Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome

Abstract

Background The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear. Results Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The transcriptomic findings were replicated in human primary hepatocytes, where iron supplementation also led to triglycerides accumulation and induced the expression of lipid and iron metabolism genes in synergy with palmitic acid. We further explored the direct impact of the microbiome on iron metabolism and liver fact accumulation through transplantation of faecal microbiota into recipient’s mice. In line with the results in humans, transplantation from ‘high ferritin donors’ resulted in alterations in several genes related to iron metabolism and fatty acid accumulation in recipient’s mice. Conclusions Altogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies.

Untargeted metabolomics and transcriptomics identified glutathione metabolism disturbance and PCS and TMAO as potential biomarkers for ER stress in lung

“…Metabolomics and transcriptomics are two methods of profiling that have been frequently used to provide information regarding pathological phenotypes 8 or for the aim of pathogenesis studies 9 , drug-target identification 10 , and biomarker recognition 11 etc. Liquid chromatography–mass spectrometry (LC–MS), as a robust and informative tool in identifying and quantifying molecules in mixtures, could be used to get reliable data regarding the metabolites in tissues, making metabolic comparison between phenotypes possible.…”

Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis

“…Hepatic steatosis has a risk of steatohepatitis, fibrosis, cirrhosis, liver failure, and HCC, and it was reported that dysregulation of microbial metabolites such as aromatic and branched-chain amino acid (AAA and BCAA) or of iron metabolism are related to liver fat accumulation and facilitate steatosis [ 46 , 47 ]; however, additional factors, such as insulin resistance, oxidative stress, ER stress, and mitochondrial dysfunction, are also involved in a disease progression [ 37 , 38 ]. Because the sequential esterification of fatty acids into a glycerol backbone to generate TG and budding as nascent LDs occur at the ER membrane, LDs are closely associated with ER homeostasis.…”

ITCH E3 ubiquitin ligase downregulation compromises hepatic degradation of branched-chain amino acids

“…In recent years, the use of metabolomics and lipidomics, alongside integration with transcriptomics data, has prompted identification of targets to further explore for treatment in, or prevention of, human NAFLD [ [40] , [41] , [42] , [43] ]. A two-stage metabolic and molecular screening of liver tissue showed that hydroquinone and nicotinic acid were inversely correlated with histological NAFLD severity [ 44 ].…”