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Breast Milk IgA Exerts Selective Pressure on the Preterm Gut Microbiome

Award Number: F30HD114316
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Breast Milk IgA Exerts Selective Pressure on the Preterm Gut Microbiome - PROJECT SUMMARY This proposal aims to characterize how breast milk IgA shapes the ecological development of the preterm gut microbiome and promotes resistance to pathobionts. Aberrant gut bacterial colonization places the preterm infant at risk for necrotizing enterocolitis (NEC). NEC is a deadly inflammatory intestinal disease that uniquely affects preterm infants and lacks curative treatments. Our laboratory has found that protection against NEC is associated with preterm gut microbiota that are bound by maternal milk-derived IgA (mIgA). Enterobacteriaceae that do not bind to mIgA predominate the gut microbiome of preterm infants who develop NEC. In contrast, infants who do not develop NEC establish a mature or ‘term-like’ microbiome comprising obligate anaerobes. We reasoned reduced mIgA binding to Enterobacteriaceae prior to NEC development is due to either: 1) variation in the mIgA repertoire over time in breast milk, or 2) genetic changes that enable specific bacterial strains to evade mIgA recognition. Interestingly, our preliminary data show that anti-bacterial mIgA reactivity remains stable over time within an individual mother. Thus, our central hypothesis is that Enterobacteriaceae escape from mIgA binding delays the maturation of the preterm infant gut microbiome. Understanding how the preterm gut microbial ecosystem resists Enterobacteriaceae colonization first requires defining how the microbiome forms, matures, and functions. To address this gap in knowledge, we will utilize novel technology developed by our laboratory that combines RNA hybridization chain reaction, flow cytometry, and direct quantitative analyses to determine whether mIgA binds to Enterobacteriaceae to restrict their colonization (Aim 1.1) and how mIgA promotes the establishment of obligate anaerobes (Aim 1.2) in longitudinally collected preterm infant stool from a prospective cohort study. In doing so, we may be able to identify signature patterns of microbiota development that differentiates patients by NEC status. To delineate the genetic mechanisms underlying how Enterobacteriaceae lose mIgA binding and potentially induce NEC, we will perform single cell microbial sequencing that incorporates anti-IgA barcoding, allowing us to link changes in genetic features with or without IgA binding to distinct strains (Aim 2). This novel approach will enable us to study ex vivo bacterial evolution as a response to mIgA binding in preterm infant stool, which has significant translational value for preterm infants with microbiome-related disease. By defining genes involved in bacterial evasion of antibody binding, this work may open new avenues for targeted therapy against NEC. This project provides a unique opportunity for me to: 1) gain computational expertise to analyze large genomic and patient-centered datasets, and 2) form clinical and research collaborations tailored to my career goal of becoming an OB/GYN physician scientist. The proposed research will enable me to create an early research niche that will be fundamental for my long-term objectives in advancing maternal-fetal health.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $55,114 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	3	1/15/2026	NON-COMPETING CONTINUATION	$54,538
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	001	3	3/24/2026	NON-COMPETING CONTINUATION	$576
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $53,974 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	2	1/1/2025	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2024 ( Subtotal = $52,694 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	1	12/9/2023	NEW	$52,694
														Subtotal = $52,694

Grand Total All Awards = $161,782

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Breast Milk IgA Exerts Selective Pressure on the Preterm Gut Microbiome

Award Number: F30HD114316

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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