修回日期: 2022-09-26
接受日期: 2022-10-24
在线出版日期: 2022-11-28
人体的肠道菌群复杂多样, 众多肠道菌群之间形成了结构及组成复杂的肠道微生态系统. 研究表明, 肠道微生态系统失衡与肝衰竭的发生、发展密切相关, 且肠道微生态失衡程度与肝衰竭严重程度有显著相关性. 因此, 肠道微生态调节在肝衰竭的治疗及改善预后中的重要作用日益凸显. 但由于肠道菌群组成及结构的复杂性及其参与肝衰竭发生发展的作用机制尚未十分明确, 使其在临床的规范应用受到一定限制, 本文就肠道菌群与肝衰竭微生态调节治疗的研究进展进行综述.
核心提要: 肠道微生态制剂可从多方面改善肝衰竭, 因此, 在肝衰竭的治疗方面具有巨大潜力.
引文著录: 陈月桥, 刘家玲. 肠道菌群与肝衰竭微生态调节治疗的研究进展. 世界华人消化杂志 2022; 30(22): 971-977
Revised: September 26, 2022
Accepted: October 24, 2022
Published online: November 28, 2022
The intestinal flora of the human body is complex and diverse, and the structure and composition of the intestinal micro-ecosystem formed by the intestinal flora are complicated. Studies have shown that the imbalance of the intestinal micro-ecosystem is closely related to the occurrence and development of liver failure, and the degree of intestinal microecological imbalance is significantly correlated with the severity of liver failure. Therefore, the role of intestinal microbiome regulation in the treatment of liver failure and the improvement of prognosis has increasingly attracting the attention of scholars. However, due to the complexity of the composition and structure of the intestinal flora and its mechanism of action involved in the development of liver failure, the application of intestinal microbiome regulation in the clinic is limited to a certain extent. In this paper, we review the research progress of microbiome regulation as a therapy for liver failure.
- Citation: Chen YQ, Liu JL. Advances in research of microbiome regulation as a therapy for liver failure. Shijie Huaren Xiaohua Zazhi 2022; 30(22): 971-977
- URL: https://www.wjgnet.com/1009-3079/full/v30/i22/971.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v30.i22.971
肝衰竭(liver failure, LF)是各种损伤因素多重打击下使肝脏合成、代谢、解毒功能障碍所致的危重症候群. 肝肠轴理论的出现表明肝肠之间存在着紧密的生理病理关系, 肠道菌群数量庞大, 结构复杂, 众多菌群之间形成肠道微生态系统, 通过肝肠轴对肝衰竭的发生发展产生显著影响. 越来越多研究表明[1,2], 肠道微生态失衡程度与肝衰竭严重程度有显著相关性, 因此, 微生态调节治疗或可成为肝衰竭患者极具潜力的治疗方法.
人体肠道菌群多样, 总量在400-1500之间变化[3], 不同菌门、纲、目、科、属的肠道微生物之间形成了结构及组成复杂的肠道微生态系统, 其中, 包括以双歧杆菌、乳酸杆菌、枯草杆菌、地衣芽孢菌为主的有益菌和肠球菌、肠杆菌、大肠埃希菌等中间菌及铜绿假单胞菌、艰难梭菌等有害菌. 正常情况下, 肠道微生态系统随着年龄、饮食、生活环境等因素的变化而变化[1,4], 各菌群之间及菌群与宿主之间维持动态平衡, 发挥营养、代谢、免疫、屏障保护等作用. 但在各种疾病及致病因素作用下, 肠道菌群的稳态被打破, 正常菌群也可转变成致病因素, 通过各种机制作用于人体, 导致各类疾病的发生. 基于肠道微生态系统, 肝肠轴、肠心轴、肠肺轴、肠脑轴及肝-肠-脑轴、肠-肾-脑轴等概念的提出, 表明了肠道微生态系统与机体器官的密切关系.
肝脏与大肠通过门静脉系统及肠系膜上下静脉形成解剖及生理联系. 传统医学即有"心与胆相通, 肝与大肠相通"、"肝寄腑于大肠"的记载, 这与现代医学"肝-肠轴"概念相吻合. 肠道微生态紊乱时, 各种病原体、毒性物质等致病因素对肝功能造成直接损伤, 在肝细胞损伤基础上, 由肠道微生态紊乱产生过度持久的内毒素血症/炎症反应、微循环障碍使免疫细胞激活及细胞因子大量释放导致免疫平衡紊乱及炎症反应造成肝脏的"二次打击", 加剧了肝细胞的凋亡、自噬、坏死. 可见"免疫失衡""炎症打击"作为核心机制贯穿肝衰竭发生、发展的全过程. 肝衰竭患者肝功能严重受损, 使肠蠕动减弱、肠上皮细胞破坏, 肠道屏障受损、肝固有免疫功能减弱等, 导致肠道菌群组成及结构改变, 肠道微生态系统失衡; 而微生态系统失衡可通过内毒素及有毒代谢产物增加、细菌易位等产生"瀑布样效应", 促进了病原体相关分子模式(pathogen-associated molecular patterns, PAMPs)和天然免疫系统的激活, 造成"炎症二次打击"加剧肝损伤及内环境紊乱, 进一步影响肝衰竭进程. 因此, 肠道微生态失衡与肝衰竭之间互为因果, 且相互影响, 恶性循环, 从而加快疾病进程. 肝衰竭患者肠道微生态失衡主要表现为有益菌减少, 有害菌过度生长及条件致病菌转为致病菌, 加快疾病进展. 多个研究表明[2,5], 肠道微生态失衡程度与肝衰竭严重程度有显著相关. 在一项前瞻性研究显示, 肝衰竭的发展及死亡率与肠道菌群组成有关, 预后较差患者的变形杆菌普遍较高[6]; 另有研究表明[6-8], 链球菌科、肠球菌科等致病菌分类的增加与肝衰竭患者死亡率高度相关, 巴氏杆菌科增加是慢加急性肝衰竭患者短期内死亡的重要危险因素.
肠道通过肠黏膜上皮屏障、免疫屏障、生物屏障保护机体免受有害微生物及病原体侵害, 其中, 肠粘膜上皮屏障是最重要的一道屏障. 肠道内有益菌可诱导杯状细胞分泌Occludin、Claudins、ZO1、MUC2等紧密连接蛋白(tight junction proteins, TJPs)与肠上皮细胞紧密连接, 构成了肠黏膜上皮屏障; 同时, TJPs为有益菌提供生态位点, 协助有益菌在肠道黏附定植, 形成"肠道定植抗力", 发挥生物屏障作用[9,10]; 有益菌还可通过分泌融菌酶C、C型凝集素、磷脂酶等抗菌肽, 抑制有害菌过度生长、提高肠上皮再生能力、调节免疫功能、为肠上皮供能、分泌粘液素等维持肠道稳态及肠道屏障的完整性[11]. 肝衰竭时, 有益菌减少, 肠杆菌及大肠埃希菌等致病菌过度生长, 不仅改变肠道菌群的组成及结构, 还可通过干扰肠粘膜生化反应, 干扰密连接蛋白的合成, 损害肠上皮细胞等改变肠道通透性, 导致肠道屏障破坏[11,12].
胃肠道可容纳体内70%淋巴细胞群, 被认为是体内最大的免疫器官[13], 在调节体内免疫稳态方面发挥其核心作用. 肠道免疫由IEC、淋巴细胞、肠道浆细胞分泌型免疫球蛋白A(secretory immunoglobulin A, SIgA)等构成, SIgA等与肠道内革兰氏阴性菌结合形成抗原抗体复合物, 不仅能阻止有害菌与肠粘膜粘附, 还可中和已潜入细胞内的病毒. 研究发现[14,15], 肠道菌群的适当定植, 可刺激模式识别受体在肠粘膜上皮细胞或免疫细胞上的表达, 诱导肠粘膜相关淋巴组织成熟. 如果良好的肠道菌群环境在生命早期未完全构建, 则会导致肠粘膜相关淋巴组织发育不全, 免疫细胞和细胞因子数量减少, 模式识别受体表达下调. 另外, 在一项无菌小鼠中进行的实验表明[16,17], 由于肠道菌群的缺失, 导致小鼠功能性CD4、CD25及Tregs降低, 免疫细胞数量减少及淋巴结缩小等免疫发育不全、抗菌能力减弱表现, 这都表明肠道菌群在免疫系统的发育及免疫功能的正常发挥中起重要作用. 上皮层的固有层含有树突状细胞, 这是重要的抗原呈递细胞, 可调节体液和细胞肠道免疫[18]. 肠道中的乳酸杆菌可刺激树突状细胞启动免疫应答, 防治细菌移位, 减低内毒素及肿瘤坏死因子-α(tumour necrosis factor α, TNF-α)水平, 从而调节免疫. 可见, 肠道菌群在免疫功能的发育及完善, 免疫功能的正常发挥方面都起着重要作用.
肝功能的受损是由病原体及毒性物质直接损害及免疫平衡失衡、炎症反应造成肝脏的"二次打击"引起的. 肠道微生态失衡导致"肠道定植抗力"下降, 肠粘膜通透性增加, 物理及生物屏障遭到破坏, 过度生长的肠球菌及酵母菌等有害菌的过度生长、肠黏膜通透性增加及肠道免疫功能受损等因素可导致病原体、毒性代谢产于通过门静脉进入肝脏, 导致肝脏直接损害[19]. 革兰氏阴性菌细胞壁上的脂多糖(lipopolysaccharides, LPS)可与模式识别受体Toll样受体4(toll-like receptor 4, TLR4)结合, LPS-TLR轴使巨噬细胞过度活化, 导致就巨噬细胞对LPS易感性增加, 持续的炎症反应促进了PAMPs释放并刺激细胞内信号级联反应导致肝脏"炎症二次打击"; 反过来, 巨噬细胞还可通过激活核苷酸结合寡聚化结构域样受体蛋白3(NOD-like receptor protein 3, NLRP3)来增加肠道通透性, 加剧了内毒素血症, 形成恶性循环, 最终导致肝功能的急剧恶化, 最终走向衰竭. 肠道内有益菌可通过调节免疫改善肝功能. 研究发现[20,21], 乳酸菌和双歧杆菌可减轻TLR4炎症瀑布反应, 氧化应激和内毒素血症. Granisetron可通过拮抗5-羟基色胺3抑制LPS后巨噬细胞释放促炎因子, 缓解脓毒症诱导的小鼠肝损伤.
肠道菌群通过维持肠道屏障稳定性、调节胆汁酸分泌与代谢、调节肠道pH值等达到抑菌作用. 如前文所述, 肠道菌群可通过各种途径维持肠道屏障的稳定性抑制致病菌的过度生长及侵害肠外机体. 肠道菌群不仅可以调节胆汁酸的分泌与代谢, 还可与胆汁酸合成的法尼醇衍生物X受体(farnesoid X receptor, FXR)促进血管生成素1(angiopoietin 1, ANG1)及RNAse家族成员4(RNase A family 4, RNASE4)等抗菌肽生成, 保护机体不受有害菌的侵害, 此外, 胆汁酸的分泌与代谢与肠道PH值相关, 通过维持肠道酸性环境抑制细菌过度生长.
肠道营养是肝脏营养代谢的主要来源, 对肝脏储备和再生能力起着重要作用. 肠道中99%-99.9%为厌氧菌, 需氧菌仅占0.1%-1%, 肠道菌群的平衡除了能使葡萄糖在肠道中充分吸收外, 还能合成维生素K及大部分水溶性B族维生素, 为机体提供能量及必要维生素, 此外, 食物在消化道通过棘皮动物门厌氧发酵产生乙酸、丙酸、丁酸等短链脂肪酸(short-chain fatty acids, SCFAs)是肠上皮细胞及肠道微生物的主要能量来源[22,23]. 研究发现[24-28], 肠道菌群失衡可导致棘皮动物科和苜蓿科等产生SCFAs微生物减少, SCFAs生成不足, 影响肠道供能, 肠道调节或可为肝衰竭患者营养支持治疗提供新思路.
肠道菌群可通过增加肠道SCFAs的产生、调节肠道微生物群及其代谢产物、调节胆汁酸代谢等途径调节脂质代谢. 研究表明[29], 肥胖小鼠较无菌小鼠肠道内SCFAs显著增加, 这可能与SCFAs可导致脂肪堆积有关. 此外, 在构建高脂肪/高胆固醇小鼠模型中, 小鼠肠道粘螺旋体, 脱硫弧菌和脱硫弧菌科依次增加, 而双歧杆菌和拟杆菌减少, 肠道细菌代谢物牛磺胆酸[(taurocholate acid, TCA), 可抑制胆固醇诱导的脂质堆积及细胞增殖]减少, 3-吲哚丙酸[(indole-3-propionic acid, IPA), 可加重胆固醇诱导的甘油三脂堆积]增加, 导致肝脏炎症及脂肪变性, 驱动非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)形成, 这种微生物及其代谢产物改变情况与高胆固醇血症患者肠道微生物改变相一致[30], 表明膳食胆固醇通过调节肠道微生物群及其代谢物在驱动NAFLD发生及发展. 另外, 肠道菌群可通过调节胆汁酸代谢, 影响FXR和G蛋白偶联胆汁酸受体(takeda G-protein-coupled receptor 5, TGR5)等受体激活, 影响脂类吸收代谢, 而研究表明[31,32], 这些受体的激活可特异性地降低了单不饱和脂肪酸(monounsaturated fatty acid, MUFA)和多不饱和脂肪酸(polyunsaturated fatty acid, PUFA)的肝脏水平.
研究表明[33], 肠道菌群失衡与脂肪肝、肝纤维化、肝硬化、肝性脑病、肝衰竭等肝脏疾病密切相关. 因而肠道微生态制剂在肝脏病的应用中具有广大的前景. 肠道微生态制剂主要包括益生菌、益生元、合生元、抗菌素、粪便移植(fecal microbiota transplantation, FMT)等.
益生菌是使用一定剂量后能对机体健康带来益处的活的微生物制剂[34-36], 主要包括乳杆菌属、双歧杆菌属、肠球菌属、芽孢杆菌属等七个菌属为主的上百个菌种[37], 益生菌可通过产生抗菌物质拮抗细菌生长、与病原体竞争黏膜上皮黏附和营养, 调节免疫及抑制毒素生长等途径改善宿主健康[38,39]. 邓桃枝等人[12,40]使用双歧杆菌三联活菌治疗肝衰竭患者的临床观察研究显示, 治疗组口服益生菌后, 双歧杆菌、肠球菌、乳杆菌等肠道内优势菌群较对照组明显增加, 且治疗组TBIL、PT等肝功能生化指标较前改善, 血浆内毒素及白介素-1(interleukin-1, IL-1)、白介素-6(interleukin- 6, IL-6)、TNFα等细胞因子水平下降, CD4+百分率、CD4+/CD8+值显著上升. 可见, 益生菌可通过调节肠道菌群结构及免疫功能, 减轻内毒素血症及过度炎症反应延缓肝衰竭进展. 此外, 张月晓等人[41,42]使用地衣芽孢杆菌活菌胶囊及酪酸梭菌活菌片等治疗肝衰竭也能不同程度的改善肠道菌群失调, 减轻内毒素血症, 改善肝功能. 虽然益生菌的使用对肝衰竭患者的治疗有一定作用, 但在使用过程中, 益生菌菌株的选择、剂量与疗程、益生菌的安全性及功能性问题目前尚未有统一标准, 长期使用益生菌的疗效及安全性尚缺乏证据支持.
益生元是一种不可存活的食物成分, 可通过刺激肠道内微生物的生长及活性从而改变肠道微生物活性及构成, 达到改善宿主健康的目的[36,37]. 益生元主要为营养结肠的有益菌群提供碳水化合物, 可作为益生菌的替代产品或作为益生菌的额外支持; 包括乳果糖、低聚半乳糖、低聚果糖等低聚糖类, 种类多达数百种, 其中, 菊粉、低聚果糖等果聚糖最常用有效. 研究发现[43], 乳果糖可抑制细菌发酵从而诱导内源性氢产生达到抑制氧化应激及炎症, 促进肝细胞再生及功能恢复作用. 一项肝衰竭神经炎症作用机制的研究显示[44], 乳果糖可通过调节肠道菌群, 抑制全身炎症反应及小胶质细胞的活化, 降低脑内氨水平达到抑制肝衰竭肝性脑病患者神经炎症反应, 改善认知功能.
合生元是益生菌及益生元结合的复合制剂, 既可发挥益生菌的生理性细菌活性, 又可选择性的增加这种细菌的数量使益生菌作用更持久. 因此, 合理选择适合的益生菌及益生元组合是发挥联合作用的关键. 目前, 以双歧杆菌和乳酸杆菌属益生菌与低聚果糖组合的合生元最为常用. 一项益生菌和益生元对急性肝损伤有效性的荟萃分析显示[45], 使用益生元及益生菌后, 回肠末端肠球菌等有害菌丰度减少, 内毒素水平降低, 紧密连接蛋白表达增加, 这表明益生菌和益生元的使用对肠道屏障的增强及内环境的稳态有改善作用. 研究发现[46], 补充干酪乳杆菌、双歧杆菌及嗜酸乳杆菌等益生菌联合低聚果糖组合的益生元后, 可抑制核因子κB(nuclear factor kappa-B, NF-κB)并减少TNF-α的产生, 可见, 合生元的正确选择可减轻肝脏炎症反应及内毒素血症, 改善肝功能. 合生元产品同时具备益生菌及益生元的特性, 既克服了益生菌在肠道内难以存活问题, 还可更大限度发挥益生元作用. 但在肝衰竭患者中由于肠道菌群的个体差异及合生元种类的多样性, 如何正确选择合适的合生元产品精准及个体化治疗仍然是一大难题.
抗生素能够清除肠道致病菌、抑制细菌移位、减少促炎细胞因子和内毒素释放. 由于肝衰竭患者肠道微生态系统紊乱, 细菌易位及免疫功能紊乱等原因, 导致肝衰竭患者自发性腹膜炎、胆道感染, 肺部感染等感染几率增加, 与肝衰竭严重程度成正相关, 并直接影响肝衰竭患者的预后[47]. 因此, 合理的抗感染方案在肝衰竭患者中显得尤为重要. 在一项抗生素预处理的肝移植小鼠实验中发现[48], 抗生素预处理的小鼠, 通过改变肠道微生物群, 增加肠道衍生物前列腺素E2(prostaglandin E2, PGE2)水平(一种肝细胞保护因子), 并降低内质网(endoplasmic reticulum, ER)应激相关蛋白CHOP蛋白的水平, 降低ER应激, 从而减少移植后肝细胞死亡, 重建缺血再灌注损伤, 减轻肝损伤, 这与抗生素预处理肝衰竭肝移植患者的结果一致[49-51]. 虽然抗生素的使用对于肝衰竭患者细菌感染及肝移植方面有一定益处, 但是, 其广泛的副作用和细菌耐药性, 以及在杀灭病菌的同时, 也会杀灭有益菌, 使肠道菌群结构更加紊乱等问题, 需要我们严格把握适应症及禁忌症, 对抗生素种类的选择、剂量、疗程等制定合理方案, 并通过联合益生菌、益生元、粪便移植等适当补充肠道微生物, 维护肠道微生态平衡, 避免恶性循环.
FMT是指将健康人粪便中的菌群移植到患者肠道内, 从而达到改善肠道微生态平衡. 由于不同疾病的FMT治疗方案差异巨大, 为提高移植成功率, 捐赠者需经过严格的供体筛查. 粪便移植可经过内窥镜、胶囊、结肠镜、灌肠等方式输送到肠道内. 在一项通过四氯化碳构建急性肝衰竭(acute hepatic failure, ALF)大鼠模型研究中[52], 经过FMT治疗, ALF大鼠白介素1β(interleukin-1β, IL-1β), TNF-α, Toll样受体9(toll-like receptor 9, TLR9)等炎症介质及谷丙转氨酶、谷草转氨酶、总胆红素、直接胆红素、碱性磷酸酶等指标下降, 且肠道通透性及血氨水平下降. 另外一项关于酒精相关性急性肝衰竭患者FMT疗效对比显示[53,54], 治疗组的短期及中期生存率明显高于对照组, 且治疗组炎症指标较前下降. 可见, FMT可通过改善肠黏膜通透性, 降低炎症反应及血氨水平来减轻肝损伤, 改善预后.
肠道菌群在肝衰竭的发生发展中起着重要作用, 但由于肠道菌群结构极易受饮食、生活环境、疾病等因素的影响以及肠道微生态制剂的多样性等, 使得微生态制剂种类、剂量、剂型的正确选择及个体化治疗方案的制定带来一定难度. 现在越来越多研究者致力于研究肠道微生物的组成及其在人类健康和疾病中的作用, 旨在建立健康的肠道微生物群, 但肠道微生物组成、结构及其对疾病作用机制的极其复杂, 至今尚未能对健康的肠道微生物群有比较准确的定义. 有赖于多学科、多机制的综合研究.
基于肠道与肝脏之间解剖和生理的紧密关系, 肠道菌群可通过稳定肠道屏障、调节免疫、改善肝功能、抑制有害菌过度生长、营养及调节脂质代谢等对肝衰竭的发生发展起重要作用. 肠道微生态制剂在肝衰竭的治疗方面具有巨大潜力, 随着肠道菌群及其参与肝衰竭发生发展的作用机制、肠道微生态治疗研究的不断深入, 肠道微生态调节治疗或可成为肝衰竭治疗的一种很有前景的疗法.
学科分类: 胃肠病学和肝病学
手稿来源地: 广西壮族自治区
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科学编辑:张砚梁 制作编辑:张砚梁
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