A very low carbohydrate, ketogenic diet suppresses tumor insulin signaling and enhances immune infiltration in women with endometrial cancer: results from a randomized feasibility study.
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PROVIDER: PRJNA1310564 | ENA |
REPOSITORIES: ENA
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Project description:Objectives: To evaluate the feasibility of a very low carbohydrate, ketogenic, diet in women with endometrial cancer and obesity, and to assess the effects of this dietary pattern on metabolism and tumor biology. Design: A multicentre, parallel, prospective, randomized, controlled feasibility study in treatment naïve women with endometrial cancer. Participants were randomized in a 2:1 fashion to a very-low carbohydrate (VLCD) diet, or to continue with their standard diet (SD) by the method of random permuted block. Setting: Eight locations from two teaching hospitals in the New York and New Jersey areas. Participants: 19 treatment naïve women with endometrial cancer (stages IA-IIIC2) and obesity. 15 completed the study. Intervention: After initial biopsy and pathology confirmation, participants received 21-28 days of VLCD and weekly nutritional counseling, followed by surgical staging. Main outcome measures: Dietary adherence, rates of attrition, and adverse effects. Changes in circulating concentration of metabolic biomarkers. Changes in immunohistochemical staining and RNA-Sequencing for insulin signaling pathway, cell apoptosis, proliferation, and immunity. Results: Of the 19 participants randomized, 15 finished the trial with an overall attrition rate of 21%. Participants in the VLCD arm reported consuming 91 ± 4% of the meals, leading to a rise in ketone bodies for all participants by day 3 or 4 and an overall weight loss of 5.5 ± 0.8%. The VLCD was well-tolerated with no grade 3/4 adverse events. Fasting plasma glucose and insulin levels were reduced by 22 ± 5.9% and 60 ± 3.8%, respectively. Total cholesterol and low-density lipoprotein (LDL) were increased by 6 ± 2.7% and 17.8 ± 8.9%, respectively. Gene Set Enrichment Analysis using RNA-Seq revealed enrichment in pathways related to fatty acid oxidation, oxidative phosphorylation, estrogen response, interferon-alpha response and CD8+ T cells (p < 0.05 and NES > 1.60). CD8+ T cells were found to infiltrate the tumor margins under VLCD compared to SD (p = 0.019). Conclusions: A VLCD is feasible and well-tolerated in obese and overweight women with endometrial cancer and leads to significant host and tumor metabolic changes that suggest potential therapeutic benefits that warrant further investigation in larger clinical trials.
2025-08-30 | GSE306395 | GEO
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:Sepsis patients suffer from severe metabolic and immunologic dysfunction that may be amplified by standard nutritional approaches relying primarily on carbohydrates. We here hypothesize that a ketogenic diet improves sepsis treatment. We conducted a monocentric open-labeled randomized controlled trial enrolling 40 adult sepsis patients. Patients were randomly assigned to either ketogenic diet (KD) or standard high-carbohydrate nutrition for 14 days and followed up until day 30. The primary outcome measure was β-hydroxybutyrate (BHB) serum concentration on day 14. We assessed feasibility and safety of KD, as well as diet-associated clinical and immunological changes. The respective nutrition protocols were successfully applied, dropouts did not occur. Regression analysis revealed a greater increase in BHB concentrations from baseline to day 14 in KD patients compared to controls. Metabolic side effects were not observed under ketogenic diet. Ventilation-free, vasopressor-free, dialysis-free and ICU-free days significantly increased in patients under ketogenic diet. Transcriptome profiling of both CD4+ and CD8+ T cells at day 14 revealed substantial differential regulation of gene expression in the KD vs. the control group indicating a reduced T-cell activation and a shift towards a more regulated immunity.
2024-06-13 | GSE240861 | GEO
Project description:Low carbohydrate ketogenic diet (LCKD) has been used for treatment obesity and epilepsy, however, the molecular mechanism of effect of a LCKD (F3666) on tissues has not been fully investigated. In this study, novel molecular targets of LCKD were explored by gene expression profiling in the liver and cerebral cortex of an LCKD-fed mouse model.
2019-06-10 | GSE115342 | GEO
Project description:This study examine the effects of very low carbohydrate diet (in which the calories requirements are mostly from fat) to the level of systemic inflammation (measured by Glasgow Prognostic Score), serum lactate and TNF Alpha levels
| 2249657 | ecrin-mdr-crc
Project description:The very low-calorie ketogenic diet (VLCKD) has emerged as an effective weight loss strategy for obese patients. It significantly reduces visceral adipose tissue (VAT), which is cardinal for mitigating metabolic complications associated with obesity. By promoting rapid weight loss, VLCKD helps to decrease insulin resistance and alleviate inflammation. Chronic liver inflammation can progress to severe conditions like non-alcoholic steatohepatitis and fibrosis, potentially resulting in liver failure and hepatocellular carcinoma. Transient elastography (FibroScan) is a known technique for assessing hepatic steatosis, with FIB E levels below 8kPa indicating low fibrosis risk (LR), while levels above 8kPa suggest a higher risk of chronic liver disease (IHR). Prevention of fibrosis includes lifestyle changes such as a healthy diet and increased physical activity. Traditional low-calorie diets often fail to achieve significant weight loss; hence, the very low-calorie ketogenic diet (VLCKD) is proposed as an effective strategy to decrease VAT and insulin resistance. Recent studies indicate extracellular vesicles (EVs), particularly small EVs (sEVs), play a crucial role in liver fibrosis by activating hepatic stellate cells. Our group identified that sEVs, to be involved in liver degeneration binded to the fibrosis. The aim of this study is to investigate the role of sEVs in 60 obese adults classified as LR and IHR based on FIB E score, enrolled in an 8-week VLCKD weight loss program. Remarkably, the cellular reactivity to sEVs derived from these patients in the early production and modulation of certain fibrosis markers, such as MMPs, and stress fibres Vimentin, and α-Actin was studied.
2024-12-19 | GSE279581 | GEO
Project description:Metaproteomics is a valuable approach to characterize the biological functions involved in the gut microbiota (GM) response to dietary interventions. Ketogenic diets (KDs) are very effective in controlling seizure severity and frequency in drug-resistant epilepsy (DRE) and in the weight loss management in obese/overweight individuals. This case study provides proof of concept for the suitability of metaproteomics to monitor changes in taxonomic and functional GM features in an individual on a short-term very low-calorie ketogenic diet (VLCKD, 4 weeks), followed by a low-calorie diet (LCD). A marked increase in Akkermansia and Pseudomonadota was observed during VLCKD and reversed after the partial reintroduction of carbohydrates (LCD), in agreement with the results of previous metagenomic studies. In functional terms, the relative increase in Akkermansia was associated with an increased production of proteins involved in response to stress and biosynthesis of gamma-aminobutyric acid. In addition, VLCKD caused a relative increase in enzymes involved in the synthesis of the beta-ketoacid acetoacetate and of the ketogenic amino acid leucine. Our data support the potential of fecal metaproteomics to investigate the GM-dependent effect of KD as a therapeutic option in obese/overweight individuals and DRE patients.
2024-12-23 | PXD055204 | Pride
Project description:The Ketogenic Diet (KD) was shown to extend lifespan and preserve memory in aged mice. We carried out RNA-seq on brains of mice aged 13-26 months on standard Carbohydrate-rich control Diet (CD) vs KD, to better understand KD's mechanism for memory preservation.
2024-10-21 | GSE230324 | GEO
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:A ketogenic diet (KD) is a very low-carbohydrate, very high-fat diet recently proposed to treat obesity and type 2 diabetes. While KD grows in popularity, its effects on metabolic health are understudied. (here) We show that, while KD protects against weight gain and induces weight loss, over long-term, mice develop hyperlipidemia, hepatic steatosis, and severe glucose intolerance. Unlike HFD-fed mice, KD mice are not insulin resistant and have low levels of insulin. Hyperglycemic clamp and ex vivo GSIS revealed cell-autonomous and whole-body impairments in insulin secretion. Major ER/Golgi stress and disrupted ER-Golgi protein trafficking was indicated by transcriptomic profiling of KD islets and confirmed by electron micrographs showing a dilated and fragmented Golgi network compatible with defects in insulin granule biogenesis and secretion. Overall, our results suggest long-term KD leads to multiple aberrations of metabolic parameters that caution its systematic use as a health promoting dietary intervention.
2025-08-18 | GSE268020 | GEO