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Background & Aims: Gallbladder enlargement is common in patients with primary sclerosing cholangitis (PSC). The gallbladder may confer hepatoprotection against bile acid overload, through the sequestration and cholecystohepatic shunt of bile acids. The aim of this study was to assess the potential impact of the gallbladder on disease features and bile acid homeostasis in PSC., Methods: Patients with PSC from a single tertiary center who underwent liver MRI with three-dimensional cholangiography and concomitant analyses of serum bile acids were included. Gallbladder volume was measured by MRI and a cut-off of 50 ml was used to define gallbladder enlargement. Bile acid profiles and PSC severity, as assessed by blood tests and MRI features, were compared among patients according to gallbladder size (enlarged vs . normal-sized) or presence (removed vs. conserved). The impact of cholecystectomy was also assessed in the Abcb4 knockout mouse model of PSC., Results: Sixty-one patients with PSC, all treated with ursodeoxycholic acid (UDCA), were included. The gallbladder was enlarged in 30 patients, whereas 11 patients had been previously cholecystectomized. Patients with enlarged gallbladders had significantly lower alkaline phosphatase, a lower tauro- vs. glycoconjugate ratio and a higher UDCA vs . total bile acid ratio compared to those with normal-sized gallbladders. In addition, gallbladder volume negatively correlated with the hydrophobicity index of bile acids. Cholecystectomized patients displayed significantly higher aspartate aminotransferase and more severe bile duct strictures and dilatations compared to those with conserved gallbladder. In the Abcb4 knockout mice, cholecystectomy caused an increase in hepatic bile acid content and in circulating secondary bile acids, and an aggravation in cholangitis, inflammation and liver fibrosis., Conclusion: Altogether, our findings indicate that the gallbladder fulfills protective functions in PSC., Impact and Implications: In patients with primary sclerosing cholangitis (PSC), gallbladder status impacts on bile acid homeostasis and disease features. We found evidence of lessened bile acid toxicity in patients with PSC and enlarged gallbladders and of increased disease severity in those who were previously cholecystectomized. In the Abcb4 knockout mouse model of PSC, cholecystectomy causes an aggravation of cholangitis and liver fibrosis. Overall, our results suggest that the gallbladder plays a protective role in PSC., Competing Interests: Nora Cazzagon, Ester Gonzalez-Sanchez, Haquima El-Mourabit, Dominique Wendum, Dominique Rainteau, Lydie Humbert, Olivier Chazouillères, Lionel Arrivé, Chantal Housset and Sara Lemoinne declare no conflict of interest related to this paper. Christophe Corpechot declares the following conflicts of interest: Intercept, Arrow, Cymabay, Ipsen, Calliditas, Gilead. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)

Background & Aims: Farnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy., Methods: Concentrations of individual bile acids and 7α-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort., Results: The bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06-1.43) and validation (adjusted HR = 1.23, 95% CI 1.03-1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis., Conclusions: Bile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation., Lay Summary: We show, by measuring the level of the metabolite C4 in the blood from patients with primary sclerosing cholangitis (PSC), that low production of bile acids in the liver predicts a more rapid progression to severe disease. Many people with PSC appear to have fully suppressed bile acid production, and both established and new drugs that aim to reduce bile acid production may therefore be futile for them. We propose C4 as a test to find those likely to respond to these treatments., Competing Interests: JRH reports receiving consultant fees from Novartis and Orkla Health, lecture honoraria from Roche, and research funding from Biogen, none of which relate to this work. HUM reports receiving consultant fees from Calliditas, Mirum, and Zealand, and lecture honoraria from Albireo, none of which relate to this work. MV reports receiving lecture honoraria from Siemens Healthineers and Intercept, none of which relate to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)

Background & Aims: The safety, tolerability, and efficacy of the non-bile acid farnesoid X receptor agonist tropifexor were evaluated in a phase II, double-blind, placebo-controlled study as potential second-line therapy for patients with primary biliary cholangitis (PBC) with an inadequate ursodeoxycholic acid response., Methods: Patients were randomised (2:1) to receive tropifexor (30, 60, 90, or 150 μg) or matched placebo orally once daily for 28 days, with follow-up on Days 56 and 84. Primary endpoints were safety and tolerability of tropifexor and reduction in levels of γ-glutamyl transferase (GGT) and other liver biomarkers. Other objectives included patient-reported outcome measures using the PBC-40 quality-of-life (QoL) and visual analogue scale scores and tropifexor pharmacokinetics., Results: Of 61 enrolled patients, 11, 9, 12, and 8 received 30-, 60-, 90-, and 150-μg tropifexor, respectively, and 21 received placebo; 3 patients discontinued treatment because of adverse events (AEs) in the 150-μg tropifexor group. Pruritus was the most frequent AE in the study (52.5% [tropifexor] vs . 28.6% [placebo]), with most events of mild to moderate severity. Decreases seen in LDL-, HDL-, and total-cholesterol levels at 60-, 90-, and 150 μg doses stabilised after treatment discontinuation. By Day 28, tropifexor caused 26-72% reduction in GGT from baseline at 30- to 150-μg doses ( p <0.001 at 60-, 90-, and 150-μg tropifexor vs . placebo). Day 28 QoL scores were comparable between the placebo and tropifexor groups. A dose-dependent increase in plasma tropifexor concentration was observed, with 5- to 5.55-fold increases in AUC 0-8h and C max between 30- and 150-μg doses., Conclusions: Tropifexor showed improvement in cholestatic markers relative to placebo, predictable pharmacokinetics, and an acceptable safety-tolerability profile, thereby supporting its potential further clinical development for PBC., Lay Summary: The bile acid ursodeoxycholic acid (UDCA) is the standard-of-care therapy for primary biliary cholangitis (PBC), but approximately 40% of patients have an inadequate response to this therapy. Tropifexor is a highly potent non-bile acid agonist of the farnesoid X receptor that is under clinical development for various chronic liver diseases. In the current study, in patients with an inadequate response to UDCA, tropifexor was found to be safe and well tolerated, with improved levels of markers of bile duct injury at very low (microgram) doses. Itch of mild to moderate severity was observed in all groups including placebo but was more frequent at the highest tropifexor dose., Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT02516605)., Competing Interests: CS is a consultant for Novartis and BiomX and has received honoraria from Falk Pharma and research funding from Galapagos and BiomX. HW is a consultant for or has received speaker fees from Falk Foundation, BMS, AbbVie, Norgine, Merz, Mallinckrodt, MYR GmbH, Gilead, MSD, and Intercept. AM has research grants from Merck and Intercept and has received speaker’s and teaching honoraria from Intercept. GMH has consulted for Intercept, Genfit, Cymabay, GSK, Novartis, Pliant, Falk Pharma. CL has research grants from Novartis, Gilead, Intercept, Enanta, NGM, Genfit, Cara Therapeutics, CymaBay, Target PharmaSolutions, Genkyotex, GSK, Durect, Pliant, High Tide and Zydus, and is a consultant for Genfit, GSK, CymaBay, Mirum, Cara therapeutics, Pliant, Shire, Target PharmaSolutions, Calliditas, and Escient. KVK is on the Advisory Committee or Review Panel of 89Bio, Gilead, CymaBay, Intercept, Genfit, and Madrigal; is a consultant for Calliditas, Intercept, HighTide, Mirum, and Novo Nordisk; has received grant/research support from Allergan, Gilead, Intercept, Genfit, Novartis, Enanta, HighTide, CymaBay, GSK, Pfizer, Madrigal, Viking, Metacrine, Pliant, and Hanmi; has received speaker’s and teaching honoraria from AbbVie, Gilead, and Intercept; and is a stock shareholder of Inipharm. PM has received speaker’s honoraria from Alfa Wasserman and Chiesi. EJ is an investigator in clinical trials sponsored by Allergan, BMS, Celgene, CymaBay, Dr Falk, Gilead, GSK, Janssen, Pfizer, MSD, Novartis, and Roche; has received speaker’s honoraria from AbbVie, BMS, Gilead, Janssen, MSD, and Roche. ESM has no conflicts of interest to disclose. LBK was an employee of Novartis until study completion and is a stockholder of Novartis. DJ has received grant funding from Intercept and Pfizer; is a consultant for Abbott, Genkyotex, GSK and Intercept; and has received speaker fees from Falk, Abbott, and Intercept. JS is a contractor with Novartis. PK, SC, and JC were employees of Novartis until manuscript finalisation. MKB is an employee and stockholder of Novartis. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)

Bile acid metabolism is altered in neonates on parenteral nutrition (PN), predisposing them to parenteral nutrition-associated liver disease. Cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the bile acid synthesis pathway, is repressed by fibroblast growth factor 19 (FGF19) and phytosterols (PS). We describe a case of a preterm infant who developed necrotizing enterocolitis (NEC) and received exclusive PN for over 2 months. Our objective was to serially assess CYP7A1 activity and plasma FGF19 and PS concentrations in this infant case compared to five healthy preterm infants. We found that CYP7A1 activity increased during the first 2 weeks of life in control infants but was undetectable in the infant case. FGF19 concentrations were high at birth in all infants and subsequently declined and did not differ between the case and control infants. As expected, PS concentrations were elevated in the infant case and continued to increase despite lipid minimization. In conclusion, CYP7A1 activity was gradually upregulated in healthy preterm infants but remained suppressed in the infant requiring prolonged PN. Preterm infants also had elevated FGF19 concentrations at birth, which decreased with advancing postnatal age.

Fatty liver disease can be triggered by a combination of excess alcohol, dysmetabolism and other environmental cues, which can lead to steatohepatitis and can evolve to acute/chronic liver failure and hepatocellular carcinoma, especially in the presence of shared inherited determinants. The recent identification of the genetic causes of steatohepatitis is revealing new avenues for more effective risk stratification. Discovery of the mechanisms underpinning the detrimental effect of causal mutations has led to some breakthroughs in the comprehension of the pathophysiology of steatohepatitis. Thanks to this approach, hepatocellular fat accumulation, altered lipid droplet remodelling and lipotoxicity have now taken centre stage, while the role of adiposity and gut-liver axis alterations have been independently validated. This process could ignite a virtuous research cycle that, starting from human genomics, through omics approaches, molecular genetics and disease models, may lead to the development of new therapeutics targeted to patients at higher risk. Herein, we also review how this knowledge has been applied to: a) the study of the main PNPLA3 I148M risk variant, up to the stage of the first in-human therapeutic trials; b) highlight a role of MBOAT7 downregulation and lysophosphatidyl-inositol in steatohepatitis; c) identify IL-32 as a candidate mediator linking lipotoxicity to inflammation and liver disease. Although this precision medicine drug discovery pipeline is mainly being applied to non-alcoholic steatohepatitis, there is hope that successful products could be repurposed to treat alcohol-related liver disease as well., Competing Interests: LV has received speaking fees from MSD, Gilead, AlfaSigma and AbbVie, served as a consultant for Gilead, Pfizer, Astra Zeneca, Novo Nordisk, Intercept, Diatech Pharmacogenetics and Ionis Pharmaceuticals, and received research grants from Gilead. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)

Background & Aims: Higher serum bile acid levels are associated with an increased risk of cirrhosis and liver-related morbidity and mortality. Herein, we report secondary analyses of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19, on the circulating bile acid profile in prospective, phase II studies in patients with metabolic or cholestatic liver disease., Methods: One hundred and seventy-six patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH) and fibrosis and elevated liver fat content (≥8% by magnetic resonance imaging-proton density fat fraction) received 0.3 mg (n = 23), 1 mg (n = 49), 3 mg (n = 49), 6 mg (n = 28) aldafermin or placebo (n = 27) for 12 weeks. Sixty-two patients with primary sclerosing cholangitis (PSC) and elevated alkaline phosphatase (>1.5× upper limit of normal) received 1 mg (n = 21), 3 mg (n = 21) aldafermin or placebo (n = 20) for 12 weeks. Serum samples were collected on day 1 and week 12 for determination of bile acid profile and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3), a direct measure of fibrogenesis., Results: Treatment with aldafermin resulted in significant dose-dependent reductions in serum bile acids. In particular, bile acids with higher hydrophobicity indices, such as deoxycholic acid, lithocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, and glycocholic acid, were markedly lowered by aldafermin in both NASH and PSC populations. Moreover, aldafermin predominantly suppressed the glycine-conjugated bile acids, rather than the taurine-conjugated bile acids. Changes in levels of bile acids correlated with changes in the novel fibrogenesis marker Pro-C3, which detects a neo-epitope of the type III collagen during its formation, in the pooled NASH and PSC populations., Conclusions: Aldafermin markedly reduced major hydrophobic bile acids that have greater detergent activity and cytotoxicity. Our data provide evidence that bile acids may contribute to sustaining a pro-fibrogenic microenvironment in the liver across metabolic and cholestatic liver diseases., Lay Summary: Aldafermin is an analogue of a gut hormone, which is in development as a treatment for patients with chronic liver disease. Herein, we show that aldafermin can potently and robustly suppress the toxic, hydrophobic bile acids irrespective of disease aetiology. The therapeutic strategy utilising aldafermin may be broadly applicable to other chronic gastrointestinal and liver disorders., Clinical Trials Registration: The study is registered at Clinicaltrials.govNCT02443116 and NCT02704364., Competing Interests: A.J.S. reports serving as an unpaid consultant to Intercept, Zydus, Echosense, Immuron, Madrigal, Galectin, Blade, Pliant, Albireo, and AMRA; is a consultant to Gilead, Allergan, Bristol-Myers Squibb, Pfizer, Merck, Galmed, Novartis, Novo Nordisk, Lilly, Siemens, Genentech, Boehringer Ingelhiem, Glympse Bio, Genfit, Coherus, Surrozen, Poxel, 89 Bio, Perspectum, AstraZeneca, Medimmune, and Lipocine; owns stock options in Indalo, Durect, Tiziana, Exhalenz, and Northsea; and is president of Sanyal Bio. L.L., A.M.D., and H.D.L. are employees and stockholders of NGM Biopharmaceuticals. U.B. reports consulting for Novartis, Intercept; grant/research support from Norwegian, American, and South African PSC patient foundations and German DCCV; received lecture fees from Abbvie, Falk Foundation, Gilead, Intercept, Novartis, Roche, Shire, and Zambon; and received research support for investigator-initiated studies from Dr. Falk Pharma and Intercept. S.A.H. reports research support from Conatus, Galectin, Galmed, Genfit, Gilead, Intercept, Madrigal, NGM, Akero, Axcella, Metacrine, Sagimet, Enyo, NorthSea, Genentech, Hepion, Cymabay, and Hightide; and is a consulting adviser for the Chronic Liver Disease Foundation, Cirius, Echosens, Akero, Galectin, Galmed, Genfit, Gilead, Intercept, Madrigal, NGM, Novartis, Perspectum, Metacrine, Medpace, Sagimet, Blade, Viking, Poxel, Axcella, Terns, HistoIndex, Hightide, Hepion, Ridgeline Therapeutics, CiVi, and Prometic. G.M.H. reports consulting for Cymabay, Genfit, Falk, Intercept, GSK, Mirum, Roche, and Pliant. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)

Background: Bile acid homeostasis is essential and imbalance may lead to liver damage and liver failure. The bile acid induced intestinal factor fibroblast growth factor 19 (FGF19) has been identified as a key protein for mediating negative feedback inhibition of bile acid synthesis. The aim of the study was to define FGF19 and bile acid concentrations in portal and systemic blood in the fasted and postprandial state. We also addressed the question if physiological portal levels of FGF19 can be extrapolated from the concentration in systemic blood., Methods: Portal and systemic blood was collected from 75 fasted patients undergoing liver surgery and from three organ donors before and after enteral nutrition. Serum concentration of FGF19 was determined with ELISA and bile acid concentration with gas chromatography-mass spectrometry., Results: Concentration of bile acids was twice as high in portal compared to systemic blood in the fasted group and 3-5 times higher in the postprandial group. FGF19 increased after enteral nutrition but did not differ between portal and systemic blood, in either group. In addition, a strong, positive correlation between bile acids and FGF19 was found., Conclusion: Our results confirm that bile acids drive the postprandial increase of circulating FGF19 but a hepatic clearance of FGF19 is unlikely. We conclude that systemic concentrations of FGF19 reflect portal concentrations of FGF19.

Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases.

FGF21 is a multifunctional metabolic regulator. The co-factor βKlotho (KLB) allows FGF21 to signal via FGF receptors. Given the widespread nature of FGFR expression and KLB presence in several organs, it remains unclear which tissue/FGFR isoform determine FGF21 action. Here we show that deletion of FGFR1 in fat (FR1KO) leads to a complete ablation of FGF21 stimulated transcriptional activity in this tissue. Furthermore, FR1KO mice showed no FGF21-mediated lowering of plasma glucose, insulin and triglycerides, altered serum levels of adipokines, no increase in energy expenditure, but preserved reductions in serum/liver FFAs as compared to wild type mice. Of importance, the anti-glycaemic actions of FGF19 were fully evident in FR1KO mice implying that FGF19 functions in a FGFR1/adipose independent manner. Taken together, our findings reveal the existence of an adipose FGFR1 driven axis of cross-tissue communication which defines several aspects of FGF21 biology and delineates mechanistic distinctions between FGF21 and FGF19.