Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome
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 met...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10256/20659 |
| Acceso en línea: | http://hdl.handle.net/10256/20659 |
| Access Level: | acceso abierto |
| Palabra clave: | Esteatosi hepàtica Liver -- Diseases Fetge -- Malalties Obesitat Obesity |
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Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome |
| title |
Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome |
| spellingShingle |
Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome Mayneris Perxachs, Jordi Esteatosi hepàtica Liver -- Diseases Fetge -- Malalties Obesitat Obesity |
| title_short |
Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome |
| title_full |
Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome |
| title_fullStr |
Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome |
| title_full_unstemmed |
Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome |
| title_sort |
Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome |
| dc.creator.none.fl_str_mv |
Mayneris Perxachs, Jordi Cardellini, Marina Hoyles, Lesley Latorre Luque, Jèssica Davato, Francesca Moreno Navarrete, José María Arnoriaga Rodríguez, María Serino, Matteo Abbott, James Barton, Richard H. Puig Alcántara, Josep Fernández-Real, Xavier Ricart, Wifredo Tomlinson, Christopher Woodbridge, Mark Gentileschi, Paolo Butcher, Sarah J. Holmes, Elaine Nicholson, Jeremy K. Pérez Brocal, Vicente Moya, Andrés Clain, Donald Mc. Burcelin, Rémy Dumas, Marc-Emmanuel Federici, Massimo Fernández-Real Lemos, José Manuel |
| author |
Mayneris Perxachs, Jordi |
| author_facet |
Mayneris Perxachs, Jordi Cardellini, Marina Hoyles, Lesley Latorre Luque, Jèssica Davato, Francesca Moreno Navarrete, José María Arnoriaga Rodríguez, María Serino, Matteo Abbott, James Barton, Richard H. Puig Alcántara, Josep Fernández-Real, Xavier Ricart, Wifredo Tomlinson, Christopher Woodbridge, Mark Gentileschi, Paolo Butcher, Sarah J. Holmes, Elaine Nicholson, Jeremy K. Pérez Brocal, Vicente Moya, Andrés Clain, Donald Mc. Burcelin, Rémy Dumas, Marc-Emmanuel Federici, Massimo Fernández-Real Lemos, José Manuel |
| author_role |
author |
| author2 |
Cardellini, Marina Hoyles, Lesley Latorre Luque, Jèssica Davato, Francesca Moreno Navarrete, José María Arnoriaga Rodríguez, María Serino, Matteo Abbott, James Barton, Richard H. Puig Alcántara, Josep Fernández-Real, Xavier Ricart, Wifredo Tomlinson, Christopher Woodbridge, Mark Gentileschi, Paolo Butcher, Sarah J. Holmes, Elaine Nicholson, Jeremy K. Pérez Brocal, Vicente Moya, Andrés Clain, Donald Mc. Burcelin, Rémy Dumas, Marc-Emmanuel Federici, Massimo Fernández-Real Lemos, José Manuel |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Esteatosi hepàtica Liver -- Diseases Fetge -- Malalties Obesitat Obesity |
| topic |
Esteatosi hepàtica Liver -- Diseases Fetge -- Malalties Obesitat Obesity |
| description |
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 |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion peer-reviewed |
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article |
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publishedVersion |
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http://hdl.handle.net/10256/20659 |
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http://hdl.handle.net/10256/20659 |
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Inglés |
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Inglés |
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info:eu-repo/semantics/altIdentifier/doi/10.1186/s40168-021-01052-7 info:eu-repo/semantics/altIdentifier/eissn/2049-2618 |
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Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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BioMed Central |
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BioMed Central |
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Microbiome, 2021, vol. 9, art.núm. 104 Articles publicats (D-CM) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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1869421096153907200 |
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Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiomeMayneris Perxachs, JordiCardellini, MarinaHoyles, LesleyLatorre Luque, JèssicaDavato, FrancescaMoreno Navarrete, José MaríaArnoriaga Rodríguez, MaríaSerino, MatteoAbbott, JamesBarton, Richard H.Puig Alcántara, JosepFernández-Real, XavierRicart, WifredoTomlinson, ChristopherWoodbridge, MarkGentileschi, PaoloButcher, Sarah J.Holmes, ElaineNicholson, Jeremy K.Pérez Brocal, VicenteMoya, AndrésClain, Donald Mc.Burcelin, RémyDumas, Marc-EmmanuelFederici, MassimoFernández-Real Lemos, José ManuelEsteatosi hepàticaLiver -- DiseasesFetge -- MalaltiesObesitatObesityBackground 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 therapiesThis work was supported by EU-FP7 FLORINASH (Health-F2-2009-241913) to R.B., M.F., J.M.F.R., E.H. and J.K.N. Infrastructure support was provided by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC). L.H. was in receipt of an MRC Intermediate Research Fellowship in Data Science (grant number MR/L01632X/1, UK Med-Bio). This work was also partly supported by funding to M.-E.D. (EU METACARDIS under agreement HEALTH-F4-2012-305312, Neuron II under agreement 291840 and the MRC MR/M501797/1) and by grants from the French National Research Agency (ANR-10-LABX-46 [European Genomics Institute for Diabetes]), from the National Center for Precision Diabetic Medicine – PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council (Agreement 20001891/NP0025517) and by the European Metropolis of Lille (MEL, Agreement 2019_ESR_11) and by Isite ULNE (R-002-20-TALENT-DUMAS), also jointly funded by ANR (ANR-16-IDEX-0004-ULNE) the Hauts-de-France Regional Council (Agreement 20002045) and by the European Metropolis of Lille (MEL). J.M.-P. is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund ‘Investing in your future’. María Arnoriaga Rodríguez is funded by a predoctoral Río Hortega contract (CM19/00190, co-funded by European Social Fund ‘Investing in your future’) from the Instituto de Salud Carlos III, Spain. This work was supported by grants to AM from the Spanish Ministry of Science and Innovation (PID2019-105969GB-I00) and Generalitat Valenciana (project Prometeo/2018/133)BioMed Central2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionpeer-reviewedapplication/pdfhttp://hdl.handle.net/10256/20659Microbiome, 2021, vol. 9, art.núm. 104Articles publicats (D-CM)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/semantics/altIdentifier/doi/10.1186/s40168-021-01052-7info:eu-repo/semantics/altIdentifier/eissn/2049-2618Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10256/206592026-05-29T05:05:01Z |
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