Gopalakrishna, Kathyayini
(2020)
Maternal immunoglobulin A shapes the early neonatal microbiota and protects against the development of necrotizing enterocolitis in preterm infants.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Neonates are protected from colonizing bacteria by antibodies secreted into maternal milk. Immunoglobulin A (IgA) plays a crucial role in maintaining the homeostasis between the microbiota and intestinal epithelium. The effect of maternal IgA is potentially important because improper handling of colonizing organisms can lead to serious complications such as sepsis, pneumonia and Necrotizing Enterocolitis (NEC). NEC is a disease of neonatal preterm infants with high morbidity and mortality that is associated with intestinal inflammation driven by the microbiota. The incidence of NEC is significantly lower in infants fed with maternal milk, though the mechanisms underlying this benefit are not clear. Here, we show that maternal Immunoglobulin A (IgA) is an important factor in protection against NEC.
Analysis of IgA-binding of fecal bacteria from preterm infants indicated that maternal milk was the predominant source of IgA in the first month of life and that a relative decrease in IgA-bound bacteria is associated with the development of NEC. We observed a heterogeneity of the IgA repertoire in the breast milk of different mothers. Sequencing of IgA-bound and unbound bacteria revealed that, prior to disease onset, NEC was associated with increasing domination of the IgA-unbound microbiota by Enterobacteriaceae.
Further, we confirmed that IgA is critical for early neonatal colonization in a murine model, where pups reared by IgA deficient mothers have increased Enterobacteriaceae in their fecal matter and developed disease similar to formula-fed pups. Our findings show that maternal IgA shapes the host-microbiota relationship of preterm neonates and that IgA is a critical and necessary factor in maternal milk for the prevention of NEC. The public health significance of this study is to amplify the benefits of feeding neonates with maternal milk as it reveals the successful association of maternal milk IgA binding to Enterobacteriaceae to prevent NEC. This study describes the invention of a novel diagnostic test to examine heterogeneity in maternal milk IgA repertoire. This test can be used to identify donor breast milk with high IgA binding to Enterobacteriaceae, which could be used prophylactically in preterm infants who are risk for the development of NEC.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
29 January 2020 |
| Date Type: |
Publication |
| Defense Date: |
6 December 2019 |
| Approval Date: |
29 January 2020 |
| Submission Date: |
20 November 2019 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
94 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Human Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Maternal IgA, neonate, necrotizing enterocolitis |
| Date Deposited: |
29 Jan 2020 21:25 |
| Last Modified: |
01 Jan 2022 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37859 |
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