The anemia of inflammation (AI) is a frequent complication of inflammatory bowel disease (IBD) and is caused by abnormally elevated expression of the hepatocyte-derived hormone hepcidin, the central regulator of systemic iron homeostasis. Inflammation-associated increases in hepcidin expression lead to intracellular iron sequestration, hypoferremia and compromised erythropoiesis. Effective treatment of AI requires detailed knowledge of the mechanisms that up-regulate hepcidin in the context of inflammation. The goal of the proposed studies is to elucidate these mechanisms using tissue culture approaches as well as mouse models of IBD. In preliminary in vivo experiments, we have found that gut microbiota composition has a significant influence on hepcidin expression during colitis and that this influence is associated with altered STAT3 activity and STAT3-dependent gene expression in the liver. In addition, we have found from in vitro studies that resident gut bacteria are able to induce the secretion of IL-1? by monocyte-macrophages, and that this cytokine acts on hepatocytes to up-regulate hepcidin by a novel mechanism involving activation of the bone morphogenetic protein (BMP) signaling pathway. Based on our findings, we hypothesize that the gut microbiota has an important, previously unappreciated, effect on hepcidin expression during intestinal inflammation, and that clarifying the molecular basis of this effect may lead to new strategies for manipulating hepcidin levels. We will test this idea in experiments that will characterize 2 mechanisms by which the microbiota influences hepcidin expression: (1) We will follow up on our preliminary in vivo observations to clarify which aspects of STAT3-dependent hepcidin up-regulation are influenced by the microbiota. We will also use metagenomic sequencing and metabolite profiling to shed light on the mechanisms that mediate the effects of the microbiota on hepcidin expression. (2) Following up on our preliminary in vitro findings, we will use a combination of in vitro and in vivo experiments to clarify how resident gut bacteria up-regulate hepcidin via the novel IL-1?-mediated, BMP signaling-dependent mechanism. We will also determine the in vivo role of this mechanism in colitis-associated hepcidin up-regulation. The results of our studies will increase understanding of AI pathogenesis in IBD, and thus facilitate development of new treatments for this problem.

Public Health Relevance

The purpose of this project is to elucidate the mechanisms involved in the effects of the gut microbiota on hepcidin expression in mouse models of inflammatory bowel disease (IBD). The results of the proposed studies will provide insights into the pathogenesis of the anemia of inflammation associated with IBD and will help to develop new strategies for the treatment of this problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI089700-06A1
Application #
9172845
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2011-06-15
Project End
2021-05-31
Budget Start
2016-06-21
Budget End
2017-05-31
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Verma, Smriti; Cherayil, Bobby J (2017) Iron and inflammation - the gut reaction. Metallomics 9:101-111
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Ward, Naomi L; Phillips, Caleb D; Nguyen, Deanna D et al. (2016) Antibiotic Treatment Induces Long-lasting Changes in the Fecal Microbiota that Protect Against Colitis. Inflamm Bowel Dis 22:2328-40
Trebicka, Estela; Shanmugam, Nanda Kumar N; Chen, Kejie et al. (2015) Intestinal Inflammation Leads to a Long-lasting Increase in Resistance to Systemic Salmonellosis that Requires Macrophages But Not B or T Lymphocytes at the Time of Pathogen Challenge. Inflamm Bowel Dis 21:2758-65
Shanmugam, Nanda Kumar N; Chen, Kejie; Cherayil, Bobby J (2015) Commensal Bacteria-induced Interleukin 1? (IL-1?) Secreted by Macrophages Up-regulates Hepcidin Expression in Hepatocytes by Activating the Bone Morphogenetic Protein Signaling Pathway. J Biol Chem 290:30637-47
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Trebicka, Estela; Shanmugam, Nanda Kumar N; Mikhailova, Anastassia et al. (2014) Effect of human immunodeficiency virus infection on plasma bactericidal activity against Salmonella enterica serovar Typhimurium. Clin Vaccine Immunol 21:1437-42
Su, Libo; Su, Chien-wen; Qi, Yujuan et al. (2014) Coinfection with an intestinal helminth impairs host innate immunity against Salmonella enterica serovar Typhimurium and exacerbates intestinal inflammation in mice. Infect Immun 82:3855-66

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