The Enterohepatic Circulation of Bile Acids

Diagrammatic representation of the enterohepatic circulation of bile acids. 

Reabsorbed bile acids are transported back to the liver in the portal blood bound to albumin, where they are taken up by parenchymal cells for excretion into bile. The uptake process has been studied in isolated rat hepato-cytes (S17), the perfused rat liver (Rl), and cultured rat hepatocytes (V5), and a bile acid receptor protein has been partially characterized in liver cell membrane preparations (Al). Taken together, these studies suggest that uptake is via a coupled membrane carrier mechanism, whereby bile salt anions are cotransported with sodium cations across the liver cell sinusoidal membrane. Although the majority of bile acids are extracted from portal blood by the liver, a small fraction (less than 1% of the total bile salt pool) 

Bile acids, which have been taken up by the liver, are transported across the hepatocyte and secreted into the bile canaliculus. Newly synthesized bile acids, in a small amount just sufftcient to balance the fraction lost by fecal excretion, join recycled bile acids for biliary secretion. Intracellular bile acid transport may be mediated by carrier proteins (B24, S42). The detailed mechanism of biliary secretion of bile acids and other organic anions into the bile canaliculus is not yet clear (B24). Possible mechanisms include vectorial vesicular transport, fticilitated diflusion, or an energy-requiring carrier-mediated transport process (B24). 

The two bile acids, cholic acid and chenodeoxycholic acid, which are synthesized from cholesterol in the liver, are termed primary bile acids. Each day, around one-third to one-quarter of the primary bile acid pool is lost or converted to secondary bile acids by anaerobic bacteria in the intestine. This is achieved by 7a-dehydroxylation, a process which converts cholic acid to deoxycholic acid (3a,12a-dihydroxy-5p-cholan-24-oic acid) and chenodeoxycholic acid into lithocholic acid (3a-hydroxy-5 -cholan-24-oic acid). 

As a consequence of the 7a-dehydroxylation process, the bile acid composition of bile in healthy subjects usually comprises around 30 to 40% conjugated cholic acid, 30 to 40% conjugated chenodeoxycholic acid, 10 to 30% conjugated deoxycholic acid, and less than 5% conjugated lithocholic acid, of which the majority is sulfated (H18). 

In the past decade, the mammalian ileum has been shown to transport conjugated bile acids unidirectionally in the absence of any electrochemical 

In addition to changing the physical properties of bile acids, conjugation also alters their physiological properties. On the basis of extremely limited evidence, it seems likely that the bile acid pool of animals with exclusively taurine conjugates is maintained chiefly by active absorption from the ileum. 

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Grundy SM, Ahrens EH, Jr., Salen G. Interruption of the enterohepatic circulation of bile acids in man comparative ef-... 

Another possible mechanism involves the effect of saponins on micelle formation. Saponins are known to alter the size or shape of micelles (Oakenfull, 1986 Oakenfull and Sidhu, 1983), an observation that is consistent with decreased bile acid absorption (Stark and Madar, 1993) and increased fecal bile acid excretion (Malinow et al., 1981 Nakamura et al.,1999). Saponins may also directly bind bile acids (Oakenfull and Sidhu, 1989), which would presumably interfere with micelle formation and decrease cholesterol absorption. Other studies have found that saponins decrease the absorption of fat-soluble vitamins (Jenkins and Atwal, 1994) and triglycerides (Han et al., 2002 Okuda and Han, 2001), indicating decreased micelle formation. However, direct evidence showing impaired micelle formation in vivo is lacking. Moreover, Harwood et al. (1993) reported no change in bile acid absorption or interruption of the enterohepatic circulation of bile acids in hamsters fed tiqueside, despite significant reductions in cholesterol absorption. 

BSEP also known as sister-P-glycoprotein (SPGP) was originally cloned from pig liver (185). BSEP is localized on the canalicular membrane of hepa-tocytes and is responsible for the secretion of bile salts across the canalicular membrane into bile. BSEP appears to be the predominant bile salt efflux system for hepatocytes, and is a critical component in the enterohepatic circulation of bile acids. A number of mutations in the transporter were found to the basis for progressive familial intrahepatic cholestasis type 2 (PFIC2) (186-188). Mutations found in PFIC2 patients include frameshifts, missense mutations, and premature termination codons. Most PFIC2 patients lack immunohistochemically detectable BSEP in their liver. Recently, seven... 

During anesthesia intestinal motility is dramatically reduced, which secondarily might influence the intestinal absorption of the candidate compound. Bile flow is relatively constant during the first 2 to 3 hours but declined during prolonged anesthesia (Fig. 1) due to the interruption of the enterohepatic circulation of bile acids. 

Since bile acids are made from endogenous cholesterol, the enterohepatic circulation of bile acids may be disrupted as a way to lower cholesterol. Bile acid sequestrants bind bile acids in the gut, preventing their re-absorption. In so doing, more endogenous cholesterol is directed to the production of bile acids, thereby lowering cholesterol levels. The sequestered bile acids are excreted in the faeces. 

Dawson PA. Bile secretion and the enterohepatic circulation of bile acids. In Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger and Fordtran s gastrointestinal and liver disease, 7th ed. Philadelphia WB Saunders, 2002 1051-64. 

Nearly all bile acids are choleretic agents that is, they increase bile flow when infused intravenously into various animal species. In all vertebrtae species examined, there is a close relationship between bile flow and the hepatic excretion rate of bile acids (B24). Acute interruption of the enterohepatic circulation of bile acids in man by diversion of bile flow causes the rate of bile secretion to decrease by about 50% (TIO). Thus, the excretion of bile acids from the liver is the major determinant of bile water and solute excretion, predominantly because of the osmotic activity of bile acids in bile. Some interesting studies in dogs have been performed with the bile salt taurodehydrocholate (taurine conjugate of 3,7,12-triketo-5fl-cholan-24-oic acid), which, for stereochemical reasons, cannot form micelles and should therefore have greater osmotic activity than other bile acids. At the same... 

The primary bile acids are defined as those formed from cholesterol in the liver. Secondary bile acids are those formed from the primary bile acids through the action of intestinal microorganisms during the enterohepatic circulation of bile acids. The secondary bile acids may be subjected to further structural modifications by liver enzymes. The main primary bile acids in most mammalian species are cholic acid and chenodeoxycholic acid.t Other... 

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. 

Fig. 17. Schematic depiction of the enterohepatic circulation of bile acids in man. In the steady state, fecal excretion equals hepatic synthesis, and accordingly hepatic synthesis may be estimated from fecal bile acid excretion. The pool size may be estimated only by isotope dilution techniques, which also give the hepatic synthesis rate (94). The mass of bile acid secreted into the small intestine is equal to the pool multiplied by the number of cycles per day this cannot be estimated by any simple means in intact man at present. The diagram does not show the complexity of intestinal absorption of bile acids, which involves passive absorption of the glycine dihydroxy bile acids from the jejunum and active absorption of all conjugated bile acids from the ileum, as well as passive absorption of probably predominantly unconjugated bile acids from the colon.

The enterohepatic circulation of bile acids may be interrupted by biliary obstruction or biliary fistula the events occurring in fat digestion in the absence of bile acids have been discussed. Of more interest are the disturbances in bile acid and fat metabolism occurring when the enterohepatic circulation of bile acids is interrupted by ileal disease or resection. 

Fig. 18. Schematic depiction of the enterohepatic circulation of bile acids in patients with slight impairment in bile acid absorption. Decreased absorption causes increased hepatic synthesis, which restores the bile acid pool size to normal. Fat digestion is essentially normal, and fat malabsorption is not present. The increased passage of bile acids into the colon causes sodium and water secretion, manifested by diarrhea which is responsive to cholestyramine. The figure does not show the complexity of the intestinal absorption in these patients. Since they have predominantly glycine-conjugated bile acids, jejunal absorption may be increased further, since the concentration of bile acids in colonic content is increased, passive absorption from the colon probably also is increased and contributes to the conservation of the bile acid pool. Since the increased synthesis, as well as alterations in the site of intestinal absorption, results in maintenance of the bile acid pool at essentially normal levels, such patients have been termed compensated. The syndrome has been termed 5,6 acid diarrhea or cholanorrheic diarrhea. ...

Studies with radioactive glycocholate or taurocholate demonstrated a virtual absence of the enterohepatic circulation of bile acids in patients with jejunotransversocolostomy (77). The small amount of absorbed bile acids contained some deconjugated cholate and deoxycholate (which had been reconjugated in the liver), indicating a rapid bacterial action during an apparently fast intestinal passage. Under these conditions, steatorrhea is apparently not solely due to bile salt deficiency induced impairment of micelle formation, but reduced absorptive area may play an important contributory role. No direct measurement of bile acid synthesis by fecal determination has been performed in this condition. 

Experiments comparing bile fistula rats with intact rats are difficult to interpret. In the bile fistula rat, the enterohepatic circulation of bile acids is interrupted, feedback inhibition by the circulating pool is abolished, and bile acid synthesis is presumably at a maximum. The effects of thyroid hormone are thus superimposed on a system that is operating already at or near maximal capacity. The stimulation of bile acid output by thyroid hormone can thus be seen more readily in the intact rat, where bile acid synthesis is under feedback regulation by the circulating bile acid pool. 

This conclusion must be considered tentative at present. The half-life of a bile acid refers to the interval from secretion by the liver to excretion in the feces. It cannot take into account the number of enterohepatic cycles undergone by a bile acid molecule before it is excreted. Presumably, it is the rate of the enterohepatic circulation of bile acids that controls the rate of bile acid biosynthesis (28), and we do not know at present what factor or factors determine the rate of excretion. In the experiments in which the enterohepatic circulation was interrupted by administering the ion exchanger, it may be postulated that synthesis was stimulated by partial removal of the bile acid pool the mechanism of this effect is not unequivocal since the circulation rate of the pool was not known. 

FIGURE 9.1 A schematic representation of diet microbe interactions and how they shape immune function within the gut. Key metabolic processes within the human gut microbiota, especially carbohydrate fermentation, the enterohepatic circulation of bile acids and biotransformation of plant bioactive polyphenols by the gut microbiota play important roles in regulating both inflammatory and metabolic processes within the intestine, but also in other body tissues, like the liver, adipose tissue and brain, which are intimately involved in regulating whole-body glucose, lipid and energy metabolism, and also the chronic low-grade inflammation characteristic of metabolic diseases like diabetes, CVD, Alzheimer s and metabolic syndrome. 

Despite our increased knowledge of the synthesis, secretion and enterohepatic circulation of bile salts, several aspects of the effects of these sterol metabolites on the physiology of the intestine itself have not been emphasized and are poorly understood. This becomes of greater significance when we consider that bile acids, particularly chenodeoxycholic acid and ursodeoxycholic acids, are employed for gallstone therapy there are several dietary influences on the enterohepatic circulation of bile acids and on bile acid excretion (e.g. fats and dietary fibers) increased colonic bile acid concentrations have been implicated in the promotion of colorectal cancer and there appears to be an inverse relationship between cholesterolemia and colon cancer. 

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