肝病中的肠-肝轴：治疗的病理生理基础,Journal of Hepatology

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肝病中的肠-肝轴：治疗的病理生理基础
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-03-01 , DOI: 10.1016/j.jhep.2019.10.003
Agustín Albillos ₁ , Andrea de Gottardi ₂ , María Rescigno ₃

Affiliation

肠-肝轴是指肠道及其微生物群和肝脏之间的双向关系，由饮食、遗传和环境因素产生的信号整合而成。这种相互作用是通过门静脉的血管通路建立的，门静脉将肠源性产物直接运送到肝脏，以及胆汁和抗体分泌到肠道的肝脏反馈通路。肠粘膜和血管屏障是功能和解剖结构，作为肠道和肝脏之间相互作用的场所，限制微生物和毒素的全身传播，同时允许营养物质进入循环并到达肝脏。微生物群落的控制对于维持肠-肝轴的稳态至关重要，作为双向交流的一部分，肝脏塑造了肠道微生物群落。酒精会在多个相互关联的层面破坏肠-肝轴，包括肠道微生物组、粘液、上皮屏障和抗菌肽的产生，从而增加微生物暴露和肝脏的促炎环境。越来越多的证据表明微生物来源的代谢物，如三甲胺、二级胆汁酸、SCFA 和乙醇，在非酒精性脂肪肝的发病机制中具有致病作用。肝硬化本身与肠道微生物群的深刻改变和肠道屏障不同防御水平的损伤有关，包括上皮、血管和免疫屏障。肝硬化中肠道屏障严重紊乱的相关性与活细菌的易位、细菌感染和疾病进展有关。识别在每种慢性肝病中主要受损的肠-肝轴的元素提供了干预的可能性。除了抗生素之外，即将推出的以肠道为中心的疗法包括新一代益生菌、细菌代谢物（后生元）、粪便微生物移植和碳纳米颗粒。FXR 激动剂同时针对肠道和肝脏，目前正在不同肝脏疾病中进行测试。最后，合成生物药物、针对特定细菌的噬菌体或在肠道和肝脏之间形成物理屏障的疗法提供了新的治疗方法。细菌感染和疾病进展。识别在每种慢性肝病中主要受损的肠-肝轴的元素提供了干预的可能性。除了抗生素之外，即将推出的以肠道为中心的疗法包括新一代益生菌、细菌代谢物（后生元）、粪便微生物移植和碳纳米颗粒。FXR 激动剂同时针对肠道和肝脏，目前正在不同肝脏疾病中进行测试。最后，合成生物药物、针对特定细菌的噬菌体或在肠道和肝脏之间形成物理屏障的疗法提供了新的治疗方法。细菌感染和疾病进展。识别在每种慢性肝病中主要受损的肠-肝轴的元素提供了干预的可能性。除了抗生素之外，即将推出的以肠道为中心的疗法包括新一代益生菌、细菌代谢物（后生元）、粪便微生物移植和碳纳米颗粒。FXR 激动剂同时针对肠道和肝脏，目前正在不同肝脏疾病中进行测试。最后，合成生物药物、针对特定细菌的噬菌体或在肠道和肝脏之间形成物理屏障的疗法提供了新的治疗方法。即将推出的以肠道为中心的疗法包括新一代益生菌、细菌代谢物（后生元）、粪便微生物移植和碳纳米颗粒。FXR 激动剂同时针对肠道和肝脏，目前正在不同肝脏疾病中进行测试。最后，合成生物药物、针对特定细菌的噬菌体或在肠道和肝脏之间形成物理屏障的疗法提供了新的治疗方法。即将推出的以肠道为中心的疗法包括新一代益生菌、细菌代谢物（后生元）、粪便微生物移植和碳纳米颗粒。FXR 激动剂同时针对肠道和肝脏，目前正在不同肝脏疾病中进行测试。最后，合成生物药物、针对特定细菌的噬菌体或在肠道和肝脏之间形成物理屏障的疗法提供了新的治疗方法。

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The gut-liver axis in liver disease: pathophysiological basis for therapy

The gut-liver axis refers to the bidirectional relationship between the gut and its microbiota, and the liver, resulting from the integration of signals generated by dietary, genetic and environmental factors. This reciprocal interaction is established through the vascular route of the portal vein that carries gut-derived products directly to the liver, and the liver feed-back route of bile and antibody secretion to the intestine. The intestinal mucosal and vascular barrier is the functional and anatomical structure that serves as a playground for the interactions between the gut and the liver, limiting the systemic dissemination of microbes and toxins while allowing nutrients to access the circulation and to reach the liver. The control of microbial communities is critical to maintain homeostasis of the gut-liver axis, and as part of the two-way communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut-liver axis at multiple interconnected levels, including the gut microbiome, mucus, epithelial barrier and antimicrobial peptides production, which increases the microbial exposure and the pro-inflammatory environment of the liver. Growing evidences indicate the pathogenetic role of microbe-derived metabolites, such as trimethylamine, secondary bile acids, SCFA and ethanol, in the pathogenesis of non-alcoholic fatty liver disease. Cirrhosis by itself is associated to profound alterations in gut microbiota and damage at the different levels of defense of the intestinal barrier, including the epithelial, the vascular and the immune barriers. The relevance of the severe disturbance of the intestinal barrier in cirrhosis has been linked to translocation of live bacteria, bacterial infections and disease progression. The identification of the elements of the gut-liver axis primarily damaged in each chronic liver disease offers possibilities to intervention. Beyond antibiotics, upcoming therapies centered in the gut include new generations of probiotics, bacterial metabolites (postbiotics), fecal microbial transplantation, and carbon nanoparticles. FXR-agonists target both the gut and the liver and are currently being tested in different liver diseases. Finally, synthetic biotic medicines, phages that target specific bacteria or therapies that create physical barriers between the gut and the liver offer new approaches of treatment.

更新日期：2020-03-01

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