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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\n                      <jats:italic>Pasteurellaceae<\/jats:italic>\n                      ,\n                      <jats:italic>Leuconostocaceae<\/jats:italic>\n                      and\n                      <jats:italic>Micrococcaea<\/jats:italic>\n                      families. It also had consistent negative associations with several\n                      <jats:italic>Veillonella<\/jats:italic>\n                      ,\n                      <jats:italic>Bifidobacterium<\/jats:italic>\n                      and\n                      <jats:italic>Lactobacillus<\/jats:italic>\n                      species, but positive associations with\n                      <jats:italic>Bacteroides<\/jats:italic>\n                      and\n                      <jats:italic>Prevotella<\/jats:italic>\n                      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,\n                      <jats:italic>Pasteurellaceae<\/jats:italic>\n                      and\n                      <jats:italic>Micrococcacea<\/jats:italic>\n                      families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of\n                      <jats:italic>GYS2<\/jats:italic>\n                      and\n                      <jats:italic>SEC24B.<\/jats:italic>\n                      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\u2019s mice. In line with the results in humans, transplantation from \u2018high ferritin donors\u2019 resulted in alterations in several genes related to iron metabolism and fatty acid accumulation in recipient\u2019s mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Altogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40168-021-01052-7","type":"journal-article","created":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T16:02:56Z","timestamp":1620403376000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":124,"title":["Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome"],"prefix":"10.1186","volume":"9","author":[{"given":"Jordi","family":"Mayneris-Perxachs","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Cardellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley","family":"Hoyles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e8ssica","family":"Latorre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Davato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Maria","family":"Moreno-Navarrete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Arnoriaga-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Serino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Abbott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard H.","family":"Barton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep","family":"Puig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Fern\u00e1ndez-Real","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wifredo","family":"Ricart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Tomlinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Woodbridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Gentileschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Butcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Holmes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy K.","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"P\u00e9rez-Brocal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Moya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald Mc","family":"Clain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9my","family":"Burcelin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-Emmanuel","family":"Dumas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Federici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9-Manuel","family":"Fern\u00e1ndez-Real","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,7]]},"reference":[{"issue":"1","key":"1052_CR1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.28431","volume":"64","author":"ZM Younossi","year":"2016","unstructured":"Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. 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For study 3, all animal experimental procedures were approved by the local ethical committee (approval number 31-278) of Rangueil University Hospital (Toulouse, France) and conducted in strict accordance with the guidelines of the European Communities Directive 86\/609\/EEC regulating animal research.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"104"}}