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Review
. 2022 Jan 17;7(1):11.
doi: 10.1038/s41392-021-00831-w.

Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations

Huiyuan Zhu #  1 , Dexi Bi #  1 , Youhua Zhang #  1 , Cheng Kong #  2   3 , Jiahao Du  2 , Xiawei Wu  2   4 , Qing Wei  5 , Huanlong Qin  6   7
Affiliations
Review

Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations

Huiyuan Zhu et al. Signal Transduct Target Ther. .

Abstract

The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The composition and metabolic effects of the ketogenic diet, which have increasingly generated interest. a The compositional features of the classic KD and its variants are shown. b The number of publications obtained for the search term “ketogenic diet” in PubMed is shown by the year of publication. Articles published before 1931 were not included due to the unavailability of PubMed records predating this timepoint
Fig. 2
Fig. 2
Summary of KD-induced changes in metabolism and gut microbiota. a, b The KD increases the levels of FA and KBs and decreases plasma glucose concentrations through different pathways. c The KD alters the composition and diversity of microbiota as follows: the increased abundance of Akkermansia muciniphila, Parabacteriodes, Lactobacillus, Ruminococcaceae, Bacteroidetes, and Roseburia, and reduced populations of Bifidobacteria, Desulfovibrio, Turicibacter, Escherichia, Salmonella, and Vibrio
Fig. 3
Fig. 3
Possible mechanisms whereby the ketogenic diet ameliorates metabolic disorders. The mechanisms, through which the ketogenic diet ameliorates endocrine and metabolic disorders, including T2DM, obesity, NAFLD, and PCOS, are shown. Ketogenic diets exert therapeutic effects on metabolic disorders through various mechanisms, including reduction of plasma glucose, glycated hemoglobin levels, and serum insulin levels; improvement of insulin sensitivity; increased satiety; and decreased inflammation
Fig. 4
Fig. 4
Mechanisms of the KD on neuromuscular and neurodegenerative diseases, including AD, PD, ALS, and epilepsy. Ketogenic diets altered the neuropathological and biochemical behavior through a variety of mechanisms including increasing mitochondrial function and ATP producing, decreasing oxidation stress and inflammation in the brain, and improving motor function and motor neuron survival
Fig. 5
Fig. 5
Summary of the potential interplay in the molecular mechanisms of the ketogenic diet (KD) and cancer. The KD exerts a therapeutic effect on tumors such as neuroblastoma, acute myeloid leukemia, glioblastoma, etc., through decreased GPR109A expression, mTORC1 activation, and glucose uptake at the tumor site, which leads to decreased tumor growth, increased survival, and increased chemotherapeutic efficacy
Fig. 6
Fig. 6
Improvements and mechanisms of the functions of the KD exert on cardiac diseases. The KD increases levels of β-HB, promotes histone acetylation of the Sirt7 promoter and activates Sirt7 transcription in cardiac fibrosis and increases the availability of non-glucose substrates in cMPC1−/− hearts
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