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(INTIMIC-085)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: The interplay between host metabolism and gut microbiota is central to the pathophysiology of metabolic diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we investigated the underexplored fecal host\u2013microbiota co-metabolism profile of male and female Wistar rats after 21 weeks of high-fat diet (HFD), a model previously validated for early MASLD. Methods: Using 1H-NMR spectroscopy, we detected and quantified metabolites in fecal samples associated with hepatic metabolism beyond short-chain fatty acids (SCFAs), such as energy-related metabolites, amino acid turnover, branched-chain amino acid (BCAA) catabolism, and microbial fermentation. Results: Distinct metabolic signatures were identified according to diet and sex, and statistical analysis was performed. Notably, alterations were observed in bile acids (BAs) such as cholate and glycocholate, suggesting disruptions in enterohepatic circulation. The presence of fucose, a sugar linked to liver pathology, was also elevated. Energy-related metabolites indicated a shift from lactate production to increased acetoacetate and malonate levels, implying redirection of pyruvate metabolism and inhibition of the TCA cycle. BCAA derivatives such as 3-methyl-2-oxovalerate and 3-aminoisobutyrate were altered, supporting earlier findings on disrupted amino acid metabolism under HFD conditions. Furthermore, microbial metabolites including methanol and ethanol showed group-specific differences, suggesting shifts in microbial activity. Conclusions: These findings complement previous longitudinal data and provide a functional interpretation of newly identified metabolites. These metabolites, previously unreported, are now functionally contextualized and linked to hepatic and microbial dysregulation, offering novel biological insights into early MASLD mechanisms.<\/jats:p>","DOI":"10.3390\/metabo15100660","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T15:48:30Z","timestamp":1759852110000},"page":"660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Hidden Players of the Fecal Metabolome: Metabolic Dysregulation Beyond SCFAs Under a High-Fat Diet"],"prefix":"10.3390","volume":"15","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"}]},{"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 Gonz\u00e1lez","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":[[2025,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119053","DOI":"10.1016\/j.atherosclerosis.2024.119053","article-title":"Lipotoxicity-driven metabolic dysfunction-associated steatotic liver disease (MASLD)","volume":"400","author":"Maccali","year":"2025","journal-title":"Atherosclerosis"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1016\/j.cgh.2023.04.015","article-title":"The Global Burden of Liver Disease","volume":"21","author":"Younossi","year":"2023","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jhep.2020.03.039","article-title":"A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement","volume":"73","author":"Eslam","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.12998\/wjcc.v11.i6.1236","article-title":"Sex dimorphism and metabolic profiles in management of metabolic-associated fatty liver disease","volume":"11","author":"Monleon","year":"2023","journal-title":"World J. Clin. Cases"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6377","DOI":"10.3390\/cimb46070381","article-title":"The Role of Microbiota-Related Co-Metabolites in MASLD Progression: A Narrative Review","volume":"46","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/s41579-023-00904-3","article-title":"The gut-liver axis and gut microbiota in health and liver disease","volume":"21","author":"Hsu","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mart\u00edn-Grau, M., Casanova, P., Moreno-Morcillo, L., Morales, J.M., Marrachelli, V.G., and Monle\u00f3n, D. (2025). Microbiota Co-Metabolism Alterations Precede Changes in the Host Metabolism in the Early Stages of Diet-Induced MASLD in Wistar Rats. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031288"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3869","DOI":"10.1007\/s00253-023-12527-y","article-title":"L-Fucose is involved in human-gut microbiome interactions","volume":"107","author":"Kim","year":"2023","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1093\/glycob\/cwx034","article-title":"Biological functions of fucose in mammals","volume":"27","author":"Schneider","year":"2017","journal-title":"Glycobiology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1111\/j.1530-0277.1993.tb00761.x","article-title":"Urinary level of L-fucose as a marker of alcoholic liver disease","volume":"17","author":"Yamauchi","year":"1993","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1186\/s12967-018-1718-x","article-title":"L-Fucose ameliorates high-fat diet-induced obesity and hepatic steatosis in mice","volume":"16","author":"Wu","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.jhep.2025.02.033","article-title":"Integrative metabolism in MASLD and MASH: Pathophysiology and emerging mechanisms","volume":"83","author":"Steinberg","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lo, E., Felicianna Xu, J.H., Zhan, Q., Zeng, Z., and El-Nezami, H. (2022). The Emerging Role of Branched-Chain Amino Acids in Liver Diseases. Biomedicines, 10.","DOI":"10.3390\/biomedicines10061444"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"101226","DOI":"10.1016\/j.plipres.2023.101226","article-title":"Monomethyl branched-chain fatty acids: Health effects and biological mechanisms","volume":"90","author":"Gozdzik","year":"2023","journal-title":"Prog. Lipid Res."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/10\/660\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:50:14Z","timestamp":1760035814000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/10\/660"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,7]]},"references-count":14,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["metabo15100660"],"URL":"https:\/\/doi.org\/10.3390\/metabo15100660","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,7]]}}}