Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics

The intestinal microbiota is now recognised to play key roles in health due to its involvement in many aspects of human physiology. Disturbance in gut microbiota (dysbiosis) is thus associated with many diseases including nonalcoholic fatty liver disease (NAFLD) which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis. The mechanisms for the effect of dysbiosis in NAFLD pathogenesis are not completely elucidated. Many explanations have been proposed to trigger dysbiosis, leading to NAFLD including inflammation, ethanol produced by the gut bacteria and lipotoxicity. Recently the roles of bile acids and nuclear receptors are highly regarded. It is well known that gut microbes produce enzymes that convert primary bile acids into secondary bile acids in the intestines. Several studies have demonstrated that disturbance of the intestinal microbiota leads to decreased synthesis of secondary bile acids, which in turn decreases activation of nuclear receptors such as farnesoid X receptor (FXR), pregnane X receptor, Takeda G-protein–coupled bile acid protein 5 and vitamin D receptor. These receptors are important in energy regulation and their dysregulation can cause NAFLD. Therefore, stimulation of nuclear receptors especially FXR has been extensively explored for the amelioration of NAFLD. However, paradoxical effects of nuclear receptor activation are a major problem for the clinical application of nuclear receptor stimuli. We further posit that microbiome restoration could be an alternative approach for the treatment of NAFLD. Several gut bacteria are now known to be involved in bile acid metabolism. It will be necessary to identify which one/ones is/are feasible. Careful selection of commensal bacteria for probiotics may lead to an effective therapy for NAFLD.     

肠道菌群与胆汁酸的互作在 相关疾病中的作用

胆汁酸在人体的胆固醇代谢、脂质消化、宿主-微生物相互作用及通路调控等方面具有重要作用。大多数胆汁酸(95%)通过肝肠循环重回收,还有约5%作为结肠内细菌生物转化的基质。胆汁酸微生物转化中涉及的各种酶可通过肠道细菌培养而被验证,证明其有种属特异性。最近,生物信息学方法揭示了这些酶有多种亚型。因此,在胆汁酸转化中肠道菌群发挥重要的作用,微生物群落结构和功能对次级胆汁酸在胆汁酸池中的分布有深刻影响。研究认为胆汁酸和胆汁酸池的组成与几种疾病有关,包括炎症性肠病、代谢综合征和结直肠癌。最近,人们的重点放在肠道菌群如何改变胆汁酸进而导致或减轻某些疾病。本文总结了肠道菌群、胆汁酸生物转化和疾病状态之间的相互作用的研究进展。     

The interplay between host cellular and gut microbial metabolism in NAFLD development and prevention

Metabolism regulation centred on insulin resistance is increasingly important in nonalcoholic fatty liver disease (NAFLD). This review focuses on the interactions between the host cellular and gut microbial metabolism during the development of NAFLD. The cellular metabolism of essential nutrients, such as glucose, lipids and amino acids, is reconstructed with inflammation, immune mechanisms and oxidative stress, and these alterations modify the intestinal, hepatic and systemic environments, and regulate the composition and activity of gut microbes. Microbial metabolites, such as short-chain fatty acids, secondary bile acids, protein fermentation products, choline and ethanol and bacterial toxicants, such as lipopolysaccharides, peptidoglycans and bacterial DNA, play vital roles in NAFLD. The microbe–metabolite relationship is crucial for the modulation of intestinal microbial composition and metabolic activity. The intestinal microbiota and their metabolites participate in epithelial cell metabolism via a series of cell receptors and signalling pathways and remodel the metabolism of various cells in the liver via the gut–liver axis. Microbial metabolic manipulation is a promising strategy for NAFLD prevention, but larger-sampled clinical trials are required for future application.     

胆汁酸功能及其与肠道细菌相互关系

胆汁酸具有多种重要生理功能. 近年研究发现,胆汁酸可作为信号分子与褐色脂肪细胞表面受体TGR5结合,可激活法尼酯衍生物X受体（nuclear receptor farnesoid X receptor, FXR）的表达. 通过激活这些不同的信号传导途径,胆汁酸可以分别起到调节体内能量代谢平衡、控制肥胖以及抑制肠道细菌过度增殖的作用. 胆汁酸与人及动物肠道细菌具有复杂的相互关系：肠道细菌对于胆汁酸的转化很重要,除了在胆汁酸的转化中发挥重要作用外,肠道微生物菌群还可以十分有效地水解已被胆汁酸清除的生物体内结合寄生物或异源物质,促进这些物质的活化或肠肝循环. 宿主拥有一些抑制细菌过度增殖的机制,这些机制包括快速转运以及利用抗菌肽、蛋白水解肽和胆汁酸等进行抑菌;而有些肠道细菌在进化中形成一些抗性机制可避免胆汁酸胁迫. 本文主要就胆汁酸控制肥胖以及抑制细菌过度增殖的机制和胆汁酸与肠道细菌相互关系进行了综述.     

Mouse ghrelin-O-acyltransferase (GOAT) plays a critical role in bile acid reabsorption

Ghrelin is a unique peptide gut hormone that requires post-translational modification to stimulate both feeding and growth hormone release. Ghrelin O-acyltransferase (GOAT) was identified as a specific acyl-transferase for ghrelin, and recent genetic deletion studies of the Goat gene (Goat(-/-)) uncovered the role of ghrelin in the regulation of glucose homeostasis. To further understand the physiological functions of the GOAT/ghrelin system, we have conducted a metabolomic and microarray profile of Goat-null mice, as well as determined Goat expression in different tissues using the lacZ reporter gene. Serum metabolite profile analysis revealed that Goat(-/-) mice exhibited increased secondary bile acids >2.5-fold. This was attributed to increased mRNA and protein expression of the ileal sodium-dependent bile acid transporter (ISBT) in the intestinal and biliary tract. Increased expression of additional solute carrier proteins, including Slc5a12 (>10-fold) were also detected in the small intestine and bile duct. Goat staining was consistently observed in the pituitary glands, stomach, and intestines, and to a lesser extent in the gallbladder and pancreatic duct. This is the first report that the GOAT/ghrelin system regulates bile acid metabolism, and these findings suggest a novel function of GOAT in the regulation of intestinal bile acid reabsorption..     

Gut microbiota–bile acid–skeletal muscle axis

The gut microbiota represents a ‘metabolic organ’ that can regulate human metabolism. Intact gut microbiota contributes to host homeostasis, whereas compositional perturbations, termed dysbiosis, are associated with a wide range of diseases. Recent evidence demonstrates that dysbiosis, and the accompanying loss of microbiota-derived metabolites, results in a substantial alteration of skeletal muscle metabolism. As an example, bile acids, produced in the liver and further metabolized by intestinal microbiota, are of considerable interest since they regulate several host metabolic pathways by activating nuclear receptors, including the farnesoid X receptor (FXR). Indeed, alteration of gut microbiota may lead to skeletal muscle atrophy via a bile acid–FXR pathway. This Review aims to suggest a new pathway that connects different mechanisms, involving the gut–muscle axis, that are often seen as unrelated, and, starting from preclinical studies, we hypothesize new strategies aimed at optimizing skeletal muscle functionality.     

Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR

Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism.     

胆汁酸对代谢性疾病的调控

胆汁酸作为一种信号分子通过激活肝、肠道和外周组织中的胆汁酸受体影响体内葡萄糖和脂质的代谢平衡,对于调节肥胖、2型糖尿病和非酒精性脂肪肝等代谢性疾病具有非常重要的意义。胆汁酸与相应核受体,如法尼醇X受体(farnesoid X receptor, FXR)和Takeda G蛋白偶联受体5 (Takeda G protein-coupled receptor 5,TGR5)的相互作用影响了这些代谢性疾病。FXR主要通过影响胆汁酸的合成及转运对非酒精性脂肪肝发挥作用,TGR5则是间接增加褐色脂肪组织中的生热作用,改善肥胖和2型糖尿病。这些调控机制的研究是非常必要的。本文综述了胆汁酸代谢及其对代谢性疾病调控的分子机制的研究进展,以期为科研工作者提供一定的参考。     

The gut microbiota and its interactions with cardiovascular disease

The intestine is colonized by a considerable community of microorganisms that cohabits within the host and plays a critical role in maintaining host homeostasis. Recently, accumulating evidence has revealed that the gut microbial ecology plays a pivotal role in the occurrence and development of cardiovascular disease (CVD). Moreover, the effects of imbalances in microbe–host interactions on homeostasis can lead to the progression of CVD. Alterations in the composition of gut flora and disruptions in gut microbial metabolism are implicated in the pathogenesis of CVD. Furthermore, the gut microbiota functions like an endocrine organ that produces bioactive metabolites, including trimethylamine/trimethylamine N-oxide, short-chain fatty acids and bile acids, which are also involved in host health and disease via numerous pathways. Thus, the gut microbiota and its metabolic pathways have attracted growing attention as a therapeutic target for CVD treatment. The fundamental purpose of this review was to summarize recent studies that have illustrated the complex interactions between the gut microbiota, their metabolites and the development of common CVD, as well as the effects of gut dysbiosis on CVD risk factors. Moreover, we systematically discuss the normal physiology of gut microbiota and potential therapeutic strategies targeting gut microbiota to prevent and treat CVD.     

LXR is crucial in lipid metabolism

Liver X receptors (LXRalpha and LXRbeta) are members of the nuclear receptor superfamily and are activated by oxysterols and intermediates in the cholesterol synthetic pathway. The pivotal role of LXRs in the metabolic conversion of cholesterol to bile acids is well established. Analysis of gene expression in LXRalpha and LXRbeta deficient mice have confirmed that LXR regulates a number of target genes involved in both cholesterol and fatty acid metabolism in liver, macrophages and intestine. The observation that LXRalpha is responsive to fatty acids and is expressed in metabolic tissues suggests that it also plays a general role in lipid metabolism. Adipose tissue is the main storage site for fat in the body and plays a crucial role in overall lipid handling. Both LXRalpha and LXRbeta are expressed and activated by endogenous and synthetic ligands, which lead to lipid accumulation into adipocytes. This indicates an important regulatory role of LXR in several metabolic signaling pathways in the adipose tissue, such as glucose uptake and de novo fatty acid synthesis. Here, we review recent studies that provide new insights into the mechanisms by which LXRs act to influence fatty acid synthesis in liver and adipose tissue.     

25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles

The CYP27 gene is expressed in arterial endothelium, macrophages, and other tissues. The gene product generates sterol intermediates that function as ligands for nuclear receptors prior to their transport to the liver for metabolism, mostly to bile acids. Most attention has been given to 27-hydroxycholesterol as a ligand for LXR activated receptors and to chenodeoxycholic acid as a ligand for farnesoid X activated receptors (FXRs). Expression of the pathway in macrophages is essential for normal reverse cholesterol transport. Thus, ABC transporter activity is upregulated, which enhances cholesterol efflux. Absence of these mechanisms probably accounts for the accelerated atherosclerosis that occurs in cerebrotendinous xanthomatosis. Accumulation of 27-hydroxycholesterol in human atheroma is puzzling and may reflect low levels of oxysterol 7alpha-hydroxylase activity in human macrophages. The same enzyme determines the proportion of mono-, di-, and tri-hydroxy bile acids synthesized in the liver. Oxysterol 7alpha-hydroxylase deficiency is a molecular basis for cholestatic liver disease. Chenodeoxycholic acid, the major normal end product, downregulates expression of cholesterol 7alpha-hydroxylase via the FXR/short heterodimer protein nuclear receptor and thus limits total bile acid production. The challenge is to quantify in a physiologic setting the magnitude of the pathway in different tissues and to further evaluate the biologic roles of all the intermediates that may function as ligands for orphan nuclear receptors or via other regulatory mechanisms.     

Amino acids and gut function

The intestine is not only critical for the absorption of nutrients, but also interacts with a complex external milieu. Most foreign antigens enter the body through the digestive tract. Dietary amino acids are major fuels for the small intestinal mucosa, as well as important substrates for syntheses of intestinal proteins, nitric oxide, polyamines, and other products with enormous biological importance. Recent studies support potential therapeutic roles for specific amino acids (including glutamine, glutamate, arginine, glycine, lysine, threonine, and sulfur-containing amino acids) in gut-related diseases. Results of these new lines of work indicate trophic and cytoprotective effects of amino acids on gut integrity, growth, and health in animals and humans.     

机体胆汁酸肠-肝轴的研究进展

机体肠道与肝脏间的交互作用形成肠-肝轴,后者的紊乱是肝脏疾病发生的重要原因,而良好的肠道稳态和肝脏的保护对维持机体内环境的稳定起着重要作用。胆汁酸(胆盐)作为肠-肝轴循环中的重要组成成分,不仅参与了机体营养物质的消化代谢,还作为一种信号分子和代谢调节因子,能够激活核受体和G蛋白偶联受体(GPCR)信号通路参与调节肝脏脂质、葡萄糖和能量平衡,维持机体代谢平衡。本文将结合近年来有关胆汁酸的研究进展,从胆汁酸的来源、在肠-肝轴中的循环以及胆汁酸在机体中的作用等方面进行综述,以加深对肠-肝轴重要性的理解。