修回日期: 2022-04-26
接受日期: 2022-05-25
在线出版日期: 2022-06-28
肠易激综合征(irritable bowel syndrome, IBS)是临床常见的一种功能性胃肠病, 其发病机制比较复杂, 严重影响患者的生活质量. 目前认为IBS发病机制主要涉及内脏感觉异常、肠道动力紊乱、免疫失调及肠道屏障损伤等. 因IBS发病存在女性偏倚, 强烈提示雌激素等性激素参与IBS的发生发展. 此外, 肠道菌群失调与IBS密切相关. 雌激素和肠道菌群如何相互影响参与IBS尚未被完全阐释. 本文对当前相关研究进展进行述评. 在梳理新发现和研究不足的基础上, 探讨今后的研究方向和需要注意的问题.
核心提要: 肠易激综合征(irritable bowel syndrome, IBS)存在明显的性别差异, 发病以女性占主导, 强烈提示雌激素等性激素与IBS密切相关. 肠道菌群的变化可以影响IBS的发生与发展. 雌激素和肠道菌群可相互影响在IBS发病中发挥作用.
引文著录: 蒋风茹, 杭露, 周盐, 冯雅, 袁建业. 雌激素-肠道菌群相互作用与肠易激综合征. 世界华人消化杂志 2022; 30(12): 511-520
Revised: April 26, 2022
Accepted: May 25, 2022
Published online: June 28, 2022
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder with a complex pathogenesis that has a serious impact on the quality of life of patients. Abnormal visceral sensation, disordered gut motility, dysregulated immunity, and damaged intestinal barrier are thought to be involved in the pathogenesis of IBS. Female predisposition to IBS strongly suggests that sex hormones such as estrogen are involved in the development of IBS. In addition, dysbiosis of the intestinal flora is closely related to IBS. The interaction between estrogen and gut microbiota in IBS has not been fully elucidated. This review summarizes and evaluates the progress of related studies. Based on the new findings and shortcomings of current studies, we discuss the directions and issues that need to be resolved in future research.
- Citation: Jiang FR, Hang L, Zhou Y, Feng Y, Yuan JY. Estrogen-gut microbiota interactions and irritable bowel syndrome. Shijie Huaren Xiaohua Zazhi 2022; 30(12): 511-520
- URL: https://www.wjgnet.com/1009-3079/full/v30/i12/511.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v30.i12.511
肠易激综合征(irritable bowel syndrome, IBS)是一种以腹痛、腹胀、伴排便习惯和粪便性状改变为主要临床表现, 呈持续或间歇发作的常见功能性肠病[1]. 据流行病学调查显示, IBS正成为世界范围内常见的功能性肠病, 全球患病率高达10%-20%[2]. 目前国际上对IBS的诊断主要采取罗马Ⅲ、Ⅳ两种标准. 罗马Ⅳ标准将IBS分为四种亚型: 腹泻型IBS(IBS with predominant diarrhea, IBS-D)、便秘型IBS(IBS with predominant constipation, IBS-C)、混合型IBS(IBS with mixed bowel habits, IBS-M)、未确定型IBS(IBS unclassified, IBS-U)[3]. IBS病情反复、病程迁延, 严重影响患者的工作和生活.IBS的病理生理机制复杂, 且尚未被完全阐明, 可能与内脏超敏反应、胃肠动力紊乱、脑肠互动异常、肠道微生物改变、免疫失调等有关[4]. 值得注意的是, IBS存在明显的性别差异, 男女患病比约为1:2, 且女性容易表现为IBS-C, 而男性容易表现为IBS-D[5,6]. 这强烈提示雌激素等性激素可能与IBS有关. 此外, 已有大量研究证实肠道菌群失调与IBS关系密切[7]. 雌激素与肠道菌群相互作用已在相关研究领域受到广泛关注. 本文对雌激素和肠道菌群相互作用参与IBS的相关研究进展进行述评, 以期为今后更好地治疗IBS提供新思路.
雌激素系一种类固醇激素, 主要由卵巢、胎盘和肾上腺皮质产生, 小部分由大脑、皮肤生成[8], 亦可在外周组织如脂肪、肝脏中转换合成, 是人类和其它动物体内最重要的激素之一. 年龄、性别和健康状况都是决定人体雌激素水平的关键因素[9]. 男性体内雌激素的产生主要依赖于性腺外靶器官组织[10].
人体中以天然雌激素形式存在的主要是雌酮(estrone, E1)、雌二醇(estradiol, E2)、雌三醇(estriol, E3)及部分结合雌激素[11]. 其中E2发挥主要生物学效应. E2主要由卵巢和胎盘产生, 小部分可由肾上腺和男性睾丸生成, 被认为是生物学代谢活性最强的雌激素[12].
雌激素可通过与不同受体结合, 经自分泌或旁分泌机制发挥不同生物学效应, 对人体健康产生有利或有害的双重影响[12,13]. 雌激素除了可以调节生殖系统功能外, 对内分泌系统、心血管系统、骨骼生长发育系统、神经系统及胃肠系统都发挥重要调节作用[12,14].
雌激素受体(estrogen receptor, ER)存在于细胞膜、细胞核、细胞质和线粒体中[12]. ER有三种亚型, 分别是核雌激素受体α(estrogen receptor α, ERα)、核雌激素受体β(estrogen receptorβ, ERβ)和膜受体G蛋白偶联雌激素受体1(G protein-coupled estrogen receptor 1, GPER1)又称GPR30. ERα、ERβ结构相似但组织分布不完全相同, ERα主要在女性生殖系统中表达, 而ERβ在各种不同类型的组织和细胞中均有表达, 虽然二者均存在于胃肠道上皮细胞、血管内皮和免疫细胞中, 但在女性体内的表达高于男性[13,15]. GPR30属于具有高亲和力、最敏感的单一结合位点雌激素受体, 可与各种类型的雌激素结合. 雌激素通过与ERs结合发挥其生物学效应[16], 对机体生殖系统、中枢神经系统、肝脏、肠和认知和新陈代谢等生理活动进行调节[17,18]. 雌激素与ERα和ERβ结合发挥长期、缓慢的经典基因组效应[19,20]; 而与GPR30结合后激活丝裂原活化蛋白激酶(mitogen-activated protein kinases, MAPK)、磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase, PI3K)、Src激酶和G蛋白等成分经第二信使系统引发快速的非基因组效应[21,22].
雌激素在不同部位或不同状态下发挥不同作用, 可能与这些部位ERα、ERβ和GPR30表达水平及雌激素浓度不同, 或与不同状态下雌激素作用平衡方式改变有关.
研究发现, IBS女性患病率高于男性[6]. IBS女性患者发病率随年龄增长而稳步下降; 但男性IBS患者发病率则相对稳定; 女性IBS患者更容易出现腹痛、腹胀、便秘, 男性IBS患者则容易表现为腹泻[23]. 此外, 男性与女性IBS患者腹痛的程度和持续时间上存在显著差异[24]. 值得注意的是, 女性在月经周期、育龄期、妊娠期、或绝经期的激素状态与IBS症状严重程度呈现一定相关性[25]. 雌激素除了参与胃肠道运动功能的调节, 还与肠黏膜免疫的激活和内脏感觉异常等IBS病理机制密切相关[26].
2.2.1 脑-肠轴调节异常: 中枢神经系统(central nervous system, CNS)、自主神经系统(autonomic nervous system, ANS)和肠神经系统(enteric nervous system, ENS)形成互动环路, 构成脑-肠轴[27]. 雌激素通过刺激CNS-ANS-ENS信号传导, 释放神经递质或脑肠肽(5-羟色胺、P物质等)刺激胃肠道引起内脏感觉异常或动力紊乱[28]. 5-羟色胺(hydroxytryptamine, 5-HT)是脑肠间信息传递的重要神经递质, 5-HT水平与IBS肠道敏感性和胃肠功能紊乱密切相关[29]. 李天津等[30]研究发现雌、孕激素可使大鼠5-HT3受体mRNA表达降低, 推测女性IBS患者雌激素等性激素可减少5-HT3受体在胃肠中的表达, 减轻内脏高敏感性和结肠收缩. 此外, 有研究发现[31]卵巢切除术(ovariectomize, OVX)可促进IBS动物模型的脊髓背角P物质表达, 调节迷走神经传入神经元对P物质的反应性, 从而调节痛觉机制. 以上研究表明雌激素可能参与调节5-HT、P物质介导的脑-肠轴功能. 亦有临床证据发现, 雌激素可直接激活位于脑-肠轴的雌激素受体, 致使沿脑-肠轴的外周和中枢敏感化, 影响胃肠运动和内脏敏感[32], 从而参与IBS的发生发展.
2.2.2 内脏敏感性改变: 脑成像显示, 与男性IBS患者相比, 女性IBS患者的杏仁核、蓝斑区等回路的敏感阈值更低. 临床研究发现[33], 经期女性卵巢雌激素水平下降, 出现的胃肠道症状比月经周期的卵泡期、排卵期、黄体期更严重; 且IBS患者在经期的直肠敏感阈值明显低于其它月经期[34]. 有趣的是, 育龄期女性雌激素水平升高可改善IBS症状, 绝经后女性采用雌激素替代疗法反而加重IBS症状, 二者出现截然相反的结果可能与自主神经功能状态有关[35]. Tillisch等人[36]发现, 与男性IBS患者相比, 女性IBS患者表现出交感神经系统激活降低而副交感神经系统激活增强.
Bi等[37]研究发现与野生型(wild type, WT)大鼠相比, 雌性血清素转运蛋白敲除(serotonin reuptake transporter knockout, SERTKO)大鼠存在明显的内脏高敏感性, 粪便颗粒排出量显著增加, 结肠5-HT浓度升高, 5-HT1B、5-HT3A等受体表达水平升高, 提示雌激素可能通过5-HT能系统参与内脏超敏反应(visceral hypersensitivity, VH)和胃肠道动力障碍. 陈瑜等[38]研究发现雌鼠内脏敏感性较雄鼠高, 血清雌激素水平与IBS雌鼠腹外斜肌对结直肠扩张(colorectal distension, CRD)刺激反应成正相关, 且OVX大鼠的内脏敏感性比高雌激素大鼠低, 表明雌激素升高可以增强直肠感觉敏感性. 与之一致的, 有研究发现[39]OVX大鼠应用雌激素替代疗法后对CRD的反应性增加. 有趣的是, 也有研究显示[40]OVX小鼠腹部、下肢表现持续的痛觉亢进状态, 给予外源性雌激素症状得以逆转. 临床和动物实验数据表明雌激素具有诱导痛觉过敏和镇痛反应的双重作用[41].
雌激素可通过外周和中枢神经调节机制改变IBS患者内脏敏感性, 主要是脊髓中枢和自主神经两条通路. 在介导应激、焦虑、疼痛的下丘脑、杏仁核、灰质等脑区皮质存在大量雌激素受体, ERβ mRNA在处理接收痛觉过敏的背根神经节(dorsal root ganglion, DRG)中广泛分布[42]. ERβ是脑胚胎发育主要雌激素受体, 调控DRG浅层的神经元形态和分化, 通过减弱阿片受体作用来调控外周和内脏痛. 雌激素能增加海马区神经元N-甲基-D-天冬氨酸受体(NMDA受体)介导的突触电位变化, NMDA受体与躯体和内脏痛有关, 雌激素可增强脊髓背角NMDA受体表达[43]. OVX动物被给予ERα激动剂后增强了对结肠扩张的敏感性, 表明脊髓ERα参与调节内脏感觉[44]. 以上均说明雌激素可通过脊髓中枢通路介导VH. 此外, 研究发现雌激素受体在外周神经广泛分布, 雌激素可能作用于外周运动神经及效应器等区域调控内脏感觉, 以上均表明雌激素很可能通过作用于外周神经传导通路影响IBS发生发展.
2.2.3 胃肠运动功能障碍: 胃肠动力异常是IBS发生的重要病理生理基础. 胃肠运动的调节由肠神经系统、胃肠道Cajal间质细胞(cajal mesenchymal cells, ICC)、平滑肌细胞协调完成. 雌激素或非选择性雌激素受体激动剂17β-雌二醇可抑制CNS区域及胃肠道电压门控钾离子通道, 从而抑制肠道平滑肌收缩延缓胃肠运动[45], 参与IBS的发生发展.
Gonenne等[46]在研究中发现, 给予绝经期女性雌激素、孕激素、雌孕激素联合治疗, 发现相较于加快结肠运动的孕激素, 单独使用雌激素或联合使用雌孕激素, 结肠运动不明显. 提示雌激素可能抑制结肠运动. 有趣的是, 健康绝经后女性, 在短期补充或暂停雌激素时结肠转运未受影响, 提示雌激素对胃肠道运动的调控可能受激素暴露剂量和作用时间的影响.
刘红霞等[47]通过慢性束缚浸水实验诱导小鼠IBS模型, 分别给予不同性激素处理, 发现雌激素组小鼠的结肠肌条收缩程度降低, 一氧化氮(nitric oxide, NO)含量较模型组和雌孕激素组均升高. 提示雌激素可能通过促进NO合成与分泌抑制束缚浸水增加的结肠肌条收缩. 亦有研究发现OVX大鼠给予E2, 大鼠神经元NO合成酶(nitric oxide synthase, NOS)及受体表达均升高[48]. NO通过激活鸟苷酸环化酶生成环状鸟苷酸(cyclic guanosine monophosphate, CGMP), 介导平滑肌松弛, 对胃肠道运动起抑制作用[49]. 雌激素可经NO通路调节胃肠道动力.
正常人体消化道内寄居着数万亿的微生物, 主要包括细菌、病毒、真核生物等, 这类微生物统称为肠道菌群. 人体中的肠道菌群主要分为四大类: 分别为厚壁菌门、拟杆菌门、变形菌门和放线菌门[50]. 肠道菌群参与机体消化吸收、新陈代谢, 影响机体炎症发生与免疫调节, 影响大脑发育和调节情绪, 对宿主发挥着复杂而有益的作用[51]. 肠道菌群易受饮食、感染、应激、抗生素等影响. 菌群的组成变化或功能紊乱被称为肠道菌群失调. 细菌发生易位可改变肠道上皮通透性, 诱发炎症, 引起局部和全身免疫反应[52]. 越来越多的研究发现, 菌群失调与IBS密切相关.
肠道微生物可能通过神经元信号转导改变内脏敏感性. 临床研究发现[53], IBS患者肠道菌群生物多样性降低, 梭状芽孢杆菌和双歧杆菌属减少, 肠杆菌科和乳酸菌科增多. 然而, 也有报道称IBS患者的粪便与黏膜样本中菌群多样性较低, 表现为拟杆菌门减少, 梭状芽胞杆菌为代表的厚壁菌门增加[54]. 菌属种类与数目变化的不一致, 推测可能与IBS亚型不同有关. IBS患者厚壁菌门/拟杆菌门(Firmicutes:Bacteroidetes, F:B)比例改变, 经益生菌治疗后腹痛、腹胀、内脏疼痛减轻[55]. 动物研究发现[56], 鼠李糖乳杆菌单独或与益生元联合降低应激诱导的大鼠模型内脏敏感性. 无菌小鼠对疼痛敏感性增加, 肠道微生物移植于无菌小鼠可改善此症状; 将IBS患者粪便移植到无菌大鼠会引起VH[57].
肠道菌群可影响肠道的运动功能. 微生物群对结肠运动的调节可能取决于上皮细胞的Toll样受体(toll-like receptors, TLRs)、NOD样受体(NLRs)[58]. 特定细菌如拟杆菌可改变参与平滑肌功能和神经传递基因的表达; 大肠杆菌可溶性因子和脂多糖(lipopolysaccharide, LPS)直接刺激平滑肌增强结肠收缩力[59].
雌激素已被证明可以激活中枢和外周神经系统的神经元, 调节内脏痛觉反应[64]. ERα和ERβ能调节感觉神经元活动、参与伤害感受器信号传导调节内脏疼痛反应[65,66], 在IBS诱导的小鼠内脏过敏模型中发挥镇痛作用[67]. Tramullas等[68]研究发现OVX在常规小鼠中诱导VH, 且VH随啮齿动物雌激素水平波动而变化; 但无菌小鼠则不然, 对无菌小鼠行OVX不导致VH. 提示OVX诱导的VH依赖于肠道微生物群驱动. 补充E2可改善OVX诱导的常规小鼠内脏敏感性升高.
未结合的雌激素经肝肠循环进入血液, 与ERα、ERβ结合影响宿主雌激素水平[69]. 肠道微生物群能通过微生物衍生的β-葡萄糖醛酸酶(glucuronidase, GUS)将分泌到胆汁中的结合雌激素重新激活成E1和E2. 肠道微生物群代谢雌激素, 然后通过作用于远端部位的ERα、ERβ引发下游基因激活触发细胞信号联级反应发挥基因组效应[70], 影响VH. 因此, 肠道菌群可能通过影响雌激素水平和雌激素受体表达介导内脏痛觉过敏参与IBS的发生发展.
ERs高度参与胃肠道运动的调节. GPER选择性受体激动剂(G-1)通过增加神经元型一氧化氮合酶(neuronal nitric oxide synthase, nNOS)表达刺激肠肌神经元NO产生, 后者在肠神经系统的神经肌肉接头处发挥抑制性神经递质作用, 影响胃肠道运动[71]. Zielińska和Li等人[67,72]研究发现, E2可通过雌激素受体影响G-1发挥抑制结肠运动的作用. Ravella等人[71]报道ERα表达增加抑制小鼠胃排空速度. 肠道微生物群中的瘤胃球菌、粪便杆菌属分泌GUS酶激活雌激素, 启动ERs, 经膜受体GPR30触发NO作用于nNOS影响胃肠动力, 参与IBS的发生发展.但目前针对ER触发NO的作用机制尚不清楚, 有待进一步研究.
给避水应激(water avoidance stress, WAS)大鼠服用乳杆菌可显著降低其结肠黏膜肥大细胞数量, 但仅能降低雌鼠炎症细胞因子水平[73]. 经反复WAS诱导的结肠微炎症模型大鼠对益生菌治疗反应也不同, 乳酸杆菌可有效治疗雌鼠, 但对雄鼠不起作用[74]. 一项慢性束缚应激(chronic restraint stress, CRS)研究发现[75], 雌性CRS组双歧杆菌种、毛螺菌科相对丰度较低, 乳杆菌目相对丰度增加. CRS小鼠经抗生素治疗后痛觉阈值下调. Gao等[76]研究发现抗生素治疗后雌、雄CRS小鼠血清代谢物存在差异. CRS雌鼠与假无菌雌鼠相比, 代谢物中苯丙氨酸、酪氨酸和色氨酸的生物合成存在差异. 雌鼠血清代谢变化主要涉及牛磺酸和亚牛磺酸以及色氨酸代谢, 其中色氨酸代谢变化最显著. 色氨酸是5-HT的前体, 参与结肠运动与内脏感觉调节. 基于CRS小鼠模型, 提示肠道微生物群影响雌激素引起血清代谢物改变调节痛觉过敏参与IBS. Johnson等[77]研究发现, 雄性和雌性小鼠肠道免疫表型存在差异, 进行抗生素处理后的微生物消耗仅对雌鼠产生自身免疫抑制, 表现为雌鼠的结肠促炎细胞因子表达水平显著降低.提示肠道菌群可能与雌激素作用影响肠道免疫表型及微生物依赖的促炎反应参与IBS.
雌激素变化可引起肠道菌群变化, 参与IBS. 临床研究发现[78], 绝经前与绝经后女性相比, 毛螺菌属和嗜胆菌属更为聚集, 革兰氏阴性菌水平升高, 厚壁菌门的代表乳酸杆菌浓度降低, F:B比值升高. 且绝经后女性拟杆菌属的丰度与体内的E1、E2及羟基化雌激素代谢物水平呈负相关[79]. 双侧卵巢切除女性体内梭状芽孢杆菌丰度增加[80]. 提示人体中雌激素水平变化会影响肠道微生物群丰度及组成. 人体雌激素水平变化主要影响梭状芽孢杆菌和瘤胃球菌丰度[81], 有研究发现[82]IBS患者中瘤胃球菌减少且IBS症状严重程度与梭状芽孢杆菌和普氏菌属的富集相关. 富含产乙酸和丙酸的乳杆菌属可刺激肠神经末梢释放5-HT加速结肠运动[58]. 此外, 肠道微生物影响胆汁酸代谢[74]. IBS-D患者红球菌属减少及胆汁酸代谢改变与内脏超敏反应相关[82]. 目前IBS病人中雌激素变化引起肠道菌群变化的直接证据还不多. 推测雌激素很有可能通过调节肠道菌群及其代谢产物参与IBS. 推测是基于以上非IBS患者人群中的发现, 但还缺乏在IBS患者中发现雌激素变化导致肠道菌群变化.
动物研究发现[83-85], 双侧OVX引起小鼠肠道微生物生态失调, 变形杆菌及LPS生物合成降低, 厚壁菌丰度升高, 拟杆菌丰度降低. 在属水平上, 厚壁菌中的瘤胃球菌丰度升高. OVX对SCFAs浓度有显著影响, 可显著降低乙酸(acetic acid, AA)、丙酸(propionic acid, PA)、丁酸(butyric acid, BA)浓度, 其中丁酸盐和丙酸盐是减少肠道炎症并保持肠道屏障完整性的重要代谢产物[86]. 17β-雌二醇可诱导肠道微生物变化, 对雄性及OVX雌鼠补充E2治疗后, 拟杆菌、放线菌、变形菌丰度改变[87], 肠道屏障保护细菌双歧杆菌相对丰度增加, 产生LPS及内毒素的变形杆菌显著减少[88], 肠道通透性降低. 随着OVX给予从低到高的E2剂量, SCFA谱甲酸盐含量随E2升高而降低, 异丁酸含量随E2增加而升高, 其中异丁酸酯作为一种支链脂肪酸可影响肠道运动[89]. 一项ERβ敲除(ERβ KO)小鼠研究发现[90], KO小鼠体内厚壁菌丰度降低, 肠上皮屏障完整性下降. Menon等[91]的研究亦发现随着小鼠ERβ状态的不同, 变形杆菌门、拟杆菌门、厚壁菌门及乳酸杆菌会发生不同程度改变. Chen等人[88]研究发现对大鼠长期使用共轭雌激素可对肠道GUS活性产生抑制作用, GUS活性降低与乳酸菌、链球菌丰度降低及红球菌科丰度增加显著相关, 雌激素通过肠肝循环直接影响肠道微生物的细菌代谢水平[92]. 一项母婴分离(maternal separation, MS)模型研究发现[93]螺旋菌属及布劳特氏菌属仅在雌鼠中减少. Park等人[94]研究发现MS雌鼠链球菌、粘螺旋菌丰度降低, 孢子菌属相对丰度增加, 雌鼠的结肠运动情况与雄鼠不同. MS提高了雌性大鼠的IL-1β水平和犬尿氨酸/色氨酸(KYN/TRP)比值. 提示雌激素很有可能通过影响肠道微生物群组成及丰度影响炎症反应和TRP-KYN代谢途径影响肠道通透性及内脏敏感性参与IBS. 以上证据均提示雌激素很有可能通过影响肠道微生物群参与IBS, 但具体发病机制还有待进一步研究. 一项结合产前LPS注射、产后MS及给予慢性轻度应激的早期多因素生活逆境动物研究[95]发现, 早期逆境模型雄鼠和雌鼠表现出不同的肠道微生物群组成, 雌鼠乳酸杆菌属和粘螺菌属相对丰度显著降低且雌鼠内脏敏感性低于雄鼠. 进一步研究发现, 多重逆境应激差异影响小鼠内侧前额叶皮层(medial prefrontal cortex, mPFC)基因表达, 表现为雌性基因表达上调和雄性基因表达下调. 提示雌激素可能与肠道菌群相互作用影响mPFC基因表达调节内脏敏感性参与IBS.
此外, 植物雌激素作为具有雌激素或抗雌激素活性的天然物质, 亦可影响肠道微生物多样性[96]. 多酚类可抑制幽门螺杆菌和葡萄球菌等致病菌影响肠道微生物群的多样性[97], 绝经后妇女食用大豆异黄酮等植物雌激素可增加有益革兰氏阳性菌双歧杆菌浓度改变绝经后妇女粪便细菌群落组成及结构, 抑制梭状芽孢杆菌生长[98].
ERβ是结肠中最丰富的雌激素受体, 雌激素与ERβ结合可直接调节细菌的新陈代谢. 厚壁菌属如粪杆菌、乳球菌与结肠转运相关, 厚壁菌的一些成员可促进脂滴形成, 拟杆菌参与结肠动力改变, 它们可能是通过肠上皮细胞的TLRs等发挥作用的. 毛螺菌属可产生大量SCFAs调节机体免疫和炎症反应[58]. ERβ可上调紧密连接蛋白和粘附分子表达, 调节上皮通透性. 拟杆菌丰度增加与肠道通透性及结肠促炎状态增强相关[99]. 雌激素通过与细胞核中ER配体结合介导基因组效应, 引起基因组构象改变[100]. 雌激素通过肠-脑-微生物轴作用于中枢和外周传导通路影响肠屏障通透性及免疫系统参与IBS[100].
此外, 雌激素可通过影响细菌代谢及致病菌的毒性, 改变肠道微生物群组成及代谢, 丁酸盐可抑制肠上皮细胞NF-κB激活, 诱导免疫细胞活化, 减缓炎症[101]. 17β-雌二醇影响树突状细胞的转化以产生IL-12和IFN-γ, 反过来激活促炎细胞因子, 由此产生的促炎环境改变肠道通透性, 导致肠道微生物群迁移到固有层中, 进一步加重炎症[102]. IBS存在持续的低度黏膜生理炎症.革兰氏阴性菌产生LPS通过肠壁转移到血液中, 引起长期低水平炎症. E2上调肠道保护酶碱性磷酸酶, 通过调节炎症通路和降低病原菌的浓度减少LPS诱导的促炎信号发挥作用参与调节IBS肠道炎症微环境[83].
近年来在不同的疾病中雌激素与肠道菌群相互作用引起了人们的广泛关注, 二者存在密切且复杂的相互作用机制, 并与IBS发生存在潜在联系. 有证据表明性别差异对人类微生物群有显著影响, 随后便引入了"微性别组"概念. 目前在临床研究中, 多是对绝经后女性提供雌激素替代疗法, 观察外源性雌激素与肠道微生物群的关系. 雌激素与肠道菌群相互作用参与IBS的直接证据还比较少. 大部分肠道微生物群组成的性别差异主要在动物研究中观察到.在动物实验中, 二者关系的研究主要集中在雌激素如何影响肠道微生物群的丰度、组成、代谢产物以及肠道微生物群改变如何影响雌激素水平, 进而驱动低雌激素或高雌激素疾病.研究的动物模型包括OVX模型、ERβ KO模型等通过改变雌激素水平或影响雌激素受体观察肠道微生物菌群变化. 均强烈提示雌激素与肠道菌群相互作用参与IBS.
肠道菌群可提供SCFAs和其它代谢物充当信号分子或代谢反应的底物, 雌激素可通过肠道微生物群产生的GUS将分泌到胆汁中的结合雌激素再激活, 重新与肠道上皮细胞或和其它组织中与不同类型的ERs结合发挥下游效应. ERs在大量组织及中枢和外周部位均有表达, 雌激素又可在肠道微生物协同下, 与ER结合通过肠-脑-微生物轴影响中枢、外周系统, 调节肠道内脏敏感性、肠动力、免疫及炎症反应等参与IBS.
但我们也应注意到目前雌激素与肠道菌群关系的大部分研究都集中在实验动物中, 啮齿动物的微生物群在属水平上存在显著差异, 肠道菌群组成的性别差异也取决于所研究的物种和菌株. 研究的结果可能与所选动物品系遗传背景、造模模型、雌激素应用剂量等有关, 并且还存在许多混杂因素. 同一物种的微生物可能产生不同的代谢物, 因此, 与性激素的相互作用亦不同. 目前存在的问题是动物肠道菌群存在性别差异, 甚至同一动物的不同种群菌群组成亦不同.将动物研究结果直接用于人体可能还需要更严谨、更细化的设计. 此外, 研究发现男性和女性结肠ERs表达有差异, 且IBS不同亚型之间结肠黏膜固有层肥大细胞中GPER表达不同, 启动的膜通路不同, 雌激素不同受体之间存在相互干扰的可能性. 此外, 肠道不同的菌株对ERs的敏感性不同. 目前的研究还没有针对IBS某一特定亚型或肠道微生物某一特定菌株进行研究, 在未来可以对雌激素与特定菌株和特定IBS亚型进行更细致的研究.
值得注意的是, OVX后单独进行E2处理也并不能完全模仿卵巢完整大鼠的肠道微生物群落特征. 因此, 谨慎的做法是研究更广泛的E2剂量, 联合激素疗法, 替代给药途径以及设计未来实验时间表参数的变化, 以更好地了解最佳激素治疗方案. 未来的研究还可以在母婴分离或避水应激等IBS模型背景下, 对动物行OVX后给予不同剂量雌激素或联合激素疗法等观察对其肠道菌群的影响.此外, ERβ在人和小鼠结肠上皮中均有表达, 使用ERβ敲除雌性小鼠的研究表明, ERβ以饮食特异性的方式影响肠道微生物群. 未来的研究可以探索肠道ERβ敲除是否会影响肠道微生物菌群代谢物SCFAs参与功能性肠道疾病如IBS. ERα对肠道微生物群的影响尚未得到直接研究, 未来可以更多探索ERα是否影响肠道微生物群及如何参与IBS. 除此之外, 肠道微生物群中GUS和雌激素之间存在一个双向调节系统来维持体内雌激素的稳态. 为了确定这种相互作用, 仍然需要做大量的工作.
同时, 我们也可以关注植物雌激素和雌激素与肠道菌群作用在人体中发挥作用的机制, 一些天然雌激素如植物雌激素及某些膳食雌激素我们仍不知道其如何改变肠道微生物以实现正常的代谢表型, 亦或肠道细菌产生的雌激素代谢物如何作为ER配体介导代谢功能. 微生物群可能代谢内源性或膳食中的雌激素是以不通过ERα、ERβ膜受体的方式还是通过产生新的ER配体介导, 我们在将来研究时可以将其作为一个着眼点, 应注意将植物雌激素、雌激素与肠道菌群相互作用的关系进行区分. 关注雌激素与肠道菌群相互作用的机制研究有助于为临床IBS治疗提供新靶点, 还需要我们更深入的探索和挖掘.
学科分类: 胃肠病学和肝病学
手稿来源地: 上海市
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