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Bile Acids, Gut Microbiome and the Road to Fatty Liver Disease

Phillip B. Hylemon, Lianyong Su, Po‐Cheng Zheng, Jasmohan S. Bajaj, Huiping Zhou

10.1002/cphy.c210024

Source: Volume 12, Issue 1, January 2022

Published online: December 2021

Full Article on Wiley Online Library



Abstract

This article describes the complex interactions occurring between diet, the gut microbiome, and bile acids in the etiology of fatty liver disease. Perhaps 25% of the world's population may have nonalcoholic fatty liver disease (NAFLD) and a significant percentage (∼20%) of these individuals will progress to nonalcoholic steatohepatitis (NASH). Currently, the only recommended treatment for NAFLD and NASH is a change in diet and exercise. A Western‐type diet containing high fructose corn syrup, fats, and cholesterol creates gut dysbiosis, increases intestinal permeability and uptake of LPS causing low‐grade chronic inflammation in the body. Fructose is a “lipogenic” sugar that induces long‐chain fatty acid (LCFA) synthesis in the liver. Inflammation decreases the oxidation of LCFA, allowing fat accumulation in hepatocytes. Hepatic bile acid transporters are downregulated by inflammation slowing their enterohepatic circulation and allowing conjugated bile acids (CBA) to increase in the serum and liver of NASH patients. High levels of CBA in the liver are hypothesized to activate sphingosine‐1‐phosphate receptor 2 (S1PR2), activating pro‐inflammatory and fibrosis pathways enhancing NASH progression. Because inflammation appears to be a major physiological driving force in NAFLD/NASH, new drugs and treatment protocols may require the use of anti‐inflammatory compounds, such as berberine, in combination with bile acid receptor agonists or antagonists. Emerging new molecular technologies may provide guidance in unraveling the complex physiological pathways driving fatty liver disease and better approaches to prevention and treatment. © 2021 American Physiological Society. Compr Physiol 11:1‐12, 2021.

Figure 1. Figure 1. Bile acid transporters in the liver hepatocyte, ileal enterocyte, and proximal convoluted tubule in the kidney. Bile acids are actively transported from the hepatocytes by the bile salt export protein (BSEP) or multidrug resistance protein 2 (MPR2) into bile duct. After secretion into the intestine, they are efficiently recovered by leal enterocytes using the apical sodium‐dependent bile acid transporter (ASBT) and into the portal vein via the heterodimeric organic solute transporter (OSTα/β) on the basolateral membrane. Bile acids may also undergo hepatic‐renal cycling, especially during cholestasis. Bile acids secreted by the kidney are usually modified by the sulfation of hydroxyl groups. The multidrug resistance‐associated proteins (MRP3 or ABCC3 and MRP4 or ABCC4) and OSTα‐OSTβ on the basolateral membrane are involved in ATP‐dependent bile acid export from hepatocytes to systemic circulation.
Figure 2. Figure 2. Synthesis of the primary bile acids cholic acid and chenodeoxycholic acid from cholesterol in liver hepatocytes and metabolism by gut bacteria. The primary bile acids, cholic acid, and chenodeoxycholic acid are synthesized in the hepatocytes from cholesterol and conjugated with taurine or glycine. Taurocholate is biotransformed by gut bacteria expressing bile salt hydrolases (BSH) to cholic acid and taurine. Gut bacteria can oxidize hydroxyl groups at the 3α, 7α, and 12α position on the steroid ring by 3α‐hydroxysteroid dehydrogenases (3α‐HSDH), 7α‐hydroxysteroid dehydrogenases (7α‐HSDH), and 12α‐hydroxysteroid dehydrogenases (12α‐HSDH), respectively. Oxo‐bile acids may be further metabolized at the 3β, 7β, or 12β position by 3β‐hydroxysteroid dehydrogenase (3β‐HSDH), 7β‐hydroxysteroid dehydrogenase (7β‐HSDH) and 12β‐hydroxysteroid dehydrogenase (12β‐HSDH), respectively, producing iso and epi bile acids. Primary bile acids can be biotransformed to secondary bile acids by removing the 7α‐hydroxyl group via a multistep 7α‐dehydroxylation (7α‐DeOH) biochemical pathway found in some species of the genus Clostridium.
Figure 3. Figure 3. Activation of the ERK1/2 and AKT signaling pathways by conjugated bile acids (CBA) via S1PR2. High levels of CBA activate S1PR2 in liver cells, enhancing the upregulation of genes encoding pro‐inflammatory and fibrosis mediators. Phosphorylated ERK1/2 is translocated into the nucleus, where it activates sphingosine kinase 2 (SphK2) via phosphorylation. SphK2 produces sphingosine‐1‐phosphate (S1P) that is a potent inhibitor of histone deacetylase 1 and 2 (HDAC1/2), allowing the epigenetic upregulation of gene transcription.
Figure 4. Figure 4. Alteration of the enterohepatic circulation of bile acids by NASH. Liver diseases interrupt the enterohepatic circulation of bile acids, enhancing gut dysbiosis. This has the downstream effect of increasing gut permeability and absorption of pro‐inflammatory mediators such as LPS. In NASH, there is an increase in the serum CBA that may activate the S1PR2 in hepatic cells, enhancing inflammation and activating pro‐fibrotic gene expression in stellate cells.
Figure 5. Figure 5. The possible role of diet, gut dysbiosis and bile acids in the development of steatosis and NASH. The road to Steatosis and NASH begins by consuming a Western‐type diet containing large amounts of HFCS and fats, resulting in constant low‐grade systemic inflammation due to gut dysbiosis and absorption of pro‐inflammatory bacterial molecules. Under these dietary conditions, there is an upregulation of long‐chain fatty acid synthesis in the liver and decreased oxidation and secretion of fats. Inflammation also downregulates bile acid transporters in the liver, slowing their enterohepatic circulation and allowing an increase in CBA in the liver, which activates S1PR2 stimulating hepatic inflammation and fibrosis pathways and promoting the development of cirrhosis and hepatocellular carcinoma (HCC).


Figure 1. Bile acid transporters in the liver hepatocyte, ileal enterocyte, and proximal convoluted tubule in the kidney. Bile acids are actively transported from the hepatocytes by the bile salt export protein (BSEP) or multidrug resistance protein 2 (MPR2) into bile duct. After secretion into the intestine, they are efficiently recovered by leal enterocytes using the apical sodium‐dependent bile acid transporter (ASBT) and into the portal vein via the heterodimeric organic solute transporter (OSTα/β) on the basolateral membrane. Bile acids may also undergo hepatic‐renal cycling, especially during cholestasis. Bile acids secreted by the kidney are usually modified by the sulfation of hydroxyl groups. The multidrug resistance‐associated proteins (MRP3 or ABCC3 and MRP4 or ABCC4) and OSTα‐OSTβ on the basolateral membrane are involved in ATP‐dependent bile acid export from hepatocytes to systemic circulation.


Figure 2. Synthesis of the primary bile acids cholic acid and chenodeoxycholic acid from cholesterol in liver hepatocytes and metabolism by gut bacteria. The primary bile acids, cholic acid, and chenodeoxycholic acid are synthesized in the hepatocytes from cholesterol and conjugated with taurine or glycine. Taurocholate is biotransformed by gut bacteria expressing bile salt hydrolases (BSH) to cholic acid and taurine. Gut bacteria can oxidize hydroxyl groups at the 3α, 7α, and 12α position on the steroid ring by 3α‐hydroxysteroid dehydrogenases (3α‐HSDH), 7α‐hydroxysteroid dehydrogenases (7α‐HSDH), and 12α‐hydroxysteroid dehydrogenases (12α‐HSDH), respectively. Oxo‐bile acids may be further metabolized at the 3β, 7β, or 12β position by 3β‐hydroxysteroid dehydrogenase (3β‐HSDH), 7β‐hydroxysteroid dehydrogenase (7β‐HSDH) and 12β‐hydroxysteroid dehydrogenase (12β‐HSDH), respectively, producing iso and epi bile acids. Primary bile acids can be biotransformed to secondary bile acids by removing the 7α‐hydroxyl group via a multistep 7α‐dehydroxylation (7α‐DeOH) biochemical pathway found in some species of the genus Clostridium.


Figure 3. Activation of the ERK1/2 and AKT signaling pathways by conjugated bile acids (CBA) via S1PR2. High levels of CBA activate S1PR2 in liver cells, enhancing the upregulation of genes encoding pro‐inflammatory and fibrosis mediators. Phosphorylated ERK1/2 is translocated into the nucleus, where it activates sphingosine kinase 2 (SphK2) via phosphorylation. SphK2 produces sphingosine‐1‐phosphate (S1P) that is a potent inhibitor of histone deacetylase 1 and 2 (HDAC1/2), allowing the epigenetic upregulation of gene transcription.


Figure 4. Alteration of the enterohepatic circulation of bile acids by NASH. Liver diseases interrupt the enterohepatic circulation of bile acids, enhancing gut dysbiosis. This has the downstream effect of increasing gut permeability and absorption of pro‐inflammatory mediators such as LPS. In NASH, there is an increase in the serum CBA that may activate the S1PR2 in hepatic cells, enhancing inflammation and activating pro‐fibrotic gene expression in stellate cells.


Figure 5. The possible role of diet, gut dysbiosis and bile acids in the development of steatosis and NASH. The road to Steatosis and NASH begins by consuming a Western‐type diet containing large amounts of HFCS and fats, resulting in constant low‐grade systemic inflammation due to gut dysbiosis and absorption of pro‐inflammatory bacterial molecules. Under these dietary conditions, there is an upregulation of long‐chain fatty acid synthesis in the liver and decreased oxidation and secretion of fats. Inflammation also downregulates bile acid transporters in the liver, slowing their enterohepatic circulation and allowing an increase in CBA in the liver, which activates S1PR2 stimulating hepatic inflammation and fibrosis pathways and promoting the development of cirrhosis and hepatocellular carcinoma (HCC).
References
 1.Acharya C, Sahingur SE, Bajaj JS. Microbiota, cirrhosis, and the emerging oral‐gut‐liver axis. JCI Insight 2: e94416, 2017.
 2.Akash MSH, Rehman K, Liaqat A. Tumor necrosis factor‐alpha: Role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus. J Cell Biochem 119: 105‐110, 2018.
 3.Ang Z, Ding JL. GPR41 and GPR43 in obesity and inflammation – Protective or causative? Front Immunol 7: 28, 2016.
 4.Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate immunity and inflammation in NAFLD/NASH. Dig Dis Sci 61: 1294‐1303, 2016.
 5.Asgharpour A, Cazanave SC, Pacana T, Seneshaw M, Vincent R, Banini BA, Kumar DP, Daita K, Min H‐K, Mirshahi F, Bedossa P, Sun X, Hoshida Y, Koduru SV, Contaifer D, Warncke UO, Wijesinghe DS, Sanyal AJ. A diet‐induced animal model of non‐alcoholic fatty liver disease and hepatocellular cancer. J Hepatol 65: 579‐588, 2016.
 6.Bajaj JS, Betrapally NS, Hylemon PB, Heuman DM, Daita K, White MB, Unser A, Thacker LR, Sanyal AJ, Kang DJ, Sikaroodi M, Gillevet PM. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology 62: 1260‐1271, 2015.
 7.Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, White MB, Monteith P, Noble NA, Unser AB, Daita K, Fisher AR, Sikaroodi M, Gillevet PM. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 60: 940‐947, 2014.
 8.Beaudoin JJ, Brouwer KLR, Malinen MM. Novel insights into the organic solute transporter alpha/beta, OSTalpha/beta: From the bench to the bedside. Pharmacol Ther 211: 107542, 2020.
 9.Boursier J, Diehl AM. Implication of gut microbiota in nonalcoholic fatty liver disease. PLoS Pathog 11: e1004559, 2015.
 10.Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56: 1761‐1772, 2007.
 11.Cao R, Cronk ZX, Zha W, Sun L, Wang X, Fang Y, Studer E, Zhou H, Pandak WM, Dent P, Gil G, Hylemon PB. Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G(alpha)i‐protein‐coupled receptors and the AKT pathway. J Lipid Res 51: 2234‐2244, 2010.
 12.Chakraborti CK. New‐found link between microbiota and obesity. World J Gastrointest Pathophysiol 6: 110‐119, 2015.
 13.Chiang JYL, Ferrell JM. Bile acid biology, pathophysiology, and therapeutics. Clin Liver Dis (Hoboken) 15: 91‐94, 2020.
 14.Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS‐induced pro‐inflammatory signaling. Cell Mol Life Sci 78: 1233‐1261, 2021.
 15.Coleman R, Lowe PJ, Billington D. Membrane lipid composition and susceptibility to bile salt damage. Biochim Biophys Acta 599: 294‐300, 1980.
 16.Cossiga V, Lembo V, Nigro C, Mirra P, Miele C, D'Argenio V, Leone A, Mazzone G, Veneruso I, Guido M, Beguinot F, Caporaso N, Morisco F. The combination of berberine, tocotrienols and coffee extracts improves metabolic profile and liver steatosis by the modulation of gut microbiota and hepatic miR‐122 and miR‐34a expression in mice. Nutrients 13: 1281, 2021.
 17.David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505: 559‐563, 2014.
 18.Dawson PA. Roles of ileal ASBT and OSTalpha‐OSTbeta in regulating bile acid signaling. Dig Dis 35: 261‐266, 2017.
 19.Dekker MJ, Su Q, Baker C, Rutledge AC, Adeli K. Fructose: A highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome. Am J Physiol Endocrinol Metab 299: E685‐E694, 2010.
 20.Deng Y, Tang K, Chen R, Nie H, Liang S, Zhang J, Zhang Y, Yang Q. Berberine attenuates hepatic oxidative stress in rats with non‐alcoholic fatty liver disease via the Nrf2/ARE signalling pathway. Exp Ther Med 17: 2091‐2098, 2019.
 21.Devlin AS, Fischbach MA. A biosynthetic pathway for a prominent class of microbiota‐derived bile acids. Nat Chem Biol 11: 685‐690, 2015.
 22.Do MH, Lee E, Oh MJ, Kim Y, Park HY. High‐glucose or ‐fructose diet cause changes of the gut microbiota and metabolic disorders in mice without body weight change. Nutrients 10: 571731, 2018.
 23.Donner MG, Schumacher S, Warskulat U, Heinemann J, Haussinger D. Obstructive cholestasis induces TNF‐alpha‐ and IL‐1‐mediated periportal downregulation of Bsep and zonal regulation of Ntcp, Oatp1a4, and Oatp1b2. Am J Physiol Gastrointest Liver Physiol 293: G1134‐G1146, 2007.
 24.Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science 308: 1635‐1638, 2005.
 25.Fiorucci S, Biagioli M, Zampella A, Distrutti E. Bile acids activated receptors regulate innate immunity. Front Immunol 9: 1853, 2018.
 26.Geier A, Zollner G, Dietrich CG, Wagner M, Fickert P, Denk H, van Rooijen N, Matern S, Gartung C, Trauner M. Cytokine‐independent repression of rodent Ntcp in obstructive cholestasis. Hepatology 41: 470‐477, 2005.
 27.Gentile CL, Weir TL. The gut microbiota at the intersection of diet and human health. Science 362: 776‐780, 2018.
 28.Gu S, Cao B, Sun R, Tang Y, Paletta JL, Wu X‐L, Liu L, Zha W, Zhao C, Li Y, Radlon JM, Hylemon PB, Zhou H, Aa J, Wang G. A metabolomic and pharmacokinetic study on the mechanism underlying the lipid‐lowering effect of orally administered berberine. Mol Biosyst 11: 463‐474, 2015.
 29.Habtemariam S. Berberine pharmacology and the gut microbiota: A hidden therapeutic link. Pharmacol Res 155: 104722, 2020.
 30.Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, Luo C, Marmorstein R, Kordula T, Milstien S, Spiegel S. Regulation of histone acetylation in the nucleus by sphingosine‐1‐phosphate. Science 325: 1254‐1257, 2009.
 31.Hajiaghamohammadi AA, Ziaee A, Samimi R. The efficacy of licorice root extract in decreasing transaminase activities in non‐alcoholic fatty liver disease: A randomized controlled clinical trial. Phytother Res 26: 1381‐1384, 2012.
 32.Hannou SA, Haslam DE, McKeown NM, Herman MA. Fructose metabolism and metabolic disease. J Clin Invest 128: 545‐555, 2018.
 33.Hirsova P, Ibrahim SH, Krishnan A, Verma VK, Bronk SF, Werneburg NW, Charlton MR, Shah VH, Malhi H, Gores GJ. Lipid‐induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 150: 956‐967, 2016.
 34.Hoskins LC, Boulding ET. Degradation of blood group antigens in human colon ecosystems. II. A gene interaction in man that affects the fecal population density of certain enteric bacteria. J Clin Invest 57: 74‐82, 1976.
 35.Hylemon PB, Takabe K, Dozmorov M, Nagahashi M, Zhou H. Bile acids as global regulators of hepatic nutrient metabolism. Liver Res 1: 10‐16, 2017.
 36.Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. J Lipid Res 50: 1509‐1520, 2009.
 37.Inagaki T, Moschetta A, Lee YK, Peng L, Zhao G, Downes M, Yu RT, Shelton JM, Richardson JA, Repa JJ, Mangelsdorf DJ, Kliewer SA. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 103: 3920‐3925, 2006.
 38.Islam KB, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, Ogura Y, Hayashi T, Yokota A. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 141: 1773‐1781, 2011.
 39.Jensen T, Abdelmalek MF, Sullivan S, Nadeau KJ, Green M, Roncal C, Nakagawa T, Kuwabara M, Sato Y, Kang DH, Tolan DR, Sanchez‐Lozada LG, Rosen HR, Lanaspa MA, Diehl AM, Johnson RJ. Fructose and sugar: A major mediator of non‐alcoholic fatty liver disease. J Hepatol 68: 1063‐1075, 2018.
 40.Kang JD, Myers CJ, Harris SC, Kakiyama G, Lee IK, Yun BS, Matsuzaki K, Furukawa M, Min HK, Bajaj JS, Zhou H, Hylemon PB. Bile acid 7alpha‐dehydroxylating gut bacteria secrete antibiotics that inhibit clostridium difficile: Role of secondary bile acids. Cell Chem Biol 26: 27‐34 e24, 2019.
 41.Kliewer SA, Mangelsdorf DJ. Bile acids as hormones: The FXR‐FGF15/19 pathway. Dig Dis 33: 327‐331, 2015.
 42.Köck K, Ferslew BC, Netterberg I, Yang K, Urban TJ, Swaan PW, Stewart PW, Brouwer KLR. Risk factors for development of cholestatic drug‐induced liver injury: Inhibition of hepatic basolateral bile acid transporters multidrug resistance‐associated proteins 3 and 4. Drug Metab Dispos 42: 665‐674, 2014.
 43.Lake AD, Novak P, Shipkova P, Aranibar N, Robertson D, Reily MD, Lu Z, Lehman‐McKeeman LD, Cherrington NJ. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease. Toxicol Appl Pharmacol 268: 132‐140, 2013.
 44.Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124: 837‐848, 2006.
 45.Li CH, Tang SC, Wong CH, Wang Y, Jiang JD, Chen Y. Berberine induces miR‐373 expression in hepatocytes to inactivate hepatic steatosis associated AKT‐S6 kinase pathway. Eur J Pharmacol 825: 107‐118, 2018.
 46.Li X, Liu R, Yang J, Sun L, Zhang L, Jiang Z, Puri P, Gurley EC, Lai G, Tang Y, Huang Z, Pandak WM, Hylemon PB, Zhou H. The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice. Hepatology 66: 869‐884, 2017.
 47.Li Y, Liu T, Yan C, Xie R, Guo Z, Wang S, Zhang Y, Li Z, Wang B, Cao H. Diammonium glycyrrhizinate protects against nonalcoholic fatty liver disease in mice through modulation of gut microbiota and restoration of intestinal barrier. Mol Pharm 15: 3860‐3870, 2018.
 48.Liu R, Li X, Hylemon PB, Zhou H. Conjugated bile acids promote invasive growth of esophageal adenocarcinoma cells and cancer stem cell expansion via sphingosine 1‐phosphate receptor 2‐mediated yes‐associated protein activation. Am J Pathol 188: 2042‐2058, 2018.
 49.Liu R, Li X, Qiang X, Luo L, Hylemon PB, Jiang Z, Zhang L, Zhou H. Taurocholate induces cyclooxygenase‐2 expression via the sphingosine 1‐phosphate receptor 2 in a human cholangiocarcinoma cell line. J Biol Chem 290: 30988‐31002, 2015.
 50.Liu R, Zhao R, Zhou X, Liang X, Campbell DJ, Zhang X, Zhang L, Shi R, Wang G, Pandak WM, Sirica AE, Hylemon PB, Zhou H. Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1‐phosphate receptor 2. Hepatology 60: 908‐918, 2014.
 51.Loo TM, Kamachi F, Watanabe Y, Yoshimoto S, Kanda H, Arai Y, Nakajima‐Takagi Y, Iwama A, Koga T, Sugimoto Y, Ozawa T, Nakamura M, Kumagai M, Watashi K, Taketo MM, Aoki T, Narumiya S, Oshima M, Arita M, Hara E, Ohtani N. Gut microbiota promotes obesity‐associated liver cancer through PGE2‐mediated suppression of antitumor immunity. Cancer Discov 7: 522‐538, 2017.
 52.Lu SS, Yu YL, Zhu HJ, Liu XD, Liu L, Liu YW, Wang P, Xie L, Wang GJ. Berberine promotes glucagon‐like peptide‐1 (7‐36) amide secretion in streptozotocin‐induced diabetic rats. J Endocrinol 200: 159‐165, 2009.
 53.Madak‐Erdogan Z, Gong P, Zhao YC, Xu L, Wrobel KU, Hartman JA, Wang M, Cam A, Iwaniec UT, Turner RT, Twaddle NC, Doerge DR, Khan IA, Katzenellenbogen JA, Katzenellenbogen BS, Helferich WG. Dietary licorice root supplementation reduces diet‐induced weight gain, lipid deposition, and hepatic steatosis in ovariectomized mice without stimulating reproductive tissues and mammary gland. Mol Nutr Food Res 60: 369‐380, 2016.
 54.Mai W, Xu Y, Xu J, Zhao D, Ye L, Yu G, Wang Z, Lu Q, Lin J, Yang T, Gu C, Liu S, Zhong Y, Yang H. Berberine inhibits nod‐like receptor family pyrin domain containing 3 inflammasome activation and pyroptosis in nonalcoholic steatohepatitis via the ROS/TXNIP axis. Front Pharmacol 11: 185, 2020.
 55.Malhi H, Kropp EM, Clavo VF, Kobrossi CR, Han J, Mauer AS, Yong J, Kaufman RJ. C/EBP homologous protein‐induced macrophage apoptosis protects mice from steatohepatitis. J Biol Chem 288: 18624‐18642, 2013.
 56.Malinen MM, Ali I, Bezencon J, Beaudoin JJ, Brouwer KLR. Organic solute transporter OSTalpha/beta is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury. Am J Physiol Gastrointest Liver Physiol 314: G597‐G609, 2018.
 57.Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 7: 189‐200, 2016.
 58.Moszak M, Szulińska M, Walczak‐Gałęzewska M, Bogdański P. Nutritional approach targeting gut microbiota in NAFLD—To date. Int J Environ Res Public Health 18: 1616, 2021.
 59.Mouries J, Brescia P, Silvestri A, Spadoni I, Sorribas M, Wiest R, Mileti E, Galbiati M, Invernizzi P, Adorini L, Penna G, Rescigno M. Microbiota‐driven gut vascular barrier disruption is a prerequisite for non‐alcoholic steatohepatitis development. J Hepatol 71: 1216‐1228, 2019.
 60.Mouzaki M, Wang AY, Bandsma R, Comelli EM, Arendt BM, Zhang L, Fung S, Fischer SE, McGilvray IG, Allard JP. Bile acids and dysbiosis in non‐alcoholic fatty liver disease. PLoS One 11: e0151829, 2016.
 61.Nagahashi M, Takabe K, Liu R, Peng K, Wang X, Wang Y, Hait NC, Wang X, Allegood JC, Yamada A, Aoyagi T, Liang J, Pandak WM, Spiegel S, Hylemon PB, Zhou H. Conjugated bile acid‐activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression. Hepatology 61: 1216‐1226, 2015.
 62.Nagahashi M, Yuza K, Hirose Y, Nakajima M, Ramanathan R, Hait NC, Hylemon PB, Zhou H, Takabe K, Wakai T. The roles of bile acids and sphingosine‐1‐phosphate signaling in the hepatobiliary diseases. J Lipid Res 57: 1636‐1643, 2016.
 63.Och A, Podgórski R, Nowak R. Biological activity of berberine—A summary update. Toxins 12: 713, 2020.
 64.O'Keefe SJ, Li JV, Lahti L, Ou J, Carbonero F, Mohammed K, Posma JM, Kinross J, Wahl E, Ruder E, Vipperla K, Naidoo V, Mtshali L, Tims S, Puylaert PG, DeLany J, Krasinskas A, Benefiel AC, Kaseb HO, Newton K, Nicholson JK, de Vos WM, Gaskins HR, Zoetendal EG. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun 6: 6342, 2015.
 65.Parker K, Salas M, Nwosu VC. High fructose corn syrup: Production, uses and public health concerns. Biotechnol Mol Biol Rev 5: 9, 2010.
 66.Perez‐Burillo S, Hinojosa‐Nogueira D, Pastoriza S, Rufian‐Henares JA. Plant extracts as natural modulators of gut microbiota community structure and functionality. Heliyon 6: e05474, 2020.
 67.Puri P, Daita K, Joyce A, Mirshahi F, Santhekadur PK, Cazanave S, Luketic VA, Siddiqui MS, Boyett S, Min HK, Kumar DP, Kohli R, Zhou H, Hylemon PB, Contos MJ, Idowu M, Sanyal AJ. The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids. Hepatology 67: 534‐548, 2018.
 68.Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz‐Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Meta HITC, Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464: 59‐65, 2010.
 69.Qin S, Tang H, Li W, Gong Y, Li S, Huang J, Fang Y, Yuan W, Liu Y, Wang S, Guo Y, Guo Y, Xu Z. AMPK and its activator berberine in the treatment of neurodegenerative diseases. Curr Pharm Des 26: 5054‐5066, 2020.
 70.Ren S, Hylemon P, Zhang ZP, Rodriguez‐Agudo D, Marques D, Li X, Zhou H, Gil G, Pandak WM. Identification of a novel sulfonated oxysterol, 5‐cholesten‐3beta,25‐diol 3‐sulfonate, in hepatocyte nuclei and mitochondria. J Lipid Res 47: 1081‐1090, 2006.
 71.Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: Unraveling a complex relationship. Gut Microbes 4: 382‐387, 2013.
 72.Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes 7: 22‐39, 2016.
 73.Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res 47: 241‐259, 2006.
 74.Rinninella E, Cintoni M, Raoul P, Lopetuso LR, Scaldaferri F, Pulcini G, Miggiano GAD, Gasbarrini A, Mele MC. Food components and dietary habits: Keys for a healthy gut microbiota composition. Nutrients 11: 2393, 2019.
 75.Schoeler M, Caesar R. Dietary lipids, gut microbiota and lipid metabolism. Rev Endocr Metab Disord 20: 461‐472, 2019.
 76.Schumacher JD, Guo GL. Pharmacologic modulation of bile acid‐FXR‐FGF15/FGF19 pathway for the treatment of nonalcoholic steatohepatitis. Handb Exp Pharmacol 256: 325‐357, 2019.
 77.Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 14: e1002533, 2016.
 78.Shi X, Yu L, Zhang Y, Liu Z, Zhang H, Zhang Y, Liu P, Du P. Glycyrrhetinic acid alleviates hepatic inflammation injury in viral hepatitis disease via a HMGB1‐TLR4 signaling pathway. Int Immunopharmacol 84: 106578, 2020.
 79.Studer E, Zhou X, Zhao R, Wang Y, Takabe K, Nagahashi M, Pandak WM, Dent P, Spiegel S, Shi R, Xu W, Liu X, Bohdan P, Zhang L, Zhou H, Hylemon PB. Conjugated bile acids activate the sphingosine‐1‐phosphate receptor 2 in primary rodent hepatocytes. Hepatology 55: 267‐276, 2012.
 80.Suga T, Yamaguchi H, Ogura J, Shoji S, Maekawa M, Mano N. Altered bile acid composition and disposition in a mouse model of non‐alcoholic steatohepatitis. Toxicol Appl Pharmacol 379: 114664, 2019.
 81.Trauner M, Arrese M, Lee H, Boyer JL, Karpen SJ. Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors. J Clin Invest 101: 2092‐2100, 1998.
 82.Wang HN, Xiang JZ, Qi Z, Du M. Plant extracts in prevention of obesity. Crit Rev Food Sci Nutr 15: 1‐14, 2020. DOI: 10.1080/10408398.2020.1852171.
 83.Wang Y, Tai YL, Zhao D, Zhang Y, Yan J, Kakiyama G, Wang X, Gurley EC, Liu J, Liu J, Liu J, Lai G, Hylemon PB, Pandak WM, Chen W, Zhou H. Berberine prevents disease progression of nonalcoholic steatohepatitis through modulating multiple pathways. Cells 10: 210, 2021.
 84.Wang Y, Zhou X, Zhao D, Wang X, Gurley EC, Liu R, Li X, Hylemon PB, Chen W, Zhou H. Berberine inhibits free fatty acid and LPS‐induced inflammation via modulating ER stress response in macrophages and hepatocytes. PLoS One 15: e0232630, 2020.
 85.Wu X, Zhang L, Gurley E, Studer E, Shang J, Wang T, Wang C, Yan M, Jiang Z, Hylemon PB, Sanyal AJ, Pandak WM, Zhou H. Prevention of free fatty acid‐induced hepatic lipotoxicity by 18β‐glycyrrhetinic acid through lysosomal and mitochondrial pathways. Hepatology 47: 1905‐1915, 2008.
 86.Xu X, Yi H, Wu J, Kuang T, Zhang J, Li Q, Du H, Xu T, Jiang G, Fan G. Therapeutic effect of berberine on metabolic diseases: Both pharmacological data and clinical evidence. Biomed Pharmacother 133: 110984, 2021.
 87.Yang L, Jiang Y, Zhang Z, Hou J, Tian S, Liu Y. The anti‐diabetic activity of licorice, a widely used Chinese herb. J Ethnopharmacol 263: 113216, 2020.
 88.Yi H, Xu D, Wu X, Xu F, Lin L, Zhou H. Isosteviol protects free fatty acid‐ and high fat diet‐induced hepatic injury via modulating PKC‐beta/p66Shc/ROS and endoplasmic reticulum stress pathways. Antioxid Redox Signal 30: 1949‐1968, 2019.
 89.Younossi Z, Tacke F, Arrese M, Chander Sharma B, Mostafa I, Bugianesi E, Wai‐Sun Wong V, Yilmaz Y, George J, Fan J, Vos MB. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 69: 2672‐2682, 2019.
 90.Younossi ZM, Loomba R, Rinella ME, Bugianesi E, Marchesini G, Neuschwander‐Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Chalasani NP, Anstee QM, Kowdley KV, George J, Goodman ZD, Lindor K. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 68: 361‐371, 2018.
 91.Zhang L, Wu X, Yang R, Chen F, Liao Y, Zhu Z, Wu Z, Sun X, Wang L. Effects of berberine on the gastrointestinal microbiota. Front Cell Infect Microbiol 10: 588517, 2020.
 92.Zhang Y, Gu Y, Ren H, Wang S, Zhong H, Zhao X, Ma J, Gu X, Xue Y, Huang S, Yang J, Chen L, Chen G, Qu S, Liang J, Qin L, Huang Q, Peng Y, Li Q, Wang X, Kong P, Hou G, Gao M, Shi Z, Li X, Qiu Y, Zou Y, Yang H, Wang J, Xu G, Lai S, Li J, Ning G, Wang W. Gut microbiome‐related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study). Nat Commun 11: 5015, 2020.
 93.Zhou H, Hylemon PB. Bile acids are nutrient signaling hormones. Steroids 86: 62‐68, 2014.
 94.Zhou J, Cui S, He Q, Guo Y, Pan X, Zhang P, Huang N, Ge C, Wang G, Gonzalez FJ, Wang H, Hao H. SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis. Nat Commun 11: 240, 2020.
 95.Zhu JZ, Yi HW, Huang W, Pang T, Zhou HP, Wu XD. Fatty liver diseases, mechanisms, and potential therapeutic plant medicines. Chin J Nat Med 18: 161‐168, 2020.

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Article Title: Bile Acids, Gut Microbiome and the Road to Fatty Liver Disease
 

How to Cite

Phillip B. Hylemon, Lianyong Su, Po‐Cheng Zheng, Jasmohan S. Bajaj, Huiping Zhou. Bile Acids, Gut Microbiome and the Road to Fatty Liver Disease. Compr Physiol 2021, 12: 2719-2730. doi: 10.1002/cphy.c210024