编者按：今年的“第68届美国肝病研究学会年会”特别设置了 “State-of-the-Art Lecture”专题，邀请在肠道微生态与肝脏、药物性肝损伤、慢加急性肝衰竭和器官移植这四大研究领域的顶级大师分享最新学术动态，为与会医生和研究者们指点江山。

 

《国际肝病》前方记者有幸采访到来自美国加州大学圣地亚哥医学院的Bernd Schnabl博士，他将在“Hans Popper Basic Science State-of-the-Art Lecture”专题中介绍肠道微生物群与肝脏联系，请他分享会上精彩内容。

 

肠道与肝癌：哪些微生物与HCC发生发展有关？

 

Bernd Schnabl教授：许多慢性肝病与肠漏综合征有关，这些患者的肠道屏障功能受到了破坏。正常情况下，诸如脂多糖和内毒素等许多微生物产物不能从肠道移位至肝脏，这是肠道和肝脏之间非常特异的特征，它们通过门静脉循环发生连接。如果已经存在肠漏，许多毒素则可以从肠道通过门静脉进入肝脏，使肝脏细胞暴露于大量的细菌毒素，进而促使肝细胞癌（HCC）的发生，特别是之前存在慢性肝病的患者更是如此。

 

最近几年，我们还认识到其他特定的代谢物也可促使HCC的发生，肠道中的微生物组可以将初级胆汁酸代谢为次级胆汁酸，脱氧胆酸是一种次级胆汁酸代谢物，这种脱氧胆酸一旦进入肝脏，可以直接促使肝脏肿瘤的发生和发展。有几个例子显示了肠道微生物组如何促使HCC的发生和进展。

 

新领域：如何通过调节肠道微生物群来治疗肝病？

 

Bernd Schnabl教授：有几种方法可用于治疗肝病相关的肠道微生物群失调问题。补充益生菌为非针对性的方法，其为有益菌，可用于恢复肠道健康。还可应用不能被人体宿主消化、而只能被微生物组消化的糖分子，这些糖类的变化可以对宿主产生许多益处，这些是非针对性方法用于治疗肠道生态失调的例子。

 

最近几年，我们还认识到可以针对特定的肠道微生物组代谢变化进行治疗，至少在动物模型（目前只是在小鼠模型）中，我们发现慢性酒精性肝病中的生态失调与肠道中长链脂肪酸的变化和消耗有关 ，一旦予以补充恢复，则可以减轻酒精性肝病，这是一种特定的针对性方法，确定所发生的代谢变化，可以进行干预。

 

然而，对宿主和微生物组的相互作用，我们确实需要更多了解，微生物组不仅包括细菌，还包括真菌、病毒和噬菌体。关于肠道微生物组中噬菌体和病毒对肝病的影响，我们几乎一无所知，但是我们最近在《Journal of Clinical Investigation》发表了一篇文章，表明真菌和细菌一样，促使酒精性肝病的发生。

 

如何通过调节肠道微生物组治疗肝病，这是个全新的研究领域。在微生物组与宿主的相互作用中，涉及哪些微生物？发生了什么变化？它们是如何促使疾病进展的？将来需要更多的研究，更好地阐明这些问题。

 

Dr Schnabl: We know that many chronic liver diseases are associated with a leaky gut syndrome. This means that the gut barrier function is disrupted and many of the microbial products, like LPS (lipopolysaccharides) and endotoxins, cannot translocate from the intestine to the liver. This is a very specific feature between the intestine and the liver. They are connected by the portal vein circulation, and if there is a pre-existing leaky gut, many of these toxins can travel from the intestines via the portal vein into the liver. When they reach the liver, the cells of the liver can receive high exposure to these bacterial toxins. This can contribute to the onset of hepatocellular carcinoma, especially when there is pre-existing chronic liver disease. We have also learned over the last couple of years that other specific metabolites can in fact contribute to the onset of HCC. One of these is deoxycholic acid, which is a secondary bile acid metabolite. The microbiome in the intestine metabolizes primary bile acids into secondary bile acids, and once they reach the liver, this deoxycholic acid has been shown to directly contribute to the onset and progression of liver tumors. These are a couple of examples of how the gut microbiome can contribute to the onset and progression of hepatocellular carcinoma.

 

Dr Schnabl: There are a couple of approaches to treating the gut microbiota with regard to liver disease. We have the untargeted approach where we use probiotics, which are good bacteria that restore intestinal health. There are also sugar molecules that cannot be digested by the human host, but can only be digested by the microbiome. Secondary to these changes in these carbohydrates and sugars, the host also receives some benefit. These are examples of untargeted approaches to treating gut dysbiosis. Over the last couple of years, we have also learned that we can target specific metabolic changes in the gut microbiome. At least in animal models, we have found that the dysbiosis in chronic alcoholic liver disease is associated with a change and depletion of long chain fatty acids in the intestine. Once we restore those with supplementation, we are able to ameliorate alcoholic liver disease (currently only in a mouse model). This is a specifically targeted approach where we identify the metabolic changes that occur and we can then intervene. However, we do need to better understand the host microbiome interaction. We have learned over the last couple of years that the microbiome consists not only of bacteria, but also fungi, viruses and bacteriophages. We know almost nothing about bacteriophages and viruses in the gut microbiome with regard to contributing to liver disease, but we have recently published a paper in the Journal of Clinical Investigations where we showed that fungi are contributing to changes as well as bacteria. These are completely novel fields of investigation for how we can approach the treatment of liver disease by modulating the gut microbiome. We need to better understand who is there, what they are changing, and how these microbes contribute to the disease process in their interaction with the human host. This needs to be better defined in the future.