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.

Intestinal Permeability in Children with Celiac Disease after the Administration of Oligofructose-Enriched Inulin into a Gluten-Free Diet—Results of a Randomized, Placebo-Controlled, Pilot Trial

“…The authors explained that on top of each villus, there are small but abundant channels allowing for the transfer of M, while in crypts, there are much bigger channels in low abundance, which allows for transport of L. It suggests that more M than L will be absorbed in a healthy gut; therefore, M excretion is used for normalization of L excretion, and an inverse relationship between the absorption of these two sugars is expected [ 46 ]. However, in our study, a moderate positive correlation between the excretion of L and M was observed (r = 0.594, p -value = 0.001), very close to correlation observed by Ordiz et al [ 46 ] in a rural population of children in Malawi. The authors challenged the interpretation of SAT, and considering M as a normalization parameter, suggesting that, if there is a leak in the intestinal barrier, then both sugars will be absorbed to a higher extent.…”

Co-occurrence of Campylobacter Species in Children From Eastern Ethiopia, and Their Association With Environmental Enteric Dysfunction, Diarrhea, and Host Microbiome

“…The lactulose absorption (L%) was measured via sugar absorption test, as previously described (24), and was used as a maker to assess the gut permeability of the children. Classification of EED severity was performed as previously described (25). The child was considered "normal" if the L% was lower than 0.2; "moderate" if the L% was between 0.2 and 0.45, and "severe" if the L% was above 0.45.…”

“…To determine the role of Campylobacter in EED, the levels of lactulose and MPO were measured as indicators of EED (24,25). Additional details concerning the prevalence of EED and stunting among children in this study are described in Chen et al (under review).…”

Transcutaneous fluorescence spectroscopy as a tool for non-invasive monitoring of gut function: first clinical experiences

“…Interestingly, measurement of the fluorescence AUC value is analogous to measurement of total lactulose recovery in urine, which is often used in L:M tests to provide a quantification of permeability 19 . Importantly, however, total recovery of lactulose in urine (or any other urinary marker) is affected by the time at which urine is collected (as longer collection times will naturally lead to more of the marker accumulating in urine) and factors such as gastric emptying rate and absorption rate.…”