The influence of lactulose on organic acid fermentation, nitrogen metabolism and excretion in the colon associated with its mechanism of action on hepatic encephalopathy was investigated. Orally administered lactulose in increasing amounts (0 to 20 to 40 to 80 to 160 gm/day) to 12 healthy volunteers decreased ammonia production in 16.6% fecal homogenates incubated 6 hr and 24 hr at 37 degrees C (mean +/- S.E.M.: from 7 +/- 1 to 0 +/- 0 and from 13 +/- 2 to 0 +/- 0 mmol/L, respectively). Every dose of lactulose was given for 3 days with intervals of 1 to 2 wk, and 24-hr stools were collected on day 3. Fecal concentrations of ammonia decreased (from 50 +/- 9 to 11 +/- 3 mmol/L), but ammonia excretions increased (from 6 +/- 2 to 17 +/- 4 mmol/24 hr). Total fecal concentrations of nitrogen decreased (from 1,043 +/- 78 to 300 +/- 136 mmol/L), but excretions of nitrogen increased fourfold (from 111 +/- 21 to 457 +/- 113 mmoL/24 hr) because of the increase in stool mass. Fecal pH declined (from 6.9 +/- 0.1 to 4.9 +/- 0.1), but total organic acids (short-chain fatty acids and DL-lactate; range = 105 to 148 mmol/L) and osmolality in feces (417 to 450 mOsm/L) did not change, although the colonic fermentation of lactulose had a major impact on the proportions between the nontoxic acetate (increased from 65% +/- 2% to 89% +/- 3%) and the potentially neurotoxic 3-6-carbon fatty acids (decreased from 35% +/- 2% to 11% +/- 2%).(ABSTRACT TRUNCATED AT 250 WORDS)