Mechanism by which bile salt disrupts the gastric mucosal barrier in the dog.

Abstract

A B S T R A C T Bile salts disrupt a functional "gastric mucosal barrier" increasing net forward-diffusion (+) of Na+ and back-diffusion (-) of H+. Studying canine Heidenhain pouches, we attempted to distinguish between two possible mechanisms for this effect: (a) mucosal uptake ofbile salt with subsequent cellular injury or (b ) dissolution ofmucosal lipids by intralumenal bile salt. A 10 mM mixture of six conjugated bile salts simulating the proportions found in human bile induced net Na+ flux of 15.5+3.2 and net H+ flux of -9.9±3.3 ,ueq/min. This change was accompanied by an increase in phospholipid efflux out ofgastric mucosa from a base-line value of 13.2+2.7 to 54.8+2.8 nmol/min (P < 0.001) and an increase in cholesterol efflux from 11.7+3.8 to 36.3+3.2 nmol/min (P< 0.001). Saturation with lecithin (25 mM) and cholesterol (50 mM) blocked disruption of the gastric mucosal barrier by bile salt (Na+ flux -1.2+±0.9, H+ flux 0.6±1.8 ,ueq/min). A 10 mM solution of taurodehydrocholate, a bile salt that does not form micelles, induced no net Na+ (-0.3 +0.8) or H+ flux (-0.7+1.4) and did not increase efflux of phospholipid (11.3+1.7) or cholesterol (10.4+2.0) over base line. Bile salt was absorbed from the mixture of six conjugates at 752±+85 nmol/min. Addition of subsaturation amounts of lecithin (4 mM) reduced bile salt absorption threefold to 252±+57 (P < 0.001), but abnormal Na+ flux (14.1+3.4) and H+ flux (-15.6±3.5) persisted. Taurodehydrocholate was absorbed to an intermediate extent (467 + 116). Dissolution ofmucosal lipids is apparently the mechanism by which bile salt disrupts the gastric mucosal barrier, and presumably at least one mechanism by which bile salt can injure the gastric mucosa.

Lecithin Protects against Plasma Membrane Disruption by Bile Salts

“…Heuman [26] noted that the extraction of alkaline phosphatase from isolated canalicular membranes by hydrophobic bile salts was attenuated by addition of lecithin vesicles. Duane and Wiegand demonstrated that the damaging effect of bile salts on the permeability of gastric epithelium was attenuated by inclusion of lecithin [27]. The protective effect of lecithin was also suggested in the studies of Sagawa and associates [28] employing erythrocytes.…”

“…Bile salts have been shown to be injurious to gastric and esophageal epithelium [27,36]. Recent studies have demonstrated that gastric epithelium contains cells that secrete lecithin into the gastric lumen providing a protective hydrophobic barrier to ionic diffusion [37].…”

Detergent Properties Do Not Fully Explain the Barrier Disruption Induced by Bile Salts

“…In 1980, Duane and Wiegand [12] proposed a simple unifying concept to explain this mechanism. They suggested that bile acids dissolve cholesterol and other lipids from the cell membranes of the gastrointestinal mucosa by their detergent action.…”

“…We studied bile salts at neutral pH 7.4, where they have been shown to act by dissolving membrane cholesterol [12]. We compared deoxycholate to detergents from each of the four major categories: nonionic, anionic, zwitterionic, and cationic.…”

Alkaline Reflux Gastritis after Partial Gastrectomy: Evidence for a Pathogenetic Role of Deoxycholic Acid

“…Experimentally some bile acids seem to exert damaging effects on the gastric mucosa more than others [2][3][4], probably because of their different detergent properties. In fact it has been shown that micellar bile acids release phospholipids and cholesterol from the gastric mucosa [5]. Several studies correlated symptoms of postoperative reflux gastritis with the amount of reflux and the concentration of bile acids [6][7][8], whereas controversial results have been re ported for the occurrence of gastritis [6][7][8][9].…”