# Cross-talk between iron metabolism and intestinal inflammation

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $458,878

## Abstract

PROJECT SUMMARY
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-1β 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-1β-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.

## Key facts

- **NIH application ID:** 9934094
- **Project number:** 5R01AI089700-10
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Bobby Joseph Cherayil
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $458,878
- **Award type:** 5
- **Project period:** 2011-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934094

## Citation

> US National Institutes of Health, RePORTER application 9934094, Cross-talk between iron metabolism and intestinal inflammation (5R01AI089700-10). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/9934094. Licensed CC0.

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