Bile acids, secondary

A portion of the primary bile acids in the intestine is subjected to further changes by the activity of the intestinal bacteria. These include deconjugation and 7a-dehydroxylation, which produce the secondary bile acids, deoxycholic acid and hthocholic acid. 

Although products of fat digestion, including cholesterol, are absorbed in the first 100 cm of small intestine, the primary and secondary bile acids are absorbed almost exclusively in the ileum, and 98—99% are returned to the liver via the portal circulation. This is known as the enterohepatic circulation (Figure 26—6). However, lithocholic acid, because of its insolubility, is not reabsorbed to any significant extent. Only a small fraction of the bile salts escapes absorption and is therefore eliminated in the feces. Nonetheless, this represents a major pathway for the elimination of cholesterol. Each day the small pool of bile acids (about 3-5 g) is cycled through the intestine six to ten times and an amount of bile acid equivalent to that lost in the feces is synthesized from cholesterol, so that a pool of bile acids of constant size is maintained. This is accomplished by a system of feedback controls. 

Bile acids within the enterohepatic circulation that undergo absorption in the terminal ileum encounter a relatively low number of species and population of bacteria and return to the liver in portal blood relatively unchanged. However, the approximately 5% of the bile-acid pool that enters the colon provides substrate for the extensive microbial population that deconjugate and oxidise hydroxyl groups leading to formation of the secondary bile acids deoxycholic and lithocholic acids that are the major bile acids in faeces. 

These deconjugated secondary bile acids are lipophilic and are believed to passively diffuse across the colon and enter the blood supply for return to the liver. Little is known of the mechanism, although in ASBT knockout mice there is an increase in OSTa/OSTp mRNA within the proximal colon.This could simply reflect reduced bile-acid uptake in the terminal ileum and a response to increased bile-acid levels entering the colon. 

Micromolar quantities of RNS are generated primarily by nitric oxide synthase 2 (NOS2), an enzyme that is up-regulated during colon-cancer progression. As discussed below, deoxycholate (DOC), a hydrophobic secondary bile acid, activates the redox-sensitive transcription factor NF-kB, resulting in increased levels of NOS2 and enhanced S-nitrosylation of proteins. Additional sources of bile-acid-induced ROS and RNS are also likely. ... 

L. A. Booth, I. T. Gilmore and R. F. Bilton, Secondary bile-acid induced DNA damage in HT29 cells are free radicals involved Free Radio. Res., 1997, 26(2), 135. 

L. A. Booth and R. F. Bilton, Genotoxic potential of the secondary bile acids a role for reactive oxygen species, in DNA and Free Radicals Techniques, Mechanisms Applications, O.I. Arouma and B. Halliwell, Editor, 1998, OICA International London, 161. 

Jenkins et al. demonstrated that the secondary bile acid, deoxycholic acid could induce micronuclei formation in the oesophageal adenocarcinoma cell line, OE33. The induction of micronuclei demonstrated a dose-dependent effect and occurred under both neutral and acidic pH conditions. An example of a micronucleus induced by treatment of the OE33 oesophageal adenocarcinoma cell line with deoxy cholic acid is shown in Figure 4.3. 

Importantly, knowledge of intestinal bile acid transport and metabolism, coupled with increased understanding of the mechanistic basis of the pro-tumorigenic activity of bile acids against CRC cells in vitro, has recently led to development and testing of bile acid-based treatment and prevention strategies for sporadic and inflammatory bowel-disease-associated CRC. Existing evidence that manipulation of the luminal secondary bile acid pool and/or therapy with ursodeoxycholic acid (UDCA) may have promise for prevention of CRC will be assessed. 

It is well recognised that the faecal bile acid content of random stool samples is highly variable with marked daily variation.Therefore, studies testing the association between luminal bile acid exposure and the presence of colorectal neoplasia have usually measured serum bile acid levels, which demonstrate less variability and are believed to reflect the total bile acid pool more accurately. Serum DCA levels have been shown to be higher in individuals with a colorectal adenoma compared with individuals without a neoplasm. Only one study has assessed future risk of CRC in a prospective study of serum bile-acid levels. The study was hampered by the small sample size (46 CRC cases). There were no significant differences in the absolute concentrations of primary and secondary bile acids or DCA/CA ratio between cases and controls although there was a trend towards increased CRC risk for those with a DCA/ CA ratio in the top third of values (relative risk 3.9 [95% confidence interval 0.9-17.0 = 0.1]). It will be important to test the possible utility of the DCA/ CA ratio as a CRC risk biomarker in larger, adequately powered studies. A recent study has demonstrated increased levels of allo-DCA and allo-LCA metabolites in the stool of CRC patients compared with healthy controls. ... 

Mechanisms of the Carcinogenic Activity of Secondary Bile Acids... 

In contrast to the effects of secondary bile acids like DCA, UDCA, which is found at a high concentration in bear bile but only in trace amounts in humans, has anti-neoplastic activity in vitro and in vivo. UDCA has significant chemopreventative activity in rodent models of sporadic and colitis-colorectal carcinogenesis induced by chemical carcinogens. 

Figure 5.2 Therapeutic interventions for decreasing colorectal mucosal bile acid exposure as a CRC chemoprevention strategy. 1) Lifestyle modifications including reduction in dietary animal fat and increased fibre intake may, at least partly, be explained by reduction in luminal primary (cholic acid [CA] and chenodeoxycholic acid [CDCA]) and secondary (deoxycholic acid [DCA] and lithocholic acid [LCA]) bile acids. 2) Reduction of secondary bile acids, which are believed to have pro-carcinogenic activity could be obtained by decreased bacterial conversion from primary bile acids. 3) Alternatively, bile acids could be sequestered by chemical binding agents, e.g. aluminium hydroxide (Al(OH)3) or probiotic bacteria. 4) Exogenous ursodeoxycholic acid (UDCA) can reduce the luminal proportion of secondary bile acids and also has direct anti-neoplastic activity on colonocytes in vitro.

The mechanistic basis of the anti-neoplastic activity of UDCA and the explanation for the significant difference in bioactivity of UDCA compared with DCA despite marked similarity in chemical structure remain unresolved. UDCA administration in healthy volunteers and colorectal adenoma patients has been demonstrated to decrease the proportion of DCA in aqueous phase stool. Therefore, one possible mechanism of the chemopreventative activity of UDCA is reduction of mucosal secondary bile acid exposure. Consistent with this idea, UDCA administration has been demonstrated to reduce the incidence of K-ras mutations and decrease Cox-2 expression in AOM-induced tumors, which is the opposite of the reported effects of DCA in the same model. However, it is clear that exogenous administration of UDCA has direct anti-neoplastic activity on human CRC cells in vitro, either alone or in combination with DCA, including anti-proliferative and anti-apoptotic effects, as well as induction of cell senescence. " ... 

Alternative potential strategies for reduction of mucosal secondary bile acid exposure are to target deconjugation of glycine/taurine bile salts by bacterial bile salt hydrolases and/or bacterial 7-dehydroxylation of primary bile acids to secondary bile acids. Sequestration of bile acids in the intestinal lumen using probiotic bacteria has also been proposed as an area for future research. ... 

P. K. Baijal, D. W. Fitzpatrick and R. P. Bird, Comparative effects of secondary bile acids, deoxycholic and lithocholic acids, on aberrant crypt foci growth in the postinitiation phases of colon carcinogenesis, Nutr. Cancer, 1998, 31, 81. 

E. Bayerdorffer, G. A. Mannes, T. Ochsenkuhn, P. Dirschedl, B. Wiebecke and G. Paumgartner, Unconjugated secondary bile acids in the serum of patients with colorectal adenomas. Gut, 1995, 36, 268. 

A and B are in cis position relative to each other (see p. 54). One to three hydroxyl groups (in a position) are found in the steroid core at positions 3, 7, and 12. Bile acids keep bile cholesterol in a soluble state as micelles and promote the digestion of lipids in the intestine (see p.270). Cholic add and cheno-deoxychoMc acid are primary bile acids that are formed by the liver. Their dehydroxylation at C-7 by microorganisms from the intestinal flora gives rise to the secondary bile acids lithocholic acid and deoxycholic acid. 

Intestinal bacteria produce enzymes that can chemically alter the bile salts (4). The acid amide bond in the bile salts is cleaved, and dehydroxylation at C-7 yields the corresponding secondary bile acids from the primary bile acids (5). Most of the intestinal bile acids are resorbed again in the ileum (6) and returned to the liver via the portal vein (en-terohepatic circulation). In the liver, the secondary bile acids give rise to primary bile acids again, from which bile salts are again produced. Of the 15-30g bile salts that are released with the bile per day, only around 0.5g therefore appears in the feces. This approximately corresponds to the amount of daily de novo synthesis of cholesterol. 

Covers, M. J., Termont, D. S., Lapre, J. A., Kleibeuker, J. H., Vonk, R. J., and van der Meer, R. (1996). Calcium in milk products precipitates intestinal fatty adds and secondary bile acids and thus inhibits colonic cytotoxicity in humans. Cancer Res. 56,3270-3275. 

Bacteria in the intestine can remove glycine and taurine from bile salts, regenerating bile acids. They can also convert some of the primary bile acids into "secondary" bile acids by removing a hydroxyl group, producing deoxycholic acid from cholic acid and lithocholic acid from chenodeoxycholic acid (Figure 18.11). 

Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95 percent) and reused. The mixture of primary and secondary bile acids and bile salts is absorbed primarily in the ileum. They are actively transported from the intestinal mucosal cells into the portal blood, and are efficiently removed by the liver parenchymal cells. [Note Bile acids are hydrophobic and require a carrier in the portal blood. Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood (see p. 179).] The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile. The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, and their subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation (see Figure 18.11). Between 15 and 30 g of bile salts are secreted from the liver into the duodenum each day, yet only about 0.5 g is lost daily in the feces. Approximately 0.5 g per day is synthesized from cholesterol in the liver to replace the lost bile acids. Bile acid sequestrants, such as cholestyramine,2 bind bile acids in the gut, prevent their reabsorption, and so promote their excretion. They are used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway. [Note Dietary fiber also binds bile acids and increases their excretion.]... 

Names and mechanism of production of the secondary bile acids... 

Bile is secreted into the intestine, and more than 95 percent of the bile acids and salts are efficiently reabsorbed. They are actively transported from the intestinal mucosal cells into the portal blood, where they are carried by albumin back to the liver (enterohepatic circulation). In the liver, the primary and secondary bile acids are reconverted to bile salts, and secreted into the bile. 

Some dietary factors can also change the bile acid species and, by doing so, alter cholesterol absorption. The liver synthesizes the primary bile acids, cholic and chenodeoxycholic acid. Bacteria in the intestine can convert some of the primary bile acids into secondary bile acids, producing deoxycholic from cholic acid and lithocholic from chenodeoxycholic acid. When certain dietary components alter the intestinal microflora, the rate of secondary bile... 

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