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) G. lamblia tissue burden determined by qPCR in duodenum compared with ileum at 8 and 64 dpi (n = 3–5 per group). The dashed line represents the PCR limit of detection. *P = 0.029; ***P = 0.001. (B) Growth curves measuring the change in weight after challenge with PBS (n = 5) or 106G. lamblia (n = 4) as indicated (*P < 0.05, day 42). (C–E) Representative H&E-stained duodenum sections of a single PBS-challenged mouse at 64 days after challenge. Vertical bar represents crypt depth (D). Black arrowhead represents mucus. Scale bars: 500 (C), 100 (D), and 50 microns (E) (inset, 20 microns). (F–H) Representative H&E-stained duodenum sections of a single G. lamblia–infected mouse at 64 dpi. Vertical bar represents crypt depth (G). Scale bars: 500 (C), 100 (D), and 50 microns (E). (H) Representative H&E-stained duodenum section at 64 days after challenge with G. lamblia showing hypercellularity in the crypts and villus base. Arrows indicate G. lamblia in ventral (lower right) and transverse (upper right) orientations, white arrowhead represents an intraepithelial eosinophil, and black arrowhead represents mucus. Scale bar: 50 microns (inset, 20 microns). (I–K) Mucosal morphometric changes at 64 dpi measured on H&E-stained duodenum sections. Original magnification, ×10. (J) *P = 0.027; (K) *P = 0.029. (L) Enumeration of eosinophils on ×20 H&E-stained duodenum sections in PBS-challenged and G. lamblia–challenged mice at 64 dpi. *P = 0.013; ***P < 0.001.