RESUMEN
This study aimed to assess the suitability of fermented food interventions to replenish damaged gut microbiota. Metagenomic assessment of published sequencing data found that fermented food interventions led to a significant increase in the gut antibiotic resistome in healthy human subjects. Antibiotic resistome and viable antibiotic-resistant (AR) bacteria were further highly prevalent in retail kimchi and artisan cheeses by metagenomic and culture analyses. Representative AR pathogens of importance in nosocomial infections, such as Klebsiella pneumoniae, Serratia marcescens, and vancomycin-resistant Enterococcus (VRE), as well as commensals and lactic acid bacteria, were characterized; some exhibited an extremely high minimum inhibitory concentration (MIC) against antibiotics of clinical significance. Exposing fermented food microbiota to representative antibiotics further led to a boost of the corresponding antibiotic and multidrug-resistance gene pools, as well as disturbed microbiota, including the rise of previously undetectable pathogens. These results revealed an underestimated public health risk associated with fermented food intervention at the current stage, particularly for susceptible populations with compromised gut integrity and immune functions seeking gut microbiota rescue. The findings call for productive intervention of foodborne AR via technology innovation and strategic movements to mitigate unnecessary, massive damages to the host gut microbiota due to orally administered or biliary excreted antibiotics.
RESUMEN
Introduction: Females of the Northern house mosquito, Culex pipiens, enter an overwintering dormancy, or diapause, in response to short day lengths and low environmental temperatures that is characterized by small egg follicles and high starvation resistance. During diapause, Culex pipiens Major Royal Jelly Protein 1 ortholog (CpMRJP1) is upregulated in females of Cx. pipiens. This protein is highly abundant in royal jelly, a substance produced by honey bees (Apis mellifera), that is fed to future queens throughout larval development and induces the queen phenotype (e.g., high reproductive activity and longer lifespan). However, the role of CpMRJP1 in Cx. pipiens is unknown. Methods: We first conducted a phylogenetic analysis to determine how the sequence of CpMRJP1 compares with other species. We then investigated how supplementing the diets of both diapausing and nondiapausing females of Cx. pipiens with royal jelly affects egg follicle length, fat content, protein content, starvation resistance, and metabolic profile. Results: We found that feeding royal jelly to females reared in long-day, diapause-averting conditions significantly reduced the egg follicle lengths and switched their metabolic profiles to be similar to diapausing females. In contrast, feeding royal jelly to females reared in short-day, diapause-inducing conditions significantly reduced lifespan and switched their metabolic profile to be similar nondiapausing mosquitoes. Moreover, RNAi directed against CpMRJPI significantly increased egg follicle length of short-day reared females, suggesting that these females averted diapause. Discussion: Taken together, our data show that consuming royal jelly reverses several key seasonal phenotypes of Cx. pipiens and that these responses are likely mediated in part by CpMRJP1.
RESUMEN
INTRODUCTION: Artificial Neural Networks (ANN) are increasingly used in metabolomics but are hard to interpret. OBJECTIVES: We aimed at developing a feature impact score that is model-agnostic, simple, and interpretable. METHODS: Feature Impact Assessment (FIA) is calculated by varying combinations of features within their observed value range and checking for changes in prediction outcomes. FIA was implemented in R and tested on metabolomics datasets. RESULTS: FIA exceeded LIME and SHAP in selecting biologically meaningful features. Values were comparable across different ANN architectures. CONCLUSION: FIA is a novel score ranking feature impact, helping interpreting ANN in the metabolomics field.
Asunto(s)
Metabolómica , Redes Neurales de la ComputaciónRESUMEN
Rapid detection of viable microbes remains a challenge in fields such as microbial food safety. We here present the application of deep learning algorithms to the rapid detection of pathogenic and non-pathogenic microbes using metabolomics data. Microbes were incubated for 4 h in a protein-free defined medium, followed by 1D 1H nuclear magnetic resonance (NMR) spectroscopy measurements. NMR spectra were analyzed by spectral binning in an untargeted metabolomics approach. We trained multilayer ("deep") artificial neural networks (ANN) on the data and used the resulting models to predict spectra of unknown microbes. ANN predicted unknown microbes in this laboratory setting with an average accuracy of 99.2% when using a simple feature selection method. We also describe learning behavior of the employed ANN and the optimization strategies that worked well with these networks for our datasets. Performance was compared to other current data analysis methods, and ANN consistently scored higher than random forest models and support vector machines, highlighting the potential of deep learning in metabolomics data analysis.
RESUMEN
The current date labeling system for pasteurized milk is based on the predicted growth of spoilage microorganisms, but inherent inaccuracies and the inability to account for environmental factors (e.g., temperature fluctuations) contribute to household and retail food waste. Improved shelf-life estimation can be achieved by monitoring milk quality in real-time. In this study, we identify and quantify metabolites changing over storage temperature and time, the main factors affecting milk stability. Pasteurized 2% fat milk was stored at 4, 10, 15, and 20 °C. Metabolite change was analyzed using untargeted and targeted nuclear magnetic resonance (NMR) metabolomics approaches. Several metabolites correlated significantly to storage time and temperature. Citric acid decreased linearly over time at a temperature-dependent rate. Ethanol, formic acid, acetic acid, lactic acid, and succinic acid increased non-linearly after an initial period of minimal increase. Butyric acid exhibited strong inverse temperature dependencies. This study provides the first analysis of the effect of time and temperature on the concentration of key metabolites during milk storage. Candidate molecules for shelf-life monitoring have been identified, and the results improve our understanding of molecular changes during milk storage. These results will inform the development of real-time shelf-life indicators for milk, helping to reduce milk waste.
RESUMEN
Pre-pregnancy obesity and excessive gestational weight gain (GWG) are risk factors for future maternal and childhood obesity. Maternal obesity is potentially communicated to the fetus in part by the metabolome, altering the child's metabolic program in early development. Fasting maternal blood samples from 37 singleton pregnancies at 25-28 weeks of gestation were obtained from mothers with pre-pregnancy body mass indexes (BMIs) between 18 and 40 kg/m2. Various health measures including GWG, diet, and physical activity were also assessed. At term (37-42 weeks), a venous umbilical cord sample was obtained. Serum metabolomic profiles were measured using nuclear magnetic resonance spectroscopy as well as a gut and metabolic hormone panel. Maternal and cord serum metabolites were tested for associations with pre-pregnancy BMI, GWG, health outcomes, and gut and metabolic hormones. While cord blood metabolites showed no significant correlation to maternal obesity status or other measured health outcomes, maternal serum metabolites showed distinct profiles for lean, overweight, and obese women. Additionally, four serum metabolites, namely, glutamate, lysine, pyruvate, and valine, allowed prediction of excessive GWG when pre-pregnancy BMI was controlled. Metabolic biomarkers predictive of GWG are reported and, if validated, could aid in the guidance of prenatal weight management plans as the majority of pregnancy weight gain occurs in the third trimester.
Asunto(s)
Ganancia de Peso Gestacional , Índice de Masa Corporal , Niño , Femenino , Sangre Fetal , Humanos , Evaluación de Resultado en la Atención de Salud , Sobrepeso , EmbarazoRESUMEN
Nutrition affects multiple aspects of insect physiology such as body size and fecundity, but we lack a detailed understanding of how nutrition influences the reproductive physiology of male insects such as mosquitoes. Given that female mosquitoes are vectors of many deadly diseases and can quickly proliferate, understanding how male nutrition impacts female fecundity could be of critical importance. To uncover the relationship between nutrition in adult male mosquitoes and its impacts on reproductive physiology, we reared larvae of the Northern house mosquito, Culex pipiens, on a standard lab diet and divided adult males among three different dietary treatments: low (3%), moderate (10%), and high (20%) sucrose. We found that although overall body size did not differ among treatments, one-week-old males raised on the 3% sucrose diet had significantly smaller male accessory glands (MAGs) compared to males that consumed the 10% and the 20% sucrose diets. Diet affected whole-body lipid content but did not affect whole-body protein content. Using nuclear magnetic resonance (NMR) spectroscopy, we found that diet altered the metabolic composition of the MAGs, including changes in lactic acid, formic acid, and glucose. We also observed changes in protein and lipid abundance and composition in MAGs. Females who mated with males on the 3% diet were found to produce significantly fewer larvae than females who had mated with males on the 10% diet. Taken together, our results demonstrate that the diet of adult male mosquitoes clearly affects male reproductive physiology and female fecundity.
Asunto(s)
Alimentación Animal , Culex/fisiología , Reproducción/fisiología , Animales , Tamaño Corporal , Culex/metabolismo , Culicidae/metabolismo , Culicidae/fisiología , Conducta Alimentaria , Fertilidad , Gónadas/fisiología , Proteínas de Insectos/metabolismo , Larva/metabolismo , Larva/fisiología , Masculino , Metabolómica , Mosquitos Vectores/metabolismo , Mosquitos Vectores/fisiologíaRESUMEN
Data from untargeted metabolomics studies employing nuclear magnetic resonance (NMR) spectroscopy oftentimes contain negative values. These negative values hamper data processing and analysis algorithms and prevent the use of such data in multiomics integration settings. New methods to deal with such negative values are thus an urgent need in the metabolomics community. This study presents affine transformation of negative values (ATNV), a novel algorithm for replacement of negative values in NMR data sets. ATNV was implemented in the R package mrbin, which features interactive menus for user-friendly application and is available for free for various operating systems within the free R statistical programming language. The novel algorithms were tested on a set of human urinary NMR spectra and were able to successfully identify relevant metabolites.
Asunto(s)
Metabolómica , Programas Informáticos , Algoritmos , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia MagnéticaRESUMEN
Caffeine-containing, nutritionally fortified energy shots are consumed at high rates by adolescents, yet little is known about their metabolic impact. The purpose of this study was to examine the consequences of small format, caffeinated energy shots on glucose metabolism and gastrointestinal hormone secretion in adolescents. Twenty participants aged 13-19 years participated in a double-blind, randomized cross-over study consisting of two trials separated by 1-4 weeks. Participants consumed a volume-matched caffeinated energy shot (CAF, 5 mg/kg) or a decaffeinated energy shot (DECAF) followed by a 2 h oral glucose tolerance test. Blood samples were collected and area under the curve (AUC) calculated for glucose, insulin and gut and metabolic hormones. Consumption of CAF resulted in a 25% increase in glucose and a 26% increase in insulin area under the curve (AUC, p = 0.037; p < 0.0001) compared to DECAF. No impact on gut hormones was observed. To further characterize responses, individuals were classified as either slow or fast caffeine metabolizers based on an allele score. Glucose intolerance was greater in genetically fast vs. slow caffeine metabolizers and differences between groups were supported by distinct serum metabolomics separation. Consumption of caffeine-containing energy shots results in acute impaired glucoregulation in healthy adolescents as characterized by hyperinsulinemia following an oral glucose challenge.
Asunto(s)
Glucemia/metabolismo , Cafeína/efectos adversos , Bebidas Energéticas , Hormonas Gastrointestinales/sangre , Intolerancia a la Glucosa/inducido químicamente , Enfermedad Aguda , Adolescente , Área Bajo la Curva , Estudios Cruzados , Método Doble Ciego , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hiperinsulinismo/inducido químicamente , Insulina/sangre , Masculino , Adulto JovenRESUMEN
Mesenchymal stem cells (MSCs) are the most commonly used cells in tissue engineering and regenerative medicine. MSCs can promote host tissue repair through several different mechanisms including donor cell engraftment, release of cell signaling factors, and the transfer of healthy organelles to the host. In the present study, we examine the specific impacts of MSCs on mitochondrial morphology and function in host tissues. Employing in vitro cell culture of inherited mitochondrial disease and an in vivo animal experimental model of low-grade inflammation (high fat feeding), we show human-derived MSCs to alter mitochondrial function. MSC co-culture with skin fibroblasts from mitochondrial disease patients rescued aberrant mitochondrial morphology from a fission state to a more fused appearance indicating an effect of MSC co-culture on host cell mitochondrial network formation. In vivo experiments confirmed mitochondrial abundance and mitochondrial oxygen consumption rates were elevated in host tissues following MSC treatment. Furthermore, microarray profiling identified 226 genes with differential expression in the liver of animals treated with MSC, with cellular signaling, and actin cytoskeleton regulation as key upregulated processes. Collectively, our data indicate that MSC therapy rescues impaired mitochondrial morphology, enhances host metabolic capacity, and induces widespread host gene shifting. These results highlight the potential of MSCs to modulate mitochondria in both inherited and pathological disease states.
RESUMEN
Plasmodium falciparum multidrug resistance constitutes a major obstacle to the global malaria elimination campaign. Specific mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) mediate resistance to the 4-aminoquinoline drug chloroquine and impact parasite susceptibility to several partner agents used in current artemisinin-based combination therapies, including amodiaquine. By examining gene-edited parasites, we report that the ability of the wide-spread Dd2 PfCRT isoform to mediate chloroquine and amodiaquine resistance is substantially reduced by the addition of the PfCRT L272F mutation, which arose under blasticidin selection. We also provide evidence that L272F confers a significant fitness cost to asexual blood stage parasites. Studies with amino acid-restricted media identify this mutant as a methionine auxotroph. Metabolomic analysis also reveals an accumulation of short, hemoglobin-derived peptides in the Dd2 + L272F and Dd2 isoforms, compared with parasites expressing wild-type PfCRT. Physiologic studies with the ionophores monensin and nigericin support an impact of PfCRT isoforms on Ca2+ release, with substantially reduced Ca2+ levels observed in Dd2 + L272F parasites. Our data reveal a central role for PfCRT in regulating hemoglobin catabolism, amino acid availability, and ionic balance in P. falciparum, in addition to its role in determining parasite susceptibility to heme-binding 4-aminoquinoline drugs.
Asunto(s)
Cloroquina/farmacología , Resistencia a Múltiples Medicamentos/genética , Eritrocitos/efectos de los fármacos , Hemoglobinas/metabolismo , Interacciones Huésped-Parásitos , Proteínas de Transporte de Membrana/genética , Plasmodium falciparum/efectos de los fármacos , Proteínas Protozoarias/genética , Amodiaquina/farmacología , Antimaláricos/farmacología , Artemisininas/farmacología , Calcio/metabolismo , Células Cultivadas , Eritrocitos/metabolismo , Eritrocitos/parasitología , Expresión Génica , Humanos , Transporte Iónico/efectos de los fármacos , Ionóforos/farmacología , Proteínas de Transporte de Membrana/metabolismo , Monensina/farmacología , Mutación , Nigericina/farmacología , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/metabolismo , Pirrolidinonas/farmacologíaRESUMEN
NMR is a widely used analytical technique with a growing number of repositories available. As a result, demands for a vendor-agnostic, open data format for long-term archiving of NMR data have emerged with the aim to ease and encourage sharing, comparison, and reuse of NMR data. Here we present nmrML, an open XML-based exchange and storage format for NMR spectral data. The nmrML format is intended to be fully compatible with existing NMR data for chemical, biochemical, and metabolomics experiments. nmrML can capture raw NMR data, spectral data acquisition parameters, and where available spectral metadata, such as chemical structures associated with spectral assignments. The nmrML format is compatible with pure-compound NMR data for reference spectral libraries as well as NMR data from complex biomixtures, i.e., metabolomics experiments. To facilitate format conversions, we provide nmrML converters for Bruker, JEOL and Agilent/Varian vendor formats. In addition, easy-to-use Web-based spectral viewing, processing, and spectral assignment tools that read and write nmrML have been developed. Software libraries and Web services for data validation are available for tool developers and end-users. The nmrML format has already been adopted for capturing and disseminating NMR data for small molecules by several open source data processing tools and metabolomics reference spectral libraries, e.g., serving as storage format for the MetaboLights data repository. The nmrML open access data standard has been endorsed by the Metabolomics Standards Initiative (MSI), and we here encourage user participation and feedback to increase usability and make it a successful standard.
Asunto(s)
Bases de Datos de Compuestos Químicos/normas , Espectroscopía de Resonancia Magnética/estadística & datos numéricos , Metabolómica/métodos , Programas InformáticosRESUMEN
Metabolites are the small biological molecules involved in energy conversion and biosynthesis. Studying metabolism is inherently challenging due to metabolites' reactivity, structural diversity, and broad concentration range. Herein, we review the common pitfalls encountered in metabolomics and provide concrete guidelines for obtaining accurate metabolite measurements, focusing on water-soluble primary metabolites. We show how seemingly straightforward sample preparation methods can introduce systematic errors (e.g., owing to interconversion among metabolites) and how proper selection of quenching solvent (e.g., acidic acetonitrile:methanol:water) can mitigate such problems. We discuss the specific strengths, pitfalls, and best practices for each common analytical platform: liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), nuclear magnetic resonance (NMR), and enzyme assays. Together this information provides a pragmatic knowledge base for carrying out biologically informative metabolite measurements.
Asunto(s)
Cromatografía Liquida/normas , Cromatografía de Gases y Espectrometría de Masas/normas , Espectroscopía de Resonancia Magnética/normas , Espectrometría de Masas/normas , Metabolómica/normas , Adenosina Trifosfato/análisis , Animales , Glutatión/análisis , Guías como Asunto , Humanos , Microextracción en Fase Líquida/métodos , Metabolómica/instrumentación , Metabolómica/métodos , Ratones , NADP/análisis , SolventesRESUMEN
BACKGROUND: Protein O-linked-ß-N-acetyl glucosamine (O-GlcNAc) is a post-translational modification to Ser/Thr residues that integrates energy supply with demand. Abnormal O-GlcNAc patterning is evident in several neurological disease states including epilepsy, Alzheimer's disease and autism spectrum disorder (ASD). A potential treatment option for these disorders includes the high-fat, low-carbohydrate, ketogenic diet (KD). The goal of this study was to determine whether the KD induces changes in O-GlcNAc in the BTBRT+tf/j (BTBR) mouse model of ASD. METHODS: Juvenile male (5weeks), age-matched C57 or BTBR mice consumed a chow diet (13% kcal fat) or KD (75% kcal fat) for 10-14days. Following these diets, brain (prefrontal cortex) and liver were examined for gene expression levels of key O-GlcNAc mediators, global and protein specific O-GlcNAc as well as indicators of energy status. RESULTS: The KD reduced global O-GlcNAc in the livers of all animals (p<0.05). Reductions were likely mediated by lower protein levels of O-GlcNAc transferase (OGT) and increased O-GlcNAcase (OGA) (p<0.05). In contrast, no differences in global O-GlcNAc were noted in the brain (p>0.05), yet OGT and OGA expression (mRNA) were elevated in both C57 and BTBR animals (p<0.05). CONCLUSIONS: The KD has tissue specific impacts on O-GlcNAc. Although levels of O-GlcNAc play an important role in neurodevelopment, levels of this modification in the juvenile mouse brain were stable with the KD despite large fluctuations in energy status. This suggests that it is unlikely that the KD exerts it therapeutic benefit in the BTBR model of ASD by O-GlcNAc related pathways.
Asunto(s)
Acetilglucosamina/metabolismo , Trastorno Autístico/metabolismo , Dieta Cetogénica , Proteínas del Tejido Nervioso/metabolismo , Corteza Prefrontal/metabolismo , Procesamiento Proteico-Postraduccional , Acetilglucosamina/genética , Animales , Trastorno Autístico/genética , Trastorno Autístico/patología , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Corteza Prefrontal/patologíaRESUMEN
A comprehensive understanding of plant metabolism could provide a direct mechanism for improving nitrogen use efficiency (NUE) in crops. One of the major barriers to achieving this outcome is our poor understanding of the complex metabolic networks, physiological factors, and signaling mechanisms that affect NUE in agricultural settings. However, an exciting collection of computational and experimental approaches has begun to elucidate whole-plant nitrogen usage and provides an avenue for connecting nitrogen-related phenotypes to genes. Herein, we describe how metabolomics, computational models of metabolism, and flux balance analysis have been harnessed to advance our understanding of plant nitrogen metabolism. We introduce a model describing the complex flow of nitrogen through crops in a real-world agricultural setting and describe how experimental metabolomics data, such as isotope labeling rates and analyses of nutrient uptake, can be used to refine these models. In summary, the metabolomics/computational approach offers an exciting mechanism for understanding NUE that may ultimately lead to more effective crop management and engineered plants with higher yields.
RESUMEN
The microbiota, the entirety of microorganisms residing in the gut, is increasingly recognized as an environmental factor in the maintenance of health and the development of disease. The objective of this analysis was to model in vivo interactions between gut microbiota and both serum and liver metabolites. Different genotypic models (C57BL/6 and BTBR(T+tf/j) mice) were studied in combination with significant dietary manipulations (chow vs ketogenic diets) to perturb the gut microbiota. Diet rather than genotype was the primary driver of microbial changes, with the ketogenic diet diminishing total bacterial levels. Fecal but not cecal microbiota profiles were associated with the serum and liver metabolomes. Modeling metabolome-microbiota interactions showed fecal Clostridium leptum to have the greatest impact on host metabolism, significantly correlating with 10 circulating metabolites, including 5 metabolites that did not correlate with any other microbes. C. leptum correlated negatively with serum ketones and positively with glucose and glutamine. Interestingly, microbial groups most strongly correlated with host metabolism were those modulating gut barrier function, the primary site of microbe-host interactions. These results show very robust relationships and provide a basis for future work wherein the compositional and functional associations of the microbiome can be modeled in the context of the metabolome.
Asunto(s)
Dieta Cetogénica , Microbioma Gastrointestinal/fisiología , Metaboloma , Modelos Biológicos , Animales , Bacteroides/aislamiento & purificación , Bacteroides/metabolismo , Bifidobacterium/aislamiento & purificación , Bifidobacterium/metabolismo , Glucemia/metabolismo , Ciego/microbiología , Clostridium/aislamiento & purificación , Clostridium/metabolismo , Enterobacteriaceae/aislamiento & purificación , Enterobacteriaceae/metabolismo , Heces/microbiología , Glutamina/sangre , Cetonas/sangre , Lactobacillus/aislamiento & purificación , Lactobacillus/metabolismo , Hígado/metabolismo , Metabolómica , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Type 2 diabetes (T2D) and its comorbidities have reached epidemic proportions, with more than half a billion cases expected by 2030. Metabolomics is a fairly new approach for studying metabolic changes connected to disease development and progression and for finding predictive biomarkers to enable early interventions, which are most effective against T2D and its comorbidities. In metabolomics, the abundance of a comprehensive set of small biomolecules (metabolites) is measured, thus giving insight into disease-related metabolic alterations. This review shall give an overview of basic metabolomics methods and will highlight current metabolomics research successes in the prediction and diagnosis of T2D. We summarized key metabolites changing in response to T2D. Despite large variations in predictive biomarkers, many studies have replicated elevated plasma levels of branched-chain amino acids and their derivatives, aromatic amino acids and α-hydroxybutyrate ahead of T2D manifestation. In contrast, glycine levels and lysophosphatidylcholine C18:2 are depressed in both predictive studies and with overt disease. The use of metabolomics for predicting T2D comorbidities is gaining momentum, as are our approaches for translating basic metabolomics research into clinical applications. As a result, metabolomics has the potential to enable informed decision-making in the realm of personalized medicine.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Metabolómica/métodos , Biomarcadores/sangre , Humanos , Investigación Biomédica TraslacionalRESUMEN
Homozygosity for a premature stop codon (X) in the ACTN3 "sprinter" gene is common in humans despite the fact that it reduces muscle size, strength and power. Because of the close relationship between skeletal muscle function and cardiometabolic health we examined the influence of ACTN3 R577X polymorphism over cardiovascular and metabolic characteristics of young adults (n = 98 males, n = 102 females; 23 ± 4.2 years) from our Assessing Inherent Markers for Metabolic syndrome in the Young (AIMMY) study. Both males and females with the RR vs XX genotype achieved higher mean VO2 peak scores (47.8 ± 1.5 vs 43.2 ±1.8 ml/O2/min, p = 0.002) and exhibited higher resting systolic (115 ± 2 vs 105 ± mmHg, p = 0.027) and diastolic (69 ± 3 vs 59 ± 3 mmHg, p = 0.005) blood pressure suggesting a role for ACTN3 in the maintenance of vascular tone. We subsequently identified the expression of alpha-actinin 3 protein in pulmonary artery smooth muscle, which may explain the genotype-specific differences in cardiovascular adaptation to acute exercise. In addition, we utilized targeted serum metabolomics to distinguish between RR and XX genotypes, suggesting an additional role for the ACTN3 R577X polymorphism in human metabolism. Taken together, these results identify significant cardiometabolic effects associated with possessing one or more functional copies of the ACTN3 gene.
Asunto(s)
Actinina/genética , Rendimiento Atlético/fisiología , Músculo Liso/fisiología , Resistencia Física/genética , Polimorfismo de Nucleótido Simple , Actinina/metabolismo , Adulto , Presión Sanguínea/fisiología , Ejercicio Físico/fisiología , Femenino , Expresión Génica , Genotipo , Humanos , Masculino , Contracción Muscular/fisiología , Músculo Esquelético/fisiología , Arteria Pulmonar/fisiología , Pruebas de Función RespiratoriaRESUMEN
Essentially all high-yielding dairy cows experience a negative energy balance during early lactation leading to increased lipomobilization, which is a normal physiological response. However, a severe energy deficit may lead to high levels of ketone bodies and, subsequently, to subclinical or clinical ketosis. It has previously been reported that the ratio of glycerophosphocholine to phosphocholine in milk is a prognostic biomarker for the risk of ketosis in dairy cattle. It was hypothesized that this ratio reflects the ability to break down blood phosphatidylcholine as a fatty acid resource. In the current study, 248 animals from a previous study were genotyped with Illumina BovineSNP50 BeadChip, and genome-wide association studies were carried out for the milk levels of phosphocholine, glycerophosphocholine, and the ratio of both metabolites. It was demonstrated that the latter two traits are heritable with h2 = 0.43 and h2 = 0.34, respectively. A major quantitative trait locus was identified on cattle chromosome 25. The APOBR gene, coding for the apolipoprotein B receptor, is located within this region and was analyzed as a candidate gene. The analysis revealed highly significant associations of polymorphisms within the gene with glycerophosphocholine as well as the metabolite ratio. These findings support the hypothesis that differences in the ability to take up blood phosphatidylcholine from low-density lipoproteins play an important role in early lactation metabolic stability of dairy cows and indicate APOBR to contain a causative variant.
Asunto(s)
Enfermedades de los Bovinos/genética , Bovinos/genética , Cetosis/veterinaria , Polimorfismo Genético , Receptores de Lipoproteína/genética , Animales , Femenino , Cetosis/genética , Leche/metabolismoRESUMEN
Metabolite profiles of individuals possessing either the cardiovascular risk or protective variants of the low-density lipoprotein cholesterol (LDL-C) associated 1p13.3 locus of the SORT1 gene (rs646776) were analyzed. Serum metabolites and lipids were assessed using LC-MS-based metabolomics in a healthy young population (n = 138: 95 males, 43 females). Although no significant differences were observed in the combined cohort, divergent sex effects were identified. Females carrying the protective allele showed increased phosphatidylcholines, very long chain fatty acids (>C20), and unsaturated fatty acids. Unsaturated fatty acids are considered to be protective against cardiovascular disease. In contrast, males carrying the protective allele exhibited decreased long-chain fatty acids (≤C20) and sphingomyelins, which is similarly considered to decrease cardiovascular disease risk. No significant changes in clinically assessed lipids such as LDL-C, high-density lipoprotein (HDL-C), total cholesterol, or triglycerides were observed in females, whereas only LDL-C was significantly changed in males. This indicates that, apart from reducing LDL-C, other mechanisms may contribute to the protective effect of the SORT1 locus. Thus, the analysis of metabolic biomarkers might reveal early disease development that may be overlooked by relying on standard clinical parameters.