Giardia lamblia infections are nearly universal among children in low-income countries and are syndemic with the triumvirate of malnutrition, diarrhea, and developmental growth delays. Amidst the morass of early childhood enteropathogen exposures in these populations, G. lamblia–specific associations with persistent diarrhea, cognitive deficits, stunting, and nutrient deficiencies have demonstrated conflicting results, placing endemic pediatric giardiasis in a state of equipoise. Many infections in endemic settings appear to be asymptomatic/subclinical, further contributing to uncertainty regarding a causal link between G. lamblia infection and developmental delay. We used G. lamblia H3 cyst infection in a weaned mouse model of malnutrition to demonstrate that persistent giardiasis leads to epithelial cell apoptosis and crypt hyperplasia. Infection was associated with a Th2-biased inflammatory response and impaired growth. Malnutrition accentuated the severity of these growth decrements. Faltering malnourished mice exhibited impaired compensatory responses following infection and demonstrated an absence of crypt hyperplasia and subsequently blunted villus architecture. Concomitantly, severe malnutrition prevented increases in B220+ cells in the lamina propria as well as mucosal Il4 and Il5 mRNA in response to infection. These findings add insight into the potential role of G. lamblia as a “stunting” pathogen and suggest that, similarly, malnourished children may be at increased risk of G. lamblia–potentiated growth decrements.
Luther A. Bartelt, James Roche, Glynis Kolling, David Bolick, Francisco Noronha, Caitlin Naylor, Paul Hoffman, Cirle Warren, Steven Singer, Richard Guerrant
(A–C) Villus and crypt architectural changes following G. lamblia infection in RP- and LP-fed mice at indicated time points after infection (n = 4–7 mice per group). Bar caps designate comparisons. *P < 0.05; **P < 0.01; ***P < 0.001 for all graphs. (D–H) Representative H&E-stained sections of a single mouse from each group as indicated. Images were selected to best represent the average morphometry in each group. Scale bars: 500 microns. (I and J) Cleaved caspase-3 immunohistochemistry staining as indicated. Scale bars: 200 microns (inset, 100 microns) (K) Number of cells positive for cleaved caspase-3 staining per villus-crypt unit. Original magnification, ×20. *P = 0.015. Representative cleaved caspase-3 immunohistochemically stained intestinal sections as indicated. (L) Congo red stain demonstrating eosinophils within the epithelium of G. lamblia–infected RP-fed mouse. (M and N) Enumeration of eosinophils on H&E staining at ×20 and ×40 magnification per villus or crypt as indicated. Bar caps designate comparisons. *P = 0.026; **P < 0.01; ***P < 0.001.