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

Microbiome

José Maria Moreno-Navarrete¹  Wifredo Ricart¹  José-Manuel Fernández-Real¹  Josep Puig¹  María Arnoriaga-Rodríguez¹  Jèssica Latorre¹  Jordi Mayneris-Perxachs¹  Donald Mc Clain²  Paolo Gentileschi³  Francesca Davato⁴  Massimo Federici⁴  Marina Cardellini⁴  Xavier Fernández-Real⁵  Rémy Burcelin⁶  Matteo Serino⁶  James Abbott⁷  Elaine Holmes⁷  Sarah A. Butcher⁷  Jeremy K. Nicholson⁷  Mark Woodbridge⁷  Richard H. Barton⁷  Christopher Tomlinson⁷  Lesley Hoyles⁸  Marc-Emmanuel Dumas⁹  Vicente Pérez-Brocal^1,10  Andrés Moya^1,10 

[1] Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona “Dr Josep Trueta”, Girona, Spain;Departament de Ciències Mèdiques, University of Girona, Girona and Biomedical Research Institute of Girona (IdibGi), Girona, Spain;CIBERobn Pathophysiology of Obesity and Nutrition, Instituto de Salud Carlos III, Girona, Spain;Department of Internal Medicine, Wake Forest School of Medicine, 27157, Winston Salem, NC, USA;The W. G. Hefner Veterans Affairs Medical Center, 28144, Salisbury, NC, USA;Department of Surgery, University of Rome Tor Vergata, Rome, Italy;Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy;EPFL, Lausanne, Switzerland;Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France;Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: ‘Intestinal Risk Factors, Diabetes, Dyslipidemia, and Heart Failure’, 31432, Toulouse Cedex 4, France;Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, Exhibition Road, SW7 2AZ, London, UK;Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, Exhibition Road, SW7 2AZ, London, UK;Department of Bioscience, School of Science and Technology, Nottingham Trent University, NG11 8NS, Nottingham, UK;Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, Exhibition Road, SW7 2AZ, London, UK;Section of Genomic and Environmental Medicine, National Heart & Lung Institute, Imperial College London, Dovehouse Street, SW3 6LY, London, UK;European Genomic Institute for Diabetes, CNRS UMR 8199, INSERM UMR 1283, Institut Pasteur de Lille, Lille University Hospital, University of Lille, 59045, Lille, France;McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montréal, H3A 0G1, QC, Canada;Unidad Mixta de Investigación en Genómica y Salud, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) and Instituto de Biología Integrativa de Sistemas, Universitat de València and Consejo Superior de Investigaciones Científicas (CSIC), València, Spain;CIBER en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain;

关键词: Systems medicine;    Ferritin;    Iron status;    Gut microbiome;    Non-alcoholic fatty liver disease;    Shotgun sequencing;    Metagenomics;    Obesity;   

DOI  :  10.1186/s40168-021-01052-7

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsHere, 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.ConclusionsAltogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies.5HRkabMBtxskC5-wBBcq1wVideo abstract

【 授权许可】

CC BY