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疾病治疗的新“窗口”:肠道微生物

2016-11-01 生物探索 生物探索

近年来,越来越多的科学家们对肠道微生物“上心”,他们发现许多机体紊乱与微生物系统之间存在直接或间接的关系。所以,粪菌移植、补充益生菌、重组细菌……科学家们希望开发出基于微生物的方法用于治疗人类疾病,例如肥胖、肠道类疾病等等。但是,在这些治疗策略实现之前,我们需要弄清楚健康微生物群的定义、影响因素等问题。 2016年5月中旬,美国白宫宣布启动“国家微生物组计划”(National Micr

近年来,越来越多的科学家们对肠道微生物“上心”,他们发现许多机体紊乱与微生物系统之间存在直接或间接的关系。所以,粪菌移植、补充益生菌、重组细菌……科学家们希望开发出基于微生物的方法用于治疗人类疾病,例如肥胖、肠道类疾病等等。但是,在这些治疗策略实现之前,我们需要弄清楚健康微生物群的定义、影响因素等问题。


2016年5月中旬,美国白宫宣布启动“国家微生物组计划”(National Microbiome Initiative, NMI),旨在推动微生物科学的发展,使个体、社区乃至全人类在卫生保健、食品生产和环境恢复等领域受益。

一时间,微生物组的研究热情空前高涨。这主要是因为我们越来越清楚认知,微生物广泛存在于我们自身以及赖以生存的环境中,与我们的健康息息相关。仅仅肠道微生物系统,其中的细菌种类就超1000种,DNA容量是人类基因组的150倍。

微生物群的重要性

“微生物群”(microbiota)的概念由著名微生物学家、1958年诺贝尔生理学或医学奖获得者乔舒亚•莱德伯格(Joshua Lederberg)创建,它泛指居住于特定生态圈的微生物群落。同时,Lederberg团队还提出了“微生物组”(microbiome)一词,专指群落里微生物遗传信息的总和。这两个概念常常互换着使用。

过去针对肠道微生物的研究受限于我们不能在实验室环境下培养它们,现在快速、低廉的DNA测序技术让我们对肠道微生物的认知跨过了培养的步骤。

以往十年关于微生物的研究揭示,它们与我们之间的共生关系远远超出想象。胃肠道中特定的微生物群对健康或者疾病有着重要影响,包括免疫系统、新陈代谢、神经和心血管系统以及癌症风险等等。相反,当宿主体内的微生物群种类和结构遭到破坏,紊乱的微生物系统易引发肥胖、糖尿病、肝脏疾病、炎症性肠病、肠易激综合征、腹泻、哮喘、自闭症、多发性硬化症甚至于衰老。

最典型的例子是治疗严重甚至于会致命的腹泻疾病,它由艰难梭状芽胞杆菌(C. diff)感染引发。而抗生素却能够清除致病性细菌。但是,不幸的是,抗生素使用过度使得细菌耐药性问题凸显,艰难梭状芽胞杆菌感染复发问题频出。

相反,移植健康的排泄物,即“粪菌移植”(Fecal microbiota transplantation,FMT)却能够有效规避的抗生素的使用。通过将健康人粪便中的功能菌群移植至患者胃肠道内,使其肠道菌群重新恢复,最终实现肠道及肠道外疾病的治疗。

肠道微生物与肥胖

相关研究已经表明,婴幼儿时期抗生素的频繁使用会增加肥胖的风险。此外,科学家们发现相比于正常小鼠,肥胖小鼠的微生物组显著不同。他们认为,这种差异同样存在于人类身上。

早在2013年,以同卵双胞胎为受试对象(1个肥胖、1个纤瘦),研究人员分别提取他们的粪便,并将其移植至实验小鼠体内。结果发现,体重轻的人的粪便会让小鼠也同样保持苗条的身材,而来源于胖子的粪便会让小鼠也变胖。随后,《Open Forum Infectious Diseases》期刊发表文章揭示了一个有趣的现象:原本,研究人员是想利用粪菌移植方法治疗艰难梭状芽胞杆菌感染,可是结果发现原本一直纤瘦的患者在接受微生物移植后变胖了!

虽然现在断定微生物与肥胖的关系还为时尚早,但是很明显这是合理的推测。肠道微生物和肥胖之间易构成“恶性循环”:肥胖会影响部分肠道微生物组成,而微生物会通过改变消化效率等方式进一步导致体重增加。当然,这一推测还需要更多的研究进一步证实。不少技术公司真正探索粪菌移植治疗疾病的可行性,这其中自然包括肥胖。

但是,需要警惕的是,既然肠道菌群关联很多生理功能,所以粪菌移植或者其他干扰微生物的手段可能会对健康产生意料之外的负面影响。


肠道微生物与中枢神经系统

除了肥胖,围绕肠道微生物研究的第二大热点是中枢神经系统。胃肠道是唯一由中枢神经、肠神经和自主神经共同支配的系统。医学上将胃肠道与中枢神经系统之间的神经网络称为“脑肠轴”(gut-brain-axis),这一网络是双向的,牵扯很多信号因素,包括细胞因子、免疫细胞、激素以及活性生物小分子。

研究发现,相比于野生小鼠,无菌小鼠对面对外界压力时的行为会出现明显的夸大和不同。此外,利用抗生素干扰正常小鼠的肠道菌群同样也会改变它们的行为。值得注意的,这种影响是双向的:微生物系统的紊乱会改变小鼠大脑突触模式,而大脑接收到胁迫后同样也会改变肠道微生物结构和功能。

此外,对小鼠进行粪菌移植处理,捐赠者的行为模式会在移植小鼠身上重现。更重要的是,越来越多的数据表明,精神类疾病会影响患者的肠道微生物组成。不少研究团队正在探索抑郁症、自闭症、精神分裂症、上瘾、多发性硬化症等多种疾病与微生物群的关系。虽然现在还处于初期,但是未来治疗精神类疾病或许可以通过改变肠道菌群来实现。

当然,基于微生物的疾病治疗方案面临着很多未知,真正投入临床之前需要解决以下问题:

1、如何定义健康的微生物组?

健康微生物组的标准是什么?至今没有明确答案。科学家们认为,健康的考核标准应该是多样性,包括微生物种类及遗传信息。当然,多样性越丰富越好。但是过去几十年,伴随着卫生的改善、抗生素的使用,微生物组的多样性已经受到了很大的消减。这一界定同样意味着,微生物多样性的改变可能会增加某些疾病发生的概率。

2、什么影响微生物群?

对于微生物群的影响因素,可以追溯至婴幼儿时期,甚至于胎儿时期,包括孕妇微生物、出生方式(顺产和剖腹产)、抗生素(包括是否接受过多种抗生素治疗)等典型因素。这些因素会对肠道微生物的组成、功能产生影响,例如顺产会增加新生儿体内乳酸菌等阴道细菌的建成,而剖腹产易让新生儿肠道菌群结构较为单一。

第二个影响因素是饮食。之前的研究证实,相比于奶粉喂养,母乳喂养的孩子其肠道菌群更为丰富,特别是富含双歧杆菌。但是有意思的是,幼儿并不能消化、吸收母乳中含有的多糖。科学家们推测,这些多糖物质是用来“喂养”幼儿肠道菌群的。

通常即便轻微改变饮食,成年人的微生物群也会相对稳定。但是,它却有着明显的地域差异,所以一旦一个西方人开始长期摄取非洲食物,他体内的微生物结构也会逐渐发生大的变化。

第三个影响因素是宿主。胃肠道负责监控共生的微生物群,防御病原体的入侵和感染。先天性免疫系统通过TLR、NOD受体调控胃肠道环境。肠道上皮及粘膜细胞会分泌许多多肽(防御素、碱性磷酸酶、细胞因子等),用于调节肠道微生物。同时,肠相关淋巴组织(GALT)也会通过炎症、T细胞干扰微生物群。通过这些因素的相互作用,宿主和微生物群达到一个稳定的平衡。

第四个影响因素是微生物本身。微生物之间也会通过竞争达到平衡。微生物会通过进化、抗菌性、群体感应、依从性等方面的努力增加自己的生存能力。所以,粪菌移植并不容易,因为微生物之间同样存在竞争。

或许最重要的影响因素是抗生素的滥用。虽然过去80年间,抗生素的出现挽救了数百万人的生命。但是抗生素的过度使用大大威胁着很多肠道微生物的生存。通常,患者接受一次抗生素疗程后,体内微生物群结构需要数周时间才得以恢复,且恢复时间会随着治疗次数叠加而延长。最终,一些细菌种类可能会永远消失。此外,抗生素的使用会导致耐药性病原体的过度扩增。抗生素滥用还易增加肥胖、糖尿病、哮喘等疾病的发生概率。

为了解决问题,生物科技公司试图通过清除肠道上游的抗生素,实现保护肠道微生物的目标。其中,有科研团队研发出富含β-内酰胺酶的药物,通过口服使得β-内酰胺酶进入体内并在小肠处释放,快速降解青霉素、头孢菌素两大最常用抗生素。这一新型药物目前已经顺利通过了临床Ⅱ期。



3、微生物群如何干扰宿主?


已有的研究还不足以彻底回答这一问题。最常见的机制是微生物易促进肠漏综合征的发生。消化系统的职责是识别、吸收营养物质,同时阻止细菌和炎症因子的入侵。但是这一肠道保护功能并不完善。细菌及其代谢物进入循环会导致慢性炎症发生,最终引发一系列疾病。因此,增强肠道屏障将对健康产生积极的影响。

4、微生物学本身存在的局限有哪些?

微生物组学伴随着下一代测序技术的更新而逐渐被科学家们重视。但是测序并不是完成精确的。对微生物组数据的分析需要排除宿主遗传信息的干扰,且对菌种的鉴定还受细菌基因数据库的限制。此外,对微生物组的研究通常会产生数十亿的数据,需要借助复杂的分析方法读取信息。

除了遗传信息,动物模型的构建同样也影响着微生物学的研究。动物建模是验证推测、提供临床前数据的重要步骤,同时它也是规避临床惨败的有效手段。

5、如何利用微生物组治疗疾病?

除了粪菌移植,最显而易见的策略是将细菌作为药用,例如补充益生菌。但是,关于益生菌对疾病的影响一直存在怀疑。此外,重组技术也是改造细菌的重要手段,科学家们可以将细菌改造成药物转载工具,让它们表面表达出能够与上皮细胞结合的蛋白,从而延长其释放药物的时间。此外,科学家们还希望通过摄入机体本身并不吸收的化合物,改变肠道微生物结构。

很多基于微生物组的治疗方案依然处于研究中。值得注意的是,这类治疗策略必须在相关部门的监管下有序进行,并确保其安全性和有效性,例如规避细菌污染、环境传播等问题。

原始出处:

Christian Furlan  Freguia, Ph.D. Tapping the Human Gut Microbiome, Part 1. GEN.October 17, 2016

Christian Furlan  Freguia, Ph.D. Tapping the Human Gut Microbiome, Part 2. GEN.October 17, 2016

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#插入话题
  1. [GetPortalCommentsPageByObjectIdResponse(id=1824698, encodeId=7a9d1824698af, content=<a href='/topic/show?id=702a5065860' target=_blank style='color:#2F92EE;'>#微生物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=50658, encryptionId=702a5065860, topicName=微生物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0b7c20, createdName=wjcjjian, createdTime=Tue May 16 04:47:00 CST 2017, time=2017-05-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1982757, encodeId=430b1982e575b, content=<a href='/topic/show?id=89c4e06902e' target=_blank style='color:#2F92EE;'>#疾病治疗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=70690, encryptionId=89c4e06902e, topicName=疾病治疗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d64f419, createdName=qindq, createdTime=Sun Oct 08 01:47:00 CST 2017, time=2017-10-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=155801, encodeId=4cf415580140, content=肠道微生物是非常重要的。, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160806/IMG57A5698BDB0244113.jpg, createdBy=32a91358059, createdName=jyzxjiangqin, createdTime=Tue Nov 15 07:23:37 CST 2016, time=2016-11-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=155133, encodeId=8cb2155133e7, content=看来帮助建立良好肠道微生物很重要, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ff901728138, createdName=1dedfe95m66(暂无匿称), createdTime=Fri Nov 11 23:15:16 CST 2016, time=2016-11-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=153944, encodeId=07881539446b, content=肠道微生物前景广阔。, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160806/IMG57A5698BDB0244113.jpg, createdBy=32a91358059, createdName=jyzxjiangqin, createdTime=Mon Nov 07 07:15:36 CST 2016, time=2016-11-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152866, encodeId=7bb315286679, content=谢谢,学习一下知识, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160718/IMG578C993D395567540.jpg, createdBy=59b81918946, createdName=flysky120, createdTime=Wed Nov 02 11:17:38 CST 2016, time=2016-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152802, encodeId=a9ed1528025e, content=棒棒哒, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2018/07/24/8a3b93006f93bd9def0ac38764a6df01.jpg, createdBy=87191974273, createdName=Chimera~yun, createdTime=Wed Nov 02 00:56:06 CST 2016, time=2016-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152632, encodeId=920d152632cc, content=不错~, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d0f31631005, createdName=保守主义, createdTime=Tue Nov 01 12:36:29 CST 2016, time=2016-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152631, encodeId=ee7f15263154, content=值得学习~, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d0f31631005, createdName=保守主义, createdTime=Tue Nov 01 12:36:15 CST 2016, time=2016-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152614, encodeId=a380152614cf, content=新的思维。新的治疗方法值得学习。谢谢编辑。, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=01bb1684217, createdName=医张生, createdTime=Tue Nov 01 12:10:33 CST 2016, time=2016-11-01, status=1, ipAttribution=)]
  2. [GetPortalCommentsPageByObjectIdResponse(id=1824698, encodeId=7a9d1824698af, content=<a href='/topic/show?id=702a5065860' target=_blank style='color:#2F92EE;'>#微生物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=50658, encryptionId=702a5065860, topicName=微生物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0b7c20, createdName=wjcjjian, createdTime=Tue May 16 04:47:00 CST 2017, time=2017-05-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1982757, encodeId=430b1982e575b, content=<a href='/topic/show?id=89c4e06902e' target=_blank style='color:#2F92EE;'>#疾病治疗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=70690, encryptionId=89c4e06902e, topicName=疾病治疗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d64f419, createdName=qindq, createdTime=Sun Oct 08 01:47:00 CST 2017, time=2017-10-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=155801, encodeId=4cf415580140, content=肠道微生物是非常重要的。, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160806/IMG57A5698BDB0244113.jpg, createdBy=32a91358059, createdName=jyzxjiangqin, createdTime=Tue Nov 15 07:23:37 CST 2016, time=2016-11-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=155133, encodeId=8cb2155133e7, content=看来帮助建立良好肠道微生物很重要, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ff901728138, createdName=1dedfe95m66(暂无匿称), createdTime=Fri Nov 11 23:15:16 CST 2016, time=2016-11-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=153944, encodeId=07881539446b, content=肠道微生物前景广阔。, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160806/IMG57A5698BDB0244113.jpg, createdBy=32a91358059, createdName=jyzxjiangqin, createdTime=Mon Nov 07 07:15:36 CST 2016, time=2016-11-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152866, encodeId=7bb315286679, content=谢谢,学习一下知识, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160718/IMG578C993D395567540.jpg, createdBy=59b81918946, createdName=flysky120, createdTime=Wed Nov 02 11:17:38 CST 2016, time=2016-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152802, encodeId=a9ed1528025e, content=棒棒哒, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2018/07/24/8a3b93006f93bd9def0ac38764a6df01.jpg, createdBy=87191974273, createdName=Chimera~yun, createdTime=Wed Nov 02 00:56:06 CST 2016, time=2016-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152632, encodeId=920d152632cc, content=不错~, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d0f31631005, createdName=保守主义, createdTime=Tue Nov 01 12:36:29 CST 2016, time=2016-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152631, encodeId=ee7f15263154, content=值得学习~, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d0f31631005, createdName=保守主义, createdTime=Tue Nov 01 12:36:15 CST 2016, time=2016-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152614, encodeId=a380152614cf, content=新的思维。新的治疗方法值得学习。谢谢编辑。, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=01bb1684217, createdName=医张生, createdTime=Tue Nov 01 12:10:33 CST 2016, time=2016-11-01, status=1, ipAttribution=)]
  3. [GetPortalCommentsPageByObjectIdResponse(id=1824698, encodeId=7a9d1824698af, content=<a href='/topic/show?id=702a5065860' target=_blank style='color:#2F92EE;'>#微生物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=50658, encryptionId=702a5065860, topicName=微生物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0b7c20, createdName=wjcjjian, createdTime=Tue May 16 04:47:00 CST 2017, time=2017-05-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1982757, encodeId=430b1982e575b, content=<a href='/topic/show?id=89c4e06902e' target=_blank style='color:#2F92EE;'>#疾病治疗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=70690, encryptionId=89c4e06902e, topicName=疾病治疗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d64f419, createdName=qindq, createdTime=Sun Oct 08 01:47:00 CST 2017, time=2017-10-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=155801, encodeId=4cf415580140, content=肠道微生物是非常重要的。, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160806/IMG57A5698BDB0244113.jpg, createdBy=32a91358059, createdName=jyzxjiangqin, createdTime=Tue Nov 15 07:23:37 CST 2016, time=2016-11-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=155133, encodeId=8cb2155133e7, content=看来帮助建立良好肠道微生物很重要, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ff901728138, createdName=1dedfe95m66(暂无匿称), createdTime=Fri Nov 11 23:15:16 CST 2016, time=2016-11-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=153944, encodeId=07881539446b, content=肠道微生物前景广阔。, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160806/IMG57A5698BDB0244113.jpg, createdBy=32a91358059, createdName=jyzxjiangqin, createdTime=Mon Nov 07 07:15:36 CST 2016, time=2016-11-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152866, encodeId=7bb315286679, content=谢谢,学习一下知识, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160718/IMG578C993D395567540.jpg, createdBy=59b81918946, createdName=flysky120, createdTime=Wed Nov 02 11:17:38 CST 2016, time=2016-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152802, encodeId=a9ed1528025e, content=棒棒哒, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2018/07/24/8a3b93006f93bd9def0ac38764a6df01.jpg, createdBy=87191974273, createdName=Chimera~yun, createdTime=Wed Nov 02 00:56:06 CST 2016, time=2016-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152632, encodeId=920d152632cc, content=不错~, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d0f31631005, createdName=保守主义, createdTime=Tue Nov 01 12:36:29 CST 2016, time=2016-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152631, encodeId=ee7f15263154, content=值得学习~, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d0f31631005, createdName=保守主义, createdTime=Tue Nov 01 12:36:15 CST 2016, time=2016-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152614, encodeId=a380152614cf, content=新的思维。新的治疗方法值得学习。谢谢编辑。, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=01bb1684217, createdName=医张生, createdTime=Tue Nov 01 12:10:33 CST 2016, time=2016-11-01, status=1, ipAttribution=)]
    2016-11-15 jyzxjiangqin

    肠道微生物是非常重要的。

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1824698, encodeId=7a9d1824698af, content=<a href='/topic/show?id=702a5065860' target=_blank style='color:#2F92EE;'>#微生物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=50658, encryptionId=702a5065860, topicName=微生物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0b7c20, createdName=wjcjjian, createdTime=Tue May 16 04:47:00 CST 2017, time=2017-05-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1982757, encodeId=430b1982e575b, content=<a href='/topic/show?id=89c4e06902e' target=_blank style='color:#2F92EE;'>#疾病治疗#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=70690, encryptionId=89c4e06902e, topicName=疾病治疗)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d64f419, createdName=qindq, createdTime=Sun Oct 08 01:47:00 CST 2017, time=2017-10-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=155801, encodeId=4cf415580140, content=肠道微生物是非常重要的。, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160806/IMG57A5698BDB0244113.jpg, createdBy=32a91358059, createdName=jyzxjiangqin, createdTime=Tue Nov 15 07:23:37 CST 2016, time=2016-11-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=155133, encodeId=8cb2155133e7, content=看来帮助建立良好肠道微生物很重要, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ff901728138, createdName=1dedfe95m66(暂无匿称), createdTime=Fri Nov 11 23:15:16 CST 2016, time=2016-11-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=153944, encodeId=07881539446b, content=肠道微生物前景广阔。, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160806/IMG57A5698BDB0244113.jpg, createdBy=32a91358059, createdName=jyzxjiangqin, createdTime=Mon Nov 07 07:15:36 CST 2016, time=2016-11-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152866, encodeId=7bb315286679, content=谢谢,学习一下知识, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160718/IMG578C993D395567540.jpg, createdBy=59b81918946, createdName=flysky120, createdTime=Wed Nov 02 11:17:38 CST 2016, time=2016-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152802, encodeId=a9ed1528025e, content=棒棒哒, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2018/07/24/8a3b93006f93bd9def0ac38764a6df01.jpg, createdBy=87191974273, createdName=Chimera~yun, createdTime=Wed Nov 02 00:56:06 CST 2016, time=2016-11-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152632, encodeId=920d152632cc, content=不错~, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d0f31631005, createdName=保守主义, createdTime=Tue Nov 01 12:36:29 CST 2016, time=2016-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152631, encodeId=ee7f15263154, content=值得学习~, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d0f31631005, createdName=保守主义, createdTime=Tue Nov 01 12:36:15 CST 2016, time=2016-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=152614, encodeId=a380152614cf, content=新的思维。新的治疗方法值得学习。谢谢编辑。, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=01bb1684217, createdName=医张生, createdTime=Tue Nov 01 12:10:33 CST 2016, time=2016-11-01, status=1, ipAttribution=)]
    2016-11-11 1dedfe95m66(暂无匿称)

    看来帮助建立良好肠道微生物很重要

    0

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    2016-11-07 jyzxjiangqin

    肠道微生物前景广阔。

    0

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    2016-11-02 flysky120

    谢谢,学习一下知识

    0

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    2016-11-02 Chimera~yun

    棒棒哒

    0

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    2016-11-01 保守主义

    不错~

    0

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    2016-11-01 保守主义

    值得学习~

    0

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    2016-11-01 医张生

    新的思维。新的治疗方法值得学习。谢谢编辑。

    0

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