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NIH grant 1K99HD122916-01: Small intestinal bacteria impair fetal and placental development
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: Kali Meredith Pruss. Award: $135378.
Start: 2026-08-26T00:00:00.
Project Summary
Currently, no reliable therapeutic interventions exist for treating intrauterine growth restriction (IUGR). Growth-
restricted infants are at increased risk for metabolic and cardiovascular disease in adulthood, as well as
neurodevelopmental and cognitive abnormalities. In most cases, IUGR results from placental dysfunction – a
disorder with ill-defined pathophysiology. Many cases of IUGR remain idiopathic.
The maternal gut microbiota has been implicated in placental function and fetal growth. The
gastrointestinal tract harbors an ecosystem of bacteria that exerts wide-ranging effects on human physiology,
including endocrine, metabolic, and immune effects. This proposal will use arrayed collections of bacteria
cultured from small intestinal samples obtained from undernourished women. Compared to a bacterial
consortium cultured from a control cohort of healthy women living in the same region, the undernourished
microbiota induced systemic inflammation during pregnancy, impaired fetal growth and placental efficiency in
gnotobiotic mice, demonstrating, for the first time, a causal role for human gut bacteria in fetal growth.
However, mechanisms underlying the contribution of the maternal gut microbiota to fetal growth remain
unknown.
The objective of this proposal is to define bacterial metabolic pathways that influence fetal growth
through immune cell function at the maternal-fetal interface. Macrophages, the most abundant immune cells in
placental villi (fetal Hofbauer cells, HBCs) and the second most abundant in the decidua (maternal decidual
macrophages, dMacs), are central to healthy fetal development. The central hypothesis is that macrophages at
the maternal-fetal interface mediate the effects of the maternal gut microbiota on fetal growth through their
response to microbial metabolites.
This proposal will test the central hypothesis through two specific aims. Aim 1 will define the respective
contributions of maternal (dMacs) and fetal (HBCs) macrophages in mediating the effect of the undernourished
versus healthy maternal gut microbiota on fetal growth using CITE-Seq and selective depletion experiments.
Aim 2 will identify functional microbial metabolic pathways by manipulating two representative bacterial
isolates: model commensal Bifidobacterium globosum and detrimental Pseudomonas aeruginosa. Mono- and
bi-colonization experiments will identify bioactive metabolites that will be validated ex vivo and ultimately tested
in vivo in germ-free dams.
The aims herein align with the first and third research priorities in the NICHD 2025 Strategic Plan: using
a humanized gnotobiotic pre-clinical model, the proposed research will identify host-microbe pathways that
underlie fetal growth. The proposed research is significant because it will elucidate an unexplored facet of the
molecular and cellular basis of development and is expected to enable steps towards development of maternal
microbiota-directed therapeutics to improve intra-uterine growth.document fetched 2026-09-06 02:47