Reyan Coskun (MSTP in PhD training)

  • Indianapolis, Indiana

  • Indiana University-Bloomington (2019)

  • Immunology

  • Jeffrey I. Gordon, M.D.

  • The effects of the gut microbiota of undernourished mothers with environmental enteric dysfunction on vascular remodeling at the fetal-placental interface

  • reyan@wustl.edu

Research

Maternal undernutrition affects 50% of the world’s female population. Intrauterine growth restriction (IUGR), stunting (low height-for-age), and wasting (low weight-for-height) caused by maternal nutritional deficits are associated with 30% of the global mortality for children under five years old. Thus, there is a great need to obtain deeper understanding about the mechanisms by which maternal malnutrition (undernutrition) impacts fetal development and postnatal growth. Perturbations of postnatal gut microbial community development are evident not only in the fecal microbiota but also in the small intestinal (SI) microbiota where they have been associated with the pathogenesis of a poorly understood enteropathy termed environmental enteric dysfunction (EED). Transmission of components of the SI microbiota of undernourished children from pregnant gnotobiotic mice to their pups leads to intestinal barrier disruption with inflammatory responses that involve innate lymphoid cells (ILCs). ILCs, particularly ILC3, are known to generate cytokines that increase proliferation and recruitment of natural killer (NK) cells. As the primary driver of vascular remodeling at the maternal-fetal interface, tissue-resident uterine NK (uNK) cells normally produce IFN-𝛾 which transforms spiral arteries into high-capacitance, low-resistance vessels which maximize nutrient delivery to the growing fetus. The goal of this project is to determine the impact of the microbiota of women with and without EED on arterial-remodeling at the maternal-fetal interface. I hypothesize is that chronic inflammation produced, at least in part, by a maternal EED-associated SI microbiota leads to dysregulated vascular remodeling by impairing uNK cell function; this in turn reduces fetal growth by limiting nutrient availability. To test this hypothesis I am using germ-free (GF) and conventionally-raised C57BL/6 mice, to determine whether the microbiota has an effect on placental/decidual histological structures, NK cell composition, and fetal development at several developmental stages of pregnancy after placentation. Then, using GF mice (ii)_ colonized with SI microbial communities from malnourished (low-BMI) Bangladeshi women or their healthy (normal BMI) counterparts and (ii) fed diets corresponding to those consumed by the SI donor populations, we will characterize the effects of the microbiota on spiral arteries, NK cell composition, and fetal development, similar to our comparisons between GF and conventionally-raised mice and correlate the presence of specific bacteria taxa with the quantity of both ILCs and local cytokine expression and production in the different portions of the intestines. These experiments should further knowledge about the role and effects of the gut microbiota on the maternal-fetal interface. This could help lead to therapies that repair the undernourished maternal microbiota to prevent growth faltering.

Last Updated: 8/22/2022 10:57:04 AM

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