2020年癌癥統(tǒng)計報告顯示，全球新增確診癌癥病例約1929萬，癌癥死亡病例約996萬，其中我國癌癥死亡人數(shù)約300萬，位居全球第一[1]。近20年來，抗腫瘤藥物發(fā)展迅速，從化療藥物到各類新型抗腫瘤藥物，包括分子靶向藥物和免疫治療藥物層出不窮，然而抗腫瘤藥物響應(yīng)率仍然有限，獲得性耐藥頻發(fā)及不良反應(yīng)問題嚴(yán)重限制了其臨床應(yīng)用[2]。
隨著高通量測序和其他“組學(xué)”的發(fā)展，“藥物微生物組學(xué)”概念興起[3]，同時越來越多的研究表明人體微生物菌群，特別是腸道菌群在抗腫瘤藥物療效中發(fā)揮重要作用[4]。本文就微生物菌群與化療藥物、分子靶向藥物、免疫治療藥物的療效及不良反應(yīng)相關(guān)性研究進行綜述，以期為臨床抗腫瘤藥物個體化治療提供參考。
1 微生物菌群對化療藥物療效及不良反應(yīng)的影響
根據(jù)微生物菌群調(diào)節(jié)化療藥物療效的機制，Alexander等將其調(diào)節(jié)作用歸納為菌群轉(zhuǎn)運（translocation）、免疫調(diào)節(jié)（immunomodulation）、菌群代謝物（metabolism）、藥物代謝酶（enzymatic）及菌群多樣性降低（reduced diversity），即“TIMER”框架[5]。
微生物菌群與化療藥物相互作用機制亦可概括為免疫調(diào)節(jié)、激素水平調(diào)節(jié)、代謝物水平調(diào)節(jié)、藥物生物轉(zhuǎn)化及跨膜轉(zhuǎn)運調(diào)節(jié)（表1）。
表1 微生物菌群對化療藥物療效及不良反應(yīng)的影響及其作用機制
1.1 調(diào)節(jié)機體免疫應(yīng)答影響化療藥物療效及不良反應(yīng)
2013年，Viaud及Iida提出腸道微生物菌群通過調(diào)節(jié)宿主免疫系統(tǒng)，影響抗腫瘤藥物療效[6-7]。研究發(fā)現(xiàn)，環(huán)磷酰胺可促進部分腸道革蘭陽性菌（約氏乳桿菌、海氏腸球菌）向次級淋巴器官轉(zhuǎn)移，增加腫瘤內(nèi)細(xì)胞毒性T細(xì)胞/調(diào)節(jié)性T細(xì)胞比例，同時革蘭陰性桿菌腸道巴恩斯氏菌可促進γδT細(xì)胞腫瘤浸潤，從而增強環(huán)磷酰胺療效[7-8]。Li等[9]也發(fā)現(xiàn)腸道菌群如糞球菌屬、Dorea及瘤胃球菌屬可引起乳腺癌患者外周血及腫瘤組織中CD4 T細(xì)胞水平升高，從而增強環(huán)磷酰胺、順鉑、卡鉑藥物療效。
微生物菌群可通過調(diào)節(jié)機體固有免疫參與化療藥物耐藥途徑，導(dǎo)致藥物療效降低。Toll樣受體(TLR)4- 髓樣分化因子88(MYD88)- 核因子κB（NF-κB）是具核梭桿菌感染的固有免疫信號通路，該通路激活可促進自噬相關(guān)蛋白表達(dá)，上調(diào)凋亡抑制蛋白BIRC3（BIRC3），導(dǎo)致結(jié)直腸癌（CRC）患者對奧沙利鉑及5-氟尿嘧啶（5-Fu）產(chǎn)生耐藥性[10-11]，提示腫瘤組織中具核梭桿菌豐度可能是預(yù)測5-Fu耐藥及患者預(yù)后的方法之一。
微生物菌群激活機體固有免疫不僅參與化療藥物耐藥途徑，還與化療藥物誘導(dǎo)的黏膜炎不良反應(yīng)相關(guān)。固有免疫細(xì)胞表達(dá)的TLR及NOD樣受體識別病原體相關(guān)模式分子可進一步激活NF-κB信號通路，導(dǎo)致腫瘤壞死因子-α（TNF-α）、白細(xì)胞介素（IL）-1β和IL-6上調(diào)引起黏膜損傷[12]。
多柔比星引起細(xì)菌內(nèi)毒素水平升高，吉西他濱誘導(dǎo)腸道中大腸桿菌及嗜黏蛋白阿克曼菌豐度上升，5-Fu、伊立替康、奧沙利鉑也可導(dǎo)致腸道菌群紊亂，涉及雙歧桿菌屬、嗜黏蛋白阿克曼菌等13個菌屬，從而激活NF-κB信號通路導(dǎo)致腸道損傷不良反應(yīng)[13-15]。
1.2 調(diào)節(jié)機體激素水平影響化療藥物不良反應(yīng)
研究顯示，接受雄激素軸靶向治療（比卡魯胺、恩雜魯胺或阿比特龍）的前列腺癌患者腸道中，能夠進行類固醇激素生物合成的細(xì)菌豐度更高[16]，Pernigoni等[17]也證實與激素敏感性前列腺癌患者相比，去勢抵抗性前列腺癌患者腸道中瘤胃球菌屬及擬桿菌屬豐度較高，其可將雄激素前體轉(zhuǎn)化為活性雄激素，降低雄激素剝奪療法的療效。
糖皮質(zhì)激素通過促進膜聯(lián)蛋白-1、IL-10的合成等發(fā)揮抗炎作用[18]，而研究發(fā)現(xiàn)小鼠腸道中大腸桿菌可降低宿主糖皮質(zhì)激素水平，阻斷糖皮質(zhì)激素受體，加劇5-Fu化療誘導(dǎo)的黏膜炎[19]。
1.3 調(diào)節(jié)機體代謝水平影響化療藥物療效及不良反應(yīng)
腸道菌群可代謝產(chǎn)生短鏈脂肪酸，包括乙酸鹽、丙酸鹽和丁酸鹽等，其中丁酸鹽具有抗炎、調(diào)節(jié)黏膜免疫/微生物群落及抑制多種致癌信號通路等功能[20]。在抗癌活性方面，丁酸鹽聯(lián)合5-Fu、吉西他濱、奧沙利鉑，通過抑制G蛋白偶聯(lián)受體109a-蛋白激酶B信號通路、促進IL-12誘導(dǎo)的CD8 T細(xì)胞活化通路等機制，促進腫瘤細(xì)胞凋亡、降低小鼠腫瘤負(fù)荷。同時，與對奧沙利鉑無應(yīng)答的腫瘤患者相比，應(yīng)答者血漿丁酸鹽水平更高，提示丁酸鹽可增強化療藥物藥效[21-23]。
在緩解化療藥物不良反應(yīng)方面，丁酸梭狀芽孢桿菌可促進雙歧桿菌、瘤胃球菌科和顫桿菌克屬等丁酸鹽產(chǎn)生菌豐度增加，提高小鼠腸道中丁酸鹽水平，緩解順鉑及吉西他濱所致的腸道黏膜炎及腎毒性[21,24]。
1.4 調(diào)節(jié)化療藥物代謝及轉(zhuǎn)運影響化療藥物療效及不良反應(yīng)
研究表明，秀麗隱桿線蟲中，大腸桿菌核糖核苷酸代謝途徑及細(xì)菌維生素B6和B9可促使5-Fu代謝為活性產(chǎn)物5-氟尿嘧啶核苷，從而增強5-Fu藥效，而降血糖藥物二甲雙胍可通過抑制細(xì)菌的一碳代謝途徑降低5-Fu療效[25-26]。
在藥物不良反應(yīng)方面，腸道菌群產(chǎn)生β-葡萄糖醛酸酶可作用于伊立替康的代謝產(chǎn)物SN-38葡萄糖醛酸苷（SN-38G）,使其轉(zhuǎn)化為活性代謝產(chǎn)物7-乙基-10-羥基喜樹堿(SN-38)，導(dǎo)致對腸道上皮細(xì)胞的劑量限制性毒性作用[27]。同時腸道菌群可使抗病毒藥物索利夫定轉(zhuǎn)化為中間體溴乙烯尿嘧啶，抑制5-Fu降解導(dǎo)致其在血液中蓄積，兩藥聯(lián)合使用曾導(dǎo)致15例患者死亡[28]。
相反，腸道中分離的植生拉烏爾菌、肺炎克雷伯菌和大腸桿菌可通過還原脫糖機制促進多柔比星代謝，從而減少多柔比星的毒性[29]。臨床試驗也表明，腸道假單胞菌中分離純化的羧肽酶G2可分解代謝和滅活甲氨蝶呤[30]，羧肽酶G2現(xiàn)已被美國食品藥品監(jiān)督管理局批準(zhǔn)靜脈用于血漿甲氨蝶呤濃度大于1 μmol/L且存在排泄延遲或腎功能損害的患者[31]。
2 微生物菌群對分子靶向藥物療效及不良反應(yīng)的影響
分子靶向藥物主要針對惡性腫瘤病理生理發(fā)生、發(fā)展的關(guān)鍵靶點進行治療，其中療效與腸道菌群密切相關(guān)的分子靶向藥物包括人表皮生長因子受體2（HER2）抑制劑曲妥珠單抗、表皮生長因子受體（EGFR）抑制劑西妥昔單抗及血管內(nèi)皮生長因子（VEGF）抑制劑貝伐珠單抗。
研究顯示，曲妥珠單抗無應(yīng)答的HER2陽性乳腺癌患者腸道中，毛螺菌科、蘇黎世桿菌科、雙歧桿菌和普雷沃氏菌呈低豐度。而在HER2陽性小鼠中使用抗生素，可損害曲妥珠單抗誘導(dǎo)的腫瘤中CD4 T細(xì)胞和顆粒酶B陽性細(xì)胞招募、樹突狀細(xì)胞（DC）活化和IL-12產(chǎn)生的過程，導(dǎo)致曲妥珠單抗療效降低[32]。同樣，經(jīng)化療藥物與西妥昔單抗或貝伐珠單抗聯(lián)合治療的CRC患者中，腸道菌群的多樣性與良好治療結(jié)局相關(guān)。而腸道中肺炎克雷伯菌、乳桿菌、雙歧桿菌及具核梭桿菌高豐度可能提示該治療方案下疾病進展的不良結(jié)局[33]。
在藥物不良反應(yīng)方面，因接受VEGF抑制劑引起腹瀉患者的腸道菌群組成中，擬桿菌豐度較高而普雷沃氏菌及雙歧桿菌屬分布較少[34]。此外，利妥昔單抗誘導(dǎo)的腸道損傷不良反應(yīng)可能與腸道菌群失調(diào)引發(fā)的免疫反應(yīng)相關(guān)，而補充羅伊氏乳桿菌后腸系膜淋巴結(jié)中致病性輔助性T細(xì)胞（Th）減少，調(diào)節(jié)性B細(xì)胞增加，從而緩解利妥昔單抗引起的胃腸道毒性[35]。
3 微生物菌群對免疫治療藥物療效及不良反應(yīng)的影響
Vétizou等[36]及Sivan等[37]首次發(fā)現(xiàn)免疫檢查點抑制劑(ICIs)的療效與腸道菌群密切相關(guān)，ICIs為阻斷腫瘤免疫逃逸通路的單克隆抗體，免疫檢查點涉及細(xì)胞毒性T淋巴細(xì)胞相關(guān)抗原4(CTLA-4)、程序性死亡［蛋白］-1(PD-1)及其配體(PD-L1)。其中小鼠腸道脆弱擬桿菌產(chǎn)生多糖激活瘤內(nèi)DC細(xì)胞，在腫瘤引流淋巴結(jié)中誘導(dǎo)Th1應(yīng)答；此外，細(xì)菌脂多糖可通過激活肥大細(xì)胞招募腫瘤浸潤T淋巴細(xì)胞，從而增強抗CTLA-4藥物療效[36,38]。而腸道雙歧桿菌屬通過激活DC刺激CD8 T細(xì)胞腫瘤浸潤，腸道副干酪乳桿菌也可促進結(jié)直腸癌小鼠中CD8 T細(xì)胞腫瘤浸潤，增強抗PD-L1的療效[37,39]。
在黑色素瘤患者中，抗PD-1療效與腸道中嗜黏蛋白阿克曼菌、長雙歧桿菌、空腸彎曲桿菌、糞腸球菌和瘤胃球菌科的豐度呈正相關(guān)，其中嗜黏蛋白阿克曼菌可誘導(dǎo)DC分泌IL-12參與PD-1阻斷治療[40-42]。而使用抗生素可導(dǎo)致晚期黑色素瘤患者及非小細(xì)胞肺癌患者對ICIs的原發(fā)耐藥性降低，總生存期（OS）和無進展生存期(PFS)縮短[43]。
同時，質(zhì)子泵抑制劑（PPI）通過影響腸道雙歧桿菌和瘤胃球菌科豐度、調(diào)節(jié)腫瘤微環(huán)境pH值及招募M2亞型巨噬細(xì)胞等機制導(dǎo)致ICIs藥效降低。研究顯示，PPI與ICIs聯(lián)合使用導(dǎo)致腫瘤患者的PFS及OS顯著縮短[44]。除腸道菌群外，定植于胃黏膜上皮的幽門螺桿菌也與免疫治療藥物療效相關(guān)。PD-1免疫療法在幽門螺桿菌血清陽性的非小細(xì)胞肺癌患者及進展期胃癌患者中療效較低，可能由于幽門螺桿菌通過影響DC的交叉呈遞從而抑制了抗腫瘤CD8 T細(xì)胞的活化[45-46]。
ICIs可提高晚期癌癥患者的總生存率，然而由于其激活自身免疫可引起結(jié)腸炎等一系列免疫治療相關(guān)不良反應(yīng)(irAEs)，其可能與腸道中厚壁菌門/擬桿菌門水平上升相關(guān)[47]。而腸道雙歧桿菌通過增加調(diào)節(jié)性T細(xì)胞水平，腸道羅伊氏乳桿菌通過降低3型先天性淋巴細(xì)胞水平[48]，可緩解ICIs誘導(dǎo)的小鼠結(jié)腸炎不良反應(yīng)[49]。
4 調(diào)控微生物菌群改善抗腫瘤藥物療效及不良反應(yīng)
4.1 抗菌藥物調(diào)控微生物菌群
抗菌藥物指具有抑制或殺滅病原菌能力的化學(xué)物質(zhì)，通過影響腸道菌群與抗腫瘤藥物產(chǎn)生相互作用?；仡櫺耘R床研究報道，靶向產(chǎn)生胞苷脫氨酶細(xì)菌的抗生素可改善胰腺導(dǎo)管腺癌患者對吉西他濱的應(yīng)答[50]。新霉素與伊立替康聯(lián)合使用，可降低患者糞便中β-葡萄糖醛酸酶活性及SN-38濃度，緩解腹瀉不良反應(yīng)[51]。然而仍有多項研究表示抗菌藥物可誘導(dǎo)腸道菌群失調(diào)，導(dǎo)致抗腫瘤藥物治療不良結(jié)局[43,52]。因此，抗菌藥物與抗腫瘤藥物的相互作用機制仍有待進一步研究。
4.2 益生菌、益生元調(diào)控微生物菌群
益生菌是有利于腸道的微生物菌群的統(tǒng)稱，多項研究表明益生菌制劑可緩解抗腫瘤藥物誘導(dǎo)的腸道黏膜炎不良反應(yīng)。如鼠李糖乳酸桿菌可恢復(fù)小鼠腸道厚壁菌門/擬桿菌門豐度比，改善5-Fu和奧沙利鉑聯(lián)合治療誘導(dǎo)的小鼠腸道黏膜炎[53]。益生菌合劑（短雙歧桿菌、嗜酸乳桿菌、干酪乳桿菌、嗜熱鏈球菌）可恢復(fù)腸道菌群失調(diào)導(dǎo)致的5-羥色胺過量產(chǎn)生，改善順鉑誘導(dǎo)的大鼠黏膜炎[54]。
益生元指促進體內(nèi)有益菌代謝和增殖的有機物質(zhì)。研究表明菊粉通過引起記憶CD8 T細(xì)胞應(yīng)答，增強CRC小鼠中抗PD-1治療療效[55]。茯苓多糖及低聚果糖可恢復(fù)小鼠腸道菌群穩(wěn)態(tài)，改善腸道上皮屏障，降低5-Fu的毒副作用[56-57]。
4.3 糞便微生物群移植調(diào)控微生物菌群
糞便微生物群移植(FMT)指將整個糞便微生物群落，包括細(xì)菌、病毒、真菌及其代謝物，從健康供體轉(zhuǎn)移至受體[58]，具有調(diào)節(jié)抗腫瘤藥物療效及不良反應(yīng)的潛在臨床價值。FMT可恢復(fù)小鼠腸道菌群穩(wěn)態(tài)，改善5-Fu誘導(dǎo)的腸道黏膜炎且不引發(fā)菌血癥，具有有效性及安全性[59]。臨床試驗也證實經(jīng)FMT治療后，抗PD-1難治性轉(zhuǎn)移性黑色素瘤患者腸道中雙歧桿菌及瘤胃球菌科的豐度提高，可改善對抗PD-1的原發(fā)耐藥性[60-61]。
5 展 望
抗腫瘤藥物的耐藥性及毒性是目前抗腫瘤治療失敗的原因之一，而微生物菌群與抗腫瘤藥物相互作用是提高抗腫瘤藥物療效、減少藥物不良反應(yīng)的潛在靶點。然而目前研究仍存在一定的局限性：（1）微生物菌群對抗腫瘤藥物存在雙重作用，細(xì)菌-免疫-抗腫瘤藥物軸機制仍需進一步研究；（2）多數(shù)研究僅基于動物模型，然而人與動物的腸道菌群種類、數(shù)量以及比例等并不完全一致，需更多臨床試驗證實微生物菌群與抗腫瘤藥物的相互作用；（3）目前研究局限于體內(nèi)共生細(xì)菌與抗腫瘤藥物的相互作用，而體內(nèi)病毒、真菌也可能影響抗腫瘤藥物的治療[62-63]。因此，未來仍需進一步探索體內(nèi)微生物與抗腫瘤藥物的相互作用機制，為腫瘤個體化治療提供新方向。
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