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Background: Environmental enteric dysfunction (EED) causes malnutrition in children in low-resource settings. Stable isotope breath tests have been proposed as non-invasive tests of altered nutrient metabolism and absorption in EED, but uncertainty over interpreting the breath curves has limited their use. The activity of sucrase-isomaltase, the glucosidase enzyme responsible for sucrose hydrolysis, may be reduced in EED. We previously developed a mechanistic model describing the dynamics of the 13C-sucrose breath test (13C-SBT) as a function of underlying metabolic processes. Objective: 1) To determine which breath test curve dynamics are associated with sucrose hydrolysis and with the transport and metabolism of the fructose and glucose moieties, and 2) to propose and evaluate a model-based diagnostic for the loss of activity of sucrase-isomaltase. Methods: We applied the mechanistic model to two sets of exploratory 13C-SBT experiments in healthy adult participants. First, 19 participants received differently labeled sucrose tracers (U-13C fructose, U-13C glucose, and U-13C sucrose) in a cross-over study. Second, 16 participants received a sucrose tracer accompanied by 0 mg, 100 mg, and 750 mg of Reducose®, a sucrase-isomaltase inhibitor. We evaluated a model-based diagnostic distinguishing between inhibitor concentrations using receiver operator curves, comparing to conventional statistics. Results: Sucrose hydrolysis and the transport and metabolism of the fructose and glucose moieties were reflected in the same mechanistic process. The model distinguishes these processes from the fraction of tracer exhaled and an exponential metabolic process. The model-based diagnostic performed as well as the conventional summary statistics in distinguishing between no and low inhibition (AUC 0.77 vs 0.66–0.79) and for low vs high inhibition (AUC 0.92 vs 0.91–0.99). Conclusions: Current summary approaches to interpreting 13C breath test curves may be limited to identifying only gross gut dysfunction. A mechanistic model-based approach improved interpretation of breath test curves characterizing sucrose metabolism.