Structure of bile acids associated with secretion in the rat cecum.

An isolated in vivo rat cecal loop technique was utilized to determine what structure of bile acids is required to stimulate net colonic secretion of water and sodium. A dose response curve for water and sodium movement was determined for deoxycholic acid (1-6 mM) and chenodeoxycholic acid (3-6 mM). Both of these bile acids were associated with significant secretion of water and sodium at 4 mM concentration. Therefore, this concentration was used for all test bile acids studied. Test solutions included the tri- and di-substituted bile acids: cholic acid, hyocholic acid, 3 alpha, 7 beta, 12 alpha-trihydroxycholanic acid, 3 alpha, 12 alpha-dihydroxy-7-ketocholanic acid, ursodeoxycholic acid, 3 alpha-hydroxy-7-ketocholanic acid, 7 alpha, 12 alpha-dihydroxycholanic acid, and hyodeoxycholic acid. Only three bile acids, deoxycholic acid, chenodeoxycholic acid, and 7 alpha, 12 alpha-dihydroxycholanic acid were associated with net secretion of water and sodium. Cecal histology after incubation with bile acids revealed mucosal alterations in those sacs in which secretion occurred, but not where absorption was noted. These data indicate that bile acid-associated water and sodium secretion in the rat cecum requires a specific bile acid structure with a definite spatial relationship of the hydroxyl groups. Secretion occurred only with two alpha-hydroxyl groups in either the 3, 7, or 12 positions.

The role of altered intestinal permeability in the pathogenesis of salmonella diarrhea in the rhesus monkey.

The pathogenesis of Salmonella diarrhea is unclear. Bacterial invasion of the ileal and colonic mucosa resulting in an intense ileocolitis regularly occurs in concert with secretion of water and sodium in jejunum, ileum, and colon. To examine the role of altered permeability in Salmonella diarrhea we studied intestinal histology, water and electrolyte transport, clearance of intravenously injected [14C]erythritol and [3H]mannitol, and changes in transmural electrical potential difference in normal and Salmonella-infected rhesus monkeys. In normal animals, absorption of water and sodium occurred in jejunum, ileum, and colon and a gradient of diminishing permeability from jejunum to ileum to colon for both erythritol and mannitol was observed. Permeability as measured by determining permeability coefficients was not increased by Salmonella infection and in fact was significantly reduced for erythritol in the jejunum of infected animals. Perfusion with hypertonic erythritol and mannitol produced the same streaming potentials (deltaPD) in control and infected animals, indicating no differences in transmucosal permeability. As a positive control, perfusion with 25 mM ethylenediaminetetraacetic acid in normal animals increased permeability, resulting in increased plasma-to-lumen isotope flux and no deltaPD in response to hypertonic perfusates. These data show that despite severe alterations in intestinal histology, transmucosal permeability remains unchanged and thus is not a contributing factor in Salmonella diarrhea.

Fluid and electrolyte transport in rhesus monkeys challenged intracecally with Shigella flexneri 2a.

Shigella flexneri 2a is an invasive enteric pathogen that may produce diarrhea when ingested by human beings and subhuman primates. We have previously shown that shigella diarrhea correlates with water and electrolyte transport abnormalities in the jejunum and colon. Dysentery alone is associated only with colonic transport abnormalities. To define the relationship between invasion and inflammation of the colon and the occurrence of jejunal transport abnormalities, we studied water and electrolyte transport, histology, and bacteriology in rhesus monkeys that were infected by introducing S. flexneri 2a directly into the cecum. In contrast to the pattern of disease seen after oral administration, cecal inoculation resulted in clinical disease in 64% of animals, of which 94% manifested dysentery alone, rarely preceded by mild diarrhea. Histologically, invasion and inflammation was limited to the colon. Secretion of water and sodium occurred in the colon of infected monkeys when compared with controls, whereas transport was normal in the jejunum and ileum. These data further demonstrate that severe dysentery can result from cecal injection of shigellae, but also suggest that the occurrence of watery diarrhea requires and may result from an undefined interaction between the jejunal mucosa and the organisms during transit through the small intestine.

Abnormal intestinal bile acid distribution in azotaemic man: a possible role in the pathogenesis of uraemic diarrhoea.

Proximal intestinal bile acids have been studied in 14 ambulatory patients with varying degrees of azotaemia. When compared with normal subjects, the azotaemic patients showed a significant decrease in deoxycholic acid. Analysis of faecal bile acids of a patient with low intestinal deoxycholic acid also showed low deoxycholic acid with a preponderance of primary bile acids, and contrast with faecal bile acids of a normal subject and a patient with normal intestinal deoxycholic acid. It is suggested that impairment of deconjugation or 7alpha-dehydroxylation might be contributing to the low deoxycholic acid observed in azotaemic patients. Unusual bile acids: ursodeoxycholic acid, 3-hydroxy-7-keto-cholanic acid, and 3,12-dihydroxy-7-keto-cholanic acid were also noted in intestinal aspirates of azotaemic patients. The presence of these bile acids in conjunction with low deoxycholic acid correlates with the symptom of diarrhoea in azotaemic patients, and may contribute to the pathogenesis of diarrhoea in these patients.

Na+-K+-activated adenosine triphosphatase and intestinal electrolyte transport. Effect of adrenal steroids.

Sodium-potassium-activated adenosine triphosphatase (Na-K-ATPase) is associated with electrolyte transport in many tissues. To help delineate its role in intestinal transport, changes in rat intestinal electrolyte and water transport induced by injecting methylprednisolone acetate 3 mg/100 g or deoxycorticosterone acetate (DOCA) 0.5 mg/100 g per day for 3 days were correlated with changes in Na-K-ATPase activity. Methylprednisolone increased sodium and water absorption, potassium secretion, transmural potential difference, and Na-K-ATPase activity in the jejunum, ileum, and colon. Examination of isolated epithelial cells demonstrated that the jejunal and ileal increase in Na-K-ATPase occurred in both the villus tip and crypermeability, Mg-ATPase, and adenylate cyclase activities were unchanged by methylprednisolone. DOCA increased sodium and water absorption, potassium secretion, transmural potential difference, and Na-K-ATPase activity in the colon alone. Colonic Mg-ATPase and adenylate cyclase activities were unaffected. Jejunal and ileal enzyme activity, electrolyte transport, and permeability were unchanged by DOCA. Methylprednisolone and DOCA were not additive in their effect on colonic Na-K-ATPase activity. Methylprednisolone and DOCA increased electrolyte and water transport and Na-K-ATPase activity concomitantly in specific segments of small intestine and colon. These data are consistent with an important role for Na-K-ATPase in intestinal electrolyte and water transport.