這是《腸道產業》第 161 篇文章
我們昨天的文章分享了發表在 Microorganism雜誌上關於益生菌與肥胖綜述的上半部分，主要以微生物組為核心，闡述了胖代謝機制的研究：萬字強文：深度剖析益生菌與肥胖（上）
今天，我們繼續分享該綜述的下半部分：主要闡述了不同飲食模式對肥胖人群的影響，以及益生菌治療肥胖的未來方向等。
以下為下半部分的編譯內容：
其它因素引起的肥胖
（1）益生菌對肥胖相關性腎病患者的影響
肥胖增加了患慢性腎臟疾病（CKD）的可能性，還提高了發展為末期腎病（ESRD）的可能性，而益生菌可以減少某些尿毒症毒素的產生。
由 Niwa 提出的蛋白代謝假說中，腎小管中的有機陰離子轉運體可以吸收由腸道微生物產生的毒素109 。
比如，鼠乳桿菌（Lactobacillus murinus）可以阻止高鹽飲食小鼠的高血壓症狀的發展113,114。
Ichii 等人發現在小鼠足細胞中的脂多糖可以引起促炎症現象、降低足細胞特異性的基因表達並且降低細胞活性115。
在末期腎病患者中大約有 190 種微生物操作分類單元（OUT），與健康狀態時相比要更為豐富116；在慢性腎臟疾病患者中，發現了普雷沃氏菌科和乳桿菌科（均為天然結腸微生物）降低，而腸球菌和腸桿菌增長了 100 倍116。
同時給患有自發性狼瘡腎炎的混合淋巴細胞反應（MLR）的小鼠添加口服補沖劑，可以降低腸道通透性，減少系統性炎症反應，從而增強腎臟功能和提高整體存活率。
另一項研究發現，在使用嗜酸乳桿菌治療自發性 5/6 高血壓腎切除大鼠（典型的 CKD 模型）時會減輕腎臟損傷，並且會加強胃腸道屏障功能、減緩內部腫脹並且積累尿毒症毒素
117。當用多種細菌治療乙酰氨基酚誘導的尿毒症大鼠和鉻誘導的氧化應激大鼠時，研究發現，脂質過氧化作用減弱，而抗氧化相關的酶類（過氧化物歧化酶和水解酶）的活性發生了提高118-120；另外，減緩氧脅迫可以減緩腎壞死119,121,122。
益生菌可以保護腎臟，避免其被損傷，具體也就是可以通過減少腫脹、凋亡和氧化應激來減少功能障礙。
某些實驗現象可能會出現不一致的結果，這可能是由於實驗過程中所用到的細菌不同、患者群體不同以及動物模型的不同所造成的。
肥胖通過改變菌群組成而引起腸道環境變化，這可能是造成腎臟損傷的原因之一。
實驗發現，特定的個人和微生物群特徵可以預測特定的葡萄糖反應，這意味著人們有可能可以通過飲食、益生元和益生菌干預進行個性化的微生物組調控123。
用益生菌調節腸道菌群平衡可能是肥胖患者改善腎功能的一種較為合適的選擇。
（2）益生元和膳食纖維在肥胖治療中的作用
FAO 和 WHO 將益生元定義為：不可消化的食物，它可以促進特定的腸道菌的活性進而對宿主產生有益的影響124。
益生元主要為不可消化和水解的碳水化合物，比如果糖寡糖（FOSs）、半乳糖寡糖（GOSs）、大豆寡糖、環糊精、菊粉、葡萄糖寡糖、木糖寡糖、乳果糖、乳蔗糖和異麥芽寡糖等，這些碳水化合物具有到達人體腸道遠端的能力
125。已有實驗證明，益生元可以對腸道菌群有促進作用，它可以促進肥胖動物腸道內的乳桿菌和雙歧桿菌的生長126。
母乳是牛奶低聚糖（可能是益生元）的豐富來源，它能促進有益菌（擬桿菌和雙歧桿菌）的生長，並抑制大腸桿菌、空腸彎曲桿菌和幽門螺桿菌等病原體的粘附127。
多項試驗都發現，低聚果糖在治療肥胖和糖尿病小鼠時會引起變化，該變化與腸內分泌細胞生長加速、葡萄糖穩態和瘦素敏感性有關
128,129。這些變化還與細胞內胰高血糖素樣肽-2（GLP-2）的高產量有關，GLP-2 與腸道通透性相關，可以減少肥胖相關性胃炎和心血管疾病。
基於此， Everard 等在用低聚果糖治療動物時發現了非肥胖代謝表型，具體表現為降低甘油三酯濃度、脂肪組織和肌肉脂質浸潤128。
關於鼠李糖乳桿菌 GG 治療兒童肥胖相關的非酒精性脂肪肝的積極影響，現在已有大量的研究支持。
在多數臨床研究中，益生元可以減少肝臟組織中甘油三酯和/或膽固醇的積累，即減少脂肪變性。這一研究現象是很有意義的，因為 25%至 75%的肥胖者患有非酒精性脂肪肝。
儘管能量攝入功能是一個問題，但研究並未發現長期補充益生元，如餐前菊粉和低聚半乳糖或短期果糖低聚糖，有任何影響130。
其它研究表明，非肥胖和肥胖個體的寡果糖或菊粉補充至少在 2 周內，可以減少他們的總能量攝入量130-133 。
對益生元的實驗發現，益生元可以對體重、腰圍、BMI、脂質分佈、脂肪沉積和慢性炎症狀態具有明顯的有益調控作用，這可能成為肥胖和相關代謝紊亂的替代治療方法123。
肥胖與免疫系統的關係及母嬰傳遞
（1）肥胖患者高脂飲食對相關免疫衰老的影響
胃腸道黏膜吸收的增加（如腸漏綜合徵），特別是與免疫變化相關的，可以引起對腸道的重大傷害。具體來講，會造成細菌、毒素、營養物質和代謝垃圾從腸道中滲漏到血液中，當這些毒素進入肝臟中時會引起嚴重的自身免疫反應134。
Moya-Pérez 等人在鼠模型中發現，具有假鏈狀雙歧桿菌 CECT7765 的腸道生態系統調節了高脂飲食（HFD）誘導的免疫細胞浸潤以及腸道和外周炎症，並改善了肥胖相關的代謝功能障礙135。
研究還發現，雙歧桿菌的抗炎症效應與 B 淋巴細胞相關的先天免疫功能和適應性免疫功能相關。
Zhang 等人發現，通過為仔豬接種兩個洛德乳桿菌菌株 ZJ617 和 ZJ615，發現 ZJ617 具有較強的黏附作用，而 ZJ615 的黏附作用較弱136。他們還進一步研究了不同粘附能力菌株的免疫調節作用。
Kowalska 等人首先在大鼠中概述了高脂飲食對瘦素水平的研究，並通過實驗進行了驗證137-140。
研究發現，與對照組大鼠相比，高脂飲食能夠引起的瘦素水平升高141，且在大鼠中，不論體重是否增加，高脂飲食均能升高瘦素水平142。這一現象的原因還未被闡明。
除此之外，還有一些其它因素共同起作用，如身體脂肪含量，可以影響免疫應答，但在不同年齡段的人群中存在顯著差異，身體脂肪含量的升高在老人和年輕人群中產生的不良反應是不相同的。
研究表明，當 BMI 達到 25（通常被認定為肥胖）的 65 歲以上老年人群生存獲益143,144。
除了脂肪組織和免疫細胞之外，其它的脂肪細胞或者參與炎症的促炎因子也會參與到免疫功能中144,146。
由於益生菌在肥胖治療中的免疫調節作用，研究者認為在飲食中添加益生菌是對健康有益的。
（2）孕婦肥胖對新生兒的影響
在近幾十年中，產前和產後變化（例如早產和低出生體重，妊娠糖尿病，妊娠期體重增加過多和配方奶餵養）與兒童肥胖的發生率上升息息相關147-150。而且這些患病風險因素在發展中國家急劇增高151-153。
妊娠期糖尿病（Gestational diabetes mellitus，GDM）增加了嬰兒肥胖和巨嬰的風險。長期妊娠期糖尿病與兒童肥胖和嬰兒代謝相關154,155。
Boyle 等人發現父母肥胖會增加臍帶間充質的分化能力，造成嬰兒肥胖
156。兒童肥胖會增加其成人時肥胖的風險，並且會增加多種代謝疾病、糖尿病和心血管疾病的風險157。腸道微生物組是悉生小鼠（一種用已知菌培養的小鼠）測序技術中的新環境因素。腸道微生物組可以通過影響能量平衡、必需和非必需食物攝取、炎症和腸道阻滯功能的調節信號影響整個機體的代謝，從而刺激體重的增加。
腸道微生物是人體中的一個特殊的實體，它具有比宿主更加龐大的基因組和基因池。
在肥胖和糖尿病之間發現存有新聯繫，即腸道微生物在腸道組織外（如脂肪組織中）的廣泛的生理功能158,159。因此腸道菌群在肥胖和糖尿病的病理中發揮重要作用。
利用無菌小鼠發現，微生物組可能通過調控宿主代謝使小鼠免於飲食誘導肥胖154,157,159。
動物研究表明，懷孕和哺乳期的益生菌可以減少母體高脂飲食誘導的與母體肥胖相關的飲食程序，說明改變雙親的腸道微生物組可能加強父母與嬰兒之間的代謝聯繫
160。Vähämiko 等人在對人體的實驗中發現，在懷孕期間補充益生菌可能影響母嬰的與肥胖相關的啟動子和基因的 DNA 甲基化程度161。
Everard 等人的實驗表明，L. rhamnosus GG 對嬰兒的影響可以從出生前一個月開始並持續到 6 個月大，具體為通過減少嬰兒非正常的體重增加從而改變兒童的發育模式。
使用益生菌可能是對妊娠期糖尿病的一個很有前景的預防或治療方法。益生菌可以治療微生物組失調，且使用益生菌已經成為一種提高早產兒健康的有效的干預方式。
基於飲食的腸道菌群控制
飲食在預防肥胖中是一個重要的健康因素，並且與調節腸道菌群密切相關。眾多研究表明遺傳性肥胖的易感性與肥胖環境（飲食重大變化影響腸道微生物、不運動、久坐的生活方式）相關163。
目前有許多常見的飲食方法，包括標準飲食和西式飲食。益生菌對人體健康的影響、新的益生菌菌株的研究是目前較為流行的研究課題。後續的內容將展示益生菌補充劑如何幫助肥胖病人降低體重並改善腸道菌群。
（1）基於正常飲食的腸道微生物組
飲食在腸道菌群的組成方面和腸型的決定方面有著重要的作用164,165。Arumugam 等人稱，腸型主要分為 3 類，分別以普雷沃菌屬，擬桿菌屬和胃瘤球菌屬為優勢種，腸型的分類不完全依據地域起源165。
特定飲食對腸型改變的影響有：擬桿菌屬的改變與高蛋白和動物脂肪飲食相關，而普雷沃菌屬的變化與高碳水化合物飲食的攝取相關（圖 3）。
Zimmer 等認為，雜食者的腸道菌群豐富度要比素食者的腸道菌群豐富度高166。
實驗結果顯示，在素食者的腸道微生物中，腸桿菌屬，擬桿菌屬，雙歧桿菌屬這些微生物所佔的比例要比雜食者的佔比少。科水平上腸桿菌科，屬水平上克雷伯氏菌屬、腸桿菌屬、檸檬酸桿菌屬和梭菌屬，這些菌在二者之間並沒有差別。
圖 3. 正常飲食的調節腸道菌群示意圖。
正常飲食、營養、能量攝入和微生物組調節之間的相關作用。條形圖代表了宏基因組門水平上的結果。餅圖表示了正常飲食代謝影響的百分比。紅色箭頭表示活性增強。
（2）基於西式飲食的腸道微生物組
在許多國家，西方化、城市化和工業化的進程導致了久坐的生活方式、高脂肪高熱量的飲食習慣100,167,168。脂肪是飲食的重要部分，是腸道菌群生長和產生短鏈脂肪酸的底物169,170。
脂肪含量高的食物比如魚油（ω-3 多不飽和脂肪酸）和豬脂肪（豬油、主要為飽和脂肪酸）對腸道菌群的調控有重要的影響，豬脂肪對擬幹菌門和變形菌門有促進增強作用，而魚油可以促進放線菌門171,172。
大量研究報道肥胖影響特定的菌門，能影響人體和齧齒動物的硬壁菌門和擬桿菌門的比率。
在消瘦人群中，微生物組的差異與糞便的能量損失相關173。當 150 kcal 的收集能量增加 20%時，相應的擬桿菌的數量會降低。據報道，肥胖人群的擬桿菌的相對比例要低於消瘦人群174。
肥胖患者腸道微生物組中硬壁菌門數量的增加，有助於從西式飲食中的熱量獲取，從而促進更好的卡路里的吸收和體重增加170。
此外，在遺傳或飲食誘導的肥胖小鼠和大鼠中，已報道了在 HFD 的對照組中硬壁菌門和擬桿菌門的比例增加107,175。
近期的實驗證明西式飲食中急劇增加的脂肪會影響腸道反應信號的調控，導致能量攝入，脂肪積累和炎症176。西式飲食會增加硬壁菌門的數量和脂肪並減少腸道菌群多樣性（圖 4）。
圖 4. 西式飲食的調節腸道菌群示意圖。
西式飲食、營養、能量攝入和微生物組調節之間的相關作用。條形圖代表了宏基因組門水平的結果。餅圖表示了西式飲食代謝影響的百分比。紅色箭頭表示活性增強。
（3）基於添加益生菌飲食的腸道微生物組
之前許多研究發現，益生菌可以減少脂肪生成、緩解炎症反應並降低體重（圖 5）。
特別的，鼠李糖乳桿菌 GG 菌株已經用於肥胖的研究中177,178，鼠李糖乳桿菌 GG 代替 HFD 治療通過增強脂聯素的分泌來抑制高脂飲食小鼠的肥胖。脂聯素可以使動物免受胰島素抗性並緩解脂肪肝179。
另外，在 HFD 小鼠中鼠李糖乳桿菌 GG 產生的胞外多糖可以減少脂肪和脂肪墊的形成，同時通過表達 Toll 樣受體 2 緩解炎症178。
當使用含有 14 種（包含雙歧桿菌、乳球菌和丙酸桿菌）混合益生菌製劑短期治療 Wistar 大鼠後，其全身和內臟脂肪組織明顯減少，並增強了對胰島素的敏感性
180。一項涉及 49 個超重和肥胖成人的臨床健康研究結果證明了艾克曼菌的丰度與代謝健康具有一定的聯繫。擁有更高的基因多樣性和艾克曼菌的人確實處於更為健康的代謝狀況，比如空腹血漿、甘油三酯和身體脂肪分佈表現更好181。
通過使用巴氏滅菌失活的艾克曼菌治療，發現其可以抑制脂肪量增加，胰島素抗性和血脂異常182,183。這種現象可能是由於 Toll 樣受體 2 和巴氏殺菌過程均與艾克曼菌細胞壁上的某種蛋白之間具有相關作用182。
圖 5. 益生菌補充的調節腸道菌群示意圖。
條形圖代表了宏基因組門水平的結果。餅圖表示了補充益生菌的西式飲食代謝影響的百分比。紅色箭頭表示活性增強，綠色表示活性減弱。
艾克曼菌對內毒素血癥和流化脂肪的緩解作用表明了益生菌在治療肥胖方面的應用價值160,162,181。
對腸道微生物宏基因組分析發現，與脂肪、蛋白代謝、碳水化合物代謝相關的 67 條代謝通路均受到了飲食干預的影響，表明了飲食對腸道微生物組代謝的影響。
（1）糞便菌群移植
糞便菌群移植（Fecal microbiota transplantation，FMT）是將糞便微生物組從特定的供體轉移到受體中，是調控腸道菌群較為簡單的方法。在多種尖端的研究中，糞菌移植中的受體一般是無菌小鼠。
糞菌移植作為一種創新有效安全的方法，經常在臨床中作為治療艱難梭菌感染的手段184。由於其菌群組成的未知性和複雜性，糞菌移植需要完全按照國際益生菌與益生元科學協會（ISAPP）的指導進行
181。近期，有研究糞菌移植調節腸道菌群並治療肥胖和代謝紊亂有效性的相關報道發佈。Gough 等人發現在 27 項研究中，糞菌移植可以對艱難梭菌感染患者產生積極影響185。糞菌移植可以消除 92%的艱難梭菌感染病例181。
目前有 8 項使用糞菌移植治療肥胖的註冊實驗186。（2）合生元調節飲食的綜合作用
合生元對腸道和宿主的健康要比單獨服用益生元或者益生菌更有效果，因為合生元可以給益生菌提供益生元，促進益生菌在腸道內的存活和生長187。合生元已經證明在改善腸道微生物組組成方面是有效的188。
在一個 12 周的研究中，Roller 等人發現使用富含低聚果糖的菊粉、鼠李糖乳桿菌 GG 和動物雙歧桿菌 Bb12 後分別可以減少 16%、18%和 31%的產氣莢膜梭狀芽胞桿菌（Clostridium perfringens）的死亡189 。體外研究表明，合生元在調節腸道菌群方面要比益生元和益生菌更有效190。（3）肥胖症治療的基因組學和代謝組學方法的相關性
對腸道微生物代謝組的研究，毫無疑問可以幫助探索腸道微生物、微生物-宿主互作的代謝途徑176,191。但是在研究人員想要研究腸道微生物在代謝組方面的代謝調控和與之相關的特定細菌時，面臨了許多困難。
宏轉錄組和宏基因組分析是腸道微生物組方面有效的分析手段192。近期 Sridharan 等人使用基於質譜（MS）的代謝組學開發了基於基因組註釋數據的代謝網絡模型，用於檢測 26 種宏基因組的代謝物193。
目前代謝產物研究最常見的方法是質譜和質子核磁共振（1HNMR）光譜80-82。1HNMR 可以產生生物液體樣本（血液、細胞、尿液）的可重複且可靠的代謝組數據，而且需要的樣本量較少。
相反，質譜更加靈敏可以檢測到濃度顯著減少的代謝產物。為了增強分辨率，質譜經常同色譜和氣相色譜聯用
83。將代謝組學同其它組學結合，比如宏蛋白組、宏基因組和宏轉錄組，可以加深我們對腸道微生物複雜的生物合成的理解。這樣的結合研究可以給肥胖的診斷、優化私人訂製醫療和提高單個飲食補充劑有效性等方面帶來貢獻。在未來，仍有眾多腸道微生物的代謝問題等待解決。
結論
本篇綜述的目的在於彙總調查使用益生菌治療肥胖的文獻資料。益生菌在動物和人體的研究中發揮了降低體重的作用，並且也發現一些抗肥胖的機制。
早前，微生物群落對代謝調控、疾病和遺傳紊亂方面的作用還是一個未知的領域。目前微生物在膽鹽、SCFAs、代謝性內毒素血癥和肥胖等的調控作用已經在多種分子測序手段如宏基因組、宏代謝組下逐漸被闡明。
然而益生菌的特異性使得確定益生菌作用機制的特定方式變得困難。對人體的研究需要利用宏基因組和宏代謝組來發現更加微小的差異，並探索益生菌用於治療肥胖和代謝疾病的潛能。
預臨床模型有望引導獨特且性價比高的益生菌菌株的開發，這將需要在未來幾年內完成大量臨床研究，以確定它們是否適合人類食用。
使用益生菌、益生元或合生元甚至於糞菌移植來恢復或者調節腸道菌群的組成是預防或治療肥胖的一種潛在的方法。
然而目前存在的一個問題是用於治療的益生菌的劑量還沒有確定。儘管有大量的實驗動物模型，但是不同的給藥方法可能會影響到先前研究的結果和結論。
我們認為，按照目前的方向一直前行，可能關於管理肥胖及其相關的代謝缺陷方面的策略將會迎來光明的前景。
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原文鏈接：https://www.mdpi.com/2076-2607/7/10/456/htm#B66-microorganisms-07-00456
作者｜Kaliyan Barathikannan 等人
翻譯｜gemiu
審校｜617
THE END
聯繫人：胡瀟航
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