Urine sugars for in vivo gut permeability: validation and comparisons in irritable bowel syndrome-diarrhea and controls

Abstract

Mucosal barrier dysfunction contributes to gastrointestinal diseases. Our aims were to validate urine sugar excretion as an in vivo test of small bowel (SB) and colonic permeability and to compare permeability in patients with irritable bowel syndrome-diarrhea (IBS-D) to positive and negative controls. Oral lactulose (L) and mannitol (M) were administered with (99m)Tc-oral solution, (111)In-oral delayed-release capsule, or directly into the ascending colon (only in healthy controls). We compared L and M excretion in urine collections at specific times in 12 patients with IBS-D, 12 healthy controls, and 10 patients with inactive or treated ulcerative or microscopic colitis (UC/MC). Sugars were measured by high-performance liquid chromatography-tandem mass spectrometry. Primary endpoints were cumulative 0-2-h, 2-8-h, and 8-24-h urinary sugars. Radioisotopes in the colon at 2 h and 8 h were measured by scintigraphy. Kruskal-Wallis and Wilcoxon tests were used to assess the overall and pairwise associations, respectively, between group and urinary sugars. The liquid in the colon at 2 h and 8 h was as follows: health, 62 ± 9% and 89 ± 3%; IBS-D, 56 ± 11% and 90 ± 3%; and UC/MC, 35 ± 8% and 78 ± 6%, respectively. Liquid formulation was associated with higher M excretion compared with capsule formulation at 0-2 h (health P = 0.049; IBS-D P < 0.001) but not during 8-24 h. UC/MC was associated with increased urine L and M excretion compared with health (but not to IBS-D) at 8-24 h, not at 0-2 h. There were significant differences between IBS-D and health in urine M excretion at 0-2 h and 2-8 h and L excretion at 8-24 h. Urine sugars at 0-2 h and 8-24 h reflect SB and colonic permeability, respectively. IBS-D is associated with increased SB and colonic mucosal permeability.

Fig. 1.

Bland-Altman plots evaluating the differences in excretion for 0–60 min and time before the arrival of >25% isotope in the colon (T_CF25%) across different mean sugar excretion rates (A). Note that the difference is similar across different mean excretion rates and that a similar pattern of the differences is observed with the 0–90-min (B) and 0–120-min (C) collections. Also note that the size of the differences appears smaller with 0–120-min than for the 0–90-min collections.

Fig. 2.

0–2-h urinary saccharide excretion (mg) and lactulose:mannitol (L:M) ratio after administration of sugars in liquid and capsule formulations. Note there was a 5:1 intake of lactulose to mannitol. Values shown are means (± SE).

Fig. 3.

0–8-h (intracolonic formulation) and 2–8-h (liquid and capsule formulations) urinary saccharide excretion (mg) and L:M ratio after administration of sugars. Note there was a 5:1 intake of lactulose to mannitol. Values shown are means (± SE).

Fig. 4.

8–24-h urinary saccharide excretion (mg) and L:M ratio with liquid and capsule formulations. Note there was a 5:1 intake of lactulose to mannitol. Values shown are means (± SE).

Fig. 5.

Cumulative excretion (mg) and L:M ratio for liquid formulation saccharides in health, irritable bowel syndrome with diarrhea (IBS-D), and ulcerative/microscopic colitis. Values shown are means (± SE).

Fig. 6.

Cumulative excretion (mg) and L:M ratio for capsule formulation saccharides in health, IBS-D, and ulcerative/microscopic colitis. Values shown are means (± SE).