Enterohepatic cycle disturbances in surgical patients

Division 2: Liver and Digestive Health
Department of Surgery

Background

What are the consequences of disturbances in the enterohepatic circulation?

Bile salts are the prototypical signaling molecules involved in bidirectional communication in the gut-liver axis. Synthesized in the liver, bile salts are secreted in the biliary network for eventual release in the proximal small intestine to aid in digestion and absorption of dietary lipids. Active reclamation of the bulk of bile salts in the terminal ileum along with passive re-uptake of bile salts spilling over into the colon, allow near-complete conservation and return of bile salts to the liver via the portal blood for re-secretion into bile. During their enterohepatic cycle (EHC), bile salts activate dedicated plasma membrane (e.g. TGR5) and nuclear bile salt receptors (e.g. FXR) in the small intestine and liver. Attendant signaling actions are pivotal for maintaining metabolic homeostasis, liver tissue homeostasis, gut barrier integrity and inflammatory control in the intestine and liver (Figures 1 and 2). 

Bile acids (exemplified as the primary bile acid CDCA) are produced in the liver by CYP7A1-initiated conversion of cholesterol in primary bile acids. Bile salts are secreted via BSEP into the canalicular lumen. In the ileum, bile salts are reabsorbed via ASBT in terminal ileum enterocytes. Here, they bind and activate FXR and this stimulates the transcription of FGF19, which encodes a protein that is secreted into the portal circulation.  In the liver, FGF19 binds to its receptor FGFR4, which activates a signalling pathway involving MAP kinases and causes repression of CYP7A1, thus downregulating bile acid synthesis. After OSTa/13- mediated secretion into the portal circulation, bile acids are taken up by the liver via NTCP, thus, completing the enterohepatic cycle. In the liver, bile acids bind to FXR, which transcriptionally upregulates a protein called SHP (not shown) that interferes with expression of CYP7A1. Oral FXR agonists will affect FXR in both liver and intestine and this strongly downregulates CYP7A1 both by FGF19-dependent and FGF19-independent effects. FGF19 additionally affects lipogenesis, gluconeogenesis and liver regeneration. Abbreviations: ASBT, apical sodium-dependent bile salt transporter; BSEP, bile salt export pump; CDCA, chenodeoxycholic acid; CYP7A1, cholesterol 7-a-monooxygenase; FGF19, fibroblast growth factor 19; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X receptor; NTCP Nattaurocholate cotransporting polypeptide; OST, organic solute transporter; SHP, small heterodimer partner. 

TGR5 signalling in skeletal muscle and brown adipose tissue results in local activation of the deiodinase D102 that generates active thyroid hormone (13), an important regulator of metabolism and energy homeostasis. Bile acids in the intestinal lumen activate TGR5 in enteroendocrine cells, resulting in release of the incretin GLP-1. In Kupffer cells and macrophages, TGR5 activation inhibits LPS-induced cytokine production. Abbreviations: D102, type II iodothyronine deiodinase; GLP-1, glucagon-like peptide 1; LPS, lipopolysaccharide; 13, active thyroid hormone; 14, inactive thyroxine; TGR5, transmembrane G protein-coupled receptor TGR5 (also known as GPBAR1). 

Disturbances in the EHC result in a loss of these signaling actions, as well as loss of physicochemical actions of bile salts. Consequences of perturbed EHC thus include fat malabsorption and deficiency of fat-soluble vitamins, small intestinal bacterial overgrowth whether or not accompanied by (portal) endotoxemia and hepatic bile salt accumulation and attendant cellular damage and inflammatory sequela. Dysregulated bile salt homeostasis/bile salt toxicity is considered an important etiological factor in liver disease in patients with EHC disturbances. Likewise,  it is linked to impaired liver regeneration and post-operative complications in (post)cholestatic patients with hepatobiliary tumors. 

What are causes of abrogated enterohepatic circulation?

Clinical scenarios giving rise to defective EHC include obstruction caused by compression of the bile ducts by a tumor mass inside (e.g. perihilar cholangiocarcinoma) or outside (e.g. head of pancreas carcinoma) the liver. This results in impaired flow of bile (i.e. cholestasis) towards the duodenum, hepatic retention and accumulation of bile salts and intestinal bile salt deficiency. In surgical patients with a proximal enterostomy or enterocutaneous fistula, bile and other digestive fluids are lost via the stomal or fistula output. This lack of intestinal continuity can give rise to intestinal failure-associated liver disease. This syndrome also occurs as a consequence of intestinal failure caused by massive resection of intestine resulting from a surgical emergencies. In patients with critical illness, gallbladder dysfunction is a common feature, with impaired expulsion of bile resulting in EHC perturbation. Likewise, patients receiving (total) parenteral nutrition lack the enteral stimuli that induce gallbladder contraction and enterohepatic bile salt cycling. 

Chyme reinfusion restores the regulatory bile salt-FGF19 axis in intestinal failure patients.

Automated chyme reinfusion (CR) in intestinal failure patients with a temporary double enterostomy restores intestinal function and protects against liver injury. CR evoked an increase in plasma FGF19 and decreased C4 levels, indicating restored regulation of bile salt synthesis via endocrine FGF19 action (Figure 6, below). Furthermore, citrulline and albumin levels were gradually rising after CR, while abnormal serum liver tests normalized after CR, indicating restored intestinal function, improved nutritional status and amelioration of liver injury. Beneficial effects of chyme reinfusion are partly mediated by recovery of the bile salt-FGF19 axis and subsequent homeostatic regulation of bile salt synthesis.