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U contributes to nearly 50% of all annual deaths in children under 5 years. Commonly termed “malnutrition,” undernutrition can have an acute, chronic or acute-on-chronic presentation and refers to children who are underweight for their age or length, too short for their age or deficient in key macro or micronutrients. Undernourished children are more vulnerable to infectious pathogens and more likely to die from infectious diseases; specifically, complications related to diarrhea, pneumonia and measles. Although there has been some progress in reducing childhood undernutrition worldwide, children living in sub-Saharan Africa and Asia continue to bear the largest burden of morbidities and mortality associated with undernutrition. Undernutrition not only impacts growth and vulnerability to severe infection, but chronic undernutrition is highly associated with lifelong cognitive delays. Thus, undernutrition deprives children from thriving to meet their full growth and cognitive potentials, introducing disadvantages that persist into adulthood. Despite strong evidence of associations between undernutrition, infection and an increased risk of death among young children, the mechanisms driving this vulnerability are not understood. Efforts to tease out causal pathways are hampered by the complex interplay between nutritional status and infection that results in a vicious cycle. In this cycle, infection results in undernutrition due to nutrient loss, reduced uptake and increased energy requirements; while undernutrition drives an increased risk of infection by reducing gut barrier function, modifying the intestinal microbiota, altering regulation of inflammatory adipocytokines and limiting the uptake of key micro and macronutrients. Here, we will explore specific components of this vicious cycle that may compromise host immunity to impact vulnerability to infection among children in low and middle-income countries (LMICs). ALTERED GUT BARRIER FUNCTION AND CHRONIC INFLAMMATION The human gut provides an essential barrier against invasion by external pathogens but can also serve as a potential entry point for microbes, pathogen-associated molecular products (PAMPs) and environmental toxins. Many children living in LMICs suffer from environmental enteric dysfunction (EED), a syndrome driven by increased environmental exposure to poor sanitation, intestinal pathogens and subsequent chronic inflammation. A hallmark of EED is increased activation of mucosal immune cells, erosion of epithelial barrier cells, villous atrophy and crypt hyperplasia. These changes cause inflammation of the small intestine, decreased nutrient absorption, increased intestinal permeability and systemic translocation of immune-stimulatory PAMPs such as lipopolysaccharide. Although the direct impact of EED on host immunity and vulnerability to early childhood infections has not been defined, chronic systematic exposure to lipopolysaccharide has been shown to significantly alter innate cytokine production, the costimulatory capacity of antigen-presenting cells, impair T-cell proliferation and induce cross-tolerance to PAMPs among both HIVinfected and uninfected adults. Such chronic immune stimulation may result in immunoparalysis that predisposes to recurrent invasive infections. Children living in LMIC where low levels of hygiene persist will have increased exposure to environmental pathogens and PAMPs. Thus, EED-driven immune Accepted for publication April 3, 2019. From the *The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi; †KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya; ‡Department of Pediatrics, Makerere University, Kampala, Uganda; §Centre for Tropical Medicine & Global Health, University of Oxford, Oxford, United Kingdom; and ¶Department of Pediatrics, Oregon Health and Science University, Portland, Oregon. Supported by Bill and Melinda Gates Foundation. The authors have no conflicts of interest to disclose. Address for correspondence: Christina Lancioni, MD, 707 SW Gaines Street, CDRC-P, Portland, OR 97239. E-mail: [email protected]. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.