# The microbiome determines organ damage development in sickle cell disease

> **NIH NIH K01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $153,846

## Abstract

Project Summary:
 Sickle cell disease (SCD) is the most common inherited blood disorder in the United States, affecting 70,000-
100,000 Americans. SCD is caused by a mutation in the β-globin gene that leads to significant deformation of
the red blood cell (RBC) membrane and promotes RBC adhesion to other cells, inducing vaso-occlusive
episodes (VOE). Chronic SCD is accompanied by progressive, systemic multi-organ dysfunction and costs over
$475 million annually in hospital admissions.
 Our recent work demonstrates that the depletion of microbiota in SCD mice by antibiotics reduces organ
damage and iron overload. Our preliminary data show that organ damage is significantly improved in germ-free
SCD mice compared to specific-pathogen-free SCD mice, confirming the importance of microbiota in organ
damage development. Analysis by 16S rDNA sequencing uncovered a candidate bacterium—Enterococcus
gallinarum (E. gallinarum)—that may promote organ damage in SCD mice. Additionally, we demonstrate that
SCD mice fed an iron-restricted diet exhibit significant reversal of organ damage compared with SCD mice fed
a control diet.
 In the current application, we propose a 5-year experimental plan to advance our understanding of the
microbiota-mediated effects on SCD disease progression and to test the manipulation of microbiota as a potential
novel SCD treatment. In Specific Aim 1, we will confirm whether E. gallinarum functions as a pathogenic
bacterium to influence the progression of organ damage in SCD mice. Additionally, we will investigate whether
an E. gallinarum–specific vaccine reduces organ damage burden in SCD mice. We will explore the microbiota-
related mechanisms that induce organ damage in SCD mice. Specifically, we will study how microbiota can
bypass the gut barrier by analyzing relevant gut permeability parameters such as tight junction and mucus layer
integrity. We hypothesize that once E. gallinarum translocates from the portal vein to the liver, it upregulates T
helper 17 (Th17) cells that recruit other inflammatory cells to induce the organ damage seen in SCD mice. In
Specific Aim 2, we will explore the role of dietary iron in gut microbiota survival and whether dietary iron is
involved in disrupting gut barrier integrity in SCD mice. These proposed studies, focused on strategies of
microbiota manipulation in SCD, will allow us to identify the key microbial species that contribute to SCD
pathophysiology and potentially provide novel, cost-effective approaches for managing SCD’s life-long
complications.

## Key facts

- **NIH application ID:** 10915724
- **Project number:** 5K01DK131401-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Huihui Li
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $153,846
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915724

## Citation

> US National Institutes of Health, RePORTER application 10915724, The microbiome determines organ damage development in sickle cell disease (5K01DK131401-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10915724. Licensed CC0.

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