Bile Acid Accumulation in Gastric Mucosal Cells

Abstract

Bile acids are one of the components of the gastric contents capable of disrupting the mucosal barrier to diffusion. The mechanism by which bile acids can damage the gastric epithelium is not completely understood. Several studies have emphasized mucosal lipid solubilization by bile acids in the pathogenesis of mucosal injury. Bile acid entry into gastric mucosal cells may be a critical and early step in the genesis of mucosal injury, but this possibility has not yet been investigated. The present study was designed to explore the interaction of bile acids with dispersed gastric mucosal cells isolated from the rabbit and guinea pig stomach. Results showed that both glycocholic and deoxycholic acid rapidly associated with the gastric cells and reached a steady state concentration by 30 min. Glycocholic acid accumulated in the cells to a concentration approximately eight times greater than that in the surrounding medium. The amount of bile acid associated with the cells was greater at an acidic than at a neutral pH, and was a function of the concentration of both the cells and the bile acid. The process did not require cellular energy, was nonsaturable, and was not species specific. Experiments with 86Rb, a cytoplasmic marker, revealed that approximately one half of the cellular glycocholic acid was associated with the cytoplasmic compartment and the rest with the membranes. These findings are consistent with a combination of intracellular entrapment of the bile acids due to intracellular ionization and bile acid binding to cellular membrane components being the mechanisms by which bile acids accumulate in cells. Acid-driven bile acid accumulation may explain how relatively low luminal concentrations of bile acid can be damaging to the gastrointestinal mucosa.

Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins

“…These data are consistent in part with a previous report using esophageal mucosal sheets of rabbits (6) and indicate that only acidic TCA and GCA can damage the barrier function. In low pH conditions, conjugated bile acids enter the mucosal cells in a nonionized form, which tends to diffuse through the mucosa more efficiently than the ionized form (4,23). These refluxed bile acids can cause intracellular damage by the dissolution of cell membranes and TJs (23,30).…”

A biliary HCO3−umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

“…pH dependency of carrier-independent cell entry and toxicity of bile acids has been established in gastric and esophageal mucosa cells. [12][13][14] Cholangiocyte apoptosis has been shown to drive autoimmunity and inflammation in primary biliary cirrhosis (PBC). 15,16 By altering sensitivity toward bile salt toxicity and increasing frequency of apoptotic events in cholangiocytes, genetic and acquired defects disrupting the biliary HCO À 3 umbrella may be a common pathogenetic factor in various cholangiopathies.…”

Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid- Induced Injury in Man

“…1–2) [15], changes in biliary pH would have a minor, negligible effect on bile salt protonation and toxicity. pH dependency of cell penetration and toxicity by bile salts has been established in gastric and esophageal mucosa cells [16,17,18]. It was the aim of the present study to test the concept of pH dependency of bile salt-induced toxicity in human cholangiocytes and to explore the role of AE2 expression in the protection against hydrophobic bile salt-induced cholangiotoxicity.…”