Bilirubin in the Liver-Gut Signaling Axis

Abstract

Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin levels are reflective of liver disease due to an injurious effect on hepatocytes. In healthy liver, bilirubin is conjugated and excreted to the intestine and converted by microbes to urobilinoids, which are reduced to the predominant pigment in feces, stercobilin, or reabsorbed. The function of urobilinoids in the gut or their physiological relevance of reabsorption is not well understood. In this review, we discuss the relationship of hepatic bilirubin signaling to the intestinal microbiota and its regulation of the liver-gut axis, as well as its capacity to mediate these processes.

Keywords: bile pigment; biliverdin reductase; fatty liver disease; gut microbiota; urobilinoids.

Figure 1. The heme catabolic pathway in liver to gut signaling

Heme is broken down by heme oxygenase to produce carbon monoxide (CO), iron (Fe), and biliverdin. In normal, healthy hepatocytes biliverdin is converted to bilirubin via biliverdin reductase A (BVRA). Bilirubin prevents hepatic steatosis by elevating the peroxisomal proliferator activated receptor α (PPARα) transcriptional activity to increase fat burning genes. Alterations in bilirubin production by BVRA result in marked steatosis in hepatocytes. Bilirubin is conjugated in hepatocytes by the UGT1A1 UDP-glucuronosyltransferase enzyme and excreted to bile eventually reaching the intestine. Conjugated bilirubin is deconjugated by the gut bacteria and reduced to urobilinoids.

Figure 2. Hepatic bilirubin elimination

Unconjugated bilirubin enters hepatocytes through the organic anion transporter (OATP) and is conjugated with glucuronic acid (GA) by UDP-glucuronyltransferase UGT1A1 and excreted by multi-drug resistant protein (MRP2) to bile. Soluble bilirubin is secreted back into the blood by MRP3.

Figure 3. Urobilinoid excretion and reabsorption

Bilirubin is excreted into the intestines and reduced to urobilinoids/urobilinogens by gut bacteria. Then, urobilinogens are either deposited into feces as the bile pigment or reabsorbed into hepatic portal circulation. Urobilinogens are taken up by the kidney and oxidized to urobilin and excreted into urine.

Figure I. Theoretical heme and bile acid hepatic conveyor

The bile acid receptor, Farnesoid X Receptor (FXR), is a transcription factor that increases heme synthesis genes and lipid-reducing genes. Heme is broken down by heme oxygenase (HO-1) to biliverdin and is further reduced to bilirubin by biliverdin reductase. Bilirubin is excreted into the intestine and further processed into urobilinoids. Unconjugated bilirubin can bind to the peroxisomal proliferator activated receptor α (PPARα) to increase fat burning genes which also activates constitutive androstane receptor (CAR) that regulates bile acid secretion. Bile acids are catabolized by gut bacteria.