FXR-FGF19 signaling in the gut-liver axis is dysregulated in patients with cirrhosis and correlates with impaired intestinal defence.
ACLD
FGF19
FXR
Gut–liver axis
Intestinal barrier
Portal hypertension
Journal
Hepatology international
ISSN: 1936-0541
Titre abrégé: Hepatol Int
Pays: United States
ID NLM: 101304009
Informations de publication
Date de publication:
08 Feb 2024
08 Feb 2024
Historique:
received:
20
07
2023
accepted:
22
12
2023
medline:
9
2
2024
pubmed:
9
2
2024
entrez:
9
2
2024
Statut:
aheadofprint
Résumé
Experimental studies linked dysfunctional Farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling to liver disease. This study investigated key intersections of the FXR-FGF19 pathway along the gut-liver axis and their link to disease severity in patients with cirrhosis. Patients with cirrhosis undergoing hepatic venous pressure gradient measurement (cohort-I n = 107, including n = 53 with concomitant liver biopsy; n = 5 healthy controls) or colonoscopy with ileum biopsy (cohort-II n = 37; n = 6 controls) were included. Hepatic and intestinal gene expression reflecting FXR activation and intestinal barrier integrity was assessed. Systemic bile acid (BA) and FGF19 levels were measured. Systemic BA and FGF19 levels correlated significantly (r = 0.461; p < 0.001) and increased with cirrhosis severity. Hepatic SHP expression decreased in patients with cirrhosis (vs. controls; p < 0.001), indicating reduced FXR activation in the liver. Systemic FGF19 (r = -0.512, p < 0.001) and BA (r = -0.487, p < 0.001) levels correlated negatively with hepatic CYP7A1, but not SHP or CYP8B1 expression, suggesting impaired feedback signaling in the liver. In the ileum, expression of FXR, SHP and FGF19 decreased in patients with cirrhosis, and interestingly, intestinal FGF19 expression was not linked to systemic FGF19 levels. Intestinal zonula occludens-1, occludin, and alpha-5-defensin expression in the ileum correlated with SHP and decreased in patients with decompensated cirrhosis as compared to controls. FXR-FGF19 signaling is dysregulated at essential molecular intersections along the gut-liver axis in patients with cirrhosis. Decreased FXR activation in the ileum mucosa was linked to reduced expression of intestinal barrier proteins. These human data call for further mechanistic research on interventions targeting the FXR-FGF19 pathway in patients with cirrhosis. NCT03267615.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
Experimental studies linked dysfunctional Farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling to liver disease. This study investigated key intersections of the FXR-FGF19 pathway along the gut-liver axis and their link to disease severity in patients with cirrhosis.
METHODS
METHODS
Patients with cirrhosis undergoing hepatic venous pressure gradient measurement (cohort-I n = 107, including n = 53 with concomitant liver biopsy; n = 5 healthy controls) or colonoscopy with ileum biopsy (cohort-II n = 37; n = 6 controls) were included. Hepatic and intestinal gene expression reflecting FXR activation and intestinal barrier integrity was assessed. Systemic bile acid (BA) and FGF19 levels were measured.
RESULTS
RESULTS
Systemic BA and FGF19 levels correlated significantly (r = 0.461; p < 0.001) and increased with cirrhosis severity. Hepatic SHP expression decreased in patients with cirrhosis (vs. controls; p < 0.001), indicating reduced FXR activation in the liver. Systemic FGF19 (r = -0.512, p < 0.001) and BA (r = -0.487, p < 0.001) levels correlated negatively with hepatic CYP7A1, but not SHP or CYP8B1 expression, suggesting impaired feedback signaling in the liver. In the ileum, expression of FXR, SHP and FGF19 decreased in patients with cirrhosis, and interestingly, intestinal FGF19 expression was not linked to systemic FGF19 levels. Intestinal zonula occludens-1, occludin, and alpha-5-defensin expression in the ileum correlated with SHP and decreased in patients with decompensated cirrhosis as compared to controls.
CONCLUSIONS
CONCLUSIONS
FXR-FGF19 signaling is dysregulated at essential molecular intersections along the gut-liver axis in patients with cirrhosis. Decreased FXR activation in the ileum mucosa was linked to reduced expression of intestinal barrier proteins. These human data call for further mechanistic research on interventions targeting the FXR-FGF19 pathway in patients with cirrhosis.
CLINICAL TRIAL NUMBER
BACKGROUND
NCT03267615.
Identifiants
pubmed: 38332428
doi: 10.1007/s12072-023-10636-4
pii: 10.1007/s12072-023-10636-4
doi:
Banques de données
ClinicalTrials.gov
['NCT03267615']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Gilead Sciences
ID : International Research Scholar
Informations de copyright
© 2024. The Author(s).
Références
Fuchs CD, Trauner M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol. 2022;19(7):432–450
pubmed: 35165436
doi: 10.1038/s41575-021-00566-7
Simbrunner B, Trauner M, Reiberger T. Therapeutic aspects of bile acid signalling in the gut-liver axis. Aliment Pharmacol Ther. 2021;54(10):1243–1262
pubmed: 34555862
pmcid: 9290708
doi: 10.1111/apt.16602
Verbeke L, et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol. 2015;185(2):409–19
pubmed: 25592258
doi: 10.1016/j.ajpath.2014.10.009
Ubeda M, et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J Hepatol. 2016;64(5):1049–1057
pubmed: 26723896
doi: 10.1016/j.jhep.2015.12.010
Sorribas M, et al. FxR-modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis. J Hepatol. 2019;67(5):1084
Lorenzo-Zuniga V, et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology. 2003;37(3):551–7
pubmed: 12601352
doi: 10.1053/jhep.2003.50116
Verbeke L, et al. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep. 2016;6:33453
pubmed: 27634375
pmcid: 5025787
doi: 10.1038/srep33453
Schwabl P, et al. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol. 2017;66(4):724–733
pubmed: 27993716
doi: 10.1016/j.jhep.2016.12.005
Verbeke L, et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology. 2014;59(6):2286–98
pubmed: 24259407
doi: 10.1002/hep.26939
Byun S, et al. Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis. Nat Commun. 2018;9(1):2590
pubmed: 29968724
pmcid: 6030054
doi: 10.1038/s41467-018-04697-5
Milkiewicz M, et al. Impaired hepatic adaptation to chronic cholestasis induced by primary sclerosing cholangitis. Sci Rep. 2016;6:39573
pubmed: 28008998
pmcid: 5180097
doi: 10.1038/srep39573
Wunsch E, et al. Expression of hepatic fibroblast growth factor 19 is enhanced in primary biliary cirrhosis and correlates with severity of the disease. Sci Rep. 2015;5:13462
pubmed: 26293907
pmcid: 4544021
doi: 10.1038/srep13462
Simbrunner B, et al. Gut-liver axis signaling in portal hypertension. World J Gastroenterol. 2019;25(39):5897–5917
pubmed: 31660028
pmcid: 6815800
doi: 10.3748/wjg.v25.i39.5897
Reiberger T, et al. Measurement of the hepatic venous pressure gradient and transjugular liver biopsy. J Vis Exp. 2020. https://doi.org/10.3791/58819
doi: 10.3791/58819
pubmed: 32628153
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25(4):402–8
pubmed: 11846609
doi: 10.1006/meth.2001.1262
Mannes GA, et al. Prognostic significance of serum bile acids in cirrhosis. Hepatology. 1986;6(1):50–3
pubmed: 3943790
doi: 10.1002/hep.1840060110
Wang X, et al. Serum bile acids are associated with pathological progression of hepatitis B-induced cirrhosis. J Proteome Res. 2016;15(4):1126–34
pubmed: 25964117
pmcid: 5660916
doi: 10.1021/acs.jproteome.5b00217
Horvatits T, et al. Serum bile acids as marker for acute decompensation and acute-on-chronic liver failure in patients with non-cholestatic cirrhosis. Liver Int. 2017;37(2):224–231
pubmed: 27416294
doi: 10.1111/liv.13201
Brandl K, et al. Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis. J Hepatol. 2018;69(2):396–405
pubmed: 29654817
pmcid: 6054564
doi: 10.1016/j.jhep.2018.03.031
Li Z, et al. Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis. PLoS One. 2017;12(6): e0178580
pubmed: 28570655
pmcid: 5453554
doi: 10.1371/journal.pone.0178580
Sauerbruch T, et al. Bile acids, liver cirrhosis, and extrahepatic vascular dysfunction. Front Physiol. 2021;12: 718783
pubmed: 34393832
pmcid: 8358446
doi: 10.3389/fphys.2021.718783
Ohkubo H, et al. Role of portal and splenic vein shunts and impaired hepatic extraction in the elevated serum bile acids in liver cirrhosis. Gastroenterology. 1984;86(3):514–20
pubmed: 6693014
doi: 10.1016/S0016-5085(84)80022-0
Lindblad L, Lundholm K, Schersten T. Bile acid concentrations in systemic and portal serum in presumably normal man and in cholestatic and cirrhotic conditions. Scand J Gastroenterol. 1977;12(4):395–400
pubmed: 560715
doi: 10.3109/00365527709181679
Lu TT, et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell. 2000;6(3):507–15
pubmed: 11030331
doi: 10.1016/S1097-2765(00)00050-2
Landrier JF, et al. The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes. Am J Physiol Gastrointest Liver Physiol. 2006;290(3):G476-85
pubmed: 16269519
doi: 10.1152/ajpgi.00430.2005
Guo C, et al. Farnesoid X receptor agonists obeticholic acid and chenodeoxycholic acid increase bile acid efflux in sandwich-cultured human hepatocytes: functional evidence and mechanisms. J Pharmcol Exp Ther. 2018;365(2):413–421
doi: 10.1124/jpet.117.246033
Lee H, et al. FXR regulates organic solute transporters alpha and beta in the adrenal gland, kidney, and intestine. J Lipid Res. 2006;47(1):201–14
pubmed: 16251721
doi: 10.1194/jlr.M500417-JLR200
Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014;11(1):55–67
pubmed: 23982684
doi: 10.1038/nrgastro.2013.151
Schwabl P, et al. The non-steroidal FXR agonist cilofexor improves portal hypertension and reduces hepatic fibrosis in a rat NASH model. Biomedicines. 2021;9(1):60
pubmed: 33435509
pmcid: 7827357
doi: 10.3390/biomedicines9010060
Königshofer P, et al. Nuclear receptors in liver fibrosis. Biochim Biophys Acta Mol Basis Dis. 2021;1867(12): 166235
pubmed: 34339839
doi: 10.1016/j.bbadis.2021.166235
D’Amico G, et al. Clinical states of cirrhosis and competing risks. J Hepatol. 2018;68(3):563–576
pubmed: 29111320
doi: 10.1016/j.jhep.2017.10.020
Boyer JL, et al. Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol. 2006;290(6):G1124-30
pubmed: 16423920
doi: 10.1152/ajpgi.00539.2005
Zollner G, et al. Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver Int. 2007;27(7):920–9
pubmed: 17696930
doi: 10.1111/j.1478-3231.2007.01506.x
McCormick WC 3rd, et al. Cholic acid synthesis as an index of the severity of liver disease in man. Gut. 1973;14(11):895–902
pubmed: 4761610
pmcid: 1412848
doi: 10.1136/gut.14.11.895
Inagaki T, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA. 2006;103(10):3920–3925
pubmed: 16473946
pmcid: 1450165
doi: 10.1073/pnas.0509592103
Holt JA, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 2003;17(13):1581–1591
pubmed: 12815072
pmcid: 196131
doi: 10.1101/gad.1083503
Inagaki T, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005;2(4):217–225
pubmed: 16213224
doi: 10.1016/j.cmet.2005.09.001
Hasegawa Y, et al. CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia. Hepatol Res. 2019;49(3):314–323
pubmed: 30156739
doi: 10.1111/hepr.13245
Schaap FG, et al. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology. 2009;49(4):1228–1235
pubmed: 19185005
doi: 10.1002/hep.22771
Obeticholic acid, in LiverTox: clinical and research information on drug-induced liver injury. 2012, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (MD)
John BV, et al. Impact of obeticholic acid exposure on decompensation and mortality in primary biliary cholangitis and cirrhosis. Hepatol Commun. 2021;5(8):1426–1436
pubmed: 34430786
pmcid: 8369937
doi: 10.1002/hep4.1720
Teltschik Z, et al. Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense. Hepatology. 2012;55(4):1154–63
pubmed: 22095436
doi: 10.1002/hep.24789
Arroyo V, et al. The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis. J Hepatol. 2021;74(3):670–685
pubmed: 33301825
doi: 10.1016/j.jhep.2020.11.048
Trebicka J, et al. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. J Hepatol. 2020;74(2):480–481
pubmed: 33279257
doi: 10.1016/j.jhep.2020.11.012
Costa D, et al. Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality. J Hepatol. 2021;74(4):819–828
pubmed: 33075344
doi: 10.1016/j.jhep.2020.10.004
Simbrunner B, et al. Systemic inflammation is linked to liver fibrogenesis in patients with advanced chronic liver disease. Liver Int. 2022;42(11):2501–2512
pubmed: 35822301
pmcid: 9804351
doi: 10.1111/liv.15365
Simbrunner B, et al. Dysregulated biomarkers of innate and adaptive immunity predict infections and disease progression in cirrhosis. JHEP Rep. 2023;5(5):100712
pubmed: 37035457
pmcid: 10074195
doi: 10.1016/j.jhepr.2023.100712
Simbrunner B, et al. Bacterial translocation occurs early in cirrhosis and triggers a selective inflammatory response. Hepatol Int. 2023;17(4):1045–1056
pubmed: 36881247
doi: 10.1007/s12072-023-10496-y
Tranah TH, et al. Targeting the gut-liver-immune axis to treat cirrhosis. Gut. 2020;70(5):982–994
pubmed: 33060124
doi: 10.1136/gutjnl-2020-320786
Llovet JM, et al. Translocated intestinal bacteria cause spontaneous bacterial peritonitis in cirrhotic rats: molecular epidemiologic evidence. J Hepatol. 1998;28(2):307–13
pubmed: 9580278
doi: 10.1016/0168-8278(88)80018-7
Llovet JM, et al. Bacterial translocation in cirrhotic rats. Its role in the development of spontaneous bacterial peritonitis. Gut. 1994;35(11):1648–1652
pubmed: 7828991
pmcid: 1375630
doi: 10.1136/gut.35.11.1648
Muñoz L, et al. Intestinal immune dysregulation driven by dysbiosis promotes barrier disruption and bacterial translocation in rats with cirrhosis. Hepatology. 2019;70(3):925–938
pubmed: 30414342
doi: 10.1002/hep.30349