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肠道菌群是人体肠道复杂的生态系统，对人体生理功能产生着广泛影响。目前肠道菌群失调已成为慢性炎症性疾病发病中最重要的环境因素之一。而肝脏是最早发现的自身免疫性攻击部位之一。近年来，随着对肠道菌群研究的深入，肠道微生物谱与肝脏疾病关系的研究日益受到重视。多项研究发现，肠道菌群可能参与了自身免疫性肝病的发病及发展，对于肠道菌群失调的治疗可能成为自身免疫性肝病治疗的重要靶点。

 

在刚刚闭幕的肝病学领域国际年度压轴盛会——美国肝病研究学会年会（AASLD2023）上，美国加利福利亚大学圣地亚哥分校Bernd Schnabl教授进行了题为“The Role of the Microbiome in Autoimmune Liver Disease”的专题报告，详细解析了肠道微生态与自身免疫性肝病的关系。《国际肝病》特别邀请到Bernd Schnabl教授就相关话题进行深入分享。访谈视频和中英文对照访谈原稿整理如下。

 

一、肠道微生态与自身免疫性肝病的相关性探索进展

 

《国际肝病》

肠道微生物组学在自身免疫性肝病的疾病进展中发挥什么作用？根据目前的研究，微生物组学与自身免疫性肝病之间的关联是什么？

 

Bernd Schnabl教授

 

总的来说，自身免疫性肝病患者的肠道微生物群的确有所改变，通常为“有害菌群”数量增加，而“有益菌群”数量减少。例如，原发性硬化性胆管炎患者体内克雷伯菌（Klebsiella）和韦荣氏球菌（Veillonella）会增多，这可能对疾病的进展起到促进作用。同时，自身免疫性肝病患者普遍存在肠道微生物群的多样性降低，这也是许多慢性疾病中常见的情况。尤其是部分自身免疫性肝病患者的肠道通透性增加，使得肠道中的一些细菌以及由细菌产生的毒素通过门静脉直接进入肝脏。

 

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。肝脏是肠道微生物产物和代谢产物在我们体内最先到达的器官，当肝脏内炎症持续存在时，患者病情就会进一步恶化。此外，自身免疫性肝病患者的肠道微生物群的某些“良好功能”也会减少。例如，最新研究发现，原发性硬化性胆管炎患者血清中维生素B6含量降低，而后者也是由肠道微生物和细菌合成的。

 

英文原文：

 

<Hepatology Digest>: What role does microbiome play in the pathogenesis of autoimmune liver diseases? What current research findings have revealed the association between the microbiome and autoimmune liver diseases?

 

Dr. Bernd Schnabl: I think this is a very important question. In general, we know that patients with autoimmune liver disease, they have changes in their gut microbiome. In general terms, there are the bad bacteria, what we call are reduced in some of the good bacteria, I am sorry, the bad bacteria are increased and the good bacteria are decreased.

 

We know for example that in patients with primary sclerosing cholangitis we have an increase in Klebsiella, but also for example, Veillonella and they can potentially contribute to the progression of disease. And then one of the overall findings that many patients with autoimmune and liver disease have they have a decrease in the diversity of the microbiota in the intestine.

 

And that is something which we commonly see actually many of the chronic diseases and specifically also some of the patients with autumn liver disease, they have what we call an increased gut leakiness, so their intestinal permeability is increased and that allows now some of the bacteria from the intestine but also some of the toxins that are produced by the bacteria to translocate out from the intestine through the portal vein and come directly to the liver and the liver is the first organ now to encounter all of these products and in conjunction with the ongoing inflammation in the liver of these patients, you get now a progression of disease.

 

In addition, we also know for example that some of the good functions of the microbiota are decreased in these patients. For example, there was a recent publication that vitamin B6 which is also synthesized by the gut microbiota and by the bacteria that this is decreased in the serum from patients with primary steroids and cholangitis.

 

二、肠道微生物态研究有利于临床患者分层与个体化治疗

 

《国际肝病》

肠道微生物组学的研究为自身免疫性肝病的诊断、预防和治疗提供了那些新理念和新方法？

 

Bernd Schnabl教授

 

在诊断方面，我认为肠道微生物组学的研究非常重要，其可以助力临床医生更好地对患者进行诊断。根据检查结果，我们可以知道哪些患者的病情会进展，哪些患者一般不会进展，进而根据这些信息将患者分层分类，并确定对应的治疗目标。理想的情况是，我们未来可以通过测序识别微生物组学标志物（无需培养），进而区分哪些患者可能对某种疗法有反应，哪些患者可能需要更多、作用更强的治疗方法。

 

例如，根据肠道微生物组学，可以识别出哪些患者的疾病与肠道通透性增加有关，而这类患者就可以尝试作用靶点在改变肠道通透性的药物治疗。这将有助于更有效的新药研发，同时减少患者接受不必要药物治疗的风险以及不良事件的发生。总的来说，我认为这是未来的研究方向，微生物组学标志物有利于临床患者分层与个体化治疗。

 

英文原文：
 

<Hepatology Digest>: How can studying the microbiome provide new insights and methods for the diagnosis, prevention, and treatment of autoimmune liver diseases?

 

Dr. Bernd Schnabl: For the diagnosis, I think this is important, that we can get, for example, to a better diagnosis for patients. For example, who we know they would progress and some patients who we know they would not progress and then we can more or less stratify the patients towards some treatment and towards treatment targets.

 

The ideal case scenario that I can admission for the future is for example that we develop a microbiome signature from culture independent sequencing where we can characterize these patients who would respond to a therapy or who we know that they would need more and stronger therapy for the future.

 

I think this is something for the diagnosis and this characterizing these patients in terms of their microbiome. It would also allow us now to better have some categories of patients, for example, whose disease is driven by a leaky gut, and whose disease, for example, is not associated with increased intestinal permeability. And if you have, for example, a drug that is targeting the increased intestinal permeability, you only have to try and treat the patients who in fact have increased intestinal permeability.

 

So, I think this will help, you know, get a better efficient drugs for the future, but also reduce some risks and adverse events in patients who do not need to be treated with these drugs. So I think this is overall, you know I see this more as a future direction that we get like a microbiome signature for these patients and then we can stratify. You know, in terms of who needs to be treated and not.

 

三、以肠道微生物组为中心的疗法探索进展与前景

 

《国际肝病》

从您的角度来看，您认为微生物组学在自身免疫性肝病以及肠道健康研究中的方向和前景是什么？

 

Bernd Schnabl教授

 

这是一个非常好的问题。以调节肠道微生物组为中心的疗法，目前主要分为靶向疗法和非靶向疗法两种。

 

先从非靶向疗法说起，目前有一些相关临床试验正在进行或已经完成。例如，使用抗生素简单地清除肠道微生物群，但这种方法并不能区分好细菌和坏细菌；或者补充益生菌，其为有益菌，可用于恢复肠道健康，为患者带来益处。此外，还有粪便微生物群移植，即将特定健康人粪便中的功能肠道菌群移植到患者肠道内，重塑失衡的肠道菌群，以实现肠道及肠道外疾病的治疗。虽然在肠道微生物组研究领域，目前已经看到了一些可喜的结果，但尚未有一种方法可以应用于临床实践，仍需经过更多的临床研究、甚至更大规模的临床数据进行验证，以保证该疗法对肝病患者的疗效和安全性。

 

目前关于靶向疗法的相关临床试验较少，最近有一项研究显示，可以针对特定的肠道微生物组代谢变化进行治疗，比如使用噬菌体治疗。噬菌体，顾名思义，是以细菌为宿主的小个子病毒，可以特异性地识别感染某些细菌，并在其中复制繁殖，杀死靶向细菌。噬菌体疗法的美妙之处在于其可从内部杀死细菌，有时还会直接造成细菌的裂解，释放出来的噬菌体可以再去寻找下一位宿主细菌。最终减少“坏细菌”数量，阻止疾病的发展。目前这一疗法还在动物模型中探索，但现阶段结果还是令人欣喜的。

 

英文原文：

 

<Hepatology Digest>: From your perspective, what do you see as the future research directions and prospects for microbiomics in autoimmune liver diseases as well as in gut health research? What breakthroughs do you envision for this field in the coming years?

 

Dr. Bernd Schnabl: This is a very good question. Thank you so much. I think we can have, if I look at microbiome centered therapies, we essentially have like targeted and untargeted therapies.

 

And untargeted therapies, if I want to start with these, they are we have some clinical trials ongoing and they have been actually already finished. And these untargeted therapies use, for example, antibiotics, which is simply just wipe out the gut microbiota that do not discriminate between good and bad bacteria. Or we can use like probiotics. Probiotics are living bacteria which confer beneficial effects to the gut microbiome and to the patient. Or we can use like other non-targeted therapies like fecal microbiota transplantation, where we essentially give healthy donor stool to the patient with a chronic disease. And there have been some good outcomes, especially with antibiotics.

 

However, none of these, the current treatment trials where you have what I call centered microbiome centered therapies, none of them made it actually to clinical practice to any guidelines for our society. So I think they need to be more clinical trials and larger trials to, to really see if these treatments are effective and not harmful for patients with liver disease.

 

And I am going to switch over now to the targeted therapies I think we have. We do not have a clinical trial for this, but there was a recent study showing that, I have talked before about the bad bacteria, where we can use like bacteriophages to target these bad bacteria. And these bacteriophages are very small viruses. They can recognize specifically these bad bacteria, they can infect them and then from the inside they can kill the bacteria. And the beauty of it about these phages are that these phages are actually replicating inside the bacteria before they kill them. So after the bacteria are killed, now the progeny of many of these phages are released and they can now infect many of the other bad bacteria.

 

So eventually they will decrease the bad bacteria and can hopefully stop the progression of disease. Now this is not entered any clinical trial so far, but in preclinical animal models, I think we have very encouraging results.

 

 

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