# Mechanisms of maternal Immunoglobulin A control over the neonatal microbiota and the development of Necrotizing Enterocolitis.

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $449,729

## Abstract

Abstract
Neonates are particularly susceptible to invasion by colonizing bacteria and thus mammalian mothers protect
their children via antibodies and in particular, Immunoglobulin A (IgA), secreted into maternal milk. Necrotizing
Enterocolitis (NEC) is a disease of premature infants characterized by invasion of the neonatal intestine by the
microbiota. Studies have shown that the incidence of NEC is significantly reduced in infants fed with breast milk,
though the mechanism is unclear. Our preliminary studies show that maternal IgA (mIgA) is an important factor
in protection against NEC. Analysis of IgA-binding on fecal samples from premature infants indicated that breast
milk was the predominant source of IgA in the first month post-delivery and that a relative drop in the fraction of
bacteria bound by IgA is associated with the development of NEC. Sequencing of IgA-bound and unbound
bacteria indicated that NEC was associated with a unique increase in IgA negative Enterobacteriaceae. Further,
we confirmed that IgA is critical in preventing NEC in the murine model, where we demonstrate that pups reared
by mIgA deficient mothers are susceptible to disease, indicating that IgA in breast milk is necessary for
protection. Together these data indicate that mIgA binding is critical in preventing the development of NEC by
shaping the neonatal microbiota. In order to mediate effects on bacterial communities IgA acts on bacterial sub-
populations. Therefore, our central hypothesis is that IgA in maternal milk modifies intestinal bacteria directly,
preventing their invasion of the neonatal intestine and the induction of inflammatory immune responses. We will
test this hypothesis in three aims. In the first aim we will investigate the mechanisms of how individual sub-
populations of Enterobacteriaceae change to elude mIgA. Further we will investigate the mIgA repertoire of
different breast milk donors to test the hypothesis that variation in this repertoire is important in binding different
intestinal bacteria. In aim 2 we will investigate the mechanism of IgA binding on the neonatal microbiota at the
community level, via 16S rRNA gene sequencing and by transcriptional analysis of a model organism in
gnotobiotic mice. Our hope is to associate these data with analysis of the role of IgA on epithelial association of
intestinal bacteria and the downstream immune responses that are induced. In the third aim we will investigate
whether the production of mammary gland antibodies that protect against NEC are dependent upon maternal T
cells. These aims will lead to a better understanding of how mIgA shapes the nascent microbiome and the
neonatal immune response. In addition, our proposal may improve provide strategies to prevent NEC via the
targeted provision of breast milk containing protective antibodies to the most at-risk children.

## Key facts

- **NIH application ID:** 10312104
- **Project number:** 5R01DK120697-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Timothy Wesley Hand
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $449,729
- **Award type:** 5
- **Project period:** 2020-01-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312104

## Citation

> US National Institutes of Health, RePORTER application 10312104, Mechanisms of maternal Immunoglobulin A control over the neonatal microbiota and the development of Necrotizing Enterocolitis. (5R01DK120697-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10312104. Licensed CC0.

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