Age and Sex Normalization of Intestinal Permeability Measures for the Improved Assessment of Enteropathy in Infancy and Early Childhood: Results from the MAL-ED Study

Margaret N. Kosek*, Gwenyth O. Lee, Richard L. Guerrant, Rashidul Haque, Gagandeep Kang, Tahmeed Ahmed, Pascal Bessong, Asad Ali, Estomih Mduma, Pablo Peñataro Yori, William A. Faubion, Aldo A.M. Lima, Maribel Paredes Olortegui, Carl Mason, Sudhir Babji, Ravinder Singh, Shahida Qureshi, Peter S. Kosek, Amidou Samie, John PascalSanjaya Shrestha, Benjamin J.J. McCormick, Jessica C. Seidman, Dennis R. Lang, Anita Zaidi, Laura E. Caulfield, Michael Gottlieb

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)


Objectives: The aim of the study was to describe changes in intestinal permeability in early childhood in diverse epidemiologic settings. Methods: In a birth cohort study, the lactulose:mannitol (L:M) test was administered to 1980 children at 4 time points in the first 24 months of life in 8 countries. Data from the Brazil site with an incidence of diarrhea similar to that seen in the United States and no growth faltering was used as an internal study reference to derive age- and sex-specific z scores for mannitol and lactulose recoveries and the L:M ratio. Results: A total of 6602 tests demonstrated mannitol recovery, lactulose recovery, and the L:M ratio were associated with country, sex, and age. There was heterogeneity in the recovery of both probes between sites with mean mannitol recovery ranging for 1.34% to 5.88%, lactulose recovery of 0.19% to 0.58%, and L:M ratios 0.10 to 0.17 in boys of 3 months of age across different sites. We observed strong sex-specific differences in both mannitol and lactulose recovery, with boys having higher recovery of both probes. Alterations in intestinal barrier function increased in most sites from 3 to 9 months of age and plateaued or diminished from 9 to 15 months of age. Conclusions: Alterations in recovery of the probes differ markedly in different epidemiologic contexts in children living in the developing world. The rate of change in the L:M-z ratio was most rapid and consistently disparate from the reference standard in the period between 6 and 9 months of age, suggesting that this is a critical period of physiologic impact of enteropathy in these populations.

Original languageEnglish
Pages (from-to)31-39
Number of pages9
JournalJournal of pediatric gastroenterology and nutrition
Issue number1
Publication statusPublished - 1 Jul 2017

Bibliographical note

Funding Information:
The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill Melinda Gates Foundation, the Foundation for the NIH, and the National Institutes of Health, Fogarty International Center.

Publisher Copyright:
© Copyright2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.


  • environmental enteropathy
  • intestinal permeability
  • lactulose
  • mannitol
  • reference values


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