體為9％。慢性便秘（以及因便秘引起的其他疾病）、腹瀉或無腹瀉、胃食道逆流、腹脹、雙醣缺乏、胃腸道發炎和腸神經系統異常是胃腸道症狀的特徵。自閉症的嚴重程度與較高的胃腸道疾病有關[163]。有趣的是，2016年發表的一篇研究證實了這些說法[164]。自閉症患者的腸道菌群組成發生了變化。一些研究指出自閉症患者的糞便中，產氣莢膜桿菌含量高而雙歧桿菌不足。在患有自閉症的兒童中，腸道代謝物與健康個體不同。例如，自閉症兒童的SCFA含量低於健康兒童[163,165]。各種益生元，例如小麥纖維，可以透過減少產氣莢膜桿菌的數量和增加雙歧桿菌來對自閉症患者產生治療效果[166]。兒茶酚胺是一種神經遞質，在自閉症患者中會增加。這些神經遞質由酪胺酸羥化酶產生。在大鼠腎上腺髓質細胞中進行的一項體外研究表明，益生元發酵產物SCFA可以誘導酪胺酸羥化酶的表現[167]。然而，需要進一步的研究以了解哪些益生元對人類自閉症具有治療作用。
▪️VII-肝腦病變：肝腦病變的主要原因是血氨濃度升高。這種情況會導致許多精神和神經系統的併發症，包括人格、言語和運動障礙以及認知障礙，最終可能導致昏迷和死亡。已有研究指出乳果糖可透過降低腸中的氨濃度來有效治療肝腦病變，進而改善肝腦病變患者的生活品質。該益生元也對肝腦病變具有預防作用[143,168,169,170]。乳果糖透過不同途徑對肝腦病變發揮有益作用。首先，乳果糖發酵的產物是乳酸，它能夠透過釋放H +來降低結腸腔的pH值。腸道中的氨與質子反應並生成銨，這種轉化形成濃度梯度，從而增加了氨從血液再吸收到胃腸道的量[171]。第二，在胃腸道中存在乳果糖的情況下，細菌是利用乳果糖發酵的能量而不是將胺基酸轉化為氨能。第三，乳果糖可抑制麩醯胺酸酶並防止麩醯胺酸產生氨[143]。最後，乳果糖縮短了結腸運送時間。因此，它可以降低胃腸道中的氨濃度。其他化合物，例如乳糖醇，在治療肝腦病變中也可能與乳果糖一樣有效。有趣的是，乳糖醇的副作用比乳果糖少得多（例如，腸胃脹氣和噁心）[172,173,174]。
4. 益生元和皮膚
食用益生元可降低發育風險以及過敏性皮膚病的嚴重性[136,137]。在暴露於紫外線的無毛小鼠中，食用GOS 12周可增強保水能力，並防止紅斑的形成[175]。另一方面，GOS可透過增加皮膚上細胞粘附和基質形成的標記表現（例如CD44和 type 1膠原蛋白）來改善皮膚屏障。腸道微生物在代謝芳香族胺基酸後，可能會生成某些化合物，例如酚類化合物，這些化合物會被轉移到皮膚中。酚類化合物例如甲酚，可能對潛在的腎臟疾病患者有毒[176]。在女性中，食用含或不含益生菌（如短雙歧桿菌）的GOS可以消除酚類引起的水份和角蛋白的減少[177,178,179,180]。
5.益生元和心血管疾病ＣＶＤ
益生元在心血管疾病的有益功能尚未得到證實。不過以下整理了益生元對CVD的一些間接影響。
益生元能夠透過減少發炎元素來降低CVD的風險。多項研究指出，攝取益生元可以改善血脂。 Letexier等人在一項隨機、雙盲和安慰劑對照的交叉臨床試驗中[182]每天用10克的菊糖治療健康個體，持續三週。他們觀察到該方式減少了血液中的三酸甘油脂（TAG）和肝臟脂肪的生成，但對膽固醇濃度沒有統計上的顯著影響。
根據這些發現，Russo等人在一項隨機、雙盲交叉試驗中[183]證明食用富含86％粗麥粉、11％菊糖和3％杜蘭麵筋粉製成的麵可降低健康個體的TAG和脂肪生成，而非膽固醇濃度。相反地Frochen和Beylot [184]指出，六個月內每天攝入10克菊糖型聚果糖對健康受試者的肝臟脂肪生成沒有顯著影響。為了在部分隨機交叉研究中評估口服L-鼠李糖和乳果糖對血脂濃度的影響，Vogt等人[185]在健康個體中，每天服用25克的這兩種益生元，持續四個星期。他們發現TAG的合成和濃度顯著降低，但膽固醇卻沒有。與此相反，1991年的另一項調查結果指出乳果糖可增加血液膽固醇（最高10％）和載脂蛋白B（最高19％）[186]。在一項對代謝症候群風險≥3的受試者進行的雙盲、隨機、安慰劑對照的交叉研究中，給予Bimuno®半乳寡醣（B-GOS）12周可降低循環膽固醇、TAG和總膽固醇/高密度脂蛋白膽固醇比率[187]。然而，在老年人中這種益生元對總膽固醇/高密度脂蛋白膽固醇的比例沒有顯著影響[139]。在一個meta-analysis研究中測量了β-葡聚醣攝入量對脂質分佈的影響。據結果顯示，食用β-葡聚醣可以降低總膽固醇和低密度脂蛋白的濃度[188]。最後，1995年至2005年間發表的相關隨機對照臨床試驗的meta-analysis指出，FOS可以降低TAG濃度，平均比率為7.5％[189]。矛盾的是，益生元可能會透過產生一些諸如脂肪酸的SCFA而對脂質分佈產生不利影響。乙酸鹽可以轉化為乙醯輔酶A-一個在肝細胞中合成脂肪酸的物質[190]。透過直腸注入乙酸鹽後，可以證明血液中膽固醇和三酸甘油酯的濃度增加[191]。但是，其他的一些SCFA，例如丙酸鹽和丁酸鹽可能會改善脂質狀況。丙酸鹽可抑制乙酸酯合成脂質[192]。益生元例如FOS和L-鼠李糖，可能透過產生乙酸鹽、丁酸鹽和丙酸鹽而具有脂肪形成作用[14,193]。因此，確定益生元的最終產品也是相當重要的。儘管在一項研究中[194]聲稱益生元對肥胖相關疾病（例如脂肪肝疾病，特別是非酒精性脂肪肝）有益，但有另一項臨床試驗駁斥了這一觀點[195]。
６.益生元和鈣的吸收
一些研究表明，每天攝取5至20g劑量的乳果糖，TOS或菊糖+FOS會顯著增加鈣的吸收。不過GOS或FOS並未觀察到這種現象[197]。
⭐️益生元的來源
寡醣：類似水溶性膳食纖維的功能，包含果寡醣、木寡醣、半乳寡醣、菊糖…等，在大蒜、洋蔥、牛蒡、蘆筍、大豆、牛乳、蜂蜜等食物中都含有。
⭐️益生元的安全性
益生元被認為是沒有嚴重的副作用的。腸內酶不能分解寡醣和多醣，它們被運送到結腸以透過腸道菌群發酵。因此，益生元的副作用主要是其滲透功能的結果，例如可能會出現滲透性腹瀉、腹脹、絞痛和腸胃脹氣等。益生元的鏈長是影響其副作用的重要參數之一。有趣的是，鏈長較短的益生元可能具有更多的副作用。這種現象的可能解釋是，較短的菊糖分子主要在近端結腸中代謝，發酵速度快。而長鏈的則在遠端結腸中代謝，發酵得較晚較慢。除了鏈長以外，益生元的劑量也會影響其安全性。例如，低劑量（2.5-10 g /天）和高劑量（40-50 g /天）的益生元分別會引起腸胃脹氣和滲透性腹瀉。注意，每天需要服用2.5-10 g的益生元才能發揮其有益於人體健康的功能。這意味著在治療劑量範圍內的益生元可以引起輕度至中度的副作用。市場上大多數益生元產品的劑量為每份1.5–5 g [206]。
作為益生菌的潛在替代品或輔助療法[207]，益生元可能也有類似的安全問題。益生菌的主要安全問題包括菌血症，敗血症或心內膜炎的風險，尤其是在免疫缺陷嚴重（例如HIV、癌症、移植）、嚴重營養不良或腸上皮屏障功能不全（例如嚴重腹瀉、NEC）的患者中[ 208]。值得注意的是，這些潛在的併發症並未在有關益生元的臨床研究中提及過。
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