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Maternal immunoglobulin A shapes the early neonatal microbiota and protects against the development of necrotizing enterocolitis in preterm infants

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 (Unpublished)

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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:
CreatorsEmailPitt UsernameORCID
Gopalakrishna, Kathyayinikpg13@pitt.edukpg130000-0001-6309-1841
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHand, Timothy Wtimothy.hand@chp.edu
Committee MemberFinegold, David Ndnf@pitt.edu
Committee MemberMorowitz, Michael Jmichael.morowitz@chp.edu
Committee MemberDemirci, Yesimfyd1@pitt.edu
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: Graduate 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: 29 Jan 2020 21:25
URI: http://d-scholarship.pitt.edu/id/eprint/37859

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