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放射性肠炎与肠道微生态的关系探究
发布时间:2020-07-06

  摘    要: 放射性肠炎(RE)是腹盆腔或腹膜后恶性肿瘤放射治疗导致的肠道最严重、最常见并发症之一。受累肠道病变广泛、复杂、迁延不愈,治疗难度极大,效果欠佳,严重者可形成短肠综合征。作为人体最大、最复杂的微生态系统,肠道菌群功能十分广泛。研究表明,肠道菌群在放射所导致的RE发病中起重要作用。本文总结了RE和肠道菌群的相关性及最新研究进展。

  关键词: 放射性肠炎; 肠道微生态; 益生菌; 放射性损伤;

  Abstract: Radioactive enteritis(RE)is one of the most serious and common complications of intestinal tract caused by radiotherapy for malignant tumors in abdominal cavity,pelvic cavity,or retroperitoneum.Involved intestinal diseases are widespread,complex,and persistent,which make treatment difficult and ineffective.Short bowel syndrome can develop in some serious cases.Gut flora is the largest and most complex micro-ecosystem in human body and has a wide range of functions.Studies have shown that intestinal flora plays an important role in radiation-induced RE.This article summarizes recent research advances in the relationship between RE and gut flora.

  Keyword: radiation enteritis; gut microecology; probiotics; radiation injury;

  近年来,恶性肿瘤发病率显着提高,全球每年新发恶性肿瘤1400万例,预计2030年将超过2300万例[1]。放射治疗(以下简称放疗)一直是恶性肿瘤综合治疗的重要组成部分,尽管放射技术取得极大进步,但放射对周围健康组织的损伤仍是放疗主要并发症。放射敏感细胞一般未分化、分裂迅速、代谢活性高[2,3],这使肠道(肠道干细胞)成为仅次于骨髓、易受放射损伤的器官。随着放疗患者数量增加及存活率提高,肠道放射损伤发生率将显着增加[4]。

  由于诊断标准缺乏共识且患者对放射性肠炎(radioactive enteritis,RE)症状报告不足,RE真实发病率尚不清楚。据报道,腹部放疗前几周,90%患者出现胃肠不适[5,6],难辨梭状芽孢杆菌感染率随之上升[7]。3%~10% 患者出现严重放射性肠损伤[5,8,9,10],其中1/3需要手术治疗,死亡率10%~22%[9,11,12]。研究表明,肠道微生态在RE发病中起关键作用,环境对于肠道微生态的影响远大于个体遗传背景[13,14]。了解RE发病与肠道微生态的关系,通过改变环境进而影响肠道微生物群,可能获得潜在治疗效益。
 

放射性肠炎与肠道微生态的关系探究
 

  放射改变肠道菌群构成及计数

  成年人肠道内定植菌群达400~500种,约1014个集落形成单位,遍布整个消化道,包括需氧菌、兼性厌氧菌和厌氧菌。成人肠道代表微生物群是硬杆菌(38.8%)和拟杆菌(27.8%),放线菌(8.2%)和变形杆菌(2.1%)比例较小[15,16]。成人肠道菌群构成相似并具稳定性。放射可使肠道微生物群发生显着改变[17,18,19,20,21,22],且改变程度存在明显个体差异。

  Johnson等[23]研究发现,接受放射2 h后,小鼠需氧菌数量明显下降;16 h后,肠杆菌、乳酸杆菌数量显着下降。Jahraus等[24]同样发现,经550Gy全身照射后,小鼠粪便中总细菌数、肠链球菌、乳酸杆菌、革兰氏阴性厌氧菌、拟杆菌数量明显下降。人体肠道菌群存在同样变化:Manichanh等[20]发现,放射可造成人体粪便菌群构成及计数发生明显变化,其改变情况与放射相关腹泻存在相关性。切尔诺贝利核事故导致附近儿童盲肠内肠杆菌、肠球菌、乳酸菌和双歧菌显着减少[25]。另有研究显示,放射可导致肠道疣微菌门、拟杆菌门和变形菌门增多,厚壁菌门和放线菌门减少,但其变化程度可能会因位置而异,如拟杆菌门在大肠内增加4%,小肠内则增加18%[19]。

  尽管上述研究证实了放射对肠道微生物群的干扰,但它们仍未阐明微生物群与肠道放射损伤的相关性。

  益生菌可预防RE发生、缓解RE症状

  大多数益生菌属于乳酸诱导菌(乳酸杆菌、链球菌和双歧杆菌),是肠道正常菌群[26,27]。益生菌能诱导淋巴细胞、肠细胞或树突状细胞产生细胞因子[28]。目前益生菌用于治疗肠道菌群失调、炎性肠病、RE相关腹泻等。动物研究表明,益生菌能竞争黏附于肠壁而抑制致病菌,对RE有预防作用[29]。含乳酸杆菌的益生菌可降低放射小鼠内毒素水平及假单胞菌菌血症发生率,减轻肠道损伤[29,30,31,32]。含鼠李糖乳杆菌的益生菌可降低放射细胞凋亡率[33]。Ki等[32]研究表明,益生菌对15Gy以下造成的小肠绒毛缩短有预防作用。

  腹泻是RE患者较常见的临床症状,可给予抗生素、硫糖铝、消炎药(美沙拉嗪)、谷氨酰胺、奥曲肽、蛋白水解酶和高压氧治疗[26,34],但效果欠佳[35]。研究表明,益生菌在降低RE相关腹泻发生率、缓解腹泻程度方面效果显着。2002年,Delia等[36]关于VSL#3益生菌预防RE相关腹泻的研究指出,与安慰剂组相比,VSL#3组腹泻发生率更低,每天排便次数更少,发生腹泻到使用洛哌丁胺控制腹泻的时间更长。2007年,Delia等[26]在一项纳入490例术后盆腔放疗患者的临床随机对照研究中发现,乳酸杆菌+双歧杆菌+嗜热链球菌三联菌在降低腹泻发生率、缓解腹泻严重程度、腹泻造成放疗中断病例数、肠蠕动次数以及洛哌丁胺用药时间等方面明显优于对照组。2008年,Giralt等[35]关于含酪乳杆菌DN- 114 001益生菌饮料是否可降低妇科恶性肿瘤患者RE相关腹泻发生率的研究表明,益生菌饮料对RE相关腹泻发生率无影响,但可显着延迟腹泻形成时间。2010年,Chitapanarux等[37]也得出类似结论,益生菌(乳酸菌+双歧杆菌)可预防盆腔放疗患者RE相关腹泻的发生。基于目前有限的、小样本研究,益生菌在预防放疗相关腹泻中推荐应用级别为C[38]。在推荐级别升级之前,需要更多随机对照试验评估益生菌安全性与有效性。

  粪便移植对肠道放射损伤具有一定治疗作用。2018年,我国报道迄今第1例粪菌移植显着缓解难治性RE的病例充分说明了肠道菌群在RE治疗中的作用[39]。Cui等[40]研究显示,将对照小鼠粪便移植到放射暴露小鼠可明显改善肠道损伤,提高存活率。目前关于微生物群移植治疗放射急性肠损伤的疗效研究正在进行,在该研究中,放射肠损伤患者将接受3次选择性微生物群移植,随后随访4周,届时将通过各种方式进行疗效评估,研究结果值得期待[41]。

  虽然益生菌在RE治疗中效果确切,但其毕竟是活菌,仍有造成宿主感染可能。有研究称,益生菌存在造成全身感染的可能[42]。所以,在给免疫功能低下、肠道出血的患者注射活细菌时,应极其慎重并事先做好预防措施。

  肠道微生物群可加重肠道放射性损伤

  肠道微生物群也可加重放射肠损伤的形成过程。Gerassy-Vainberg等[43]研究证明,人上皮细胞(HT29细胞系)与放射性直肠炎小鼠粪便细菌悬浮液共培养可使白细胞介素(interleukin,IL)- 1β含量明显升高(临床应用IL- 1受体拮抗剂Anakina可有效改善放射对损伤和炎症的影响);对照小鼠粪便细菌则不能。将放射性直肠炎和对照小鼠粪便菌悬液分别输送至正常无菌小鼠体内,接受放射性直肠炎小鼠粪便细菌悬浮液的正常无菌小鼠表现出更严重的肠道损伤,这与右旋糖酐硫酸钠(dextran sulfate sodium,DSS)诱导无菌小鼠发生的化学性直肠炎相似。

  Crawford等[44]研究也发现,与普通小鼠相比,无菌小鼠抗放射能力更强,即在同等放射剂量下,无菌小鼠小肠绒毛间质血管内皮细胞、淋巴细胞凋亡率及个体死亡率均明显低于普通小鼠。这可能是因为放射破坏了肠道结构及免疫功能,使肠道致病菌更易侵犯机体组织,加重肠道损伤。

  肠道菌群发挥保护作用的信号通路

  目前,已发现较为重要的信号通路是Toll样受体(Toll-like receptors,TLR)。TLR是一种蛋白质,由巨噬细胞、中性粒细胞、树突状细胞及上皮细胞等多种免疫细胞表达,配体主要为细菌或其组分,在先天免疫中发挥重要作用。研究表明,放射前注射TLR5配体CBLB502(鞭毛蛋白)可降低小鼠和灵长类动物肠隐窝细胞及固有层细胞凋亡率[45],即鞭毛蛋白或CBLB502-TLR5途径。放射前注射TLR9配体胞苷-磷酸-鸟苷(cytidine-phosphate-guanosine,CpG)可通过MyD88信号依赖通路减轻小鼠放射肠损伤[46],即CpG-TLR9途径。此外,激活TLR2和TLR4受体也可抵抗放射损伤,即脂多糖-TLR4途径[47]和乳酸杆菌-TLR2途径[33]。细菌鞭毛蛋白、CpG、脂多糖均为肠道细菌重要组分,以上述物质为主要成分的肠道定殖菌如大肠杆菌、变形杆菌是否具有肠道放射保护作用,临床上尚缺乏大样本随机对照研究证实。

  肠道菌群还可通过激活TLR,调节Apex2、Gadd45B和Rad21等DNA损伤修复相关基因的表达,减轻肠道黏膜损伤[48]。TLR通路同样能加强上皮细胞紧密连接的完整性,抑制肠道炎症,维持肠道稳态[49]。细菌及其产物也可通过AP- 1蛋白保护肠道上皮细胞免受放射诱导凋亡[50]。肠道菌群还能通过够激活免疫通路,维持免疫细胞平衡以及缓解肠道黏膜屏障损害,抵抗放射性肠道损害[51]。

  另一方面,TLR3、TLR4激活似乎能加重肠道辐射损伤。辐照前注射TLR3配体poly I:C(病毒中天然存在)可加重胃肠道损伤。TLR3基因敲除后的小鼠表现出肠上皮细胞凋亡下降和肠隐窝存活率升高的抗放射特性。TLR4拮抗剂C34预处理可减少放射诱导的细胞损伤和死亡[1]。

  总之,肠道微生物群与放射性肠损伤的关系极其复杂,不是肠道单一细菌与单一细胞作用的结果。此外,TLR配体的研究是通过全身注射TLR激动剂和全身照射或局部照射进行的,全身照射对全身免疫系统也有影响。因此,这些化合物在放射性肠损伤中放射防护作用是继发于它们对全身免疫系统的影响也未可知。

  肠道菌群未来发展趋势

  放射治疗、放射性损伤、肠道菌群之间关系复杂。虽然益生菌预防、治疗放射性肠损伤的有效性得到确认,但目前对肠道菌群的了解尚不能对现有研究结果、临床现象做出充分解释,这可能与肠道微生态的复杂性、作用的网络化有关。因此,对肠道菌群研究,要从单一菌种的研究逐步过渡到对多菌群、多信号通路的相互作用研究,并不断深入,希望在未来,能够高效、精确地利用肠道菌群预防和治疗肠道放射损伤和其他疾病。

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