As these GEITP pages often discuss, every trait (phenotype) represents the contribution of genetics (DNA sequence) epigenetic factors (DNA methylation, RNA interference, histone modifications, chromatin remodeling), environmental effects (diet, lifestyle, smoking), endogenous influences (cardiopulmonary disease, renal status), and each person’s microbiome (gut and other microbes we live with). The environmental “signal” in this article is iron, “endogenous influence” is gut inflammation, and the “gene response” includes hepcidin regulation of iron metabolism. On top of all this, there is competition (for available iron) between intestinal epithelial cells and most bacteria in the microbiome.
Iron metabolism is tightly controlled at both cellular and systemic levels: iron deficiency leads to anemia; iron excess can result in liver disease, heart problems, and diabetes (related to iron-mediated oxidative stress). Authors [see attached article & editorial] show (in mice) an intriguing mechanism of iron metabolism control — that occurs in the gut and is mediated by the interplay between dendritic cells (antigen-presenting cells linking innate immunity with adaptive immunity) and the microbiome — by means of the hormone hepcidin; this cross-talk is essential for recovery from intestinal inflammation. It is well established that mammalian cells, and most of the bacteria in the gut microbiota, both rely on iron for many cellular processes, and therefore they compete with each other for iron procurement.
Under normal homeostatic conditions (and with adequate intake of dietary iron), this competition is not harmful because iron is not generally excreted from the body, and only small amounts that are lost (through bleeding, sweating, or urinary excretion) are quickly replaced through normal diet. However, during intestinal inflammation and associated bleeding, the massive amount of iron — that is lost in the intestinal lumen — can have two major consequences: [a] it can promote growth of iron-dependent bacteria (e.g. potentially pathogenic enterobacteria), and [b] it deprives the host of iron, which has to be reabsorbed from the intestinal lumen.
Iron metabolism is controlled within the cell by iron regulatory proteins that bind iron-responsive transcriptional factors that regulate the expression of iron metabolism genes. This process is controlled systemically by hepcidin, which induces the degradation of the iron exporter ferroportin and thereby limits extracellular efflux of iron. High hepcidin serum levels occur in inflammatory bowel disease (IBD) patients (Crohn disease, in particular), and high serum hepcidin is associated with chronic anemia. Authors demonstrate that mice lacking hepcidin are as susceptible to dextran sodium sulfate (DSS)–induced experimental colitis as wild-type animals — but, upon removal of the inflammatory insult, they struggle to recover body weight and have slowed mucosal healing.
Authors thus found that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the mouse intestine after (experimental colitis) damage; this effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Unexpectedly, authors identified conventional dendritic cells (cDCs) to be a source of hepcidin — which is [a] induced by microbial stimulation in mice, [b] prominent in the inflamed intestine of humans, and [c] essential for tissue repair. cDC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration (which regulates the microbiota and consequently facilitated intestinal repair). Collectively, these data identify a pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through a mechanism of nutritional immunity.
DwN
Science 10 Apr 2020; 368: 186-189 & editorial pp 129-130