# Microbiota-dependent regulation of primitive hematopoieses

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $452,479

## Abstract

PROJECT SUMMARY/ABSTRACT
 Bone marrow suppression is a common adverse effect of long-term antibiotic administration, which can
in turn leave patients at substantial risk for future infections. Depletion of commensal intestinal bacteria has
recently been uncovered as the proximal cause of antibiotic-mediated bone marrow suppression, implicating the
microbiome in maintenance of normal hematopoiesis. Commensal bacteria, acting via type I interferon and
STAT1, a major transcription factor downstream of interferon signaling, are necessary to promote the normal
function of hematopoietic progenitors in the bone marrow. However, because commensal bacteria in the gut are
stimulating effects in the distal compartment of the bone marrow, the cell type(s) mediating these responses are
unknown. Further, the sufficiency of type I interferon signaling to maintain hematopoiesis, or which commensal
bacterial signaling pathways interact with this pathway to drive hematopoiesis, are unknown.
 Using a murine model of antibiotic-mediated bone marrow suppression to explore these critical questions,
this proposal aims to interrogate the pathways and mechanisms underlying the microbiome’s effects on
hematopoiesis. Studies will identify in which tissue and cell type(s) type I interferon and STAT1 signaling are
required to promote hematopoiesis, specifically by analyzing STAT1 phosphorylation in different tissues,
generating bone marrow chimeras, and testing conditional knock-out mice. The sufficiency of type I interferon
signaling to maintain hematopoiesis will be determined by characterizing the potential of recombinant interferons
or interferon-stimulatory bacterial products to rescue hematopoiesis in antibiotic-treated mice. Finally, this
proposal will interrogate interactions between STAT1 and signaling through NOD1, a bacterial product receptor,
because both have been implicated in microbiome-mediated hematopoietic regulation. Experiments will define
whether these immune factors act in the same pathway, and identify novel factors linking the microbiota with
cytokines and metabolites in the bone marrow niche.
 These rigorous studies build upon both published and preliminary data to clarify the mechanisms
underlying the regulation of hematopoiesis by the commensal microbiome. Successful completion of these aims
will serve as a critical basis for future studies to develop preventive and therapeutic approaches to combat
antibiotic-associated bone marrow suppression. This work is a close collaboration between Dr. Megan Baldridge,
expert in the effects on the commensal microbiome on the innate immune system, at Washington University
School of Medicine and Dr. Katherine King, expert in immunologic regulation of primitive hematopoiesis, at
Baylor College of Medicine, and leverages these complementary areas of expertise to explore the novel field of
microbiome-mediated hematopoietic regulation.

## Key facts

- **NIH application ID:** 10053705
- **Project number:** 5R01AI141716-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Megan T Baldridge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $452,479
- **Award type:** 5
- **Project period:** 2018-11-07 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053705

## Citation

> US National Institutes of Health, RePORTER application 10053705, Microbiota-dependent regulation of primitive hematopoieses (5R01AI141716-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10053705. Licensed CC0.

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