Non-alcoholic fatty liver disease (NAFLD) results from excessive fat build-up in the liver, affecting people who drink little to no alcohol, which can induce type 2 diabetes and cardiovascular risks. In the liver, iron induces the synthesis of ferritin, which is frequently too high in patients with NAFLD. Only a small part of the iron taken from the diet is absorbed so most of the iron remains available for the gut microbiome. Literature data showed a correlation between the gut microbiome and iron in the pathogenesis of NAFLD, but their cross-talk remains unclear.
In the present study by Mayneris-Perxachs and colleagues, they have characterized mechanisms responsible for the interaction between the gut microbiome and iron metabolism in NAFLD by applying an integrative systems medicine approach (faecal metagenomics, plasma, and urine metabolomics, hepatic transcriptomics) studying 2 human cohorts with individuals with obesity compared to a cohort of individuals without obesity.
In obesity cohorts’ respect to the control cohort, serum ferritin increased with the severity of liver fat accumulation. The authors found a significant correlation between serum ferritin and gut microbiome composition with a consistent decrease in Firmicutes, Actinobacteria, and Proteobacteria bacteria families, in particular Pasteurellaceae, Leuconostocaceae and Micrococcaceae, and negative associations of several Veillonella, Bifidobacterium, and Lactobacillus species. Serum ferritin was positively correlated with Bacteroides and Prevotella species. Notably, analysis of bacterial metagenomes identified several bacterial functions related to iron-related genes associated with serum ferritin concentrations.
Moreover, the authors showed that, among the microbiome-associated transcriptomic signature of iron, the GYS2 gene, involved in the synthesis of glycogen, showed the strongest negative association with NAFLD. Notably, disruption of GYS2 is known to result in impaired glucose deposition and liver fat accumulation in mice.
To validate the association between iron and gut microbiome composition uncovered in humans, the authors verified whether the dietary iron content affects the microbiome in vivo through microbiota faecal transplantation into a mouse model. As in humans, data showed the alteration of genes associated with iron metabolism and fat accumulation.
In conclusion, this study showed the influence of the gut microbiome biodiversity to expression of iron metabolism genes, disclosing potential targets for future therapy.
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