Environmental enteric dysfunction: gut and microbiota adaptation in pregnancy and infancy

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.

Fig. 1 ∣. Maternal gut health and fetal growth in the context of environmental enteric dysfunction.

The energy demands of pregnancy dictate adaptations in the maternal gut that enable increased nutrient absorption. In women with environmental enteric dysfunction (EED), accommodating the nutritional demands of pregnancy could be challenged by increased intestinal epithelial barrier disruption, altered microbial communities and malabsorption. These features of EED might also contribute to impaired fetal growth. Maternal intestinal inflammation, which is itself energetically costly, might exacerbate this condition.

Fig. 2 ∣. Expansion of small intestinal absorptive capacity during pregnancy and lactation.

The extreme metabolic demands of pregnancy and lactation require the expansion of small intestinal absorptive capacity. a, Maximum sustained human metabolic scope (fold-increase in basal metabolic rate, BMR) versus duration of extreme endurance events flattens out at 2.5× BMR. Cumulative average metabolic scope is shown for elite cyclists over a touring season, Arctic trekking, Race Across The USA runners, and pregnancy and lactation. The sustained metabolic demands over the duration of pregnancy and lactation are equivalent to model estimates for ultramarathons and other extreme endurance events lasting 9 months or more. b, Direct changes in small intestinal mass due to feeding in lactating mice. c, Indirect changes in small intestinal mass due to increasing litter mass. Part a adapted with permission of AAAS from ref. , © The Authors, some rights reserved; exclusive licensee AAAS, distributed under a CC BY-NC 4.0 License (http://creativecommons.org/licenses/by-nc/4.0/). Parts b and c adapted from ref. , Springer Nature Limited. Part b also adapted with permission from ref. , The University of Chicago Press.

Fig. 3 ∣. The effect of maternal environmental enteric dysfunction on child development: potential mechanisms and consequences.

Mothers with environmental enteric dysfunction (EED) might harbour altered immune cells and signals, epigenetic modifications, nutrition and microbiota during pregnancy. These signals could influence development in utero and thereafter be passed on to infants. In early life, infant growth is shaped by breast milk, the gut microbiota, infection and nutrition. These factors are likely to be interrelated and act in concert to shape attained height, metabolism, immunity and cognition at adulthood. Dotted arrows indicate areas requiring additional investigation, whereas solid arrows indicate more established connections. Anti-LPS IgG, anti-lipopolysaccharide immunoglobulin G.

Fig. 4 ∣. Long-term implications of maternal environmental enteric dysfunction.

Maternal gut inflammation is a risk factor for poor fetal growth and adverse birth outcomes in multiple enteropathies. Infants inherit a substantial proportion of their gut microbiota from their mothers; thus, the maternal microbiome can play a part in shaping immunity in both mother and child. Altered maternal and infant gut function can have lifelong health consequences, including susceptibility to infection, oral vaccine responses, cognitive development and metabolic tone. EED, environmental enteric dysfunction.