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

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Mayneris-Perxachs, J., Cardellini, M., Hoyles, L. ORCID: 0000-0002-6418-342X, Latorre, J., Davato, F., Moreno-Navarrete, J.M., Arnoriaga-Rodríguez, M., Serino, M., Abbott, J., Barton, R., Puig, J., Fernandez-Real, X., Ricart, W., Tomlinson, C., Woodbridge, M., Gentileschi, P., Butcher, S., Holmes, E., Nicholson, J., Pérez-Brocal, V., Moya, A., McClain, D., Burcelin, R., Dumas, M.-E., Federici, M. and Fernández-Real, J.M., 2021. Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome. Microbiome, 9: 104. ISSN 2049-2618

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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.

Item Type:

Journal article

Publication Title:

Microbiome

Creators:

Mayneris-Perxachs, J., Cardellini, M., Hoyles, L., Latorre, J., Davato, F., Moreno-Navarrete, J.M., Arnoriaga-Rodríguez, M., Serino, M., Abbott, J., Barton, R., Puig, J., Fernandez-Real, X., Ricart, W., Tomlinson, C., Woodbridge, M., Gentileschi, P., Butcher, S., Holmes, E., Nicholson, J., Pérez-Brocal, V., Moya, A., McClain, D., Burcelin, R., Dumas, M.-E., Federici, M. and Fernández-Real, J.M.

Publisher:

BioMed Central Ltd.

Date:

7 May 2021

Volume:

ISSN:

2049-2618

Identifiers:

Number	Type
10.1186/s40168-021-01052-7	DOI
1426429	Other

Rights:

© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data

Divisions:

Schools > School of Science and Technology

Record created by:

Jonathan Gallacher

Date Added:

22 Mar 2021 10:01

Last Modified:

31 May 2021 15:03

URI:

https://irep.ntu.ac.uk/id/eprint/42552