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Cell Research Oct 2019Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD...
Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.
Topics: Alzheimer Disease; Amino Acids; Animals; Anti-Bacterial Agents; Bacteria; Clinical Trials, Phase III as Topic; Cognitive Dysfunction; Disease Models, Animal; Disease Progression; Gastrointestinal Microbiome; Humans; Isoleucine; Mannose; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Oligosaccharides; Phenylalanine; Th1 Cells
PubMed: 31488882
DOI: 10.1038/s41422-019-0216-x -
Oncogene Oct 2020Metabolic reprogramming fulfils increased nutrient demands and regulates numerous oncogenic processes in tumors, leading to tumor malignancy. Branched-chain amino acids... (Review)
Review
Metabolic reprogramming fulfils increased nutrient demands and regulates numerous oncogenic processes in tumors, leading to tumor malignancy. Branched-chain amino acids (BCAAs, i.e., valine, leucine, and isoleucine) function as nitrogen donors to generate macromolecules such as nucleotides and are indispensable for human cancer cell growth. The cell-autonomous and non-autonomous roles of altered BCAA metabolism have been implicated in cancer progression and the key proteins in the BCAA metabolic pathway serve as possible prognostic and diagnostic biomarkers in human cancers. Here we summarize how BCAA metabolic reprogramming is regulated in cancer cells and how it influences cancer progression.
Topics: Amino Acids, Branched-Chain; Animals; Carcinogenesis; Disease Models, Animal; Disease Progression; Gene Expression Regulation, Neoplastic; Glutamic Acid; Humans; Ketoglutaric Acids; Metabolic Networks and Pathways; Neoplasms; Nitrogen; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 32978521
DOI: 10.1038/s41388-020-01480-z -
Journal of Translational Medicine Oct 2022Although anxiety disorders are one of the most prevalent mental disorders, their underlying biological mechanisms have not yet been fully elucidated. In recent years,...
BACKGROUND
Although anxiety disorders are one of the most prevalent mental disorders, their underlying biological mechanisms have not yet been fully elucidated. In recent years, genetically determined metabolites (GDMs) have been used to reveal the biological mechanisms of mental disorders. However, this strategy has not been applied to anxiety disorders. Herein, we explored the causality of GDMs on anxiety disorders through Mendelian randomization study, with the overarching goal of unraveling the biological mechanisms.
METHODS
A two-sample Mendelian randomization (MR) analysis was implemented to assess the causality of GDMs on anxiety disorders. A genome-wide association study (GWAS) of 486 metabolites was used as the exposure, whereas four different GWAS datasets of anxiety disorders were the outcomes. Notably, all datasets were acquired from publicly available databases. A genetic instrumental variable (IV) was used to explore the causality between the metabolite and anxiety disorders for each metabolite. The MR Steiger filtering method was implemented to examine the causality between metabolites and anxiety disorders. The standard inverse variance weighted (IVW) method was first used for the causality analysis, followed by three additional MR methods (the MR-Egger, weighted median, and MR-PRESSO (pleiotropy residual sum and outlier) methods) for sensitivity analyses in MR analysis. MR-Egger intercept, and Cochran's Q statistical analysis were used to evaluate possible heterogeneity and pleiotropy. Bonferroni correction was used to determine the causative association features (P < 1.03 × 10). Furthermore, metabolic pathways analysis was performed using the web-based MetaboAnalyst 5.0 software. All statistical analysis were performed in R software. The STROBE-MR checklist for the reporting of MR studies was used in this study.
RESULTS
In MR analysis, 85 significant causative relationship GDMs were identified. Among them, 11 metabolites were overlapped in the four different datasets of anxiety disorders. Bonferroni correction showing1-linoleoylglycerophosphoethanolamine (OR = 1.04; 95% CI 1.021-1.06; P = 4.3 × 10) was the most reliable causal metabolite. Our results were robust even without a single SNP because of a "leave-one-out" analysis. The MR-Egger intercept test indicated that genetic pleiotropy had no effect on the results (intercept = - 0.0013, SE = 0.0006, P = 0.06). No heterogeneity was detected by Cochran's Q test (MR-Egger. Q = 7.68, P = 0.742; IVW. Q = 12.12, P = 0.436). A directionality test conducted by MR Steiger confirmed our estimation of potential causal direction (P < 0.001). In addition, two significant pathways, the "primary bile acid biosynthesis" pathway (P = 0.008) and the "valine, leucine, and isoleucine biosynthesis" pathway (P = 0.03), were identified through metabolic pathway analysis.
CONCLUSION
This study provides new insights into the causal effects of GDMs on anxiety disorders by integrating genomics and metabolomics. The metabolites that drive anxiety disorders may be suited to serve as biomarkers and also will help to unravel the biological mechanisms of anxiety disorders.
Topics: Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Leucine; Isoleucine; Anxiety Disorders; Valine; Bile Acids and Salts
PubMed: 36266699
DOI: 10.1186/s12967-022-03691-2 -
Cell Metabolism May 2021Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the...
Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
Topics: Adipose Tissue, White; Amino Acids, Branched-Chain; Animals; Body Mass Index; Diet; Energy Metabolism; Fibroblast Growth Factors; Humans; Isoleucine; Liver; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Protein Serine-Threonine Kinases; Uncoupling Protein 1; Valine
PubMed: 33887198
DOI: 10.1016/j.cmet.2021.03.025 -
Cancer Cell Feb 2020Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers,... (Review)
Review
Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer.
Topics: Amino Acids, Branched-Chain; Epigenomics; Humans; Intracellular Signaling Peptides and Proteins; Isoleucine; Leucine; Neoplasms
PubMed: 32049045
DOI: 10.1016/j.ccell.2019.12.011 -
Nutrients Mar 2020L-histidine (HIS) is an essential amino acid with unique roles in proton buffering, metal ion chelation, scavenging of reactive oxygen and nitrogen species,... (Review)
Review
L-histidine (HIS) is an essential amino acid with unique roles in proton buffering, metal ion chelation, scavenging of reactive oxygen and nitrogen species, erythropoiesis, and the histaminergic system. Several HIS-rich proteins (e.g., haemoproteins, HIS-rich glycoproteins, histatins, HIS-rich calcium-binding protein, and filaggrin), HIS-containing dipeptides (particularly carnosine), and methyl- and sulphur-containing derivatives of HIS (3-methylhistidine, 1-methylhistidine, and ergothioneine) have specific functions. The unique chemical properties and physiological functions are the basis of the theoretical rationale to suggest HIS supplementation in a wide range of conditions. Several decades of experience have confirmed the effectiveness of HIS as a component of solutions used for organ preservation and myocardial protection in cardiac surgery. Further studies are needed to elucidate the effects of HIS supplementation on neurological disorders, atopic dermatitis, metabolic syndrome, diabetes, uraemic anaemia, ulcers, inflammatory bowel diseases, malignancies, and muscle performance during strenuous exercise. Signs of toxicity, mutagenic activity, and allergic reactions or peptic ulcers have not been reported, although HIS is a histamine precursor. Of concern should be findings of hepatic enlargement and increases in ammonia and glutamine and of decrease in branched-chain amino acids (valine, leucine, and isoleucine) in blood plasma indicating that HIS supplementation is inappropriate in patients with liver disease.
Topics: Amino Acids, Branched-Chain; Ammonia; Chelating Agents; Contraindications; Dermatitis, Atopic; Dietary Supplements; Filaggrin Proteins; Free Radical Scavengers; Glutamine; Histamine; Histidine; Humans; Hypertrophy; Liver; Liver Diseases; Metabolic Syndrome; Nervous System Diseases; Organ Preservation Solutions
PubMed: 32235743
DOI: 10.3390/nu12030848 -
Molecular Cell Jan 2022Quantitative subcellular metabolomic measurements can explain the roles of metabolites in cellular processes but are subject to multiple confounding factors. We... (Comparative Study)
Comparative Study
Quantitative subcellular metabolomic measurements can explain the roles of metabolites in cellular processes but are subject to multiple confounding factors. We developed stable isotope labeling of essential nutrients in cell culture-subcellular fractionation (SILEC-SF), which uses isotope-labeled internal standard controls that are present throughout fractionation and processing to quantify acyl-coenzyme A (acyl-CoA) thioesters in subcellular compartments by liquid chromatography-mass spectrometry. We tested SILEC-SF in a range of sample types and examined the compartmentalized responses to oxygen tension, cellular differentiation, and nutrient availability. Application of SILEC-SF to the challenging analysis of the nuclear compartment revealed a nuclear acyl-CoA profile distinct from that of the cytosol, with notable nuclear enrichment of propionyl-CoA. Using isotope tracing, we identified the branched chain amino acid isoleucine as a major metabolic source of nuclear propionyl-CoA and histone propionylation, thus revealing a new mechanism of crosstalk between metabolism and the epigenome.
Topics: Acyl Coenzyme A; Animals; Cell Compartmentation; Cell Differentiation; Cell Nucleus; Chromatography, Liquid; Cytosol; Energy Metabolism; Epigenesis, Genetic; Hep G2 Cells; Histones; Humans; Isoleucine; Metabolome; Metabolomics; Mice; Mitochondria; Oxygen; Protein Processing, Post-Translational; Spectrometry, Mass, Electrospray Ionization
PubMed: 34856123
DOI: 10.1016/j.molcel.2021.11.006 -
Gastroenterology Feb 2022Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with altered gut microbiota...
BACKGROUND AND AIMS
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with altered gut microbiota composition. Phylogenetic groups of gut bacteria involved in the metabolism of short chain fatty acids (SCFAs) were depleted in SARS-CoV-2-infected patients. We aimed to characterize a functional profile of the gut microbiome in patients with COVID-19 before and after disease resolution.
METHODS
We performed shotgun metagenomic sequencing on fecal samples from 66 antibiotics-naïve patients with COVID-19 and 70 non-COVID-19 controls. Serial fecal samples were collected (at up to 6 times points) during hospitalization and beyond 1 month after discharge. We assessed gut microbial pathways in association with disease severity and blood inflammatory markers. We also determined changes of microbial functions in fecal samples before and after disease resolution and validated these functions using targeted analysis of fecal metabolites.
RESULTS
Compared with non-COVID-19 controls, patients with COVID-19 with severe/critical illness showed significant alterations in gut microbiome functionality (P < .001), characterized by impaired capacity of gut microbiome for SCFA and L-isoleucine biosynthesis and enhanced capacity for urea production. Impaired SCFA and L-isoleucine biosynthesis in gut microbiome persisted beyond 30 days after recovery in patients with COVID-19. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs and L-isoleucine in patients with COVID-19 before and after disease resolution. Lack of SCFA and L-isoleucine biosynthesis significantly correlated with disease severity and increased plasma concentrations of CXCL-10, NT- proB-type natriuretic peptide, and C-reactive protein (all P < .05).
CONCLUSIONS
Gut microbiome of patients with COVID-19 displayed impaired capacity for SCFA and L-isoleucine biosynthesis that persisted even after disease resolution. These 2 microbial functions correlated with host immune response underscoring the importance of gut microbial functions in SARS-CoV-2 infection pathogenesis and outcome.
Topics: Adult; Biomarkers; COVID-19; Case-Control Studies; Fatty Acids, Volatile; Feces; Female; Gastrointestinal Microbiome; Humans; Immunity; Isoleucine; Male; Metagenomics; Middle Aged; Phylogeny; SARS-CoV-2; Severity of Illness Index
PubMed: 34687739
DOI: 10.1053/j.gastro.2021.10.013 -
International Journal of Molecular... Apr 2022Branched chain amino acids (BCAAs), leucine, isoleucine and valine, are essential amino acids widely studied for their crucial role in the regulation of protein... (Review)
Review
The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology.
Branched chain amino acids (BCAAs), leucine, isoleucine and valine, are essential amino acids widely studied for their crucial role in the regulation of protein synthesis mainly through the activation of the mTOR signaling pathway and their emerging recognition as players in the regulation of various physiological and metabolic processes, such as glucose homeostasis. BCAA supplementation is primarily used as a beneficial nutritional intervention in chronic liver and kidney disease as well as in muscle wasting disorders. However, downregulated/upregulated plasma BCAAs and their defective catabolism in various tissues, mainly due to altered enzymatic activity of the first two enzymes in their catabolic pathway, BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKD), have been investigated in many nutritional and disease states. The current review focused on the underlying mechanisms of altered BCAA catabolism and its contribution to the pathogenesis of a numerous pathological conditions such as diabetes, heart failure and cancer. In addition, we summarize findings that indicate that the recovery of the dysregulated BCAA catabolism may be associated with an improved outcome and the prevention of serious disease complications.
Topics: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); Amino Acids, Branched-Chain; Humans; Leucine; Transaminases
PubMed: 35409380
DOI: 10.3390/ijms23074022