{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T09:03:25Z","timestamp":1781687005298,"version":"3.54.5"},"reference-count":36,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015550","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RC2026"],"award-info":[{"award-number":["RC2026"]}],"id":[{"id":"10.13039\/501100015550","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Ketogenic diets induce profound metabolic reprogramming; however, their impact on systemic metabolism in patients with hepatic fibrosis remains insufficiently characterized. This study aimed to investigate serum metabolic changes induced by Very Low Energy Ketogenic Therapy (VLEKT) and to assess the influence of hepatic fibrosis development on these metabolic adaptations. Methods: Fifty serum samples from 25 obese patients were analyzed using 1D 1H CPMG NMR spectroscopy at baseline (T0) and after 8 weeks of VLEKT (T1). Patients were stratified according to the FIB-E fibrosis index into a low-risk group (LR; FIB-E &lt; 8) and an intermediate-high-risk group (IHR; FIB-E \u2265 8) for hepatic fibrosis onset. Results: An integrated approach combining NMR-based metabolomics and pathway enrichment analysis revealed a marked metabolic shift following VLEKT, characterized by increased ketone bodies (including \u03b2-hydroxybutyric acid and acetone), together with changes in amino acids and lipid-related signals. Among these, acetone provided a robust and quantifiable NMR signal, consistent with enhanced ketogenesis. Stratified analysis indicated differential metabolic flexibility: LR patients exhibited enhanced modulation of tricarboxylic acid (TCA) cycle-related metabolites, whereas IHR patients showed persistent alterations in aromatic amino acids and lipid signals. Significant correlations between tyrosine and \u03b2-alanine with clinical biochemical markers further supported the presence of a fibrosis-dependent metabolic signature. Conclusions: These findings highlight the potential of circulating metabolites as sensitive and non-invasive indicators of hepatic vulnerability and determinants of metabolic adaptability to VLEKT. Moreover, the study underscores the value of NMR-based metabolomics as an innovative tool for improving the non-invasive assessment of metabolic and hepatic health.<\/jats:p>","DOI":"10.3390\/nu18121950","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T08:22:56Z","timestamp":1781684576000},"page":"1950","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Very Low Energy Ketogenic Therapy Effects on Fibrosis-Dependent Metabolic Reprogramming: A Serum NMR Pilot Study"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9140-673X","authenticated-orcid":false,"given":"Rossella","family":"Donghia","sequence":"first","affiliation":[{"name":"Data Science Unit, National Institute of Gastroenterology IRCCS \u201cS. de Bellis\u201d, Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7799-5155","authenticated-orcid":false,"given":"Biagia","family":"Musio","sequence":"additional","affiliation":[{"name":"Dipartimento di Ingegneria Civile, Ambientale, del Territorio, Edile e di Chimica, Politecnico di Bari, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7827-7742","authenticated-orcid":false,"given":"Maria","family":"De Luca","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, National Institute of Gastroenterology IRCCS \u201cS. de Bellis\u201d, Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8853-3533","authenticated-orcid":false,"given":"Francesco","family":"Balestra","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, National Institute of Gastroenterology IRCCS \u201cS. de Bellis\u201d, Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Panzetta","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, National Institute of Gastroenterology IRCCS \u201cS. de Bellis\u201d, Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7863-3105","authenticated-orcid":false,"given":"Stefano","family":"Todisco","sequence":"additional","affiliation":[{"name":"Dipartimento di Ingegneria Civile, Ambientale, del Territorio, Edile e di Chimica, Politecnico di Bari, Via Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8841-458X","authenticated-orcid":false,"given":"Pietro","family":"Mastrorilli","sequence":"additional","affiliation":[{"name":"Dipartimento di Ingegneria Civile, Ambientale, del Territorio, Edile e di Chimica, Politecnico di Bari, Via Orabona 4, 70125 Bari, Italy"},{"name":"Innovative Solutions S.r.l.\u2014Spin-Off Company of the Polytechnic University of Bari, Zona H 150\/B, Noci, 70015 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3359-7010","authenticated-orcid":false,"given":"Sergio","family":"Coletta","sequence":"additional","affiliation":[{"name":"Core Facility Biobank, National Institute of Gastroenterology IRCCS \u201cS. de Bellis\u201d, Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2759-8347","authenticated-orcid":false,"given":"Martina","family":"Di Chito","sequence":"additional","affiliation":[{"name":"Center of Nutrition for the Research and the Care of Obesity and Metabolic Diseases, National Institute of Gastroenterology IRCCS \u201cS. de Bellis\u201d, Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5140-8060","authenticated-orcid":false,"given":"Gianluigi","family":"Giannelli","sequence":"additional","affiliation":[{"name":"Scientific Direction, National Institute of Gastroenterology IRCCS \u201cS. de Bellis\u201d, Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2926-3106","authenticated-orcid":false,"given":"Vito","family":"Gallo","sequence":"additional","affiliation":[{"name":"Dipartimento di Ingegneria Civile, Ambientale, del Territorio, Edile e di Chimica, Politecnico di Bari, Via Orabona 4, 70125 Bari, Italy"},{"name":"Innovative Solutions S.r.l.\u2014Spin-Off Company of the Polytechnic University of Bari, Zona H 150\/B, Noci, 70015 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0812-4441","authenticated-orcid":false,"given":"Maria Principia","family":"Scavo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Medicine, National Institute of Gastroenterology IRCCS \u201cS. de Bellis\u201d, Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, 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