Interplay between gut microbiota and the master iron regulator, hepcidin, in the pathogenesis of liver fibrosis

Abstract

Introduction: There is a proven role for hepcidin and the composition of gut microbiota and its derivatives in the pathophysiology of liver fibrosis.

Area covered: This review focuses on the literature search regarding the effect of hepcidin and gut microbiota on regulating liver physiology. We presented the regulating mechanisms of hepcidin expression and discussed the possible interaction between gut microbiota and hepcidin regulation. Furthermore, we investigated the importance of the hepcidin gene in biological processes and bacterial interactions using bioinformatics analysis.

Expert opinion: One of the main features of liver fibrosis is iron accumulation in hepatic cells, including hepatocytes. This accumulation can induce an oxidative stress response, inflammation, and activation of hepatic stellate cells. Hepcidin is a crucial regulator of iron by targeting ferroportin expressed on hepatocytes, macrophages, and enterocytes. Various stimuli, such as iron load and inflammatory signals, control hepcidin regulation. Furthermore, a bidirectional relationship exists between iron and the composition and metabolic activity of gut microbiota. We explored the potential of gut microbiota to influence hepcidin expression and potentially manage liver fibrosis, as the regulation of iron metabolism plays a crucial role in this context.

Keywords: Gut microbiota; hepcidin; iron homeostasis; liver Fibrosis.

Figure 1.

The effects of downregulated hepcidin in induction of liver fibrosis.

Figure 2.

The bar plot of the HAMP gene in A) biological processes and B) pathogenic phenotypes. In biological processes, iron metabolism, positive and negative self-regulation in the formation of hemoglobin by this gene are highly evident. Also, in diseases related to liver fibrosis, there has been a more significant observation of liver mass and iron metabolism in the liver.

Figure 3.

The scatter plot of the degree of accumulation and the correlation of HAMP expression with various bacterial strains and microbes.

Figure 4.

The possible interaction between gut microbiota and hepatic hepcidin expression in the determination of normal liver function and pathological fibrosis; in a symbiosis state, the liver has normal functioning due to fine-tuning of hepcidin gene expression in hepatocytes. Hepcidin controls liver physiology by suppressing HSCs activation (by degrading FPN and suppressing SMADs signaling to produce ECM) and inhibiting intracellular hepatic iron overload through inhibiting iron over-efflux from enterocytes and macrophages to circulation. Also, intestinal iron absorption could be desired by the normal function of DMT-1 and DCYTB and an intact gut barrier to inhibit the over-translocation of immunological components to lamina propria and circulation, which control inflammatory signals in the liver. Gut microbiota components, such as LPS, could regulate hepcidin expression by direct (stimulation of TLR-4) and macrophage-mediated (activation of IL-6 receptor) effects in hepatocytes. Under a dysbiotic state, the perturbed gut barrier function increases bacterial translocation, inducing pro-inflammatory responses, and exacerbating hepatic fibrogenic reactions. The inhibitory hepcidin effect on the activated HSCs is disrupted which results to elevated activation of HSCs and excessive accumulation of ECM. On the other hand, the plasma iron level and hepatic intracellular iron overload could be affected by gut microbiota, their components, and metabolites via influencing the expression of iron abortive proteins, such as DMT-1 and DCYTB, and iron efflux pump, FPN.