Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System

Abstract

Bile acids are best known as detergents involved in the digestion of lipids. In addition, new data in the last decade have shown that bile acids also function as gut hormones capable of influencing metabolic processes via receptors such as FXR (farnesoid X receptor) and TGR5 (Takeda G protein-coupled receptor 5). These effects of bile acids are not restricted to the gastrointestinal tract, but can affect different tissues throughout the organism. It is still unclear whether these effects also involve signaling of bile acids to the central nervous system (CNS). Bile acid signaling to the CNS encompasses both direct and indirect pathways. Bile acids can act directly in the brain via central FXR and TGR5 signaling. In addition, there are two indirect pathways that involve intermediate agents released upon interaction with bile acids receptors in the gut. Activation of intestinal FXR and TGR5 receptors can result in the release of fibroblast growth factor 19 (FGF19) and glucagon-like peptide 1 (GLP-1), both capable of signaling to the CNS. We conclude that when plasma bile acids levels are high all three pathways may contribute in signal transmission to the CNS. However, under normal physiological circumstances, the indirect pathway involving GLP-1 may evoke the most substantial effect in the brain.

Keywords: CNS; FGF19; FXR; GLP-1; TGR5; bile acids; brain.

Figure 1

Schematic representation of bile acid synthesis pathways in humans. Bile acid synthesis from cholesterol occurs via different pathways. The classic pathway occurs in the liver and is responsible for the majority of bile acid synthesis. This pathway is initiated by the enzyme cholesterol 7α-hydroxylase (encoded by CYP7A1) and results in the formation of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA). Key enzymes for the formation of CA or CDCA are sterol 12α-hydroxylase (CYP8B1) and sterol-27 hydroxylase (CYP27A1), respectively. In rodents, the primary bile acids formed are CA and muricholic acid (MCA). The primary bile acids are conjugated to the amino acids glycine (G, mainly in humans) or taurine (T, mainly in rodents) forming conjugated bile acids and bile salts. The formation of secondary bile acids occurs in the intestine under the control of gut flora and when returned to the liver these secondary bile acids can also be conjugated to glycine and taurine. The alternative pathway of bile acid synthesis also occurs in other tissues besides the liver. This pathway is initiated by CYP27A1 and also involves CYP7B1. After several metabolic steps CDCA is formed. The last pathway occurs in the brain and is believed to be important for neuronal cholesterol clearance. Cholesterol is converted to 24(S)-hydroxycholesterol by CYP46A1 and subsequently exits the brain and enters the bloodstream (dotted line). In the liver, bile acid synthesis continues involving CYP39A1 resulting in CDCA after several steps.

Figure 2

Schematic representation of the enterohepatic circulation of bile acids. Bile acids are synthesized in the liver and stored in the gallbladder. Following food intake, bile acids are released into the duodenum. Traveling down the intestine, the majority of bile acids are taken up by enterocytes. In the jejunum and colon passive diffusion of unconjugated and uncharged bile acids takes place and the ileum is the main site for active uptake of conjugated bile acids by bile salt transporters. About 95% of the bile acids are reabsorbed in the ileum and consequently only a small portion (~5%) of the bile acids is lost through fecal output. The bile acids that are absorbed by the enterocytes are released into the portal vein and redirected to the liver for recycling. Only a small portion escapes the enterohepatic circulation and reaches the systemic circulation. The liver extracts 80–90% of the portal total bile acids.

Figure 3

Schematic overview of the bile acid signaling pathways to the central nervous system. Bile acids in the intestinal lumen can signal to the central nervous system (CNS) via different pathways, in this review we focused on the direct pathway (A), the indirect pathway via farnesoid X receptor-fibroblast growth factor 19 (FXR-FGF19) signaling (B), and the indirect pathway via Takeda G protein-coupled receptor-glucagon-like peptide-1 (TGR5-GLP-1) signaling (C). (A) Bile acids in the intestine escape the enterohepatic circulation and reach the systemic circulation. Bile acids need to pass the blood-brain barrier (BBB) in order to interact with receptors in the brain, e.g., FXR and TGR5. Deoxycholic acid (DCA) and chenodeoxy cholic acid (CDCA) have been found to interact with gap junction proteins, resulting in a leaky BBB. (B) Bile acids taken up by enterocytes can activate the nuclear receptor FXR, which results in the release of FGF19. FGF19 is released by the enterocyte and reaches the portal vein, a small portion of FGF19 will not be taken up by the liver and enters the systemic circulation. FGF19 needs to cross the BBB to interact with FGF receptors (1–4) in the brain. The protein β-klotho is necessary for the formation of a stable receptor-complex. (C) in the intestine, a specific group of enteroendocrine cells, L-cells, produces GLP-1 upon the activation of TGR5 which can be triggered by bile acids. GLP-1 is quickly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4, not shown), consequently high concentrations of GLP-1 are only found in the lamina propria of the intestine. A small portion of intact GLP-1 reaches the portal vein and even a smaller portion reaches the systemic circulation. It is questionable whether sufficient intact GLP-1 reaches the brain to interact with GLP-1 receptors, hence the dashed line. GLP-1 receptors are also expressed on afferent terminals of the vagal nerve present in the lamina propria and portal vein. The vagal nerve projects to the nucleus of the solitary tract (NTS) in the brainstem, from where projections are directed toward other brain regions, e.g. the hypothalamus (the vagal-brainstem-hypothalamic pathway).