Very Low Energy Ketogenic Therapy Effects on Fibrosis-Dependent Metabolic Reprogramming: A Serum NMR Pilot Study

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 < 8) and an intermediate-high-risk group (IHR; FIB-E ≥ 8) for hepatic fibrosis onset. Results: An integrated approach combining NMRbased metabolomics and pathway enrichment analysis revealed a marked metabolic shift following VLEKT, characterized by increased ketone bodies (including β-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 β-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.