Giardia hinders growth by disrupting nutrient metabolism independent of inflammatory enteropathy

• Authors: Natasa Giallourou, Imperial College Faculty of Medicine; Jason Arnold, The University of North Carolina at Chapel Hill; Elizabeth McQuade, Emory University; Muyiwa Awoniyi, The University of North Carolina at Chapel Hill; Rose Viguna Thomas Becket, The University of North Carolina at Chapel Hill; Kenneth Walsh, The University of North Carolina at Chapel Hill; Jeremy Herzog, The University of North Carolina at Chapel Hill; Ajay S Gulati, The University of North Carolina at Chapel Hill; Ian M Carroll, The University of North Carolina at Chapel Hill; Stephanie Montgomery, The University of North Carolina at Chapel Hill; Pedro Henrique Quintela, Universidade Federal do Ceará; Angela M Faust, Waterborne, Inc; Steven M Singer, Georgetown University; Anthony A Fodor, The University of North Carolina at Charlotte; Tahmeed Ahmad, International Centre for Diarrhoeal Disease Research Bangladesh; Mustafa Mahfuz, International Centre for Diarrhoeal Disease Research Bangladesh; Esto Mduma, Haydom Lutheran Hospital; Thomas Walongo, Haydom Lutheran Hospital; Richard L Guerrant, University of Virginia; R Balfour Sartor, The University of North Carolina at Chapel Hill; Jonathan R Swann, University of Southampton, Faculty of Medicine; Margaret N Kosek, University of Virginia; Luther A Bartelt, The University of North Carolina at Chapel Hill
• Journal Title: Nature Communications
• Volume: Volume 14, Number 1
• Publisher: Springer Nature Limited | 2023-12-01, Pages 2840-2840
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41467-023-38363-2
• Subjects: Health Sciences, Nutrition; Health Sciences, Epidemiology
• Keywords: Mice; Animals; Giardia; Giardiasis; Inflammatory Bowel Diseases; Nutrients; Inflammation; Amino Acids

Abstract

Giardia lamblia (Giardia) is among the most common intestinal pathogens in children in low- and middle-income countries (LMICs). Although Giardia associates with early-life linear growth restriction, mechanistic explanations for Giardia-associated growth impairments remain elusive. Unlike other intestinal pathogens associated with constrained linear growth that cause intestinal or systemic inflammation or both, Giardia seldom associates with chronic inflammation in these children. Here we leverage the MAL-ED longitudinal birth cohort and a model of Giardia mono-association in gnotobiotic and immunodeficient mice to propose an alternative pathogenesis of this parasite. In children, Giardia results in linear growth deficits and gut permeability that are dose-dependent and independent of intestinal markers of inflammation. The estimates of these findings vary between children in different MAL-ED sites. In a representative site, where Giardia associates with growth restriction, infected children demonstrate broad amino acid deficiencies, and overproduction of specific phenolic acids, byproducts of intestinal bacterial amino acid metabolism. Gnotobiotic mice require specific nutritional and environmental conditions to recapitulate these findings, and immunodeficient mice confirm a pathway independent of chronic T/B cell inflammation. Taken together, we propose a new paradigm that Giardia-mediated growth faltering is contingent upon a convergence of this intestinal protozoa with nutritional and intestinal bacterial factors.