In this application, I am requesting support from a career development award to support my research proposal titled ?Microbiota, Inflammation and Environmental Enteric Dysfunction?. I will be undertaking this work with the mentorship of Dr. Jeffrey Gordon (Primary US mentor) at the Washington University, St Louis and Dr. Asad Ali (Primary LMIC mentor) at the Aga Khan University. This project builds on our existing studies of Environmental Enteric Dysfunction (EED), funded by the Bill and Melinda Gates Foundation. The current application aims to improve our understanding of the pathogenesis of EED by studying the evolution of gut microbial configuration in children who have clinical and histological evidence of EED. EED is common in children living in impoverished conditions with limited access to clean drinking water and sanitation. Histopathological changes of EED in small bowel mucosa include alteration in crypt to villous ratio along with lymphocytic infiltration of the villous epithelium and lamina propria. Although studies involving biopsies of small bowel mucosa are critical to study EED, these studies are uncommon because of logistic challenges involving performing endoscopies in field settings in LMICs. We have previously demonstrated in an ongoing BMGF funded study that we are able to safely obtain such biopsies, we now have a unique opportunity to study the relationship between gut microbiome evolution and EED in this cohort. The central hypothesis of the current application is that children with histological confirmation of EED have shared features of a bacterial community which is different from healthy controls and non-EED subjects, and that such changes in bacterial configuration are associated with enteric and systemic inflammation. For testing these hypotheses, evaluation of gut microbiome in healthy and stunted children will be carried out to identify the age discriminatory bacterial taxa in children with and without confirmation of EED. Dr. Gordon will be providing mentorship and experience in gut microbiome and microbiota analysis. Dr. Ali will provide the needed infrastructure of the field site and laboratory facilities, along with linking the microbiome analysis with clinical and histological outcomes of interest. The Aga Khan University is a leading regional research institute with multiple support systems for junior investigators which will be vital for my career transition as an independent scientist. My long term goal is to be the principal investigator of my own laboratory, focusing on studying the gut microbiome and its relationship with communicable and non-communicable diseases. I envision working on microbiota derived therapy for EED, and to find targets in the inflammatory pathways driven by changes in gut homeostasis.
Globally, Pakistan has the third highest rate of stunting among children aged < 5 years. Environmental Enteric Dysfunction (EED) is proposed to be a critical factor responsible for chronic growth faltering in children in resource limited settings. This research utilizes an innovative approach to study a program of postnatal gut microbiome development in children and its impact on child growth. This proposal will provide an ideal training platform for a translational scientist, covering the domains of mucosal immunology, histopathology, computational analysis, microbiome analysis and host immune responses. The skills learnt from this project will be critical for the capacity development of both the LMIC institution and the candidate herself.
