Bile acids BAs are detergent like amphipathic molecules
Bile acids (BAs) are detergent-like amphipathic molecules synthesized from cholesterol in the liver, stored in the gallbladder, and released into the intestine after food intake in order to facilitate the PHA-848125 of dietary lipids and liposoluble vitamins. BAs travel along the intestine and once in the distal ileum 95% of them are actively absorbed and returned to the liver via the portal vein in the so-called enterohepatic circulation. Only 5% of BAs escape this recycling process, reach the colon and are lost through feces (Love and Dawson, 1998). De novo BA synthesis takes place in the liver via a chain of several enzymatic reactions, whose rate limiting enzyme is the cholesterol 7α-hydroxylase (CYP7A1) that ultimately transforms cholesterol intermediate metabolites into the primary BAs, namely cholic acid (CA) and chenodeoxycholic acid (CDCA) (Russell, 2003). Primary BAs are conjugated with amino acids taurine or glycine before being actively secreted into the canalicular lumen. This process renders BAs less hydrophobic and less cytotoxic (Vessey et al., 1977), ready to exploit their physiological function in the intestine. Once in the colon, enteric bacteria deconjugate primary BAs into their secondary forms, namely deoxycholic acid (DCA), lithocholic acid (LCA) (Russell, 2003, Ridlon et al., 2006) and ursodeoxycholic acid (UDCA). While UDCA has a cytoprotective action, the main fecal BAs DCA and LCA are the most hydrophobic (Hofmann, 1999a, Hofmann, 1999b), therefore the most cytotoxic ones. Hydrophobicity is a distinctive attribute of BA toxicity ranking UDCA as the most hydrophilic and LCA as the most hydrophobic BA (BA hydrophobicity scale: UDCA < CA < CDCA < DCA < LCA). Experimental studies in rodents and human epidemiological data have shown that tumor promoting activity of Western-style/high fat diet is associated with increased colonic BA concentrations and higher fecal BA levels, as detected in patients diagnosed with CRC (Bianchini et al., 1989, Reddy and Wynder, 1973, Reddy and Wynder, 1977). Furthermore, cholecystectomy, which leads to an increased intestinal exposure to BAs, has been suggested as a predisposing factor to the development of CRC (Reddy and Wynder, 1977, Giovannucci et al., 1993, Lagergren et al., 2001). Due to the link between high colonic BA levels and increased CRC risk, consequences of prolonged exposure of the intestinal mucosa to hydrophobic BAs have been extensively investigated (Nagengast et al., 1995). It has been shown that cellular responses to BAs in the initiation and post-initiation phases of colon tumorigenesis include, directly or indirectly, activation of β-catenin signalling and p53 degradation (Ridlon and Bajaj, 2015), DNA oxidative damage, impaired mitotic activities and cell death (Bajor et al., 2010, Pearson et al., 2009), all leading to colonic cell hyperproliferation and invasiveness. CA, DCA and LCA may promote tumor formation in the large intestine by a direct proliferative effect on undifferentiated mucosal epithelial cells (Debruyne et al., 2001, Debruyne et al., 2002, Zimber et al., 1994, Zimber et al., 2000, Zimber and Gespach, 2008). Hyperproliferative effect of DCA has been shown in a variety of colon cancer cell lines (Huang et al., 1992, Moschetta et al., 2003). Also, there are observations on the damaging effects of BAs disrupting the integrity of the cell membrane of colonic mucosa (Rafter et al., 1986, Vahouny et al., 1984) causing a compensatory cell renewal of the colonic epithelium (Craven et al., 1986). High colonic DCA concentration induces cell proliferation via epidermal growth factor receptor (EGFR) activation and extracellular signal-regulated kinase (ERK) signalling (Cheng and Raufman, 2005). Also, BAs have been suggested to promote colonic epithelial proliferation acting in a phorbol ester-like manner, stimulating protein kinase C (PKC) (Huang et al., 1992, Craven et al., 1987). Furthermore, prolonged exposure of colonic cells to sub-lethal BA levels has been proposed to trigger apoptosis resistance, potentially contributing to colon carcinogenesis progression (Bernstein et al., 1999). Elevated DCA and LCA levels promote apoptosis primarily through activation of the intrinsic apoptotic pathway involving stimulation of mitochondrial oxidative stress, generation of reactive oxygen species (ROS), cytochrome C (cytC) release and activation of cytosolic caspases (Amaral et al., 2009). Along with hyperproliferation, increased BA levels also cause nuclear factor κappa B (NF-κB) pathway activation and promote the release of arachidonic acid (Ridlon and Bajaj, 2015). Chronic intestinal inflammation as occurs in idiopathic inflammatory bowel disease (IBD) is associated with increased risk of tumor formation, proportionally higher to prolonged disease duration, family history of sporadic CRC, frequent recurrence of active colonic inflammation, and associated primary sclerosing cholangitis (PSC) (Ullman and Itzkowitz, 2011). In fact, patients with ulcerative colitis (UC) and associated colonic dysplasia or carcinoma display higher fecal BA concentrations compared to UC patients without neoplasia (Hill et al., 1987). It is important to note, however, that BAs are considered tumor promoters and not mutagens since they are unable to induce tumor formation in animal models without a carcinogen or a genetic alteration. Indeed, as observed in different CRC rodent models, both DCA and LCA act as tumor promoters in the post-initiation early stages of colon carcinogenesis (Hori et al., 1998, Reddy et al., 1977a, Sutherland and Bird, 1994, DeRubertis et al., 1984).