TY - JOUR
T1 - Dietary iron restriction protects against vaso-occlusion and organ damage in murine sickle cell disease
AU - Li, Huihui
AU - Kazmi, Jacob S.
AU - Lee, Sungkyun
AU - Zhang, Dachuan
AU - Gao, Xin
AU - Maryanovich, Maria
AU - Torres, Lidiane
AU - Verma, Divij
AU - Kelly, Libusha
AU - Ginzburg, Yelena Z.
AU - Frenette, Paul S.
AU - Manwani, Deepa
N1 - Funding Information:
The authors thank Colette Prophete and Peng Guo for technical assistance and members of the Frenette laboratory for helpful discussions. This work was supported by the R01 grant from the National Heart, Lung, and Blood Institute (R01 HL069438 to P.S.F and L.K.). H.L. acknowledges the support of the National Heart, Lung, and Blood Institute (1F32HL142243) and National Institute of Diabetes and Digestive and Kidney Diseases (1K01DK131401). Y.Z.G. acknowledges the support of the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK107670 and DK095112). M.M. was supported by the EMBO European Commission FP7 (Marie Curie Actions; EMBOCOFUND2012, GA-2012-600394, ALTF 447-2014), by the New York Stem Cell Foundation Druckenmiller fellowship, and by the American Society of Hematology Research Restart Award. We thank the Flow Cytometry, Histopathology, and Analytical Imaging of Albert Einstein College of Medicine for technical assistance, supported by P250 high-capacity slide scanner (1S10OD019961-01). Contribution: H.L. designed and performed experiments, analyzed data and wrote the manuscript; J.S.K. participated in experiments, data analysis, and the manuscript preparation; S.L. D.Z. X.G. M. M. L.T. and D.V. advised on experimental design and helped with experiments; L.K. and Y.Z.G. participated in study design and revised the manuscript; P.S.F. supervised the study; D.M. supervised the study and wrote the manuscript; and all authors discussed the results and contributed to the manuscript.
Funding Information:
This work was supported by the R01 grant from the National Heart, Lung, and Blood Institute ( R01 HL069438 to P.S.F and L.K.). H.L. acknowledges the support of the National Heart, Lung, and Blood Institute ( 1F32HL142243 ) and National Institute of Diabetes and Digestive and Kidney Diseases ( 1K01DK131401 ). Y.Z.G. acknowledges the support of the National Institute of Diabetes and Digestive and Kidney Diseases ( R01 DK107670 and DK095112 ). M.M. was supported by the EMBO European Commission FP7 (Marie Curie Actions; EMBOCOFUND2012, GA-2012-600394, ALTF 447-2014), by the New York Stem Cell Foundation Druckenmiller fellowship, and by the American Society of Hematology Research Restart Award. We thank the Flow Cytometry, Histopathology, and Analytical Imaging of Albert Einstein College of Medicine for technical assistance, supported by P250 high-capacity slide scanner (1S10OD019961-01).
Publisher Copyright:
© 2023 The American Society of Hematology
PY - 2023/1/12
Y1 - 2023/1/12
N2 - Sickle cell disease (SCD) is an inherited disorder resulting from a β-globin gene mutation, and SCD patients experience erythrocyte sickling, vaso-occlusive episodes (VOE), and progressive organ damage. Chronic hemolysis, inflammation, and repeated red blood cell transfusions in SCD can disrupt iron homeostasis. Patients who receive multiple blood transfusions develop iron overload, and another subpopulation of SCD patients manifest iron deficiency. To elucidate connections between dietary iron, the microbiome, and SCD pathogenesis, we treated SCD mice with an iron-restricted diet (IRD). IRD treatment reduced iron availability and hemolysis, decreased acute VOE, and ameliorated chronic organ damage in SCD mice. Our results extend previous studies indicating that the gut microbiota regulate disease in SCD mice. IRD alters microbiota load and improves gut integrity, together preventing crosstalk between the gut microbiome and inflammatory factors such as aged neutrophils, dampening VOE, and organ damage. These findings provide strong evidence for the therapeutic potential of manipulating iron homeostasis and the gut microbiome to ameliorate SCD pathophysiology. Many treatments, which are under development, focus on lowering the systemic iron concentration to relieve disease complications, and our data suggest that iron-induced changes in microbiota load and gut integrity are related- and novel-therapeutic targets.
AB - Sickle cell disease (SCD) is an inherited disorder resulting from a β-globin gene mutation, and SCD patients experience erythrocyte sickling, vaso-occlusive episodes (VOE), and progressive organ damage. Chronic hemolysis, inflammation, and repeated red blood cell transfusions in SCD can disrupt iron homeostasis. Patients who receive multiple blood transfusions develop iron overload, and another subpopulation of SCD patients manifest iron deficiency. To elucidate connections between dietary iron, the microbiome, and SCD pathogenesis, we treated SCD mice with an iron-restricted diet (IRD). IRD treatment reduced iron availability and hemolysis, decreased acute VOE, and ameliorated chronic organ damage in SCD mice. Our results extend previous studies indicating that the gut microbiota regulate disease in SCD mice. IRD alters microbiota load and improves gut integrity, together preventing crosstalk between the gut microbiome and inflammatory factors such as aged neutrophils, dampening VOE, and organ damage. These findings provide strong evidence for the therapeutic potential of manipulating iron homeostasis and the gut microbiome to ameliorate SCD pathophysiology. Many treatments, which are under development, focus on lowering the systemic iron concentration to relieve disease complications, and our data suggest that iron-induced changes in microbiota load and gut integrity are related- and novel-therapeutic targets.
UR - http://www.scopus.com/inward/record.url?scp=85144776620&partnerID=8YFLogxK
U2 - 10.1182/blood.2022016218
DO - 10.1182/blood.2022016218
M3 - Article
C2 - 36315910
AN - SCOPUS:85144776620
SN - 0006-4971
VL - 141
SP - 194
EP - 199
JO - Blood
JF - Blood
IS - 2
ER -