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BAs undergo an enterohepatic circulation that depends on active transport systems in the liver and the intestine (Figure 1.2). More specifically, BAs are excreted from hepatocytes into bile through BSEP/ABCB11 at the bile canaliculus, reabsorbed in the ileum by the apical sodium‐dependent bile salt transporter (ASBT/SLC10A2), and return through the portal blood to the liver, where they are taken up by hepatocytes via the basolateral transport systems NTCP/SLC10A1 for conjugated BAs and OATPs/SLCO/SLC21 family for unconjugated BAs, thus limiting the amount of BA spillover into the systemic circulation. BAs complete the enterohepatic circulation six to eight times a day and are highly efficiently conserved. BAs that escape ileal reabsorption reach the colon, where they are deconjugated and metabolized (e.g. dehydroxylated) by gut microbiota to secondary BAs, which can still be passively absorbed as unconjugated BAs in the colon. Unconjugated BAs are partially reconjugated (and rehydroxylated) during their passage through the liver before being excreted into bile again, which completes their enterohepatic cycle. In addition, BAs are filtered by the glomeruli and then reabsorbed in renal tubules, again limiting their renal loss.

BAs may also cycle between cholangiocytes and hepatocytes through a cholehepatic shunt pathway. Unconjugated BAs induce a greater degree of bile flow per BA molecule excreted in bile. To account for this hypercholeretic effect, it was proposed that unconjugated BAs may be passively absorbed by bile ducts, enter the peribiliary plexus adjacent to intrahepatic bile ducts, and then forwarded to the hepatic sinusoids to be returned to cholangiocytes by hepatocyte secretion. Cholehepatic shunting initiated by passive absorption of non‐ionized bile salt results in the generation of HCO₃^–‐rich hypercholeresis [4,5].

Figure 1.2 Enterohepatic circulation of bile acids (BAs). After hepatic synthesis and biliary secretion, BAs undergo enterohepatic circulation. The BSEP (ABCB11) is the main canalicular transporter for BAs. After reabsorbtion by ASBT/SLC10A1 in the ileum, BAs (and exit through OSTα/β from enterocytes; not shown) are transported back to the liver through the portal blood. Reuptake of conjugated BA from portal blood through NTCP/SLC10A1 (and OATPs for unconjugated BAs; not shown) into the hepatocytes completes the enterohepatic circulation. ASBT, apical sodium‐dependent bile salt transporter; BSEP, bile salt export pump; NTCP, sodium taurocholate cotransporting polypeptide; OATPs, organic anion transporters; OST, organic solute transporter α/β.

Source: Trauner et al. [5]. Reproduced with permission of John Wiley and Sons.