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

What was reviewed?

This minireview examined gut microbiota, hepcidin liver fibrosis as an intertwined biological axis driving hepatic iron overload, inflammation, and fibrogenesis. Drawing on mechanistic and translational literature, the authors synthesized how the liver’s master iron hormone hepcidin (HAMP) is regulated by iron status and inflammatory cues, and how gut microbiota composition and metabolites can reshape iron absorption, immune signaling, and hepatocyte hepcidin expression through the gut–liver axis. The review also incorporated a bioinformatics-based component exploring HAMP’s enriched biological processes and disease associations, plus reported microbial strain correlations linked to HAMP expression, to frame potential host–microbe regulatory loops relevant to fibrosis pathogenesis.

Who was reviewed

The article did not review a single patient cohort; instead, it integrated evidence across experimental models (including germ-free and colonized mice, diet-induced liver injury models, and cellular systems involving hepatocytes, macrophages, dendritic cells, and hepatic stellate cells) alongside human observational and clinical contexts such as NAFLD/NASH, alcoholic liver disease, HBV/HCV-related fibrosis, cholestatic injury (e.g., biliary atresia), cirrhosis, and hepatocellular carcinoma. The microbial dimension spanned commensals implicated in iron handling (e.g., Bifidobacterium longum, Bacteroides fragilis, B. thetaiotaomicron, Faecalibacterium prausnitzii, Lactobacillus spp.) as well as pathogens associated with HAMP-linked immune/iron biology (e.g., Mycobacterium tuberculosis, Brucella suis).

Most important findings

The central claim is a bidirectional feedback loop: liver injury and iron dysregulation can induce gut dysbiosis, and dysbiosis can amplify liver injury by increasing barrier permeability, bacterial translocation, and pro-fibrotic immune signaling. Hepcidin downregulation promotes ferroportin (FPN)-mediated iron efflux from enterocytes and macrophages, raising circulating iron and driving hepatic iron accumulation; this fuels oxidative stress (Fenton chemistry), inflammatory cytokine release (including Kupffer-cell–linked pathways), and hepatic stellate cell activation with extracellular matrix deposition. The review highlights two microbiome-facing levers for hepcidin control: microbial products like LPS activating hepatocyte TLR4 pathways (directly or via macrophage IL-6/STAT3 signaling) and microbiota-dependent modulation of intestinal iron transporter expression (DMT1, DCYTB, FPN) and luminal iron chemistry via SCFAs. Specific commensals were noted to upregulate hepcidin in macrophage-stimulated contexts through BMP/SMAD signaling with IL-1β, while microbial metabolites (e.g., reuterin, 1,3-diaminopropane) may suppress intestinal HIF-2α–driven iron transport programs and increase ferritin storage, potentially reducing systemic iron loading. Figures in the paper synthesize these pathways (notably the “symbiosis vs dysbiosis” schematic linking gut barrier failure, LPS signaling, and hepcidin/FPN control of stellate-cell activation).

Key implications

Clinically, the review reframes liver fibrosis as partly an iron–microbiome disease: hepcidin is not only an iron hormone but also an immune effector that shapes microbial ecology and inflammatory tone. This supports therapeutic concepts that combine iron modulation (e.g., reducing iron load, restoring appropriate hepcidin signaling) with microbiome-targeted approaches (dietary strategies influencing luminal iron, probiotics/commensal consortia that favor balanced hepcidin induction, and metabolite-centered interventions that regulate intestinal iron transport). Importantly, the authors emphasize that antifibrotic strategies may be safer and more durable if they restore physiological intercellular crosstalk (hepatocytes–Kupffer cells–HSCs) and gut–liver signaling rather than only suppressing downstream fibrosis pathways.

Citation

Ahmadi Badi SA, Bereimipour A, Rohani P, Khatami S, Siadat SD. Interplay between gut microbiota and the master iron regulator, hepcidin, in the pathogenesis of liver fibrosis. Pathogens and Disease. 2024;82:ftae005. doi:10.1093/femspd/ftae005