The Role of Bile Acids in Chronic Diarrhea

Abstract

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.

Figure 1.. A graphical representation of the enterohepatic circulation.

Left panel indicates bile acid circulation in healthy individuals. Bile acids are reabsorbed in the ileum, activate FXR and increase FGF-19 synthesis. FGF-19 then binds to the FGFR-4 and klotho β receptors to decrease C4 and subsequent hepatic bile acid synthesis. Right panel: In bile acid malabsorption, bile acids are reabsorbed, but FGF-19 remains low, or there are mutations within the FGFR-4 or klotho β receptors that do not inhibit hepatic bile acid synthesis. Bile acids that enter the colon bind to the GPBAR1 receptor and cause increased colonic transit and secretion. IBS=irritable bowel syndrome. Reproduced with permission from ref. 34, Camilleri M. Physiological underpinnings of irritable bowel syndrome: neurohormonal mechanisms. J Physiol 2014;592:2967–80.

Figure 2.. Synthesis, secretion and enterohepatic circulation of bile acids in humans.

(1) Primary bile acids (BAs) are synthesized in hepatocytes from cholesterol. (2) BAs are conjugated to glycine and taurine and are stored in the gallbladder at high concentrations. (3) After feeding, conjugated BAs are secreted in the intestine where they emulsify dietary fats and form mixed micelles that facilitate digestion and absorption of the products of triglyceride digestion. (4) Conjugated BAs are actively absorbed by the apical sodium BA co-transporter [ASBT (IBAT)] at the apical membrane of enterocytes of the terminal ileum. (5) In the colon, bacteria deconjugate and dehydroxylate primary BAs to form secondary BAs, which are passively absorbed. (6) Conjugated and unconjugated BAs enter the portal vein and recirculate to the liver for re-use. BA=bile acid; CA=cholic acid; CDCA=chenodeoxycholic acid; DCA=deoxycholic acid; LCA=lithocholic acid; UDCA=ursodeoxycholic acid; Na=sodium Reproduced with permission from ref. 1, Bunnett NW. Neuro-humoral signalling by bile acids and the TGR5 receptor in the gastrointestinal tract. J Physiol 2014;592:2943–50.

Figure 3.. Primary bile acids alone or in combination with total fecal bile acids are equivalent to fecal bile acids in the ability to detect elevated fecal weight, a validated correlate of bile acid diarrhea. Receiver operating characteristic (ROC) curves of total fecal bile acids (larger central image), primary bile acids (bottom left ROC curve), and primary bile acids with total fecal bile acids (lower right ROC curve) predict fecal weight >400 grams.

AUC=area under the curve; BA=bile acids; 7α-hydroxy-4-cholesten-3-one=7αC4; CA=cholic acid; CDCA=chenodeoxycholic acid; DCA=deoxycholic acid; LCA=lithocholic acid Reproduced from ref. 43, Vijayvargiya P, Camilleri M. Commentary: Current practice in the diagnosis of bile acid diarrhea. Gastroenterology 2019;156:1233–8.