Studying 16 children (9 mos. to 3 yrs.), with protracted diarrhea and malnutrition, we found that unconjugated bile salts (UBS), were not clearly elevated in the jejunal luminal contents, whereas UBS in their serum was high (DC 14.7±8.3 uM), and not detectable in sera of healthy controls. We, therefore, studied the effects of DC in the circulation on the jejunal mucosal handling of water, sodium, glucose, and glycine. We perfused in situ the lumen of a 30 cm segment of proximal jejunum in dogs, using phenol red as a non-absorbable marker. The supplying mesenteric arterial branch was infused with DC solutions in normal saline, calculated to reach tissue level at successive concentrations of 0, 7.5, 15, 30, and 60 uM. For each concentration of DC infused a 30-minute equilibration period was allowed and, thereafter, four 15-minute aliquots of effluent perfusate were collected. Results: The addition of DC to the arterial supply of the jejunal segment was associated with a significant decrease in the absorption rates of water, sodium, glucose, and glycine; the magnitude of this effect correlated with the concentrations of DC employed. Mucosal activity of Na+ -K+ -ATPase was practically abolished by infusion of DC at 30 uM. No structural abnormalities of the mucosa were seen on light microscopy. Our experiments indicate that UBS (e.g. DC), in the circulation are detrimental to small intestinal mucosal function, and may, thus, contribute to the perpetuation of diarrheal disease.