TY - JOUR
T1 - The bacterial microbiota regulates normal hematopoiesis via metabolite-induced type 1 interferon signaling
AU - Yan, Hannah
AU - Walker, Forrest C.
AU - Ali, Arushana
AU - Han, Hyojeong
AU - Tan, Lin
AU - Veillon, Lucas
AU - Lorenzi, Philip L.
AU - Baldridge, Megan T.
AU - King, Katherine Y.
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (R01 AI141716 to M.T.B. and K.Y.K.) and the National Heart, Lung, and Blood Institute (R35HL155672 to K.Y.K.). H.Y. was supported by National Heart, Lung, and Blood Institute grant F31 HL147514, and F.C.W. was supported by National Institute of General Medical Sciences grant T32 GM007067. This project depended on the support of Joel Sederstrom and the BCM Cytometry and Cell Sorting Core with funding from the NIH (National Center for Research Resources grant S10RR024574, National Institute of Allergy and Infectious Diseases grant AI036211, and National Cancer Institute grant P30CA125123),
Funding Information:
NIH Office of the Director grant S10 OD020066, and the Dan L. Duncan Cancer Center. The MDACC Metabolomics Core Facility is supported by NIH Office of the Director grant S10OD012304-01 and National Cancer Institute grant P30CA016672.
Funding Information:
Funding support for this article was provided by the National Institutes of Health (R01 AI141716, R35 HL155672, F31 HL147514, T32 GM007067, S10 RR024574, AI036211, P30CA125123)
Publisher Copyright:
© 2022 by The American Society of Hematology.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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 reported 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 knockout 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 on type I interferons (IFNs). Indeed, basal type I IFN signaling was reduced in hematopoietic progenitor cells with antibiotic treatment. In addition, we discovered that oral administration of a commensal-derived product, NOD1 ligand, rescues the hematopoietic defects induced by antibiotics in mice. Using metabolomics, we identified additional microbially produced candidates that can stimulate type I IFN signaling to potentially rescue the hematopoietic defects induced by antibiotics, including phosphatidylcholine and g-glutamylalanine. Overall, our studies define a signaling pathway through which microbiota promotes normal hematopoiesis and identify microbial metabolites that may serve as therapeutic agents to ameliorate antibiotic-induced bone marrow suppression and cytopenia.
AB - 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 reported 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 knockout 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 on type I interferons (IFNs). Indeed, basal type I IFN signaling was reduced in hematopoietic progenitor cells with antibiotic treatment. In addition, we discovered that oral administration of a commensal-derived product, NOD1 ligand, rescues the hematopoietic defects induced by antibiotics in mice. Using metabolomics, we identified additional microbially produced candidates that can stimulate type I IFN signaling to potentially rescue the hematopoietic defects induced by antibiotics, including phosphatidylcholine and g-glutamylalanine. Overall, our studies define a signaling pathway through which microbiota promotes normal hematopoiesis and identify microbial metabolites that may serve as therapeutic agents to ameliorate antibiotic-induced bone marrow suppression and cytopenia.
UR - http://www.scopus.com/inward/record.url?scp=85127538516&partnerID=8YFLogxK
U2 - 10.1182/BLOODADVANCES.2021006816
DO - 10.1182/BLOODADVANCES.2021006816
M3 - Article
C2 - 35143611
AN - SCOPUS:85127538516
VL - 6
SP - 1754
EP - 1765
JO - Blood advances
JF - Blood advances
SN - 2473-9529
IS - 6
ER -