Bile-ology: from bench to bedside

Bile-ology: from bench to bedside 胆汁学:从研究到临床 1 2 first-author 1 3 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:whuang@coh.org †E-mail:whuang@coh.org whuang@coh.org Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA State Key Laboratory of Cellular Stress Biology; Innovation Center for Cell Signaling Network; School of Life Sciences, Xiamen University, Xiamen 361005, China State Key Laboratory of Cellular Stress Biology; Innovation Center for Cell Signaling Network; School of Life Sciences, Xiamen University, Xiamen 361005, China College of Life Science, Zhejiang University, Hangzhou 310058, China College of Life Science, Zhejiang University, Hangzhou 310058, China Bile acids (BAs) are originally known as detergents essential for the digestion and absorption of lipids. In recent years, extensive research has unveiled new functions of BAs as gut hormones that modulate physiological and pathological processes, including glucose and lipid metabolism, energy expenditure, inflammation, tumorigenesis, cardiovascular disease, and even the central nervous system in addition to cholesterol homeostasis, enterohepatic protection and liver regeneration. BAs are closely linked with gut microbiota which might explain some of their crucial roles in organs. The signaling actions of BAs can also be mediated through specific nuclear receptors and membrane-bound G protein-coupled receptors. Several pharmacological agents or bariatric surgeries have demonstrated efficacious therapeutic effects on metabolic diseases through targeting BA signaling. In this mini-review, we summarize recent advances in bile-ology, focusing on its translational studies. 胆汁酸广为人知的功能是帮助脂类的消化和吸收.近几年的大量研究表明:胆汁酸除了在胆固醇代谢平衡、肝肠循环以及调节肝脏再生等方面的作用以外,还可以作为一类肠道激素调节机体的生理和病理反应,包括糖脂代谢、能量消耗、炎症、肿瘤、心血管疾病和神经系统疾病等.胆汁酸与肠道菌群关系密切,这可能也是其在各器官中发挥重要功能的原因之一.胆汁酸调节的信号主要通过其特异的胆酸核受体与G蛋白偶联的胆酸膜受体进行调节.研究表明一些药理制剂或者外科减肥手术在代谢性疾病中的疗效也是通过靶向胆汁酸信号实现的.本文主要总结了胆汁学最新的研究进展,重点关注了与胆汁酸信号通路调节相关的转化医学研究进展. Bile acid Gut microbiota Farnesoid X receptor G protein-coupled bile acid receptor Metabolic disease 胆汁酸 肠道菌群 法尼醇受体 G蛋白偶联胆汁酸受体 代谢性疾病 Introduction 1 Bile acids (BAs) are amphipathic molecules synthesized from cholesterol in the liver and efficiently retained within an enterohepatic circulation through a complex biosynthetic pathway, biliary secretion, bacterial modification, ileum reabsorption, and liver reflux (Slijepcevic and van de Graaf, 2017 2017 ). Because of their unique detergent properties, BAs have long been known to facilitate the absorption, transport, and metabolism of dietary fats and lipid-soluble nutrients. Excitingly, extensive research in the last decade has demonstrated that in addition to the role in cholesterol homeostasis, fat absorption and digestion, BAs play important roles as signaling molecules in regulating physiological and pathological processes including glucose and lipid metabolism, energy expenditure, inflammation, cancer, heart failure, Alzheimer’s disease (AD), and aging. In this mini-review, we summarize recent advances in the understanding of BA signaling, gut microbiota, and the related regulatory functions in metabolic diseases (Fig. 1 1 ), and discuss the development of new BA-based therapeutics for the treatment of metabolic diseases by targeting nuclear BA receptor farnesoid X receptor (FXR) and membrane Takeda G protein-coupled BA receptor (GPBAR or TGR5). Farnesoid X receptor (FXR) regulates the expression of Takeda G protein-coupled bile acid (BA) receptor (TGR5). Both as BA receptors, FXR and TGR5 are closely involved in BA signaling and the balance of gut microbiota, resulting in the regulation of BA-related diseases. NAFLD, non-alcoholic fatty liver disease; IBD, inflammatory bowel disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis BAs, gut microbiota, and related metabolic diseases 1 BAs’ synthesis and their enterohepatic circulation have been elaborately reviewed previously (Li and Chiang, 2014 2014 ; Mertens et al., 2017 2017 ). BAs and gut microbiota are closely linked. Gut microbiota is involved in the biotransformation of BAs through deconjugation, dehydroxylation, and reconjugation of BAs (Ridlon et al., 2006 2006 ). The gut-to-liver axis of microbiota plays a crucial role in the regulation of BA metabolism, BA pool size, and enterohepatic circulation of BAs (Chiang and Ferrell, 2018 2018 ). Reciprocally, BAs shape the gut microbiome to regulate host metabolism. BAs have antimicrobial activity by damaging the bacterial cell membrane and thus inhibiting bacteria outgrowth (Inagaki et al., 2006 2006 ; Kurdi et al., 2006 2006 ). Importantly, BAs link the gut microbiota to both hepatic and intestinal metabolism, and this tripartite relationship has been implicated in different metabolic diseases, which we will highlight below. Obesity 2 Obesity has become one of the most prevalent public health concerns worldwide. Being overweight is related to the incidence of several comorbidities, including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) (Golay and Ybarra, 2005 2005 ; Esser et al., 2014 2014 ), cardiovascular disease (Sommer and Twig, 2018 2018 ), stroke and cancer (Xu and Mishra, 2018 2018 ). Elevated serum BA levels have been observed a long time ago in overweight subjects as compared to those with an ideal weight (Halmy et al., 1986 1986 ). Later, many studies have found increased total BA levels in humans with obesity (Prinz et al., 2015 2015 ; Chávez-Talavera et al., 2017 2017 ). This evidence indicates that BAs may be closely related to the pathogenesis of obesity. Bariatric surgery represents a viable clinical intervention to efficaciously remit obesity and its associated complications. Interestingly, it has been reported that bariatric surgeries, including Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), increase circulating BA concentrations (Nakatani et al., 2009 2009 ; Gerhard et al., 2013 2013 ). Serum BA levels were higher in obese patients who received RYGB when compared to controls (no RYGB), and elevated levels of BAs were sustained for at least 2 years post-surgery (Nakatani et al., 2009 2009 ; Patti et al., 2009 2009 ). Further investigation demonstrated that the mechanism is due to the regulation of specific BAs (Wang et al., 2017 2017 ; Browning et al., 2019 2019 ). This might also be explained by the evidence that plasma BAs were negatively correlated with cognitive restraint of eating (Prinz et al., 2015 2015 ). Obesity is mainly due to a long-term excess energy intake above energy expenditure. Studies using isolated rodent tissues indicated that a BA mixture (cholic acid (CA), deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA) in both un-conjugated and glycine-and taurine-conjugated forms) increased secretion of glucose-dependent insulinotropic peptide, glucagon-like peptide-1 (GLP-1), polypeptide YY and neurotensin through activating TGR5, leading to metabolic improvement (Kuhre et al., 2018 2018 ). BAs are also identified as regulators of energy expenditure. In brown adipose tissue (BAT), BAs activate TGR5, resulting in increased concentrations of cyclic adenosine 3',5'-monophosphate (cAMP); cAMP subsequently activates type-2 deiodinase (D2) which induces active triiodothyronine (T3), and this cascade results in enhanced energy expenditure in both murine and human BAT by inducing the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and uncoupling protein 1 (UCP1) (Watanabe et al., 2006 2006 ; Broeders et al., 2015 2015 ). Accumulating evidence indicates that the gut microbiota plays a significant role in the development of obesity and obesity-associated disorders (Shen et al., 2013 2013 ) by impacting the composition and relative abundance of BA species (Ridaura et al., 2013 2013 ). Turnbaugh et al. ( 2006 2006 ) found that the obese microbiome has an increased capacity to harvest energy from the diet. In this process, the relative abundance of the two dominant bacterial divisions, Bacteroidetes and Firmicutes, contributes to energy homeostasis. Recently, Worthmann et al. ( 2017 2017 ) found that BAs are also involved in energy homeostasis regulated by gut microbiota stimulated by cold. They found that cold-induced conversion of cholesterol to BAs in mice shapes the gut microbiome and promotes adaptive thermogenesis. In this process, the crucial enzyme for the alternative BA synthetic pathway, sterol 27-hydroxylase (CYP27A1), is selectively activated in the liver, and thus modulates gut-microbiome composition (Kuipers and Groen, 2017 2017 ). This research provides a BAT–liver–intestine axis in connecting the BA homeostasis with obesity. Taken together, BAs play dual roles by regulating both energy intake and energy expenditure in balancing body weight. Interestingly, the obesity-treating strategies by targeting BAs also display some conflicting results. Diet-induced obesity is ameliorated by BA-binding resin (Kobayashi et al., 2007 2007 ). An additional series of studies demonstrated that BA sequestrants improve metabolic diseases (Beysen et al., 2012 2012 ; Hansen et al., 2017 2017 ). The profile of BAs is fluctuated delicately according to many factors, including circumstance temperature (Worthmann et al., 2017 2017 ), nutrient intake (Matysik et al., 2011 2011 ; Schmid et al., 2016 2016 ), drug treatment (Camilleri and Gores, 2015 2015 ), surgery (Tian et al., 2017 2017 ), etc. Thus, these reports implicate the sophisticated mechanism of obesity regulated by BA signaling, and pinpoint the importance of analyzing the composition of BAs in different conditions in terms of therapeutic strategies. T2D 2 Changes in circulating BA profile have been implicated in the pathogenesis of insulin resistance and T2D including gestational diabetes mellitus (Haeusler et al., 2013 2013 ; Maghsoodi et al., 2019 2019 ). T2D is associated with an increase in the hydrophobicity of the circulating BA pool in humans (Haeusler et al., 2013 2013 ). Consistent with this, hydrophilic BA subtypes, such as tauroursodeoxycholic acid (TUDCA), have been shown to protect against inflammation and improve insulin sensitivity in rodent models and patients with T2D (Mahmoud and Elshazly, 2014 2014 ; Shima et al., 2018 2018 ). The mechanism of metformin also confirms this observation (Sun et al., 2018 2018 ). Sun et al. ( 2018 2018 ) found that metformin acts through lowering levels of Bacteroides fragilis in the gut, resulting in a decrease in the enzyme bile salt hydrolase and a subsequent increase of hydrophilic glycoursodeoxycholic acid (GUDCA), which might inhibit intestinal FXR and increase the level of liver BAs, leading to improvement of metabolic dysfunction including hyperglycemia. T2D is also proposed to be associated with the ratio of 12α-hydroxylated BAs (CA and DCA) to non-12α-hydroxylated BAs (CDCA and lithocholic acid (LCA)). It has been reported that ratios of 12α-hydroxylated/non-12α-hydroxylated BAs were associated with key features of insulin resistance, including higher insulin, proinsulin, glucose, glucagon and triglyceride levels, and lower high-density lipoprotein associated cholesterol by comparing a cohort of 200 healthy subjects and 35 T2D patients (Haeusler et al., 2013 2013 ). A similar result was also reported that in patients with verified insulin resistance, enhanced BA synthesis and increased ratio of 12α-hydroxylated (CA and DCA) to non-12α-hydroxylated (CDCA, LCA, and ursodeoxycholic acid (UDCA)) BAs were observed (Kaur et al., 2015 2015 ). Consistently, sterol 12α-hydroxylase knockout ( Cyp8b1 −/− ) mice with low levels of 12α-hydroxylated BAs showed increased GLP-1 and improved glucose tolerance (Kaur et al., 2015 2015 ). Non-12α-hydroxylated BAs were also reported to be negatively correlated with fasting glucose in women with previous gestational diabetes mellitus with homeostatic model assessment of insulin resistance (HOMA-IR) > 2.8 (Maghsoodi et al., 2019 2019 ). These results suggest 12α-hydroxylated BAs as negative regulators of insulin action. However, in a randomized trial of lifestyle-induced weight loss in 74 non-smoking men with metabolic syndrome, data show that individuals with improved metabolic control by lifestyle modifications have lower serum levels of BAs and GLP-1, and changes in serum BA composition towards an increased 12α-hydroxylated/non-12α-hydroxylated ratio (Biemann et al., 2016 2016 ). Although this might due to the difference in the specific health condition of individuals, nevertheless the conflicting results suggest that metabolism is regulated by a dynamically changing profile of BAs. NAFLD 2 The prevalence of NAFLD that is comprised of non-alcoholic fatty liver (NAFL) and its exacerbated condition non-alcoholic steatohepatitis (NASH) is increasing worldwide, reflecting the current epidemics of obesity, insulin resistance and T2D, and metabolic syndrome (Mullish et al., 2018 2018 ). The relationship between BAs and NAFLD has been extensively investigated previously (Carr and Reid, 2015 2015 ; Chávez-Talavera et al., 2017 2017 ). BAs were found to be significantly increased in NASH patients over that when they were in simple steatosis (Bechmann et al., 2013 2013 ; Jiao et al., 2018 2018 ). The ratio of CDCA was lower while DCA was significantly increased in NASH patients, and there was a comparable CA and UDCA ratio, suggesting that the elevated 12α-hydroxylated (CA and DCA)/non-12α-hydroxylated (CDCA and UDCA) ratio may also highly correlate with the progress of NAFLD in addition to T2D. Surprisingly, the fibroblast growth factor 19 (FGF19)-FXR pathway was suppressed in NASH patients, indicating that the 12α-hydroxylated/non-12α-hydroxylated ratio of BAs, but not the BA pool size, could be the major regulatory element for NASH (Jiao et al., 2018 2018 ). Recently, Puri et al. ( 2018 2018 ) found that the presence and severity of NASH are associated with specific changes in circulating BAs. Increase of key BAs was associated with higher grades of steatosis (taurocholic acid (TCA)), lobular (glycocholic acid (GCA)) and portal inflammation (taurolithocholic acid (TLCA)), and hepatocyte ballooning (TCA). Conjugated CA and TCA directly correlated, while the secondary to primary BA ratio inversely correlated to the NAFLD activity score. A higher ratio of total secondary to primary BA decreased and higher conjugated cholate increased the likelihood of significant fibrosis. These observations further provide evidence to support the idea that specific BAs affect specific aspects of NASH. Gut microbes produce enzymes that convert primary BAs into secondary BAs in the intestines. Consistently, specific species of gut microbe control a diverse effect on NAFLD. For instance, Parabacteroides distasonis is one of the 18 core members in the gut microbiota of humans (Falony et al., 2016 2016 ). Treatment with live P. distasonis dramatically altered the BA profile with elevated LCA and UDCA that reduced hyperlipidemia by activating the FXR pathway and repairing gut barrier integrity (Wang et al., 2019 2019 ). Actinobacteria and Firmicutes are the gut phyla capable of degrading all conjugated BAs, with Bacteroidetes limited to tauro-conjugation activities, exclusively (Jones et al., 2014 2014 ). It has also been shown that the gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD (Soderborg et al., 2018 2018 ). Another example is that Bilophila wadsworthia aggravates high-fat diet (HFD)-induced metabolic dysfunctions in mice. B. wadsworthia acts on both host and microbiota by worsening HFD-induced intestinal inflammation, inhibiting pathways involved in metabolic homeostasis, favoring increased lipopolysaccharides production and translocation, and decreasing butyrate production by the microbiota (Natividad et al., 2018 2018 ). In the HFD setting, increased production of taurine-conjugated BAs had been proposed to underlie the expansion of B. wadsworthia (Devkota et al., 2012 2012 ). Many studies have investigated the shift of the gut microbiome in NAFLD (Chen et al., 2019 2019 ). These results further support the idea that different genera of bacteria exert different functions in gut, suggesting that microbiome restoration could be an alternative approach for the treatment of NAFLD. Inflammatory bowel disease (IBD) 2 BAs significantly affect gastrointestinal motor, sensory and secretory functions, intestinal barrier permeability and regulation of the inflammatory response (Panek-Jeziorna and Mulak, 2017 2017 ). In the healthy gut, these primary BAs aid in the digestion of lipids and are deconjugated by microbes to secondary BAs, while the primary BAs including CA and CDCA were enriched in IBD (Franzosa et al., 2019 2019 ). The relative overabundance of primary BAs in the guts of IBD patients is consistent with the disruption of BA transformation activities in the IBD microbiome (Duboc et al., 2013 2013 ). High-level fecal DCA may act as an endogenous danger signal to activate nod-like receptor protein 3 (NLRP3) inflammasome and contribute to HFD-related colonic inflammation (Zhao et al., 2016 2016 ). It has also been reported that LCA specifically inhibits NLRP3 inflammasome activation via activating TGR5–cAMP–protein kinase A (PKA) axis (Guo CS et al., 2016 2016 ). The anti-inflammatory function of TGR5 in protection against IBD is also mediated by inhibition of nuclear factor κB (NF-κB)-dependent proinflammatory cytokine production (Yoneno et al., 2013 2013 ). Although there has been an increasing number of studies on the role of BAs in IBD (Hegyi et al., 2018 2018 ; Tiratterra et al., 2018 2018 ), no cure has been found for treating IBD. Further understanding of the pathogenic mechanisms underlying IBD is still urgently needed. Other diseases 2 BAs, especially secondary BAs, have been well known as strong carcinogens or promoters of colon cancers (Nguyen et al., 2018 2018 ). The BA receptors FXR and TGR5 not only play key roles in regulating BA homeostasis but also are essential in suppressing BAs’ carcinogenic effects (Modica et al., 2008 2008 ; Wang et al., 2013 2013 ). This is supported by the facts that FXR-null mice have increased BA pool and spontaneous hepatocarcinogenesis (Kim et al., 2007 2007 ; Yang et al., 2007 2007 ; Wang et al., 2008 2008 ), and deficiency of TGR5 enhances chemically induced liver carcinogenesis (Chen et al., 2013 2013 ). Additionally, Lee et al. ( 2019 2019 ) recently reported that BAs activate yes-associated protein (YAP) through the nuclear vitamin D receptor, resulting in tumor metastasis to lymph nodes. On the other hand, BA metabolism is also involved in antitumor immunosurveillance. Ma et al. ( 2018 2018 ) found that gut microbiome-mediated primary-to-secondary BA conversion provides BA messengers to control a chemokine-dependent accumulation of hepatic natural killer T (NKT) cells, leading to selective antitumor in the liver. Therefore, the hypothesis of treating cancer by targeting BAs still needs further detailed investigation. In addition to the above described metabolic diseases, BAs also participate in the development and progression of cardiovascular diseases, including heart failure. This has been extensively reviewed recently (Tang et al., 2019 2019 ). BA receptors FXR and TGR5 are expressed in endothelial cells, and a variety of FXR ligands show efficacious antihypertensive effects (He et al., 2006 2006 ; Verbeke et al., 2014 2014 ; Schwabl et al., 2017 2017 ), implying the involvement of BA signaling in hypertension. Recent work suggests that microbial disturbances linked to BA profiles are implicated in neurodegenerative disorders. Because of their involvement in immune, neuroendocrine, and neural pathways, gut microbiota has been shown to regulate microglial maturation and function, and may contribute to AD (Nho et al., 2019 2019 ). Interestingly, BAs might also be closely related to aging because diet enriched in CA enhances health span and lifespan of progeria mice (Bárcena et al., 2018 2018 ). All of these results demonstrate the importance of maintaining the homeostasis of BAs as well as gut microbiota. The BA/gut microbiome axis might be a promising therapeutic target for the treatment of these diseases (Fig. 1 1 ). Therapeutic strategies by targeting BA signaling 1 Drug discovery by targeting BA receptors 2 BAs are metabolic regulators that act as signaling molecules through receptor-dependent and -independent pathways. The most prominent signaling molecules mediating BA signaling are the nuclear receptor FXR and the membrane receptor TGR5. Both are implicated in the regulation of lipid, glucose, energy metabolism, and inflammation. Dysregulation of these pathways might contribute to the development of the diseases summarized above. 3.1.1 Drug discovery by targeting FXR FXR is expressed in various tissues but its roles in BA signaling have mostly been studied in the liver and the intestine. FXR regulates a network of genes in hepatic BA synthesis, biliary BA secretion, intestinal BA absorption, and hepatic BA uptake, and thus plays a key role in the regulation of BA homeostasis and related gut microbiota composition that has been extensively reviewed (Li and Chiang, 2014 2014 ). Extensive research has been undertaken to elucidate the molecular mechanism of BA signaling-related diseases regulated by FXR, including nuclear translocation (Liu et al., 2015 2015 ; Thompson et al., 2018 2018 ), post translational modifications (Kemper et al., 2009 2009 ; Byun et al., 2018 2018 ; Blokker et al., 2019 2019 ), and the transcription activity of FXR (Li and Chiang, 2014 2014 ). FXR is a promising drug target for metabolic diseases. As a transcriptional factor, the activity of FXR is mediated by ligand binding and regulates BA signaling-related diseases (Jin and Li, 2010 2010 ; Ding et al., 2015 2015 ). Several BAs regulate FXR activity as ligands, for example, CDCA, DCA, LCA, and CA may activate FXR, while UDCA, tauro-α-muricholic acid (T-α-MCA) and T-β-MCA may antagonize FXR. Dozens of FXR ligands, including agonists, antagonists, and selective modulators, have been identified to bind FXR and regulate metabolism by modulating BA homeostasis. The FXR agonists include steroid compounds such as BAs and their derivatives, 17β-(4-hydroxybenzoyl) androsta-3,5-diene-3-carboxylic acid (MFA-1), and non-steroid ligands including isoxazole GW4064 and derivatives (Feng et al., 2009 2009 ), benzopyran fexaramine and derivatives (Downes et al., 2003 2003 ), azapyrene WAY-362450 and derivatives (Flatt et al., 2009 2009 ), benzimidazolyl amide compounds (Richter et al., 2011 2011 ), etc. Additionally, some drugs on the market are identified as novel FXR modulators and have been repurposed to show promising potential in treating BA-mediated diseases by targeting FXR, such as the anti-parasitic drug ivermectin and its analogues (Jin et al., 2013 2013 , 2015 2015 ), and anti-hypertension drugs 1,4-dihydropyridines (DHPs) (Wei et al., 2018 2018 ). There are also many natural products identified as FXR ligands. Many of them have been in clinical trial for treating FXR-mediated diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), NASH, duodenal polyps, etc. (Jia et al., 2018 2018 ). Among them, obeticholic acid (OCA, a derivative of CDCA) and UDCA have been approved by the US Food and Drug Administration (FDA) in treating PBC. OCA is currently the only FDA-designated breakthrough therapy in development for NASH with compensated cirrhosis. The FXR ligands in clinical trials are summarized in Fig. 2 2 . The development of these candidates strongly supports the feasibility and value of FXR as a target for metabolic diseases. 3.1.2 Drug discovery by targeting TGR5 TGR5 is widely expressed in the intestine, gall bladder, adipose tissue, skeletal muscle, pancreas, and the hepatic sinusoidal endothelial cells and Kupffer cells but is not expressed in hepatocytes (Maruyama et al., 2002 2002 ; Keitel and Häussinger, 2011 2011 ). Among all BAs, TLCA is the most potent TGR5 agonist, followed by taurodeoxycholic acid (TDCA), taurochenodeoxycholic acid (TCDCA), and TCA (Li and Chiang, 2014 2014 ). Both as BA receptors, interestingly, the transcription of TGR5 is directly regulated by FXR through binding to the promoter of Tgr5 (Pathak et al., 2017 2017 ). The molecular signaling pathways regulated by TGR5 have been extensively reviewed (Guo C et al., 2016 2016 ). As a metabolic regulator, TGR5 is involved in energy homeostasis, BA homeostasis, as well as glucose metabolism and has been extensively investigated in the current decade (Duboc et al., 2014 2014 ; Velazquez-Villegas et al., 2018 2018 ; Donkers et al., 2019 2019 ; Ferrell et al., 2019 2019 ; Schmid et al., 2019 2019 ). Thus, in recent years, TGR5 has been the target of drug discovery efforts in the hope of identifying effective treatments for metabolic diseases including T2D, obesity, atherosclerosis, fatty liver disease, and cancer (Hodge and Nunez, 2016 2016 ; Tian et al., 2017 2017 ). Recently, Finn et al. ( 2019 2019 ) identified an orally administered TGR5 agonist RXD8940 that can induce incretin (GLP-1, GLP-2, and peptide YY) secretion which improves liver steatosis and insulin sensitivity in NASH and NAFLD. Berberine exerts powerful renoprotective effects on diabetic nephropathy by activating TGR5 and inhibiting sphingosine 1-phosphate receptor 2 (S1P2)/mitogen-activated protein kinase (MAPK) signaling (Yang et al., 2016 2016 ). A selective TGR5 agonist SB756050 in clinical trial phase I showed good tolerance and safety, but without therapeutic effects on T2D (Hodge et al., 2013 2013 ). There are also several dual TGR5/FXR agonists in trial (Fig. 2 2 ), but tolerance and side effects are still critical obstacles for their development. Aside from BAs, a class of plant natural triterpenes, including betulinic acid, oleanolic acid, and ursolic acid, were identified as selective TGR5 agonists with physiologic functions (Sato et al., 2007 2007 ; Genet et al., 2010 2010 ; Lo et al., 2017 2017 ; Chianese et al., 2019 2019 ). These natural oleanane-type triterpenes have been non-BA drug templates for target TGR5 (Castellano et al., 2013 2013 ) but not for FXR even though FXR and GPBAR1 have similar binding pockets for BAs. Lu et al. ( 2018 2018 ) found that a structurally similar triterpene, hedragonic acid, selectively activates FXR. These results suggest the oleanane-type triterpene may be a novel structure template for drug design of a selective modulator for FXR or TGR5, or dual FXR/TGR5 agonist with pharmaceutical value. Bariatric surgeries 2 In addition to pharmacological agents, there are other therapies which target BA signaling. Bariatric surgery is the most effective strategy, to date, for the treatment of obesity and its comorbidities. The outcomes and mechanisms for bariatric surgery are under extensive investigation (Tian et al., 2017 2017 ; Sandoval, 2019 2019 ). The BA receptors FXR and TGR5 are shown as two potential targets for bariatric surgery VSG (Ryan et al., 2014 2014 ; Ding et al., 2016 2016 ; McGavigan et al., 2017 2017 ). The mRNA expression of FXR, small heterodimer partner (SHP), and peroxisome proliferator-activated receptor α (PPARα) in the liver was significantly higher in the laparoscopic sleeve gastrectomy (SG) group than in the Sham-operated group (Watanabe et al., 2018 2018 ), further supporting the idea that the therapeutic effect of SG on NAFLD may also be by targeting the FXR signaling pathway. Duodenal-jejunal bypass surgery has a direct effect on NASH improvement. The increase of plasma BA level followed by the stimulation of FXR signaling may contribute to this phenomenon (Tsuchiya et al., 2018 2018 ). CYP8B1 is a BA synthetic enzyme expressed primarily in hepatocytes (Wang et al., 2005 2005 , 2007 2007 ). CYP8B1 is required for the synthesis of 12α-hydroxylated BAs and thereby determines the ratio of 12α-hydroxylated to non-12α-hydroxylated BAs (Li and Chiang, 2014 2014 ). The BA profile hydrophobicity plays a crucial role in intestinal fat absorption, and Cyp8b1 ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption (Bertaggia et al., 2017 2017 ). Genetic ablation of Cyp8b1 decreases BA profile hydrophobicity and protects against several metabolic diseases, including obesity and T2D, in mice (Zaborska and Cummings, 2018 2018 ). Of note, the percentage of 12α-hydroxylated BAs was reduced after SG, associated with overexpression of V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG) and lower mRNA and protein levels of CYP8B1 (Wang et al., 2017 2017 ). Interestingly, MAFG is an FXR target gene that transcriptionally represses CYP8B1 expression (de Aguiar Vallim et al., 2015 2015 ); these results suggest that in addition to FXR and TGR5, the downstream CYP8B1 may present an alternative target for bariatric surgery. Future perspectives 1 Although there are some conflicting reports about the BA level in metabolic diseases, as mentioned in this review, there is increasing evidence that the BA composition plays a more important role than the total BA level in regulating gut microbiome and metabolism. One important example is the BA hydrophobicity modulated by the ratio of 12α-hydroxylated to non-12α-hydroxylated BAs that is switched by the activity of CYP8B1. However, FXR suppresses expression of both CYP7A1 and CYP8B1, implying a possible mechanism for the side effects of FXR agonists. Selective regulation of CYP8B1 expression may lead to the development of BA-based therapeutics with fewer adverse side effects. TGR5 has been shown to reduce hepatic CYP8B1 protein expression with no effect on hepatic CYP7A1 expression (McGavigan et al., 2017 2017 ), whereas drug development by targeting TGR5 shows other side effects beyond BA signaling. Thus, specific genetic modulation or inhibition by directly targeting CYP8B1 may be a promising therapeutic modality for metabolic diseases. There is also a conundrum on whether activating or inhibiting FXR will be beneficial for maintaining the homeostasis of metabolism. Numerous data demonstrate that FXR agonists exert efficacious therapeutic effects on metabolic diseases. This can be supported by the drug development processes mentioned in Fig. 2 2 . However, there is increasing evidence that FXR antagonists ameliorate the disease condition by inhibiting the activity of FXR, especially in the intestine. HFD-fed intestine-specific FXR-null mice show lower diet-induced obesity; tempol improves obesity via inhibition of intestinal FXR by T-β-MCA (Li et al., 2013 2013 ). It is well known that throughout the gastroenteric tract the most crucial role of FXR is to maintain the BA homeostasis, associated with the homeostasis of gut microbiota, resulting in the final metabolic homeostasis. The regulation of FXR activity by the BAs in the intestine may mainly be the intermediate steps involved in this homeostasis maintenance. With the slow process of drug development targeting BA receptors including FXR and TGR5, side effects are the most difficult obstacles, suggesting over activating of the BA receptors might cause side effects because of the interruption of this homeostasis, and fine tuning by modulators might be more feasible. Furthermore, directly modulating the downstream enzymes included in BA synthesis might be an alternative strategy for BA-related diseases. In a similar way, it will be necessary to identify which gut microbes are beneficial and feasible. Careful selection of commensal bacteria for probiotics may lead to an effective therapy for metabolic diseases. Therefore, with an increasing understanding of the complicated interaction between the gut microbiota and host, studies on single gut symbioses are urgently required to define the exact functions of a given bacterium in causing disease or maintaining health. It is important to note that, to date, most findings on the crosstalk among BAs, gut microbiota and metabolic diseases are from rodent models. However, the BA composition of rodents and humans is different. In mice, the majority of CDCA is converted to α-muricholic acid (MCA) and β-MCA, and accordingly, CA and MCAs are the major primary BAs in the mouse BA pool. Therefore, it is not well known whether alterations of BAs in mice also occur in humans. It is noteworthy that inconsistent results have been seen in a few human studies. Thus the differences in BA composition between humans and mice need to be considered when interpreting data from mice studies. Additionally, it is of particular importance to elucidate how a human gut microbiota influences BA composition. To improve the clinical trial of drug candidates, testing on large animals such as monkeys in preclinical trial might be helpful for the medical translation. References C Bárcena , PM Quirós , S Durand , 等 . Methionine restriction extends lifespan in progeroid mice and alters lipid and bile acid metabolism . Cell Rep , 2018 . 24 ( 9 ): 2392 - 2403 . 30157432 DOI: 10.1016/j.celrep.2018.07.089 http://doi.org/10.1016/j.celrep.2018.07.089 . Methionine restriction extends lifespan in progeroid mice and alters lipid and bile acid metabolism LP Bechmann , P Kocabayoglu , JP Sowa , 等 . Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis . Hepatology , 2013 . 57 ( 4 ): 1394 - 1406 . 23299969 DOI: 10.1002/hep.26225 http://doi.org/10.1002/hep.26225 . Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis E Bertaggia , KK Jensen , J Castro-Perez , 等 . Cyp8b1 ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption . Am J Physiol Endocrinol Metab , 2017 . 313 ( 2 ): E121 - E133 . 28377401 DOI: 10.1152/ajpendo.00409.2016 http://doi.org/10.1152/ajpendo.00409.2016 . Cyp8b1 ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption C Beysen , EJ Murphy , K Deines , 等 . Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study . Diabetologia , 2012 . 55 ( 2 ): 432 - 442 . 22134839 DOI: 10.1007/s00125-011-2382-3 http://doi.org/10.1007/s00125-011-2382-3 . Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study R Biemann , M Penner , K Borucki , 等 . Serum bile acids and GLP-1 decrease following telemetric induced weight loss: results of a randomized controlled trial . Sci Rep, 6:30173 , 2016 . DOI: 10.1038/srep30173 http://doi.org/10.1038/srep30173 . Serum bile acids and GLP-1 decrease following telemetric induced weight loss: results of a randomized controlled trial BA Blokker , M Maijo , M Echeandia , 等 . Fine-tuning of sirtuin 1 expression is essential to protect the liver from cholestatic liver disease . Hepatology , 2019 . 69 ( 2 ): 699 - 716 . 30229970 DOI: 10.1002/hep.30275 http://doi.org/10.1002/hep.30275 . Fine-tuning of sirtuin 1 expression is essential to protect the liver from cholestatic liver disease EPM Broeders , EBM Nascimento , B Havekes , 等 . The bile acid chenodeoxycholic acid increases human brown adipose tissue activity . Cell Metab , 2015 . 22 ( 3 ): 418 - 426 . 26235421 DOI: 10.1016/j.cmet.2015.07.002 http://doi.org/10.1016/j.cmet.2015.07.002 . The bile acid chenodeoxycholic acid increases human brown adipose tissue activity MG Browning , BM Pessoa , J Khoraki , 等 . Changes in bile acid metabolism, transport, and signaling as central drivers for metabolic improvements after bariatric surgery . Curr Obes Rep, Epub ahead of print , 2019 . DOI: 10.1007/s13679-019-00334-4 http://doi.org/10.1007/s13679-019-00334-4 . Changes in bile acid metabolism, transport, and signaling as central drivers for metabolic improvements after bariatric surgery S Byun , DH Kim , D Ryerson , 等 . Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis . Nat Commun , 2018 . 9 ( 1 ): 2590 29968724 DOI: 10.1038/s41467-018-04697-5 http://doi.org/10.1038/s41467-018-04697-5 . Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis M Camilleri , GJ Gores . Therapeutic targeting of bile acids . Am J Physiol Gastrointest Liver Physiol , 2015 . 309 ( 4 ): G209 - G215 . 26138466 DOI: 10.1152/ajpgi.00121.2015 http://doi.org/10.1152/ajpgi.00121.2015 . Therapeutic targeting of bile acids RM Carr , AE Reid . FXR agonists as therapeutic agents for non-alcoholic fatty liver disease . Curr Atheroscler Rep , 2015 . 17 ( 4 ): 16 DOI: 10.1007/s11883-015-0500-2 http://doi.org/10.1007/s11883-015-0500-2 . FXR agonists as therapeutic agents for non-alcoholic fatty liver disease JM Castellano , A Guinda , T Delgado , 等 . Biochemical basis of the antidiabetic activity of oleanolic acid and related pentacyclic triterpenes . Diabetes , 2013 . 62 ( 6 ): 1791 - 1799 . 23704520 DOI: 10.2337/db12-1215 http://doi.org/10.2337/db12-1215 . Biochemical basis of the antidiabetic activity of oleanolic acid and related pentacyclic triterpenes O Chávez-Talavera , A Tailleux , P Lefebvre , 等 . Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease . Gastroenterology , 2017 . 152 ( 7 ): 1679 - 1694e3 . 28214524 DOI: 10.1053/j.gastro.2017.01.055 http://doi.org/10.1053/j.gastro.2017.01.055 . Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease JZ Chen , M Thomsen , L Vitetta . Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics . J Cell Biochem , 2019 . 120 ( 3 ): 2713 - 2720 . 30443932 DOI: 10.1002/jcb.27635 http://doi.org/10.1002/jcb.27635 . Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics WD Chen , D Yu , BM Forman , 等 . Deficiency of G-protein-coupled bile acid receptor Gpbar1 (TGR5) enhances chemically induced liver carcinogenesis . Hepatology , 2013 . 57 ( 2 ): 656 - 666 . 22911633 DOI: 10.1002/hep.26019 http://doi.org/10.1002/hep.26019 . Deficiency of G-protein-coupled bile acid receptor Gpbar1 (TGR5) enhances chemically induced liver carcinogenesis G Chianese , SD Golin-Pacheco , O Taglialatela-Scafati , 等 . Bioactive triterpenoids from the caffeine-rich plants guayusa and maté . Food Res Int , 2019 . 115 504 - 510 . 30599971 DOI: 10.1016/j.foodres.2018.10.005 http://doi.org/10.1016/j.foodres.2018.10.005 . Bioactive triterpenoids from the caffeine-rich plants guayusa and maté JYL Chiang , JM Ferrell . Bile acid metabolism in liver pathobiology . Gene Expr , 2018 . 18 ( 2 ): 71 - 87 . 29325602 DOI: 10.3727/105221618X15156018385515 http://doi.org/10.3727/105221618X15156018385515 . Bile acid metabolism in liver pathobiology TQ de Aguiar Vallim , EJ Tarling , H Ahn , 等 . MAFG is a transcriptional repressor of bile acid synthesis and metabolism . Cell Metab , 2015 . 21 ( 2 ): 298 - 310 . 25651182 DOI: 10.1016/j.cmet.2015.01.007 http://doi.org/10.1016/j.cmet.2015.01.007 . MAFG is a transcriptional repressor of bile acid synthesis and metabolism S Devkota , YW Wang , MW Musch , 等 . Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in il 10 −/− mice . Nature , 2012 . 487 ( 7405 ): 104 - 108 . 22722865 DOI: 10.1038/nature11225 http://doi.org/10.1038/nature11225 . Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in il10−/− mice LL Ding , L Yang , ZT Wang , 等 . Bile acid nuclear receptor FXR and digestive system diseases . Acta Pharm Sin B , 2015 . 5 ( 2 ): 135 - 144 . 26579439 DOI: 10.1016/j.apsb.2015.01.004 http://doi.org/10.1016/j.apsb.2015.01.004 . Bile acid nuclear receptor FXR and digestive system diseases LL Ding , KM Sousa , LH Jin , 等 . Vertical sleeve gastrectomy activates GPBAR-1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice . Hepatology , 2016 . 64 ( 3 ): 760 - 773 . 27312543 DOI: 10.1002/hep.28689 http://doi.org/10.1002/hep.28689 . Vertical sleeve gastrectomy activates GPBAR-1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice JM Donkers , RLP Roscam Abbing , SFJ van de Graaf . Developments in bile salt based therapies: a critical overview . Biochem Pharmacol , 2019 . 161 1 - 13 . 30582898 DOI: 10.1016/j.bcp.2018.12.018 http://doi.org/10.1016/j.bcp.2018.12.018 . Developments in bile salt based therapies: a critical overview M Downes , MA Verdecia , AJ Roecker , 等 . A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR . Mol Cell , 2003 . 11 ( 4 ): 1079 - 1092 . 12718892 DOI: 10.1016/S1097-2765(03)00104-7 http://doi.org/10.1016/S1097-2765(03)00104-7 . A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR H Duboc , S Rajca , D Rainteau , 等 . Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases . Gut , 2013 . 62 ( 4 ): 531 - 539 . 22993202 DOI: 10.1136/gutjnl-2012-302578 http://doi.org/10.1136/gutjnl-2012-302578 . Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases H Duboc , Y Taché , AF Hofmann . The bile acid TGR5 membrane receptor: from basic research to clinical application . Dig Liver Dis , 2014 . 46 ( 4 ): 302 - 312 . 24411485 DOI: 10.1016/j.dld.2013.10.021 http://doi.org/10.1016/j.dld.2013.10.021 . The bile acid TGR5 membrane receptor: from basic research to clinical application N Esser , S Legrand-Poels , J Piette , 等 . Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes . Diabetes Res Clin Pract , 2014 . 105 ( 2 ): 141 - 150 . 24798950 DOI: 10.1016/j.diabres.2014.04.006 http://doi.org/10.1016/j.diabres.2014.04.006 . Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes G Falony , M Joossens , S Vieira-Silva , 等 . Population-level analysis of gut microbiome variation . Science , 2016 . 352 ( 6285 ): 560 - 564 . 27126039 DOI: 10.1126/science.aad3503 http://doi.org/10.1126/science.aad3503 . Population-level analysis of gut microbiome variation S Feng , MM Yang , ZS Zhang , 等 . Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist . Bioorg Med Chem Lett , 2009 . 19 ( 9 ): 2595 - 2598 . 19328688 DOI: 10.1016/j.bmcl.2009.03.008 http://doi.org/10.1016/j.bmcl.2009.03.008 . Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist JM Ferrell , P Pathak , S Boehme , 等 . Deficiency of both farnesoid X receptor and Takeda G protein-coupled receptor 5 exacerbated liver fibrosis in mice . Hepatology , 2019 . 30664797 DOI: 10.1002/hep.30513 http://doi.org/10.1002/hep.30513 . Deficiency of both farnesoid X receptor and Takeda G protein-coupled receptor 5 exacerbated liver fibrosis in mice PD Finn , D Rodriguez , J Kohler , 等 . Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice . Am J Physiol Gastrointest Liver Physiol , 2019 . 316 ( 3 ): G412 - G424 . 30605011 DOI: 10.1152/ajpgi.00300.2018 http://doi.org/10.1152/ajpgi.00300.2018 . Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice B Flatt , R Martin , TL Wang , 等 . Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR) . J Med Chem , 2009 . 52 ( 4 ): 904 - 907 . 19159286 DOI: 10.1021/jm8014124 http://doi.org/10.1021/jm8014124 . Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR) EA Franzosa , A Sirota-Madi , J Avila-Pacheco , 等 . Gut microbiome structure and metabolic activity in inflammatory bowel disease . Nat Microbiol , 2019 . 4 ( 2 ): 293 - 305 . 30531976 DOI: 10.1038/s41564-018-0306-4 http://doi.org/10.1038/s41564-018-0306-4 . Gut microbiome structure and metabolic activity in inflammatory bowel disease C Genet , A Strehle , C Schmidt , 等 . Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes . J Med Chem , 2010 . 53 ( 1 ): 178 - 190 . 19911773 DOI: 10.1021/jm900872z http://doi.org/10.1021/jm900872z . Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes GS Gerhard , AM Styer , GC Wood , 等 . A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass . Diabetes Care , 2013 . 36 ( 7 ): 1859 - 1864 . 23801799 DOI: 10.2337/dc12-2255 http://doi.org/10.2337/dc12-2255 . A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass A Golay , J Ybarra . Link between obesity and type 2 diabetes . Best Pract Res Clin Endocrinol Metab , 2005 . 19 ( 4 ): 649 - 663 . 16311223 DOI: 10.1016/j.beem.2005.07.010 http://doi.org/10.1016/j.beem.2005.07.010 . Link between obesity and type 2 diabetes C Guo , WD Chen , YD Wang . TGR5, not only a metabolic regulator . Front Physiol, 7:646 , 2016 . DOI: 10.3389/fphys.2016.00646 http://doi.org/10.3389/fphys.2016.00646 . TGR5, not only a metabolic regulator CS Guo , SJ Xie , ZX Chi , 等 . Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome . Immunity , 2016 . 45 ( 4 ): 802 - 816 . 27692610 DOI: 10.1016/j.immuni.2016.09.008 http://doi.org/10.1016/j.immuni.2016.09.008 . Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome RA Haeusler , B Astiarraga , S Camastra , 等 . Human insulin resistance is associated with increased plasma levels of 12α-hydroxylated bile acids . Diabetes , 2013 . 62 ( 12 ): 4184 - 4191 . 23884887 DOI: 10.2337/db13-0639 http://doi.org/10.2337/db13-0639 . Human insulin resistance is associated with increased plasma levels of 12α-hydroxylated bile acids L Halmy , T Fehér , K Steczek , 等 . High serum bile acid level in obesity: its decrease during and after total fasting . Acta Med Hung , 1986 . 43 ( 1 ): 55 - 58 . 3774418 . High serum bile acid level in obesity: its decrease during and after total fasting M Hansen , DP Sonne , KH Mikkelsen , 等 . Bile acid sequestrants for glycemic control in patients with type 2 diabetes: a systematic review with meta-analysis of randomized controlled trials . J Diabetes Complications , 2017 . 31 ( 5 ): 918 - 927 . 28238556 DOI: 10.1016/j.jdiacomp.2017.01.011 http://doi.org/10.1016/j.jdiacomp.2017.01.011 . Bile acid sequestrants for glycemic control in patients with type 2 diabetes: a systematic review with meta-analysis of randomized controlled trials FT He , J Li , Y Mu , 等 . Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells . Circ Res , 2006 . 98 ( 2 ): 192 - 199 . 16357303 DOI: 10.1161/01.RES.0000200400.55539.85 http://doi.org/10.1161/01.RES.0000200400.55539.85 . Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells P Hegyi , J Maléth , JR Walters , 等 . Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease . Physiol Rev , 2018 . 98 ( 4 ): 1983 - 2023 . 30067158 DOI: 10.1152/physrev.00054.2017 http://doi.org/10.1152/physrev.00054.2017 . Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease RJ Hodge , DJ Nunez . Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype? . Diabetes Obes Metab , 2016 . 18 ( 5 ): 439 - 443 . 26818602 DOI: 10.1111/dom.12636 http://doi.org/10.1111/dom.12636 . Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype? RJ Hodge , J Lin , LS Vasist Johnson , 等 . Safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB-756050, in type 2 diabetes . Clin Pharmacol Drug Dev , 2013 . 2 ( 3 ): 213 - 222 . 27121782 DOI: 10.1002/cpdd.34 http://doi.org/10.1002/cpdd.34 . Safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB-756050, in type 2 diabetes T Inagaki , A Moschetta , YK Lee , 等 . Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor . Proc Natl Acad Sci USA , 2006 . 103 ( 10 ): 3920 - 3925 . DOI: 10.1073/pnas.0509592103 http://doi.org/10.1073/pnas.0509592103 . Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor W Jia , GX Xie , WP Jia . Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis . Nat Rev Gastroenterol Hepatol , 2018 . 15 ( 2 ): 111 - 128 . 29018272 DOI: 10.1038/nrgastro.2017.119 http://doi.org/10.1038/nrgastro.2017.119 . Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis N Jiao , SS Baker , A Chapa-Rodriguez , 等 . Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD . Gut , 2018 . 67 ( 10 ): 1881 - 1891 . 28774887 DOI: 10.1136/gutjnl-2017-314307 http://doi.org/10.1136/gutjnl-2017-314307 . Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD LH Jin , Y Li . Structural and functional insights into nuclear receptor signaling . Adv Drug Deliv Rev , 2010 . 62 ( 13 ): 1218 - 1226 . 20723571 DOI: 10.1016/j.addr.2010.08.007 http://doi.org/10.1016/j.addr.2010.08.007 . Structural and functional insights into nuclear receptor signaling LH Jin , XH Feng , H Rong , 等 . The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism . Nat Commun, 4:1937 , 2013 . DOI: 10.1038/ncomms2924 http://doi.org/10.1038/ncomms2924 . The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism LH Jin , R Wang , YL Zhu , 等 . Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease . Sci Rep, 5:17288 , 2015 . DOI: 10.1038/srep17288 http://doi.org/10.1038/srep17288 . Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease ML Jones , CJ Martoni , JG Ganopolsky , 等 . The human microbiome and bile acid metabolism: dysbiosis, dysmetabolism, disease and intervention . Expert Opin Biol Ther , 2014 . 14 ( 4 ): 467 - 482 . 24479734 DOI: 10.1517/14712598.2014.880420 http://doi.org/10.1517/14712598.2014.880420 . The human microbiome and bile acid metabolism: dysbiosis, dysmetabolism, disease and intervention A Kaur , JV Patankar , W de Haan , 等 . Loss of Cyp8b1 improves glucose homeostasis by increasing GLP-1 . Diabetes , 2015 . 64 ( 4 ): 1168 - 1179 . 25338812 DOI: 10.2337/db14-0716 http://doi.org/10.2337/db14-0716 . Loss of Cyp8b1 improves glucose homeostasis by increasing GLP-1 V Keitel , D Häussinger . TGR5 in the biliary tree . Dig Dis , 2011 . 29 ( 1 ): 45 - 47 . 21691103 DOI: 10.1159/000324127 http://doi.org/10.1159/000324127 . TGR5 in the biliary tree JK Kemper , Z Xiao , B Ponugoti , 等 . FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states . Cell Metab , 2009 . 10 ( 5 ): 392 - 404 . 19883617 DOI: 10.1016/j.cmet.2009.09.009 http://doi.org/10.1016/j.cmet.2009.09.009 . FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states I Kim , K Morimura , Y Shah , 等 . Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice . Carcinogenesis , 2007 . 28 ( 5 ): 940 - 946 . 17183066 DOI: 10.1093/carcin/bgl249 http://doi.org/10.1093/carcin/bgl249 . Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice M Kobayashi , H Ikegami , T Fujisawa , 等 . Prevention and treatment of obesity, insulin resistance, and diabetes by bile acid-binding resin . Diabetes , 2007 . 56 ( 1 ): 239 - 247 . 17192488 DOI: 10.2337/db06-0353 http://doi.org/10.2337/db06-0353 . Prevention and treatment of obesity, insulin resistance, and diabetes by bile acid-binding resin RE Kuhre , NJ Wewer Albrechtsen , O Larsen , 等 . Bile acids are important direct and indirect regulators of the secretion of appetite-and metabolism-regulating hormones from the gut and pancreas . Mol Metab , 2018 . 11 84 - 95 . 29656109 DOI: 10.1016/j.molmet.2018.03.007 http://doi.org/10.1016/j.molmet.2018.03.007 . Bile acids are important direct and indirect regulators of the secretion of appetite-and metabolism-regulating hormones from the gut and pancreas F Kuipers , AK Groen . An unexpected role for bile acid synthesis in adaptation to low temperature . Nat Med , 2017 . 23 ( 7 ): 800 - 802 . 28697185 DOI: 10.1038/nm.4365 http://doi.org/10.1038/nm.4365 . An unexpected role for bile acid synthesis in adaptation to low temperature P Kurdi , K Kawanishi , K Mizutani , 等 . Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria . J Bacteriol , 2006 . 188 ( 5 ): 1979 - 1986 . 16484210 DOI: 10.1128/JB.188.5.1979-1986.2006 http://doi.org/10.1128/JB.188.5.1979-1986.2006 . Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria B Laffitte , B Liu , Y Kim , 等 . Development of LMB763, a novel, orally bioavailable, clinical farnesoid X receptor agonist for the treatment of non-alcoholic steatohepatitis and hepatobiliary disorders . J Hepatol , 2017 . 66 ( S1 ): S166 DOI: 10.1016/S0168-8278(17)30609-8 http://doi.org/10.1016/S0168-8278(17)30609-8 . Development of LMB763, a novel, orally bioavailable, clinical farnesoid X receptor agonist for the treatment of non-alcoholic steatohepatitis and hepatobiliary disorders CK Lee , SH Jeong , C Jang , 等 . Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation . Science , 2019 . 363 ( 6427 ): 644 - 649 . 30733421 DOI: 10.1126/science.aav0173 http://doi.org/10.1126/science.aav0173 . Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation F Li , CT Jiang , KW Krausz , 等 . Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity . Nat Commun, 4:2384 , 2013 . DOI: 10.1038/ncomms3384 http://doi.org/10.1038/ncomms3384 . Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity TG Li , JY Chiang . Bile acid signaling in metabolic disease and drug therapy . Pharmacol Rev , 2014 . 66 ( 4 ): 948 - 983 . 25073467 DOI: 10.1124/pr.113.008201 http://doi.org/10.1124/pr.113.008201 . Bile acid signaling in metabolic disease and drug therapy XJ Liu , XW Zhang , LL Ji , 等 . Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma . Oncotarget , 2015 . 6 ( 6 ): 4226 - 4238 . 25650661 . Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma SH Lo , YX Li , KC Cheng , 等 . Ursolic acid activates the TGR5 receptor to enhance GLP-1 secretion in type 1-like diabetic rats . Naunyn Schmiedebergs Arch Pharmacol , 2017 . 390 ( 11 ): 1097 - 1104 . 28756460 DOI: 10.1007/s00210-017-1409-9 http://doi.org/10.1007/s00210-017-1409-9 . Ursolic acid activates the TGR5 receptor to enhance GLP-1 secretion in type 1-like diabetic rats Y Lu , WL Zheng , SC Lin , 等 . Identification of an oleanane-type triterpene hedragonic acid as a novel farnesoid X receptor ligand with liver protective effects and anti-inflammatory activity . Mol Pharmacol , 2018 . 93 ( 2 ): 63 - 72 . 29162643 DOI: 10.1124/mol.117.109900 http://doi.org/10.1124/mol.117.109900 . Identification of an oleanane-type triterpene hedragonic acid as a novel farnesoid X receptor ligand with liver protective effects and anti-inflammatory activity C Ma , MJ Han , B Heinrich , 等 . Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells . Science , 2018 . 360 ( 6391 ): eaan5931 29798856 DOI: 10.1126/science.aan5931 http://doi.org/10.1126/science.aan5931 . Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells N Maghsoodi , N Shaw , GF Cross , 等 . Bile acid metabolism is altered in those with insulin resistance after gestational diabetes mellitus . Clin Biochem , 2019 . 64 12 - 17 . 30508519 DOI: 10.1016/j.clinbiochem.2018.11.016 http://doi.org/10.1016/j.clinbiochem.2018.11.016 . Bile acid metabolism is altered in those with insulin resistance after gestational diabetes mellitus AA Mahmoud , SM Elshazly . Ursodeoxycholic acid ameliorates fructose-induced metabolic syndrome in rats . PLoS ONE , 2014 . 9 ( 9 ): e106993 25202970 DOI: 10.1371/journal.pone.0106993 http://doi.org/10.1371/journal.pone.0106993 . Ursodeoxycholic acid ameliorates fructose-induced metabolic syndrome in rats T Maruyama , Y Miyamoto , T Nakamura , 等 . Identification of membrane-type receptor for bile acids (M-BAR) . Biochem Biophys Res Commun , 2002 . 298 ( 5 ): 714 - 719 . 12419312 DOI: 10.1016/S0006-291x(02)02550-0 http://doi.org/10.1016/S0006-291x(02)02550-0 . Identification of membrane-type receptor for bile acids (M-BAR) S Matysik , J Martin , M Bala , 等 . Bile acid signaling after an oral glucose tolerance test . Chem Phys Lipids , 2011 . 164 ( 6 ): 525 - 529 . 21679700 DOI: 10.1016/j.chemphyslip.2011.05.003 http://doi.org/10.1016/j.chemphyslip.2011.05.003 . Bile acid signaling after an oral glucose tolerance test AK McGavigan , D Garibay , ZM Henseler , 等 . TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice . Gut , 2017 . 66 ( 2 ): 226 - 234 . 26511794 DOI: 10.1136/gutjnl-2015-309871 http://doi.org/10.1136/gutjnl-2015-309871 . TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice KL Mertens , A Kalsbeek , MR Soeters , 等 . Bile acid signaling pathways from the enterohepatic circulation to the central nervous system . Front Neurosci, 11:617 , 2017 . DOI: 10.3389/fnins.2017.00617 http://doi.org/10.3389/fnins.2017.00617 . Bile acid signaling pathways from the enterohepatic circulation to the central nervous system S Modica , S Murzilli , L Salvatore , 等 . Nuclear bile acid receptor FXR protects against intestinal tumorigenesis . Cancer Res , 2008 . 68 ( 23 ): 9589 - 9594 . 19047134 DOI: 10.1158/0008-5472.CAN-08-1791 http://doi.org/10.1158/0008-5472.CAN-08-1791 . Nuclear bile acid receptor FXR protects against intestinal tumorigenesis BH Mullish , R Forlano , P Manousou , 等 . Non-alcoholic fatty liver disease and cardiovascular risk: an update . Expert Rev Gastroenterol Hepatol , 2018 . 12 ( 12 ): 1175 - 1177 . 30791787 DOI: 10.1080/17474124.2018.1533117 http://doi.org/10.1080/17474124.2018.1533117 . Non-alcoholic fatty liver disease and cardiovascular risk: an update H Nakatani , K Kasama , T Oshiro , 等 . Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery . Metabolism , 2009 . 58 ( 10 ): 1400 - 1407 . 19570554 DOI: 10.1016/j.metabol.2009.05.006 http://doi.org/10.1016/j.metabol.2009.05.006 . Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery JM Natividad , B Lamas , HP Pham , 等 . Bilophila wadsworthia aggravates high fat diet induced metabolic dysfunctions in mice . Nat Commun , 2018 . 9 ( 1 ): 2802 30022049 DOI: 10.1038/s41467-018-05249-7 http://doi.org/10.1038/s41467-018-05249-7 . Bilophila wadsworthia aggravates high fat diet induced metabolic dysfunctions in mice TT Nguyen , TT Ung , NH Kim , 等 . Role of bile acids in colon carcinogenesis . World J Clin Cases , 2018 . 6 ( 13 ): 577 - 588 . 30430113 . Role of bile acids in colon carcinogenesis K Nho , A Kueider-Paisley , S Mahmoudiandehkordi , 等 . Altered bile acid profile in mild cognitive impairment and Alzheimer’s disease: relationship to neuroimaging and CSF biomarkers. Alzheimer ’ . s Dement , 2019 . 15 ( 2 ): 232 - 244 . DOI: 10.1016/j.jalz.2018.08.012 http://doi.org/10.1016/j.jalz.2018.08.012 . Altered bile acid profile in mild cognitive impairment and Alzheimer’s disease: relationship to neuroimaging and CSF biomarkers. Alzheimer’ M Panek-Jeziorna , A Mulak . The role of bile acids in the pathogenesis of bowel diseases . Postepy Hig Med Dosw (Online) , 2017 . 71 ( 1 ): 737 - 746 . 28894048 . The role of bile acids in the pathogenesis of bowel diseases P Pathak , HL Liu , S Boehme , 等 . Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism . J Biol Chem , 2017 . 292 ( 26 ): 11055 - 11069 . 28478385 DOI: 10.1074/jbc.M117.784322 http://doi.org/10.1074/jbc.M117.784322 . Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism ME Patti , SM Houten , AC Bianco , 等 . Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism . Obesity (Silver Spring) , 2009 . 17 ( 9 ): 1671 - 1677 . 19360006 DOI: 10.1038/oby.2009.102 http://doi.org/10.1038/oby.2009.102 . Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism P Prinz , T Hofmann , A Ahnis , 等 . Plasma bile acids show a positive correlation with body mass index and are negatively associated with cognitive restraint of eating in obese patients . Front Neurosci, 9:199 , 2015 . DOI: 10.3389/fnins.2015.00199 http://doi.org/10.3389/fnins.2015.00199 . Plasma bile acids show a positive correlation with body mass index and are negatively associated with cognitive restraint of eating in obese patients P Puri , K Daita , A Joyce , 等 . The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids . Hepatology , 2018 . 67 ( 2 ): 534 - 548 . DOI: 10.1002/hep.29359 http://doi.org/10.1002/hep.29359 . The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids HGF Richter , GM Benson , D Blum , 等 . Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes . Bioorg Med Chem Lett , 2011 . 21 ( 1 ): 191 - 194 . 21134747 DOI: 10.1016/j.bmcl.2010.11.039 http://doi.org/10.1016/j.bmcl.2010.11.039 . Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes VK Ridaura , JJ Faith , FE Rey , 等 . Gut microbiota from twins discordant for obesity modulate metabolism in mice . Science , 2013 . 341 ( 6150 ): 1241214 24009397 DOI: 10.1126/science.1241214 http://doi.org/10.1126/science.1241214 . Gut microbiota from twins discordant for obesity modulate metabolism in mice JM Ridlon , DJ Kang , PB Hylemon . Bile salt biotransformations by human intestinal bacteria . J Lipid Res , 2006 . 47 ( 2 ): 241 - 259 . 16299351 DOI: 10.1194/jlr.R500013-JLR200 http://doi.org/10.1194/jlr.R500013-JLR200 . Bile salt biotransformations by human intestinal bacteria KK Ryan , V Tremaroli , C Clemmensen , 等 . FXR is a molecular target for the effects of vertical sleeve gastrectomy . Nature , 2014 . 509 ( 7499 ): 183 - 188 . 24670636 DOI: 10.1038/nature13135 http://doi.org/10.1038/nature13135 . FXR is a molecular target for the effects of vertical sleeve gastrectomy DA Sandoval . Mechanisms for the metabolic success of bariatric surgery . J Neuroendocrinol, e12708 , 2019 . DOI: 10.1111/jne.12708 http://doi.org/10.1111/jne.12708 . Mechanisms for the metabolic success of bariatric surgery H Sato , C Genet , A Strehle , 等 . Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea . Biochem Biophys Res Commun , 2007 . 362 ( 4 ): 793 - 798 . 17825251 DOI: 10.1016/j.bbrc.2007.06.130 http://doi.org/10.1016/j.bbrc.2007.06.130 . Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea A Schmid , H Neumann , T Karrasch , 等 . Bile acid metabolome after an oral lipid tolerance test by liquid chromatography-tandem mass spectrometry (LC-MS/MS) . PLoS ONE , 2016 . 11 ( 2 ): e0148869 26863103 DOI: 10.1371/journal.pone.0148869 http://doi.org/10.1371/journal.pone.0148869 . Bile acid metabolome after an oral lipid tolerance test by liquid chromatography-tandem mass spectrometry (LC-MS/MS) A Schmid , J Schlegel , M Thomalla , 等 . Evidence of functional bile acid signaling pathways in adipocytes . Mol Cell Endocrinol , 2019 . 483 1 - 10 . 30543876 DOI: 10.1016/j.mce.2018.12.006 http://doi.org/10.1016/j.mce.2018.12.006 . Evidence of functional bile acid signaling pathways in adipocytes P Schwabl , E Hambruch , BA Seeland , 等 . The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction . J Hepatol , 2017 . 66 ( 4 ): 724 - 733 . 27993716 DOI: 10.1016/j.jhep.2016.12.005 http://doi.org/10.1016/j.jhep.2016.12.005 . The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction J Shen , MS Obin , LP Zhao . The gut microbiota, obesity and insulin resistance . Mol Aspects Med , 2013 . 34 ( 1 ): 39 - 58 . 23159341 DOI: 10.1016/j.mam.2012.11.001 http://doi.org/10.1016/j.mam.2012.11.001 . The gut microbiota, obesity and insulin resistance KR Shima , T Ota , KI Kato , 等 . Ursodeoxycholic acid potentiates dipeptidyl peptidase-4 inhibitor sitagliptin by enhancing glucagon-like peptide-1 secretion in patients with type 2 diabetes and chronic liver disease: a pilot randomized controlled and add-on study . BMJ Open Diabetes Res Care , 2018 . 6 ( 1 ): e000469 29607050 DOI: 10.1136/bmjdrc-2017-000469 http://doi.org/10.1136/bmjdrc-2017-000469 . Ursodeoxycholic acid potentiates dipeptidyl peptidase-4 inhibitor sitagliptin by enhancing glucagon-like peptide-1 secretion in patients with type 2 diabetes and chronic liver disease: a pilot randomized controlled and add-on study D Slijepcevic , SFJ van de Graaf . Bile acid uptake transporters as targets for therapy . Dig Dis , 2017 . 35 ( 3 ): 251 - 258 . 28249291 DOI: 10.1159/000450983 http://doi.org/10.1159/000450983 . Bile acid uptake transporters as targets for therapy TK Soderborg , SE Clark , CE Mulligan , 等 . The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD . Nat Commun , 2018 . 9 ( 1 ): 4462 30367045 DOI: 10.1038/s41467-018-06929-0 http://doi.org/10.1038/s41467-018-06929-0 . The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD A Sommer , G Twig . The impact of childhood and adolescent obesity on cardiovascular risk in adulthood: a systematic review . Curr Diab Rep , 2018 . 18 ( 10 ): 91 30167798 DOI: 10.1007/s11892-018-1062-9 http://doi.org/10.1007/s11892-018-1062-9 . The impact of childhood and adolescent obesity on cardiovascular risk in adulthood: a systematic review LL Sun , C Xie , G Wang , 等 . Gut microbiota and intestinal FXR mediate the clinical benefits of metformin . Nat Med , 2018 . 24 ( 12 ): 1919 - 1929 . 30397356 DOI: 10.1038/s41591-018-0222-4 http://doi.org/10.1038/s41591-018-0222-4 . Gut microbiota and intestinal FXR mediate the clinical benefits of metformin WHW Tang , DY Li , SL Hazen . Dietary metabolism, the gut microbiome, and heart failure . Nat Rev Cardiol , 2019 . 16 ( 3 ): 137 - 154 . 30410105 DOI: 10.1038/s41569-018-0108-7 http://doi.org/10.1038/s41569-018-0108-7 . Dietary metabolism, the gut microbiome, and heart failure MD Thompson , A Moghe , P Cornuet , 等 . β-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis . Hepatology , 2018 . 67 ( 3 ): 955 - 971 . 28714273 DOI: 10.1002/hep.29371 http://doi.org/10.1002/hep.29371 . β-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis JY Tian , S Huang , SM Sun , 等 . Bile acid signaling and bariatric surgery . Liver Res , 2017 . 1 ( 4 ): 208 - 213 . 30034914 DOI: 10.1016/j.livres.2017.12.007 http://doi.org/10.1016/j.livres.2017.12.007 . Bile acid signaling and bariatric surgery E Tiratterra , P Franco , E Porru , 等 . Role of bile acids in inflammatory bowel disease . Ann Gastroenterol , 2018 . 31 ( 3 ): 266 - 272 . 29720851 . Role of bile acids in inflammatory bowel disease M Trauner , A Gulamhusein , B Hameed , 等 . The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis . Hepatology, Epub ahead of print , 2019 . DOI: 10.1002/hep.30509 http://doi.org/10.1002/hep.30509 . The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis T Tsuchiya , T Naitoh , M Nagao , 等 . Increased bile acid signals after duodenal-jejunal bypass improve non-alcoholic steatohepatitis (NASH) in a rodent model of diet-induced NASH . Obes Surg , 2018 . 28 ( 6 ): 1643 - 1652 . 29235014 DOI: 10.1007/s11695-017-3065-z http://doi.org/10.1007/s11695-017-3065-z . Increased bile acid signals after duodenal-jejunal bypass improve non-alcoholic steatohepatitis (NASH) in a rodent model of diet-induced NASH PJ Turnbaugh , RE Ley , MA Mahowald , 等 . An obesity-associated gut microbiome with increased capacity for energy harvest . Nature , 2006 . 444 ( 7122 ): 1027 - 1031 . 17183312 DOI: 10.1038/nature05414 http://doi.org/10.1038/nature05414 . An obesity-associated gut microbiome with increased capacity for energy harvest LA Velazquez-Villegas , A Perino , V Lemos , 等 . TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue . Nat Commun, 9:245 , 2018 . DOI: 10.1038/s41467-017-02068-0 http://doi.org/10.1038/s41467-017-02068-0 . TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue L Verbeke , R Farre , J Trebicka , 等 . Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats . Hepatology , 2014 . 59 ( 6 ): 2286 - 2298 . 24259407 DOI: 10.1002/hep.26939 http://doi.org/10.1002/hep.26939 . Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats J Wang , S Greene , LC Eriksson , 等 . Human sterol 12α-hydroxylase ( CYP8B1 ) is mainly expressed in hepatocytes in a homogenous pattern . Histochem Cell Biol , 2005 . 123 ( 4-5 ): 441 - 446 . 15891895 DOI: 10.1007/s00418-005-0779-0 http://doi.org/10.1007/s00418-005-0779-0 . Human sterol 12α-hydroxylase (CYP8B1) is mainly expressed in hepatocytes in a homogenous pattern J Wang , M Olin , B Rozell , 等 . Differential hepatocellular zonation pattern of cholesterol 7α-hydroxylase ( Cyp7a1 ) and sterol 12α-hydroxylase ( Cyp8b1 ) in the mouse . Histochem Cell Biol , 2007 . 127 ( 3 ): 253 - 261 . 17237956 DOI: 10.1007/s00418-006-0239-5 http://doi.org/10.1007/s00418-006-0239-5 . Differential hepatocellular zonation pattern of cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) in the mouse K Wang , MF Liao , N Zhou , 等 . Parabacteroides distasonis alleviates obesity and metabolic dysfunctions via production of succinate and secondary bile acids . Cell Rep , 2019 . 26 ( 1 ): 222 - 235e5 . 30605678 DOI: 10.1016/j.celrep.2018.12.028 http://doi.org/10.1016/j.celrep.2018.12.028 . Parabacteroides distasonis alleviates obesity and metabolic dysfunctions via production of succinate and secondary bile acids MG Wang , QZ Wu , HB Xie , 等 . Effects of sleeve gastrectomy on serum 12α-hydroxylated bile acids in a diabetic rat model . Obes Surg , 2017 . 27 ( 11 ): 2912 - 2918 . 28508276 DOI: 10.1007/s11695-017-2714-6 http://doi.org/10.1007/s11695-017-2714-6 . Effects of sleeve gastrectomy on serum 12α-hydroxylated bile acids in a diabetic rat model XC Wang , XH Fu , C van Ness , 等 . Bile acid receptors and liver cancer . Curr Pathobiol Rep , 2013 . 1 ( 1 ): 29 - 35 . 23420103 DOI: 10.1007/s40139-012-0003-6 http://doi.org/10.1007/s40139-012-0003-6 . Bile acid receptors and liver cancer YD Wang , WD Chen , MH Wang , 等 . Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response . Hepatology , 2008 . 48 ( 5 ): 1632 - 1643 . 18972444 DOI: 10.1002/hep.22519 http://doi.org/10.1002/hep.22519 . Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response K Watanabe , M Ohta , H Takayama , 等 . Effects of sleeve gastrectomy on nonalcoholic fatty liver disease in an obese rat model . Obes Surg , 2018 . 28 ( 6 ): 1532 - 1539 . 29280057 DOI: 10.1007/s11695-017-3052-4 http://doi.org/10.1007/s11695-017-3052-4 . Effects of sleeve gastrectomy on nonalcoholic fatty liver disease in an obese rat model M Watanabe , SM Houten , C Mataki , 等 . Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation . Nature , 2006 . 439 ( 7075 ): 484 - 489 . 16400329 DOI: 10.1038/nature04330 http://doi.org/10.1038/nature04330 . Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation YJ Wei , Y Lu , YL Zhu , 等 . Structural basis for the hepatoprotective effects of antihypertensive 1,4-dihydropyridine drugs . Biochim Biophys Acta Gen Subj , 2018 . 1862 ( 10 ): 2261 - 2270 . 30048741 DOI: 10.1016/j.bbagen.2018.07.022 http://doi.org/10.1016/j.bbagen.2018.07.022 . Structural basis for the hepatoprotective effects of antihypertensive 1,4-dihydropyridine drugs A Worthmann , C John , MC Rühlemann , 等 . Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis . Nat Med , 2017 . 23 ( 7 ): 839 - 849 . 28604703 DOI: 10.1038/nm.4357 http://doi.org/10.1038/nm.4357 . Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis YXZ Xu , S Mishra . Obesity-linked cancers: current knowledge, challenges and limitations in mechanistic studies and rodent models . Cancers , 2018 . 10 ( 12 ): 523 DOI: 10.3390/cancers10120523 http://doi.org/10.3390/cancers10120523 . Obesity-linked cancers: current knowledge, challenges and limitations in mechanistic studies and rodent models F Yang , XF Huang , TS Yi , 等 . Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor . Cancer Res , 2007 . 67 ( 3 ): 863 - 867 . 17283114 DOI: 10.1158/0008-5472.CAN-06-1078 http://doi.org/10.1158/0008-5472.CAN-06-1078 . Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor ZY Yang , J Li , FX Xiong , 等 . Berberine attenuates high glucose-induced fibrosis by activating the G protein-coupled bile acid receptor TGR5 and repressing the S1P2/MAPK signaling pathway in glomerular mesangial cells . Exp Cell Res , 2016 . 346 ( 2 ): 241 - 247 . 27292312 DOI: 10.1016/j.yexcr.2016.06.005 http://doi.org/10.1016/j.yexcr.2016.06.005 . Berberine attenuates high glucose-induced fibrosis by activating the G protein-coupled bile acid receptor TGR5 and repressing the S1P2/MAPK signaling pathway in glomerular mesangial cells K Yoneno , T Hisamatsu , K Shimamura , 等 . TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn’s disease . Immunology , 2013 . 139 ( 1 ): 19 - 29 . 23566200 DOI: 10.1111/imm.12045 http://doi.org/10.1111/imm.12045 . TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn’s disease KE Zaborska , BP Cummings . Rethinking bile acid metabolism and signaling for type 2 diabetes treatment . Curr Diab Rep , 2018 . 18 ( 11 ): 109 30232649 DOI: 10.1007/s11892-018-1092-3 http://doi.org/10.1007/s11892-018-1092-3 . Rethinking bile acid metabolism and signaling for type 2 diabetes treatment SN Zhao , ZZ Gong , JF Zhou , 等 . Deoxycholic acid triggers NLRP3 inflammasome activation and aggravates DSS-induced colitis in mice . Front Immunol, 7:536 , 2016 . DOI: 10.3389/fimmu.2016.00536 http://doi.org/10.3389/fimmu.2016.00536 . Deoxycholic acid triggers NLRP3 inflammasome activation and aggravates DSS-induced colitis in mice We have to apologize that we are not able to include all relevant publications in this review because of space limitation. Compliance with ethics guidelines Li-hua JIN, Zhi-peng FANG, Min-jie FAN, and Wen-dong HUANG declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1900158 Project supported by the National Cancer Institute (No. 2R01CA139158) and John Hench Foundation to Wen-dong HUANG, and the National Natural Science Foundation of China (Nos. 81471084 and 81773793) to Li-hua JIN 2019-03-28 2019-04-05 2022-01-05 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2019 2019 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 05 20