Bile acids from feces

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. 

Pharmacology Bile acid sequestering resins bind bile acids in the intestine to form an insoluble complex, which is excreted in the feces. This results in a partial removal of bile acids from the enterohepatic circulation, preventing their absorption. 

The primary action of BARs is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bUe acids and a markedly increased excretion of acidic steroids in the feces. This decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the number of LDL receptors on the hepatocyte membrane. 

The extraction of bile acids from solid material, such as feces or tissues, requires a different approach since bile acids are likely to be firmly bound to bacteria or proteins. A variety of solvents have been used, such as alcoholic alkali (G14), toluene-acetic acid (E4), methanol-acetone (B35), and methanol-chloroform (El), sometimes with refluxing or Soxhlet extraction (B17, El). The state of ionization of the carboxyl group of bile salts, and thus the solvent pH, would be expected to affect the efficiency of extraction with organic solvents, with better extraction at acid pH. However, in practice an... 

Figure 8.8. Biosynthesis of bile acids and the enterohepatic circulation. Bile acids are synthesized from cholesterol in the liver under feedback regulation of the nuclear orphan receptors famesoid X receptor (FXR) and lignane X receptor (LXR). They are stored in the gallbladder and released through the bile duct into the duodenum, where they aid in the digestion of dietary fats. Intestinal uptake of bile acids takes place alongthe entire length of the small intestine, but active reabsorption is confined to the distal ileum to minimize loss of bile salts in the feces. The portal circulation carries bile acids from the intestine to the liver, where they are actively absorbed by hepatoc5Tesand secreted into bile.

The hydrolysis of bile acid conjugates is probably the initial reaction catalyzed by intestinal bacteria. Therefore, primarily free bile acids are isolated from the feces of man and animals [1-5]. The bulk of the free bile acids in feces of man is deoxycholic acid and lithocholic acid which are generated by the 7 -dehydroxylation of cholic acid and chenodeoxycholic acid, respectively. A portion of fecal acids is absorbed from the intestinal tract, returned to the liver where they are conjugated and again secreted via biliary bile. Therefore, the final composition of biliary bile acids is the result of a complex interaction between liver enzymes and enzymes in intestinal bacteria. 

Colestipol is a bile acid sequestrant that increases removal of bile acids from the body by forming insoluble complexes in intestine, which are then excreted in feces. As the body... 

The enterohepatic circulation of bile acids is characterized by a large pool of bile acids (2,15,26) which cycles many times (probably six to ten) each day. The size of the pool is determined by the efficiency of intestinal absorption and by the rate of hepatic synthesis of bile acids from cholesterol (94). The efficiency of absorption is high—in health probably greater than 98 %— and the amount of bile acids not absorbed is balanced by hepatic synthesis (Fig. 17). Bile acids are excreted only in feces, and their nucleus is considered invulnerable to bacterial attack therefore, the measurement of fecal bile acids either by chemical estimation or isotope dilution techniques indicates hepatic synthesis (94). The pool size may be estimated directly by isotope dilution, and an indirect estimate of pool size can be obtained by measuring jejunal bile acid concentration during digestion of a test meal. 

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). 

The amount of secondary products of neutral steroids and bile acids in feces of patients with ulcerative colitis appears to be reduced as compared to normal subjects (88). Thus bacterial action on steroids is decreased, probably owing to enhanced colonic motility, and may lead to reduced absorption of primary and especially secondary bile acids from the colon. This may explain the absence or low level of lithocholic acid in serum (188,193) of these patients and does not support the concept that lithocholic acid causes the liver damage (212) found frequently in ulcerative colitis. 

Cholesterol is supplied by absorption from diet (0.3-0.5 gfday in human) and biosynthesis (1.0-1.2 g/day) and is excreted mainly as bile acids into feces (0.8-1.3 g/day) (8). To reduce body cholesterol, three major strategies can be considered (a) inhibition of cholesterol absoipticm by a compound such as sitosterol, (b) inhibition of bile acid reabsorption by a compound such as cholestyramine, and (c) inhibition of cholesterol biosynthesis. Since more chan 70% of the total input of body cholesterol in humans is derived from de novo synthesis, it is expected that plasma cholesterol levels can be reduced by inhibition of cholesterol biosynthesis. 

Quantitative recoveries of endogenously labeled bile acids in homogenized human feces can be obtained by continuous extraction for 48 hr with hot chloroform-methanol, 1 1 (18). After saponification, acidification, and continuous diethyl ether extraction, the bile acids are purified on silicic acid (Section IIIB 4 and Ref. 18) to give one mono- and disubstituted, and one trisubstituted bile acid fraction. For identification purposes further subfractionation can be made [see Table V (69, 77, 126, 127)]. The subfrac-ticns are subsequently subjected to small-scale preparative thin-layer chromatography of methylated bile acids. The fractions eluted from the thin-layer plates are next subjected to peak-shift analyses followed by final identification by gas chromatography-mass spectrometry. When the fecal bile acid composition has been elucidated in this way the mono-, di- and trisubstituted bile acids from the first silicic acid column may be quantitated after methyla-tion and by analysis on QF-1. These results are then compared with those obtained after trifluoroacetylation of the bile acid methyl esters. (18). 

Cholesterol is present endogenously by both absorption from diet and biosynthesis and is excreted mainly as bile acids into feces [2]. In order to reduce body cholesterol, three major strategies for the inhibition of cholesterol biosynthesis can be considered. 

About 1 g of cholesterol is ehminated from the body per day. Approximately half is excreted in the feces after conversion to bile acids. The remainder is excreted as cholesterol. Coprostanol is the principal sterol in the... 

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. 

Wells JE, PB Hylemon (2000) Identification and characterization of a bile acid 7a-dehydroxylation operon in Clostridium sp. strain TO-931, a highly active 7a-dehydroxylating strain isolated from human feces. Appl Environ Microbiol 66 1107-1113. 

Cholestyramine, colestipol, and colesevelam are the bile acidbinding resins or sequestrants (BAS) currently available in the United States. Resins are highly charged molecules that bind to bile adds (which are produced from cholesterol) in the gut. The resin-bile acid complex is then excreted in the feces. The loss of bile causes a compensatory conversion of hepatic cholesterol to bile, reducing hepatocellular stores of cholesterol resulting in an up-regulation of LDL receptors to replenish hepatocellular stores which then result in a decrease in serum cholesterol. Resins have been shown to reduce CHD events in patients without CHD.26... 

Bile acids and salts have been found to enhance the absorption of both calcium and vitamin D hence, to increase calcium absorption both directly and indirectly (3,37). However, the ability of some dietary fibers such as lignin and pectin to absorb conjugated and deconjugated bile salts onto their surfaces to be excreted in the feces (a mechanism credited to the hypocholesterolemic effect of some dietary fibers) may result in an overall decrease in calcium absorption from the gastrointestinal tract (7,33,38-40). 

Mechanism of Action A lipid-bile acid sequestrant and nonsystemic polymer that binds with bile acids in the intestines, preventing their reabsorption and removing them from the body Therapeutic Effect Decreases LDL cholesterol. Pharmacokinetics Not absorbed. Primarily eliminated in feces. 

The ring structure of cholesterol cannot be metabolized to C02 and HfeO in humans. Rather, the intact sterol nucleus is eliminated from the body by conversion to bile acids and bile salts, which are excreted in the feces, and by secretion of cholesterol into the bile, which transports it to the intestine for elimination. Some of the cholesterol in the intestine is modified by bacteria before excretion. The primary compounds made are the isomers coprostanol and cholestanol, which are reduced derivatives of cholesterol. Together with cholesterol, these compounds make up the bulk of (neutral fecal sterols. 

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.]... 

FIG. 1 Movement of cholesterol (CHOL) and bile acids (BA) between the liver and small intestine. CHOL and BA in the liver are secreted into the gallbladder where they are stored temporarily until a fat-containing meal causes their secretion into the intestinal lumen. BA are absorbed with high efficiency (95%) and are recycled back to the liver via the hepatic portal vein. CHOL is absorbed less efficiently (50-60%) and must be incorporated into lipoproteins (chylomicrons) for transport back to the fiver via the systemic circulation. Accumulation of CHOL in the liver can promote secretion of CHOL into plasma, thus increasing LDL-CHOL concentration. Loss of CHOL and BA in feces represents the primary route of CHOL elimination from the body. 

The mass of bile acids per 0.5 g feces = mass in 1 ml methanol x dpm 14C-taurocholate added/dpm recovered in 1 ml methanol. As for neutral sterols, the total excreted per 3 days is calculated from the total fecal mass collected and data are reported as mass (or moles) excreted per day per gram body weight. 

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