修回日期: 2016-04-04
接受日期: 2016-04-11
在线出版日期: 2016-05-28
肥胖发病率逐年上升, 已经成为全球性公共健康问题. 肥胖的发生常伴有亚临床炎症表现, 引起炎症水平升高与免疫功能紊乱, 而这又与肠道菌群紊乱密切相关. 肠道菌群与肠黏膜免疫构成动态平衡, 其结构及功能异常均可引起机体免疫紊乱. 肥胖性炎症反应的启动途径, 涉及Toll样受体(Toll-like receptors, TLRs)活化、内质网应激与肠道菌群改变. 其中, TLR4在感应肠道病原菌、诱导炎症与胰岛素抵抗进程中, 扮演中心角色. 另一方面, 代谢、遗传与免疫等因素, 整合性调控TLR功能. 因此, 我们从肥胖-肠道菌群-TLRs的复杂交互作用着手, 阐释肠道菌群、肠道免疫与肥胖等代谢性疾病的高度相关性, 以期发现这类疾病的新治疗靶点.
核心提示: 肥胖是全球性公共卫生难题, 其形成和进展与肠道菌群紊乱, 以Toll样受体为代表的肠道黏膜免疫异常直接相关. 三者交互作用机制的研究, 可望深化肥胖病理认识, 提高肥胖疗效.
引文著录: 司原成, 苗维纳, 何嘉悦, 王晓芳, 汪弋力, 丁维俊. 肥胖-肠道菌群-Toll样受体交互调控作用的研究进展. 世界华人消化杂志 2016; 24(15): 2361-2367
Revised: April 4, 2016
Accepted: April 11, 2016
Published online: May 28, 2016
The rapidly increasing incidence of obesity has resulted in a severe public problem globally. Obesity is associated with subclinical inflammation, causing elevated levels of inflammatory cytokines, as well as disorders of the immune function, which are involved in the dysfunction of intestinal flora. Intestinal flora maintains a dynamic equilibrium with intestinal mucosal immunity. Obesity-related inflammation is mainly trigged by endoplasmic reticulum stress, Toll-like receptor 4 (TLR4) activation and changes of gut flora. Among them, TLR4 plays a central role in sensing intestinal pathogens and inducing mucosal immunity. On the other hand, metabolism, genetics, gut flora and immune state are integrally regulating the TLR function. In the present paper we explore the intricate interactions of obesity, intestinal flora and TLRs, in order to find novel targets for the treatment of obesity.
- Citation: Si YC, Miao WN, He JY, Wang XF, Wang YL, Ding WJ. Intricate interactions of obesity, intestinal flora and Toll-like receptors. Shijie Huaren Xiaohua Zazhi 2016; 24(15): 2361-2367
- URL: https://www.wjgnet.com/1009-3079/full/v24/i15/2361.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i15.2361
肥胖发病率逐年上升, 已经成为全球性的公共健康问题[1]. 众多因素参与肥胖发展进程, 如能量代谢失衡、棕色脂肪减少、长期低水平炎症刺激等[2]. 近年研究[3]发现, 肠道菌群与机体的消化、免疫、能量代谢等紧密联系. 在免疫功能紊乱或者降低时, 病原微生物大量繁殖, 引起肥胖、糖尿病等多种疾病. 近期研究发现,肠道菌群与机体免疫功能异常, 同肥胖发生发展高度相关,但其具体作用机制与关键环节仍不十分清楚[4-6]. 因此, 本文综述相关研究进展, 以期阐释肠道菌群、肠道免疫与肥胖等代谢性疾病的高度相关性, 发现这类疾病的新治疗靶点.
人体肠道中寄生着大量的微生物, 种类超过10000种, 总量达1014数量级, 是肠道微生态平衡的重要组成部分[7,8]. 肠道菌群与宿主具有复杂的交互作用关系. 在物质代谢方面, 机体供给肠道微生物生长所需养分, 而肠道微生物则合成维生素K等机体不能合成的营养物质, 并帮助机体消化纤维素[9]. 在免疫方面, 部分肠道细菌保持肠黏膜的完整性, 激活宿主免疫系统, 阻止有害病原体通过黏膜进入体内[10]. 但是, 肠道菌群也含有部分有害菌, 可以产生内毒素等物质, 引起炎症反应、糖尿病、肥胖及部分癌症.
肠道菌群在肥胖发生发展中起到重要作用. Harley等[11]发现肥胖患者肠道厚壁菌门/拟杆菌属的比值与患者肥胖程度呈正相关. 肠道菌群能够通过慢性炎症状态影响肥胖[12]. Zarrinpar等[13]发现饮食和进食方式的改变, 可引起肥胖患者肠道菌群的结构改变, 造成壁厚菌门和变形菌门水平升高, 拟杆菌门降低. 肠道菌群通过其代谢产物来调节脑-肠-菌轴, 促进肥胖进程. 短链脂肪酸中的丁酸和丙酸通过互补机制积极参与糖代谢. 丁酸通过增加肠上皮细胞cAMP的含量直接增加糖质新生基因的表达; 丙酸作为FFAR3激动剂, 通过脑-肠-菌轴诱导糖新生, 促进食物的吸收和糖代谢[14]. 超重者肠道丙酸呈显著性升高[15-18]. Poutahidis等[19]给予肥胖鼠口服PL60不仅可以降低肥胖鼠的腹部脂肪含量, 还能显著改变CD4+ T细胞和白介素-10(interleukin 10, IL-10)依赖的免疫细胞功能. Walker等[20]也发现, 拟杆菌门具有明显的抑制脂肪细胞增长的作用. Ridaura等[21]通过大范围筛选出体质量差异明显的双胞胎, 将肥胖患者的肠道菌群植入到无菌小鼠体内, 发现小鼠的体质量相对植入不肥胖的正常组小鼠显著增加. 因此, 以肠道菌群为治疗肥胖靶点, 可望为减肥新药的研发提供新的思路.
炎症是机体对有害刺激做出的应激性反应, 以维持机体稳态. 肥胖患者存在明显慢性亚临床炎症反应[5,6], 其不仅涉及诸多经典炎症途径[22], 同时亦有其特殊性[23]. 肥胖性炎症源于过剩的营养物质堆积而引起的慢性炎症, 涉及长期能量代谢紊乱引起的固有免疫功能异常. 当体质量下降后, 脂肪细胞功能趋于正常, 慢性代谢炎症得以缓解甚至消除[24]. 肥胖进程中肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)、IL-1β、CCK等炎症细胞因子起到主要作用[25]. 巨噬细胞、肥大细胞及自然杀伤细胞(natural killer cell, NK)细胞等免疫细胞, 亦明显增加, 进而加重炎症反应[26].
脂肪组织是肥胖性炎症启动和产生的重要场所, 其分泌的炎性细胞因子可直接引发胰岛素抵抗. 如Guilherme等[27]发现肥胖患者TNF-α水平升高, 伴有胰岛素分泌和糖摄取降低. Solinas等[28]揭示, JNK、IKK、PKR等炎症反应之上游信号分子, 在炎症过程中起主要作用. Lu等[29]进一步阐明, 引起肥胖促进炎症因子释放的炎症激酶, 通过调节AP-1、核因子-κB(nuclear factor-κB, NF-κB)、IRF等炎症反应的下游信号通路, 维持慢性炎症反应. 此外, 在肥胖亚临床炎症中促炎症因子IL-6异常增高, 抑炎症信号过氧化物酶体增殖物激活受体-γ(peroxisome proliferator-activated receptor γ, PPAR-γ)活性显著下调, 亦有助于维持慢性炎症反应[30,31].
肥胖脂肪组织的慢性低水平的炎症, 是长期双向刺激产生的恶性循环. 这一刺激过程与肠道病原微生物密切相关. 健康状态下, 肠道菌群的各种细菌数量、结构达到一个相互制约、相互协同的平衡状态. 一旦菌群紊乱, 益生菌减少而病原菌相对增加, 肠道菌群产生的致炎因子增多, 遂引起机体低水平的炎症反应. 其中, Toll样受体(Toll-like receptors, TLRs)家族在调节肠道菌群引起的炎症反应中起重要作用.
TLRs是模式识别受体家族中的一种重要受体, 能够激活NF-κB、丝裂原活化蛋白激酶等炎症相关信号通路, 在肠道菌群介导的炎症反应中起着重要的桥梁作用[4]. TLRs最早发现在果蝇体内, 随后在无脊椎动物、脊椎动物及植物中陆续被发现. 不同物种的TLRs具有高度同源性, 均承担识别致病菌和启动防御机制等功能[32]. TLRs广泛存在于细胞膜、细胞质及细胞核内, 参与机体各种免疫应答过程, 尤其在诱导、促进炎症方面作用突出[33]. 在树突状细胞、B细胞、T细胞中发现大量TLRs, 在识别有害物质、启动免疫应答过程中起到关键作用[34]. 除开免疫细胞, TLRs还分布在成纤维细胞及黏膜上皮细胞[35], 参与慢性炎症等病理过程. TLR2主要检测细菌肽聚糖、脂多糖及磷壁酸的含量变化[36,37], 通过NF-κB通路诱导炎症反应[38]. TLR1、TLR6与TLR2是同源异构体, 均能识别LPS及脂肽[39]. TLR2与TLR6均能与支原体二酰基脂蛋白结合, 产生生物学效应[40]. TLR4是革兰阴性细菌脂多糖的重要结合配体[41], 其在肥胖鼠肠黏膜上皮细胞中呈现过度表达状态; 激活的TLR4可诱导多种促炎症细胞因子的产生, 引起并维持肥胖型低水平炎症[42]. 细菌鞭毛蛋白可激活TLR5信号通路, 产生炎症效应[43]. TLR3、TLR7、TLR8、TLR9存在于细胞质中, 参与病原体核酸等识别. 其中, TLR3识别肠道病原微生物中存在的大量病毒, 这些病毒在肥胖形成、发展进程中, 起到促进作用[44].
肠黏膜是人体最大的免疫器官, 监管着1014数量级的肠道微生物[45-48]. 其包含的各种免疫细胞以及分泌的多种免疫因子协同作用, 构成对正常菌群与致病菌的精确辨别能力. 但是, 该能力容易受到饮食、肥胖等因素干扰. 免疫细胞同神经元一样, 均属于高能耗细胞, 对机体脂代谢及葡萄糖浓度极为敏感. 因此, 肥胖或其他代谢性疾病, 理论上都可引起免疫学功能改变[45-48]. 大量研究发现, 肥胖对肠道黏膜免疫系统、免疫细胞、免疫分子与免疫相关基因表达, 构成多层次的干扰. 如Mantovani等[46]发现, 肥胖鼠肝脏脂肪样变性源于肥胖诱导的淋巴细胞高反应性, 而减肥可以逆转该病理过程. 肥胖患者脂肪细胞所分泌的超量Leptin, 作为神经-内分泌-免疫系统之间的重要连接者, 通过多个信号轴调控免疫与炎症反应[47,48]. 肥胖患者脂肪细胞合成的大量炎症细胞因子, 导致炎症、自身免疫病及其他肥胖继发症的发病率增加[49].
肠道正常菌群参与机体代谢、营养、免疫等功能, 对维持黏膜免疫功能、肠壁稳定性与营养吸收等十分重要[49]. 例如, 脆弱类杆菌等益生菌, 合成两性离子多糖(zwitterionic polysaccharides, ZPS)、多糖A(polysaccharides A, PSA)等免疫调节多糖, 指导免疫系统发育[47]. 但是, 肥胖等代谢性疾病使患者肠道益生菌明显减少, 肠黏膜免疫功能发育与维持受到明显影响. 肠道菌群可直接影响机体胆固醇、脂蛋白与胆盐代谢[45], 调整机体免疫防御功能与炎症水平. 肥胖患者胃肠道功能失调、高脂食物、胆盐代谢异常等, 均是肠道菌群失调的重要病因. Burcelin等[50]提出, 失调的肠道菌群产生炎性细胞因子、毒素等, 导致内毒素血症, 诱导肠黏膜上皮细胞免疫基因表达亢进, 进而引起慢性炎症、胰岛素抵抗与肥胖. 实际上, 失调的肠道菌群影响黏膜免疫功能, 黏膜免疫功能紊乱又通过改变肠道微环境加重肠道菌群失调, 从而构成恶性循环, 造成肥胖患者肠道黏膜免疫功能进一步紊乱. 基于其与肥胖、糖尿病等代谢性疾病高度相关, 肠道菌群与肠道免疫可望成为这类疾病新的治疗靶点[51].
TLRs等固有免疫系统的病原菌感应分子, 是肠黏膜屏障、肠道菌群、免疫系统之间的交互作用界面[52-55]. 主要由肠道病原菌激活的TLRs通路, 与多种类型感染及炎症反应相关[52]. 另一方面, 肠道糖脂代谢环境、机体及肠道菌群遗传调控模式、宿主免疫状态等因素, 整合性调控TLR功能[52-55]. 因此, TLRs处于肥胖、肠道菌群失调与肠黏膜免疫的交互调控界面, 其基本功能包括: (1)识别不同病原成分: TLRs是识别肠道病原菌的主要受体, 是调控肠黏膜免疫的关键分子. 不同TLR识别不同的病原模体, 如TLR2识别革兰阳性细菌, TLR3识别双链RNA病毒, TLR5识细菌鞭毛, TLR8识别单链RNA病毒. 不同肠黏膜细胞的TLR谱, 实际上是其功能谱的基本体现[53-55]; (2)协调肠道免疫功能: TLRs是肠道微生物与肠壁黏膜免疫细胞之间的重要信使, 通过诱生抗菌肽、促进黏膜上皮细胞增殖等途径, 稳定肠黏膜免疫功能. TLRs广泛分布在多种肠壁细胞, 对维持肠道免疫功能稳定至关重要[55]; (3)维持肠黏膜结构完整: 如TLR2促进紧密连接蛋白产生, 维持肠黏膜完整. TLR4通过诱生IL-10调控多种肠道炎症反应, 维持肠黏膜免疫功能可塑性[54]; (4)促进免疫细胞成熟与抗体类别转换: IgA2对细菌合成消化酶的耐受性较强. He等[56]发现, TLRs感应肠道病原菌后, 诱导IgM抗体转换为IgA2抗体类型; (5)TLR具有重要诊断学意义: 在炎症性肠炎、肥胖等病理状况下, TLR的异常表达是重要的致病因子, 同时也具有重要的诊断学意义[4,57,58]; (6)TLR与肥胖性炎症反应直接相关: 肥胖导致肠道菌群改变, 降低肠壁完整性, 使得细菌脂多糖与脂肪酸渗漏入血增加, 激活TLR4与系统性炎症应答. 同时, 脂肪酸也通过启动内质网应急而激活TLR4. 因此, TLR4等与肥胖性炎症反应直接相关, 居于肥胖-肠道菌群-TLRs三者间的关键调控节点.
肥胖的发生发展, 与肠道菌群及其以TLRs为代表的肠道黏膜免疫直接相关. 肥胖-肠道菌群-TLRs三者间的复杂交互作用机制, 正逐渐被揭示. 肥胖是引起肠道菌群失调与肠道黏膜免疫紊乱的重要因素, 肠道菌群与肠黏膜免疫构成动态平衡, 持续地受到肥胖等代谢性疾病的冲击, 进而出现恶性循环. TLRs作为肠道固有免疫反应中最主要的病原菌感受分子, 居于肥胖-肠道菌群-肠道黏膜免疫之间的关键调控节点. 因此, 通过肥胖-肠道菌群-TLRs的复杂交互作用研究, 可望阐释肠道菌群、肠道免疫与肥胖等代谢性疾病的高度相关性, 进而发现肥胖等代谢性疾病的新型治疗靶点.
肥胖-肠道菌群-Toll样受体(Toll-like receptors, TLRs)三者之间存在紧密的生理病理联系. 肥胖引起肠道菌群结构与功能紊乱, 肠黏膜免疫异常; 肠道菌群、肠道免疫异常又反过来促进肥胖进程.
吴军, 研究员, 军事医学科学院生物工程研究所; 杜潇, 副教授, 四川大学华西医院胃肠外科; 王道荣, 主任医师, 江苏省苏北人民医院胃肠外科
以往研究肥胖多关注于脂质代谢方面, 缺乏肥胖-肠道菌群-免疫功能交互作用的整合性研究. 本文基于TLRs探究三者之间的关系, 有助于更完整揭示肥胖发生发展的整体性病理机制.
目前, 关于肥胖的研究还局限在某种方法干预下肠道菌群相关细菌种属升高或者降低, 进而推断该种属与肥胖的形成有关系, 如Zarrinpar等研究饮食及喂养方式对肠道菌群的动态变化的影响.
本文归纳和总结了近5年来研究肥胖的最新进展, 阐述肥胖-肠道菌群-TLRs之间的相互关系, 揭示TLRs在三者之间的桥梁作用, 为进一步深入探究肥胖成因, 寻找治疗肥胖的最佳治疗方法, 提供新的思路和研究平台.
本文对肥胖-肠道菌群-TLRs三者关系做了深入的探讨, 对进一步研究肥胖的治疗有重要意义, 为搭建新的肥胖研究平台, 新的治疗肥胖药物靶点的探究意义非凡, 在接下来的肥胖研究中, 这三者的关系不容忽视.
TLRs: Toll样受体, 位于细胞膜表面或者细胞核内, 是进化中比较保守的一个受体家族, 至少包括10个成员, 能特异地识别病原相关的分子模式, 承担识别致病菌和启动防御机制的功能.
TLRs是介导肠道菌群与肥胖之间的关键信号蛋白, 本文将三者进行综述分析, 揭示肥胖形成的内在机制, 为肥胖症的深入研究有重要意义, 为肥胖的治疗搭建新的平台有着指导意义.
编辑:于明茜 电编:都珍珍
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