Intervention and Mechanisms of Alanyl-glutamine for Inflammation, Nutrition, and Enteropathy: A Randomized Controlled Trial

Abstract

Objective: Determine the minimum dosage of alanyl-glutamine (Ala-Gln) required to improve gut integrity and growth in children at risk of environmental enteropathy (EE).

Methods: This was a double-blinded randomized placebo-controlled dose-response trial. We enrolled 140 children residing in a low-income community in Fortaleza, Brazil. Participants were 2 to 60 months old and had weight-for-age (WAZ), height-for-age (HAZ), or weight-for-height (WHZ) z-scores less than -1. We randomized children to 10 days of nutritional supplementation: Ala-Gln at 3 g/day, Ala-Gln at 6 g/day, Ala-Gln at 12 g/day, or an isonitrogenous dose of glycine (Gly) placebo at 12.5 g/day. Our primary outcome was urinary lactulose-mannitol excretion testing. Secondary outcomes were anthropometry, fecal markers of inflammation, urine metabolic profiles, and malabsorption (spot fecal energy).

Results: Of 140 children, 103 completed 120 days of follow-up (24% dropout). In the group receiving the highest dose of Ala-Gln, we detected a modest improvement in urinary lactulose excretion from 0.19% on day 1 to 0.17% on day 10 (P = 0.05). We observed significant but transient improvements in WHZ at day 10 in 2 Ala-Gln groups, and in WHZ and WAZ in all Ala-Gln groups at day 30. We detected no effects on fecal inflammatory markers, diarrheal morbidity, or urine metabolic profiles; but did observe modest reductions in fecal energy and fecal lactoferrin in participants receiving Ala-Gln.

Conclusions: Intermediate dose Ala-Gln promotes short-term improvement in gut integrity and ponderal growth in children at risk of EE. Lower doses produced improvements in ponderal growth in the absence of enhanced gut integrity.

Trial registration: ClinicalTrials.gov NCT01832636.

FIGURE 1.

Flow diagram of study population and protocol. *The dosage of Gly placebo was isonitrogenous to the Ala-Gln 12 g/day group. †Markers of fecal inflammation: lactoferrin, myeloperoxidase, neopterin, Reg-1β, and fecal IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFN-γ, TNF-α. ‡Markers of intestinal permeability: fecal alpha-1-antitrypsin. Ala-Gln = alanyl-glutamine.

FIGURE 2.

Intermediate dose Ala-Gln (12 g/day) supplementation improves percent lactulose excretion, WHZ, and WAZ in children at risk of environmental enteropathy. (A) Percent lactulose excretion in children treated with Ala-Gln 12 g/day, solid lines represent medians. (B) Effect of Ala-Gln on cumulative WHZ between days 1 and 10, (C) effect of Ala-Gln on cumulative WHZ between days 1 and 30, (D) effect of Ala-Gln on cumulative WAZ between days 1 and 30. In (B), (C), and (D), violin plots depict data distribution and density, solid lines represent means. Ala-Gln = alanyl-glutamine.