Page 149 - Human Bile Acid Metabolism: a Postprandial Perspective

Clinical data 8 Before the discovery of TGR5, a study showed that infusion of deoxycholic acid
into the colon of human participants induced a dose-dependent increase in
peptide YY (PYY) and glucagon-related compounds.42 Rectal administration
of taurocholic acid prompted a dose-dependent GLP-1 response and suppressed appetite in both patients with type 2 diabetes and healthy participants.43 However, intrajejunal infusion of taurocholic acid alone did not seem to affect plasma glucose concentrations or GLP-1 secretion whereas coadministration of glucose and taurocholic acid increased GLP-1 secretion, suggesting a glucose-dependent effect of bile acids on GLP-1 secretion.44 A small study in healthy participants45
Review: clinical relevance of TGR5
Panel 2: Enterohepatic circulation of the bile acid pool
The enterohepatic cycle of bile acids through liver, gallbladder, intestine, and portal vein back to the liver (figure 1) is highly dynamic. Its timing is dependent on the chemical structure and conjugation status of the bile acids. Upon meal ingestion, concentrated bile from the liver and gallbladder flows into the intestinal lumen where it aids digestion by emulsifying lipids. Generally, conjugated bile acids do not pass the enterocyte membrane and are taken up by active transport more distally in the small intestine.21 After absorption, the liver efficiently extracts most bile acids from the portal vein for re-secretion. Bile acids that are not taken up form a postprandial peak in plasma total bile acid concentration
of approximately 1−20 μmol/L 30–90 min after a meal.22 Thus, extraintestinal tissues are exposed to bile acid concentrations that are high enough to activate TGR5 (figure 1).23 The dynamics of plasma bile acid concentrations are mainly a function of rate of absorption from the gastrointestinal tract.22 Approximately 5% of the bile acid pool is not reabsorbed and is lost in the faeces. This loss of bile acids is compensated for by de-novo bile acid synthesis from cholesterol in the liver, refuelling the enterohepatic cycle. Synthesis of
bile acids and the expression of various intestinal and hepatic transporters are regulated through feedback inhibition via the nuclear bile acid receptor FXR (reviewed elsewhere24).
A mixture of bile acids, differing in TGR5 affinity and hydrophilicity, constitutes the
bile acid pool (figure 2). A shift in pool composition affects TGR5-mediated pathways.23
In human beings, the primary bile acids cholic acid and chenodeoxycholic acid are
the endpoint of bile acid synthesis. Primary bile acids are dehydroxylated by the gut microbiota in the distal ileum and the colon into their corresponding secondary bile acids: lithocholic acid from chenodeoxycholic acid and deoxycholic acid from cholic acid. The most abundant bile acid species in human beings are cholic acid, deoxycholic acid, and chenodeoxycholic acid, whereas they are cholic acid and muricholic acid in rodents and chenodeoxycholic acid and hyocholic and hyodeoxycholic acid in pigs.21,23,25
Because of their soap-like nature, bile acids are cytotoxic in high concentrations. Conjugation decreases cytotoxicity and increases solubility, aiding secretion into bile. Although intestinal bacteria deconjugate bile acids, the majority of the human bile acid pool (~80%) is in its conjugated form throughout the enterohepatic cycle.21 Bile acids
are preferentially conjugated to taurine, which is reflected in the predominance of these conjugates in the murine bile acid pool. Because taurine is less prevalent in the human diet, the human bile acid pool is predominantly glycine conjugated.26
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