The gut-liver axis and the intersection with the microbiome
肠-肝轴和与微生物组的交集

Anupriya Tripathi $^{1, 2, 3}$ , Justine Debelius $^{2}$ , David A. Brenner $^{4}$ , Michael Karin $^{2, 5}$ , Rohit Loomba $^{4, 8}$ , Bernd Schnabl $^{6, 7, 8}$ and Rob Knight $^{(0)}^{2, 5, 8 *}$
Anupriya Tripathi $^{1, 2, 3}$ ， Justine Debelius $^{2}$ ， David A. Brenner $^{4}$ ， Michael Karin $^{2, 5}$ ， Rohit Loomba $^{4, 8}$ ， Bernd Schnabl $^{6, 7, 8}$ 和 Rob Knight $^{(0)}^{2, 5, 8 *}$

Abstract 抽象

In the past decade, an exciting realization has been that diverse liver diseases - ranging from nonalcoholic steatohepatitis, alcoholic steatohepatitis and cirrhosis to hepatocellular carcinoma - fall along a spectrum. Work on the biology of the gut-liver axis has assisted in understanding the basic biology of both alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD). Of immense importance is the advancement in understanding the role of the microbiome, driven by high-throughput DNA sequencing and improved computational techniques that enable the complexity of the microbiome to be interrogated, together with improved experimental designs. Here, we review gut-liver communications in liver disease, exploring the molecular, genetic and microbiome relationships and discussing prospects for exploiting the microbiome to determine liver disease stage and to predict the effects of pharmaceutical, dietary and other interventions at a population and individual level. Although much work remains to be done in understanding the relationship between the microbiome and liver disease, rapid progress towards clinical applications is being made, especially in study designs that complement human intervention studies with mechanistic work in mice that have been humanized in multiple respects, including the genetic, immunological and microbiome characteristics of individual patients. These ‘avatar mice’ could be especially useful for guiding new microbiome-based or microbiome-informed therapies.
在过去的十年中，一个令人兴奋的认识是，从非酒精性脂肪性肝炎、酒精性脂肪性肝炎和肝硬化到肝细胞癌，各种肝脏疾病都属于一个谱系。肠-肝轴生物学的工作有助于理解酒精性脂肪性肝病和非酒精性脂肪性肝病（NAFLD）的基本生物学。极其重要的是，在高通量 DNA 测序和改进的计算技术的推动下，人们在理解微生物组的作用方面取得了进步，这些技术使微生物组的复杂性能够得到解答，同时也改进了实验设计。在这里，我们回顾了肝病中的肠-肝通讯，探索了分子、遗传和微生物组的关系，并讨论了利用微生物组来确定肝病分期和预测药物、饮食和其他干预措施在人群和个人水平上的影响的前景。尽管在了解微生物组与肝病之间的关系方面仍有许多工作要做，但临床应用正在取得快速进展，尤其是在研究设计中，这些研究设计通过在小鼠中进行机械工作来补充人类干预研究，这些小鼠在多个方面已被人源化，包括个体患者的遗传、免疫学和微生物组特征。这些“化身小鼠”对于指导新的基于微生物组或微生物组的疗法可能特别有用。

The crosstalk between the gut and liver is increasingly recognized, strengthened by the parallel rise in incidence of liver diseases and gastrointestinal and immune disorders

^{1, 2}

. The most common type of liver disease, nonalcoholic fatty liver disease (NAFLD), affects

> 65

million Americans with a cost burden of US

$ 103

billion annually within the USA

^{3}

. To manage the socioeconomic burden of gastrointestinal-associated liver diseases by developing new therapeutic modalities, specific molecular events that facilitate interaction between the gut and the liver must be elucidated. As we begin to appreciate these links, animal models

^{4 - 6}

and well-designed clinical studies

^{7 - 9}

are already revealing key components of these interactions.
肠道和肝脏之间的串扰越来越受到认可，肝脏疾病和胃肠道和免疫疾病

^{1, 2}

发病率的同步上升加强了这种相互作用。最常见的肝病类型是非酒精性脂肪性肝病（NAFLD），每年影响

> 65

数百万美国人，在美国每年造成数十亿美元的

$ 103

成本负担

^{3}

。为了通过开发新的治疗方式来管理胃肠道相关肝病的社会经济负担，必须阐明促进肠道和肝脏之间相互作用的特定分子事件。当我们开始认识到这些联系时，动物模型

^{4 - 6}

和精心设计的临床研究

^{7 - 9}

已经揭示了这些相互作用的关键组成部分。

The present understanding of the aetiology of the spectrum of liver diseases (FIG. 1) is underpinned by proinflammatory changes in the host. Intestinal dysbiosis (anomalous or imbalanced gut microbial composition) and increased intestinal permeability lead to translocation of microorganisms and microbial products, including cell wall components (endotoxins from Gram-negative bacteria and

β

-glucan from fungi) and DNA, together referred to as microbial-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs).
目前对肝病谱病因学的理解（图 1）以宿主的促炎变化为基础。肠道菌群失调（肠道微生物组成异常或不平衡）和肠道通透性增加导致微生物和微生物产物易位，包括细胞壁成分（革兰氏阴性菌的内毒素和

β

真菌的葡聚糖）和 DNA，统称为微生物相关分子模式（MAMP）或病原体相关分子模式（PAMP）。

These patterns are recognized by immune receptors on liver cells (such as Kupffer cells and hepatic stellate cells) and intestinal lamina propria (an immune-cell-rich tissue beneath the intestinal epithelium), which initiate and maintain inflammatory cascades that ultimately lead to liver damage in the form of fibrosis

^{10 - 13}

. This damage can progress from cirrhosis (severe fibrosis) to hepatocellular carcinoma (HCC), the most predominant form (

> 80 %

) of primary liver cancer

^{14}

. Previously demonstrated associations between intestinal health and several different types of neoplasia suggest a potential role of the microbiota in

{HCC}^{15, 16}

. Additionally, the liver and microbiota engage in co-metabolism of xenobiotics, including carcinogens (such as diet-derived 2-amino-3-methylimidazo[4,5-f] quinoline), which can independently predispose the host to

{HCC}^{17, 18}

.
这些模式被肝细胞（如库普弗细胞和肝星状细胞）和肠固有层（肠上皮下富含免疫细胞的组织）上的免疫受体识别，它们启动并维持炎症级联反应，最终导致肝损伤以纤维化的形式

^{10 - 13}

出现。这种损伤可以从肝硬化（严重纤维化）发展为肝细胞癌（HCC），这是原发性肝癌

^{14}

最主要的形式（

> 80 %

）。先前证明的肠道健康与几种不同类型的肿瘤之间的关联表明微生物群在

{HCC}^{15, 16}

中的潜在作用。此外，肝脏和微生物群参与外源性物质的共代谢，包括致癌物（如饮食衍生的 2-氨基-3-甲基咪唑[4,5-f] 喹啉），它们可以独立地使宿主易感。

{HCC}^{17, 18}

The missing links in the complex interaction network between host and microorganisms are being discovered piece by piece using various experimental designs (detailed later). These findings encourage microbiomeoriented therapeutic modalities to treat liver-associated and other metabolic diseases. Here, we review the current understanding of the aetiology of liver diseases and highlight the open research questions (BOX 1) to motivate
正在使用各种实验设计逐个发现宿主和微生物之间复杂相互作用网络中缺失的环节（稍后详述）。这些发现鼓励以微生物组为导向的治疗方式来治疗肝脏相关疾病和其他代谢疾病。在这里，我们回顾了目前对肝病病因学的理解，并强调了开放性研究问题（BOX 1）以激励

Key points 要点

The liver and intestine communicate extensively through the biliary tract, portal vein and systemic mediators.
肝脏和肠道通过胆道、门静脉和全身介质进行广泛交流。
Liver products primarily influence the gut microbiota composition and gut barrier integrity, whereas intestinal factors regulate bile acid synthesis, glucose and lipid metabolism in the liver.
肝脏产品主要影响肠道菌群组成和肠道屏障完整性，而肠道因子则调节肝脏中胆汁酸的合成、葡萄糖和脂质代谢。
Diverse liver diseases (including nonalcoholic fatty liver disease and alcoholic liver disease) are not unrelated but converge along a common path of progression; pro-inflammatory changes in the liver and intestine mediate development of fibrosis, cirrhosis and, ultimately, hepatocellular carcinoma.
不同的肝病（包括非酒精性脂肪性肝病和酒精性肝病）并非无关，而是沿着共同的进展路径汇聚;肝脏和肠道的促炎变化介导纤维化、肝硬化的发展，并最终介导肝细胞癌的发展。
Alcoholic and nonalcoholic fatty liver diseases share key characteristics, such as intestinal dysbiosis, gut permeability and shifts in levels of bile acids, ethanol and choline metabolites.
酒精性和非酒精性脂肪肝疾病具有共同的关键特征，例如肠道菌群失调、肠道通透性以及胆汁酸、乙醇和胆碱代谢物水平的变化。
Precise contributions of the microbiome to liver diseases could differ based on aetiology; improvements in experimental design and development of animal models are rapidly elucidating causal mechanisms.
微生物组对肝脏疾病的确切贡献可能因病因而异;动物模型实验设计和开发的改进正在迅速阐明因果机制。
Advances in understanding the gut-liver axis could encourage research into microbiome-based, diagnostic, prognostic and therapeutic modalities to improve management of liver diseases.
了解肠道-肝脏轴的进展可以鼓励对基于微生物组的诊断、预后和治疗方式的研究，以改善肝脏疾病的管理。
focused research in this area with special attention to the role of the microbiome.
专注于该领域的研究，特别关注微生物组的作用。

How do the liver and gut communicate?
肝脏和肠道如何交流？

The gut and liver communicate via tight bidirectional links through the biliary tract, portal vein and systemic circulation (FIG. 2). The liver communicates with the intestine by releasing bile acids and many bioactive mediators into the biliary tract and the systemic circulation. In the intestine, host and microorganisms metabolize endogenous (bile acids and amino acids) as well as exogenous (from diet and environmental exposure) substrates, the products of which translocate to the liver through the portal vein and influence liver functions

^{19}

. Some crucial links between the gut and liver are discussed herein.
肠道和肝脏通过胆道、门静脉和体循环通过紧密的双向连接进行交流（图 2）。肝脏通过将胆汁酸和许多生物活性介质释放到胆道和体循环中来与肠道进行交流。在肠道中，宿主和微生物代谢内源性（胆汁酸和氨基酸）以及外源性（来自饮食和环境暴露）底物，其产物通过门静脉转移到肝脏并影响肝功能

^{19}

。本文讨论了肠道和肝脏之间的一些关键联系。

Enterohepatic circulation of bile acids
胆汁酸的肠肝循环

Bile acids (BAs) are amphipathic molecules synthesized from cholesterol in the pericentral hepatocytes. These primary BAs are reconjugated to glycine or taurine and released in the biliary tract. On reaching the small intestine through the duodenum, BAs, together with other biliary components, facilitate emulsification and absorption of dietary fats, cholesterol and fat-soluble vitamins. About

95 %

of the BAs are actively reabsorbed in the terminal ileum and transported back to the liver

^{20, 21}

. The remaining

5 %

are deconjugated, dehydrogenated and dehydroxylated by the colonic microbiota to form
胆汁酸（BAs）是由中枢周围肝细胞中的胆固醇合成的两亲性分子。这些原代 BA 与甘氨酸或牛磺酸再结合并在胆道中释放。通过十二指肠到达小肠后，BAs 与其他胆道成分一起促进膳食脂肪、胆固醇和脂溶性维生素的乳化和吸收。大约

95 %

BA 在末端回肠中被主动重吸收并运回肝脏

^{20, 21}

。其余

5 %

的被结肠微生物群解离、脱氢和去羟基化，形成

secondary BAs, which reach the liver via passive absorption into the portal circulation

^{22}

. The liver recycles BAs and secretes them back to the biliary tract, completing the so-called enterohepatic circulation, that is, a system of exchange between the gut and the liver.
继发性 BAs，通过被动吸收到门静脉循环

^{22}

中到达肝脏。肝脏回收 BA 并将其分泌回胆道，完成所谓的肠肝循环，即肠道和肝脏之间的交换系统。

A carrier-mediated process transports hydrophilic primary BAs across cell membranes for uptake into intestinal epithelial cells. Regulatory effects of BAs have been best studied with respect to farnesoid X receptor (FXR; also known as NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1; also known as TGR5). BAs bind to FXR in the enterocytes and induce transcription of an enterokine, fibroblast growth factor 19 (FGF19; FGF15 in mouse

^{23}

. FGF19 reaches the liver through the portal vein and downregulates de novo BA synthesis by inhibiting cholesterol

7 α

-monooxygenase (CYP7A1) in hepatocytes, forming a feedback system for modulating BA production

^{23}

. FXR activation is known to affect glucose and lipid metabolism

^{24, 25}

. Additionally, BAs bind to TGR5 on the plasma membrane and act on tissues beyond enterohepatic circulation. This binding mediates host energy expenditure

^{26, 27}

, glucose homeostasis

^{28}

and anti-inflammatory immune responses

^{29, 30}

.
载体介导的过程将亲水性原代 BA 转运穿过细胞膜，以便被肠上皮细胞吸收。BA 的调节作用在法尼醇 X 受体（FXR，也称为 NR1H4）和 G 蛋白偶联胆汁酸受体 1 （GPBAR1，也称为 TGR5）方面得到了最好的研究。BA 与肠上皮细胞中的 FXR 结合并诱导肠因子成纤维细胞生长因子 19 （FGF19;小鼠

^{23}

中的 FGF15。FGF19 通过门静脉到达肝脏，通过抑制肝细胞中的胆固醇

7 α

单加氧酶（CYP7A1）下调 BA 合成，形成调节 BA 产生的

^{23}

反馈系统。已知 FXR 激活会影响葡萄糖和脂质代谢

^{24, 25}

。此外，BA 与质膜上的 TGR5 结合，并作用于肠肝循环以外的组织。这种结合介导宿主能量消耗

^{26, 27}

、葡萄糖稳态

^{28}

和抗炎免疫反应

^{29, 30}

。

BAs and the gut microbiota closely interact and modulate each other; BAs exert direct control on the intestinal microbiota. By binding to FXR, they induce production of antimicrobial peptides (AMPs) such as angiogenin 1 and RNase family member 4 , which are directly involved in inhibiting gut microbial overgrowth and subsequent gut barrier dysfunction

^{31, 32}

. Intestinal dysbiosis shifts the balance between primary and secondary BAs and their subsequent enterohepatic cycling, the metabolic effects of which are not comprehensively understood. However, because of differences in the affinity of these two classes of BAs for FXR, these shifts have been associated with changes in hepatic bile acid synthesis and metabolic stress

^{22, 33 - 35}

. An imbalance in BAs and gut bacteria elicits a cascade of host immune responses relevant to the progression of liver diseases (discussed later).
BA 和肠道微生物群密切相互作用并相互调节;BAs 直接控制肠道微生物群。通过与 FXR 结合，它们诱导抗菌肽（AMP）的产生，例如血管生成素 1 和 RNase 家族成员 4 ，这些肽直接参与抑制肠道微生物过度生长和随后的肠道屏障功能障碍

^{31, 32}

。肠道菌群失调改变了原发性和继发性 BAs 之间的平衡及其随后的肠肝循环，其代谢效应尚不清楚。然而，由于这两类 BA 对 FXR 的亲和力存在差异，这些变化与肝胆汁酸合成和代谢应激

^{22, 33 - 35}

的变化有关。BAs 和肠道细菌的不平衡会引发与肝病进展相关的一连串宿主免疫反应（稍后讨论）。

Intestinal permeability 肠道通透性

The central components of the intestinal barrier are enterocytes that are tightly bound to adjacent cells by apical junctional proteins that include claudins, occludins, E-cadherins, desmosomes and junctional adhesion molecules

^{36}

. This barrier restricts movement of microorganisms and molecules from the gut lumen while allowing permselective, active transport of nutrients across the tight junctions. The intestinal barrier is further strengthened by several additional lines of defence. Mucins (heavily glycosylated protein aggregates) form a physical barrier between luminal bacteria and the underlying epithelial layer

^{37}

, and antibacterial lectins, such as regenerating islet-derived protein III

γ

(REG3G), are produced by intestinal Paneth cells to target bacteria associated with mucosal lining

^{38, 39}

. Moreover, immunoglobulins (specifically secretory immunoglobulin A (IgA)) produced by plasma cells and transported into the lumen through the intestinal epithelial cells neutralize microbial pathogens by blockading epithelial receptors

^{40}

. Finally, commensal bacteria are closely associated with the gut mucosa and reinforce barrier integrity
肠道屏障的核心成分是肠上皮细胞，它们通过顶端连接蛋白与相邻细胞紧密结合，这些连接蛋白包括密蛋白、咬合素、E-钙粘蛋白、桥粒和连接粘附分子

^{36}

。该屏障限制了微生物和分子从肠道腔的运动，同时允许营养物质通过紧密连接进行选择性、主动运输。肠道屏障通过几道额外的防线进一步加强。粘蛋白（高度糖基化的蛋白质聚集体）在管腔细菌和下面的上皮层

^{37}

之间形成物理屏障，抗菌凝集素，如再生胰岛衍生蛋白 III

γ

（REG3G），由肠道 Paneth 细胞产生，以靶向与粘膜衬里

^{38, 39}

相关的细菌。此外，浆细胞产生并通过肠上皮细胞运输到管腔中的免疫球蛋白（特别是分泌型免疫球蛋白 A （IgA））通过阻断上皮受体来中和微生物病原体

^{40}

。最后，共生菌与肠粘膜密切相关，并增强屏障完整性

Fig. 1 | Physiological manifestations of liver injury along a spectrum of progression. Risk factors such as alcohol abuse, unbalanced diet, infection (HBV or HCV) or immune dysfunction (primary biliary cholangitis or primary sclerosing cholangitis) can independently lead to liver injury. Individuals who abuse alcohol and individuals with obesity often develop steatosis (fatty liver), which is characterized by increased intestinal permeability and dysbiosis. Subsequently, bile acid and choline homeostasis are disturbed along with increased translocation of microbial-associated molecular patterns (MAMPs) across the gut barrier, leading to steatohepatitis, the progressive form of liver damage. Both steatosis-dependent and steatosis-independent liver damage can progress to cirrhosis (end-stage liver damage), which is marked by translocation of viable bacteria to the liver and severe inflammation. As liver function is progressively compromised, tumour-promoting metabolites and xenobiotics accumulate. These could activate oncogenic pathways causing hepatocellular carcinoma, the most predominant form of primary liver cancers. ALD, alcoholic liver disease; ASH, alcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.
图 1 |肝损伤沿一系列进展的生理表现。酗酒、饮食不均衡、感染（HBV 或 HCV）或免疫功能障碍（原发性胆汁性胆管炎或原发性硬化性胆管炎）等风险因素可独立导致肝损伤。酗酒者和肥胖者经常患上脂肪变性（脂肪肝），其特征是肠道通透性增加和菌群失调。随后，胆汁酸和胆碱稳态受到干扰，微生物相关分子模式（MAMP）跨肠道屏障的易位增加，导致脂肪性肝炎，即肝损伤的进行性形式。脂肪变性依赖性和非脂肪变性肝损伤均可进展为肝硬化（终末期肝损伤），其特征是活菌转移到肝脏和严重炎症。随着肝功能逐渐受损，促肿瘤代谢物和外源性物质会积累。这些可能会激活导致肝细胞癌的致癌途径，肝细胞癌是原发性肝癌的最主要形式。ALD，酒精性肝病;ASH，酒精性脂肪性肝炎;NAFLD，非酒精性脂肪性肝病;NASH，非酒精性脂肪性肝炎。
by stimulating cell-mediated immunity via Toll-like receptor (TLR)-mediated signalling

^{38, 41}

or by producing metabolites that directly strengthen tight junctions (short-chain fatty acids (SCFAs))

^{42 - 44}

and inhibit other microorganisms

^{45 - 47}

.
通过 Toll 样受体（TLR）介导的信号传导刺激细胞介导的免疫

^{38, 41}

力，或通过产生直接加强紧密连接（短链脂肪酸（SCFA））

^{42 - 44}

和抑制其他微生物的代谢物

^{45 - 47}

。

Breakdown of one or more of these barrier components compromises gut barrier integrity. The major drivers of increased permeability include gut inflammation and dysbiosis

^{48, 49}

, which have been linked to consumption of a high-fat Western diet

^{50 - 52}

, chronic alcohol consumption

^{53 - 55}

, prolonged antibiotic usage

^{56}

and immune-mediated inflammatory diseases such as IBD

^{57}

. An important association between the gut microbiota, inflammation and gut barrier integrity is provided by Akkermansia muciniphila, a Gram-negative anaerobe that colonizes the intestinal mucous layer. Reduced abundance of

A

. muciniphila has been associated with thinning of the mucous layer (compromising gut barrier integrity) and increased inflammation, which promote both alcoholic and nonalcoholic liver damage

^{58, 59}

. When the gut barrier is compromised, microorganisms and microorganism-derived molecules can translocate to the liver through the portal system, causing inflammation and hepatic injury

^{13}

. Some translocated intestinal products might also directly interact with host factors and contribute to exacerbation of liver disease

^{60 - 65}

(FIG. 3).
这些屏障成分中的一个或多个分解会损害肠道屏障的完整性。通透性增加的主要驱动因素包括肠道炎症和生态失调

^{48, 49}

，这与食用高脂肪西餐

^{50 - 52}

、长期饮酒

^{53 - 55}

、长期使用

^{56}

抗生素和免疫介导的炎症性疾病（如 IBD

^{57}

）有关。嗜粘蛋白阿克曼菌（Akkermansia muciniphila）提供了肠道微生物群、炎症和肠道屏障完整性之间的重要关联，嗜粘蛋白是一种定植于肠粘膜层的革兰氏阴性厌氧菌。.

A

嗜粘蛋白与粘膜层变薄（损害肠道屏障完整性）和炎症增加有关，这会促进酒精性和非酒精性肝损伤

^{58, 59}

。当肠道屏障受损时，微生物和微生物衍生的分子可以通过门静脉系统转移到肝脏，引起炎症和肝损伤

^{13}

。一些易位的肠道产物也可能直接与宿主因子相互作用，并导致肝病

^{60 - 65}

恶化（图 3）。

Systemic circulation 体循环

Bacteria and MAMPs. Intestinal permeability is characterized by compromised tight junctions between enterocytes and is consistently seen across the spectrum of liver diseases

^{66, 67}

. Liver damage is associated with small intestinal bacterial overgrowth (SIBO) and dysbiosis of the lower gastrointestinal tract

^{68}

. Together, these processes
细菌和 MAMP。肠道通透性的特征是肠上皮细胞之间的紧密连接受损，并且在肝病

^{66, 67}

谱中始终可见。肝损伤与小肠细菌过度生长（SIBO）和下消化道菌群失调有关

^{68}

。这些过程共同
lead to increased translocation of MAMPs into the portal circulation. On reaching the liver, MAMPs induce localized inflammation through pattern-recognition receptors (PRRs) on Kupffer cells

^{69}

and hepatic stellate cells

^{70, 71}

. Endotoxin-mediated activation of TLR4 (REFS

^{69, 70}

), TLR9 (activated by methylated DNA)

^{71}

and TLR2 (activated by Gram-positive bacteria)

^{72}

are the primary drivers of immune response in liver disease. TLR signalling in Kupffer cells activates a downstream proinflammatory cascade, leading to myeloid differentiation primary response protein (MYD88)-mediated activation of nuclear factor-

κ B

(NF-кB)

^{13}

. Additionally, TLR4 signalling also promotes fibrosis by downregulating BMP and activin membrane-bound inhibitor homologue (BAMBI) (a decoy receptor for transforming growth factor-

β

(TGF

β

)) in hepatic stellate cells

^{13}

. These steps lead to expression of inflammatory cytokines, oxidative and endoplasmic reticulum (ER) stress and subsequent liver damage

^{73}

.
导致 MAMP 向门静脉循环的易位增加。到达肝脏后，MAMP 通过 Kupffer 细胞

^{69}

和肝星状细胞

^{70, 71}

上的模式识别受体（PRR）诱导局部炎症。内毒素介导的 TLR4 （REFS

^{69, 70}

）激活、TLR9 （由甲基化 DNA 激活）

^{71}

和 TLR2 （由革兰氏阳性菌激活）

^{72}

是肝病免疫反应的主要驱动因素。Kupffer 细胞中的 TLR 信号转导激活下游促炎级联反应，导致髓样分化初级反应蛋白（MYD88）介导的核因子 -

κ B

（NF-кB）

^{13}

激活。此外，TLR4 信号传导还通过下调肝星状细胞

^{13}

中的 BMP 和激活素膜结合抑制剂同源物（BAMBI）（一种转化生长因子（

β

TGF

β

）的诱饵受体）来促进纤维化。这些步骤导致炎性细胞因子的表达、氧化和内质网（ER）应激以及随后的肝损伤

^{73}

。

Choline metabolites. Choline is a macronutrient that is important for liver function, brain development, nerve function, muscle movement and for maintaining a healthy metabolism

^{74}

; notably, rodents fed a cholinedeficient diet have been used to model human nonalcoholic steatohepatitis (NASH)

^{75 - 77}

. Choline is processed into phosphatidylcholine (lecithin) by the host, which assists in excretion of VLDL particles from the liver. This process prevents hepatic accumulation of triglycerides (liver steatosis)

^{78}

. Additionally, choline can also be converted to trimethylamine (TMA) by intestinal bacteria; TMA can translocate to the liver through the portal circulation where it is converted to trimethylamine N -oxide (TMAO)

^{79}

. The importance of methylamines is increasingly being recognized with respect to liver,
胆碱代谢物。胆碱是一种常量营养素，对肝功能、大脑发育、神经功能、肌肉运动和维持健康的新陈代谢很重要

^{74}

;值得注意的是，喂食胆碱缺乏症饮食的啮齿动物已被用于模拟人类非酒精性脂肪性肝炎（NASH）。

^{75 - 77}

胆碱被宿主加工成磷脂酰胆碱（卵磷脂），有助于 VLDL 颗粒从肝脏排泄。这个过程可以防止甘油三酯的肝脏积累（肝脂肪变性）。

^{78}

此外，胆碱也可以被肠道细菌转化为三甲胺（TMA）;TMA 可以通过门静脉循环转移到肝脏，在那里它转化为三甲胺 N -氧化物（TMAO）。

^{79}

甲胺在肝脏方面的重要性越来越得到认可，

*e-mail: robknight@ ucsd.edu
*电子邮件：robknight@ ucsd.edu
https://doi.org/10.1038/ s41575-018-0011-z
Author addresses 作者地址
$^{1}$ Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
$^{1}$ 加州大学圣地亚哥分校生物科学部，美国加利福尼亚州拉霍亚。
$^{2}$ Department of Pediatrics, University of California, San Diego, CA, USA.
$^{2}$ 美国加利福尼亚州圣地亚哥加州大学儿科系。
$^{3}$ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA.
$^{3}$ 美国加利福尼亚州圣地亚哥加州大学斯卡格斯药学与制药科学学院。
$^{4}$ NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California, San Diego, CA, USA.
$^{4}$ 美国加利福尼亚州圣地亚哥加州大学医学系胃肠病学部 NAFLD 研究中心。
$^{5}$ Department of Computer Science and Engineering, University of California, San Diego, CA, USA.
$^{5}$ 美国加州大学圣地亚哥分校计算机科学与工程系。
$^{6}$ Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
$^{6}$ 加州大学圣地亚哥分校医学系，美国加利福尼亚州拉霍亚。
$^{7}$ Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
$^{7}$ 美国加利福尼亚州圣地亚哥弗吉尼亚州圣地亚哥医疗保健系统医学系。
$^{8}$ Center for Microbiome Innovation, University of California, San Diego, CA, USA.
$^{8}$ 美国加利福尼亚州加州大学圣地亚哥分校微生物组创新中心。

The gut-liver axis and the intersection with the microbiome 肠-肝轴和与微生物组的交集