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The Ketogenic Diet: Biochemical Mechanisms and Clinical Applications
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The Ketogenic Diet: Biochemical Mechanisms and Clinical Applications

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Clinical Nutrition".

Deadline for manuscript submissions: closed (25 January 2026) | Viewed by 21078

Special Issue Editor

Prof. Dr. Jose M. Soriano del Castillo

E-Mail Website
Guest Editor
1. Food & Health Laboratory, Institute of Materials Science, University of Valencia, 46980 Paterna, Spain
2. Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, University of Valencia-Health Research Institute La Fe, 46026 Valencia, Spain
Interests: nutrition; medicinal plants; natural products; human health; bioactive compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The ketogenic diet (KD) is a high-fat, low-carbohydrate, and moderate-protein nutritional strategy that induces ketosis, a metabolic state in which the body primarily utilizes ketone bodies for energy instead of glucose. Initially developed for treating refractory epilepsy, the KD has expanded its relevance across various clinical domains. This narrative review synthesizes current evidence regarding the biochemical mechanisms, therapeutic applications, and limitations of the KD. At the physiological level, the KD modulates key metabolic pathways, reduces insulin secretion, enhances mitochondrial efficiency, and influences signaling cascades such as AMPK and mTOR. These mechanisms contribute to the KD’s reported benefits in metabolic conditions like obesity, type 2 diabetes, and polycystic ovary syndrome, as well as in neurological disorders and certain cancers. Despite its therapeutic potential, concerns remain regarding long-term adherence, nutritional deficiencies, and possible adverse effects, particularly in specific populations. The KD should be implemented with medical supervision and tailored to individual needs.

This Special Issue highlights both the promise and the complexity of the KD. While evidence supports its short- and medium-term use in select conditions, more rigorous and long-term studies are needed. Standardized protocols and a personalized approach are essential to maximize its safety and efficacy in clinical practice.

Prof. Dr. Jose M. Soriano del Castillo
Guest Editor

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Keywords

  • ketogenic diet
  • ketosis
  • metabolic pathways
  • therapeutic applications
  • personalized nutrition
  • long-term adherence
  • insulin modulation

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Published Papers (4 papers)

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Research

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14 pages, 1151 KB  
Article
Effect of Oral Ketone Body Intake on Human CD8+ T-Cell Immunometabolism
by David Effinger, Simon Hirschberger, Thore Arntjen, Michaela Zell, Lesca Miriam Holdt and Simone Kreth
Nutrients 2026, 18(5), 778; https://doi.org/10.3390/nu18050778 - 27 Feb 2026
Viewed by 558
Abstract
Background/Objectives: The ketogenic diet (KD) has been shown to exert beneficial effects on human immunity by enhancing cytotoxic T lymphocyte function through metabolic reprogramming. However, strict dietary restrictions limit adherence and complicate its use in clinical practice. Exogenous ketone supplements have therefore [...] Read more.
Background/Objectives: The ketogenic diet (KD) has been shown to exert beneficial effects on human immunity by enhancing cytotoxic T lymphocyte function through metabolic reprogramming. However, strict dietary restrictions limit adherence and complicate its use in clinical practice. Exogenous ketone supplements have therefore been promoted as a more feasible alternative to elevate ketone body levels without the need for dietary changes. The objective of this study was to assess whether ketone salt or ketone ester supplementation can reproduce KD-mediated immunometabolic effects on CD8+ T cells in healthy individuals. Methods: In a prospective interventional study, healthy volunteers received either ketone salts (KS) or ketone esters (KE) for three weeks. Plasma β-hydroxybutyrate (BHB) concentrations were determined, and CD8+ T-cell cytokine secretion, functional responses, and mitochondrial energy metabolism were analyzed. In a subgroup, KS supplementation was combined with a carbohydrate-restricted, non-ketogenic diet. Results: While KS supplementation resulted in a short-lived increase in plasma BHB concentrations followed by increased BHB uptake in immune cells, KE supplementation led to more sustained plasma BHB levels, however, without detectable intracellular BHB accumulation. Neither intervention affected CD8+ T-cell cytokine production, functional capacity, or mitochondrial energy metabolism, and KS intake combined with a carbohydrate-restricted, non-ketogenic diet likewise did not alter CD8+ T-cell immunometabolic parameters. Conclusions: Transient elevation of circulating ketone body levels through supplementation seems insufficient to reproduce the immunometabolic effects of a KD, which likely require broader metabolic adaptations. Thus, the impact of exogenous ketones on adaptive immunity in healthy individuals appears limited. Full article
(This article belongs to the Special Issue The Ketogenic Diet: Biochemical Mechanisms and Clinical Applications)
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17 pages, 1273 KB  
Article
Effect of Exogenous Ketones as an Adjunct to Low-Calorie Diet on Metabolic Markers
by Eliza J. Roeth, Genevieve Parker, Ella F. Cooper-Leavitt, Colson G. Beus, Cameron R. Braithwaite, Madeline D. Morris, Asher P. Reynolds, Ethan P. Evans, Jack H. Radford, Fischer D. Davis, Paul R. Reynolds, R. Ryley Parrish and Benjamin T. Bikman
Nutrients 2025, 17(22), 3582; https://doi.org/10.3390/nu17223582 - 16 Nov 2025
Cited by 1 | Viewed by 6967
Abstract
Background/Objectives: Overweight and obesity affect a majority of adults, contributing to metabolic disorders. Caloric restriction often leads to undesirable lean mass loss alongside fat reduction. This study investigated whether exogenous β-hydroxybutyrate (BHB) supplementation, as an adjunct to a hypocaloric diet, improves body composition [...] Read more.
Background/Objectives: Overweight and obesity affect a majority of adults, contributing to metabolic disorders. Caloric restriction often leads to undesirable lean mass loss alongside fat reduction. This study investigated whether exogenous β-hydroxybutyrate (BHB) supplementation, as an adjunct to a hypocaloric diet, improves body composition and metabolic markers in overweight and obese adults by preferentially reducing fat mass while preserving lean mass. Methods: In this 8-week randomized, double-blind, placebo-controlled trial, 51 adults were assigned to receive either racemic BHB mineral salts or placebo (maltodextrin) twice daily, alongside modest caloric restriction. Assessments at baseline and week 8 included dual-energy X-ray absorptiometry for body composition, indirect calorimetry for resting metabolic rate (RMR), and venous blood analyses for cardiometabolic biomarkers (e.g., lipids, HOMA-IR, uric acid, liver enzymes). Results: Body mass decreased in both groups over the intervention (p < 0.01 within placebo and p < 0.001 within BHB). Within the BHB group, fat mass decreased significantly (−2 kg; p < 0.05 vs. baseline), body fat percentage improved (p < 0.01 vs. baseline), and lean-to-fat mass ratio increased (p < 0.05 vs. baseline); no such significant changes were observed within the placebo group. Group × time interactions were not significant for these body composition variables (p > 0.05). Furthermore, lean mass was largely preserved, with no declines in RMR. Within the BHB group, LDL cholesterol was reduced (p < 0.05 vs. baseline), while other lipids, HOMA-IR, and uric acid remained stable, with liver enzymes showing a positive change. Conclusions: Exogenous BHB supplementation may enhance the quality of diet-induced weight loss through within-group improvements in fat mass reduction and lean mass preservation, with no adverse metabolic impacts. Full article
(This article belongs to the Special Issue The Ketogenic Diet: Biochemical Mechanisms and Clinical Applications)
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Review

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32 pages, 1323 KB  
Review
Modulation of Gut Microbiome and Metabolome as One of the Potential Mechanisms of Ketogenic Diet Effect in the Treatment of Epilepsy
by Katarzyna Kowalcze, Damian Dyńka, Wiktoria Klus, Magdalena Dudzińska and Agnieszka Paziewska
Nutrients 2026, 18(1), 31; https://doi.org/10.3390/nu18010031 - 21 Dec 2025
Viewed by 1406
Abstract
Background/Objectives: The over 100-year-old practice of using ketogenic diet (KD) in the treatment of epilepsy has consolidated its position as an effective therapeutic tool. The available publications suggest a significant influence of KD on gut microbiome and metabolome and, on the other hand, [...] Read more.
Background/Objectives: The over 100-year-old practice of using ketogenic diet (KD) in the treatment of epilepsy has consolidated its position as an effective therapeutic tool. The available publications suggest a significant influence of KD on gut microbiome and metabolome and, on the other hand, a correlation between microbiome and metabolome changes and the course of epilepsy. The conclusion is therefore justified that KD can exert a therapeutic effect in epilepsy through the mechanism of gut microbiome and metabolome modulation. Methods:This article is a narrative review aimed at a comprehensive analysis of the literature to gather existing evidence on the relationship between ketogenic diet, its antiepileptic effects and modulation of gut microbiome and metabolome. Results: It has been demonstrated that a ketogenic diet exerts a significant effect on intestinal bacteria and their metabolites, among other actions, increasing the Bacteroides to Firmicutes (B/F) ratio, alleviating dysbiosis, reducing the inflammatory condition in the gut and whole body, increasing the number of specific strains associated with antiepileptic effect, mediating the production of neurotransmitters (GABA, serotonin), exerting influence on the dopaminergic system, on a number of metabolic pathways, on inhibition of genotoxicity and production of short-chain fatty acids (SCFA) in the intestine. Conclusions: Further studies are needed, since the effect of KD on gut microbiome and metabolome modulation in the treatment of epilepsy is an extremely promising and trendsetting direction of research. Full article
(This article belongs to the Special Issue The Ketogenic Diet: Biochemical Mechanisms and Clinical Applications)
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54 pages, 3153 KB  
Review
Beyond GLP-1 Agonists: An Adaptive Ketogenic–Mediterranean Protocol to Counter Metabolic Adaptation in Obesity Management
by Cayetano García-Gorrita, Nadia San Onofre, Juan F. Merino-Torres and Jose M. Soriano
Nutrients 2025, 17(16), 2699; https://doi.org/10.3390/nu17162699 - 20 Aug 2025
Cited by 3 | Viewed by 11385
Abstract
Background/Objectives: Long-term obesity management consistently fails due to two major barriers: poor adherence, exacerbated by ultra-processed foods with addictive potential, and post-weight loss metabolic adaptation that reduces energy expenditure by approximately 500 kcal/day. Current paradigms—static diets and GLP-1 receptor agonists—address these barriers only [...] Read more.
Background/Objectives: Long-term obesity management consistently fails due to two major barriers: poor adherence, exacerbated by ultra-processed foods with addictive potential, and post-weight loss metabolic adaptation that reduces energy expenditure by approximately 500 kcal/day. Current paradigms—static diets and GLP-1 receptor agonists—address these barriers only partially. The objectives of this thesis-driven review are: (1) to conduct a focused evidence-mapping of Ketogenic–Mediterranean Diet (KMD) protocols; (2) to analyze why existing protocols have not explicitly countered metabolic adaptation; and (3) to present the Adaptive Ketogenic–Mediterranean Protocol (AKMP). Methods: Hybrid methodology—an argumentative narrative review anchored by a structured evidence-mapping search (PRISMA-style flow for transparency). Results: We identified 29 studies implementing KMD protocols with significant weight loss and superior adherence. However, none of the published protocols explicitly implement anti-adaptive strategies, despite an estimated ketogenic metabolic advantage (≈100–300 kcal/day), context-dependent and more consistently observed in longer trials and during weight-maintenance settings. Conclusions: Unlike GLP-1 receptor agonists—which primarily suppress appetite, require ongoing pharmacotherapy, and do not directly mitigate the decline in energy expenditure—the AKMP couples a Mediterranean foundation for adherence with a ketogenic metabolic advantage and a biomarker-guided adjustment system explicitly designed to counter metabolic adaptation, aiming to improve the durability of weight loss and patient self-management. As a theoretical construct, the AKMP requires confirmation in prospective, controlled studies; accordingly, we outline a pragmatic 24-week pilot design in “Pragmatic Pilot Trial to Validate the AKMP–Incretin Sequencing”. Full article
(This article belongs to the Special Issue The Ketogenic Diet: Biochemical Mechanisms and Clinical Applications)
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