Lactulose has been proposed to be beneficial in treating inflammatory bowel disease (IBD). The hypothesis is based on the prebiotic potential of lactulose. A practical approach to testing its usefulness is to determine colonic adaptation to tolerable doses in patients with IBD. Our objective was to determine if a 3-week course of lactulose will decrease BH2 and symptoms in response to an acute lactulose challenge test in control subjects and IBD patients. The design was a prospective cohort study. Subjects were given a 30-g lactulose challenge test (test 1), and then ingested 10 g of lactulose twice a day for 3 weeks before being retested (Test 2). A third test was given after a further 5-week washout period. The main outcomes were the change in 4-hr sum of BH2 (sum(4HrBH2)) values obtained every 30 min, peak BH2, and 4-hr sum of symptom score (sum(4HrSS)) during the lactulose challenge test. In addition, we also report the change in self-reported symptoms and diarrhea during the 3-week administration of lactulose. In controls, sum(4HrBH2) decreased from test 1 (380.5 +/- 56.6 ppm) to test 2 (288.6 +/- 57.4 ppm) (P < 0.05), and returned toward test 1 levels by test 3 (307.5 +/- 53.1, P > 0.5). Unlike controls, the sum(4HrBH2) in patients failed to achieve significance between test 1 (444.5 +/- 55.8 ppm), test 2 (366.5 +/- 80.7 ppm, P > 0.2) or test 3 (411.6 +/- 62.5 ppm, P > 0.2). Sum(4HrSS) results in controls followed a pattern similar to sum(4HrBH2), achieving significance only in test 2 (P < 0.02). Symptoms during the intertest periods decreased by the third week in controls (P < 0.05), but not in patients (P > 0.5). Symptoms were lower in patients and varied insignificantly both in challenges and intertest periods. In conclusion, although controls adapt to a 3-week period of lactulose ingestion, IBD patients fail to meet the criteria for adaptation. However, longer studies may be needed to establish whether IBD patients are slower to adapt.