Fecal secondary bile acids

Thus, the excretory pattern of fecal secondary bile acids observed in these studies correlated with colon tumor incidences in animal models. These studies also suggest that high dietary intake of certain types of fat may be necessary for the full expression of risk for colon cancer. 

The role of dietary fat in cancer development may be a result of its influence on fecal bile acid concentrations. The release of bile acids is stimulated following ingestion of dietary fat. These acids are then converted by colonic flora to secondary bile acids, which are associated with bowel mucosal irritation and cell proliferation responses and may promote tumor growth. ... 

Several mechanisms have been proposed for the protective action of the dietary hber found in whole grains. Increased fecal bulk and decreased transit time allow less opportunity for fecal mutagens to interact with the intestinal epithelium. Secondary bile acids are thought to promote cell proliferation, thus allowing increased opportunity for mutations to occur and abnormal cells to multiply. The effect of fiber on the actions of bile adds may be attributable to the binding or diluting of bile adds. 

Animal experiments, in particular, have been useful in testing various hypotheses about the relative effectiveness of different kinds of dietary fiber and about possible mechanisms of fiber effects. Thus, studies of bulking action (9-10), of selective secondary bile acid binding (11-12), of increased intestinal transit times (13), of altered bacterial activities and secondary bile acid production (14-19), and selective binding of carcinogens (16-19) have been carried out in laboratory animals. Several related studies have been conducted in humans as well. Among the latter are investigations of the relationship between the bulk fiber content of diets and fecal bile acids or other steroids (4.20-21). 

Most of the bile acids which escape from the terminal ileum into the colon undergo under normal conditions a transformation to secondary bile acids via the action of colonic bacteria (1,4). The amount of primary bile acids in feces is thus negligible, if any, the mixture of fecal bile acids consisting of compounds with a wide range of polarity (38-41). However, in contrast to neutral sterols, bile acids are not degraded to any appreciable extent into undetectable metabolites during the intestinal passage (42). 

Colonic reabsorption of secondary bile acids seems to be clearly established. The presence of deoxycholic acid as a normal biliary constituent indicates that it has been absorbed from the colon. Furthermore, the human bile contains a variety of other bacterial transformation products such as lithocholic acid and other cholanic acids, some of which may have been further metabolized by the liver (44-47). In contrast to the case in some other mammalian species, human liver is not able to convert deoxycholic acid back to cholic acid. Colonic perfusion with different labeled bile acids has clearly shown that colonic absorption takes place in man (48). Administration of labeled cholic acid into the lumen of the large bowel during operation for cholecystectomy is followed by the appearance of labeled cholic acid and deoxycholic acid in the T-tube bile, the recovery from the T-tube being about 60% of the dose (49). This clearly shows that cholic acid is converted to deoxycholic acid in the human colon and that both of them are absorbed from the large bowel. Colonic reabsorption has been calculated to amount to 200 mg/ day (49). The colonic absorption of secondary bile salts could be even higher if the physical state of some bile acids were not unfavorable for absorption. Lithocholic acid, for example, is a very nonpolar compound and precipitates in the colonic content in addition, it and other secondary bile acids as well are partially associated with fecal debris and bacteria (41). As a result of poor absorption, the amount of secondary bile acids, other than deoxycholic acid, is usually low in human bile. After a continuous biliary drainage, secondary bile acids disappear from the bile in a few days (49-51). 

Fecal characteristics like a low bulk, high pH and a high concentration of (secondary) bile acids observed in correlation studies, are also related to a high incidence of colonic cancer[4-7] For this reason we studied the effects on fecal bulk, defecation frequency, fecal pH and fecal bile acids of diets with different amounts and types of animal protein. The diets were chosen not only on account of differences in origin of protein, but also in order to provide customary diets containing meat, plant foods and milk-based products (lactovegetarian) or plant foods only (vegan). 

Cholestyramine was originally developed in the 1960s to treat pruritus secondary to elevated plasma concentrations of bile acids in patients with cholestasis. Its ability to bihd (i.e., to hold or to sequester) bile acids and to increase their fecal eliminafion was subsequently shown to produce beneficial effects in lowering serum cholesterol levels. In 1973, cholestyramine was approved for fhe treatment of hypercholesterolemia ih patiehts who do hot respond to dietary modifications. Colestipol and colesevelam, which retain the key structural features required to bind bile acids, were approved in 1977 and 2000, respectively (7,15). 

Most bile salts excreted in the feces are of the secondary type. Their formation is discussed in Section VII. The daily fecal excretion of bile salts in healthy subjects is highly variable and easily influenced by dietary alterations. Values from several studies are given in Table VIII. Bile salts virtually disappear from the stools during prolonged fasting, and turnover nearly ceases (19). Primary bile salts appear in the stools of patients with diarrhea (1). Patients taking cholestyramine excrete the usual pattern of secondary bile salts (57), so that apparently bacterial dehydroxylation of bile salts can occur in the presence of this resin. Patients with total external bile fistulas have no bile salts in the feces (2) this does not exclude transintestinal excretion of bile salts but makes it unlikely. As mentioned earlier, the predominance of chenodeoxycholic acid in blood and bile is often reflected in a predominance of lithocholate over deoxycholate in the feces (27). 

Neomycin is a polybasic, poorly absorbed antibiotic which forms insoluble precipitates with bile salts (99). It lowers serum cholesterol concentrations in man (100-102) and chickens (99) and increases fecal bile acid excretion. It inhibits the hepatotoxic effects of lithocholic acid ingestion in chickens (99) and prevents bacterial conversion of cholate to deoxycho-late (103). Neomycin, 6-12 g/day, induces a malabsorption syndrome, with mucosal changes similar to those of sprue (104). Bile salt metabolism is thus affected in at least three ways by neomycin (1) a binding effect similar to that of cholestyramine, (2) suppression of deconjugation and secondary bile formation caused by antimicrobial properties, and (3) possible impairment of absorption of bile salts by intestinal mucosa. The first probably accounts for most of the increased fecal excretion of bile salts. 

Interpopulation studies have demonstrated considerable differences in the fecal concentrations of bile acids. Our own studies in nineteen populations[30] have revealed that subjects consuming a diet typical of a rural third world population excreted relatively low concentrations of bile acids when compared to subjects consuming a western style diet (Table 2). Bile acid degradation to secondary substrates is also apparently reduced in these third world groups consuming a low animal fat and protein diet which is also high in fiber. 

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