修回日期: 2021-07-13
接受日期: 2021-08-25
在线出版日期: 2021-10-08
肠易激综合征(irritable bowel syndrome, IBS)是一种发病机制尚未完全明确的功能性肠病. 以不规则的腹痛、腹胀、排便习惯和粪便性状改变为主要临床表现. 肠道菌群失调作为IBS的病理机制之一, 在IBS发生发展中扮演着极其重要的角色. 绝大多数的短链脂肪酸(short-chain fatty acids, SCFAs)是由肠道菌群和宿主饮食在结肠相互作用后产生的. 作为肠道菌群的主要代谢产物之一, SCFAs在肠道中发挥着维护肠道屏障功能、免疫调节、抗炎、调节内脏敏感性等作用. 近几年来, 随着人们对于SCFAs关注度的增加, 探讨SCFAs与IBS之间关系的研究越来越多. 本文对近五年来SCFAs与IBS关系的研究进展进行总结.
核心提要: 短链脂肪酸(short-chain fatty acids, SCFAs)是肠道菌群的重要代谢产物之一, 具有维护肠道屏障功能和调节内脏敏感性等功能, 粪便中SCFAs的改变可以反映肠道菌群的变化. 因此, 深入了解SCFAs的来源、影响因素、参与肠易激综合征(irritable bowel syndrome, IBS)的病理生理机制, 有利于将其开发成治疗IBS的靶标.
引文著录: 杭露, 周盐, 孟杨杨, 冯雅, 王殷姝, 袁建业. 短链脂肪酸与肠易激综合征关系的研究进展. 世界华人消化杂志 2021; 29(19): 1102-1109
Revised: July 13, 2021
Accepted: August 25, 2021
Published online: October 8, 2021
Irritable bowel syndrome (IBS) is a functional intestinal disease whose pathogenesis has not yet been fully defined. The main clinical manifestations of IBS are irregular abdominal pain, abdominal distension, and changes in stool character and defecation habits. As one of the pathogeneses of IBS, intestinal flora imbalance plays an important role in the development of IBS. The vast majorities of short chain fatty acids (SCFAs) are produced through the interaction of intestinal flora with host diet in the colon. As one of the main metabolites of intestinal flora, SCFAs have the effects of intestinal barrier protection, immune regulation, anti-inflammation, and regulation of visceral sensitivity in the intestine. In recent years, with the increasing attention to SCFAs, studies on the relationship between SCFAs and IBS are emerging. This review summarizes the progress in the understanding of the relationship between SCFAs and IBS in recent five years.
- Citation: Hang L, Zhou Y, Meng YY, Feng Y, Wang YS, Yuan JY. Progress in understanding of relationship between short chain fatty acids and irritable bowel syndrome. Shijie Huaren Xiaohua Zazhi 2021; 29(19): 1102-1109
- URL: https://www.wjgnet.com/1009-3079/full/v29/i19/1102.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v29.i19.1102
肠易激综合征(irritable bowel syndrome, IBS)是一种以腹痛、腹胀、排便习惯和粪便性状改变为主要临床表现的功能性肠病[1,2]. 因IBS症状往往持续存在和反复发作, 所以严重影响了患者的生活质量[3]. 目前对IBS的诊断主要采取罗马Ⅲ、Ⅳ这两种标准. 一项关于IBS的流行病学调查显示: 按照罗马Ⅲ标准, 该病全球患病率约为9.2%; 而按照罗马Ⅳ标准, 其患病率约为3.8%. 此外, 该病存在明显的年龄和性别差异, 多见于18-30岁的青年人, 男女比为1:1.46左右[4]. IBS大致可以分为: 便秘型(IBS-C)、腹泻型(IBS-D)、混合型(IBS-M)、未分类型(IBS-U)四种亚型[5]. 值得注意的是, 根据罗马Ⅲ标准, IBS-M是最常见的亚型; 而根据罗马Ⅳ标准, IBS-D这一亚型则更常见[4]. 有趣的是, 女性患者易表现为IBS-C, 男性患者更易表现为IBS-D[6].
已有大量研究证实肠道菌群的失调与IBS的发生有关. 短链脂肪酸(short-chain fatty acids, SCFAs)是肠道菌群的重要代谢产物之一, 具有维护肠道屏障功能、对抗炎症反应、调节免疫和调节内脏敏感性等功能. 由此看来, 深入研究探讨SCFAs与IBS的关系有助于明确IBS的发病机制和治疗靶标.
SCFAs主要是由饮食物中可发酵纤维与肠道微生物在结肠内相互作用后产生的, 它们的水平反映了肠道微生物的代谢活性以及结肠的生理状态[7]. 目前发现的SCFAs主要包括甲酸、乙酸、丙酸、异丁酸、丁酸、异戊酸和戊酸. 在结肠中, 乙酸、丙酸和丁酸的含量约占SCFAs总量的90%左右[8].
人体内的肠道菌群主要分为厚壁菌门、拟杆菌门、变形菌门和放线菌门这四大类, 是SCFAs主要来源. 乙酸主要由放线菌门的双歧杆菌和乳酸杆菌生成; 丙酸主要由厚壁菌门的韦荣球菌生成; 丁酸主要由厚壁菌门的普劳氏菌和直肠真杆菌生成[9,10]. 此外, 当体内摄入的可发酵纤维过少时, 一些细菌可以主动选择氨基酸和蛋白质作为发酵底物, 这在一定程度上也促进了SCFAs的生成[11].
除了肠道菌群的变化外, 人体内SCFAs的生成还受到其他多种因素的影响. 包括肠道内pH的改变、饮食物的构成、肠道气体的产生, 宿主自身因素等.
首先, 厚壁菌门和放线菌门对不同pH的耐受程度存在差异, 当pH值较低时, 会引起结肠中丙酸生成的减少、丁酸生成的增加[12]. 其次, 低脂、高纤维饮食下产丁酸的直肠真杆菌明显增多, 进一步引起结肠丁酸生成增加[13]; 低碳水化合物饮食下, 结肠中丁酸生成减少[14]; 饮食中缺铁会同时导致丙酸和丁酸生成的减少[15,16]. 此外, 肠道中的气体(如氢气和氧气等), 在肠道发酵过程中会发生各种化学反应, 也会影响SCFAs的生成[17]. 宿主结肠吸收能力的强弱和转运时间的长短对SCFAs的生成也有一定的影响.
现有的研究主要关注乙酸、丙酸和丁酸在肠道中的作用. 乙酸可以维持肠道内渗透压的稳定, 并对产丁酸细菌发挥一定的保护作用[7]; 丙酸不仅可以促进肠上皮细胞的更新和修复, 还能与丁酸发生协同效应, 共同发挥抗炎作用[18]; 丁酸能为结肠细胞提供约70%的能量, 促进粘蛋白(mucoprotein, MUC)等肠道分泌物的分泌[19], 调节紧密连接蛋白(tight junction protein, TJP)的表达以维持肠上皮屏障功能[19], 调节离子、水和电解质的吸收以维持肠道渗透压的稳定, 降低肠道病原体定植能力并促进氧化应激反应以发挥重要的抗炎作用[20].
SCFAs在肠道中的转运, 主要依靠单羧酸转运蛋白1(monocarboxylate transporter 1, MCT1)和钠偶联的单羧酸转运蛋白1(sodium-coupled monocarboxylate transporter 1, SMCT1). MCT1是一种H+偶联的低亲和力转运蛋白, 在结肠基底外侧膜和结肠上皮顶膜中表达, 发生电性的SCFA-H+共转运, 主要转运乳酸和丙酮酸[21]. 而SMCT1是一种Na+偶联的高亲和力转运蛋白, 仅在结肠上皮顶膜表达, 发生电性的SCFA-2Na+的共转运[7], 优先转运丁酸, 其次是丙酸和乙酸. 转运后, SCFAs可以自由地从结肠上皮细胞流入管腔或从管腔流入细胞.
SCFAs在肠道中发挥作用, 主要涉及两种机制: (1)激活G蛋白偶联受体 (G Protein-Coupled Receptors, GPRs). 在结肠中, SCFAs激活的GPRs主要包括GPR41、GPR43、GPR109A、GPR164和GPR42等. 丁酸可以激活表达于结肠上皮细胞中的GPR41、GPR43、GPR109A和GPR164; 丙酸能激活在结肠和交感神经中表达的GPR41和GPR43; 乙酸只能激活GPR43[7]. SCFAs与其受体特异性结合后, 可能会抑制NOD样受体蛋白3(NOD-like receptor protein 3, NLRP3)炎症小体的表达、诱导调节性T细胞(regulatory cells, Tregs)的分化从而发挥抗炎作用[22], 也可能直接参与胃肠动力的调节[23]; (2)抑制组蛋白脱乙酰基酶 (histone deacetylase, HDAC)[24,25]. SCFAs通过抑制HDAC, 直接影响基因的转录和表达. 一方面, 促进巨噬细胞(Macrophages, mø)等细胞的分泌, Toll样受体(toll-like receptor, TLR)4等受体的表达、白介素(interleukin, IL)-10等抗炎因子的释放; 另一方面, 抑制核因子-κB(nuclear factor-κB, NF-κB)、肿瘤坏死因子(tumor necrosis factor, TNF)、IL-8等细胞因子的表达, 发挥抗炎和维持肠道屏障功能等作用[25].
与健康人相比, IBS-D患者粪便和血清中总SCFAs浓度均升高, 主要表现为丙酸、丁酸含量的增加; 而IBS-C患者总SCFAs浓度降低, 主要表现为丙酸、丁酸含量的减少[26,27]. 最近的一项研究表明, IBS患者体内SCFAs水平存在明显的性别差异, 与女性IBS-D患者相比, 男性IBS-D患者粪便中丙酸含量明显增加[28].
此外, SCFAs水平与IBS患者粪便的黏稠度有关[28]. 以便秘为主要临床表现的IBS-C患者粪便质地偏干, 对应的SCFAs含量也降低; 以腹泻为主要临床表现的IBS-D患者粪便质地偏稀, 对应的SCFAs含量增加[29].
已知的IBS病理生理机制主要包括: 胃肠动力异常、内脏敏感性异常、肠道屏障功能障碍、肠道炎症反应等. 越来越多的研究表明, SCFAs参与IBS的各种病理生理机制.
2.2.1 胃肠动力异常: 研究表明[30], IBS患者的胃肠动力异常可能与结肠平滑肌中L型钙离子通道和5-羟色胺(5-hydroxytryptamine, 5-HT)受体的异常表达有关. 与之相一致的是, 丁酸可以通过直接增加胆碱能神经元的数量引起神经元或平滑肌细胞兴奋性增加或者间接刺激Ca2+内流引起平滑肌中L型钙通道兴奋性的提高[31], 发挥促进胃肠运动的作用. 与之相反地, 丁酸可以抑制胆碱能神经末梢乙酰胆碱受体, 发挥减慢结肠运动的作用[31,32].
此外, 丙酸可以直接激活GPR43[33]引起结肠运动功能的亢进; 丙酸和丁酸可以依赖MCT1和SMCT1的转运进入近段结肠, 引起肠内分泌细胞(enteroendocrine cell, EEC)释放5-HT, 进一步激活迷走神经上的5-HT3和5-HT4受体, 使结肠蠕动反射增强. 相反地, SCFAs还可以介导EEC释放肽YY(PeptideYY, PYY), 使结肠蠕动反射减弱[34].
2.2.2 内脏敏感性异常: 内脏感觉功能异常是IBS一个重要的病理生理学基础, 主要包括肠壁自身、内脏传导、高级中枢调控这三个方面感觉的异常[35].
Zhang等[37]在研究中观察到, 肠道乙酸含量的增加伴随血脑屏障通透性的降低. 据此估计, 乙酸与GPR41或GPR43的特异性结合激活了中枢神经系统的主要免疫细胞-小胶质细胞, 导致内脏高敏感性的发生. 在有些动物实验中, 还会采用结肠内注射丁酸或丁酸盐的方法建立IBS大鼠内脏高敏感性模型[18,38,39]. 一项动物实验发现, 丁酸通过激活大鼠背根神经元(dorsal root neurons, DRG)中的细胞外信号调节激酶(extracellular signal-regulated kinase, ERK) 1/2信号诱导大鼠内脏高敏感性[40]. Chen等[41]、Asano等[18]研究发现丁酸与5-HT2受体在调节内脏敏感性上可能存在相互作用, 丁酸通过增加肠道内5-HT水平, 进一步激活5-HT2受体诱导内脏高敏反应. 此外, Long等[38]研究发现丁酸通过促进神经生长因子(nerve growth factor, NGF)的表达, 诱导了IBS患者的内脏高敏感性.
2.2.3 肠上皮屏障功能障碍: 肠上皮屏障功能的改变也是IBS的病理生理机制之一[42]. 肠上皮屏障由上皮细胞、TJP和肠道分泌物三部分组成. SCFAs对肠道上皮细胞的调节通过识别TLRs、激活GPRs以及抑制HDAC这三个途径[43]. 低浓度的SCFAs可以促进肠道上皮细胞增殖; 高浓度的SCFAs诱导上皮细胞的调亡[44].
丙酸作为上皮细胞更新的重要调节因子, 可以通过抑制HDAC、激活GPR43和转录激活因子(signal transduction and activator of transcription, STAT)3促进上皮细胞的增殖, 维护肠上皮的稳定[44]. Xia等[45]的研究进一步发现, 丙酸可以通过促进结肠ERK1/2和P38MAPK信号(被认为是GPRs的下游信号)传导, 增加闭锁连接蛋白(zonula occludens, ZO)-1、Claudin8和Occludin的生成, 发挥维护肠上皮屏障功能的作用.
此外, 丁酸钠可以通过与GPR109A结合促进蛋白激酶B(protein kinase B, PKB)信号通路的传导, 使Claudin-3在结肠中的表达增加[46]; 丁酸可以通过抑制HDAC, 诱导肌动蛋白结合蛋白-突触足蛋白(synaptopod protein, SYNPO)和肌动蛋白4(actin4, ACTN4)的表达或者抑制外周促肾上腺皮质激素释放因子(corticotropin-releasing factor, CRF)受体和TLR4等特定信号分子的表达, 使TJP的合成增加, 共同发挥发挥维持肠上皮屏障完整的功能[47]. 近来, Blaak等[21]研究发现丁酸可以通过合成前列腺素E1促进MUC2基因的表达, 使MUC2分泌增加.
2.2.4 肠道炎症反应: 由应激、感染等引起的肠道通透性增加, 最终会导致肠道炎症反应的发生[48,49]. Chen等[50]研究发现应激诱导的IBS模型小鼠肠道炎症反应加剧伴随着粪便中SCFAs含量增加, 表明SCFAs与肠道炎症反应有关.
SCFAs除了作为底物直接诱导炎症反应外, 还可以通过抑制Tregs分化降低IL-10的表达[35], 通过刺激树突状细胞分化增强IL-23的表达[36], 导致肠道炎症反应的增加.
与之相反地, 也有研究[24,51,52]发现丙酸和丁酸可以直接诱导T细胞的分化, 以提高IL-10等抗炎细胞因子的表达, 发挥抗炎作用. 丁酸发挥抗炎作用也可能与过氧化物酶体增殖物激活受体(peroxisome proliferators-activated receptors, PPARs)的激活有关, 因为PPARs可以降低结肠细胞通透性[52,53]. 除了PPARs, 丁酸还可以通过抑制NF-κB和IFN-γ等信号发挥抗炎作用[54].
3.1.1 益生菌: 研究发现, 益生菌可以定植在宿主体内, 促进结肠中其共生体的生长和代谢, 特别是增加丁酸的产生, 调节肠道菌群的生态平衡[55]. 目前临床上使用的益生菌主要是乳酸菌和双歧杆菌.
Markowiak-Kopeć等[56]研究发现IBS患者乳酸菌定植会引起结肠中以丁酸为主的SCFAs增加; Moens等[57]研究发现服用帕拉凯西乳酸菌CNCMI-1572后, IBS患者肠道中乙酸和丁酸的生成增加, 与此同时, IL-15等促炎细胞因子显著减少. Cremon等[58]发现双歧杆菌可以利用母乳低聚糖(human milk oligosaccharides, HMOs)中衍生的岩藻糖促进母乳喂养婴儿体内甲酸的生成. 此外, 双歧杆菌也可以提高结肠丁酸的水平[11]. 最新的研究发现, 鸡白痢酪球菌作为一种产丁酸的益生菌可以促进IBS患者结肠丁酸的生成, 发挥抗炎、维持肠上皮屏障等作用, 却不会破坏肠道中正常微生群的结构和代谢活性[59]. 冯超等[60]在对丁酸梭菌的研究中也观察到丁酸梭菌可以提高肠道中丁酸含量, 降低肠道通透性, 从而改善IBS患者临床症状.
由此看来, 乳酸菌和双歧杆菌等益生菌可以通过提高肠道中甲酸、乙酸、丁酸等的水平, 发挥一定的抗炎作用, 从而减轻IBS患者的腹痛症状.
3.1.2 益生元: 益生元是指一类不能被宿主消化吸收, 却能被体内诸如双歧杆菌、乳酸菌等有益菌选择性利用, 促进宿主健康的一类物质的总称[61].
Araújo等[62]研究发现山羊乳清可以改善高浓度乙酸引起的肠道损伤症状. 最近, Oliver等[63]发现了一种具有很高发酵能力的新型葡萄衍生益生元Previpect, 它可以在一定程度上促进IBS患者结肠丁酸的生成, 有助于肠道菌群恢复, 从而改善IBS患者腹痛症状.
3.1.3 抗抑郁药: Asano等[18]研究发现盐酸氯丙嗪能够抑制丁酸诱导的肠道5-HT合成增加和5-HT2受体激活, 从而改善IBS大鼠的内脏过敏.
3.1.4 低可发酵型碳水化合物饮食: 低可发酵型碳水化合物饮食(low fermentable carbohydrate diet, LFD) , 即以低发酵的寡糖、二糖、单糖和多元醇等一类不易消化的碳水化合物为主的饮食方式. 研究发现LFD 3周后, IBS患者粪便中普拉氏梭杆菌(丁酸的主要生产菌)和丁酸生成显著减少[13,64], IBS患者腹痛症状得到明显改善. 此外, Hustoft等[65]发现LFD后, IBS患者粪便中总SCFAs水平和丁酸水平明显降低, 促炎细胞因子IL-6和IL-8表达减少, IBS患者腹痛、腹胀等症状被有效缓解. 有趣的是, Valeur等[66]的研究除了观察到LFD可以引起IBS患者粪便中乙酸和丁酸水平降低外, 还观察到放置24 h后的粪便中异丁酸和异戊酸生成增加, 提示LFD可以引起肠道微生物对蛋白质水解发酵的增加. Yan等[67]研究发现在LFD中添加一种特定的纤维固定剂可以促进肠道内微生物发酵, 引起以丁酸为主的SCFAs增加, 有效缓解IBS患者腹痛、腹胀症状. 此外, 添加了这种特定纤维固定剂的LFD还可以通过脑-肠轴途径降低血脑屏障通透性改善IBS患者的睡眠质量.
3.1.5 粪菌移植: El-Salhy等[68]研究发现粪菌移植(fecal microbiota transplantation, FMT)会引起IBS患者粪便中SCFAs水平的变化, 变化的程度与FMT剂量及IBS亚型密切相关. FMT后, IBS患者肠道中丁酸的水平与腹痛、腹泻等症状的改善呈负相关[69]. 此外, Chen等[70]研究也发现供体粪便中肠道菌群的丰度、丁酸的水平与FMT的疗效显著相关.
有意思的是, 一项研究发现IBS患者FMT一年后, 粪便中异丁酸和异戊酸水平显著性升高, 进一步证明了微生物可以自发地从糖酵解模式转变为蛋白水解模式[71].
3.2.1 中药相关治疗: Zhang等[37]发现中药黄连的活性成分黄连素能够提高肠中乙酸、丙酸及总SCFAs的生成, 使IBS大鼠内脏敏感性降低, 同时, 还激活了参与脑-肠轴活动的腰脊髓背面肥大细胞和小胶质细胞. 在另一项研究中, 刘世锋等[72]采用体外模拟系统模拟人体肠道微生态, 发现黄芩提取物可以促进肠发酵罐中丁酸的生成并发挥抗炎作用. 此外, 黄芩提取物还通过抑制异戊酸的合成, 上调α-氨-3-羟基-5-甲基-4-异恶唑丙酸(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, AMPA)受体的表达, 发挥抗抑郁作用. 花海莹等[73]研究发现生脉散能显著提高肠道菌群失衡模型SCFAs的含量, 降低肠道内的pH, 有效抑制有害菌的增殖.
3.2.2 针灸治疗: Chen等[74]研究发现"调神健脾"针法可以减少肠道中SCFAs的生成, 从而有效改善IBS-D患者腹痛和腹泻症状.
SCFAs主要是宿主饮食物中可发酵纤维与肠道菌群在结肠内相互作用后的代谢产物, 粪便中SCFAs的改变在一定程度上反映了肠道菌群的变化.
深入了解SCFAs的来源、影响因素、参与IBS的病理生理机制, 有利于将SCFAs开发成治疗IBS的靶标. 首先, 在使用益生菌治疗IBS患者时, 可以利用各亚型IBS患者体内SCFAs水平不同这一特点, 有针对性的补充缺少的SCFAs或者补充可以产生该种SCFAs的肠道菌群, 使IBS患者肠道内SCFAs水平趋于稳定和平衡, 从而有助于肠道功能的恢复. 其次, 不同类型和来源的膳食纤维在胃肠道发挥不同的生理作用. 与不溶性纤维相比, 可溶性纤维通过缓慢发酵可以更好地将SCFAs输送到远端结肠. LFD虽然可以改善IBS患者腹痛、腹胀等症状, 但是大量的纤维摄入意味着肠道气体产生的增加, 这可能导致更严重的腹胀. 因而, 对LFD的定义和标准的进一步细化和规范, 对临床应用其改善IBS患者症状有很重要的意义. 此外, 人体内铁浓度在很大程度上影响肠道微生物群的组成和活性, 缺铁或者摄入铁过多都会造成不良影响, 我们需要通过进一步研究, 寻找人体内铁浓度的最佳范围, 为IBS患者肠道功能的恢复提供帮助. 目前对于FMT的研究仍停留在只关注肠道菌群本身的层面, 关注SCFAs并将其作为靶标进行FMT的研究很少. 而且, 现有的研究也只是发现FMT可以通过引起丁酸含量变化在一定程度上改善IBS患者的腹痛和腹泻症状.
毋庸置疑, SCFAs在治疗IBS上有很大的潜力. 但目前对于SCFAs的研究还有待深入, 已有的关于SCFAs参与IBS的研究主要集中在乙酸、丙酸和丁酸上, 至于其它SCFAs, 如异丁酸、异戊酸和戊酸等是否参与IBS的病理生理机制, 具体发挥那些作用、如何发挥作用以及在哪些部位发挥作用等问题, 我们尚不清楚. 此外, 我们对某一特定SCFAs参与IBS的详细机制了解的还不够深入, 导致我们无法从这一角度对IBS患者进行针对性的治疗. 因而, 我们需要进一步明确总SCFAs和具体的SCFAs与IBS、IBS亚型的关系, 需要明确它的"多"与"少"和IBS症状的关系或者是否存在一定的线性关系. 大体说来, SCFAs参与IBS的病理生理机制, 主要涉及GPRs的激活和HDAC抑制这两条途径. 值得肯定地是, 诸如ERK1/2和p38MAPK等GRRS下游信号以及PPARs, SYNPO, MUC2基因和ACTN4等与SCFAs相关的细胞信号分子的发现, 可以启发我们进一步研究其它与GPRs激活和HDAC抑制有关的信号通路和信号分子, 探究它们与IBS患者腹痛、腹泻和腹胀等症状的相关性.
此外, 我们还可以考虑从SCFAs中寻找潜在的诊断IBS、区分IBS亚型的特异性标志物, 使IBS的诊断更加精确和快速. 但是具体哪些SCFAs可以作为标志物, 还需要利用质谱分析仪、高效液相色谱仪等现代化的仪器设备, 对大规模的IBS患者粪便、尿液和血清等生物样本中各种SCFAs进行分析, 并将它们的变化与IBS患者特定的症状做相关性分析.
学科分类: 胃肠病学和肝病学
手稿来源地: 上海市
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科学编辑:张砚梁 制作编辑:张砚梁
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