Grant: CIHR Fellowship

Background & Rationale: Undernutrition in early life, measured in terms of poor growth, underlies almost half of all child deaths globally and has long-term negative effects on education and productivity. HIV infection further compounds these effects in sub-Saharan Africa. The World Health Organization (WHO) recommends daily co-trimoxazole (CTX) to prevent infections in HIV+ children. In addition to reducing deaths from infections, CTX also improves growth possibly by altering the gut microbiota. The gut microbiota is an ecosystem of microbes in the intestines that are essential to health, and to releasing and absorbing nutrients from food. Recent experimental studies suggest a causal effect of the gut microbiota on child growth using animal models, but the specific microbiota changes that contribute to growth are unclear. Antibiotic use may improve growth through changes in microbiota composition and function that result from regrowth of the microbes that survive. However, antibiotic use also poses the risk of resistance and may lead to overgrowth of antibiotic resistant microbes and loss of beneficial bacteria. Understanding how antibiotics impact growth is important for child health and survival. Hypotheses & Methods: I will test the hypotheses that continued daily CTX use in HIV+ children causes: an increase in the number of CTX resistance genes in the gut microbiota; a decrease in the number of genes that encode proteins involved in nutrient harvesting (e.g. carbohydrate digestion); an increase in genes that encode proteins involved in causing illness; and that these changes drive the effect of CTX on growth. I will test these hypotheses using longitudinal growth measurements and clinical data from the ARROW trial. ARROW was a randomized trial designed to determine the impact of continued CTX use on a number of health outcomes in HIV+ children in Zimbabwe. Changes to the microbiota will be characterized from stool specimens using DNA sequencing methods