# Impact of Anemia and Its Treatment on Gut Injury in Preterm Infants

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $612,219

## Abstract

Summary: Treatment of neonatal anemia is largely based on measured hemoglobin concentrations (Hb).
Historically, neonatologists developed a conservative approach to blood management, using lower Hb thresholds
to trigger transfusions. However, our recent multicenter prospective cohort investigation demonstrated that
significant anemia in preterm infants (Hb ≤8g/dL) is associated with the development of necrotizing enterocolitis
(NEC), a serious intestinal disease and major cause of death in preterm neonates. Our long-term objective is to
identify key mechanisms that regulate anemia-induced alterations in neonatal immunity that contribute to gut
inflammation and injury and thus may predispose neonates to inflammatory conditions such as NEC. Our central
hypothesis is that variability in anemia-induced alterations in immunosuppressive erythroid progenitors (IEPs)
and hypoxia-induced inflammation can differentially impact immune function in the gut, directly predisposing
neonates to gut injury that may cause NEC. Our hypothesis is formulated on the basis of our recent discovery
that severe anemia in preterm infants can result in impaired gut oxygenation, as measured by near infrared
spectroscopy (NIRS), and significantly increased serum levels of pro-inflammatory interferon gamma (IFNg).
Using a preclinical model, our data also demonstrate that anemia drives IFNg production by intestinal
macrophages that induces intestinal injury, consistent with previous studies that demonstrate that IFNg can
directly compromise epithelial barrier function. Importantly, anemia also induces the development of erythroid
progenitors, which not only possess the ability to facilitate increased red blood cell (RBC) production, but also
appear to be intrinsically immunosuppressive. Consistent with this, IEPs isolated from cord blood possess the
ability to suppress macrophage activation, while removal of IEPs in our pre-clinical model exacerbates anemia-
induced gut macrophage activation and intestinal injury. Taken together, these results suggest that individual
variation in the hypoxic response to lower Hb values, coupled with alterations in anemia-induced IEP numbers
and function, creates imbalances that alter local macrophage activity leading to distinct responses in the gut that
predispose neonates to intestinal inflammation and place them at higher risk of NEC. To test our central
hypothesis, we will pursue the following specific aims: Aim 1: Define the correlation between anemia and its
treatment on IEP number and function, and how these relate to serum cytokines, pro-inflammatory monocyte
differentiation, and markers of intestinal oxygenation, inflammation, and injury. Aim 2: Define the impact of
anemia-induced IEPs on macrophage pro-inflammatory cytokine secretion, intestinal inflammation and injury
following different thresholds, durations and treatments of anemia in a pre-clinical model. We think these aims
provide a unique opportunity to define key factors that r...

## Key facts

- **NIH application ID:** 10232158
- **Project number:** 5R01HL138714-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** CASSANDRA D JOSEPHSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $612,219
- **Award type:** 5
- **Project period:** 2020-08-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232158

## Citation

> US National Institutes of Health, RePORTER application 10232158, Impact of Anemia and Its Treatment on Gut Injury in Preterm Infants (5R01HL138714-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10232158. Licensed CC0.

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