Standardising the lactulose mannitol test of gut permeability to minimise error and promote comparability

Abstract

Background: Lactulose mannitol ratio tests are clinically useful for assessing disorders characterised by changes in gut permeability and for assessing mixing in the intestinal lumen. Variations between currently used test protocols preclude meaningful comparisons between studies. We determined the optimal sampling period and related this to intestinal residence.

Methods: Half-hourly lactulose and mannitol urinary excretions were determined over 6 hours in 40 healthy female volunteers after administration of either 600 mg aspirin or placebo, in randomised order at weekly intervals. Gastric and small intestinal transit times were assessed by the SmartPill in 6 subjects from the same population. Half-hourly percentage recoveries of lactulose and mannitol were grouped on a basis of compartment transit time. The rate of increase or decrease of each sugar within each group was explored by simple linear regression to assess the optimal period of sampling.

Key results: The between subject standard errors for each half-hourly lactulose and mannitol excretion were lowest, the correlation of the quantity of each sugar excreted with time was optimal and the difference between the two sugars in this temporal relationship maximal during the period from 2½-4 h after ingestion. Half-hourly lactulose excretions were generally increased after dosage with aspirin whilst those of mannitol were unchanged as was the temporal pattern and period of lowest between subject standard error for both sugars.

Conclusion: The results indicate that between subject variation in the percentage excretion of the two sugars would be minimised and the differences in the temporal patterns of excretion would be maximised if the period of collection of urine used in clinical tests of small intestinal permeability were restricted to 2½-4 h post dosage. This period corresponds to a period when the column of digesta column containing the probes is passing from the small to the large intestine.

Figure 1. Half-hourly percentage urinary recovery of ingested dose of mannitol (A&B) and lactulose (C&D) in 40 healthy female volunteers following dosage with placebo (A&C) or aspirin (B&D).

*The classification of the data into periods (I, 0–2 h, corresponding to the passage of probes from the stomach to the SI; II, 2½-4 h, corresponding to passage from the SI to the colon; III, 4½-6 h, corresponding to the passage from the proximal to distal colon) was based on the early peak in mean % recovery of mannitol and on the later peak in mean % recovery of lactulose viewed in conjunction with the data from SmartPill (see text). Arrows on X axis indicate the time of passage of the SmartPill into subsequent segments of the gut. Dots indicate the mean ±SE of the % half hourly recoveries of the sugars. Horizontal bars indicate the temporal range of the peak in % recovery of each of the sugars between subjects.

Figure 2. Simple linear regressions of pooled half-hourly percentage urinary recoveries of mannitol and lactulose against time, during period II and period III after dosage with placebo or aspirin, in forty healthy female volunteers.

Vertical bars are standard errors.

Figure 3. Comparison of calculated 5 h cumulative recoveries of mannitol (A) and lactulose (B) in forty healthy female volunteers following dosage with placebo (a) or 600 mg aspirin (b) with those reported for subjects with pro-inflammatory conditions i.e. coeliac disease (c , d [42]) and Crohn’s disease(e [41]).

Figure 4. Comparison of temporal patterns of half-hourly urinary mannitol (mg) excretion from 40 healthy female volunteers with calculated half-hourly glucose absorbed (mg/½h) based on published blood sugar values of women with non-insulin dependent diabetes (NIDDN, n = 12) and those with normal glucose tolerance (NGT; n = 67) .