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【盘点】肠道微生物和癌症有怎样的关联?

       肠道微生物值得就是我们通常所说的“肠道菌群”,这类微生物数量超过人体自身细胞的10倍以上,对营养物质代谢、人体自身发育、免疫及疾病的产生等方面都起到极其重要的作用。
       近年来,随着研究深入全球科学家都将目光转移到研究肠道微生物上,很多研究结果都表明肠道微生物和多种疾病发病直接相关,尤其是癌症,本文中小编盘点了近年来肠道微生物和癌症之间的关联性研究报道。
【1】PNAS:经过改造的乳酸菌逆转了小鼠的结肠癌
doi:10.1073/pnas.1207230109
        一项刊登在PNAS上的研究揭示了,食用经过遗传改造的嗜酸乳酸杆菌能重置小鼠的可能导致癌症的免疫应答,并缩小前癌结肠息肉。此前对益生肠道微生物嗜酸乳酸杆菌的研究已经表明,通过删除被称为脂磷壁酸(LTA)的细胞表面分子的基因,这种细菌可以减少导致小鼠结肠炎的炎症应答。
       为了研究脂磷壁酸(LTA)是否也是越来越被怀疑促进了肿瘤的过度活跃的炎症应答的参与因素之一,Mansour Mohamadzadeh及其同事让有病理性炎症和前癌结肠息肉的小鼠口服了缺乏脂磷壁酸(LTA)的嗜酸乳酸杆菌。这组作者说,这种疗法重置了过度活跃的炎症应答,并且把试验对象的肠内环境恢复到了健康的平衡态,因此也就把肠粘膜解放出来,从而处理结肠息肉并使其退化。
【2】Science:肠道细菌可帮助治疗癌症
doi: 10.1126/science.1240527
       据两项新的报告披露,生活在我们肠道中的细菌群落可帮助确定某些抗癌疗法的功效,其中包括那些先前被认为直接作用于肿瘤细胞的药物。在这两种情况下,肠道微生物群似乎能调节由这些治疗所引发的免疫系统的反应。研究人员发现,在肠道无菌的小鼠中,这些疗法在攻击肿瘤上的效果较差。
       Noriho Iida及其同事发现,抗癌免疫疗法及一种铂类化疗都对没有肠道微生物群的小鼠效果较差。在这种情况下,需要有细菌来激活某种抗肿瘤的先天免疫反应。
【3】J Natl Cancer Inst.:肠道微生物组降低与结肠癌有关
doi: 10.1093/jnci/djt300
       近期发表在Journal of the National Cancer Institute上的文章称,人类肠道微生物多样性降低与结肠癌相关。
       在肠道微生物与结肠癌相关性问题上,基础研究与流行病学研究结论向左。所以该问题还没有一个很明确的结论。
       纽约大学公共卫生学院的Jiyoung Ahn博士收集了47位结肠癌病人和94位性别,身高体重指数都与病人相吻合的正常人的排泄物,并从中提取了DNA。接下来科学家对所有的DNA进行测序,确定病人组和对照组的肠道菌群的基因组。结果发现结肠癌患者体内的微生物种类减少。
       科学家进一步分析了结肠癌患者的肠道菌群种类。发现梭状芽胞杆菌种类减少,而梭状芽胞杆菌能够将食用纤维降解为丁酸盐,丁酸盐或能预防结肠癌变和炎症反应。同时梭菌属和卟啉单胞菌属细菌增加,这类细菌与口腔和消化道炎症相关。
【4】Science:肠道细菌有望成为癌症治疗新帮手
doi: 10.1126/science.1240537
       人体内微生物的数量比细胞的十倍还多,这些微生物发挥着巨大的作用:它们维护人体健康,调节免疫系统,维持消化系统“有活力地”运转。现在,《科学》杂志上的两篇文章指出,这些微生物还有助于治疗疾病。
       这些研究以小鼠为研究对象。结果表明,肠道细菌有助于增强3种抗癌疗法的疗效。在每一个案例中,当小鼠体内的某类微生物缺失时,治疗的效果就降低很多。美国北卡罗来纳大学教堂山分校结构生物学家Matthew Redinbo说:“实验证明,细菌发挥了至关重要的作用。”2010年,Redinbo通过研究证实,一种细菌酶能抑制一类抗癌药物的毒副反应。“这些发现使我们对哺乳动物—微生物的共生关系有了更深的认识。”
       达拉斯市得克萨斯大学西南医学中心免疫学家 Lora Hooper认为,由于癌症患者的免疫系统被极大削弱,很多病人不得不使用抗生素对抗感染,这些微生物最终会对临床实践产生影响。Hooper说:“抗生素治疗可能会有副作用,这一点在之前没有被充分认识到。”然而,将在小鼠身上得到的发现应用于人体,研究者对此持谨慎态度。小鼠体内的肠道细菌和人体肠道内的细菌并不相同,细菌在摧毁癌细胞的过程中具体发挥了怎样的作用目前仍是一个谜。
【5】Nat Med:肠道细菌“对话”小肠上皮细胞促进结直肠癌
doi:10.1038/nm.4072
       最近,国际学术期刊Nature Medicine在线发表了德国科学家的一项最新研究进展,他们发现了一种可能参与结直肠癌发育过程的重要分子,同时证明肠道细菌与小肠上皮细胞之间的交互在结直肠癌发育过程中发挥重要作用。
       结直肠癌又称大肠癌,是最常见的胃肠道恶性肿瘤之一。近年来我国结直肠癌的发病率和死亡率呈不断上升的趋势,已经成为人类生命的一个严重威胁。结直肠癌是一个多阶段、多步骤的病理过程,与多个癌基因激活和抑癌基因失活有关。不过迄今为止,人们没有完全理解这种疾病的真正病因和调控机制。
       有研究表明炎症相关信号通路在小肠上皮细胞中发生激活会促进结直肠癌的发生。除此之外,还有研究发现一种叫做钙调神经磷酸酶的分子在结直肠癌细胞中表达增加,该分子是NFAT转录因子家族激活所必须的一种磷酸酶。而钙调神经磷酸酶是否在小肠肿瘤发育过程中发挥重要作用没有得到深入研究。
【6】美法科研人员发现肠道细菌控制人体对抗癌药反应
       人体肠道内寄生着数十万亿个细菌,它们能影响体重和消化能力、抵御感染和自体免疫疾病的患病风险。美国和法国的科研人员日前发现,肠道菌群还能控制人体对癌症治疗药物的反应。
       法国巴斯德研究所等机构的研究人员在美国期刊《科学》上报告说,常用于癌症化疗的药物环磷酰胺能够破坏肠道黏液层,让肠道细菌进入循环系统,其中一些到达脾和淋巴结的细菌能促进形成免疫细胞,而后者会攻击癌细胞。但当研究人员用抗生素杀死实验鼠的肠道细菌后,环磷酰胺间接促生免疫细胞的能力会大大降低。
       《科学》同期发表的美国国家癌症研究院的另一项研究显示,科研人员选取正接受化疗、存活率为70%的癌症实验鼠,并用抗生素杀死其肠道细菌。结果导致这些实验鼠摄入的化疗药物不再起作用,它们的存活率在两个月后下降到20%。
【7】PLOS ONE:肠道细菌或可帮助抑制癌症发生
doi:10.1371/journal.pone.0151190
       如今科学家们已经发现多种类型的肠道细菌是促进或者抑制机体肥胖等多种疾病的特殊因子,近日来自加州大学洛杉矶分校(University Of California Los Angeles)的研究人员又通过研究发现,肠道菌群或可被用来降低机体患某些癌症的风险,相关研究刊登于国际杂志PLoS ONE上,相关研究结果表明,抗炎性的健康有益肠道菌群或可减缓或阻断某些类型癌症的发生。
       研究者Robert Schiestl表示,临床医生们往往通过分析机体肠道细菌的水平和类型来减少个体患癌的风险,随后医生们会开一些益生菌来替代或增强机体肠道细菌的抗炎特性;数百万年以来,肠道细菌在机体中会进化成为有益的肠道菌群或有害的肠道菌群,有益肠道细菌往往具有抗炎性特性,而有害的细菌则会促进炎症发生,相比一万亿个人类细胞而言,机体通常包含有10亿个细菌细胞。
【8】JCEM:肠道菌群多样性高的个体不易患乳腺癌
doi:10.1210/jc.2014-2222
       近日,来自美国国家癌症研究所的研究人员通过研究表示,绝经后女性如果机体中携带有多样化的肠道菌群,那么其机体的雌激素代谢产物或许对其健康更加有益,相关研究刊登于国际杂志Journal of Clinical Endocrinology & Metabolism (JCEM)上。
       从20世纪70年代开始,科学家们就研究发现构成肠道微生物组的肠道细菌会影响女性机体雌激素的功能,雌激素是女性机体最原始的性激素;肠道细菌的定殖会决定雌激素产生后是存留在机体内还是会随着尿液和粪便而排出体外,此前研究显示,循环在机体中的雌激素和其代谢产物的水平和女性绝经后患乳腺癌的风险直接相关。
       研究者James Goedert表示,相比肠道菌群多样性较低的女性来讲,那些机体肠道菌群多样化的女性,其机体中的雌激素的代谢产物存留的水平往往较高,这就暗示了含有较高水平雌激素的女性患乳腺癌的风险会降低。随后研究人员对招募的60名绝经女性进行研究,分析了其尿液和粪便样品,这些女性的年龄都在55至69岁之间,在研究前的6至8周研究人员对其进行了乳房x光检查,结果显示正常;对尿液和粪便样品分析后研究人员表示,机体肠道菌群的多样性和雌激素片段的比率直接相关,而后者则是乳腺癌的一个指示器。
【9】Science:肠道微生物竟然影响癌症免疫治疗效果?!
DOI:10.1126/science.aac4255
       检查点抑制剂是能够唤醒免疫系统抵抗肿瘤的新型药物,对癌症的治疗具有显著的疗效。然而一些临床结果表明该类药物对一部分病人并没有效果。最近两篇研究文章对此内在的机理进行了阐释。作者们认为这部分病人体内的微生物种群存在异常,因而不能正常地产生免疫反应。
       这两项研究第一次将免疫检查点抑制剂与肠道的菌群联系起来。正常情况下,免疫细胞表面的一些受体能够限制其对自体组织进行杀伤。然而肿瘤组织同样能够激活这些受体,导致特异性的免疫细胞无法对其进行识别与杀伤。像ipilimumab等免疫检查点抑制剂则能够通过阻止肿瘤细胞对这些受体的激活而维持免疫细胞的活性。
       这项新的研究能够改变医生用药的方式。“这两篇文章证明了微生物能够影响治疗效果”,来自NIH的过敏与传染病研究所的免疫学家Yasmine Belkaid说到。过去研究者们经常专注于寻找患者基因组中的的突变,并以此解释为何免疫检查点抑制剂药物治疗效果存在个体差异。而如今的这两篇研究指出除基因组之外,微生物可能也有同样的影响。
【10】Cell:改变肠道菌群 预防结肠癌
DOI:10.1016/j.cell.2015.06.001
       近日,来自美国St.Jude儿童医院的科学家们发现一种表达于免疫系统的基因在决定结肠癌侵袭性方面发挥着重要作用。他们发现这种叫作AIM2的基因发生缺失会导致小肠细胞增殖失控,同时,研究人员还发现AIM2能够影响肠道菌群,在肠道中增加"好"细菌的数量可能对于预防结肠癌的发生具有重要意义。最近,这一研究的相关研究成果发表在国际学术期刊cell上,这些发现将在结肠癌的预防,诊断和治疗方面发挥重要作用。
       许多研究已经证明AIM2基因突变在结肠癌病人中比较常见,但一直以来人们只知道AIM2在免疫系统中具有重要作用,它能够感知细菌和病毒入侵,帮助免疫系统对抗细菌和病毒感染,AIM2在肿瘤发生中的机制问题一直没有得到很好的了解。
       在该项研究中,研究人员利用化合物处理小鼠模拟结肠癌的发生,在这一过程中,他们发现AIM2功能活性明显下降,这一点也得到了结肠癌病人结果的支持。他们还发现利用遗传学方法降低AIM2功能,再结合化合物处理,会产生更多的肠道肿瘤。研究人员的研究结果还发现,AIM2除了发挥免疫学功能,还能够抑制小肠干细胞群的异常扩张,而当AIM2发生功能异常,其对小肠干细胞异常增殖的抑制作用就会解除。

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