EB 2017 Article: Interpretation of the lactulose:mannitol test in rural Malawian children at risk for perturbations in intestinal permeability

Abstract

The dual sugar absorption test, specifically the lactulose:mannitol test, is used to assess gut health. Lactulose absorption is said to represent gut damage and mannitol absorption is used as a measure of normal small bowel function and serves as normalizing factor for lactulose. A underappreciated limitation of this common understanding of the lactulose:mannitol test is that mannitol is not absorbed to any substantial extent by a transcellular process. Additionally, this interpretation of lactulose:mannitol is not consistent with current understanding of paracellular pathways, where three pathway types exist: pore, leak, and unrestricted. Pore and leak pathways are regulated biological constructions of the small bowel barrier, and unrestricted pathways represent micropathological damage. We analyzed 2334 lactulose:mannitol measurements rigorously collected from 622 young rural Malawian children at high risk for poor gut health in light of the pathway model. An alternative method of normalizing for gut length utilizing autopsy data is described. In our population, absorbed lactulose and mannitol are strongly correlated, r = 0.68 P <0.0001, suggesting lactulose and mannitol are traversing the gut barrier via the same pathways. Considering measurements where pore pathways predominate, mannitol flux is about 14 times that of lactulose. As more leak pathways are present, this differential flux mannitol:lactulose falls to 8:1 and when increased numbers of unrestricted pathways are present, the differential flux of mannitol:lactulose is 6:1. There was no substantial correlation between the lactulose:mannitol and linear growth. Given that mannitol will always pass through a given pathway at a rate at least equal to that of lactulose, and lactulose absorption is a composite measure of flux through both physiologic and pathologic pathways, we question the utility of the lactulose:mannitol test. We suggest using lactulose alone is as informative as lactulose:mannitol in a sugar absorption testing in subclinical gut inflammation. Impact statement Our work integrates the standard interpretation of the lactulose:mannitol test (L:M), with mechanistic insight of intestinal permeability. There are three paracellular pathways in the gut epithelium; pore, leak, and unrestricted. Using thousands of L:M measurements from rural Malawian children at risk for increased intestinal permeability, we predict the differential flux of L and M through the pathways. Our findings challenge the traditional notions that little L is absorbed through a normal epithelial barrier and that M is a normalizing factor for L. Our observations are consistent with pore pathways allowing only M to pass. And that substantial amounts of L and M pass through leak pathways which are normal, regulated, cell-junctional adaptations. So M is a composite measure of all pathways, and L is not a measure solely of pathologic gut damage. Using L alone as a probe will yield more information about gut health than L:M.

Keywords: Environmental enteric dysfunction; dual sugar absorption test; gut health; lactulose:mannitol test; paracellular permeability.

Figure 1.

Model of the three different epithelial permeability pathways. With respect to the dual sugar absorption test, k1, k2 and k3 are the rate constants by which mannitol (M) passes through pore, leak and unrestricted pathways, respectively, and k4 and k5 are the rate constants by which lactulose (L) passes through leak and unrestricted pathways, respectively.

Figure 2.

Lactulose and mannitol excretion in rural Malawian children at risk for environmental enteric dysfunction. The units of lactulose and mannitol are % of oral dose that was excreted by weight. The solid line indicates the best fit line and the dotted lines the 95% CI of the line. A strong positive correlation exists between absorption of the mono- and disaccharide, Pearson’s r = 0.58, P < 0.0001 and Spearman’s r = 0.68 P < 0.0001.

Figure 3.

Lactulose and mannitol excretion in rural Malawian children at risk for environmental enteric dysfunction. The data are expressed as a histogram and the units of lactulose and mannitol are µmoles. The plot was divided visually into four sections: A: where L and M increase at a constant rate and are present in low quantities, B: where L increases by 50% and M is unchanged, C: where L increases by 150% and M changes by 40%, D: where L increases by 15% and M is at least 15% greater than sections A, B or C.