修回日期: 2019-06-10
接受日期: 2019-07-15
在线出版日期: 2019-07-28
炎症性肠病(inflammatory bowel disease, IBD)是一组难以控制的慢性炎症性肠道疾病, 包括克罗恩病(crohn's disease, CD)和溃疡性结肠炎(ulcerative colitis, UC). 近年来, 亚洲国家的IBD发病率明显上升, 尤其是在我国. 最近的研究中发现IBD患者体内存在肠道产丁酸菌数量和构成的改变, 提示产丁酸菌与IBD的发生和发展存在一定联系. 本综述着重介绍了产丁酸菌通过产生丁酸及丁酸盐发挥的抗炎作用, 以及Roseburia intestinalis, Faecalibacterium prausnitzii和Clostridium butyricum三种产丁酸菌通过菌体本身的结构和免疫特性发挥的抗炎作用. 这些机制的发现可为防治IBD提供新的思路和研究线索.
核心提要: 近年来, 有研究发现肠道产丁酸菌数量和构成的变化与炎症性肠病(inflammatory bowel disease, IBD)的发生发展息息相关. 除了产生丁酸和丁酸盐外, 部分产丁酸菌还可以通过菌体结构和自身免疫特性发挥抗IBD作用. 本文就肠道产丁酸菌防治IBD的作用机制进行综述.
引文著录: 陈映宇, 毛联智, 刘华缓, 孙素霞. 肠道产丁酸菌防治炎症性肠病的机制研究进展. 世界华人消化杂志 2019; 27(14): 907-912
Revised: June 10, 2019
Accepted: July 15, 2019
Published online: July 28, 2019
Inflammatory bowel disease (IBD) represents a group of intestinal disorders with uncontrolled and chronic inflammation which include Crohn¡¯s disease (CD) and ulcerative colitis (UC). The incidence of IBD is increasing dramatically in Asian countries, especially in China. Recent studies have observed changes in the amount and structure of the gut butyrate-producing bacteria in IBD patients, which suggested that butyrate-producing bacteria might be related to the occurrence and development of IBD. This review will focus on the anti-inflammatory effects of butyrate-producing bacteria by producing butyric acid and butyrate and inhibiting inflammation as well as the immune characteristics of three species of butyrate-producing bacteria: Roseburia intestinalis, Faecalibacterium prausnitzii, and Clostridium butyricum. These mechanisms provide some new ideas and clues for IBD prevention and treatment.
- Citation: Chen YY, Mao LZ, Liu HH, Sun SX. Mechanism of gut butyric acid producing bacteria for prevention and treatment of inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2019; 27(14): 907-912
- URL: https://www.wjgnet.com/1009-3079/full/v27/i14/907.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v27.i14.907
炎症性肠病(inflammatory bowel disease, IBD)是一种慢性、复发性胃肠道炎症, 溃疡性结肠炎(ulcerative colitis, UC)和克罗恩病(crohn's disease, CD)是临床上定义的IBD的两种主要类型. IBD临床症状多样, 可波及多个器官系统, 具有较高的误诊率[1]. IBD在西方国家多发, 美国有超过100万居民, 欧洲有超过250万居民患有IBD, 而近年来亚洲, 南美洲及中东地区的患病率也在不断上升, IBD已经演变成了一种全球性疾病[2]. 我国IBD的发病率不及西方国家, 但呈现明显上升的趋势, 是亚洲IBD发病率最高的国家[3], 达到3.14/10万人, 其中UC的发病率为2.05/10万人, CD为1.09/10万人[4]. 人体是由真核细胞与体内共生的细菌共同组成的"超级生物体", 肠道是细菌定植的主要场所之一[5]. 肠道菌群的失调与IBD的发生发展密切相关, 是IBD发病的基础[6]. 肠道菌群对肠上皮细胞的生长与分化、宿主的营养、代谢和免疫功能的调节等方面都起到非常重要的作用[7]. 某些肠道菌群可以在结肠内发酵未消化的膳食纤维产生短链脂肪酸(short chain fatty acid, SCFA), 主要包括乙酸, 丙酸和丁酸[8]. 有研究者在IBD患者和相关动物模型中观察到一些产丁酸细菌的数量和多样性下降, 如Faecalibacterium prausnitzii和Roseburia菌属[9], 但产丁酸菌与IBD之间的相互关系尚未清晰. 肠道产丁酸菌可以调节免疫细胞生成的数量, 维护肠上皮细胞屏障功能, 以及通过产生的丁酸发挥抗IBD的作用. 本文就肠道产丁酸菌及其在IBD中的作用及其机制进行综述.
哺乳动物的肠道中聚集着数万亿的细菌, 可以在人体内介导多种生物化学反应. 肠道菌群结构复杂, 在结肠中的种类和数量尤为丰富, 有300-400种, 数量可超过1011/g水平[10]. 肠道菌群可分解并发酵膳食中的低聚糖等膳食纤维, 生成SCFA[11]. 肠道菌群在维护免疫和代谢稳态以及预防疾病方面发挥重要作用, 其组成的改变与许多炎症性疾病的发病机理息息相关[12]. 近年来, 产丁酸菌因其在抗肠道炎症方面的作用被广泛认识. 产丁酸菌在肠道中产生的丁酸可以为结肠上皮细胞提供能量, 提高肠上皮细胞屏障的完整性, 调节肠道菌群的种类和数量, 促进人和动物的肠道健康[13,14]. 产丁酸菌主要分布在结肠和盲肠中, 以厚壁菌门(Firmicutes)为主[15], 包括梭杆菌属(Fusobactierium)、真杆菌属(Eubacterium)、梭菌属(Clostridium)、罗氏菌属(Roseburia)等[16]. 梭杆菌属的Faecalibacterium prausnitzii和真杆菌属的Eubacterium rectale的数量在人结肠菌群中占比最高[17], 将Faecalibacterium prausnitzii和罗氏菌属的Roseburia intestinalis分离后在M2G培养基中进行体外培养发酵, 其产丁酸量高于10 mmol/L, 以上三种菌可能是人和动物肠道中的优势产丁酸菌[18,19]. 梭菌属的Clostridium butyricum也是人和动物肠道中常见的共生菌, 因为其强大的产丁酸能力而命名[20]. 此外, Eubacterium hallii、Roseburia faecis、Roseburia hominis、Eubacterium ramulus也是肠道产丁酸菌的重要组成类别[15]. 随着基因测序等生物技术及色谱、质谱等仪器分析方法的进步和发展, Mediterraneibacter butyricigenes[21], Clostridium composti[22]等新型产丁酸菌种也被不断发现和分离.
过往的研究中人们普遍认为IBD的发生与肠道菌群的失调及代谢变化密切相关. Takahashi等[23]利用Illumina MiSeq TM Ⅱ系统对10名CD患者和10名健康人的粪便样本进行16S rRNA测序. 结果显示, 与健康人相比, CD病人体内的产丁酸菌种, 如Blautia faecis, Roseburia inulinivorans, Ruminococcus torques, Clostridium lavalense, Bacteroides uniformis和Faecalibacterium prausnitzii均显著减少. Halfvarson等[24]建立了128名IBD患者和9名健康人对照的研究队列, 通过对16s rRNA基因的V4区域测序, 发现病人体内产丁酸菌Faecalibacterium prauznitzii的丰度与正常个体相比明显下降. Machiels等[25]采用变性梯度凝胶电泳技术分析了127名UC患者和87名健康人的粪便微生物群, 通过实时定量PCR, 与对照组相比, UC患者体内两种产丁酸菌Faecalibacterium prauznitzii和 Roseburia hominis的丰度显著降低. Al-Bayati等[26]调查了40名UC患者和40名正常人结肠肠道菌群的组成, 观察到患者结肠镜活检标本中产丁酸菌Faecalibacterium prauznitzii数量减少. 但由于菌群难以在体外培养、菌群在肠黏膜与粪便中分离出的样本成分存在差异、多数研究使用的16s核糖体RNA标记测序对菌群分类的精确度不足、研究结果大多基于横断面研究等原因, 尚不能证明肠道菌群的成分变化与IBD的发病存在确切的因果关系[27]. 对于产丁酸菌与IBD的关系, 目前大多数研究仅能阐述发病过程中产丁酸菌群在肠道中的数量及成分变化, 人们对其内在机制知之甚少. 但以上研究结果提示产丁酸菌与IBD之间存在一定的关系, 为从产丁酸菌角度防治IBD提供线索.
有研究和相关的临床证据表明, 丁酸及丁酸盐被认为具有保护肠道黏膜, 调节免疫平衡的作用, 是治疗IBD的潜在药物. 丁酸盐可以为肠上皮细胞提供能量, 通过促进其增殖分化提高肠黏膜的完整性, 阻止致病因子及其他外源性物质入血导致炎症发生[28]. 丁酸盐还可作为一种组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDACi)参与基因的转录调控[29], 使DNA与组蛋白八聚体解离, 松弛核小体, 促进转录因子与特异位点结合从而激活转录过程. 除此之外, 丁酸盐作为HDACi能激活肠上皮细胞的AP-1通路[30], 下调炎症因子的表达水平, 并能增加Fas蛋白的表达量诱导T细胞凋亡[31], 抑制炎症的发生. 丁酸盐也可影响调节性T细胞(regulatory T, Treg)的增殖分化发挥抗炎作用. Treg可表达一种对自身免疫和增殖分化有关键作用的Foxp3蛋白, 丁酸盐能抑制促炎因子IL-6的表达并通过HDACi作用促使初始T细胞分化为Treg细胞, 增加对Foxp3蛋白的表达发挥抗炎作用[32,33]. 丁酸钠还具有激活G蛋白偶联受体(G protein-coupled receptors, GPRs)的作用, 特别是GPR43和GPR109a. 其作用主要是通过激活GPRs抑制下游MEK-ERK、NF-κB等信号通路, 减少促炎因子的分泌, 增加抗菌肽LL-37的分泌来抑制炎症反应[34]. 此外, 丁酸盐可以抑制JAK2的活性以及γ-干扰素诱导的STAT1蛋白上酪氨酸和丝氨酸的磷酸化, 从而抑制 JAK-STAT 通路的活性, 使促炎细胞因子和一氧化氮合酶的合成减少[35]. 综上所述, 产丁酸菌能通过产生丁酸及丁酸盐提高肠道的免疫屏障作用, 促进Treg的增殖分化, 激活GPRs, 以及抑制炎症通路如NF-κB、JAK-STAT来控制炎症的发生和发展, 进而发挥其抗IBD作用.
除了通过产生丁酸发挥抗炎作用外, 有部分产丁酸菌还可不依赖丁酸及丁酸盐, 而是通过菌体本身的结构和免疫特性发挥抗炎作用. 本文挑选了三种具有这些作用的肠道产丁酸菌, 分别为Roseburia intestinalis, Faecalibacterium prausnitzii和Clostridium butyricum, 总结近期研究工作者提出或发现的关于这些菌种在IBD中的作用及其机制.
Roseburia菌属由多种革兰阳性专性厌氧菌构成, 有R.intestinalis, R.hominis, R.inulinivorans, R.faecis和R.cecicola五种, 属于Clostridium ClusterXIVa亚群. 目前对于Roseburia intestinalis菌种抗IBD的机制有较多新的研究进展. Shen等[36]发现Roseburia intestinalis可以增加Treg细胞的数量, 提高结肠炎小鼠体内抗炎细胞因子IL-10, TGF-β, TSLP的表达水平, 参与由脂多糖诱导的CaCo-2细胞抗炎途径, 发挥抗炎作用. Quan等[37]通过在小鼠的UC样品中的微阵列分析和基因测定, 发现Roseburia intestinalis的鞭毛蛋白可能通过增加stat1磷酸化激活H1F1A-AS2启动子, 下调TNF-α, IL-1β, IL-6和IL-12等炎性细胞因子介导抗炎作用. Zhu等[38]利用三硝基苯磺酸溶液在小鼠体内造IBD模型, 通过炎症发生前后的病理学评分及炎症细胞因子的分泌量对比, 表明Roseburia intestinalis可以通过NCM460细胞抑制由脂多糖诱导的炎症细胞因子IL-17分泌, 并能增加Treg细胞的数量对抗IBD. 综上所述, 这些新的研究着重阐述了Roseburia intestinalis通过调控Treg等免疫细胞, 增加体内抗炎细胞因子的分泌, 下调促炎细胞因子的表达水平, 以及利用鞭毛蛋白激活启动子等方面的抗炎机制, 为IBD的治疗提供了新的思路.
Faecalibacterium prausnitzii是人体内含量最丰富的菌种之一, 属于Clostridium Cluster IV亚群, 占人体细菌总量的6%-8%[39]. Faecalibacterium prausnitzii是肠道中重要的丁酸盐生产者, 除了通过产生丁酸盐发挥SCFA的抗炎作用外, 其本身也可以通过多条免疫通路来调节肠道炎症反应. 2008年Sokol等[40]人从人粪中分离了Faecalibacterium prausnitzii的上清液, 通过腹腔注射使其进入IBD小鼠体内. 结果显示, 用Faecalibacterium prausnitzii处理的两组IBD小鼠TNF-α, IL-12的分泌水平显著低于IBD对照组, 且用其上清液处理小鼠的结肠可诱导IL-10分泌. Sokol等[40]认为, 这种抗炎途径不是由于丁酸盐的存在, 而是Faecalibacterium prausnitzii独立的抗炎机制. 近期许多由Faecalibacterium prausnitzii介导的新抗炎途径也被不断提出和发现. Alameddine等[41]首次提出Faecalibacterium prausnitzii可诱导树突状细胞(dendritic cell, DC)表达一系列独特的Tr1/Treg极化分子, 包括IL-27, CD39, IDO-1和PDL-1等抗炎细胞因子, 并在TLR4刺激下, 抑制炎性细胞因子的分泌, 达到抗炎的效果. Sarrabayrouse等[42]则认为肠黏膜CD4CD8ααT淋巴细胞也可以参与表达Foxp3 Treg细胞并分泌IL-10, 而CD4CD8ααT淋巴细胞的表达水平与Faecalibacterium prausnitzii的含量存在高度相关性, 他们猜测Faecalibacterium prausnitzii参与激活了该免疫通路. Faecalibacterium prausnitzii在IBD中的作用机制是肠道菌群抗炎机制中较为热门的研究方向, DC和CD4CD8ααT淋巴细胞发挥的抗炎作用在过往的研究中较少提及, 许多学者将通过进一步的临床试验和研究证实其作用.
Clostridium butyricum是一种严格厌氧的革兰阴性芽孢杆菌, 因为其强大的产丁酸能力而命名, 是人和动物肠道中常见的共生菌[20]. 多种动物实验和临床实践中都证实其抗炎作用, 现已作为一种商业化的益生菌菌种[20]. Cai等[43]用Clostridium butyricum胶囊治疗UC患者, 检测到患者血清中特异性IgE, IL-4和TNF-α的水平下降, 提出Clostridium butyricum具有改善UC的作用. Xiao等[44]通过实时PCR及荧光原位杂交技术观察到Clostridium butyricum在结肠炎模型小鼠体内促进miR-200c的表达, 减少促炎细胞因子的产生; 还可以增长肠道上皮微绒毛, 减少上皮细胞的通透性, 抑制炎症的发生. Li等[45]认为Clostridium butyricum可以修复肠道紧密连接蛋白, 调节肠道乳酸杆菌等微生物的生长, 保护肠上皮细胞的免疫屏障. Kashiwagi等[46]用Clostridium butyricum等梭菌属混合物定植于结肠炎模型小鼠中, 发现Clostridium butyricum可以依赖Toll样受体2, 激活ERK-AP-1激酶通路, 诱导肠壁固有层的树突细胞中的TGF-β1促进肠道中Treg的形成, 调节肠道的免疫功能. 综上所述, Clostridium butyricum既可通过修复肠道结构提高肠道免疫力, 也可通过调节miR-200c等分子的表达水平或激活相关免疫通路发挥其抗炎作用(表1).
| 细胞因子 | 产丁酸菌 | 表达 | 机制 | 参考文献 |
| IL-10 | Roseburia intestinalis | 上调 | 未知 | [36] |
| Faecalibacterium prausnitzii | 上调 | 诱导DC表达Tr1/Treg极化分子 | [41] | |
| IL-12和TNF-α | Roseburia intestinalis | 下调 | 激活H1F1A-AS2启动子 | [36] |
| Faecalibacterium prausnitzii | 下调 | TLR4刺激下抑制 | [41] | |
| Clostridium butyricum | 下调 | miR-200c的表达抑制 | [44] | |
| IL-6和IL-1β | Roseburia intestinalis | 下调 | 激活H1F1A-AS2启动子 | [37] |
| TGF-β | Roseburia intestinalis | 上调 | 未知 | [36] |
| Clostridium butyricum | 上调 | 激活ERK-AP-1激酶通路, 诱导肠壁固有层的DC产生 | [44] |
肠道产丁酸菌以Firmicutes为主, 包括Fusobactierium、Eubacterium、Clostridium、Roseburia等菌属. IBD患者和模型动物中的产丁酸菌数量和多样性的减少, 提示产丁酸菌的变化与IBD的发病有密切联系. 多项动物实验及临床实践研究表明产丁酸菌发挥抗IBD作用, 其主要机制可分为以下两大方面: 一是产丁酸菌可通过产生丁酸和丁酸盐保护肠道黏膜, 发挥HDACi作用, 并可调节Treg细胞的增殖分化, 以及激活GPRs, 抑制NF-κB、JAK-STAT等信号通路产生抗炎作用. 二是产丁酸菌可以通过自身的结构和免疫特性发挥抗炎作用. 除了通过增加Treg细胞数量, 下调炎症因子表达水平等常见途径外, 有研究者还提出了新的抗炎部位和免疫通路. 如Roseburia intestinalis利用鞭毛蛋白通过增加stat1磷酸化激活H1F1A-AS2启动子等方式保护肠道组织; Faecalibacterium prausnitzii诱导树突状细胞, CD4CD8ααT淋巴细胞参与的免疫调节作用被逐步发现; Clostridium butyricum能增长肠道微绒毛, 增强肠道上皮细胞的屏障作用, 防止IBD的发生和发展. 但由于在目前的研究中, 产丁酸菌群难以在体外培养, 且多数研究使用的16s核糖体RNA标记测序对菌群分类的精确度不足, 菌群在肠黏膜与粪便中分离出的样本成分存在差异, 因此菌群与IBD发生发展之间的因果关系尚不十分明确. 产丁酸菌抗IBD的作用除了本文所阐述的机制外, 在实验过程中是否存在其他抗炎途径和干扰因素, 目前的研究也没有准确的定论. 因此, 有必要进一步了解宿主与细菌相互作用的分子基础, 为今后通过这些机制提高IBD病人体内产丁酸菌的数量和种类, 改善肠道菌群的生态失调, 进而达到改善和治疗IBD提供策略.
学科分类: 胃肠病学和肝病学
手稿来源地: 广东省
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编辑:崔丽君 电编:刘继红
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