Di Ciaula A, Wang DQH, Molina-Molina E, Lunardi BR, Calamita G, Palmieri VO, Portincasa P

Idioma: Ingles.
Referencias bibliográficas: 237
Paginas: 87-105
Archivo PDF: 3428.18 Kb.

RESUMEN

Sin resumen.

REFERENCIAS (EN ESTE ARTÍCULO)

1. Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Aspects Med 2017; 56: 54-65.

2. van Erpecum KJ, Wang DQ, Moschetta A, Ferri D, Svelto M, Portincasa P, Hendrickx JJ, et al. Gallbladder histopathology during murine gallstone formation: relation to motility and concentrating function. J Lipid Res 2006; 47: 32-41.

3. Portincasa P, Calamita G. Water channel proteins in bile formation and flow in health and disease: when immiscible becomes miscible. Mol Aspects Med 2012; 33: 651-64.

4. Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res 2006; 47: 241-59.

5. Wang DQH, Neuschwander-Tetri BA, Portincasa P. The Biliary System. 2nd Ed. Morgan & Claypool Life Sciences; 2017.

6. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 2000; 6: 517-26.

7. Miao J, Choi SE, Seok SM, Yang L, Zuercher WJ, Xu Y, Willson TM, et al. Ligand-Dependent Regulation of the Activity of the Orphan Nuclear Receptor, Small Heterodimer Partner (SHP), in the Repression of Bile Acid Biosynthetic CYP7A1 and CYP8B1 Genes. Mol Endocrinol 2011; 25: 1159-69.

8. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, Mc- Donald JG, Luo G, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005; 2: 217-25.

9. Jones S. Mini-review: endocrine actions of fibroblast growth factor 19. Mol Pharm 2008; 5: 42-8.

10. Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 2003; 17: 1581-91.

11. Kim I, Ahn S-H, Inagaki T, Choi M, Ito S, Guo GL, Kliewer SA, et al. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 2007; 48: 2664-72.

12. Volle DH. Bile acids, roles in integrative physiology and pathophysiology. Mol Aspects Med 2017; 56: 1.

13. Li T, Chiang JYL. Bile Acid Signaling in Metabolic Disease and Drug Therapy. Pharmacological Reviews 2014; 66: 948.

14. Martinot E, Sedes L, Baptissart M, Lobaccaro JM, Caira F, Beaudoin C, Volle DH. Bile acids and their receptors. Mol Aspects Med 2017; 56: 2-9.

15. Zhou H, Hylemon PB. Bile acids are nutrient signaling hormones. Steroids 2014; 86: 62-8.

16. Chavez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease. Gastroenterology 2017; 152: 1679-94 e3.

17. Vitek L, Haluzik M. The role of bile acids in metabolic regulation. J Endocrinol 2016; 228: R85-96.

18. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999; 284: 1365-8.

19. Li M, Cai SY, Boyer JL. Mechanisms of bile acid mediated inflammation in the liver. Mol Aspects Med 2017; 56: 45-53.

20. Merlen G, Ursic-Bedoya J, Jourdainne V, Kahale N, Glenisson M, Doignon I, Rainteau D, et al. Bile acids and their receptors during liver regeneration: Dangerous protectors. Mol Aspects Med 2017; 56: 25-33.

21. Sèdes L, Martinot E, Baptissart M, Baron S, Caira F, Beaudoin C, Volle DH. Bile acids and male fertility: From mouse to human? Mol Aspects Med 2017; 56: 101-9.

22. McIlvride S, Dixon PH, Williamson C. Bile acids and gestation. Mol Aspects Med 2017; 56: 90-100.

23. Albaugh VL, Banan B, Ajouz H, Abumrad NN, Flynn CR. Bile acids and bariatric surgery. Mol Aspects Med 2017; 56: 75- 89.

24. Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, Bernstein H. Carcinogenicity of deoxycholate, a secondary bile acid. Arch Toxicol 2011; 85: 863- 71.

25. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Bile acids as carcinogens in human gastrointestinal cancers. Mutat Res 2005; 589: 47-65.

26. Debruyne PR, Bruyneel EA, Li X, Zimber A, Gespach C, Mareel MM. The role of bile acids in carcinogenesis. Mutat Res 2001; 480-481: 359-69.

27. Rosignoli P, Fabiani R, De Bartolomeo A, Fuccelli R, Pelli MA, Morozzi G. Genotoxic effect of bile acids on human normal and tumour colon cells and protection by dietary antioxidants and butyrate. Eur J Nutr 2008; 47: 301-9.

28. Duan JH, Fang L. MicroRNA-92 promotes gastric cancer cell proliferation and invasion through targeting FXR. Tumour Biol 2014; 35: 11013-9.

29. Peng Z, Raufman JP, Xie G. Src-mediated cross-talk between farnesoid X and epidermal growth factor receptors inhibits human intestinal cell proliferation and tumorigenesis. PLoS One 2012; 7: e48461.

30. Bailey AM, Zhan L, Maru D, Shureiqi I, Pickering CR, Kiriakova G, Izzo J, et al. FXR silencing in human colon cancer by DNA methylation and KRAS signaling. Am J Physiol Gastrointest Liver Physiol 2014; 306: G48-58.

31. Liu J, Tong SJ, Wang X, Qu LX. Farnesoid X receptor inhibits LNcaP cell proliferation via the upregulation of PTEN. Exp Ther Med 2014; 8: 1209-12.

32. Cook JW. Cancer-Producing Chemical Compounds. Nature 1940; 145: 335-8.

33. Payne CM, Bernstein C, Dvorak K, Bernstein H. Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis. Clin Exp Gastroenterol 2008; 1: 19-47.

34. Barrasa JI, Olmo N, Lizarbe MA, Turnay J. Bile acids in the colon, from healthy to cytotoxic molecules. Toxicol In Vitro 2013; 27: 964-77.

35. Yang F, Hu Y, Liu HX, Wan YJ. MiR-22-silenced cyclin A expression in colon and liver cancer cells is regulated by bile acid receptor. J Biol Chem 2015; 290: 6507-15.

36. Matsuzaki J, Suzuki H, Tsugawa H, Watanabe M, Hossain S, Arai E, Saito Y, et al. Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis. Gastroenterology 2013; 145: 1300-11.

37. Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B, et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992; 359: 235-7.

38. Liu T, Zhang X, So CK, Wang S, Wang P, Yan L, Myers R, et al. Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis 2007; 28: 488-96.

39. Gadaleta RM, Garcia-Irigoyen O, Moschetta A. Bile acids and colon cancer: Is FXR the solution of the conundrum? Mol Aspects Med 2017.

40. Guan B, Li H, Yang Z, Hoque A, Xu X. Inhibition of farnesoid X receptor controls esophageal cancer cell growth in vitro and in nude mouse xenografts. Cancer 2013; 119: 1321-9.

41. Hu H, Wu LL, Han T, Zhuo M, Lei W, Cui JJ, Jiao F, et al. Correlated high expression of FXR and Sp1 in cancer cells con fers a poor prognosis for pancreatic cancer: A study based on TCGA and tissue microarray. Oncotarget 2017; 8: 33265- 75.

42. Joshi S, Cruz E, Rachagani S, Guha S, Brand RE, Ponnusamy MP, Kumar S, et al. Bile acids-mediated overexpression of MUC4 via FAK-dependent c-Jun activation in pancreatic cancer. Mol Oncol 2016; 10: 1063-77.

43. Alasmael N, Mohan R, Meira LB, Swales KE, Plant NJ. Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential. Cancer Lett 2016; 370: 250-9.

44. Cao H, Xu M, Dong W, Deng B, Wang S, Zhang Y, Wang S, et al. Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis. Int J Cancer 2017; 140: 2545-56.

45. Vaninetti N, Williams L, Geldenhuys L, Porter GA, Guernsey DL, Casson AG. Regulation of CDX2 expression in esophageal adenocarcinoma. Molecular carcinogenesis 2009; 48: 965-74.

46. Cao W, Tian W, Hong J, Li D, Tavares R, Noble L, Moss SF, et al. Expression of bile acid receptor TGR5 in gastric adenocarcinoma. Am J Physiol Gastrointest Liver Physiol 2013; 304: G322-7.

47. Wang X, Sun L, Wang X, Kang H, Ma X, Wang M, Lin S, et al. Acidified bile acids enhance tumor progression and telomerase activity of gastric cancer in mice dependent on c-Myc expression. Cancer Med 2017; 6: 788-97.

48. Hara E. Relationship between Obesity, Gut Microbiome and Hepatocellular Carcinoma Development. Dig Dis 2015; 33: 346-50.

49. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499: 97-101.

50. Xie G, Wang X, Huang F, Zhao A, Chen W, Yan J, Zhang Y, et al. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. Int J Cancer 2016; 139: 1764-75.

51. Feng HY, Chen YC. Role of bile acids in carcinogenesis of pancreatic cancer: An old topic with new perspective. World J Gastroenterol 2016; 22: 7463-77.

52. Kitamura T, Srivastava J, DiGiovanni J, Kiguchi K. Bile acid accelerates erbB2-induced pro-tumorigenic activities in biliary tract cancer. Molecular Carcinogenesis 2015; 54: 459- 72.

53. Liu N, Zhao J, Wang J, Teng H, Fu Y, Yuan H. Farnesoid X receptor ligand CDCA suppresses human prostate cancer cells growth by inhibiting lipid metabolism via targeting sterol response element binding protein 1. Am J Transl Res 2016; 8: 5118-24.

54. Goldberg AA, Titorenko VI, Beach A, Sanderson JT. Bile acids induce apoptosis selectively in androgen-dependent and -independent prostate cancer cells. PeerJ 2013; 1: e122.

55. Journe F, Durbecq V, Chaboteaux C, Rouas G, Laurent G, Nonclercq D, Sotiriou C, et al. Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients. Breast Cancer Res Treat 2009; 115: 523-35.

56. Spassieva S, Bieberich E. The gut-to-breast connection - interdependence of sterols and sphingolipids in multidrug resistance and breast cancer therapy. Anticancer Agents Med Chem 2011; 11: 882-90.

57. Krishnamurthy K, Wang G, Rokhfeld D, Bieberich E. Deoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide. Breast Cancer Res 2008; 10: R106.

58. Costarelli V, Sanders TA. Plasma deoxycholic acid concentration is elevated in postmenopausal women with newly diagnosed breast cancer. Eur J Clin Nutr 2002; 56: 925-7.

59. Ackehed G, Hedenborg G, Wisen O, Norman A. Faecal bile acid excretion during detoxification in patients with alcohol abuse. Scand J Gastroenterol 1996; 31: 1205-10.

60. Axelson M, Mork B, Sjovall J. Ethanol has an acute effect on bile acid biosynthesis in man. FEBS Lett 1991; 281: 155-9.

61. Kakiyama G, Hylemon PB, Zhou H, Pandak WM, Heuman DM, Kang DJ, Takei H, et al. Colonic inflammation and secondary bile acids in alcoholic cirrhosis. Am J Physiol Gastrointest Liver Physiol 2014; 306: G929-37.

62. Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes 2013; 4: 382-7.

63. Chanda D, Kim YH, Li T, Misra J, Kim DK, Kim JR, Kwon J, et al. Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. PLoS One 2013; 8: e68845.

64. Crowley-Weber CL, Dvorakova K, Crowley C, Bernstein H, Bernstein C, Garewal H, Payne CM. Nicotine increases oxidative stress, activates NF-kappaB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis. Chem Biol Interact 2003; 145: 53-66.

65. Aiyer HS, Li Y, Harper N, Myers SR, Martin RC. Molecular changes in the esophageal epithelium after a subchronic exposure to cigarette smoke in the presence of bile-acid reflux. Inhal Toxicol 2011; 23: 304-11.

66. Lu K, Abo RP, Schlieper KA, Graffam ME, Levine S, Wishnok JS, Swenberg JA, et al. Arsenic exposure perturbs the gut microbiome and its metabolic profile in mice: an integrated metagenomics and metabolomics analysis. Environ Health Perspect 2014; 122: 284-91.

67. Gao B, Bian X, Mahbub R, Lu K. Sex-Specific Effects of Organophosphate Diazinon on the Gut Microbiome and Its Metabolic Functions. Environ Health Perspect 2017; 125: 198-206.

68. Reygner J, Joly Condette C, Bruneau A, Delanaud S, Rhazi L, Depeint F, Abdennebi-Najar L, et al. Changes in Composition and Function of Human Intestinal Microbiota Exposed to Chlorpyrifos in Oil as Assessed by the SHIME(R) Model. Int J Environ Res Public Health 2016; 13.

69. Zhang L, Nichols RG, Correll J, Murray IA, Tanaka N, Smith PB, Hubbard TD, et al. Persistent Organic Pollutants Modify Gut Microbiota-Host Metabolic Homeostasis in Mice Through Aryl Hydrocarbon Receptor Activation. Environ Health Perspect 2015; 123: 679-88.

70. Lee WS, Jung JH, Panchanathan R, Yun JW, Kim DH, Kim HJ, Kim GS, et al. Ursodeoxycholic Acid Induces Death Receptor- mediated Apoptosis in Prostate Cancer Cells. J Cancer Prev 2017; 22: 16-21.

71. Amaral JD, Viana RJ, Ramalho RM, Steer CJ, Rodrigues CM. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res 2009; 50: 1721-34.

72. Phelan JP, Reen FJ, Dunphy N, OConnor R, O'Gara F. Bile acids destabilise HIF-1alpha and promote anti-tumour phenotypes in cancer cell models. BMC Cancer 2016; 16: 476.

73. Serfaty L, Bissonnette M, Poupon R. Ursodeoxycholic acid and chemoprevention of colorectal cancer. Gastroenterol Clin Biol 2010; 34: 516-22.

74. Peng S, Huo X, Rezaei D, Zhang Q, Zhang X, Yu C, Asanuma K, et al. In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids. Am J Physiol Gastrointest Liver Physiol 2014; 307: G129-39.

75. Araki Y, Andoh A, Bamba H, Yoshikawa K, Doi H, Komai Y, Higuchi A, et al. The cytotoxicity of hydrophobic bile acids is ameliorated by more hydrophilic bile acids in intestinal cell lines IEC-6 and Caco-2. Oncol Rep 2003; 10: 1931-6.

76. Stenman LK, Holma R, Eggert A, Korpela R. A novel mechanism for gut barrier dysfunction by dietary fat: epithelial disruption by hydrophobic bile acids. Am J Physiol Gastrointest Liver Physiol 2013; 304: G227-34.

77. Huo X, Juergens S, Zhang X, Rezaei D, Yu C, Strauch ED, Wang JY, et al. Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-kappaB activation in benign Barrett's epithelial cells. Am J Physiol Gastrointest Liver Physiol 2011; 301: G278-86.

78. Abdel-Latif MM, Inoue H, Reynolds JV. Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells. Eur J Cancer Prev 2016; 25: 368-79.

79. Ojima E, Fujimura T, Oyama K, Tsukada T, Kinoshita J, Miyashita T, Tajima H, et al. Chemoprevention of esophageal adenocarcinoma in a rat model by ursodeoxycholic acid. Clin Exp Med 2015; 15: 343-50.

80. Lim SC, Choi JE, Kang HS, Han SI. Ursodeoxycholic acid switches oxaliplatin-induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53- caspase 8 pathway in HepG2 hepatocellular carcinoma. Int J Cancer 2010; 126: 1582-95.

81. Benz C, Angermuller S, Otto G, Sauer P, Stremmel W, Stiehl A. Effect of tauroursodeoxycholic acid on bile acid-induced apoptosis in primary human hepatocytes. Eur J Clin Invest 2000; 30: 203-9.

82. Smith AF, Longpre J, Loo G. Inhibition by zinc of deoxycholate- induced apoptosis in HCT-116 cells. J Cell Biochem 2012; 113: 650-7.

83. Zeng H, Claycombe KJ, Reindl KM. Butyrate and deoxycholic acid play common and distinct roles in HCT116 human colon cell proliferation. J Nutr Biochem 2015; 26: 1022-8.

84. Wang X, Zhou P, Sun X, Zheng J, Wei G, Zhang L, Wang H, et al. Acidified bile acids increase hTERT expression via cmyc activation in human gastric cancer cells. Oncol Rep 2015; 33: 3038-44.

85. Raimondi F, Santoro P, Barone MV, Pappacoda S, Barretta ML, Nanayakkara M, Apicella C, et al. Bile acids modulate tight junction structure and barrier function of Caco-2 monolayers via EGFR activation. Am J Physiol Gastrointest Liver Physiol 2008; 294: G906-13.

86. Song P, Zhang Y, Klaassen CD. Dose-response of five bile acids on serum and liver bile Acid concentrations and hepatotoxicty in mice. Toxicol Sci 2011; 123: 359-67.

87. Bernstein H, Bernstein C, Payne CM, Dvorak K. Bile acids as endogenous etiologic agents in gastrointestinal cancer. World J Gastroenterol 2009; 15: 3329-40.

88. Kundu S, Kumar S, Bajaj A. Cross-talk between bile acids and gastrointestinal tract for progression and development of cancer and its therapeutic implications. IUBMB Life 2015; 67: 514-23.

89. Shi Y, Wei Y, Zhang T, Zhang J, Wang Y, Ding S. Deoxycholic Acid Could Induce Apoptosis and Trigger Gastric Carcinogenesis on Gastric Epithelial Cells by Quantitative Proteomic Analysis. Gastroenterol Res Pract 2016; 2016: 9638963.

90. Tatsugami M, Ito M, Tanaka S, Yoshihara M, Matsui H, Haruma K, Chayama K. Bile acid promotes intestinal metaplasia and gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev 2012; 21: 2101-7.

91. Cronin J, Williams L, McAdam E, Eltahir Z, Griffiths P, Baxter J, Jenkins G. The role of secondary bile acids in neoplastic development in the oesophagus. Biochem Soc Trans 2010; 38: 337-42.

92. Hong J, Behar J, Wands J, Resnick M, Wang LJ, Delellis RA, Lambeth D, et al. Bile acid reflux contributes to development of esophageal adenocarcinoma via activation of phosphatidylinositol-specific phospholipase Cgamma2 and NADPH oxidase NOX5-S. Cancer Res 2010; 70: 1247-55.

93. Martinot E, Sedes L, Baptissart M, Lobaccaro JM, Caira F, Beaudoin C, Volle DH. Bile acids and their receptors. Mol Aspects Med 2017.

94. Taoka H, Yokoyama Y, Morimoto K, Kitamura N, Tanigaki T, Takashina Y, Tsubota K, et al. Role of bile acids in the regulation of the metabolic pathways. World J Diabetes 2016; 7: 260-70.

95. Ding L, Yang L, Wang Z, Huang W. Bile acid nuclear receptor FXR and digestive system diseases. Acta Pharm Sin B 2015; 5: 135-44.

96. Gadaleta RM, Cariello M, Sabba C, Moschetta A. Tissuespecific actions of FXR in metabolism and cancer. Biochim Biophys Acta 2015; 1851: 30-9.

97. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, et al. Identification of a nuclear receptor for bile acids. Science 1999; 284: 1362-5.

98. Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, Rupar MJ, Gunyuzlu PL, et al. Generation of multiple farnesoid- X-receptor isoforms through the use of alternative promoters. Gene 2002; 290: 35-43.

99. Sun L, Beggs K, Borude P, Edwards G, Bhushan B, Walesky C, Roy N, et al. Bile acids promote diethylnitrosamine- induced hepatocellular carcinoma via increased inflammatory signaling. Am J Physiol Gastrointest Liver Physiol 2016; 311: G91-G104.

100. Chow MD, Lee Y-H, Guo GL. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol Aspects Med 2017; 56: 34-44.

101. Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the US. Hepatology 2014; 59: 2188-95.

102. Bonfrate L, Grattagliano I, Palasciano G, Portincasa P. Dynamic carbon 13 breath tests for the study of liver function and gastric emptying. Gastroenterol Rep (Oxf) 2015; 3: 12-21.

103. Krawczyk M, Portincasa P, Lammert F. PNPLA3-associated steatohepatitis: toward a gene-based classification of fatty liver disease. Semin Liver Dis 2013; 33: 369-79.

104. Palasciano G, Moschetta A, Palmieri VO, Grattagliano I, Iacobellis G, Portincasa P. Non-alcoholic fatty liver disease in the metabolic syndrome. Curr Pharm Des 2007; 13: 2193-8.

105. Vecchione G, Grasselli E, Voci A, Baldini F, Grattagliano I, Wang DQ, Portincasa P, et al. Silybin counteracts lipid excess and oxidative stress in cultured steatotic hepatic cells. World J Gastroenterol 2016; 22: 6016-26.

106. Ferslew BC, Xie G, Johnston CK, Su M, Stewart PW, Jia W, Brouwer KL, et al. Altered bile acid metabolome in patients with nonalcoholic steatohepatitis. Digestive Diseases and Sciences 2015; 60: 3318-28.

107. Huang XF, Zhao WY, Huang WD. FXR and liver carcinogenesis. Acta Pharmacol Sin 2015; 36: 37-43.

108. Langhi C, Pedraz-Cuesta E, Donate Y, Marrero PF, Haro D, Rodriguez JC. Regulation of N-Myc downstream regulated gene 2 by bile acids. Biochem Biophys Res Commun 2013; 434: 102-9.

109. Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 2007; 67: 863-7.

110. Kong B, Zhu Y, Li G, Williams JA, Buckley K, Tawfik O, Luyendyk JP, et al. Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis. Am J Physiol Gastrointest Liver Physiol 2016; 310: G295-302.

111. Zhang W, Zhou L, Yin P, Wang J, Lu X, Wang X, Chen J, et al. A weighted relative difference accumulation algorithm for dynamic metabolomics data: long-term elevated bile acids are risk factors for hepatocellular carcinoma. Sci Rep 2015; 5: 8984.

112. Araki Y, Katoh T, Ogawa A, Bamba S, Andoh A, Koyama S, Fujiyama Y, et al. Bile acid modulates transepithelial permeability via the generation of reactive oxygen species in the Caco-2 cell line. Free Radic Biol Med 2005; 39: 769-80.

113. Kim EK, Choi EJ. Compromised MAPK signaling in human diseases: an update. Arch Toxicol 2015; 89: 867-82.

114. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798-809.

115. He G, Karin M. NF-kappaB and STAT3 - key players in liver inflammation and cancer. Cell Res 2011; 21: 159-68.

116. Degirolamo C, Modica S, Vacca M, Di Tullio G, Morgano A, D'Orazio A, Kannisto K, et al. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation. Hepatology 2015; 61: 161-70.

117. Zhou M, Wang X, Phung V, Lindhout DA, Mondal K, Hsu JY, Yang H, et al. Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19. Cancer Res 2014; 74: 3306-16.

118. Alvarez-Sola G, Uriarte I, Latasa MU, Urtasun R, Barcena- Varela M, Elizalde M, Jimenez M, et al. Fibroblast Growth Factor 15/19 in Hepatocarcinogenesis. Dig Dis 2017; 35: 158-65.

119. Aguilar-Olivos NE, Carrillo-Cordova D, Oria-Hernandez J, Sanchez-Valle V, Ponciano-Rodriguez G, Ramirez-Jaramillo M, Chable-Montero F, et al. The nuclear receptor FXR, but not LXR, up-regulates bile acid transporter expression in non-alcoholic fatty liver disease. Ann Hepatol 2015; 14: 487-93.

120. Fiorucci S, Distrutti E, Ricci P, Giuliano V, Donini A, Baldelli F. Targeting FXR in cholestasis: hype or hope. Expert opinion on therapeutic targets 2014; 18: 1449-59.

121. Trivedi PJ, Lammers WJ, van Buuren HR, Pares A, Floreani A, Janssen HL, Invernizzi P, et al. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut 2016; 65: 321-9.

122. Sato H, Macchiarulo A, Thomas C, Gioiello A, Une M, Hofmann AF, Saladin R, et al. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies. J Med Chem 2008; 51: 1831-41.

123. Pellicciari R, Sato H, Gioiello A, Costantino G, Macchiarulo A, Sadeghpour BM, Giorgi G, et al. Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- and 6,23-alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5. J Med Chem 2007; 50: 4265-8.

124. Nguyen A, Bouscarel B. Bile acids and signal transduction: role in glucose homeostasis. Cell Signal 2008; 20: 2180-97.

125. Yang JI, Yoon JH, Myung SJ, Gwak GY, Kim W, Chung GE, Lee SH, et al. Bile acid-induced TGR5-dependent c-Jun-N terminal kinase activation leads to enhanced caspase 8 activation in hepatocytes. Biochem Biophys Res Commun 2007; 361: 156-61.

126. Wang X, Fu X, Van Ness C, Meng Z, Ma X, Huang W. Bile Acid Receptors and Liver Cancer. Curr Pathobiol Rep 2013; 1: 29-35.

127. Jolly AJ, Wild CP, Hardie LJ. Sodium deoxycholate causes nitric oxide mediated DNA damage in oesophageal cells. Free Radic Res 2009; 43: 234-40.

128. Abdel-Latif MM, Inoue H, Kelleher D, Reynolds JV. Factors regulating nuclear factor-kappa B activation in esophageal cancer cells: Role of bile acids and acid. J Cancer Res Ther 2016; 12: 364-73.

129. Carino A, Graziosi L, D’Amore C, Cipriani S, Marchiano S, Marino E, Zampella A, et al. The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines. Oncotarget 2016; 7: 61021-35.

130. GLOBOCAN 2012 v1.0. Cancer Incidence and Mortality Worldwide. 2013. http://globocan.iarc.fr/Pages/ fact_sheets_ cancer.aspx?cancer¼colorectal.

131. Bajor A, Gillberg P-G, Abrahamsson H. Bile acids: short and long term effects in the intestine. Scand J Gastroenterol 2010; 45: 645-64.

132. McGarr SE, Ridlon JM, Hylemon PB. Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature. J Clin Gastroenterol 2005; 39: 98-109.

133. Hori T, Matsumoto K, Sakaitani Y, Sato M, Morotomi M. Effect of dietary deoxycholic acid and cholesterol on fecal steroid concentration and its impact on the colonic crypt cell proliferation in azoxymethane-treated rats. Cancer Lett 1998; 124: 79-84.

134. Reddy BS, Watanabe K, Weisburger JH, Wynder EL. Promoting effect of bile acids in colon carcinogenesis in germfree and conventional F344 rats. Cancer Res 1977; 37: 3238-42.

135. Giovannucci E, Colditz GA, Stampfer MJ. A meta-analysis of cholecystectomy and risk of colorectal cancer. Gastroenterology 1993; 105: 130-41.

136. Zimber A, Gespach C. Bile acids and derivatives, their nuclear receptors FXR, PXR and ligands: role in health and disease and their therapeutic potential. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 2008; 8: 540-63.

137. Moschetta A, Portincasa P, van Erpecum KJ, Debellis L, vanBerge-Henegouwen GP, Palasciano G. Sphingomyelin protects against apoptosis and hyperproliferation induced by deoxycholate: potential implications for colon cancer. Dig Dis Sci 2003; 6 1094-101.

138. Rafter J, Eng V, Furrer R, Medline A, Bruce W. Effects of calcium and pH on the mucosal damage produced by deoxycholic acid in the rat colon. Gut 1986; 27: 1320-9.

139. Cheng K, Raufman J-P. Bile acid-induced proliferation of a human colon cancer cell line is mediated by transactivation of epidermal growth factor receptors. Biochem Pharmacol 2005; 70: 1035-47.

140. Huang X, Fan X, Desjeux J, Castagna M. Bile acids, nonphorbol- ester-type tumor promoters, stimulate the phosphorylation of protein kinase C substrates in human platelets and colon cell line HT29. International Journal of Cancer 1992; 52: 444-50.

141. Bernstein C, Bernstein H, Garewal H, Dinning P, Jabi R, Sampliner RE, McCuskey MK, et al. A bile acid-induced apoptosis assay for colon cancer risk and associated quality control studies. Cancer Research 1999; 59: 2353-7.

142. Ridlon JM, Bajaj JS. The human gut sterolbiome: bile acidmicrobiome endocrine aspects and therapeutics. Acta Pharmaceutica Sinica B 2015; 5: 99-105.

143. Portincasa P, Bonfrate L, de Bari O, Lembo A, Ballou S. Irritable bowel syndrome and diet. Gastroenterol Rep (Oxf) 2017.

144. Arora T, Bäckhed F. The gut microbiota and metabolic disease: current understanding and future perspectives. J Intern Med 2016; 280: 339-49.

145. Arumugam M, Raes J, Pelletier E, Paslier D, Yamada T, Mende DR, Fernandes GR, et al. Enterotypes of the human gut microbiome. Nature 2011; 473: 174-80.

146. O'Keefe S. Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol 2016; 13: 691-706.

147. Bonfrate L, Krawczyk M, Lembo A, Grattagliano I, Lammert F, Portincasa P. Effects of dietary education, followed by a tailored fructose-restricted diet in adults with fructose malabsorption. Eur J Gastroenterol Hepatol 2015; 27: 785-96.

148. Fung KY, Cosgrove L, Lockett T, Head R, Topping DL. A review of the potential mechanisms for the lowering of colorectal oncogenesis by butyrate. Br J Nutr 2012; 108: 820-31.

149. Bultman SJ, Jobin C. Microbial-derived butyrate: an oncometabolite or tumor-suppressive metabolite? Cell Host & Microbe 2014; 16: 143-5.

150. Beyer-Sehlmeyer G, Glei M, Hartmann E, Hughes R, Persin C, Böhm V, Schubert R, et al. Butyrate is only one of several growth inhibitors produced during gut flora-mediated fermentation of dietary fibre sources. British Journal of Nutrition 2003; 90: 1057-70.

151. Clinton SK, Bostwick DG, Olson LM, Mangian HJ, Visek WJ. Effects of ammonium acetate and sodium cholate on N-methyl- N-nitro-N-nitrosoguanidine-induced colon carcinogenesis of rats. Cancer Research 1988; 48: 3035-9.

152. Windey K, De Preter V, Verbeke K. Relevance of protein fermentation to gut health. Mol Nutr Food Res 2012; 56: 184-96.

153. Ignacio Barrasa J, Olmo N, Perez-Ramos P, Santiago- Gomez A, Lecona E, Turnay J, Antonia Lizarbe M. Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells. Apoptosis 2011; 16: 1054-67.

154. Lax S, Schauer G, Prein K, Kapitan M, Silbert D, Berghold A, Berger A, et al. Expression of the nuclear bile acid receptor/ farnesoid X receptor is reduced in human colon carcinoma compared to nonneoplastic mucosa independent from site and may be associated with adverse prognosis. Int J Cancer 2012; 130: 2232-9.

155. Modica S, Murzilli S, Salvatore L, Schmidt DR, Moschetta A. Nuclear bile acid receptor FXR protects against intestinal tumorigenesis. Cancer Res 2008; 68: 9589-94.

156. Selmin OI, Fang C, Lyon AM, Doetschman TC, Thompson PA, Martinez JD, Smith JW, et al. Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells. J Nutr 2016; 146: 236-42.

157. Degirolamo C, Modica S, Palasciano G, Moschetta A. Bile acids and colon cancer: Solving the puzzle with nuclear receptors. Trends Mol Med 2011; 17: 564-72.

158. Maran RR, Thomas A, Roth M, Sheng Z, Esterly N, Pinson D, Gao X, et al. Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development. J Pharmacol Exp Ther 2009; 328: 469-77.

159. De Gottardi A, Touri F, Maurer CA, Perez A, Maurhofer O, Ventre G, Bentzen CL, et al. The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer. Dig Dis Sci 2004; 49: 982-9.

160. Swales KE, Korbonits M, Carpenter R, Walsh DT, Warner TD, Bishop-Bailey D. The farnesoid X receptor is expressed in breast cancer and regulates apoptosis and aromatase expression. Cancer Res 2006; 66: 10120-6.

161. Giaginis C, Karandrea D, Alexandrou P, Giannopoulou I, Tsourouflis G, Troungos C, Danas E, et al. High Farnesoid X Receptor (FXR) expression is a strong and independent prognosticator in invasive breast carcinoma. Neoplasma 2017; 64.

162. You W, Chen B, Liu X, Xue S, Qin H, Jiang H. Farnesoid X receptor, a novel proto-oncogene in non-small cell lung cancer, promotes tumor growth via directly transactivating CCND1. Sci Rep 2017; 7: 591.

163. Casaburi I, Avena P, Lanzino M, Sisci D, Giordano F, Maris P, Catalano S, et al. Chenodeoxycholic acid through a TGR5-dependent CREB signaling activation enhances cyclin D1 expression and promotes human endometrial cancer cell proliferation. Cell Cycle 2012; 11: 2699-710.

164. De Fabiani E, Mitro N, Gilardi F, Galmozzi A, Caruso D, Crestani M. When food meets man: the contribution of epigenetics to health. Nutrients 2010; 2: 551-71.

165. Mazzio EA, Soliman KF. Basic concepts of epigenetics: impact of environmental signals on gene expression. Epigenetics 2012; 7: 119-30.

166. Xin M, Qiao Z, Li J, Liu J, Song S, Zhao X, Miao P, et al. miR- 22 inhibits tumor growth and metastasis by targeting ATP citrate lyase: evidence in osteosarcoma, prostate cancer, cervical cancer and lung cancer. Oncotarget 2016; 7: 44252-65.

167. Koufaris C, Valbuena GN, Pomyen Y, Tredwell GD, Nevedomskaya E, Lau CH, Yang T, et al. Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells. Oncogene 2016; 35: 2766-76.

168. Alvarez-Diaz S, Valle N, Ferrer-Mayorga G, Lombardia L, Herrera M, Dominguez O, Segura MF, et al. MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative, antimigratory and gene regulatory effects in colon cancer cells. Hum Mol Genet 2012; 21: 2157-65.

169. Zhang J, Yang Y, Yang T, Liu Y, Li A, Fu S, Wu M, et al. microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer 2010; 103: 1215-20.

170. Qiao DD, Yang J, Lei XF, Mi GL, Li SL, Li K, Xu CQ, et al. Expression of microRNA-122 and microRNA-22 in HBV-related liver cancer and the correlation with clinical features. Eur Rev Med Pharmacol Sci 2017; 21: 742-7.

171. Clurman BE, Porter P. New insights into the tumor suppression function of P27(kip1). Proc Natl Acad Sci USA 1998; 95: 15158-60.

172. Pereira MA, Wang W, Kramer PM, Tao L. DNA hypomethylation induced by non-genotoxic carcinogens in mouse and rat colon. Cancer Lett 2004; 212: 145-51.

173. Kouzarides T. Chromatin modifications and their function. Cell 2007; 128: 693-705.

174. Narlikar GJ, Fan HY, Kingston RE. Cooperation between complexes that regulate chromatin structure and transcription. Cell 2002; 108: 475-87.

175. Rosenfeld MG, Lunyak VV, Glass CK. Sensors and signals: a coactivator/corepressor/epigenetic code for inte grating signal-dependent programs of transcriptional response. Genes Dev 2006; 20: 1405-28.

176. Kemper JK. Regulation of FXR transcriptional activity in health and disease: Emerging roles of FXR cofactors and post-translational modifications. Biochim Biophys Acta 2011; 1812: 842-50.

177. Ferrari A, Fiorino E, Giudici M, Gilardi F, Galmozzi A, Mitro N, Cermenati G, et al. Linking epigenetics to lipid metabolism: focus on histone deacetylases. Mol Membr Biol 2012; 29: 257-66.

178. Smith Z, Ryerson D, Kemper JK. Epigenomic regulation of bile acid metabolism: emerging role of transcriptional cofactors. Mol Cell Endocrinol 2013; 368: 59-70.

179. Miao J, Fang S, Lee J, Comstock C, Knudsen KE, Kemper JK. Functional specificities of Brm and Brg-1 Swi/Snf ATPases in the feedback regulation of hepatic bile acid biosynthesis. Mol Cell Biol 2009; 29: 6170-81.

180. Kemper JK, Kim H, Miao J, Bhalla S, Bae Y. Role of an mSin3A-Swi/Snf chromatin remodeling complex in the feedback repression of bile acid biosynthesis by SHP. Mol Cell Biol 2004; 24: 7707-19.

181. Garcia-Rodriguez JL, Barbier-Torres L, Fernandez-Alvarez S, Gutierrez-de Juan V, Monte MJ, Halilbasic E, Herranz D, et al. SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling. Hepatology 2014; 59: 1972-83.

182. Chanda D, Xie YB, Choi HS. Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation. Nucleic Acids Res 2010; 38: 4607-19.

183. Li G, Kong B, Zhu Y, Zhan L, Williams JA, Tawfik O, Kassel KM, et al. Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice. Toxicol Appl Pharmacol 2013; 272: 299-305.

184. Zou A, Lehn S, Magee N, Zhang Y. New Insights into Orphan Nuclear Receptor SHP in Liver Cancer. Nucl Receptor Res 2015; 2.

185. Park MJ, Kim KH, Kim HY, Kim K, Cheong J. Bile acid induces expression of COX-2 through the homeodomain transcription factor CDX1 and orphan nuclear receptor SHP in human gastric cancer cells. Carcinogenesis 2008; 29: 2385-93.

186. Duboc H, Rajca S, Rainteau D, Benarous D, Maubert MA, Quervain E, Thomas G, et al. Connecting dysbiosis, bileacid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 2013; 62: 531-9.

187. Alnouti Y. Bile Acid sulfation: a pathway of bile acid elimination and detoxification. Toxicol Sci 2009; 108: 225-46.

188. Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol 2014; 30: 332-8.

189. Hofmann AF. The enterohepatic circulation of bile acids in mammals: form and functions. Front Biosci 2009; 14: 2584-98.

190. Hofmann AF, Hagey LR. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci 2008; 65: 2461-83.

191. Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE, Nicholson JK, et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci USA 2011; 108(Suppl. 1): 4523-30.

192. Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, Angelin B, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013; 17: 225-35.

193. Thaiss CA, Zeevi D, Levy M, Zilberman-Schapira G, Suez J, Tengeler AC, Abramson L, et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 2014; 159: 514-29.

194. Leone V, Gibbons SM, Martinez K, Hutchison AL, Huang EY, Cham CM, Pierre JF, et al. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe 2015; 17: 681-9.

195. Candela M, Biagi E, Maccaferri S, Turroni S, Brigidi P. Intestinal microbiota is a plastic factor responding to environmental changes. Trends Microbiol 2012; 20: 385-91.

196. Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM, Cusack S, Harris HM, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 2012; 488: 178-84.

197. Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, Almeida M, et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013; 500: 541-6.

198. Karlsson FH, Tremaroli V, Nookaew I, Bergstrom G, Behre CJ, Fagerberg B, Nielsen J, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013; 498: 99-103.

199. Bonfrate L, Tack J, Grattagliano I, Cuomo R, Portincasa P. Microbiota in health and irritable bowel syndrome: current knowledge, perspectives and therapeutic options. Scand J Gastroenterol 2013; 48: 995-1009.

200. Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Perez HE, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 2014; 509: 183-8.

201. Liou AP, Paziuk M, Luevano JM, Jr., Machineni S, Turnbaugh PJ, Kaplan LM. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med 2013; 5: 178ra41.

202. Tabibian JH, O'hara SP, Trussoni CE, Tietz PS, Splinter PL, Mounajjed T, Hagey LR, et al. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology 2016; 63: 185-96.

203. Gao B, Chi L, Mahbub R, Bian X, Tu P, Ru H, Lu K. Multi-Omics Reveals that Lead Exposure Disturbs Gut Microbiome Development, Key Metabolites, and Metabolic Pathways. Chem Res Toxicol 2017; 30: 996-1005.

204. Fazeli M, Hassanzadeh P, Alaei S. Cadmium chloride exhibits a profound toxic effect on bacterial microflora of the mice gastrointestinal tract. Hum Exp Toxicol 2011; 30: 152-9.

205. Liu Y, Li Y, Liu K, Shen J. Exposing to cadmium stress cause profound toxic effect on microbiota of the mice intestinal tract. PLoS One 2014; 9: e85323.

206. Breton J, Massart S, Vandamme P, De Brandt E, Pot B, Foligne B. Ecotoxicology inside the gut: impact of heavy metals on the mouse microbiome. BMC Pharmacol Toxicol 2013; 14: 62.

207. Joly C, Gay-Queheillard J, Leke A, Chardon K, Delanaud S, Bach V, Khorsi-Cauet H. Impact of chronic exposure to low doses of chlorpyrifos on the intestinal microbiota in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) and in the rat. Environ Sci Pollut Res Int 2013; 20: 2726-34.

208. Joly Condette C, Bach V, Mayeur C, Gay-Queheillard J, Khorsi-Cauet H. Chlorpyrifos Exposure During Perinatal Period Affects Intestinal Microbiota Associated With Delay of Maturation of Digestive Tract in Rats. J Pediatr Gastroenterol Nutr 2015; 61: 30-40.

209. Zhao Y, Zhang Y, Wang G, Han R, Xie X. Effects of chlorpyrifos on the gut microbiome and urine metabolome in mouse (Mus musculus). Chemosphere 2016; 153: 287-93. 210. Khandekar MJ, Cohen P, Spiegelman BM. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer 2011; 11: 886-95.

210. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444: 1022-3.

211. Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, Caviglia JM, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012; 21: 504-16.

212. Sears CL, Garrett WS. Microbes, microbiota, and colon cancer. Cell Host Microbe 2014; 15: 317-28.

213. Payne CM, Weber C, Crowley-Skillicorn C, Dvorak K, Bernstein H, Bernstein C, Holubec H, et al. Deoxycholate induces mitochondrial oxidative stress and activates NF-κB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis 2007; 28: 215-22.

214. Mühlbauer M, Allard B, Bosserhoff A, Kiessling S, Herfarth H, Rogler G, Schölmerich J, et al. Differential effects of deoxycholic acid and taurodeoxycholic acid on NF-κB signal transduction and IL-8 gene expression in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 2004; 286: G1000-G8.

215. Lee DK, Park SY, Baik SK, Kwon SO, Chung JM, Oh ES, Kim HS. [Deoxycholic acid-induced signal transduction in HT-29 cells: role of NF-kappa B and interleukin-8]. Korean J Gastroenterol 2004; 43: 176-85.

216. Da Silva M, Jaggers GK, Verstraeten SV, Erlejman AG, Fraga CG, Oteiza PI. Large procyanidins prevent bile-acid-induced oxidant production and membrane-initiated ERK1/2, p38, and Akt activation in Caco-2 cells. Free Radic Biol Med 2012; 52: 151-9.

217. Kim HI, Koh YK, Kim TH, Kwon SK, Im SS, Choi HS, Kim KS, et al. Transcriptional activation of SHP by PPAR-gamma in liver. Biochem Biophys Res. Commun 2007; 360: 301-6.

218. Dzutsev A, Goldszmid RS, Viaud S, Zitvogel L, Trinchieri G. The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. Eur J Immunol 2015; 45: 17-31.

219. Perez-Chanona E, Trinchieri G. The role of microbiota in cancer therapy. Curr Opin Immunol 2016; 39: 75-81.

220. Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 1995; 18: 321-36.

221. Axelson M, Sjovall J. Potential bile acid precursors in plasma-- possible indicators of biosynthetic pathways to cholic and chenodeoxycholic acids in man. J Steroid Biochem 1990; 36: 631-40.

222. Ressom HW, Xiao JF, Tuli L, Varghese RS, Zhou B, Tsai TH, Ranjbar MR, et al. Utilization of metabolomics to identify serum biomarkers for hepatocellular carcinoma in patients with liver cirrhosis. Anal Chim Acta 2012; 743: 90-100.

223. Zhang A, Sun H, Yan G, Han Y, Ye Y, Wang X. Urinary metabolic profiling identifies a key role for glycocholic acid in human liver cancer by ultra-performance liquid-chromatography coupled with high-definition mass spectrometry. Clin Chim Acta 2013; 418: 86-90.

224. Lee DH, Keum N, Giovannucci EL. Colorectal Cancer Epidemiology in the Nurses' Health Study. Am J Public Health 2016; 106: 1599-607.

225. Mysuru Shivanna L, Urooj A. A Review on Dietary and Non-Dietary Risk Factors Associated with Gastrointestinal Cancer. J Gastrointest Cancer 2016; 47: 247-54.

226. Mutlu EA, Gillevet PM, Rangwala H, Sikaroodi M, Naqvi A, Engen PA, Kwasny M, et al. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol 2012; 302: G966-78.

227. Wu W, Zhu B, Peng X, Zhou M, Jia D, Gu J. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease. Biochem Biophys Res Commun 2014; 443: 68-73.

228. Xie G, Zhong W, Li H, Li Q, Qiu Y, Zheng X, Chen H, et al. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption. FASEB J 2013; 27: 3583-93.

229. Biedermann L, Zeitz J, Mwinyi J, Sutter-Minder E, Rehman A, Ott SJ, Steurer-Stey C, et al. Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans. PLoS One 2013; 8: e59260.

230. Muller-Lissner SA. Bile reflux is increased in cigarette smokers. Gastroenterology 1986; 90: 1205-9.

231. Chen B, You WJ, Xue S, Qin H, Zhao XJ, Zhang M, Liu XQ, et al. Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease. J Thorac Dis 2016; 8: 3063-74.

232. Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T, Knuechel R, et al. Nuclear factor κB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 1998; 115: 357-69.

233. Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, Klomp LW, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011; 60: 463-72.

234. Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008; 48: 1632-43.

235. Cameron RG, Imaida K, Tsuda H, Ito N. Promotive effects of steroids and bile acids on hepatocarcinogenesis initiated by diethylnitrosamine. Cancer Research 1982; 42: 2426-8.

236. Kitazawa S. Studies on initiating activity of secondary bile acids for rat hepatocarcinogenesis. [Hokkaido Igaku Zasshi] The Hokkaido Journal of Medical Science 1993; 68: 110-20.

237. Knisely A, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 2006; 44: 478-86.