title: Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer.
abstract: Because of increasingly widespread sedentary lifestyles and diets high in fat and sugar, the global diabetes and obesity epidemic continues to grow unabated. A substantial body of evidence has been accumulated which associates diabetes and obesity to dramatically higher risk of cancer development, particularly in the liver and gastrointestinal tract. Additionally, diabetic and obese individuals have been shown to suffer from dysregulation of bile acid (BA) homeostasis and dysbiosis of the intestinal microbiome. Abnormally elevated levels of cytotoxic secondary BAs and a pro-inflammatory shift in gut microbial profile have individually been linked to numerous enterohepatic diseases including cancer. However, recent findings have implicated a detrimental interplay between BA dysregulation and intestinal dysbiosis that promotes carcinogenesis along the gut-liver axis. This review seeks to examine the currently investigated interactions between the regulation of BA metabolism and activity of the intestinal microbiota and how these interactions can drive cancer formation in the context of diabesity. The precarcinogenic effects of BA dysregulation and gut dysbiosis including excessive inflammation, heightened oxidative DNA damage, and increased cell proliferation are discussed. Furthermore, by focusing on the mediatory roles of BA nuclear receptor farnesoid x receptor, ileal transporter apical sodium dependent BA transporter, and G-coupled protein receptor TGR5, this review attempts to connect BA dysregulation, gut dysbiosis, and enterohepatic carcinogenesis at a mechanistic level. A better understanding of the intricate interplay between BA homeostasis and gut microbiome can yield novel avenues to combat the impending rise in diabesity-related cancers.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California at Davis Medical Center, Sacramento, CA 95831, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tsuei
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California at Davis Medical Center, Sacramento, CA 95831, USA.
authors.forename: Thinh
authors.initials: T
authors.lastname: Chau
authors.affiliation: Department of Food Science and Technology, Department of Viticulture and Enology, Foods for Health Institute, University of California, Davis, CA 95616, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mills
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California at Davis Medical Center, Sacramento, CA 95831, USA yjywan@ucdavis.edu.
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
mesh_terms: D001647:Bile Acids and Salts / Q000378:metabolism*; D004249:DNA Damage; D064806:Dysbiosis / Q000150:complications*; D005770:Gastrointestinal Neoplasms / Q000453:epidemiology* / Q000209:etiology*; D041981:Gastrointestinal Tract / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000150:complications*; D018384:Oxidative Stress
chemical_list: D001647:Bile Acids and Salts
keywords: G-protein-coupled BA receptor 1 (TGR5); Gut–liver axis; apical sodium dependent bile acid transporter; bacterial translocation; bile acids; diabetes; farnesoid X receptor; gastrointestinal carcinogenesis; gut dysbiosis; inflammation; intestinal microbiota; metabolic syndrome; obesity; polymorphism