Interactions between the Gut Microbiome, Intestinal Development and Metabolic Health after Fetal Growth Restriction

PROJECT SUMMARY/ABSTRACT Fetal growth restriction (FGR) impacts 10-20% of pregnancies worldwide and increases the offspring’s risk for later development of obesity and type 2 diabetes due to incompletely understood mechanisms. The focus of this proposal is the nexus of intestinal development and gut microbiome establishment. Gut microbial composition represents an important and modifiable factor that contributes to postnatal intestinal function and systemic health and has been understudied in FGR. Our preliminary studies demonstrate impaired glucose tolerance in adult FGR males after high fat diet challenge and gut microbial dysbiosis into adulthood. The purpose of this work is to test the reciprocal relationship between the intestine and microbiome in FGR, and how a microbiome-directed nutritional intervention can impact that relationship. The central hypothesis is that impaired intestinal and gut microbial development in FGR increases risk for adverse outcomes which can be mitigated by postnatal dietary interventions. Aim 1 will use our established mouse model of FGR to test the function of intestinal stem, goblet, Paneth, and enteroendocrine cells. Organoid formation and single cell RNA sequencing of ileal and colonic cells will further characterize intestinal development differences between control and FGR animals. Aim 2 examines whether FGR animals can sustain transplanted fecal microbiome from control animals, testing for intrinsic defects of microbiome establishment. Aim 3 tests the ability of early supplementation with human milk oligosaccharide 2’- fucosyllactose (2’FL) to protect against adverse metabolic outcomes in adult FGR mice. Control and FGR offspring will be challenged with a high fat diet with or without 2’FL supplementation. At age 24 weeks we will assess glucose homeostasis, body composition, energy balance, and microbiome composition. The interdisciplinary approach is innovative as it examines a potential mechanistic role for the gut microbiome in adverse metabolic outcomes after FGR. The proposal is significant as it addresses a critical and prevalent clinical problem with high translation potential. The proposed research is translational to human health as 2’FL has demonstrated safety in infants and known associations with growth and intestinal health. Complementary to the proposed research plan, a five-year mentored career development training plan has been devised, incorporating didactic learning in statistical methods and organoids in addition to hands-on training in bioinformatic analyses, intestinal pathophysiology, intestinal organoids, fecal microbiome transplant, and evaluation of glucose metabolism. The candidate requires mentorship by a multidisciplinary team and has assembled a group with expertise in fetal growth restriction, intestinal pathophysiology, microbiome, host- intestine interactions, and glucose homeostasis. The candidate’s long-term career goal is to become an independent investigator studying early childhood dietary interventions to improve lifelong after FGR.