The role of environmental enteric dysfunction in drug absorption and the pathogenesis of anemia among young children with pathogens affecting the gut

Rhode Island Hospital, Providence RI

Investigators

Abstract

PROJECT SUMMARY . Schistosomiasis causes significant morbidity in the gut as eggs traverse the intestinal barrier, disrupting the integrity of the small intestine wall. In this way, schistosomiasis contributes to environmental enteric dysfunction (EED), a common condition in low- and middle-income countries that is characterized by small intestinal inflammation, diminished absorptive capacity, and increased intestinal permeability. In children, a key cause of morbidity in schistosomiasis is due to anemia of inflammation, which is also thought to be due, in part, to systemic immune activation. However, the mechanistic pathway leading to anemia of inflammation in schistosomiasis is unknown. Praziquantel is the mainstay of treatment for schistosomiasis, however, younger children need higher doses than adults to achieve adequate cure rates. The role of EED in praziquantel absorption, a possible cause of this variability, remains unknown. To address these questions, this study will leverage data from a large scale, NIH funded double blind randomized controlled trial (PI Friedman, project mentor) of N=354 children under the age of 4 in Uganda with schistosomiasis and were randomized to receive 40 or 80 mg/kg of praziquantel. Pharmacokinetic (PK) measurements (i.e., plasma concentration and area under the curve (AUC)) were obtained following praziquantel administration and key measures of anemia, iron status, and EED biomarkers were captured. With this well- characterized clinical and PK data, this proposal will use samples already available in our laboratory, adding novel biomarkers to assess EED and anemia of inflammation. The goals of this proposal are to a) examine the role of EED in the uptake efficacy and oral bioavailability of praziquantel among young children with schistosomiasis utilizing pharmacokinetic modeling, supported by the Pharmacology Core and b) employ sophisticated Structural Equation Modeling techniques with the support of biostatistician co-investigators to understand the mechanisms through which schistosomiasis causes anemia, hypothesizing that EED culminates in systemic immune activation and anemia of inflammation. Successful execution of these aims will foster Dr. Barry’s path to research independence, investigate the role of EED as a barrier to praziquantel absorption, and the role of EED as a novel mechanism mediating anemia of inflammation.