Rebuttal To: the Benevolent Bile: Bile Acids As Stimulants of Liver Regeneration

See Point-Counterpoint articles on pages 1474 and 1478. See Point-Counterpoint articles on pages 1474 and 1478. Bhushan and Apte1Bhushan Bharat Apte Udayan The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration.Cell Mol Gastroenterol Hepatol. 2022; 13: 1478-1480Google Scholar highlight the beneficial effects of bile acids (BAs), such that increasing BA levels stimulate regeneration and recovery after partial hepatectomy (PH) or drug-induced acute liver injury. Although we agree with the protective role of BAs in liver regeneration, increasing evidence points to the fact that the composition of the BA pool is crucial for downstream signaling. Hydrophobic BAs induce cytotoxicity while hydrophilic BAs alleviate liver injury, and the ratio of BAs in the pool determines the hydrophobic index. Deletion of small heterodimer partner2Park Y.J. Qatanani M. Chua S.S. LaRey J.L. Johnson S.A. Watanabe M. Moore D.D. Lee Y.K. Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis.Hepatology. 2008; 47: 1578-1586Google Scholar and a lithocholic acid–enriched diet3Fickert P. Fuchsbichler A. Marschall H.U. Wagner M. Zollner G. Krause R. Zatloukal K. Jaeschke H. Denk H. Trauner M. Lithocholic acid feeding induces segmental bile duct obstruction and destructive cholangitis in mice.Am J Pathol. 2006; 168: 410-422Google Scholar both can increase the hydrophobic BA pool, causing bile infarcts, bile duct obstruction, and liver injury. Moreover, altered BA composition after PH has been noted with a particular increase in cholic acid and a reduction in chenodeoxycholic acid, resulting in a more hydrophilic BA pool during regeneration. Mechanistically, the membrane Takeda G-protein–coupled receptor activation modulates BA composition to become more hydrophilic, and thus protects against cytotoxic BA accumulation.4Bidault-Jourdainne V. Merlen G. Glenisson M. Doignon I. Garcin I. Pean N. Boisgard R. Ursic-Bedoya J. Serino M. Ullmer C. Humbert L. Abdelrafee A. Golse N. Vibert E. Duclos-Vallee J.C. Rainteau D. Tordjmann T. TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload.JHEP Rep. 2021; 3100214Google Scholar However, if the BA composition became more hydrophobic, it correlates with increased liver injury after PH in human beings and mice.4Bidault-Jourdainne V. Merlen G. Glenisson M. Doignon I. Garcin I. Pean N. Boisgard R. Ursic-Bedoya J. Serino M. Ullmer C. Humbert L. Abdelrafee A. Golse N. Vibert E. Duclos-Vallee J.C. Rainteau D. Tordjmann T. TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload.JHEP Rep. 2021; 3100214Google Scholar Mouse models with hydrophobic BA composition, including Cyp2c70 knockout and Cyp2a12/Cyp2c70 double-knockout mice, show inflammation and injury in the liver despite having a reduced overall BA concentration.5Honda A. Miyazaki T. Iwamoto J. Hirayama T. Morishita Y. Monma T. Ueda H. Mizuno S. Sugiyama F. Takahashi S. Ikegami T. Regulation of bile acid metabolism in mouse models with hydrophobic bile acid composition.J Lipid Res. 2020; 61: 54-69Google Scholar In addition, increasing evidence has shown that changes in BA composition can modulate immune responses in the liver and contribute to the pathogenesis of inflammatory diseases.6Evangelakos I. Heeren J. Verkade E. Kuipers F. Role of bile acids in inflammatory liver diseases.Semin Immunopathol. 2021; 43: 577-590Google Scholar BAs also activate cell death and survival pathways, and the balance between these signals determines the beneficial or toxic effects of specific BAs in the liver. For example, hydrophilic ursodeoxycholic acid induces hepatocyte apoptosis to clear them from inherent BA toxicity, whereas taurine conjugate of a slightly hydrophobic BA, chenodeoxycholic acid, facilitates survival pathways and hepatocyte proliferation.7Guicciardi M.E. Gores G.J. Bile acid-mediated hepatocyte apoptosis and cholestatic liver disease.Dig Liver Dis. 2002; 34: 387-392Google Scholar Apart from receptor-based cellular signaling, more recent data have uncovered the role of the gut microbiota–BA axis in several liver diseases. In fact, gut microbiota can facilitate the production of novel phenylalanine- and tyrosine-conjugated cholic acids that are enriched in disease conditions in human beings.8Quinn R.A. Melnik A.V. Vrbanac A. Fu T. Patras K.A. Christy M.P. Bodai Z. Belda-Ferre P. Tripathi A. Chung L.K. Downes M. Welch R.D. Quinn M. Humphrey G. Panitchpakdi M. Weldon K.C. Aksenov A. da Silva R. Avila-Pacheco J. Clish C. Bae S. Mallick H. Franzosa E.A. Lloyd-Price J. Bussell R. Thron T. Nelson A.T. Wang M. Leszczynski E. Vargas F. Gauglitz J.M. Meehan M.J. Gentry E. Arthur T.D. Komor A.C. Poulsen O. Boland B.S. Chang J.T. Sandborn W.J. Lim M. Garg N. Lumeng J.C. Xavier R.J. Kazmierczak B.I. Jain R. Egan M. Rhee K.E. Ferguson D. Raffatellu M. Vlamakis H. Haddad G.G. Siegel D. Huttenhower C. Mazmanian S.K. Evans R.M. Nizet V. Knight R. Dorrestein P.C. Global chemical effects of the microbiome include new bile-acid conjugations.Nature. 2020; 579: 123-129Google Scholar Furthermore, in patients with intrahepatic cholangiocarcinoma, gut microbiota correlate with BA levels and composition along with inflammatory cytokines.9Jia X. Lu S. Zeng Z. Liu Q. Dong Z. Chen Y. Zhu Z. Hong Z. Zhang T. Du G. Xiang J. Wu D. Bai W. Yang B. Li Y. Huang J. Li H. Safadi R. Lu Y. Characterization of gut microbiota, bile acid metabolism, and cytokines in intrahepatic cholangiocarcinoma.Hepatology. 2020; 71: 893-906Google Scholar Therefore, appropriate regulation of BA composition, hydrophobic index, and overall concentration will influence if the outcome in the liver will be harmful or beneficial. “Light. Darkness. A balance.” -The Last Jedi The Benevolent Bile: Bile Acids as Stimulants of Liver RegenerationCellular and Molecular Gastroenterology and HepatologyVol. 13Issue 5PreviewBile acids are amphiphilic signaling molecules involved in a number of pathophysiological processes including digestion and adsorption of fats, inflammation, cell proliferation, and cancer.1–3 Whereas an increase in the intracellular levels of bile acid is generally associated with pathogenic outcomes, bile acids are critical for multiple nondigestive physiological processes at normal levels. One such process is liver regeneration, where bile acid plays a critical regulatory role.4–7 The liver is known for its remarkable capacity to regenerate after surgical resection or injury induced by viruses and chemicals. Full-Text PDF Open Access