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under the umbrella of the European Joint Programming Initiative \u201cA Healthy Diet for a Healthy Life\u201d (JPI HDHL) and of the ERA-NET cofound ERA-HDHL of the EU Horizon 2020 Research and Innovation Programme","award":["PCIN2017-117"],"award-info":[{"award-number":["PCIN2017-117"]}]},{"name":"VLC-BIOCLINIC initiative of the University of Valencia and the INCLIVA, and GUTMOM (INTIMIC-085) from the EU Joint Programming Initiative Healthy Diet Healthy Life (HDHL) ISCIII, Instituto de Salud Carlos III (Spain); under the umbrella of the European Joint Programming Initiative \u201cA Healthy Diet for a Healthy Life\u201d (JPI HDHL) and of the ERA-NET cofound ERA-HDHL of the EU Horizon 2020 Research and Innovation Programme","award":["IDIFEDER\/2021\/072"],"award-info":[{"award-number":["IDIFEDER\/2021\/072"]}]},{"name":"VLC-BIOCLINIC initiative of the University of Valencia and the INCLIVA, and GUTMOM (INTIMIC-085) from the EU Joint Programming Initiative Healthy Diet Healthy Life (HDHL) ISCIII, Instituto de Salud Carlos III (Spain); under the umbrella of the European Joint Programming Initiative \u201cA Healthy Diet for a Healthy Life\u201d (JPI HDHL) and of the ERA-NET cofound ERA-HDHL of the EU Horizon 2020 Research and Innovation Programme","award":["CIAICO\/2022\/181"],"award-info":[{"award-number":["CIAICO\/2022\/181"]}]},{"name":"VLC-BIOCLINIC initiative of the University of Valencia and the INCLIVA, and GUTMOM (INTIMIC-085) from the EU Joint Programming Initiative Healthy Diet Healthy Life (HDHL) ISCIII, Instituto de Salud Carlos III (Spain); under the umbrella of the European Joint Programming Initiative \u201cA Healthy Diet for a Healthy Life\u201d (JPI HDHL) and of the ERA-NET cofound ERA-HDHL of the EU Horizon 2020 Research and Innovation Programme","award":["INVEST\/2023\/180"],"award-info":[{"award-number":["INVEST\/2023\/180"]}]},{"name":"VLC-BIOCLINIC initiative of the University of Valencia and the INCLIVA, and GUTMOM (INTIMIC-085) from the EU Joint Programming Initiative Healthy Diet Healthy Life (HDHL) ISCIII, Instituto de Salud Carlos III (Spain); under the umbrella of the European Joint Programming Initiative \u201cA Healthy Diet for a Healthy Life\u201d (JPI HDHL) and of the ERA-NET cofound ERA-HDHL of the EU Horizon 2020 Research and Innovation Programme","award":["AP-2021-016-BREIC"],"award-info":[{"award-number":["AP-2021-016-BREIC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic-dysfunction-associated steatotic liver disease (MASLD) affects around 30% of the global population. The sexual dimorphism and gut microbiota play an important role in the early development of MASLD. The main objective of this research was to investigate metabolic changes during the early subclinical MASLD progression, for identifying the sequence of events and evaluating the impact of sexual dimorphism and the microbiota on the initial stages of MASLD development. Male and female Wistar rats 18 weeks old were randomly divided into different groups and fed a chow diet or a 45% high-fat diet for 21 weeks. Every three weeks, samples of serum, urine, and faeces were collected and studied by metabolomics. Furthermore, the liver was analysed at the endpoint. In addition, the gut microbiota was analysed from faecal samples over time using 16S rRNA gene-targeted group-specific primers. Our results revealed that three weeks on an HFD reduced the bacterial diversity in the faecal microbiota of Wistar rats, accompanied by changes in the faecal and urine metabolome. The HFD-induced alterations in microbiota-related co-metabolites in the liver, blood, urine, and faeces indicate a significant role of host\u2013microbiota co-metabolism changes in the early stages of MASLD. In this study, we provide a comprehensive longitudinal analysis, detailing the sequence of events in the early development of MASLD. Our findings suggest that alterations in the gut microbiota diversity and co-metabolism occur before changes in host metabolism in the early onset of liver steatosis, a subclinical phase of MASLD.<\/jats:p>","DOI":"10.3390\/ijms26031288","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T04:36:51Z","timestamp":1738557411000},"page":"1288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Microbiota Co-Metabolism Alterations Precede Changes in the Host Metabolism in the Early Stages of Diet-Induced MASLD in Wistar Rats"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8781-5952","authenticated-orcid":false,"given":"Mar\u00eda","family":"Mart\u00edn-Grau","sequence":"first","affiliation":[{"name":"Departament de Patologia, Universitat de Val\u00e8ncia, 46010 Valencia, Spain"},{"name":"INCLIVA Biomedical Research Institute, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0227-6096","authenticated-orcid":false,"given":"Pilar","family":"Casanova","sequence":"additional","affiliation":[{"name":"Departament de Patologia, Universitat de Val\u00e8ncia, 46010 Valencia, Spain"},{"name":"INCLIVA Biomedical Research Institute, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Moreno-Morcillo","sequence":"additional","affiliation":[{"name":"Departament de Patologia, Universitat de Val\u00e8ncia, 46010 Valencia, Spain"},{"name":"INCLIVA Biomedical Research Institute, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4404-6735","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Morales","sequence":"additional","affiliation":[{"name":"Departament de Patologia, Universitat de Val\u00e8ncia, 46010 Valencia, Spain"},{"name":"INCLIVA Biomedical Research Institute, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4097-3312","authenticated-orcid":false,"given":"Vannina G.","family":"Marrachelli","sequence":"additional","affiliation":[{"name":"INCLIVA Biomedical Research Institute, 46010 Valencia, Spain"},{"name":"Departament de Fisiologia, Universitat de Val\u00e8ncia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4803-1573","authenticated-orcid":false,"given":"Daniel","family":"Monle\u00f3n","sequence":"additional","affiliation":[{"name":"Departament de Patologia, Universitat de Val\u00e8ncia, 46010 Valencia, Spain"},{"name":"INCLIVA Biomedical Research Institute, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.jhep.2024.04.031","article-title":"EASL\u2013EASD\u2013EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD)","volume":"81","author":"Tacke","year":"2024","journal-title":"J. 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