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.

Public Health Relevance

Patients are commonly prescribed long-term antibiotics to treat bacterial infections, but antibiotics can cause serious side effects, including a suppression of the immune cells of the blood and bone marrow. Antibiotics suppress immune cell production indirectly by acting on the healthy bacteria that live in the gut, which normally send signals to the blood and bone marrow to maintain the immune system. Understanding how bacteria in the gut signal to the immune system may provide new insights into preventing or treating these important off-target effects of antibiotics and thus help patients recover more rapidly from infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI141716-02
Application #
9819766
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Rothermel, Annette L
Project Start
2018-11-07
Project End
2023-10-31
Budget Start
2019-11-01
Budget End
2020-10-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130