The bacterial microbiota regulates normal hematopoiesis via metabolite-induced type 1 interferon signaling
Antibiotic therapy, especially when administered long-term, is associated with adverse hematologic effects such as cytopenia. Signals from the intestinal microbiota are critical to maintain normal hematopoiesis, and antibiotics can cause bone marrow suppression through depletion of the microbiota.
We demonstrated previously that STAT1 signaling is necessary for microbiota-dependent hematopoiesis, but the precise mechanisms by which the gut microbiota signals to the host bone marrow to regulate hematopoiesis remain undefined. We sought to identify the cell type(s) through which STAT1 promotes microbiota-mediated hematopoiesis and to elucidate which upstream signaling pathways trigger STAT1 signaling.
Using conditional knock out and chimeric mice, we found that the microbiota induced STAT1 signaling in non-myeloid hematopoietic cells to support hematopoiesis, and that STAT1 signaling was specifically dependent upon type I interferons (IFNs).Indeed, basal type I IFN signaling was reduced in hematopoietic progenitor cells upon antibiotic treatment. Additionally, we discover that oral administration of the commensal-derived product, NOD1 ligand (NOD1L), rescues the hematopoietic defects induced by antibiotics in mice.
Using metabolomics, we identify additional microbially-produced candidates that can stimulate type I IFN signaling to potentially rescue the hematopoietic defects induced by antibiotics,includingphosphatidylcholine and gamma-glutamylalanine. Overall, our studies define a signaling pathway through which microbiota promote normal hematopoiesis and identifymicrobial metabolites that may serve as therapeutic agents to ameliorate antibiotic-induced bone marrow suppression and cytopenia.
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Published: 12 Feb 2022
Blood advances; DOI: https://doi.org/10.1182/bloodadvances.2021006816
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