ABSTRACT
Maternal undernutrition affects 50% of the world’s female population. Maternal weight before pregnancy is a
strong predictor of intrauterine growth restriction (IUGR), low birth weight, and future childhood stunting. While
humanitarian efforts to improve nutritional status have focused primarily on children; there is little
understanding of mechanisms underlying maternal undernutrition and its transmission to children.
Our lab has identified perturbations in postnatal gut microbiota development that are evident in feces and the
small intestine (SI). Our gnotobiotic mouse models have provided preclinical evidence that the SI microbiota of
Bangladeshi children with stunting is causally related to the pathogenesis of a poorly understood enteropathy
[environmental enteric dysfunction (EED)] characterized by loss of SI villi, reduction in intestinal absorptive
area, epithelial barrier dysfunction and associated intestinal and systemic inflammation. The goal my project is
to determine the impact of the SI microbiota of women with and without EED on arterial-remodeling at the
maternal-fetal interface and maternal immune responses to inflammation at the maternal-fetal interface.
Tissue-resident, non-cytotoxic uterine natural killer (uNK) cells produce IFN- to remodel uterine spiral arteries
into large luminal decidual arteries that maximize blood flow and nutrient delivery to the fetus. I hypothesize
that 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, Aim 1 will use
germ-free (GF), conventionally-raised (CONV-R), and conventionalized mice (CONV-D = GF mice gavaged
with CONV-R cecal contents) to first characterize the effects of the gut microbiota on placental/fetal
development, including placental/decidual histological structures, NK cell composition at early (E11.5) and late
(E17.5) stages of pregnancy. Bulk RNA-seq, single-nucleus RNA-seq, flow cytometry, multiplex assays of
tissue/serum proteins, and histo/immunohistochemical methods will be used to define the cellular
transcriptional/signaling/metabolic profiles of their placenta, decidua, and intestines. The resulting datasets will
be analyzed using a suite of computational tools that I have applied to a substantial amount of preliminary
results. Aim 2 will use groups of gnotobiotic mice colonized with i) a consortium of cultured SI bacteria from
undernourished (low-BMI) Bangladeshi women with EED (based on histopathology of their duodenal mucosa
obtained by endoscopy) and ii) a consortium of cultured SI bacteria from healthy (normal BMI) Bangladeshi
women without histologic evidence of EED. I will apply methods from Aim 1 to E11.5 and E17.5 mice
representing the 2 treatments groups to characterize placental/fetal development (transcriptional, signaling,
metabolic and immunologic characteristics of placenta, decidua, and intestines including spiral artery
development and NK cell biology). These experiments should advance knowledge about how the SI microbiota
in EED impacts the maternal-fetal interface and could yield new therapeutic concepts/targets.
