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通讯作者:

刘煜,E-mail:drliuyu@njmu.edu.cn

中图分类号:R392.9

文献标识码:A

文章编号:1007-4368(2023)03-421-07

DOI:10.7655/NYDXBNS20230319

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目录contents

    摘要

    肠道微生物群的组成或功能失调与多种疾病相关。粪便微生物群移植(fecal microbiota transplantation,FMT)是通过将供体微生物群移植至受体肠道内,重建受体肠道微生态结构,进而治疗与肠道微生物群失调相关慢性疾病的一种微生态疗法,其适应证已从肠道疾病扩展到肠道外疾病。尽管FMT可治愈90%的复发性艰难梭菌感染,然而FMT在其他复杂疾病中的疗效不尽相同,且在治疗相同疾病患者时存在显著的个体差异,这表明存在多种因素影响FMT治疗疾病的疗效。本文从供体和受体两方面对FMT中供体微生物群植入和临床疗效的影响予以综述。

    Abstract

    Gut dysbiosis has been identified as a potential factor that may drive a variety of diseases. Fecal microbiota transplantation(FMT)is a microecological therapy which delivers fecal microbiota of screened healthy donor into the recipient intestine. By restructuring the recipient gut microbiota with donor fecal samples,FMT has been used to treat a number of gastrointestinal and non - gastrointestinal disorders. Although FMT could cure 90% of recurrent Clostridioides difficile infections,the efficacy of FMT in other diseases is variable. These suggests that there are multiple factors influence the efficacy of FMT. This article will discuss the impact of both donor and recipient factors on donor microbiota engraftment and clinical efficacy in FMT.

  • 肠道微生物群的组成或功能失调与多种疾病相关,粪便微生物群移植(fecal microbiota transplan⁃ tation,FMT)被认为是一种重建患者肠道内微生物群的微生态疗法,它是将来自健康供体粪便中的功能菌群移植到患者肠道内,进而恢复受体肠道微生物群多样性或减少不利微生物种类的相对丰度,最终实现肠道及肠道外疾病的治疗。自2013年一项随机对照试验(randomized controlled trial,RCT)使用 FMT治疗人类疾病以来,FMT作为缓解一些疾病的潜在治疗方法受到越来越多的关注[1-2]。FMT已被写入多项指南用于治疗复发性或难治性艰难梭菌感染(Clostridioides difficile infection,CDI),近年来发现其他肠道疾病如炎症性肠病(inflammatory bowel disease,IBD)、肠易激综合征(irritable bowel syn⁃ drome,IBS)及非胃肠道疾病包括代谢性疾病等均可能是FMT的潜在治疗靶点[3]

  • 然而 FMT 在治疗相同疾病的不同患者时存在疗效差异,这表明存在多种因素影响FMT 的疗效。目前证实供体粪便来源、菌液移植方法及受体自身的基线肠道微生物群、饮食生活方式、基线临床状态和药物使用情况等多种因素均可影响移植微生物的功能、在受体肠道内的重建及定植维持的时间。本文将从供体和受体两方面因素对 FMT 中供体微生物群植入和临床疗效的影响予以综述。

  • 1 供体相关因素

  • FMT是将供体粪便中的复杂微生物群(包括细菌、病毒、真菌及其代谢产物)转移至受体肠道内的过程。细菌是肠道微生物群最主要的组分,研究发现人类肠道细菌的基因数量占肠道微生物总基因的99%以上。除细菌外,病毒和真菌也以共生微生物的形式存在于肠道中。越来越多的研究发现 FMT疗效与供体粪便内肠道微生物群的特征相关。

  • 1.1 供体粪便的细菌多样性和组成

  • 供体粪便的细菌多样性是 FMT 治疗成功的可靠预测指标,有学者用“超级供体”一词描述导致 FMT疗效显著高于其他供体的粪便供体[4]。多项研究证实,供体粪便内较高的细菌多样性对恢复受体肠道内稳定的共生微生物群落至关重要[5]。Paramsothy 等[6] 同样发现溃疡性结肠炎(ulcerative colitis,UC) 患者在FMT后存在疗效差异,供体粪便中拟杆菌属 (Bacteroides)丰度与 FMT 后 UC 患者临床症状缓解相关,而供体粪便中的链球菌属(Streptococcus)丰度与 UC 患者临床症状未缓解相关,这表明供体粪便中的特定组成同样影响FMT疗效。

  • 在 FMT 治疗代谢性疾病时存在类似现象。代谢综合征(metabolic syndrome,MetS)患者肠道细菌多样性显著低于健康人群,Vrieze 等[7] 将 MetS 患者随机分配至异体(健康供者)和自体粪菌移植组进行FMT治疗,FMT后移植健康供体粪菌的MetS患者肠道内微生物多样性、胰岛素敏感性均显著高于自体移植组。Wilson等[8] 使用多个健康供体来源的粪便菌液对肥胖青少年患者进行FMT治疗,发现多个健康供体中两个供体粪便微生物群主导受试者肠道内菌株的植入,这两个供体粪便均具有高细菌多样性的特征。

  • 目前认为,供体粪便中较高的细菌多样性,高丰度的毛螺菌科(Lachnospiraceae)、瘤胃球菌科(Ru⁃ minococcaceae)、脆弱拟杆菌(Bacteroides fragilis)及低丰度的变形菌门(Proteobacteria)与 FMT 后 UC 患者获得较好的临床疗效显著相关。因此,供体粪便内细菌多样性及特定细菌的丰度是决定 FMT 疗效的主要因素之一。

  • 1.2 供体粪便的病毒多样性和组成

  • 肠道病毒群落以噬菌体为主,噬菌体通常有助于控制入侵的病原体、调节菌群结构及维护肠道稳态,温和性病毒为优势是人类健康粪便的典型特征[9]。FMT可将供体粪便内的病毒组分随细菌共同移植至受体肠道,从而在受体肠道内发挥与供体相似的潜在功能[10-11]

  • 供体粪便内噬菌体的多样性及特定组分会影响 FMT 的疗效。Park 等[12] 发现 FMT 治疗 CDI 患者成功的供体粪便内噬菌体α多样性较高,噬菌体相对丰度较低。Zuo等[13] 发现FMT治疗CDI的疗效与供体来源的尾噬菌体目(Caudovirales)在受体肠道的定植水平高度相关,特别是当供体粪便中尾噬菌体目的丰度高于受体时疗效最佳。有趣的是,供体来源的尾噬菌体目在 FMT 应答者肠道内的定植水平与肠道内细菌的丰富度和多样性呈正相关。

  • 目前,已有多项研究探索采用粪便病毒组移植 (fecal viral transfer,FVT)替代传统的FMT进行疾病治疗。Ott 等[14] 发现 5 例 CDI 患者在接受 FVT 治疗后临床缓解且疗效维持6个月以上,FVT 后患者肠道病毒群落结构发生改变。在动物水平同样发现 FVT 可发挥与 FMT 相当的疗效。Draper 等[15] 将抗生素干预前的小鼠粪便经自体 FVT 定植至干预后的小鼠肠道,发现 FVT 后小鼠肠道微生物群重塑,微生物群特征更接近于抗生素干预前。Rasmussen 等[16] 将瘦型小鼠盲肠的病毒群落经 FVT 定植至肥胖小鼠肠道,发现与对照组相比,FVT组小鼠体重增加减少,葡萄糖耐量改善,且这种效应是由FVT后肠道微生物群的改变引起的。这表明供体粪便病毒组在FMT治疗成功中同样有着不可或缺的作用。

  • 综上所述,供体粪便的病毒组可随FMT转移至受体肠道,供体粪便的病毒组可直接缓解特定疾病的临床症状。供体粪便内噬菌体多样性及尾噬菌体目的丰度是影响FMT疗效的因素之一。

  • 1.3 供体粪便的真菌多样性和组成

  • 肠道内共有 50 多种真菌属,其中假丝酵母菌 (Candida)、酵母菌(Saccharomyces)、枝孢菌(Clado⁃ sporium)和马拉色菌(Malassezia)最为丰富[17]。肠道内真菌与细菌之间存在共生和拮抗的关系,真菌与微生物组装和免疫发育之间存在因果关联[18]。此外,多种疾病存在肠道真菌群的失调,提示肠道真菌在疾病发病中的关键作用[19-20]

  • FMT 涉及真菌从供体至受体肠道的转移,且 FMT 治疗的成功与供体来源的特定真菌分类群有关,特别是白假丝酵母菌的丰度。Zuo 等[21] 发现对 FMT治疗有应答的CDI患者肠道酵母菌和曲霉属相对丰度较高,而对FMT无应答的CDI患者肠道内念珠菌属占主导地位。供体粪便内高丰度的白假丝酵母菌与CDI患者FMT疗效降低相关,供体小鼠粪便中的丝状真菌——青霉菌(Penicillium brocae)和帚状曲霉菌(Aspergillus penicillioides)可减低FMT对 CDI感染小鼠的治疗效果。

  • 2 受体相关因素

  • 人们普遍认为,供体及粪便样本的处理是FMT 成功的关键因素,然而在使用同一供体粪便对相同疾病患者进行FMT治疗时仍存在疗效差异,这表明受体因素对FMT的治疗效果同样发挥重要作用。

  • 2.1 受体基线肠道微生物群的特征

  • FMT 后移植的供体微生物群与受体基线微生物群相互作用,最终形成供体、受体基线及新生微生物共同定植的微生物网络稳态[22]。在接受相同供体粪便移植的MetS患者之间存在肠道微生物定植的显著差异,Li等[23] 发现若受体基线肠道内已存在某一菌种,则供体粪便中该菌种在受体肠道定植的可能性更大;反之,则供体粪便中该菌种在受体肠道定植的可能性较小。Smillie等[22] 同样发现FMT 治疗CDI患者时受体基线的细菌丰富度和分类特征是预测FMT成功的关键因素,且供体同一菌种内的菌株以全有或全无的方式在受体肠道内定植。

  • 大量临床试验表明,受体基线肠道内特定细菌的丰度会影响 FMT 对不同疾病的疗效。在肠道疾病中,UC患者基线肠道内高丰度的梭杆菌属(Fuso⁃ bacterium)和萨特氏菌(Sutterella)与 FMT 治疗无效密切相关[24],克罗恩病(Crohn’s disease,CD)患者 FMT治疗无效与其基线肠道内γ⁃变形菌纲(如克雷伯氏菌、放线杆菌和嗜血杆菌)的丰度相关[25]。在肠道外疾病MetS的治疗中发现,FMT应答者基线肠道内舌下肌菌(Subdoligranulum variabile)和多尔氏菌属(Dorea)的相对丰度高于FMT无应答者,而凸腹真杆菌(Eubacterium ventriosum)和胃瘤球菌(Rumino⁃ coccus torque)的相对丰度低于FMT无应答者[26]

  • 除细菌外,受体基线肠道内真菌及病毒的丰度同样对FMT疗效起关键作用。CDI患者基线肠道内低丰度的白假丝酵母菌与FMT疗效呈正相关[21],而 UC患者基线肠道内高丰度的白假丝酵母菌与FMT 疗效呈正相关,且与FMT后肠道细菌多样性增加相关[27]。Gogokhia 等[28] 发现 FMT 治疗 UC 患者时,应答者基线肠道内尾噬菌体目的丰度高于无应答者,提示UC患者基线肠道的尾噬菌体目丰度与FMT疗效相关。

  • 因此,受体基线肠道微生物群(包括细菌、真菌及病毒)在重建受体肠道微生态结构中发挥一定作用,受体基线肠道微生物群可能会以疾病依赖性的方式影响FMT疗效。

  • 2.2 受体的饮食和生活方式

  • 饮食是塑造肠道微生物群的重要因素之一。饮食可在几天或几周内迅速改变肠道微生物群的结构[29]。多项研究证实受体的饮食模式是维持 FMT疗效长短的关键因素。

  • 在FMT治疗肠道疾病时发现,与单独接受FMT 治疗的UC患者相比,接受FMT联合果胶治疗的UC 患者肠道微生物多样性丧失的速率减慢,临床症状改善更显著[30]。饮食模式同样影响 FMT 治疗代谢性疾病的疗效。Mocanu等[31] 发现单剂量FMT联合每日低发酵膳食纤维补充可在FMT后6周显著提高严重肥胖和MetS患者的胰岛素敏感性。Rinott等[32] 发现与对照组相比,接受绿色地中海饮食干预的肥胖受试者进行自体FMT后体重反弹显著降低,代谢参数改善,临床指标的改善与受试者肠道微生物群的改变密切相关,即FMT后受试者肠道内与减重相关的特定细菌和微生物代谢通路恢复。

  • FMT联合生活方式干预可进一步增强肥胖2型糖尿病患者肠道内有益微生物的植入。Ng等[33] 发现与单独FMT干预相比,接受FMT联合生活方式干预的肥胖 2 型糖尿病受试者在 FMT 后第 4、16 周的肠道细菌丰富度显著增加,肠道内双歧杆菌和乳酸杆菌丰度增加,肠道微生物群发生更有利的改变,且受试者低密度脂蛋白胆固醇较基线时降低。

  • 因此,受体的饮食与生活方式可通过干预FMT 后受体肠道内重建的微生物群组成,进而影响FMT 疗效及维持时间。

  • 2.3 受体基线临床状态

  • FMT治疗CDI患者的多项临床试验均发现受体基线临床症状的轻重及有无严重合并症是影响 FMT疗效的重要因素之一。

  • Ianiro 等[34] 发现 31%的复发性 CDI 患者经单次 FMT后症状无法缓解,需要多次FMT治疗,重度CDI 是单次 FMT 治疗失败的独立预测因素。在多中心治疗CDI患者的研究中可得到类似的结论,Fischer 等[35] 对多中心FMT治疗的CDI患者进行追踪随访,共有18.6%的患者出现单次FMT治疗的早期失败,他们发现严重和复杂的适应证、FMT期间患者的临床状态以及既往与 CDI 相关的住院次数均与单次 FMT治疗的早期失败相关。对20项涉及FMT治疗复发性/难治性 CDI 患者的临床试验进行荟萃分析,发现重度 CDI、既往 CDI 相关住院治疗史及住院期间的状态不佳均是 FMT 治疗失败的重要预测因素[36]。此外,Gallo 等[37] 发现需要多次 FMT 治疗的CDI患者在第1次FMT治疗前的肠道炎症发生率高于仅需要单次FMT治疗的患者。

  • 因此,对特定疾病患者进行FMT治疗时可能需要考虑选择合适的治疗时机及适应证,Moayyedi等[4] 发现 FMT 对新诊断的 CD 患者可能更有效,这表明早期诊断的UC 存在FMT 治疗的潜在机会窗,肠道微生态紊乱可能在这一时期更易恢复。此外,以上研究均集中于FMT治疗CDI或UC患者,目前尚无临床试验证实肠道外疾病患者的基线临床状态对FMT 疗效的影响,需要更多的证据支持这一观点。

  • 2.4 受体在FMT治疗期间的药物使用情况

  • FMT前受体通常需要进行肠道准备,以促进供体粪便微生物群在受体肠道内的定植,研究表明肠道准备不充足与FMT治疗CDI患者失败相关[34],肠道准备过程中最常用的药物为广谱抗生素或聚乙二醇。

  • 抗生素在 FMT 治疗期间的使用仍存在争议。抗生素可能诱发IBD患者出现不良反应或造成抗生素耐药菌的富集[38]。一些临床研究表明 FMT 治疗前进行抗生素预处理可增加FMT治疗UC患者的有效率,但这些研究均缺乏未使用抗生素进行预处理的对照组[39-40]。在动物模型中,Le等[41] 发现抗生素预处理并不会增加供体小鼠肠道微生物群在受体小鼠肠道内的定植,而Ji等[42] 发现对受体小鼠进行抗生素的预处理可通过促进肠道黏膜内异种微生物群的定植进而提高整体肠道微生物群重组的效率。Allegretti等[43] 发现在FMT后8周内使用抗生素可能会破坏受体肠道内移植的微生物并降低 FMT 治疗的有效性。因此,应尽量避免在FMT后使用抗生素,且受体在进行FMT前至少停用抗生素24 h以上[44]

  • 除抗生素外,几种常用非抗生素类药物与肠道微生物群多样性的减少或特定菌株过度生长有关[45]。 ①质子泵抑制剂(proton pump inhibitor,PPI):PPI可减少胃酸分泌,可能对受体肠道移植的微生物群有一定保护作用,它被建议用于FMT经上消化道治疗途径[46]。然而 PPI 被证实可显著影响肠道微生物群,Imhann等[47] 发现PPI服用者肠道微生物群多样性显著降低,20%的细菌分类群发生变化且多种口腔细菌在粪便微生物群的比例增加。②二甲双胍:二甲双胍是一种用于治疗 2 型糖尿病的口服降糖药,多项研究证实二甲双胍可通过增加短链脂肪酸 (short chain fatty acid,SCFA)含量和有益菌嗜黏蛋白阿克曼菌(Akkermansia muciniphila)、产 SCFA 菌的丰度等发挥降糖作用[48]。③免疫抑制剂:可能通过直接影响免疫细胞和肠道炎症对肠道微生物群产生影响[49]

  • 尽管上述常用药物会影响肠道微生物群,但这些药物是否会对供体粪便微生物的定植或 FMT 后受体肠道内重建的微生物造成干扰,并影响FMT的疗效仍需要更多的研究进行探索。

  • 3 展望

  • FMT 是通过将健康供体粪便菌液移植至受体肠道内,进而重建患者肠道内微生物群并缓解特定疾病临床症状的微生态疗法。尽管目前已开展多项临床试验进行 FMT 对肠道及肠道外疾病的探索性治疗,但 FMT 仍存在以下问题:①FMT 后患者临床症状改善维持的时间较短,如MetS[726] 及活动性 CD 患者[50] FMT 后临床症状缓解维持时间均为4个月左右;②FMT在治疗相同疾病患者时存在疗效差异,即存在FMT应答者和无应答者[2651-52]

  • 目前 FMT 正在步入精准医疗时代。精准 FMT 主要包括:①根据患者的临床、微生物、免疫和代谢指标选择合适的FMT受试者;②对供体的饮食结构及生活习惯等进行持续追踪,尽量避免供体的微生物群受到年龄、饮食和生活方式等因素的影响,以维持供体肠道微生态结构的动态稳定[53];③根据受体特征筛选合适的供体,或以疾病特异性的方式对细菌、噬菌体和真菌进行组合后转移至受体,最终确保供体微生物群的植入[54-55]。He 等[56] 构建了一种基于肠型的供体选择(enterotype⁃based donor se⁃ lection,EDS)模型,他们发现 EDS 模型可为不同肠型的CDI和IBD患者选择合适的FMT供体,以提高 FMT疗效;④根据受体和疾病特征对FMT的设计进行优化,如通过洗涤菌群移植(washed microbiota trans⁃ plantation,WMT)优化菌液制备及移植途径[57]、确定最佳的肠道准备方法、通过饮食和生活方式联合干预控制受体肠道环境等。

  • 综上所述,FMT 中供体、受体因素均会影响 FMT 的疗效。基于 FMT 疗效差异带来的启示以及微生物组学、代谢组学等多组学技术的研究,开展综合考虑供体及受体因素的精准FMT将是FMT的重要发展方向。

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