title: Intestinal inflammation modulates expression of the iron-regulating hormone hepcidin depending on erythropoietic activity and the commensal microbiota.
abstract: States of chronic inflammation such as inflammatory bowel disease are often associated with dysregulated iron metabolism and the consequent development of an anemia that is caused by maldistribution of iron. Abnormally elevated expression of the hormone hepcidin, the central regulator of systemic iron homeostasis, has been implicated in these abnormalities. However, the mechanisms that regulate hepcidin expression in conditions such as inflammatory bowel disease are not completely understood. To clarify this issue, we studied hepcidin expression in mouse models of colitis. We found that dextran sulfate sodium-induced colitis inhibited hepcidin expression in wild-type mice but upregulated it in IL-10-deficient animals. We identified two mechanisms contributing to this difference. Firstly, erythropoietic activity, as indicated by serum erythropoietin concentrations and splenic erythropoiesis, was higher in the wild-type mice, and pharmacologic inhibition of erythropoiesis prevented colitis-associated hepcidin downregulation in these animals. Secondly, the IL-10 knockout mice had higher expression of multiple inflammatory genes in the liver, including several controlled by STAT3, a key regulator of hepcidin. The results of cohousing and fecal transplantation experiments indicated that the microbiota was involved in modulating the expression of hepcidin and other STAT3-dependent hepatic genes in the context of intestinal inflammation. Our observations thus demonstrate the importance of erythropoietic activity and the microbiota in influencing hepcidin expression during colitis and provide insight into the dysregulated iron homeostasis seen in inflammatory diseases.
authors: Department of Pediatrics, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129; and.
authors: Nanda Kumar N
authors: NK
authors: Shanmugam
authors: Department of Pediatrics, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129; and.
authors: Estela
authors: E
authors: Trebicka
authors: Department of Pediatrics, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129; and Food Safety Key Laboratory of Zhejiang Province, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310035, People's Republic of China.
authors: Ling-Lin
authors: LL
authors: Fu
authors: Department of Pediatrics, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129; and.
authors: Hai Ning
authors: HN
authors: Shi
authors: Department of Pediatrics, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129; and cherayil@helix.mgh.harvard.edu.
authors: Bobby J
authors: BJ
authors: Cherayil
mesh_terms: D000818:Animals; D001441:Bacteroides fragilis / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D016264:Dextran Sulfate / Q000008:administration & dosage; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000235:genetics / Q000276:immunology*; D004921:Erythropoietin / Q000097:blood / Q000378:metabolism*; D005260:Female; D064451:Hepcidins / Q000096:biosynthesis / Q000235:genetics*; D006706:Homeostasis / Q000276:immunology; D018836:Inflammation Mediators / Q000097:blood*; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007501:Iron / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D013289:Streptococcaceae / Q000276:immunology
chemical_list: D064451:Hepcidins; C556062:IL10 protein, mouse; D018836:Inflammation Mediators; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D004921:Erythropoietin; D016753:Interleukin-10; D016264:Dextran Sulfate; D007501:Iron