短链脂肪酸在肝性脑病中的免疫调节作用及潜在诊疗价值

Immunomodulatory effect of short-chain fatty acids in hepatic encephalopathy and its potential diagnostic value

摘要

肝性脑病（HE）作为临床常见的严重肝病终末期并发症，其有效救治率亟需提升，发病机制亟待攻克。肝脏是重要的免疫调节中心，免疫稳态失衡在HE的病理机制中占主导地位。短链脂肪酸（SCFA）作为肠道菌群的主要代谢物之一，在先天性免疫和适应性免疫的生物学过程中扮演着重要角色，能够调控免疫细胞的增殖分化、维持肠道微环境稳态和屏障功能完整性。研究表明，SCFA通过免疫调节途径与肝-肠-脑轴进行双向、动态的交互反应和信号传递，在HE的诊疗和预后评估方面具有不可忽视的作用。基于此，本文以SCFA的免疫调节效应为切入点，就SCFA与肝-肠-脑轴的串扰关系，以及SCFA在HE诊疗中的重要意义进行归纳和探讨，以期为优化HE临床防治方案提供新的思路。

Abstract

Hepatic encephalopathy （HE） is a common complication of severe liver disease in the end stage， and it is urgently needed to improve the rate of effective treatment and clarify the pathogenesis of HE. The liver is a crucial hub for immune regulation， and disruption of immune homeostasis is a key factor in the pathological mechanisms of HE. As the main metabolites of intestinal flora， short-chain fatty acids （SCFAs） play a vital role in the biological processes of both innate and adaptive immunity and can regulate the proliferation and differentiation of immune cells maintain the homeostasis of intestinal microenvironment and the integrity of barrier function. Studies have shown that SCFAs participate in bidirectional and dynamic interactions with the liver-gut-brain axis through immunomodulatory pathways， thereby playing an important role in the diagnosis， treatment， and prognostic evaluation of HE. Starting from the immunoregulatory effect of SCFAs， this article summarizes and analyzes the crosstalk relationship between SCFAs and the liver-gut-brain axis and the significance of SCFAs in the diagnosis and treatment of HE， in order to provide new ideas for optimizing clinical prevention and treatment strategies.

Graphical abstract

关键词

肝性脑病 / 脂肪酸类， 挥发性 / 免疫调节 / 胃肠道微生物组

Key words

Hepatic Encephalopathy / Fatty Acids， Volatile / Immunomodulation / Gastrointestinal Microbiome

肝性脑病（hepatic encephalopathy，HE）是严重肝病常见的、以代谢紊乱为基础的致死性并发症，临床表现可从轻微认知障碍到明显的定向力障碍、行为异常，甚至昏迷，给患者生活质量和社会医疗经济带来了沉重的负担^［1］。HE的临床救治颇为棘手，尽管抗生素、代谢性氨清除剂、菌群移植等防治手段不断迭代更新，但流行病学研究显示，仍有30%～40%的肝病患者并发HE^［2］，且一旦出现HE，患者的1年生存率仅为48.3%，中位生存期仅为0.92年^［3］。HE的发生发展是一个复杂的级联反应，目前对HE发病机制的研究聚焦于肝-肠-脑轴的双向、动态信号传递。其中，肠道菌群代谢物短链脂肪酸（short-chain fatty acid，SCFA）既是肝细胞、结肠上皮细胞的主要能量底物，又可参与中枢神经系统功能调节，在肝-肠-脑轴中发挥关键的中介作用^［4］。本文以SCFA的免疫调节作用为切入点，重点论述SCFA与肝-肠-脑轴的交互关系，以及SCFA的免疫调节作用在HE中的潜在价值，以期为防治HE提供新的角度和依据。

1 SCFA的生成及其功能

肠道菌群由细菌、真菌、病毒和古细菌等大量微生物组成，是人体内数量最多、种类最丰富的微生物组，被誉为“人类第二基因组”。SCFA是肠道菌群的重要代谢物之一，主要通过分解难以消化的膳食纤维而生成。肠道中SCFA主要包括乙酸盐、丙酸盐和丁酸盐，正常人体内三者的含量比例约为3∶1∶1，共占肠道内SCFA总量的95%以上^［5］。肠道菌群代谢具有显著的菌株特异性，乙酸盐和丙酸盐主要由肠道中的拟杆菌门代谢产生，而丁酸盐的生成与厚壁菌门的菌株代谢密切相关^［6］。SCFA的产生及其与肠道菌群代谢之间的相互串扰是一个复杂的调控过程，肠道菌群的结构和功能失调可直接改变肠道内SCFA的代谢水平，继而影响机体能量代谢和免疫功能调节。

SCFA经结肠上皮细胞吸收后，通过β-氧化和cAMP（环磷酸腺苷）依赖性机制等途径进一步代谢，在三羧酸（tricarboxylic acid，TCA）循环过程中释放能量，约占人体所需能量的10%，对于维持能量稳态至关重要^［7-8］。丁酸盐是结肠上皮细胞的首要能量来源，此外还能增加黏蛋白的合成，在肠道中形成保护性黏液层，既可促进结肠上皮细胞的正常生长分化，又可拮抗肠道癌性细胞的增殖，在维持肠道屏障的完整性方面扮演着多重角色^［9］。乙酸盐和丙酸盐在肝脏能量代谢中发挥着不可或缺的作用。乙酸盐作为肠道内含量最多的SCFA，经肠上皮细胞吸收后，通过血液循环及有机阴离子转运蛋白、单羧酸转运蛋白等转运蛋白跨膜运输，参与肝脏中脂肪酸合成和葡萄糖代谢^［10］。丙酸盐在肠道吸收后，经门静脉输送至肝脏，作为肝脏糖异生的前体转化为葡萄糖，维持血糖平衡，以保证机体能量供应^［11］。

SCFA能诱导机体免疫微环境中促炎与抗炎作用之间的转换，是炎症反应发生和扩散的恶性反馈调节机制中的重要环节，该过程主要分为先天性免疫和适应性免疫两部分。SCFA对先天性免疫调控作用涉及树突状细胞、巨噬细胞、中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、固有淋巴样细胞（innate lymphoid cell，ILC）等免疫细胞的增殖和分化，而适应性免疫调节与T细胞、B细胞形成的免疫稳态关系密切。SCFA通过激活G蛋白偶联受体（G protein-coupled receptor，GPCR）信号传导、抑制组蛋白去乙酰化酶（histonedeacetylases，HDAC）活性等多种机制介导广泛的免疫调节。GPCR作为肠上皮细胞和免疫细胞中发挥免疫表达调控作用的主要受体，SCFA可直接结合并激活GPR41、GPR43和GPR109A等GPCR的表达，进而抑制核因子κB（nuclear factor kappa-B，NF-κB）和丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信号通路活化，以减少促炎细胞因子的释放^［12］。此外，SCFA还可作为表观遗传修饰因子，通过抑制HDAC活性，从而调节赖氨酸甲基化、乙酰化、巴豆酰化等蛋白质翻译后修饰的水平，以维持免疫稳态，该作用还能抑制促炎细胞因子的转录过程，协同发挥积极的免疫应答效应^［13］。由此可见，SCFA具有免疫多效性，在错综复杂的免疫交互网络中实现对非自身抗原的免疫耐受和维持免疫平衡（表1）。

2 SCFA与肝-肠-脑轴的交互关系

2.1 SCFA与肝脏的相关性

肝脏是吸收和代谢SCFA的重要器官，肠道内SCFA通过血液循环经门静脉系统运输至肝脏，其中丙酸盐和丁酸盐进入肝脏后被高效代谢，仅有少量在血液中积累，而乙酸盐在血液中的含量通常比丙酸盐、丁酸盐更高，且分布更为广泛^［44］。SCFA的免疫稳态失衡主要通过两种途径诱导肝脏疾病的发生和发展：一是SCFA的代谢紊乱介导黏蛋白合成不足，以及occludin、claudin等紧密连接蛋白的表达受损，造成肠道屏障的完整性和通透性破坏，发生肠道泄露和细菌易位，增加脂多糖的释放，引发肝脏炎症反应；二是SCFA通过GPCR信号传导等途径异常调控免疫细胞的抗炎效应，导致Treg的数量减少或功能减弱，进而对肝脏的免疫耐受和免疫应答产生负面影响。

多项临床研究数据证实，肠道菌群来源的SCFA代谢紊乱与多种肝脏疾病的发病机制有关^［45-47］，尤其在非酒精性脂肪性肝病，以及自身免疫性肝炎、原发性硬化性胆管炎等自身免疫性肝病中起到核心驱动作用。SCFA含量降低是非酒精性脂肪性肝病的高危致病因素。在肝脏代谢的过程中，SCFA可降低肝脏中脂肪酸合酶的活性，减少脂质的合成和储存，同时促进脂肪酸的氧化代谢，进而减少肝脏中的脂质积累^［48］。与此同时，SCFA还能激活细胞内能量感应器AMPK（腺苷酸活化蛋白激酶），进而沉默PPAR-γ（过氧化物酶体增殖物激活受体γ）依赖性途径，激活脂肪酸氧化的基因表达以启动从脂质合成转换为脂质降解，减少肝脏中的脂质沉积^［49-50］。采用16S rRNA测序技术检测自身免疫性肝炎、原发性硬化性胆管炎患者的肠道微生物群落组成和动态变化时均发现，产生SCFA的菌株丰度明显降低，SCFA含量显著减少，其中在原发性硬化性胆管炎患者中低水平的SCFA加速了肝脏促炎反应和纤维化进程，产生SCFA特异性菌株的丰度水平还与Mayo风险评分界定的临床病情严重程度呈负相关^{［45，51-52］}。值得注意的是，上述肝脏疾病虽是肝细胞癌形成的重要中间阶段，但SCFA的功能在肝细胞癌进程中却展现出截然相反的调节作用。肠道和门静脉SCFA水平的升高可能通过改变肝脏的免疫及代谢状态形成T细胞免疫抑制表型，扩增血液循环中抑制性Treg的数量，沉默CD8⁺ T细胞的抗肿瘤效应，营造有助于肝癌细胞生长的肿瘤微环境，发挥潜在的促癌作用，与肝细胞癌患者临床免疫治疗耐药性和不良预后相关^［53-54］。

因此，尽管SCFA在生理条件下具有多种有益作用，但当其含量过高或在长期暴露的情况下，可能会触发反向调控机制，从而为癌细胞的生长和存活创造肿瘤微环境。SCFA在肝脏疾病中的利与弊，实则反映出其在肝脏不同病理阶段的作用差异，基于SCFA分期靶向调控的治疗策略尚需进一步的探索和论证。

2.2 SCFA与肠道的相关性

肠道具有吸收营养和免疫防御的双重作用，其中肠道微生物群和肠黏膜协同调节免疫反应，既可抵御外部病原体的侵入，又可防止免疫系统过度反应以维持免疫平衡。SCFA作为肠道菌群代谢物之一，有充分的证据表明其可通过激活GPCR信号传导和抑制HDAC活性调节机体的免疫反应，促进抗炎表型的形成，并增强肠道屏障的功能，最终维持免疫系统的稳定^［55-56］。结肠是肠道中微生物密集度最高的部位，约占肠道微生物总量的70%，而占主导地位的菌群正是与SCFA生成密切相关的厚壁菌门和拟杆菌门^［57］。结肠内不同区域的SCFA含量存在差异，盲肠和近端结肠是SCFA产生的主要场所，而在远端结肠中其含量明显降低^［58］。与SCFA在肠道延伸中逐渐减少的趋势相适应，结肠不同区域的肠上皮细胞也展现出差异化的吸收机制。SCFA主要通过扩散、MCT1（单羧酸转运体1）的被动转运和SMCT1（钠偶联单羧酸转运体1）的主动转运三种方式被结肠上皮细胞吸收，在此过程中，SCFA高含量部位通过扩散和被动转运就足以满足需求，而处于低浓度条件时，SMCT1的主动转运确保了SCFA的持续吸收^［59］。由此可见，SCFA转运蛋白在结肠上皮细胞的多重吸收机制中扮演着重要角色，维持了肠道功能的高效运作。

近年来，SCFA在维持肠道健康方面的重要性引起了广泛关注，其参与结肠上皮细胞生物学过程的机制主要包括调节免疫反应、增强屏障防御功能和促进肠组织愈合。已有研究表明，结肠中SCFA水平下降与结肠炎、结肠癌的发病机制相关^［60-61］，在正常免疫微环境中，SCFA的抗炎效应可有效改善结肠炎的临床症状，并促进癌细胞凋亡，降低慢性结肠炎进展为结肠癌的风险。GPR109A在树突状细胞和巨噬细胞中高度表达，对于促进抗炎信号传导和调节脂质稳态至关重要。SCFA能够激活结肠中GPR109A的表达，促使抗炎细胞因子IL-10释放以拮抗肠道免疫失衡，同时SCFA通过抑制HDAC活性以驱动FOXP3基因启动子上组蛋白H3乙酰化，与IL-10协同介导Treg分化，从而减轻肠道炎症^［33-34］。持续的肠道炎症会损坏肠道屏障功能的完整性和通透性，使外部病原体渗入肠道内壁触发免疫反应，造成“炎症打击”的恶性循环。一方面，SCFA能够刺激肠道中的杯状细胞增加黏液分泌，黏液层覆盖在肠道内壁上，可有效减少病原体、脂多糖等直接接触和穿透肠道上皮细胞；另一方面，SCFA还能促进肠道上皮细胞之间紧密连接的形成和稳定，防止脂多糖等有害物质经细胞间隙进入肠内^［62］。值得关注的是，SCFA还参与肠道内的组织修复过程，能够促进肠道上皮细胞的增殖和分化，对组织炎症损伤愈合具有潜在的有益作用^［63］。目前，鉴于SCFA对肠道保护的积极影响，使用益生菌、益生元等增加SCFA水平的治疗策略有望成为预防和治疗结肠炎、结肠癌等肠道相关疾病的优效干预措施，拥有广阔的开发价值和前景。

2.3 SCFA与中枢神经系统的相关性

肠道菌群代谢物功能的发挥并未局限于消化、代谢过程，其还能通过跨肠脑轴的神经免疫通信机制影响中枢神经系统（central nervous system，CNS）的生理和行为机能^［64］。肠道与CNS之间的通信网络主要由两部分组成，一是肠神经系统通过交感神经和副交感神经的信号传递与CNS进行双向串扰，二是肠道菌群代谢物通过跨肠脑轴与CNS进行动态、连续的交互反应。SCFA在后者的调控机制中展现出巨大的潜力，其既有助于保持血脑屏障的完整性和稳定性，还能经跨肠脑轴直接影响神经元的能量代谢过程，更重要的是调节体内免疫平衡，以诱导脑内小胶质细胞、巨噬细胞等免疫细胞的促炎和抗炎表型转换，对维持CNS稳态具有重要意义^［65］。

迄今为止，跨肠脑轴的神经免疫通信机制为从肠道菌群及其代谢物角度阐明CNS病理改变提供了有力的证据链，而具有免疫调节作用的SCFA也被认为是阿尔兹海默症、脑卒中等多种CNS疾病的潜在非侵入性生物标志物和治疗靶标。Liu等^［66］在探讨SCFA中乙酸盐对阿尔兹海默症小鼠模型的神经保护机制时发现，乙酸盐能上调GPR41水平，并抑制ERK/JNK/NF-κB信号通路活化，从而降低阿尔兹海默症关键病理产物β-淀粉样蛋白的沉积，以及减少促炎细胞因子COX-2（环氧合酶-2）和IL-1β的表达，有效拮抗神经炎症和改善认知功能障碍。Chen等^［67］研究证实，缺血性脑卒中可诱发肠道菌群结构和功能紊乱，增加肠道屏障的通透性，显著降低SCFA水平，以丁酸盐的含量减少尤为突出，而移植富含SCFA的肠道微生物群成为该病的有效治疗手段。在神经免疫微环境中，小胶质细胞与星形胶质细胞的交互作用协同保障脑内免疫稳态，其中小胶质细胞作为大脑中的常驻免疫细胞，对病原体防御和CNS病理损伤起到首要的“卫士”职责。研究表明，肠道菌群衍生的SCFA与CNS中小胶质细胞的稳态密切相关^［68-69］，清除SCFA后的无菌小鼠出现了小胶质细胞发育异常和功能缺陷，以及抑制紧密连接蛋白表达进而导致血脑屏障通透性升高，造成神经免疫和屏障功能受损，重建肠道菌群补充SCFA能一定程度逆转以上改变。据报道，SCFA中乙酸盐是星形胶质细胞的特异性氧化代谢标志物^［70］，在CNS能量供给和神经保护中发挥着无可替代的作用。此外，SCFA还能独立于CNS进行自主神经功能调节^［71］，提示其可能更快速且直接地响应免疫反应和能量调节信号，突破了跨肠脑轴调控机制的桎梏，为神经退行性疾病的早期防治提供新的视角。

3 SCFA对HE的免疫调节作用

HE是由严重肝功能障碍引发的CNS异常表现，肝-肠-脑轴作为重要的双向通讯回路在该病的发病机制中起到广泛调节作用。肝脏与肠道之间由胆管、体循环和门静脉系统相互联系，HE的病理损伤可直接改变肠道菌群及其代谢物水平，以及破坏肠道屏障的结构和功能，导致肠道免疫失衡；反之，肠道菌群及其代谢物也参与了肝脏的胆汁酸代谢和糖脂代谢，肠道微生态失稳又可加剧肝硬化、肝癌等终末期肝病的恶性进展^［72］。已有研究证据表明，HE存在肠道菌群多样性和功能的显著改变^［73-75］。肠道菌群紊乱是诱发CNS免疫反应的关键因素，SCFA作为肠道菌群衍生的生物活性分子之一，前文已阐述其在肝-肠-脑轴的交互关系中作为有效媒介，通过先天性免疫和适应性免疫功能的发挥，对恢复HE的动态免疫平衡具有治疗潜力（图1）。

在多项临床队列研究中发现，肝硬化及HE患者肠道微生态紊乱，肠道菌群多样性减少，产生SCFA的菌株丰度显著下降，代谢生成SCFA水平受限，且肠内SCFA含量与患者的临床病情严重程度呈负相关^{［74，76］}。然而，一项新近研究结果区别于上述研究的结论^［75］，指出肝硬化及HE患者粪便SCFA水平虽低于健康对照组，但两者之间的含量无统计学差异，侧面反映出SCFA可能与病情进展无关。此外，该研究还发现HE患者的血清SCFA水平明显高于肝硬化组，究其原因，可能与HE患者肠道屏障功能减弱和通透性增大，继而促进SCFA吸收入血有关。值得注意的是，既往Juanola等^［77］研究结果与此结论相反，其认为肝硬化患者血清SCFA水平与门静脉高压、内毒素血症和全身性炎症等HE高危诱因呈负相关，SCFA含量下降提示终末期肝病病情可能出现恶性演变。

由此可见，鉴于肠道屏障的存在，HE中粪便与血清SCFA的具体分布情况尚需深入探索，由于临床研究样本量小、HE分型和分期不同等多种因素可能造成了以上数据差异，SCFA对于HE的早期诊断和预后评估有待进一步强化检测手段和临床应用验证。但肠内SCFA的治疗价值不容忽视，其水平降低与HE的发生发展密切相关，该结论在重建肠道菌群补充SCFA用以治疗HE的确切疗效中得以充分体现。通过粪便微生物群移植和补充益生菌、益生元等方式进行HE的肠道微生物组靶向治疗，可显著恢复肠道微生态平衡，增加肠内SCFA含量以提高机体免疫调节能力，安全且有效地控制疾病发展进程，同时降低HE的复发率^［78］。

4 小结与展望

HE是临床诊疗面临的重大挑战，其高病死率、高医疗资源消耗及尚未明晰的复杂病理机制形成三重困境，探索新的诊断、治疗和预后评估手段将成为该领域的研究热点。肝-肠-脑轴作为HE神经免疫通信起始、应答与沟通的核心级联机制，肠道菌群来源的SCFA在此交互过程中可能作为免疫启动和免疫抑制的中心介质，从而参与HE免疫调节反应的全过程。作为一种无创、安全的防治手段，目前SCFA在癌症、消化系统及神经系统等众多疾病的动物实验和临床研究中均发挥了有益的影响，靶向SCFA免疫调节活性的相关诊治策略展现出巨大的发展前景。但在HE中，针对SCFA的精准诊疗仍面临诸多挑战。例如，HE的发病时间窗短，且病情进展迅速，如何在有限时间内提高肠内或血清SCFA预测和诊断的准确性亟待进一步研究；通过粪便微生物群移植改善SCFA水平，虽是一种很有前景的新疗法，但经粪便传播导致的不良感染也可能迅速打破HE患者的免疫防御壁垒。此外，中药保留灌肠治疗HE临床疗效斐然，针对SCFA的中药药理作用研究也有望从中医视角阐明SCFA的免疫调控机制，助力SCFA干预药物的研发进程。

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