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  • Review Article
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Environmental enteric dysfunction: gut and microbiota adaptation in pregnancy and infancy

Nature Reviews Gastroenterology & Hepatology volume 20, pages 223–237 (2023)Cite this article

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Abstract

Environmental enteric dysfunction (EED) is a subclinical syndrome of intestinal inflammation, malabsorption and barrier disruption that is highly prevalent in low- and middle-income countries in which poverty, food insecurity and frequent exposure to enteric pathogens impair growth, immunity and neurodevelopment in children. In this Review, we discuss advances in our understanding of EED, intestinal adaptation and the gut microbiome over the ‘first 1,000 days’ of life, spanning pregnancy and early childhood. Data on maternal EED are emerging, and they mirror earlier findings of increased risks for preterm birth and fetal growth restriction in mothers with either active inflammatory bowel disease or coeliac disease. The intense metabolic demands of pregnancy and lactation drive gut adaptation, including dramatic changes in the composition, function and mother-to-child transmission of the gut microbiota. We urgently need to elucidate the mechanisms by which EED undermines these critical processes so that we can improve global strategies to prevent and reverse intergenerational cycles of undernutrition.

Key points

  • Maternal and neonatal anthropometry are key predictors of childhood stunting, highlighting the intergenerational nature of undernutrition and pinpointing the first 1,000 days of life as a critical window for development.

  • Pregnancy and lactation are metabolically demanding, requiring an expansion of small intestinal absorptive capacity; enteropathies adversely affect perinatal outcomes.

  • Environmental enteric dysfunction (EED) is characterized by inflammation, increased barrier permeability, and reduced absorptive capacity. Its prevalence and consequences in mothers in low and middle-income countries warrant urgent investigation.

  • Gut microbial communities are disrupted during EED and undernutrition in humans, and confer aspects of these phenotypes to gnotobiotic mice; nutrient processing, absorption and regulation of immunity are potential mechanisms.

  • Infants inherit a substantial portion of their microbiome from their mothers. Maternal microorganisms, breast milk and epigenetics are implicated in intergenerational undernutrition.

  • Gut microbial communities in early life shape host immunity, with potential consequences for survival, growth and cognitive development.

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Fig. 1: Maternal gut health and fetal growth in the context of environmental enteric dysfunction.
Fig. 2: Expansion of small intestinal absorptive capacity during pregnancy and lactation.
Fig. 3: The effect of maternal environmental enteric dysfunction on child development: potential mechanisms and consequences.
Fig. 4: Long-term implications of maternal environmental enteric dysfunction.

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Acknowledgements

The authors were supported by the US National Institutes of Health (awards R01HD105729 (to C.A.C.), D43TW007585 (to S.R.M., S.S., Z.J. and S.A.A.), K23DK117061 (to S.S.), K43TW010697 (to N.I.) and U19AI116491 (to S.R.M.)); and by the Bill and Melinda Gates Foundation (grants OPP1144149 (to S.R.M.) and OPP1138727 (to S.A.A.)). The authors gratefully acknowledge insights derived from conversations with Bill and Melinda Gates Foundation programme officers R. Elliott, C. Damman, J. Yan, H. Gammill and V. Ridaura.

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  1. Division of Paediatric Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Child Health Research Center, University of Virginia, Charlottesville, VA, USA

    Carrie A. Cowardin, Sana Syed & Sean R. Moore

  2. Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan

    Sana Syed, Najeeha Iqbal, Zehra Jamil, Kamran Sadiq, Junaid Iqbal & Syed Asad Ali

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S.R.M. and C.A.C. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed/edited the manuscript before submission. S.S., N.I., Z.J. and J.I. researched data for the article, wrote the article, and reviewed/edited the manuscript before submission. K.S. wrote the article and reviewed/edited the manuscript before submission. S.A.A. researched data for the article, made a substantial contribution to discussion of content, and reviewed/edited the manuscript before submission.

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S.R.M. was a paid consultant for Takeda on paediatric short bowel syndrome in 2020. S.R.M. receives royalties from UpToDate for a chapter entitled “Persistent diarrhoea in children in resource-limited countries”. The other authors declare no competing interests.

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Cowardin, C.A., Syed, S., Iqbal, N. et al. Environmental enteric dysfunction: gut and microbiota adaptation in pregnancy and infancy. Nat Rev Gastroenterol Hepatol 20, 223–237 (2023). https://doi.org/10.1038/s41575-022-00714-7

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