Fexaramine, a gut-restricted farnesoid X receptor (FXR) agonist, promotes glucose and lipid homeostasis, improves insulin sensitivity, promotes white adipose tissue browning, and stimulates nonshivering thermogenesis. Enhancement in energy expenditure due to an increase in amount of energy burned by brown and 'beige' adipocytes results in subsequent weight loss. Fexaramine is poorly absorbed into circulation when delivered orally, which limits systemic FXR activation and toxicity. An increase in β3-adrenoceptor signaling, activation of Takeda G protein-coupled receptor 5/glucagon-like peptide-1 (TGR5/GLP-1) signaling, and induction of fibroblast growth factor (FGF)-19/FGF-15 play crucial roles in fexaramine metabolic actions. Intestinal FXR activation is a promising, potentially safe approach for treating obesity and metabolic syndrome.

A consistent feature of chronic liver diseases and the hallmark of pathologic repair is the so-called "ductular reaction." This is a histologic abnormality characterized by an expansion of dysmorphic cholangiocytes inside and around portal spaces infiltrated by inflammatory, mesenchymal, and vascular cells. The ductular reaction is a highly regulated response based on the reactivation of morphogenetic signaling mechanisms and a complex crosstalk among a multitude of cell types. The nature and mechanism of these exchanges determine the difference between healthy regenerative liver repair and pathologic repair. An orchestrated signaling among cell types directs mesenchymal cells to deposit a specific extracellular matrix with distinct physical and biochemical properties defined as portal fibrosis. Progression of fibrosis leads to vast architectural and vascular changes known as "liver cirrhosis." The signals regulating the ecology of this microenvironment are just beginning to be addressed. Contrary to the tumor microenvironment, immune modulation inside this "benign" microenvironment is scarcely known. One of the reasons for this is that both the ductular reaction and portal fibrosis have been primarily considered a manifestation of cholestatic liver disease, whereas this phenomenon is also present, albeit with distinctive features, in all chronic human liver diseases. Novel human-derived cellular models and progress in "omics" technologies are increasing our knowledge at a fast pace. Most importantly, this knowledge is on the edge of generating new diagnostic and therapeutic advances. Here, we will critically review the latest advances, in terms of mechanisms, pathophysiology, and treatment prospects. In addition, we will delineate future avenues of research, including innovative translational opportunities.

Primary sclerosing cholangitis (PSC) is a chronic biliary inflammation associated with periductular fibrosis of the intrahepatic and extrahepatic bile ducts leading to strictures, bacterial cholangitis, decompensated liver disease and need for liver transplantation. This rare focal liver disease affects all races and ages, with a predominance of young males. There is an up to 88% association with inflammatory bowel disease. Although the aetiology is unknown and the pathophysiology is poorly understood, PSC is regarded as an autoimmune liver disease based on a strong immunogenetic background. Further, the associated risk for various malignancies, particularly cholangiocellular carcinoma, is also poorly understood. No medical therapy has been approved so far nor has been shown to improve transplant-free survival. However, ursodeoxycholic acid is widely used since it improves the biochemical parameters of cholestasis and is safe at low doses. MRI of the biliary tract is the primary imaging technology for diagnosis. Endoscopic interventions of the bile ducts should be limited to clinically relevant strictures for balloon dilatation, biopsy and brush cytology. End-stage liver disease with decompensation is an indication for liver transplantation with recurrent PSC in up to 38% of patients. Several novel therapeutic strategies are in various stages of development, including apical sodium-dependent bile acid transporter and ileal bile acid transporter inhibitors, integrin inhibitors, peroxisome proliferator-activated receptor agonists, CCL24 blockers, recombinant FGF19, CCR2/CCR5 inhibitors, farnesoid X receptor bile acid receptor agonists, and nor-ursodeoxycholic acid. Manipulation of the gut microbiome includes faecal microbiota transplantation. This article summarizes present knowledge and defines unmet medical needs to improve quality of life and survival.

Cholestasis, characterized by impaired bile flow, is associated with an increased risk of cholangiocarcinoma (CCA), a malignancy originating from the biliary epithelium and hepatocytes. Hepatic nuclear receptors (NRs) are pivotal in regulating bile acid and metabolic homeostasis, and their dysregulation is implicated in cholestatic liver diseases and the progression of liver cancer. This review elucidates the role of various hepatic NRs in the pathogenesis of cholestasis-to-CCA progression. It explores their impact on bile acid metabolism as well as their interactions with other signaling pathways implicated in CCA development. Additionally, it introduces available murine models of cholestasis/primary sclerosing cholangitis leading to CCA and discusses the clinical potential of targeting hepatic NRs as a promising approach for the prevention and treatment of cholestatic liver diseases and CCA. Understanding the complex interplay between hepatic NRs and cholestasis-to-CCA pathology holds promise for the development of novel preventive and therapeutic strategies for this devastating disease.

Little is known on the mechanism of liver injury mediated by bile acids following Kasai portoenterostomy (KPE) in biliary atresia (BA). We sought to quantify individual serum bile acids, 7-alpha-hydroxy-4-cholesten-3-one (C4), and fibroblast growth factor 19 (FGF19) after KPE and to evaluate their prognostic utility and transcriptomic regulation.

Serum (n=244) and liver specimens (n=105) prospectively obtained from BA patients (n=54) after KPE were included. Bile acids were analyzed using mass spectrometry, gene expression with quantitative PCR, and histopathology using a neural network model.

Following KPE, serum bile acids correlated positively with biochemical liver injury, pediatric end-stage liver disease score, liver stiffness, histological ductular reaction, and liver fibrosis. Bile acids were higher among patients who developed portal hypertension (79.6 vs. 11.9 μmol/l, p<0.0001), esophageal varices (91.6 vs. 16.2 μmol/l, p<0.0001), or required liver transplantation (LT, 115.3 vs. 22.0 μmol/l, p<0.0001) during follow up; bile acids predicted these outcomes in time-dependent regression models. Accumulation of conjugated bile acids, cholic acid, and taurine conjugates predicted LT risk while associating with histological liver injury. Serum C4 (0.04 vs. 0.00 μmol/l, p=0.04) and liver CYP7A1 were higher in native liver survivors than in LT patients (fold-change 16.9 vs. 7.0, p=0.02). Primary bile acids correlated negatively with C4 (R=-0.38, p<0.001) and CYP7A1 (R=-0.49, p=0.01). Unlike in native liver survivors (R=-0.19, p=0.66), serum FGF19 correlated with liver FGF19 (R=0.59, p=0.04) without an inverse association with serum primary bile acids in LT patients (R=0.26, p=0.08).

Accumulation and altered composition of serum bile acids predicted progressive liver disease and poorer transplant-free survival following KPE. Poor prognosis was associated with low bile acid synthesis and aberrantly increased liver FGF19.

Biliary atresia (BA), a fibro-obliterating biliary disease of infants, remains the most common indication for pediatric liver transplantation caused by rapid progression of liver injury. To identify predictive biomarkers of disease progression and to elucidate the pathophysiology of BA liver injury, we profiled serum bile acids and studied their liver metabolism after Kasai portoenterostomy. Accumulation and altered composition of circulating bile acids predicted progression of liver disease and need for liver transplantation. Patients with poor prognosis showed low bile acid synthesis and abnormal liver expression of fibroblast growth factor 19.

A clinical unmet need persists for medications capable of modulating the progression of primary sclerosing cholangitis (PSC). This study aimed to assess the clinical feasibility of HK-660S (beta-lapachone) in PSC.

In this multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2 trial, participants were assigned in a 2:1 ratio to receive either 100 mg of HK-660S or a placebo twice daily for 12 weeks. The primary outcomes were the reduction in serum alkaline phosphatase (ALP) levels and the percentage of participants showing improvements in PSC severity, as determined by magnetic resonance cholangiopancreatography with the Anali score. Secondary endpoints included changes in liver stiffness and adverse events.

The analysis included 21 patients, 15 receiving HK-660S, and six receiving a placebo. Improvements in the Anali score were observed in 13.3% of the HK-660S group, with no improvements in the placebo group. HK-660S treatment resulted in a 15.2% reduction in mean ALP levels, compared to a 6.6% reduction in the placebo group. A stratified ad-hoc analysis based on baseline ALP levels showed a statistically significant response in the HK-660S group among those with ALP levels greater than twice the upper limit of normal, with a 50% responder rate (p=0.05). Additionally, 26.7% of the HK-660S group showed improvements in the enhanced liver fibrosis score, with no improvements in the placebo group. HK-660S was generally well tolerated.

HK-660S is well tolerated among patients with PSC and may improve bile duct strictures, decrease serum ALP levels, and reduce liver fibrosis (cris.nih.go.kr, Number KCT0006590).

Cyp2c70 knockout (KO) mice lack the liver enzyme responsible for synthesis of 6-hydroxylated muricholate bile acid species and possess a more hydrophobic human-like bile acid composition. Cyp2c70 KO mice develop cholestatic liver injury that can be prevented by the administration of an ileal bile acid transporter (IBAT) inhibitor. In this study, we investigated the potential of an ileal bile acid transporter (IBAT) inhibitor (SC-435) and steroidal farnesoid X receptor (FXR) agonist (cilofexor) to modulate established hepatobiliary injury and the consequent relationship of intrahepatic bile acid content and hydrophobicity to the cholestatic liver injury phenotype. Oral administration of SC-435, cilofexor, or combined treatment for 2 wk markedly reduced serum markers of liver injury and improved histological and gene expression markers of fibrosis, liver inflammation, and ductular reaction in male and female Cyp2c70 KO mice, with the greatest benefit in the combination treatment group. The IBAT inhibitor and FXR agonist significantly reduced intrahepatic bile acid content but not hepatic bile acid pool hydrophobicity, and markers of liver injury were strongly correlated with intrahepatic total bile acid and taurochenodeoxycholic acid accretion. Biomarkers of liver injury increased linearly with similar hepatic thresholds for pathological accretion of hydrophobic bile acids in male and female Cyp2c70 KO mice. These findings further support targeting intrahepatic bile acid retention as a component of treatments for cholestatic liver disease.NEW & NOTEWORTHY Bile acids are implicated as a common contributor to the pathogenesis and progression of cholestatic liver disease. Using a mouse model with a humanized bile acid composition, we demonstrated that mono and combination therapy using an IBAT inhibitor and FXR nonsteroidal agonist were effective at reducing hepatic bile acid accretion and reversing liver injury, without reducing hepatic bile acid hydrophobicity. The findings support the concept of a therapeutically tractable threshold for bile acid-induced liver injury.

The objective of this study was to compare the safety profiles of OCA and UDCA for the treatment of PBC using the FDA Adverse Event Reporting System database.

We extracted reports for OCA from 2016 to 2023 and UDCA from 2004 to 2023. Demographic details, adverse events (AEs), and concomitant medications were analyzed using descriptive statistics and signal detection methods.

The most common for OCA were pruritus (1345 cases, ROR 20.96) and fatigue (528 cases, ROR 3.46). UDCA was more frequently associated with hepatocellular carcinoma (22 cases, ROR 16.37) and type I hypersensitivity reactions (11 cases, ROR 12.77). OCA was also linked to a higher frequency of constipation (161 cases, ROR 3.92) and increased blood alkaline phosphatase levels (145 cases, ROR 44.27).

This study reveals distinct safety profiles for OCA and UDCA in the treatment of PBC. OCA is associated with a higher frequency of pruritus, fatigue, constipation, and increased blood alkaline phosphatase levels, while UDCA is linked to hepatocellular carcinoma and type I hypersensitivity reactions. These findings support personalized treatment approaches based on individual patient characteristics.

Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.

This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis.

Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers and pharmacodynamic biomarkers of bile acid homeostasis.

Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug-related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7 to -7.4) for alanine transaminase, -13.0% (-21.9 to -8.6) for alkaline phosphatase, -43.5% (-52.1 to -30.8) for γ-glutamyl transferase, -12.7% (-25.0 to 0.0) for total bilirubin, and -21.2% (-40.0 to 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8 to -31.6) for C4 and -60.5% (-81.8 to -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration.

Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to primary sclerosing cholangitis (NCT04060147).

Farnesoid X receptor (FXR) is a vital receptor for bile acids and plays an important role in the treatment of cholestatic liver disease. In addition to traditional bile acid-based steroidal agonists, synthetic alkaloids are the most commonly reported non-steroidal FXR agonists. Sarmentol H is a nor-sesquiterpenoid obtained from Sedum sarmentosum Bunge, and in vitro screening experiments have shown that it might be related to the regulation of the FXR pathway in a previous study.

To investigate the therapeutic effects of sarmentol H on cholestasis and to determine whether sarmentol H directly targets FXR to mitigate cholestasis. Furthermore, this study aimed to explore the key amino acid residues involved in the binding of sarmentol H to FXR through site-directed mutagenesis.

An intrahepatic cholestasis mouse model was established to investigate the therapeutic effects of sarmentol H on cholestasis. In vitro experiments, including Co-Ip and FXR-EcRE-Luc assays, were performed to assess whether sarmentol H activates FXR by recruiting the receptor coactivator SRC1. CETSA, SIP, DARTS, and ITC were used to determine the binding of sarmentol H to FXR protein. The key amino acid residues for sarmentol H binding to FXR were analyzed by molecular docking and site-directed mutagenesis. Finally, we conducted in vivo experiments on wild-type and Fxr-/- mice to further validate the anticholestatic target of sarmentol H.

Sarmentol H had significant ameliorative effects on the pathological conditions of cholestatic mice induced with ANIT. In vitro experiments suggested that it is capable of activating FXR and regulating downstream signaling pathways by recruiting SRC1. The target validation experiments showed that sarmentol H had the ability to bind to FXR as a ligand (KD = 2.55 μmol/L) and enhance the stability of its spatial structure. Moreover, site-directed mutagenesis revealed that THR292 and TYR365 were key binding sites for sarmentol H and FXR. Furthermore, knockout of the Fxr gene resulted in a significantly higher degree of ANIT-induced cholestatic liver injury than that in wild-type cholestatic mice, and the amelioration of cholestasis or regulatory effects on FXR downstream genes by sarmentol H also disappeared in Fxr-/- cholestatic mice.

Sarmentol H is an FXR agonist. This is the first study to show that it exerts a significant therapeutic effect on cholestatic mice, and can directly bind to FXR and activate it by recruiting the coactivator SRC1.

Primary sclerosing cholangitis (PSC) is a bile duct disorder characterized by ductular reaction, hepatic inflammation, and liver fibrosis. The pathogenesis of PSC is still undefined, and treatment options for patients are limited. Previous clinical trials evaluated drug candidates targeting various cellular functions and pathways, such as bile acid signaling and absorption, gut bacteria and permeability, and lipid metabolisms. However, most of phase III clinical trials for PSC were disappointing, except vancomycin therapy, and there are still no established medications for PSC with efficacy and safety confirmed by phase IV clinical trials.

This review summarizes the currently ongoing or completed clinical studies for PSC, which are phase II or further, and discusses therapeutic targets and strategies, limitations, and future directions and possibilities of PSC treatments. A literature search was conducted in PubMed and ClinicalTrials.gov utilizing the combination of the searched term 'primary sclerosing cholangitis' with other keywords, such as 'clinical trials,' 'antibiotics,' or drug names. Clinical trials at phase II or further were included for consideration.

Only vancomycin demonstrated promising therapeutic effects in the phase III clinical trial. Other drug candidates showed futility or inconsistent results, and the search for novel PSC treatments is still ongoing.

The farnesoid X receptor (FXR) is a nuclear receptor that controls bile acid, lipid, and cholesterol metabolism. FXR-targeted drugs have shown promise in late-stage clinical trials for non-alcoholic steatohepatitis. Herein, we used clinical results from our first non-steroidal FXR agonist, 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid (Px-102), to develop cilofexor, a potent, non-steroidal FXR agonist with a more manageable safety profile. Px-102 demonstrated the anticipated pharmacodynamic (PD) effects in healthy volunteers but caused a 2-fold increase in alanine aminotransferase (ALT) activity and changes in cholesterol levels. These data guided development of a high fat diet mouse model to screen FXR agonists based on ALT and cholesterol changes. Cilofexor was identified to elicit only minor changes in these parameters. The differing effects of cilofexor and Px-102 on ALT/cholesterol in the model could not be explained by potency or specificity, and we hypothesized that the relative contribution of intestinal and liver FXR activation may be responsible. Gene expression analysis from rodent studies revealed that cilofexor, but not Px-102, had a bias for FXR transcriptional activity in the intestine compared with the liver. Fluorescent imaging in hepatoma cells demonstrated similar subcellular localization for cilofexor and Px-102, but cilofexor was more rapidly washed out, consistent with a lower membrane residence time contributing to reduced hepatic transcriptional effects. Cilofexor demonstrated antisteatotic and antifibrotic efficacy in rodent models and antisteatotic efficacy in a monkey model, with the anticipated PD and a manageable safety profile in human phase I studies. SIGNIFICANCE STATEMENT: Farnesoid X receptor (FXR) agonists have shown promise in treating non-alcoholic steatohepatitis and other liver diseases in the clinic, but balancing efficacy with undesired side effects has been difficult. Here, we examined the preclinical and clinical effects of the first-generation FXR agonist, 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid, to enable the selection of an analog, cilofexor, with unique properties that reduced side effects yet maintained efficacy. Cilofexor is one of the few remaining FXR agonists in clinical development.

Advances in the understanding of bile salt synthesis, transport and signalling show the potential of modulating bile salt homeostasis as a therapeutic strategy in cholestatic liver diseases. Here, recent developments in (pre)clinical research in this field is summarized and discussed.

Inhibition of the apical sodium-dependent bile salt transporter (ASBT) and Na + -taurocholate cotransporting polypeptide (NTCP) seems effective against cholestatic liver diseases, as well as Farnesoid X receptor (FXR) agonism or a combination of both. While approved for the treatment of primary biliary cholangitis (PBC) and intrahepatic cholestasis of pregnancy (ICP), ursodeoxycholic acid (UDCA) has retrospectively shown carefully promising results in primary sclerosing cholangitis (PSC). The side chain shortened derivate norUDCA is of further therapeutic interest since its mechanisms of action are independent of the bile salt transport machinery. In the pathogenesis of sclerosing cholangiopathies, a skewed T-cell response with alterations in gut microbiota and bile salt pool compositions are observed. In PSC pathogenesis, the bile salt receptor Takeda G-protein-coupled receptor 5 (TGR5) in cholangiocytes is implicated, whilst in immunoglobulin G4-related cholangitis the autoantigens annexin A11 and laminin 511-E8 are involved in protecting cholangiocytes.

Modulating bile salt homeostasis has proven a promising treatment strategy in models of cholestasis and are continuously being further developed. Confirmatory clinical studies are needed in order to assess the proposed treatment strategies in patients allowing for a broader therapeutic arsenal in the future.

Cholestasis is a disorder of bile secretion and excretion caused by a variety of etiologies. At present, there is a lack of functional foods or drugs that can be used for intervention. Forsythiaside A (FTA) is a natural phytochemical component isolated from the medicinal plant Forsythia suspensa (Thunb.) Vahl, which has a significant hepatoprotective effect. In this study, we investigated whether FTA could alleviate liver injury induced by cholestasis. In vitro, FTA reversed the decrease in viability of human intrahepatic bile duct epithelial cells, the decrease in antioxidant enzymes (SOD1, CAT and GSH-Px), and cell apoptosis induced by lithocholic acid. In vivo, FTA protected mice from 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury, abnormal serum biochemical indexes, abnormal bile duct hyperplasia, and inflammatory infiltration. Furthermore, FTA treatment alleviated liver fibrosis by inhibiting collagen deposition and HSC activation. The metabonomic results showed that DDC-induced bile acid disorders in the liver and serum were reversed after FTA treatment, which may benefit from the activation of the FXR/BSEP axis. In addition, FTA treatment increased the levels of antioxidant enzymes in the serum and liver. Meanwhile, FTA treatment inhibited ROS and MDA levels and cleaved caspase 3 protein expression, thereby reducing DDC-induced hepatic oxidative stress and apoptosis. Further studies showed that the antioxidant effects of FTA were dependent on the activation of the BRG1/NRF2/HO-1 axis. In a word, FTA has a significant hepatoprotective effect on cholestatic liver injury, and can be further developed as a functional food or drug to prevent and treat cholestatic liver injury.

The nuclear receptor farnesoid X receptor (FXR) is a key regulator of hepatic bile acid (BA) and lipid metabolism, inflammation and fibrosis. Here, we aimed to explore the potential of cilofexor (GS-9674), a non-steroidal FXR agonist, as a therapeutic approach for counteracting features of cholestatic liver injury by evaluating its efficacy and mechanisms in the Mdr2/Abcb4 knockout (-/-) mouse model of sclerosing cholangitis.

FVB/N wild-type and Mdr2-/- or BALB/c wild-type and Mdr2-/- mice were treated with 0, 10, 30 or 90 mg/kg cilofexor by gavage every 24 h for 10 weeks. Serum biochemistry, gene expression profile, hydroxyproline content, and picrosirius red and F4/80 immunostaining, were investigated. Bile flow, biliary bicarbonate and BA output, and hepatic BA profile, were assessed.

Cilofexor treatment improved serum levels of aspartate aminotransferase, alkaline phosphatase as well as BAs in Mdr2-/- animals. Hepatic fibrosis was improved, as reflected by the reduced picrosirius red-positive area and hydroxyproline content in liver sections of cilofexor-treated Mdr2-/- mice. Intrahepatic BA concentrations were lowered in cilofexor-treated Mdr2-/- mice, while hepatobiliary bile flow and bicarbonate output were increased.

Collectively the current data show that cilofexor treatment improves cholestatic liver injury and decreases hepatic fibrosis in the Mdr2-/- mouse model of sclerosing cholangitis.

Treatment with cilofexor, a non-steroidal farnesoid X receptor (FXR) agonist, improved histological features of sclerosing cholangitis, cholestasis and hepatic fibrosis in the Mdr2-/- mouse model. These findings indicate, that pharmacological stimulation of intestinal FXR-mediated gut-liver signaling, via fibroblast growth factor 15 (thereby reducing bile acid synthesis), may be sufficient to attenuate cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis, thus arguing for potential therapeutic properties of cilofexor in cholestatic liver diseases.

Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.

Surrogate endpoints are needed to estimate clinical outcomes in primary sclerosing cholangitis (PSC). Serum alkaline phosphatase was among the first markers studied, but there is substantial variability in alkaline phosphatase levels during the natural history of PSC without intervention. The Mayo risk score incorporates noninvasive variables and has served as a surrogate endpoint for survival for more than two decades. Newer models have better test performance than the Mayo risk score, including the primary sclerosing risk estimate tool (PREsTo) model and UK-PSC score that estimate hepatic decompensation and transplant free survival, respectively. The c-statistics for transplant-free survival for the Mayo risk model and the long-term UK-PSC model are 0.68 and 0.85, respectively. The c-statistics for hepatic decompensation for the Mayo risk model and PREsTo model are 0.85 and 0.90, respectively. The Amsterdam-Oxford model included patients with large duct and small duct PSC and patients with PSC-autoimmune hepatitis overlap and had a c-statistic of 0.68 for transplant-free survival. Other noninvasive tests that warrant further validation include magnetic resonance imaging, elastography and the enhanced liver fibrosis score. Prognostic models, noninvasive tests or a combination of these surrogate endpoints may not only serve to be useful in clinical trials of investigational agents, but also serve to inform our patients about their prognosis.

Liver fibrosis accompanies the progression of chronic liver diseases independent of etiologies, such as hepatitis viral infection, alcohol consumption, and metabolic-associated fatty liver disease. It is commonly associated with liver injury, inflammation, and cell death. Liver fibrosis is characterized by abnormal accumulation of extracellular matrix components that are expressed by liver myofibroblasts such as collagens and alpha-smooth actin proteins. Activated hepatic stellate cells contribute to the major population of myofibroblasts. Many treatments for liver fibrosis have been investigated in clinical trials, including dietary supplementation (e.g., vitamin C), biological treatment (e.g., simtuzumab), drug (e.g., pegbelfermin and natural herbs), genetic regulation (e.g., non-coding RNAs), and transplantation of stem cells (e.g., hematopoietic stem cells). However, none of these treatments has been approved by Food and Drug Administration. The treatment efficacy can be evaluated by histological staining methods, imaging methods, and serum biomarkers, as well as fibrosis scoring systems, such as fibrosis-4 index, aspartate aminotransferase to platelet ratio, and non-alcoholic fatty liver disease fibrosis score. Furthermore, the reverse of liver fibrosis is slowly and frequently impossible for advanced fibrosis or cirrhosis. To avoid the life-threatening stage of liver fibrosis, anti-fibrotic treatments, especially for combined behavior prevention, biological treatment, drugs or herb medicines, and dietary regulation are needed. This review summarizes the past studies and current and future treatments for liver fibrosis.

Cholestasis is a condition characterized by decrease in bile flow due to progressive pathological states that lead to chronic cholestatic liver diseases which affect the biliary tree at the intrahepatic level and extrahepatic level. They induce complications such as cirrhosis, liver failure, malignancies, bone disease and nutritional deficiencies that merit close follow-up and specific interventions. Furthermore, as those conditions progress to liver cirrhosis, there will be an increase in mortality but also an important impact in quality of life and economic burden due to comorbidities related with liver failure. Therefore, it is important that clinicians understand the treatment options for cholestatic liver diseases. With a general view of therapeutic options and their molecular targets, this review addresses the pathophysiology of cholangiopathies. The objective is to provide clinicians with an overview of the safety and efficacy of the treatment of cholangiopathies based on the current evidence.

Emerging evidence suggests the complex interactions between gut microbiota and bile acids, which are crucial end products of cholesterol metabolism. Cholestatic liver disease is characterized by dysfunction of bile production, secretion, and excretion, as well as excessive accumulation of potentially toxic bile acids. Given the importance of bile acid homeostasis, the complex mechanism of the bile acid-microbial network in cholestatic liver disease requires a thorough understanding. It is urgent to summarize the recent research progress in this field. In this review, we highlight how gut microbiota regulates bile acid metabolism, how bile acid pool shapes the bacterial community, and how their interactions contribute to the pathogenesis of cholestatic liver disease. These advances might provide a novel perspective for the development of potential therapeutic strategies that target the bile acid pathway.

Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/β-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.