Pan-Cancer Analysis of Glycolytic and Ketone Bodies Metabolic Genes: Implications for Response to Ketogenic Dietary Therapy

2021 ◽  
Author(s):  
Liyuan Qian ◽  
Yunzheng Li ◽  
Yajuan Cao ◽  
Gang Meng ◽  
Jin Peng ◽  
...  
Keyword(s):  
Ketone Bodies ◽  
Dietary Therapy ◽  
Metabolic Genes ◽  
Pan Cancer

scholarly journals Integrative Analysis Reveals Comprehensive Altered Metabolic Genes Linking with Tumor Epigenetics Modification in Pan-Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Yahui Shi ◽  
Jinfen Wei ◽  
Zixi Chen ◽  
Yuchen Yuan ◽  
Xingsong Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Histone Acetylation ◽  
Epigenetic Modification ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Altered Expression ◽  
Metabolic Genes ◽  
Cancer Types ◽  
Pan Cancer

Background. Cancer cells undergo various rewiring of metabolism and dysfunction of epigenetic modification to support their biosynthetic needs. Although the major features of metabolic reprogramming have been elucidated, the global metabolic genes linking epigenetics were overlooked in pan-cancer. Objectives. Identifying the critical metabolic signatures with differential expressions which contributes to the epigenetic alternations across cancer types is an urgent issue for providing the potential targets for cancer therapy. Method. The differential gene expression and DNA methylation were analyzed by using the 5726 samples data from the Cancer Genome Atlas (TCGA). Results. Firstly, we analyzed the differential expression of metabolic genes and found that cancer underwent overall metabolism reprogramming, which exhibited a similar expression trend with the data from the Gene Expression Omnibus (GEO) database. Secondly, the regulatory network of histone acetylation and DNA methylation according to altered expression of metabolism genes was summarized in our results. Then, the survival analysis showed that high expression of DNMT3B had a poorer overall survival in 5 cancer types. Integrative altered methylation and expression revealed specific genes influenced by DNMT3B through DNA methylation across cancers. These genes do not overlap across various cancer types and are involved in different function annotations depending on the tissues, which indicated DNMT3B might influence DNA methylation in tissue specificity. Conclusions. Our research clarifies some key metabolic genes, ACLY, SLC2A1, KAT2A, and DNMT3B, which are most disordered and indirectly contribute to the dysfunction of histone acetylation and DNA methylation in cancer. We also found some potential genes in different cancer types influenced by DNMT3B. Our study highlights possible epigenetic disorders resulting from the deregulation of metabolic genes in pan-cancer and provides potential therapy in the clinical treatment of human cancer.

scholarly journals Crosstalk between the Ketogenic Diet and Epilepsy: From the Perspective of Gut Microbiota

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Yuying Fan ◽  
Hua Wang ◽  
Xueyan Liu ◽  
Junmei Zhang ◽  
Gang Liu
Keyword(s):  
Gut Microbiota ◽  
Ketogenic Diet ◽  
Gut Microbiome ◽  
Ketone Bodies ◽  
Positive Impact ◽  
Neurological Diseases ◽  
Dietary Therapy ◽  
Neuroprotective Effects ◽  
Wide Range ◽  
Underlying Mechanisms

Given the association between a range of neurological disorders and changes in the gut microbiota, interest in the gut microbiota has recently increased. In particular, the significant involvement of the autoimmune processes in the development of epilepsy, one of the most serious and widespread neurological diseases, has led to a suggested link with the gut microbiome. Because the constitution of the gut microbiome can be influenced by diet, dietary therapy has been shown to have a positive impact on a wide range of conditions via alteration of the gut microbiota. An example of one such diet is the ketogenic diet (KD), which promotes a diet that contains high levels of fat, adequate levels of protein, and low levels of carbohydrate. Due to the near-total elimination of carbohydrates from the individual’s food in this ultra-high-fat diet, ketone bodies become an important source of energy. Although the ketogenic diet has proven successful in the treatment of refractory epilepsy and other illnesses, the underlying mechanisms of its neuroprotective effects have yet to be fully elucidated. Nevertheless, recent studies strongly indicate a role for the gut microbiota in the effective treatment of epilepsy with the ketogenic diet. The latest advances regarding the links between the ketogenic diet, gut microbiota, and epilepsy are reviewed in this article, with a particular focus on the role of the gut microbiota in the treatment outcome.

scholarly journals Pan-Cancer Analysis of Glycolytic and Ketone Bodies Metabolic Genes: Implications for Response to Ketogenic Dietary Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Liyuan Qian ◽  
Yunzheng Li ◽  
Yajuan Cao ◽  
Gang Meng ◽  
Jin Peng ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Cancer Cell ◽  
Warburg Effect ◽  
Ketone Bodies ◽  
Aerobic Glycolysis ◽  
System Level ◽  
Dietary Therapy ◽  
Joint Analysis ◽  
Ketogenic Diets ◽  
The Warburg Effect

BackgroundThe Warburg effect, also termed “aerobic glycolysis”, is one of the most remarkable and ubiquitous metabolic characteristics exhibited by cancer cells, representing a potential vulnerability that might be targeted for tumor therapy. Ketogenic diets (KDs), composed of high-fat, moderate-protein and low carbohydrates, are aimed at targeting the Warburg effect for cancer treatment, which have recently gained considerable attention. However, the efficiency of KDs was inconsistent, and the genotypic contribution is still largely unknown.MethodsThe bulk RNA-seq data from The Cancer Genome Atlas (TCGA), single cell RNA sequencing (scRNA-seq), and microarray data from Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) were collected. A joint analysis of glycolysis and ketone bodies metabolism (KBM) pathway was performed across over 10,000 tumor samples and nearly 1,000 cancer cell lines. A series of bioinformatic approaches were combined to identify a metabolic subtype that may predict the response to ketogenic dietary therapy (KDT). Mouse xenografts were established to validate the predictive utility of our subtypes in response to KDT.ResultsWe first provided a system-level view of the expression pattern and prognosis of the signature genes from glycolysis and KBM pathway across 33 cancer types. Analysis by joint stratification of glycolysis and KBM revealed four metabolic subtypes, which correlated extensively but diversely with clinical outcomes across cancers. The glycolytic subtypes may be driven by TP53 mutations, whereas the KB-metabolic subtypes may be mediated by CTNNB1 (β-catenin) mutations. The glycolytic subtypes may have a better response to KDs compared to the other three subtypes. We preliminarily confirmed the idea by literature review and further performed a proof-of-concept experiment to validate the predictive value of the metabolic subtype in liver cancer xenografts.ConclusionsOur findings identified a metabolic subtype based on glycolysis and KBM that may serve as a promising biomarker to predict the clinical outcomes and therapeutic responses to KDT.

scholarly journals Two microbiota subtypes identified in Irritable Bowel Syndrome with distinct responses to the low-FODMAP diet

2021 ◽  
Author(s):  
Kevin Vervier ◽  
Stephen Moss ◽  
Nitin Kumar ◽  
Anne Adoum ◽  
Meg Barne ◽  
...  
Keyword(s):  
Clinical Response ◽  
Dietary Therapy ◽  
Metabolic Genes ◽  
Unsupervised Analysis ◽  
Irritable Bowel ◽  
Fodmap Diet ◽  
Stool Microbiota ◽  
Functional Profiles ◽  
And Control ◽  
Usual Diet

Objective: Reducing FODMAPs can be clinically beneficial in IBS but the mechanism is poorly understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action. Design: We used metagenomics to determine high-resolution taxonomic and functional profiles of the stool microbiota from IBS cases and household controls (n=56 pairs) on their usual diet. Clinical response and microbiota changes were studied in 41 pairs after 4 weeks on a low FODMAP diet. Results. Unsupervised analysis of baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBSP (pathogenic-like) and IBSH (health-like) subtypes. IBSP microbiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species. IBSH microbiomes were similar to controls. On the low FODMAP diet IBSH and control microbiota were unaffected, but the IBSP signature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalization of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBSP subjects compared to IBSH (p = 0.02). Conclusion: 50% of IBS cases manifested a 'pathogenic' gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBSP cases showed an enhanced clinical responsiveness to the dietary therapy. The effectiveness of FODMAP exclusion in IBSP may result from the alterations in gut microbiota and metabolites produced. Microbiota signatures could be useful as biomarkers to guide IBS treatment; and investigating IBSP species and metabolic pathways might yield insights regarding IBS pathogenic mechanisms.

scholarly journals A pan-cancer metabolic atlas of the tumor microenvironment

2020 ◽  
Author(s):  
Neha Rohatgi ◽  
Umesh Ghoshdastider ◽  
Probhonjon Baruah ◽  
Anders Jacobsen Skanderup
Keyword(s):  
Cancer Cells ◽  
Stromal Cells ◽  
Metabolic Genes ◽  
Metabolic States ◽  
Tryptophan Catabolism ◽  
Tumor Types ◽  
Rate Limiting ◽  
Pan Cancer ◽  
The Warburg Effect

AbstractTumors are heterogeneous cellular environments with entwined metabolic dependencies. Here, we used a tumor transcriptome deconvolution approach to profile the metabolic states of cancer and non-cancer (stromal) cells in bulk tumors of 20 solid tumor types. We identified metabolic genes and processes recurrently altered in cancer cells across tumor types, including pan-cancer upregulation of deoxythymidine triphosphate (dTTP) production. In contrast, the tryptophan catabolism rate limiting enzymes, IDO1 and TDO2, were highly overexpressed in stroma, suggesting that kynurenine-mediated suppression of antitumor immunity is predominantly constrained by the stroma. Oxidative phosphorylation was unexpectedly the most upregulated metabolic process in cancer cells compared to both stromal cells and a large atlas of cancer cell lines, suggesting that the Warburg effect may be less pronounced in cancer cells in vivo. Overall, our analysis highlights fundamental differences in metabolic states of cancer and stromal cells inside tumors and establishes a pan-cancer resource to interrogate tumor metabolism.

scholarly journals Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet

Gut ◽  
2021 ◽  
pp. gutjnl-2021-325177
Author(s):  
Kevin Vervier ◽  
Stephen Moss ◽  
Nitin Kumar ◽  
Anne Adoum ◽  
Meg Barne ◽  
...  
Keyword(s):  
Clinical Response ◽  
Dietary Therapy ◽  
Metabolic Genes ◽  
Unsupervised Analysis ◽  
Irritable Bowel ◽  
Fodmap Diet ◽  
Stool Microbiota ◽  
Functional Profiles ◽  
And Control ◽  
Usual Diet

ObjectiveReducing FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) can be clinically beneficial in IBS but the mechanism is incompletely understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action.DesignWe used metagenomics to determine high-resolution taxonomic and functional profiles of the stool microbiota from IBS cases and household controls (n=56 pairs) on their usual diet. Clinical response and microbiota changes were studied in 41 pairs after 4 weeks on a low FODMAP diet.ResultsUnsupervised analysis of baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBSP (pathogenic-like) and IBSH (health-like) subtypes. IBSP microbiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species. IBSH microbiomes were similar to controls. On the low FODMAP diet, IBSH and control microbiota were unaffected, but the IBSP signature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalisation of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBSP subjects compared with IBSH (p=0.02).Conclusion50% of IBS cases manifested a ‘pathogenic’ gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBSP cases showed an enhanced clinical responsiveness to the dietary therapy. The effectiveness of FODMAP reduction in IBSP may result from the alterations in gut microbiota and metabolites produced. Microbiota signatures could be useful as biomarkers to guide IBS treatment; and investigating IBSP species and metabolic pathways might yield insights regarding IBS pathogenic mechanisms.

scholarly journals Ketogenic Diet as an Adjunctive Therapy on the Treatment of Oral Tumor (P05-020-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jacquelyne Motta ◽  
Fabiola Donadao ◽  
Carolina Giuberti
Keyword(s):  
Ketogenic Diet ◽  
Adjunctive Therapy ◽  
Ketone Bodies ◽  
Conventional Medicine ◽  
Mesenchymal Cell ◽  
Surgical Excision ◽  
Dietary Therapy ◽  
Survival Times ◽  
Funding Sources ◽  
Oral Tumor

Abstract Objectives This case is here to demonstrate the effectiveness of the Ketogenic Diet (KD) as adjunctive therapy in the treatment of oral fibrosarcoma tumor. Methods Brad, a five-year-old male mix-breed-dog was submitted on a ketogenic diet after mandibulectomy of the oral tumor. KD a high-fat/low-carbohydrate/adequate-protein diet has recently been proposed as adjuvant therapy in cancer treatment. KDs target the Warburg effect, a biochemical phenomenon in which cancer cells predominantly utilize glycolysis instead of oxidative phosphorylation to produce ATP; therefore, some cancers cannot metabolize ketone bodies, due to mitochondrial dysfunction and down-regulation of enzymes necessary for ketone utilization. Furthermore, by reducing blood glucose, insulin and insulin-like growth factor, the drivers of cancer cell proliferation, are also reduced in the bloodstream. Results This cancer, whose origin is a mesenchymal cell and consists of a malignant tumor of fibroblasts has a reported survival times after surgical excision ranging from 7.0 to 12.2 months. After eighteen months of dietary therapy, the tumor-associated inflammation was completely reduced, and no more lesions were found during clinical exams. The dog in this study showed significant improvement and came back to his normal life and activities right at the beginning of the therapy. Today, he has a healthy happy and very active life. Conclusions There are alternatives other than conventional medicine. The therapy plans must include diet either as an adjuvant or whenever possible as the main treatment. Nutrition plays an important role in the future of Medicine. Nontoxic metabolic therapy is effective, and those interested in cancer prevention should know about this. Although the study was managed in a dog, the ketogenic diet is effective in preventing and reducing cancer risks in humans. Integrative Medicine conducted with criteria and responsibility leads to health and vitality for patients. Funding Sources N/A. Supporting Tables, Images and/or Graphs

scholarly journals Environmental factors shape methionine metabolism in p16/MTAP deleted cells

2018 ◽  
Author(s):  
Sydney M. Sanderson ◽  
Peter Mikhael ◽  
Ziwei Dai ◽  
Jason W. Locasale
Keyword(s):  
Tumor Suppressor ◽  
Environmental Factors ◽  
Nutrient Availability ◽  
Methionine Metabolism ◽  
Metabolic Signature ◽  
Metabolic Genes ◽  
Comparative Metabolomics ◽  
Tissue Of Origin ◽  
Pan Cancer ◽  
Modest Effect

AbstractThe co-deletion of a common tumor suppressor locus and neighboring metabolic gene is an attractive possible synthetic dependency of tumor suppression on metabolism. However, the general impact that these co-deletions have on metabolism, which also dependent on nutrient availability and the tissue of origin, is unknown. As a model to investigate this question, we considered a set of tissue-matched cancer cells with homozygous co-deletions in CDKN2a and MTAP, genes respectively encoding the most commonly deleted tumor suppressor p16 and an enzyme involved in methionine metabolism. A comparative metabolomics analysis revealed that while there exists a definite pan-cancer metabolic signature of MTAP-deletion, this signature was not preserved when cells were subjected to changes in the availability of methionine, serine, or cysteine, nutrients related to methionine metabolism. Notably, the heterogeneity exhibited by these cells in their responsiveness to nutrient availability dominated both MTAP status and tissue-of-origin. Furthermore, re-expression of MTAP exerted a modest effect on metabolism. Together these findings demonstrate that environmental factors, particularly nutrition and tissue identity, may overwhelm the genetic effects of collateral deletions of metabolic genes.

Pan-cancer analysis of thyroid hormone signaling pathway reveals new possible targets for combinations therapy

2019 ◽  
Author(s):  
Karolina Hanusek ◽  
Piotr Popławski ◽  
Agnieszka Piekiełko-Witkowska
Keyword(s):  
Thyroid Hormone ◽  
Signaling Pathway ◽  
Hormone Signaling ◽  
Pan Cancer
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