2023, Vol. 18
2. 中国人民解放军923医院消化内科，广西 南宁 530021
2. Department of Gastroenterology, 923Th Hospital of PLA Joint Logistics Support Force, Nanning 530021, Guangxi Zhuang Autonomous Region, China
粪菌移植技术(fecal microbiota transplantation，FMT)在治疗复发性艰难拟梭菌的感染(recurrent Clostridioides difficile infection，rCDI)中得到广泛的应用，是公认有效的治疗手段[1]。近年来，其治疗潜力不仅局限于胃肠道疾病，而且在其他与微生物相关的疾病中也被不断挖掘[2]，如炎症性肠病(inflammatory bowel disease，IBD)[3]、肠易激综合征(irritable bowel syndrome，IBS)[4]、肥胖和糖尿病等代谢性疾病[5]、移植物抗宿主病(graft versus host disease，GVHD)[6]及自闭症(autism spectrum disorders，ASD)[7]、癌症[8]等。FMT移植了一个完整且复杂的微生态组合，包括细菌、噬菌体、真菌及其代谢产物，这可能是其在使用抗生素后修复中有效的原因[9]。长期以来，人们一直将FMT的有效性与肠道细菌联系在一起[10-11]，涉及细菌的测序技术以及生物信息分析技术更容易进行，而绝大多数噬菌体序列与参考数据库几乎没有同源性[12]，肠道噬菌体在疾病治疗中的作用尚未得到充分研究。近几年，探索肠道噬菌体深度测序和组装方法的研究加强了对噬菌体的了解，并且肠道噬菌体参考的数据库也取得了重大的进展[13]。越来越多的研究证据表明，肠道噬菌体不仅是肠道微生物组的重要组成部分[14]，而且与肠道细菌合作调节宿主的生理和免疫[15]，维持整个微生态的平衡，在人类疾病的发生中扮演着重要的角色，其对FMT的疗效日益明显。本综述总结FMT中肠道噬菌体群落的变化及其与FMT结局的关系，促进了对噬菌体在FMT疗效中发挥作用的潜在机制理解，推动了FMT的应用发展。
1 肠道噬菌体的生物学健康人类的肠道病毒群约90% 是由肠道噬菌体组成[16]。噬菌体的遗传物质为单链或双链的DNA或RNA，遗传物质包裹在多面体、丝状的、不定形或者与尾部相连的衣壳中。其中微小噬菌体科(Microviridae)、被脂噬菌体科(Corticoviridae)、复层噬菌体科(Tectiviridae)、光滑噬菌体科(Leviviridae)和囊状噬菌体科(Cystoviridae)的遗传物被包裹在多面体衣壳中，丝杆状噬菌体科(Inoviridae)的遗传物被包裹在丝状衣壳中，原质噬菌体科(Plasmaviridae)的遗传物被包裹在不定形衣壳中，有尾噬菌体目(Caudovirales)的遗传物被包裹在与尾部相连的衣壳，其受体结合蛋白(用于识别宿主)位于尾部纤维末端或者底座。目前，已知的肠道噬菌体组主要由DNA噬菌体组成，其中大多数属于有尾噬菌体目(Caudovirales)和微小噬菌体科(Microviridae)[13, 17-18]。而在全球分布最广泛的肠道噬菌体是crAss样噬菌体(crAss-like bacteriophages)，是一种可感染拟杆菌细菌的新型噬菌体，也是人类肠道最稳定的共生体[19]。
根据在宿主细菌内生活周期的不同，噬菌体可分为烈性噬菌体和温和噬菌体[20]。感染宿主细菌时，噬菌体首先作用于宿主细胞的受体，附着后注入其基因组。随后的复制策略取决于噬菌体是烈性的还是温和的。烈性噬菌体(如T4噬菌体)只会通过裂解循环进行复制，这一过程包括产生子代噬菌体并将其从被感染的细胞中释放，即在短时间内连续完成吸附、侵入、增殖、装配和裂解释放5个阶段[21]。而温和噬菌体(如λ噬菌体)侵入宿主菌后并不发生裂解, 而是将基因整合到细菌基因组中，这种与细胞宿主同时进行增殖但又不裂解的现象被称为溶原现象，整合到细菌基因组的噬菌体则被称为原噬菌体(prophage)，在应激条件下，原噬菌体可以改变溶原现象，并会有更多的病毒颗粒从细菌中释放出来。通常子代噬菌体会通过溶解细胞释放到环境中，导致细菌死亡[22]。健康人肠道病毒组主要由温和噬菌体控制，在宿主炎症和应激期间从温和转变为裂解，噬菌体通过裂解、溶原、基因水平转移等方式影响宿主的生命周期和进化，发挥重要的生态作用[23]。
细菌基因组中的大量遗传信息来自噬菌体，噬菌体介导的基因转移可分为2种方式，一种是普遍性转导(generalized transduction)，另一种是局限性转导(localized transduction)[24]。普遍性转导中，噬菌体可以转导供体染色体的任何部分到受体细胞中。而噬菌体局限性转导只能传递原噬菌体整合位置附近的供体染色体的基因，引起整合位点附近基因的转移，这表明以这种方式转移的基因数量是有限的，但赋予了局限性转导噬菌体特殊的功能。CRISPR/Cas系统(CRISPR associate system)是细菌和古细菌在长期演化过程中形成的一种适应性免疫防御，可用来对抗入侵的病毒及外源DNA[25]。在相关噬菌体介导基因转移系统的应用中，可将噬菌体携带的Cas识别位点重新编辑，使其定位至细菌的耐药基因，破坏含有抗生素耐药基因的质粒，同时对不含耐药基因的质粒进行免疫，在耐药基因转入时被Cas及时破坏，以防止质粒携带耐药基因的传播，可利用噬菌体CRISPR / Cas9系统应对抗生素的耐药性，从而开发特异性抗菌剂[26]。
2 肠道噬菌体主要的生物信息学分析策略肠道微生物组是一个复杂的微生物生态系统，对人类健康和发展具有重要作用[27]。噬菌体在微生物组中含量丰富，并能通过噬菌体捕食、溶菌作用和水平基因转移影响微生物生态系统过程[28]。得益于细菌组高通量测序技术与生物信息学的快速发展，学界对细菌在FMT中发挥的作用有了更深入的了解。然而，噬菌体传统实验培养方法的局限性、噬菌体基因的特异性，病毒组数据库的不完善性、缺乏病毒分析标准等因素，导致对肠道噬菌体的研究较少[29]。目前对肠道微生物组的噬菌体及病毒基因组进行测序主要有宏病毒组测序、宏基因组测序2种方法。宏病毒组学是宏基因组学的一个分支，须先采用沉淀或过滤等方法富集样品中的病毒颗粒，再获取病毒群体的基因组序列信息[30-33]。许多研究已经利用宏病毒基因组测序技术从人类粪便样本中识别出各种表型的噬菌体基因组[34-36]。为了整合这些不同的数据集，Soto-Perez等[37]采用1 831个公共样本(包括皮肤、粪便、肺和血液)形成了人类病毒组数据库(HuVirDB)。Gregory等[38]采用2 697个公共样本形成了肠道病毒组数据库(GVD)。Paez-Espino等[39]通过从宏基因组(包括人类微生物组计划中的490个粪便样本)中识别病毒，形成了IMG/VR数据库。Camarillo-Guerrero等[40]将来自6大洲28个国家的28 060个人类肠道宏基因组，共142 809个非冗余噬菌体基因组和2 898个培养的肠道细菌基因组汇编入肠道噬菌体数据库(GPD)。Nayfach等[18]对来自61个先前发表的研究的11 810个人类粪便样本的宏基因组进行了大规模的病毒基因组鉴定，形成了宏基因组肠道病毒(metagenomic gut virus，MGV)目录，其中包含189 680个病毒基因组草图，估计完整度大于50%，代表 54 118个候选病毒物种。随着高通量测序和生物信息学以及机器学习技术的发展，许多专门研究噬菌体及病毒组的生物信息分析软件的开发与应用，使得噬菌体的多样性、进化分支、相应宿主细菌以及功能得以揭示。深入探寻肠道噬菌体对人体的影响，进而为FMT中肠道噬菌体在疾病的诊断与治疗提供新的策略。
对于噬菌体的研究还需要更多的工作和新方法来预测病毒基因组中的蛋白质功能，如深度学习和功能性宏基因组检测，未来的研究可以使用转录组组学数据来研究RNA病毒或基因的表达模式。
3 FMT中肠道噬菌体对疾病的影响从研究疾病人群和健康人群之间噬菌体特征差异的角度，可知肠道噬菌体生态失调与疾病状态密切相关[41-42]，有研究表明，与健康人相比，肠道疾病如抗生素后微生物群失调[43]、肠应激综合征[44]、炎症性肠病[45-46]的患者体内肠道噬菌体组明显不一样，由此可知疾病状态也会影响肠道噬菌体，而肠道噬菌体群落失调主要由有尾噬菌体目(Caudovirales) 扩张驱动形成的[47]。此外，研究人员发现一些非肠道疾病患者体内也存在肠道噬菌体群改变的现象[48]，包括肥胖症[49]、2型糖尿病[50]、帕金森病[51]等。另一个研究角度是FMT疗效和重叠病毒群落之间的关联也可以体现肠道噬菌体对FMT的疗效，越来越多的研究证据发现噬菌体成功地从供体转移到受体后会使受体肠道噬菌体群落发生变化，并发挥积极作用(见表 1)。
| 来源 | FMT中肠道噬菌体的变化特征 | ||
| 胃肠道疾病 | CDI | Zuo等[14] | 受体含有供体来源的有尾噬菌体目(Caudovirales)丰富度的增加，会使受体具有更好的应答反应 |
| Park等[52] | 疗效较好的供体本身具有较高的噬菌体α多样性 | ||
| Fujimoto等[53] | 在FMT治疗成功时，可以观察到受体的病毒组成与供体具有相似性的特征，以及病毒群落功能恢复 | ||
| Broecker等[54] | 不同种类的病毒组成改变，并且受体的病毒组成与供体具有相似性特征 | ||
| Draper等[55] | 在FMT治疗成功时，受体的病毒组成与供体病毒组成具有相似性 | ||
| IBD | Conceição-Neto等[56] | 受体应答者显示，在基线时真核病毒的丰富度较低 | |
| Chehoud等[57] | 长尾噬菌体科(Siphoviridae)较其他病毒群落更易发生转移，并且大量受体病毒的VLP重叠群显示出与供体VLP重叠群高质量的对齐 | ||
| Nusbaum等[58] | 受体的病毒组成特征向供体病毒组成特征转变 | ||
| 非胃肠道疾病 | GVDH | Zhang等[6] | 病毒组多样性稳定，受体中细环病毒(Torque teno)的相对丰度降低，而有尾噬菌体目(Caudovirales)的相对丰度增加，并且受体来自供体来源的病毒组成比例增加 |
| ASD | Kang等[59] | 在ASD受体中均发现有来自供体的噬菌体群落的植入 | |
| MS | Wortelboer等[60] | 受体的噬菌体以及病毒体组成发生了显著改变 | |
| FMT: fecal microbiota transplantation(粪菌移植)；CDI: recurrent Clostridioides difficile infection(复发性艰难拟梭菌感染)；IBD: inflammatory bowel disease(炎症性肠病)；GVHD: graft-versus-host disease(移植物抗宿主病)；ASD：autism spectrum disorders(自闭症)；MS: metabolic syndrome(代谢综合征)。 | |||
FMT对治疗复发性艰难拟梭菌的感染(recurrent Clostridioides difficile infection，rCDI)是非常有效的(疗效约90%)[61]。然而，FMT起疗效的背后的作用机制仍然不清晰，FMT中微生物群落的成分很复杂，含有细菌、噬菌体、真菌、古菌以及代谢物等。众所周知，细菌特别是活菌在FMT中发挥着重要的作用，然而FMT中噬菌体的调节对治疗疾病也具有重要作用。在初步临床研究中，Zuo等[14]使用宏基因组测序来比较rCDI患者(n=24)和健康对照(n=20)的肠道噬菌体变化，rCDI患者肠道病毒组的特征是有尾噬菌体目(Caudovirales)丰度显著增加而多样性降低，表明rCDI患者存在肠道噬菌体失调。此外，对FMT治疗后成功应答的患者进行纵向评估可知，其来自健康供体的有尾噬菌体目(Caudovirales)的植入率高于对FMT治疗无应答的患者，这表明噬菌体可能在FMT疗效中发挥作用。Broecker等[62]的研究表明，患者的腹泻症状在FMT治疗两周后得到缓解，在微生物成分变化的分析中，患者的细菌组成变化直到7个月后才发生，但在FMT后患者的噬菌体短期内变化并与供体的组成相似，这表明来自供体的FMT的噬菌体成分可能足以诱导临床疗效改善。还有一些类似研究显示，FMT后受体的噬菌体多样性和丰富度均增加，并且噬菌体变化具有供体相似性[52-55]。Ott等[63]的研究表明，在治疗rCDI患者时移植了健康供体的无菌粪便滤液，使患者恢复了正常的大便习惯并消除了复发性艰难拟梭菌的感染症状，提示噬菌体作为无菌粪便滤液的主要成分在FMT治疗机制中可能发挥了重要的作用，并且也表明受体噬菌体组成与供体的噬菌体组成非常相似。这些研究表明，肠道噬菌体群落的恢复可能在肠道微生态中发挥了关键作用，肠道噬菌体在未来可成为对FMT供体筛选的标志物之一。
FMT治疗IBD的疗效因溃疡性结肠炎(ulcerative colitis，UC)和克罗恩病(Crohn’s disease，CD)而异。60项研究(包括观察性研究和随机对照试验)的meta分析数据表明[64]，UC患者FMT后的临床缓解率约为35.0%，CD患者为47.6%。Norman等[45]对英国和美国174名IBD患者进行研究表明，与健康对照组相比，患病人群的粪便噬菌体中有尾噬菌体目(Caudovirales)的丰度增加，细菌多样性降低。Zuo等[46]对91例UC患者的分析表明，与健康人相比，UC患者的直肠黏膜组织具有高丰度的有尾噬菌体目(Caudovirales)。研究表明，IBD疾病中会有肠道噬菌体失调的现象，而肠道噬菌体群落失调主要由有尾噬菌体目(Caudovirales)扩张驱动形成的[47]。Chehoud等[57]研究表明，FMT治疗IBD疾病期间，FMT后受体中易检测到供体中存在的病毒重叠群，受体样本中出现多达32种不同的供体病毒重叠群, 这些重叠群中许多被注释为噬菌体，并且噬菌体溶原性与有效的病毒转移有关。Nusbaum等[58]研究表明，FMT后UC患者的噬菌体变化与供体的组成相似。这些研究表明，肠道噬菌体群落的恢复可能在肠道微生态中发挥了关键作用。
3.2 非胃肠道疾病目前有些研究发现，FMT在治疗移植物抗宿主病(graft-versus-host disease，GVHD)方面有一定的疗效，但总体疗效尚不清楚[6, 65]。Zhang等[6]研究报道了GVHD患者接受了4轮FMT治疗后，观察到粪便噬菌体多样性增加，而尾状病毒噬菌体的相对丰度也增加。此结果与之前报道的FMT对复发性艰难拟梭菌感染患者的噬菌体定植结果的影响相似，FMT中供体有尾噬菌体的移植似乎也与GVHD的阳性治疗结果相关。未来还须设计大样本量的临床研究来解决FMT和噬菌体调节在GVHD中的治疗效果问题[66]。一项小型开放标签临床试验评估了FMT对18名自闭症谱系障碍(autism spectrum disorders，ASD)儿童的疗效，表明FMT后胃肠道症状减少了80%，其中便秘、腹泻、消化不良和腹痛以及行为症状得到显著改善，也观察到所有ASD患者噬菌体的组成有来自供体的噬菌体的植入[59]。2023年发表的一项研究报告了24名代谢综合征患者被随机分配到来自瘦且健康的供体(n=12)和安慰剂(n=12)的粪便滤液移植中，结果表明，来自健康供体的肠道噬菌体能够瞬间改变接受体的肠道微生物群[60]。总之，这些发现表明肠道噬菌体转移与FMT治疗各种疾病的临床功效有联系。
4 FMT中肠道噬菌体移植的安全问题研究数据表明FMT期间的噬菌体移植对疾病治疗成功是一个有利因素，但不良的病毒以及噬菌体的传播可能导致严重的安全问题，尤其是在免疫受损的患者中表现得更为明显。据报道，诺如病毒可通过FMT传播给CDI患者，这些患者在FMT后出现诺如病毒肠胃炎的症状[67]。所以为了防止FMT期间病原性的病毒以及噬菌体转移，在筛选供体时应进行严格的粪便筛查以确保FMT的安全性。此外，由噬菌体介导的从一种细菌菌株到另一种细菌的水平基因转移可能是抗生素抗性基因、毒力基因等传播的重要因素[68]。2019年的一项研究发现，一种温和的丝状噬菌体整合到铜绿假单胞菌的基因组中，这导致抗病毒免疫反应和宿主细菌感染清除能力受损[69]。这一证据表明，有些噬菌体的整合行为也可能给患者带来健康问题。噬菌体介导抗生素耐药基因(antibiotic resistance genes，ARGs) 转移导致抗生素耐药菌株出现，对人体健康以及公共卫生安全造成了重大威胁[70]。许多噬菌体编码毒素(如白喉毒素、志贺毒素和红细胞毒素)，在溶原转化过程中提高了其细菌宿主的存活率和毒力[71-72]。FMT可能会将携带这些毒素基因以及抗生素耐药基因的噬菌体转移到受体肠道中成为共同驻留的噬菌体，从而赋予其毒性表型并带来耐药性的传播风险，从而引发健康问题，这值得关注。因此，建议在未来的FMT实践中筛查并排除携带毒素以及抗生素耐药基因的噬菌体。FMT中肠道噬菌体的安全问题以及解决方案具体如表 2所示。
肠道噬菌体一方面可以通过与宿主细菌的相互作用，调节肠道菌群的结构，如传递新的细菌表型，调节细菌群落组成以及基因表达和进化，进而影响人类肠道健康[28]；另一方面，肠道噬菌体可以直接或间接调节免疫系统[20]。
5.1 FMT中噬菌体移植可以调节肠道菌群的分类组成和功能在FMT中噬菌体通过调节肠道菌群的分类组成及功能，间接影响人体微生物组间关系，最终影响人体健康，从而帮助FMT起到治疗疾病的效果。其中，噬菌体与细菌的相互作用可通过噬菌体和细菌之间的“捕食者”关系直接调节[74]，也可通过肠道中宿主细菌的噬菌体对旁观者细菌产生级联效应，从而改变肠道菌群结构[75-76]，还可以通过调节细菌代谢和活力来影响肠道细菌的功能[77]。有研究表明，在噬菌体定植后，肠道菌群和多种代谢产物发生了变化，几乎包括所有的代谢途径(如氨基酸、肽、碳水化合物、脂质、核苷酸、辅因子、维生素和外源性物质)[76]。Campbell等[78]的研究表明，类杆菌噬菌体BV01改变了其细菌宿主的全基因组转录组谱和胆盐水解酶活性，从而改变了胆汁酸谱，已知胆汁酸可调节宿主微生物群落和宿主生理学[79]。因此，噬菌体定植引起的肠道噬菌体组成和功能的这种变化对宿主的健康非常重要。
5.2 FMT中噬菌体可以直接或间接调节免疫系统在FMT中噬菌体可以直接或间接调节免疫系统。实际上，噬菌体可以定殖于肠黏液层，通过其衣壳直接与糖蛋白的黏蛋白家族结合，并为宿主提供肠屏障的防御机制[80]。噬菌体可以通过各种方式与宿主免疫系统相互作用，通过诱导先天防御细菌定植，刺激炎性细胞因子的产生，从而激活树突状细胞和先天淋巴细胞产生干扰素。噬菌体可以被固有宿主受体识别，如toll样受体家族，从而调节免疫系统[81]。这些研究表明，噬菌体的定植对调节宿主的免疫系统和生理机能至关重要。
5.3 FMT中供-受体噬菌体的匹配效应FMT与供体的噬菌体特异性植入有关，会增加病毒的多样性和丰富度，并且FMT后受体噬菌体组成与供体组成相似。Zuo等[14]通过研究FMT治疗艰难拟梭菌的感染(recurrent Clostridioides difficile infection，rCDI)发现，在FMT成功应答的受体中含有来自健康供体的有尾噬菌体目(Caudovirales)的植入，会具有更好的临床疗效，供受体噬菌体的匹配效应对FMT的成功具有重要意义。Park等[52]对19例艰难拟梭菌感染患者的FMT疗效进行回顾性队列研究，发现当受体肠道噬菌体的增加部分被供体来源的分类群占据时，FMT后治愈的可能性更大，还有一些类似研究[6, 53, 55, 57-59]强调了受体噬菌体组成与供体组成的相似性以及供体-受体匹配对FMT临床疗效的重要性。
6 总结大量研究表明，FMT具有重塑许多疾病的微生物组成和功能的作用，可知FMT的疗效不仅归因于肠道细菌的恢复，其肠道噬菌体也起了很大的作用。但对肠道噬菌体的了解还不够深入，这会限制其在FMT中发挥的作用。由于最先进的宏基因组测序和生物信息学技术的发展和应用，肠道“暗物质”正在逐渐被揭晓。本文讨论了肠道噬菌体的生物学特性及其在健康和疾病中的变化特征，并剖析了肠道细菌、病毒/噬菌体和人类宿主之间复杂的相互作用以及供受体噬菌体的匹配效应，这些都是FMT发挥疗效的基础，也将进一步增强对噬菌体的重要性及其在FMT中作用的理解。
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