The pathophysiologic mechanism(s) responsible for cobalamin deficiency after Roux-en-Y gastric bypass for clinically severe obesity remains unexplained. Inadequate secretion of intrinsic factor has been postulated, but decreased gastric acid secretion resulting in maldigestion and inadequate liberation of free cobalamin from its native protein-bound form is also possible. The aim of this study was to determine prospectively secretion of gastric acid and absorption of crystalline (free) and protein-bound cobalamin before and after gastric bypass. Eight patients (two men, six women) underwent orogastric intubation of the intact stomach preoperatively and the proximal gastric pouch postoperatively. Gastric acid secretion in the basal and stimulated (pentagastrin, 6 micrograms/kg) states was determined by a perfused, nonabsorbable marker technique to quantitate recovery of gastric secretion. Absorption of radiolabeled (57Co) crystalline and protein-bound cobalamin was assessed on separate days by 24-hr urinary excretion. After gastric bypass, acid secretion (mean +/- SEM) was markedly reduced in basal (9.1 +/- 3.6 vs 0.005 +/- 0.003 meq/hr; P = 0.04) and stimulated (12.8 +/- 1.8 vs 0.008 +/- 0.003 meq/30 min; P = 0.002) states. Absorption of crystalline cobalamin was decreased (15.8 +/- 2.5 vs 9.4 +/- 1.4%; P = 0.08) to a lesser extent than was protein-bound cobalamin (5.9 +/- 1.0 vs 1.1 +/- 0.3%; P = 0.004). In summary, gastric acid secretion from the gastric pouch is negligible after gastric bypass, and food-bound cobalamin is maldigested and subsequently malabsorbed presumably due to pouch achlorhydria. Decreased absorption of free cobalamin suggests decreased cobalamin-intrinsic factor complex formation.(ABSTRACT TRUNCATED AT 250 WORDS)