Ketogenic Diet as an Epigenetic Therapy in SETD1B-Related Epilepsy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE319821 | GEO | 2026/05/11
REPOSITORIES: GEO
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Project description:Background Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can ‘open’ chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. Methods Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n=4) versus controls (n=4). Findings Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. A 12-year-old boy with KS, suffering from recurrent episodes of cognitive decline, exhibited improved cognitive function and neuropsychological assessment performance after 12 months on the ketogenic diet, with concomitant improvement in transcriptomic ribosomal protein dysregulation.
2024-06-05 | GSE261686 | GEO
Project description:The ketone body β-hydroxybutyrate (BHB) is produced during dietary restriction, fasting, and exercise. A ketogenic diet (KD) results in long-term production of BHB outside of these contexts. We sought to determine a protein-matched, non-obese ketogenic diet (KD) would affect the longevity and healthspan of C57BL/6 male mice. We find that feeding KD every-other-week to prevent obesity (cyclic KD) reduces mid-life mortality but does not affect maximum lifespan. Similar feeding of a non-ketogenic high-fat/low-carbohydrate (HF) diet may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite measures of healthspan. RNAseq gene expression analysis identifies down-regulation of insulin, TOR, and fatty acid synthesis pathways as possible longevity mechanisms common to KD and HF. However, up-regulation of fasting-related PPARα target genes is unique to KD, consistent across tissues, and preserved in old age, suggesting a mechanism for an incremental benefit from KD. In all, we show that a non-obese ketogenic diet improves survival, memory, and healthspan into old age. These gene expression studies were carried out on 12 month-old male C56BL/6 mice from the NIA Aged Rodent Colony, habituated to AIN-93M control diet and then either maintained on this diet or switched for one week to a 75% kcal fat non-ketogenic high-fat diet or a 90% kcal fat ketogenic diet (all diets with 10% kcal from carbohydrates). Tissues were harvested in the middle of the nighttime feeding period (MN-3am).
2017-09-05 | GSE101657 | GEO
Project description:The ketogenic diet has long been used to treat epilepsy, but its mechanism is not yet clearly understood. To explore the potential mechanism, the changes in gene expression induced by the ketogenic diet in the rat kainic acid (KA) epilepsy model were analyzed. Two-condition experiment, Normal diet-fed rat brain vs. Ketogenic diet-fed rat brain. Duplicate per array
2010-05-19 | E-GEOD-19277 | biostudies-arrayexpress
Project description:Rationale: Sepsis patients suffer from severe metabolic and immunologic dysfunction that may be amplified by standard carbohydrate-based nutritional regimes. We therefore hypothesize that a ketogenic diet improves sepsis treatment. Objectives: We investigated the safety and feasibility of a ketogenic diet in sepsis patients. Methods: We conducted a monocentric open-labeled randomized controlled trial (DRKS00017710) enrolling adult sepsis patients randomly assigned to either ketogenic or standard high-carbohydrate diet for 14 days with follow-up until day 30. The primary outcome measure was β-hydroxybutyrate serum concentration on day 14. Secondary outcomes included safety, clinical and immunological changes. Measurements and Main Results: 40 critically ill septic patients were assigned to the study groups. Increase in β-hydroxybutyrate concentrations from baseline to day 14 was markedly greater under ketogenic diet (1.2 ±0.9) compared to controls (-0.3 ±0.4); estimated mean difference 1.4 (95%-CI 1.0-1.8; p<0.0001). During ketogenic diet, no patient required insulin treatment beyond day 4, whereas 35% to 60% of control patients did (p=0.0095). Metabolic side effects were not observed under ketogenic diet. Ventilation-free (IRR 1.7; 95%-CI: 1.5 to 2.1; p<0.0001), vasopressor-free (IRR 1.7; 95%-CI: 1.5 to 2.0; p<0.0001), dialysis-free (IRR 1.5; 95%-CI: 1.3 to 1.8; p<0.0001), and ICU-free days (IRR 1.7; 95%-CI: 1.4 to 2.1; p<0.0001) significantly increased in patients under ketogenic diet. There was no difference in 30-day mortality. Analyses indicated favorable changes towards immune homeostasis. Conclusions: Ketogenic diet is a feasible and safe nutritional regimen in septic patients promoting recovery from sepsis-related organ dysfunction and could become a new tool in modern treatment concepts.
2024-06-13 | PXD046061 | Pride
Project description:Influenza A virus (IAV) infection-associated morbidity and mortality are a key global healthcare concern, necessitating the identification of novel therapies capable of reducing the severity of IAV infections. In this study, we show that the consumption of a low-carbohydrate, high-fat ketogenic diet (KD) protects mice from lethal IAV infection and disease. KD feeding resulted in an expansion of γδ T cells in the lung that improved barrier functions, thereby enhancing anti-viral resistance. Expansion of these protective γδ T cells required metabolic adaptation to a ketogenic diet, as neither feeding mice a high-fat high-carbohydrate diet nor providing chemical ketone body substrate that bypasses hepatic ketogenesis protected against infection. Therefore, KD mediated immune-metabolic integration represents a viable avenue towards preventing or alleviating influenza disease.
2019-08-29 | GSE136536 | GEO
Project description:Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can ‘open’ chromatin and encourage gene expression. Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n=4) versus controls (n=4). Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. Our data reveals that lysine methyltransferase epigenetic regulation is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders.
2024-06-23 | PXD050547 | Pride
Project description:Specific pathogen free wild-type C57Bl/6 male mice fed ketogenic diet (Bio-Serv AIN-76-A) for 4 weeks Keywords: RNA Expression Array Hearts from 12 week-old mice that were maintained on a standard polysacchardide-rich chow until the age of 8 weeks, at which time they were switched to a ketogenic diet (ad libitum) and maintained for 4 additional weeks prior to collection of tissues
2010-06-16 | E-GEOD-21368 | biostudies-arrayexpress
Project description:Interventions: Nutrition counseling We provide outpatient nutritional guidance once a month for 30 minutes. It can be calculated once a month as an outpatient nutrition dietary guidance fee. The modified MCT ketogenic diet is 2-3 meals a day, prepared under the supervision of a registered dietitian, and you can cook your own food according to the following rules, or obtain low-carbohydrate foods at the supermarket or the Internet. .. Meal purchase funds will be borne by the patient. Cooking recipes will be distributed at the start of clinical research. 7 rules of dietary intake 1. The target energy intake is 35-40 kcal per body weight. 2. Eat 1.6-2.0 g of protein-rich foods (meat, fish, eggs, soy products) per body weight. 3. Take at least 4g of EPA daily. 4. Limit the amount of sugar to 25 g or less per day (when the body weight is 50 kg). 5. Ingest 60 to 100 g of medium-chain fatty acids per day in terms of MCT oil. 6. The weight of the meal is morning: noon: evening = 4: 10: 6, and the weight is adjusted so that the person feels hungry before going to bed. 7. The target ketone ratio is 1.4 to 1.6: 1. Estimated implementation period and meal contents (see A and B below) 1. First 3 months: Super ketogenic. 2. From 3 months to 1 year: Continue to eat ketogenic diet, mainly super ketogenic. 3. After the above research period is exceeded, we will instruct them to continue ketogenic and semi-ketogenic Level of carbohydrate restriction 1. Semi-ketogenic Ketone ratio Lipid: Sugar + Protein = 1: 1 Sugar intake 80 g / day or less Lipid intake: flaxseed oil 30 g / day, MCT oil 80 mg / day (total fat 110 g) 2. Ketogenic Ketone ratio Lipid: Sugar + Protein = 1.4: 1 Sugar intake 40 g / day or less Lipid intake: flaxseed oil 30 g / day, MCT oil 80 mg / day (total fat 110
Primary outcome(s): Safety Presence or absence of diarrhea or allergic symptoms b. Dehydration, symptomatological hypoglycemia, excessive ketosis, gastrointestinal symptoms Nutritional status (body weight, body composition analysis using In Body (BIA), serum albumin, serum cholinesterase, serum transthyretin, CRP), QOL score (EORTCQLQ-CR38 Japanese version, POMS2 Japanese version)
Study Design: Single arm Non-randomized
| 2723656 | ecrin-mdr-crc
Project description:While ketogenic nutrition shows promise as an adjunct to conventional cancer therapies, its efficacy varies depending on the type of cancer and its specific metabolic characteristics. How ketone bodies affect tumorigenesis and how the ketogenic pathway becomes deregulated in cancer remain to be fully understood. Using T-cell acute lymphoblastic leukemia (T-ALL) as a model, we here demonstrate that ketogenic metabolite β-hydroxybutyrate (BHB) plays a remarkable pro-leukemogenic role in mice. T-ALL cells generally exhibited greater expression of β-hydroxybutyrate dehydrogenase (BDH1), the metabolic enzyme that leads to cell autonomous synthesis of BHB. Mechanistically, aberrant CDK4 activation enables direct phosphorylation of BDH1 at the serine 296 residue and enhances its protein stability. Importantly, BDH1 deficiency leads to robust growth inhibition and cell death of human T-ALL cells, and markedly impedes NOTCH1-induced T-ALL progression in mice. BDH1-mediated production of BHB enhances the histone modification of β-hydroxybutyrylation (Kbhb), thereby leading to transcriptional activation of pro-leukemogenic genes MYC and NKX3.1. These findings shed light on how oncogenic CDK4 deregulates ketogenesis and promotes leukemia progression via an epigenetic mechanism. Therefore, ketogenic diets or ketone supplements should be taken with caution by cancer patients. Therapeutic interventions targeting key ketogenic enzymes may hold great promise for leukemia treatment.
2026-05-05 | GSE270920 | GEO
Project description:While ketogenic nutrition shows promise as an adjunct to conventional cancer therapies, its efficacy varies depending on the type of cancer and its specific metabolic characteristics. How ketone bodies affect tumorigenesis and how the ketogenic pathway becomes deregulated in cancer remain to be fully understood. Using T-cell acute lymphoblastic leukemia (T-ALL) as a model, we here demonstrate that ketogenic metabolite β-hydroxybutyrate (BHB) plays a remarkable pro-leukemogenic role in mice. T-ALL cells generally exhibited greater expression of β-hydroxybutyrate dehydrogenase (BDH1), the metabolic enzyme that leads to cell autonomous synthesis of BHB. Mechanistically, aberrant CDK4 activation enables direct phosphorylation of BDH1 at the serine 296 residue and enhances its protein stability. Importantly, BDH1 deficiency leads to robust growth inhibition and cell death of human T-ALL cells, and markedly impedes NOTCH1-induced T-ALL progression in mice. BDH1-mediated production of BHB enhances the histone modification of β-hydroxybutyrylation (Kbhb), thereby leading to transcriptional activation of pro-leukemogenic genes MYC and NKX3.1. These findings shed light on how oncogenic CDK4 deregulates ketogenesis and promotes leukemia progression via an epigenetic mechanism. Therefore, ketogenic diets or ketone supplements should be taken with caution by cancer patients. Therapeutic interventions targeting key ketogenic enzymes may hold great promise for leukemia treatment.
2025-12-09 | GSE270919 | GEO