Advances in the relationship between gut microbiota and colorectal cancerdevelopment and treatment
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摘要:
结直肠癌作为全球发病和死亡居首位的消化系统恶性肿瘤，其与肠道菌群的关系越来越受到关注。肠道菌群可以与宿主细胞相互作用，调节包括新陈代谢和免疫反应在内的多种生理过程。近年来，随着研究不断深入，已经揭示了宿主与肠道菌群之间的相互作用在结直肠癌的起源和进展中发挥重要作用。本综述旨在通过描述结直肠癌相关的肠道微生物群以及瘤内微生物群，讨论肠道菌群参与结直肠癌的发生、侵袭、转移过程的具体机制，及其对结直肠癌治疗反应和预后的影响，为深入了解肠道菌群与结直肠癌的关系提供参考，并为开发菌群干预结直肠癌提供治疗思路。
Abstract:Colorectal cancer (CRC), the most common malignant tumor of the digestive system with the highest morbidity and mortality worldwide, has received increasing attention for its relationship with the gut microbiota. The gut microbiota interacts with the host cells to regulate various physiological processes, including metabolism and immune responses. Recently, increasing research has revealed that the interaction between the host and gut microbiota plays a significant role in the origin and progression of CRC. In this review, we discuss the specific mechanisms of the gut microbiota involvement in the carcinogenesis, invasion, and metastasis of CRC, as well as its impact on the therapeutic response and prognosis, by describing the gut and intratumoral microbiota associated with CRC. This information serves as a reference for understanding the relationship between gut microbiota and CRC, and provides therapeutic ideas for the development of microbiota-based interventions for CRC treatment.
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结直肠癌（colorectal cancer，CRC）作为常见的恶性肿瘤之一，是全球发病和死亡首位的消化系统恶性肿瘤[1]。结直肠癌的发生发展由各种遗传和环境因素共同介导，然而估计的 CRC 的遗传率仅为 12%～35%[2]，提示环境因素的重要性。多项荟萃分析证明了肠道菌群失调与 CRC 发生发展的相关性。对结直肠腺瘤-腺癌肠菌分析表明，在癌变早期到晚期阶段具核梭杆菌（Fusobacterium nucleatum，F. nucleatum）和摩尔梭菌（Solobacteriummoorei）的丰度逐渐增加，提示肠道菌群可能参与结直肠腺瘤-腺癌途径[3-4]。然而，菌群失调和 CRC 进展的因果关系仍不清楚，有待进一步探索。
随着基因测序技术的不断进步，研究者们发现大部分肿瘤样本的癌细胞和免疫细胞中都含有细菌。目前认为瘤内细菌可能来源于黏膜屏障侵犯、邻近组织转移和血液转移[5]，然而对肿瘤微生物群落（OCS） 的了解仍然有限。Mouradov等[6]确定了一个基于微生物群的CRC分类系统，将肿瘤分为3个不同的OCS亚组，分别是以口腔病原体为特征的OCS1、以多个核心肠道共生菌为特征的OCS2和以肿瘤富集的变形杆菌为特征的OCS3，并且每个亚组在患者临床分子和预后关联方面都有显著性差异。
肠道菌群对肿瘤的影响是多方面的，本文旨在综述肠道菌群对肿瘤的发生、侵袭、转移以及治疗预后的影响，为深入了解肠道菌群与CRC的关系提供参考，并为开发菌群干预 CRC 提供治疗思路。
1. 肠道菌群参与CRC发生、侵袭和转移的分子机制
F. nucleatum和肠毒素脆弱拟杆菌 （Enterotoxigenic Bacteroides fragilis，ETBF）已被证明是导致CRC恶化的致癌因素，并且在多项研究中被证明存在于结直肠肿瘤的内部[7-10]。肠道菌群能够通过多种机制促进 CRC 发生和进展。
1.1 宿主遗传学变化
近期关联研究将与癌症相关的遗传改变与特定肠道微生物的富集或减少联系起来。Liu 等[9]发现一些菌属的细菌在KRAS突变的 CRC 患者（如消化链球菌属和微小单胞菌属）和腺瘤患者（如消化链球菌属和梭状芽胞杆菌属）中高度富集。此外，Takashima等[11]发现非产毒性脆弱拟杆菌组织丰度与CIMP-高和MSI-高相关，而ETBF丰度与CIMP-高和BRAF突变相关。
微生物可通过直接产生基因毒素破坏结肠上皮细胞的 DNA。大肠杆菌素是由基因毒性大肠杆菌的pks基因簇合成的，可引起链间交联（ICL）和双链断裂（DSB）[12]。进一步研究发现，基因毒性大肠杆菌显著增加了单碱基替换突变（SBS-pks）和插入缺失特征（ID-pks）[13]。细胞致死膨胀毒素（CDT）被证明由致病性大肠杆菌和空肠弯曲杆菌 （Campylobacter jejuni）产生[14]。CDT 具有 DNase 和磷酸酶双重活性，以依赖CdtB亚基基因毒性的方式诱导DNA 双链断裂、细胞周期停滞和细胞凋亡[15]。吲哚亚胺是最近发现的由IBD和CRC相关物种摩氏摩根氏菌（Morganella morganii）产生的，同样具有DNA损伤活性，并通过增加肠道通透性促进CRC发生[16]。
1.2 激活致癌信号通路
目前有充分的证据提示，从正常细胞到肿瘤细胞的转化是细胞信号调控机制发生紊乱造成的（表1）。Okuda 等[17]通过研究宿主信号通路与瘤内菌之间的关系，发现弯曲杆菌（Campylobacter）和硒单胞菌（Selenomonas）与 PI3K 信号转导和补体激活信号转导途径有关。梭杆菌（Fusobacterium）和链球菌（Streptococcus）与细胞周期系统有关。许多病原体通过直接与结肠上皮细胞的表面受体相互作用来转导其信号。F. nucleatum通过其表面黏附素FadA，与结肠上皮细胞上的 E-cadherin 结合，激活Wnt/β-Catenin信号通路，介导促瘤效应[18]。F. nucleatum还能通过其凝集素Fap2与 CRC 细胞表面的 Gal-GalNAc 相互作用，介导细菌的转移和定植[19]。另一个 CRC 富集菌牙龈卟啉单胞菌 （Porphyromonas gingivalis）也能够入侵宿主细胞，通过其毒力因子牙龈蛋白酶激活 MAPK/ERK 信号通路并促进结直肠癌细胞增殖[20]。厌氧消化链球菌（Peptostreptococcus anaerobius， P. anaerobius）的表面蛋白 PCWBR2 通过α2/β1整合素与结肠癌细胞系直接相互作用，通过磷酸化局灶黏附激酶诱导激活 CRC 细胞中的 PI3K-Akt 通路[21]。以上均提示干扰细菌与宿主细胞受体的相互作用可阻断致癌信号通路的激活，为结直肠肿瘤的治疗提供思路。
表 1 肠道菌群与致癌信号通路1.3 表观遗传修饰改变
越来越多的证据表明，肠道微生物也可能驱动CRC 的表观遗传改变。在CRC的DNA样本中检测到多个肿瘤抑制基因的高甲基化。F. nucleatum和哈式梭菌（Hungatella hathewayi，H. hathewayi）被确定为甲基化调节瘤内菌的前两位。H. hathewayi和Streptococcus spp分别与CDX2和MLH1启动子超甲基化相关[25]，而F. nucleatum与CDKN2A启动子 CpG 岛超甲基化[26]和MLH1甲基化相关[27]。此外，A型微小微单胞菌（Parvimonas micra, P. micra）可改变肿瘤抑制基因、致癌基因和上皮间质转化基因的启动子的 DNA 甲基化图谱[28]。
肠道菌群的致癌机制也与某些非编码 RNA 有关。F. nucleatum感染会刺激CRC细胞产生富含miR-1246、miR-92b-3p和miR-27a-3p的外泌体，这些外泌体被输送到未感染的细胞中，从而促进肿瘤转移[29]。F. nucleatum能够调节 miR-21[30]、miR-
4474 /4717 [31]、miR-1322 [32]和lncRNA ENO1-IT1[33]的表达，它们分别参与激活MAPK 信号通路、激活Wnt/β-catenin信号通路、激活CCL20并诱导 M2 巨噬细胞极化、调节糖酵解代谢。脆弱拟杆菌相关 lncRNA（BFAL1） 可激活 Ras 同源物，激活RHEB/mTOR通路，并通过调节 miR-155-5p 和 miR-200a-3p 改变RHEB的表达[34]。此外，ETBF 和P. micra可分别下调miR-149-3p[35]和上调miR-218-5p[36]的表达，促进CRC的发展。1.4 诱导慢性炎症
慢性炎症已被证实是肿瘤发生发展的元凶之一。Chang 等[36]发现在结肠炎相关CRC的初期阶段，肠道菌群衍生的脂多糖（LPS）通过结合TLR4 受体，促进Th17细胞扩增并诱导 M2 型巨噬细胞极化。F. nucleatum可通过ALPK1/TIFA途径[37]，或TLR4 信号通路[38]，激活CAC 相关的 NF-κB信号通路，增加CAC 中致癌基因ZFP90的表达，并增加炎性细胞因子 IL-8 和两个已知与 CRC 有关的抗凋亡基因BIRC3和TNFAIP3的表达。Han 等[39]发现ETBF 毒素能够触发 STAT3-NF-κB 依赖性促炎信号级联，释放炎性细胞因子。Chung等[40]发现致毒大肠杆菌的定植会导致小鼠体内促炎性 IL-17 的产生增加以及随后的 DNA 损伤，加速 CRC 的发展。
值得注意的是，与散发性 CRC 不同的是在炎症驱动的 CRC 中，早期可以检测到TP53的突变，而且已知这种突变会增强 TNF、NF-κB和 STAT3 信号传导[41-42]。此外，长期的慢性炎症最终会诱导免疫抑制微环境，促进肿瘤进展[43]。
1.5 调节免疫微环境
肠道菌群可以通过促进免疫抑制微环境的形成和诱导免疫细胞的失活来逃避宿主抗肿瘤免疫。Li 等[44]发现肠道微生物群失衡诱导肿瘤细胞分泌与转移相关的分泌蛋白cathepsin K（CTSK），CTSK能与TLR4结合，通过依赖mTOR的途径刺激巨噬细胞M2极化。 Chen 等[45]发现缺乏尿素分解功能的致病菌富集，积累的尿素可进入巨噬细胞，抑制 p-STAT1 与SAT1启动子区域的结合，并刺激巨噬细胞M2极化。F. nucleatum感染可激活CCL20促进巨噬细胞浸润，同时诱导M2巨噬细胞极化[32]。此外，摄入高纤维食物可诱发肠道菌群失调并促进肠癌的发生，同时激活 MCP-1/CCR2 轴，极化 M2 型巨噬细胞[46]。
菌群除了通过诱导M2型巨噬细胞分化塑造免疫抑制微环境外，研究发现F. nucleatum还能结合并激活人淋巴细胞上表达的T 细胞免疫受体[47]和癌胚抗原细胞黏附分子 1（CEACAM1）受体[48]，从而抑制抗肿瘤免疫。Borowsky等[49]发现F. nucleatum的数量与肿瘤基质CD3+淋巴细胞成反比，特别是基质CD3+CD4+CD45RO+细胞，提示F. nucleatum可能会通过抑制T细胞促进CRC的发生。此外，F. nucleatum能够以一种依赖于 FFAR2 的方式影响 Th17 反应，F. nucleatum的肠道定植增加了IL-17A 和 IL-17F 的表达，同时增加了结肠固有层IL23p19 的表达，从而影响肠道免疫，促进肿瘤进展[50]。
2. 肠道菌群影响CRC治疗疗效的分子机制
有研究表明，肠道菌群对CRC患者化疗的治疗反应有着不可忽视的影响。Yu等[51]发现在化疗后复发的大肠癌患者的癌组织中，F. nucleatum的丰度占优。F. nucleatum通过靶向TLR4、MYD88通路和特定的微小RNA，激活自噬通路并改变化疗响应。F. nucleatum还能调节Hippo通路，促进癌基因BCL2的表达，从而抑制化疗药物诱导的Caspase-3/GSDME热蛋白沉积相关通路[52]。F. nucleatum感染可通过TLR4/NF-κB通路诱导CRC细胞中BIRC3基因上调，从而抑制肿瘤细胞凋亡，降低对化疗的敏感性[53]。F. nucleatum通过代谢、致癌信号通路、致癌基因表达等多种途径介导化疗耐药，提示干预F. nucleatum来恢复化疗疗效的潜能。此外de Oliveira Alves等[54]利用空间代谢组学分析技术和 16SrRNA 测序发现右侧结直肠癌中主要存在产大肠杆菌素大肠杆菌（CoPEC），CoPEC通过建立具有较低免疫原性的高甘油磷脂微环境，为肿瘤细胞提供能量的同时，减少CD8+T细胞的浸润。此外，CoPEC能够通过促进上皮间质转化和诱导癌症干细胞，增强对化疗药物的耐药性[55]。
在结直肠肿瘤免疫治疗方面，Jiang等[56]发现对免疫疗法不应答的转移性患者中，F. nucleatum产生的琥珀酸抑制了cGAS-IFNβ通路，使肿瘤中的趋化因子CCL5和CXCL10水平降低，从而限制CD8+T细胞向肿瘤微环境迁移。肠道微生物群来源的次级胆汁酸脱氧胆酸（DCA）通过靶向质膜Ca2+ATP酶（PMCA）抑制Ca2+/NFAT2信号传导来抑制CD8+T细胞反应[57]。虽然还需要更多的研究来阐明不同细菌与肿瘤免疫治疗之间的关系，但通过改变肠道微生物群的组成和丰度来调节肿瘤免疫微环境，是癌症治疗的一个新方向。如，Kong等[58]证明通过菌群调节可改变瘤内菌群的丰度和多样性，并破坏菌群和肿瘤微环境的代谢途径，解除肿瘤的耐药性。多项研究发现肠道益生菌能够产生不同代谢产物增强CD8+T细胞的功能，提高治疗疗效，例如鸡乳杆菌 （Lactobacillus gallinarum）衍生的吲哚-3-羧酸（ICA）[59]、约氏乳杆菌（Lactobacillus johnsonii） 与生孢梭菌（Clostridium sporogenes）共同产生的吲哚-3-丙酸（IPA）[60]、植物乳杆菌（Lactobacillus plantarum）来源的吲哚-3-乳酸（ILA）[61]。活泼瘤胃球菌（Ruminococcus gnavus）、经黏液真杆菌属的Blautia producta可通过降解溶血甘油磷脂，维持 CD8+T 细胞的免疫监视功能[62]；此外，罗伊氏乳杆菌 （Lactobacillus reuteri）通过产生吲哚-3-乳酸 （ILA）靶向RORγt，减少Th17细胞分化，并通过激活肠上皮AHR改善屏障完整性[63]。
近期，许多临床研究强调了肠道菌群作为免疫治疗反应的预后生物标志物的潜力（图1）。如，对于接受西妥昔单抗联合阿维鲁单抗的转移性CRC患者，真杆菌属（Agathobacter）和经黏液真杆菌属 （Blautia）被确定为与抗肿瘤活性相关的潜在关键因素[64]。在一项瑞戈非尼联合特瑞普利单抗治疗CRC的Ⅰb/Ⅱ期研究中，对基线粪便样本进行的肠道微生物组分析表明，非应答患者的Fusobacterium相对丰度和阳性检出率明显高于应答患者[65]。此外，粪便微生物群移植（FMT）作为一种可操纵肠道微生物的干预措施，被证明可辅助抗肿瘤免疫治疗，以达到客观缓解[66]。
3. 结语
目前，随着测序分析技术的不断进步，肠道菌群和 CRC 关联研究的数量和样本量都在增加，这为全面描绘 CRC 患者的微生物景观提供了可能。并且，功能研究也使我们对肠道菌群在 CRC中发挥的重要作用有了较为清晰的了解。CRC微环境中存在着微生物已被证实，然而这些微生物究竟是不是CRC发生、发展的“驱动”因子，尚待更多研究进一步验证。希望随着更多肠道菌群相关新技术的突破和新概念的提出，人们对CRC的发生、发展和临床诊治能得到更加丰富的线索和机会。
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