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NIH grant 1R01HD121742-01: Gut microbiota-aryl hydrocarbon receptor cross talk in pregnancy
Institute: {'code': 'HD', 'abbreviation': 'NICHD', 'name': 'Eunice Kennedy Shriver National Institute of Child Health and Human Development', 'admin_org_id': '12500030', 'admin_funding_url': ''}. PI: Medha Priyadarshini. Award: $665163.
Start: 2026-09-05T00:00:00.
Pregnancy is a diabetogenic state with increase in insulin resistance during later stages that returns to normal
postpartum. Exact mechanisms underlying the regulation of gestational insulin resistance are not clearly defined.
However, its aberrant regulation results in gestational diabetes with short- and long-term adverse effects on the
mothers and their offspring. We have found that precursors of gestational insulin resistance originate in the gut
microbiota. Specifically, we show that the dysbiotic gut microbiome of late pregnancy is marked by increased
inflammatory potential but reduced capacity for generation of a specific class of metabolites called indoles. This
decline is magnified in women and mouse models predisposed to gestational diabetes. We have also found a
potential mechanism by which dysbiotic gestational gut microbiota limits indole production, i.e., through
differential regulation of intestinal microRNAs, particularly, miR-709. Indoles serve as ligands for aryl
hydrocarbon receptor (AHR). Mounting evidence suggest that impaired production of gut microbiota derived AHR
ligands is associated with metabolic disorders in humans and mice. Their role in gestational metabolism is not
known. We, therefore, hypothesize that gestational gut microbiome induced disruption of AHR ligand production
via miR-709 promotes gestational insulin resistance. The Specific Aims are: 1. Examine the role of gut
microbiome derived AHR signaling in gestational metabolism-that will be determined through dietary
pharmacologic, microbial and genetic mouse models; 2. Determine how gestational gut microbiome-microRNA
interaction limits indole arm of gut tryptophan metabolism-that will be analyzed by integrative omics analyses of
miR transcriptome and gut microbiome datasets, and through specific silencing/overexpression of miR-709 in
intestinal epithelial cells; 3. Examine the presence and role of gut microbiome-AHR axis in human pregnancy-
for translation of our data we will analyze levels of gut microbially derived indoles in stool and serum of human
pregnancy cohort and examine trimester specific AHR signaling using human gut derived enteroids. Using diet-
based and genetic mouse models of gestational diabetes as an approach to its different etiologies, we will also
examine role of gut microbiome-AHR axis in disease pathogenesis. The outcomes will reveal a novel mechanism
by which gestational gut microbiome modulates pregnancy metabolism via AHR. As gut microbiome-AHR link is
modifiable through diet/probiotics, the results may promote identification of biotherapeutic interventions against
gestational insulin resistance.document fetched 2026-09-13 02:45