# Liver-Gut Axis in Neonatal Anemia and Its Role in RBC Transfusion Associated Gut Injury

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $455,376

## Abstract

Project summary
Anemia is a nearly universal diagnosis in preterm infants, caused primarily by phlebotomy essential for medical
care, though also exacerbated by a variety of factors inherent to immaturity in the ex utero environment. When
severe enough to be treated with RBC transfusion, clinicians must be aware of the risk of critical adverse effects
such as necrotizing enterocolitis (NEC), an inflammatory bowel necrosis characterized by infiltration of
macrophage precursor(s), and a leading cause of mortality in those born between 22- and 28-weeks’ gestation.
We have recently elucidated the connection between anemia and NEC, specifically, the “leaky gut” presentation
characterized by monocytic infiltration, RBC transfusion-associated activation of infiltrated monocytes, and the
resulting intestinal mucosal injury. Our long-term objective is to study the anemia-induced immunity changes in
the neonatal liver and their contribution to gut mucosal injury during RBC transfusion. Our preliminary studies
using our existing pre-clinical murine model of anemia demonstrate that anemia is associated with intestinal
recruitment of a unique population of monocytes (CD11bhiLy6Cmid) expressing triggered myeloid receptor 1
(trem1), similarly to monocytes developing in the neonatal liver but unlike those in the bone marrow or spleen.
Consistent with this, neonatal anemic liver monocytes displayed greater inflammatory activation to heme (found
in stored RBC) than did bone-marrow derived cells. This inflammatory response could be dampened either by
the use of anti-trem1 antibody treatment or by silencing monocyte trem1 expression. Taken together, the
investigators propose a novel hypothesis that in the setting of anemia, a gut-liver-gut boomerang effect takes
place as the leaky gut and associated bacterial translocation during anemia communicate via the portal vein to
the liver, triggering the expansion of hepatic leukocyte populations developing in situ which proceed to infiltrate
the anemic intestine, predisposing to RBC-associated gut injury. To test our central hypothesis, we will pursue
the following specific aims: Aim 1: Elucidate the ontogeny of monocytes recruited to the neonatal intestine during
anemia. Aim 2: Define the role of trem1 signaling on the migration of hepatic monocytes into the anemic intestine,
and on inflammatory activation during RBC transfusion. Aim 3: Determine whether therapeutic targeting of
hepatic trem1+ monocytes during anemia can prevent/attenuate RBC-transfusion associated NEC-like injury.
Accomplishment of the proposed aims will develop an effective therapeutic strategy of inhibiting the hepatic
response during anemia without suppressing protective innate immune mechanisms.

## Key facts

- **NIH application ID:** 10811628
- **Project number:** 5R01HL163043-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Mohan Kumar Krishnan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $455,376
- **Award type:** 5
- **Project period:** 2023-03-20 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811628

## Citation

> US National Institutes of Health, RePORTER application 10811628, Liver-Gut Axis in Neonatal Anemia and Its Role in RBC Transfusion Associated Gut Injury (5R01HL163043-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10811628. Licensed CC0.

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