Medical Physiology, 3rd Edition

Enterohepatic Circulation of Bile Acids

The enterohepatic circulation of bile acids is a loop consisting of secretion by the liver, reabsorption by the intestine, and return to the liver in portal blood for repeat secretion into bile

Bile acids are important for promoting the absorption of dietary lipids in the intestine. The quantity of bile acid that the liver normally secretes in a day varies with the number of meals and the fat content of these meals, but it typically ranges between 12 and 36 g. The liver's basal rate of synthesis of bile acids from cholesterol (see Fig. 46-9) is only ~600 mg/day in healthy humans, sufficient to replace the equivalent losses of bile acid in the feces. Obviously, the gastrointestinal tract must have an extremely efficient mechanism for recycling the bile acids secreted by the liver (Fig. 46-13). This recycling, known as the enterohepatic circulation, occurs as the terminal ileum and colon reabsorb bile acids and return them to the liver in the portal blood. The total pool of bile acids in the gastrointestinal tract is ~3 g. This pool must recirculate ~4 to 12 times per day, or as many as 5 or more times for a single fat-rich meal. If reabsorption of bile acids is defective, as can happen after resection of the ileum, de novo synthesis of bile acids by the liver can be as high as 4 to 6 g/day.


FIGURE 46-13 Enterohepatic circulation of bile acids. The bile acids that the liver delivers to the duodenum in the bile are primarily conjugated to taurine or glycine (BA-Z), and these conjugates enter the portal blood in the terminal ileum to return to the liver. Some unconjugated bile acids and secondary bile acids also return to the hepatocyte for resecretion.

Efficient intestinal conservation of bile acids depends on active apical absorption in the terminal ileum and passive absorption throughout the intestinal tract

Most of the bile secreted into the duodenum is in the conjugated form. Very little of these bile salts is reabsorbed into the intestinal tract until they reach the terminal ileum, an arrangement that allows the bile salts to remain at high levels throughout most of the small intestine, where they can participate in lipid digestion (see pp. 925–929) and absorption (see pp. 929–933). However, the enterohepatic circulation must eventually reclaim 95% or more of these secreted bile salts. Some of the absorption of bile acids by the intestines is passive and occurs along the entire small intestine and colon. Nevertheless, the major component of bile acid absorption is active and occurs only in the terminal ileum (see Fig. 46-13).

Passive absorption of bile acids occurs along the entire small intestine and colon (see Fig. 46-13), but it is less intensive than active absorption. The mechanism of bile acid uptake across the apical membrane may consist of either ionic or nonionic diffusion (see pp. 784–785). Nonionic diffusion—or passive diffusion of the protonated or neutral form of the bile acid—is 10-fold greater than ionic diffusion. The extent of nonionic diffusion for a given bile acid depends on the concentration of its neutral, protonated form, which is maximized when the luminal pH is low and the pK of the bile acid is high. At the normal intestinal pH of 5.5 to 6.5, few of the taurine-conjugated bile salts are protonated, a small amount of the glycine-conjugated bile salts are protonated, and ~50% of unconjugated bile acids are protonated. Thus, the unconjugated bile acids are in the best position to be reabsorbed by nonionic diffusion, followed by the glycine-conjugated bile acids and then finally by the taurine-conjugated bile acids. Among these unconjugated bile acids, more lipophilic bile acids, such as chenodeoxycholate and deoxycholate, diffuse more readily through the apical membrane than do hydrophilic bile acids such as cholic acid. Nonionic diffusion also depends on the total concentration of the bile acid (i.e., neutral plus charged form), which, in turn, depends on the maximum solubilizing capacity of bile-salt micelles for that bile acid.

Active absorption of bile acids in the intestine is restricted to the terminal ileum (see Fig. 46-13). This active process preferentially absorbs the negatively charged conjugated bile salts—the form not well absorbed by the passive mechanisms. Active uptake of bile salts involves saturation kinetics, competitive inhibition, and a requirement for Na+. The Na+-dependent transporter responsible for the apical step of active absorption is known as the apical Na/bile-salt transporter (ASBT or SLC10A2), a close relative of the hepatocyte transporter NTCP (see Fig. 46-5C). After bile salts enter ileal enterocytes across the apical membrane, they exit across the basolateral membrane via the heteromeric organic solute transporter OSTα-OSTβ.

Because the most polar bile salts are poorly absorbed by nonionic diffusion, it is not surprising that the ASBT in the apical membrane of the enterocytes of the terminal ileum has the highest affinity and maximal transport rates for these salts. For example, ASBT is primarily responsible for absorbing the ionized, taurine-conjugated bile salts in the ileum. Conversely, ASBT in the ileum is relatively poor at absorbing the more lipophilic bile acids, which tend to be absorbed passively in the upper intestine.

On their entry into portal blood, the bile acids are predominantly bound to albumin and, to a lesser extent, lipoproteins. The liver removes or clears these bile acids from portal blood by the transport mechanisms outlined above in Figure 46-5C. Hepatic clearance of bile acids is often expressed as the percentage of bile acids removed during a single pass through the liver. The hepatic extraction of bile acids is related to bile acid structure and the degree of albumin binding. It is greatest for hydrophilic bile acids and lowest for protein-bound, hydrophobic bile acids.

The small fraction of bile acids that escapes active or passive absorption in the small intestine is subject to bacterial modification in the colon. This bacterial modification takes two forms. First, the bacteria deconjugate the bile. Second, the bacteria perform a 7α-dehydroxylation reaction with the formation of secondary bile acids. These secondary bile acids include deoxycholate and lithocholate (see Fig. 46-9). The deconjugated secondary bile acids may then be either absorbed passively in the colon or excreted in the feces; their fate depends on their physicochemical properties and their binding to luminal contents. Up to one third of the deoxycholate formed in the colon may be reabsorbed by nonionic diffusion. Lithocholate, which is relatively insoluble, is absorbed to a much lesser extent. The secondary bile acids formed by colonic bacteria and recycled back to the liver may undergo biotransformation through conjugation to glycine and taurine.

Thus, the enterohepatic circulation of bile acids is driven by two mechanical pumps: (1) the motor activity of the gallbladder, and (2) peristalsis of the intestines to propel the bile acids to the terminal ileum and colon. It is also driven by two chemical pumps: (1) energy-dependent transporters located in the terminal ileum, and (2) energy-dependent transporters in the hepatocyte.

The bile acid receptor FXR, a member of the nuclear receptor family (see Table 3-6), controls multiple components of the enterohepatic circulation of bile acids. Primary bile acids are potent agonists of FXR, which transcriptionally regulates several genes involved in bile acid homeostasis, producing negative feedback by four mechanisms:

1. FXR in hepatocytes induces expression of a transcription factor called the small heterodimer partner (SHP); SHP, in turn, inhibits another nuclear receptor, the liver receptor homolog 1 (LRH-1), which is required for CYP7A1 expression. The result is that FXR inhibits the expression of cholesterol 7α-hydroxylase (CYP7A1)—the rate-limiting enzyme for bile acid synthesis (see Fig. 46-9).

2. FXR in the ileum increases the synthesis and secretion into portal blood of FGF19, which then activates the FGF receptor 4 signaling pathway in the liver, repressing CYP7A1.

3. FXR in hepatocytes upregulates BSEP (which increases bile acid secretion; see Fig. 46-5C) and downregulates NTCP (which decreases bile acid uptake; see Fig. 46-5C) by SHP-dependent mechanisms. The net result is a reduction of intracellular bile acids.

4. FXR in the ileum, via SHP, downregulates ASBT (see Fig. 46-13, inset), thereby reducing bile acid uptake. FXR also induces the expression of basolateral OSTα-OSTβ, thereby increasing bile acid efflux. The net result is a reduction of intracellular bile acids.

Thus, FXR coordinates bile acid synthesis and transport by the liver and intestine. The bile acid signaling network also includes the G protein–coupled receptor TGR5, which is highly expressed in the apical membrane and primary cilium of cholangiocytes and gallbladder epithelial cells, but minimally in hepatocytes. Activation of TGR5 by bile acids in the biliary tract leads to a rise in [cAMP]i, which causes Clsecretion to increase (Box 46-3).

Box 46-3


During hemolytic anemias, small, dark pigment gallstones may form secondary to the excess production and excretion of bilirubin. However, most gallstones (~80%) consist mainly of cholesterol. Thus, cholelithiasis is largely a disturbance of bile secretion and cholesterol elimination. When cholesterol and phospholipids are secreted together into the bile, they form unilamellar bilayered vesicles. These vesicles become incorporated into mixed micelles that form because of the amphiphilic properties of bile acids. Micellation allows cholesterol to remain in solution in its passage through the biliary tree. However, if the concentration of bile acids is insufficient to maintain all the cholesterol in the form of mixed micelles, the excess cholesterol is left behind as vesicles in the aqueous phase. These cholesterol-enriched vesicles are relatively unstable and are prone to aggregate and form large multilamellar vesicles, from which cholesterol crystals nucleate. Growth of crystals may result in the formation of gallstones. An excess of biliary cholesterol in relation to the amount of phospholipids and bile acids can result from hypersecretion of cholesterol, inadequate secretion of bile acids, or both. Cholelithiasis may be further promoted by other factors, such as gallbladder mucin and other nonmucous glycoproteins, as well as by stasis of bile in the gallbladder. Polymorphisms in the hepatic cholesterol transporter ABCG5/G8 and the bilirubin-conjugating enzyme UGT1A1 (see p. 955) contribute to the formation of gallstones in humans.




Length (m)



Area of apical plasma membrane (m2)









Crypts or glands






Nutrient absorption



Active Na+ absorption



Active K+ secretion