Taurine-conjugated bile acids and their link to hepatic S1PR2 play a significant role in hepatitis C-related liver disease.
Humans
Bile Acids and Salts
/ metabolism
Male
Taurine
/ blood
Female
Middle Aged
Liver
/ metabolism
Sphingosine-1-Phosphate Receptors
/ metabolism
Hepatitis C, Chronic
/ drug therapy
Liver Cirrhosis
/ metabolism
Gastrointestinal Microbiome
Sustained Virologic Response
NLR Family, Pyrin Domain-Containing 3 Protein
/ metabolism
Adult
Aged
Journal
Hepatology communications
ISSN: 2471-254X
Titre abrégé: Hepatol Commun
Pays: United States
ID NLM: 101695860
Informations de publication
Date de publication:
01 Jul 2024
01 Jul 2024
Historique:
received:
15
12
2023
accepted:
26
04
2024
medline:
5
7
2024
pubmed:
5
7
2024
entrez:
5
7
2024
Statut:
epublish
Résumé
Bile acids mediate gut-liver cross-talk through bile acid receptors. Serum, hepatic, and microbial bile acid metabolism was evaluated in HCV-compensated chronic liver disease. Patients underwent liver biopsy; portal and peripheral blood were obtained before (HCVi), and 6 months after sustained virologic response (SVR), splenic blood was obtained only after SVR. The fecal microbiome and liver transcriptome were evaluated using RNA-Seq. Twenty-four bile acids were measured in serum, summed as free, taurine-conjugated bile acids (Tau-BAs), and glycine-conjugated bile acids. Compared to SVR, HCVi showed elevated conjugated bile acids, predominantly Tau-BA, compounded in HCVi cirrhosis. In the liver, transcription of bile acids uptake, synthesis, and conjugation was decreased with increased hepatic spillover into systemic circulation in HCVi. There was no difference in the transcription of microbial bile acid metabolizing genes in HCVi. Despite an overall decrease, Tau-BA remained elevated in SVR cirrhosis, mainly in splenic circulation. Only conjugated bile acids, predominantly Tau-BA, correlated with serum proinflammatory markers and hepatic proinflammatory pathways, including NLRP3 and NFKB. Among hepatic bile acid receptors, disease-associated conjugated bile acids showed the strongest association with hepatic spingosine-1-phosphate receptor 2 (S1PR2). Enhanced expression of hepatic S1PR2 in HCVi and HCVi-cirrhosis and strong associations of S1PR2 with Tau-BAs suggest pathological relevance of Tau-BA-hepatic S1PR2 signaling in chronic liver disease. These findings have therapeutic implications in chronic liver diseases.
Sections du résumé
BACKGROUND
BACKGROUND
Bile acids mediate gut-liver cross-talk through bile acid receptors. Serum, hepatic, and microbial bile acid metabolism was evaluated in HCV-compensated chronic liver disease.
METHODS
METHODS
Patients underwent liver biopsy; portal and peripheral blood were obtained before (HCVi), and 6 months after sustained virologic response (SVR), splenic blood was obtained only after SVR. The fecal microbiome and liver transcriptome were evaluated using RNA-Seq. Twenty-four bile acids were measured in serum, summed as free, taurine-conjugated bile acids (Tau-BAs), and glycine-conjugated bile acids.
RESULTS
RESULTS
Compared to SVR, HCVi showed elevated conjugated bile acids, predominantly Tau-BA, compounded in HCVi cirrhosis. In the liver, transcription of bile acids uptake, synthesis, and conjugation was decreased with increased hepatic spillover into systemic circulation in HCVi. There was no difference in the transcription of microbial bile acid metabolizing genes in HCVi. Despite an overall decrease, Tau-BA remained elevated in SVR cirrhosis, mainly in splenic circulation. Only conjugated bile acids, predominantly Tau-BA, correlated with serum proinflammatory markers and hepatic proinflammatory pathways, including NLRP3 and NFKB. Among hepatic bile acid receptors, disease-associated conjugated bile acids showed the strongest association with hepatic spingosine-1-phosphate receptor 2 (S1PR2).
CONCLUSIONS
CONCLUSIONS
Enhanced expression of hepatic S1PR2 in HCVi and HCVi-cirrhosis and strong associations of S1PR2 with Tau-BAs suggest pathological relevance of Tau-BA-hepatic S1PR2 signaling in chronic liver disease. These findings have therapeutic implications in chronic liver diseases.
Identifiants
pubmed: 38967598
doi: 10.1097/HC9.0000000000000478
pii: 02009842-202407010-00024
pii:
doi:
Substances chimiques
Bile Acids and Salts
0
Taurine
1EQV5MLY3D
Sphingosine-1-Phosphate Receptors
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Références
Macpherson AJ, Heikenwalder M, Ganal-Vonarburg SC. The liver at the nexus of host-microbial interactions. Cell Host Microbe. 2016;20:561–571.
Shapiro H, Kolodziejczyk AA, Halstuch D, Elinav E. Bile acids in glucose metabolism in health and disease. J Exp Med. 2018;215:383–396.
Fiorucci S, Biagioli M, Zampella A, Distrutti E. Bile acids activated receptors regulate innate immunity. Front Immunol. 2018;9:1853.
Agus A, Clément K, Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut. 2020;70:1174–1182.
Fiorucci S, Distrutti E. The Pharmacology of Bile Acids and Their Receptors. In: Fiorucci S, Distrutti E, eds. Bile Acids and Their Receptors Handbook of Experimental Pharmacology. Springer International Publishing; 2019:3–18.
Keitel V, Stindt J, Häussinger D. Bile Acid-Activated Receptors: GPBAR1 (TGR5) and Other G Protein-Coupled Receptors. In: Fiorucci S, Distrutti E, eds. Bile Acids and Their Receptors Handbook of Experimental Pharmacology. Springer International Publishing; 2019:19–49.
Keitel V, Dröge C, Häussinger D. Targeting FXR in Cholestasis. In: Fiorucci S, Distrutti E, eds. Bile Acids and Their Receptors Handbook of Experimental Pharmacology. Springer International Publishing; 2019:299–324.
Ali RO, Quinn GM, Umarova R, Haddad JA, Zhang GY, Townsend EC, et al. Longitudinal multi-omics analyses of the gut–liver axis reveals metabolic dysregulation in hepatitis C infection and cirrhosis. Nat Microbiol . 2023;8:12–27.
Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatol Baltim Md. 1981;1:431–435.
Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696–699.
Evans A, Bridgewater BR. High resolution mass spectrometry improves data quantity and quality as compared to unit mass resolution mass spectrometry in high-throughput profiling metabolomics. J Postgenomics Drug Biomark Dev. 2014;04:1–7.
Kanehisa M, Sato Y, Kawashima M, Furumichi M, Tanabe M. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 2016;44:D457–D462.
Langfelder P, Horvath S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinform. 2008;9:559.
Luo W, Friedman MS, Shedden K, Hankenson KD, Woolf PJ. GAGE: Generally applicable gene set enrichment for pathway analysis. BMC Bioinform. 2009;10:161.
Takahashi S, Fukami T, Masuo Y, Brocker CN, Xie C, Krausz KW, et al. Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. J Lipid Res. 2016;57:2130–2137.
García-Cañaveras JC, Donato MT, Castell JV, Lahoz A. Targeted profiling of circulating and hepatic bile acids in human, mouse, and rat using a UPLC-MRM-MS-validated method. J Lipid Res. 2012;53:2231–2241.
Xiao Y-T, Cao Y, Zhou K-J, Lu L-N, Cai W. Altered systemic bile acid homeostasis contributes to liver disease in pediatric patients with intestinal failure. Sci Rep. 2016;6:39264.
Nakashima T, Yoh T, Sumida Y, Kakisaka Y, Mitsuyoshi H. Differences in the efficacy of ursodeoxycholic acid and bile acid metabolism between viral liver diseases and primary biliary cirrhosis. J Gastroenterol Hepatol. 2001;16:541–547.
Bell LN, Wulff J, Comerford M, Vuppalanchi R, Chalasani N. Serum metabolic signatures of primary biliary cirrhosis and primary sclerosing cholangitis. Liver Int. 2015;35:263–274.
Luo L, Aubrecht J, Li D, Warner RL, Johnson KJ, Kenny J, et al. Assessment of serum bile acid profiles as biomarkers of liver injury and liver disease in humans. PLoS One. 2018;13:e0193824.
Puri P, Daita K, Joyce A, Mirshahi F, Santhekadur PK, Cazanave S, et al. The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids. Hepatology. 2018;67:534–548.
Ridlon JM, Kang D-J, Hylemon PB, Bajaj JS. Gut microbiota, cirrhosis, and alcohol regulate bile acid metabolism in the gut. Dig Dis. 2015;33:338–345.
Pandak WM, Kakiyama G. The acidic pathway of bile acid synthesis: Not just an alternative pathway. Liver Res. 2019;3:88–98.
Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature. 2012;487:104–108.
Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Aspects Med. 2017;56:54–65.
Hao H, Cao L, Jiang C, Che Y, Zhang S, Takahashi S, et al. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metab. 2017;25:856–867.e5.
Chen W, Wei Y, Xiong A, Li Y, Guan H, Wang Q, et al. Comprehensive analysis of serum and fecal bile acid profiles and interaction with gut microbiota in primary biliary cholangitis. Clin Rev Allergy Immunol. 2020;58:25–38.
Brandl K, Hartmann P, Jih LJ, Pizzo DP, Argemi J, Ventura-Cots M, et al. Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis. J Hepatol. 2018;69:396–405.
Lee G, You HJ, Bajaj JS, Joo SK, Yu J, Park S, et al. Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD. Nat Commun. 2020;11:4982.
Smirnova E, Muthiah MD, Narayan N, Siddiqui MS, Puri P, Luketic VA, et al. Metabolic reprogramming of the intestinal microbiome with functional bile acid changes underlie the development of NAFLD. Hepatology. 2022;76:1811–1824.
Wachtel N, Emerman S, Javitt NB. Metabolism of cholest-5-ene-3β, 26-diol in the rat and hamster. J Biol Chem. 1968;243:5207–5212.
Chiang JY. Recent advances in understanding bile acid homeostasis. F1000Res. 2017;6:2029.
Lake AD, Novak P, Shipkova P, Aranibar N, Robertson D, Reily MD, et al. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease. Toxicol Appl Pharmacol. 2013;268:132–140.
Pabst O, Hornef MW, Schaap FG, Cerovic V, Clavel T, Bruns T. Gut–liver axis: Barriers and functional circuits. Nat Rev Gastroenterol Hepatol. 2023;20:447–461.
Smith LP, Nierstenhoefer M, Yoo SW, Penzias AS, Tobiasch E, Usheva A. The bile acid synthesis pathway is present and functional in the human ovary. PLoS One. 2009;4:e7333.
Baloni P, Funk CC, Yan J, Yurkovich JT, Kueider-Paisley A, Nho K, et al. Metabolic network analysis reveals altered bile acid synthesis and metabolism in Alzheimer’s disease. Cell Rep Med. 2020;1:100138.
Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347:1260419.
Ohkubo H, Okuda K, Iida S, Ohnishi K, Ikawa S, Makino I. Role of portal and splenic vein shunts and impaired hepatic extraction in the elevated serum bile acids in liver cirrhosis. Gastroenterology. 1984;86:514–520.
D’Ambrosio R, Aghemo A, Rumi MG, Ronchi G, Donato MF, Paradis V, et al. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatol Baltim Md. 2012;56:532–543.
Wang Y, Aoki H, Yang J, Peng K, Liu R, Li X, et al. The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice. Hepatol Baltim Md. 2017;65:2005–2018.
McMillin M, Frampton G, Grant S, Khan S, Diocares J, Petrescu A, et al. Bile acid-mediated sphingosine-1-phosphate receptor 2 signaling promotes neuroinflammation during hepatic encephalopathy in mice. Front Cell Neurosci. 2017;11:191.
Zhao X, Yang L, Chang N, Hou L, Zhou X, Yang L, et al. Neutrophils undergo switch of apoptosis to NETosis during murine fatty liver injury via S1P receptor 2 signaling. Cell Death Dis. 2020;11:1–14.
Petti L, Rizzo G, Rubbino F, Elangovan S, Colombo P, Restelli S, et al. Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer. J Exp Clin Cancer Res. 2020;39:253.
Zhang G, Yang L, Kim GS, Ryan K, Lu S, O’Donnell RK, et al. Critical role of sphingosine-1-phosphate receptor 2 (S1PR2) in acute vascular inflammation. Blood. 2013;122:443–455.
Wahlström A, Sayin SI, Marschall H-U, Bäckhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24:41–50.