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Personalized nutrition (PN) has gained much attention as a tool for empowerment of consumers to promote changes in dietary behavior, optimizing health status and preventing diet related diseases. Generalized implementation of PN faces different obstacles, one of the most relevant being metabolic characterization of the individual. Although omics technologies allow for assessment the dynamics of metabolism with unprecedented detail, its translatability as affordable and simple PN protocols is still difficult due to the complexity of metabolic regulation and to different technical and economical constrains. In this work, we propose a conceptual framework that considers the dysregulation of a few overarching processes, namely Carbohydrate metabolism, lipid metabolism, inflammation, oxidative stress and microbiota-derived metabolites, as the basis of the onset of several non-communicable diseases. These processes can be assessed and characterized by specific sets of proteomic, metabolomic and genetic markers that minimize operational constrains and maximize the information obtained at the individual level. Current machine learning and data analysis methodologies allow the development of algorithms to integrate omics and genetic markers. Reduction of dimensionality of variables facilitates the implementation of omics and genetic information in digital tools. This framework is exemplified by presenting the EU-Funded project PREVENTOMICS as a use case.
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PURPOSE: Bacillus coagulans GBI-30, 6086 (BC30) was previously shown to improve nutrient digestibility and amino acid absorption from milk protein in vitro. However, the effect of supplementation with this probiotic on lactose digestibility has not yet been evaluated in vivo. METHODS: Wistar female rats were exposed to an acute high-lactose diet (LD; 35% lactose) meal challenge after 7 days of administration of BC30 (LD-BC; n = 10) or vehicle (LD-C; n = 10). Rats treated with vehicle and exposed to control diet (CD; 35% corn starch) meal were used as controls (CD-C; n = 10). Carbohydrate oxidation (CH_OX) and lipid oxidation (L_OX) were monitored by indirect calorimetry before and after lactose challenge. After the challenge, rats were treated daily with vehicle or probiotic for an additional week and were fed with CD or LD ad libitum to determine the effects of BC30 administration in a lactose-induced diarrhoea and malnutrition model. RESULTS: LD-C rats showed lower CH_OX levels than CD rats, while LD-BC rats showed similar CH_OX levels compared to CD rats during the lactose challenge, suggesting a better digestion of lactose in the rats supplemented with BC30. BC30 completely reversed the increase in the small intestine length of LD-C animals. LD-BC rats displayed increased intestinal mRNA Muc2 expression. No significant changes were observed due to BC30 administration in other parameters, such as serum calprotectin, intestinal MPO activity, intestinal A1AT and SGLT1 levels or intestinal mRNA levels of Claudin2 and Occludin. CONCLUSION: Treatment with BC30 improved the digestibility of lactose in an acute lactose challenge and ameliorated some of the parameters associated with lactose-induced malnutrition.
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Bacillus coagulans , Desnutrição , Ratos , Feminino , Animais , Bacillus coagulans/metabolismo , Lactose/metabolismo , Ratos Wistar , Dieta , DigestãoRESUMO
Biomarkers are important in the assessment of health and disease, but are poorly studied in still healthy individuals with a (potential) different risk for metabolic disease. This study investigated, first, how single biomarkers and metabolic parameters, functional biomarker and metabolic parameter categories, and total biomarker and metabolic parameter profiles behave in young healthy female adults of different aerobic fitness and, second, how these biomarkers and metabolic parameters are affected by recent exercise in these healthy individuals. A total of 102 biomarkers and metabolic parameters were analysed in serum or plasma samples from 30 young, healthy, female adults divided into a high-fit (VÌO2peak ≥ 47 mL/kg/min, N = 15) and a low-fit (VÌO2peak ≤ 37 mL/kg/min, N = 15) group, at baseline and overnight after a single bout of exercise (60 min, 70% VÌO2peak). Our results show that total biomarker and metabolic parameter profiles were similar between high-fit and low-fit females. Recent exercise significantly affected several single biomarkers and metabolic parameters, mostly related to inflammation and lipid metabolism. Furthermore, functional biomarker and metabolic parameter categories corresponded to biomarker and metabolic parameter clusters generated via hierarchical clustering models. In conclusion, this study provides insight into the single and joined behavior of circulating biomarkers and metabolic parameters in healthy females, and identified functional biomarker and metabolic parameter categories that may be used for the characterisation of human health physiology.
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Consumo de Oxigênio , Aptidão Física , Adulto , Humanos , Feminino , Aptidão Física/fisiologia , Consumo de Oxigênio/fisiologia , Exercício Físico/fisiologia , Nível de Saúde , BiomarcadoresRESUMO
BACKGROUND: Several findings suggest neuroinflammation as a contributing factor for the onset of psychiatric disorders such as Alzheimer's disease, depression, and anxiety. There is increasing evidence pointing out that the Mediterranean diet influences brain and behavior. Mediterranean herbs and spices have been shown to be within those components of the Mediterranean diet involved in cognitive enhancement. Thus, we investigated the influence of Mediterranean natural extracts (MNE), Rosemary extract (RE) and Glycyrrhiza glabra root extract (GGRE), on cognitive behavior. RESULTS: Adult zebrafish were exposed to RE or GGRE (100 and 250 mg/L) treatments. Both MNE improved memory retention during the T-maze test, although no improvements were observed during the novel object preference. Similarly, chronic administration of RE (150 mg/Kg) and GGRE (150 mg/Kg) improved, respectively, spatial and retention memory, as assessed by the Morris Water Maze (MWM), and the Elevated Plus Maze (EPM) in healthy male rats. However, no improvements were observed during the novel object recognition. Finally, male, and female rats were chronically treated with lipopolysaccharide [(LPS) 300 ug/kg] and orally administered with RE. Interestingly, RE reversed LPS-induced cognitive deficit during the MWM and EPM in female rats. CONCLUSIONS: We found that MNE improved cognition in both zebrafish and rats. Moreover, MNE rescued LPS-induced cognitive impairment in a gender-specific manner. Therefore, our study supports the view that zebrafish represent a valuable preclinical model for drug discovery in neuroscience. These findings contribute to an exciting and growing body of research suggesting that MNE may play an important role in the prevention of cognitive impairment.
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Disfunção Cognitiva , Lipopolissacarídeos , Animais , Cognição , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Hipocampo , Lipopolissacarídeos/efeitos adversos , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Peixe-ZebraRESUMO
Chronic inflammation is an important risk factor in a broad variety of physical and mental disorders leading to highly prevalent non-communicable diseases (NCDs). However, there is a need for a deeper understanding of this condition and its progression to the disease state. For this reason, it is important to define metabolic pathways and complementary biomarkers associated with homeostatic disruption in chronic inflammation. To achieve that, male Wistar rats were subjected to intraperitoneal and intermittent injections with saline solution or increasing lipopolysaccharide (LPS) concentrations (0.5, 5 and 7.5 mg/kg) thrice a week for 31 days. Biochemical and inflammatory parameters were measured at the end of the study. To assess the omics profile, GC-qTOF and UHPLC-qTOF were performed to evaluate plasma metabolome; 1H-NMR was used to evaluate urine metabolome; additionally, shotgun metagenomics sequencing was carried out to characterize the cecum microbiome. The chronicity of inflammation in the study was evaluated by the monitoring of monocyte chemoattractant protein-1 (MCP-1) during the different weeks of the experimental process. At the end of the study, together with the increased levels of MCP-1, levels of interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α) and prostaglandin E2 (PGE2) along with 8-isoprostanes (an indicative of oxidative stress) were significantly increased (p-value < 0.05). The leading features implicated in the current model were tricarboxylic acid (TCA) cycle intermediates (i.e., alpha-ketoglutarate, aconitic acid, malic acid, fumaric acid and succinic acid); lipids such as specific cholesterol esters (ChoEs), lysophospholipids (LPCs) and phosphatidylcholines (PCs); and glycine, as well as N, N-dimethylglycine, which are related to one-carbon (1C) metabolism. These metabolites point towards mitochondrial metabolism through TCA cycle, ß-oxidation of fatty acids and 1C metabolism as interconnected pathways that could reveal the metabolic effects of chronic inflammation induced by LPS administration. These results provide deeper knowledge concerning the impact of chronic inflammation on the disruption of metabolic homeostasis.
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Ácidos Graxos , Lipopolissacarídeos , Animais , Carbono , Homeostase , Humanos , Inflamação , Lipopolissacarídeos/toxicidade , Masculino , Metaboloma , Ratos , Ratos WistarRESUMO
The gut is a selective barrier that not only allows the translocation of nutrients from food, but also microbe-derived metabolites to the systemic circulation that flows through the liver. Microbiota dysbiosis occurs when energy imbalances appear due to an unhealthy diet and a sedentary lifestyle. Dysbiosis has a critical impact on increasing intestinal permeability and epithelial barrier deterioration, contributing to bacterial and antigen translocation to the liver, triggering non-alcoholic fatty liver disease (NAFLD) progression. In this study, the potential therapeutic/beneficial effects of a combination of metabolic cofactors (a multi-ingredient; MI) (betaine, N-acetylcysteine, L-carnitine, and nicotinamide riboside) against NAFLD were evaluated. In addition, we investigated the effects of this metabolic cofactors' combination as a modulator of other players of the gut-liver axis during the disease, including gut barrier dysfunction and microbiota dysbiosis. Diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (NAFLD group) or with a combination of metabolic cofactors (NAFLD-MI group), and small intestines were harvested from all animals for histological, molecular, and omics analysis. The MI treatment ameliorated gut morphological changes, decreased gut barrier permeability, and reduced gene expression of some proinflammatory cytokines. Moreover, epithelial cell proliferation and the number of goblet cells were increased after MI supplementation. In addition, supplementation with the MI combination promoted changes in the intestinal microbiota composition and diversity, as well as modulating short-chain fatty acids (SCFAs) concentrations in feces. Taken together, this specific combination of metabolic cofactors can reverse gut barrier disruption and microbiota dysbiosis contributing to the amelioration of NAFLD progression by modulating key players of the gut-liver axis.
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Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Disbiose , Ácidos Graxos Voláteis/farmacologiaRESUMO
The surgically induced remission of liver disease represents a model to investigate the signalling processes that trigger the development of nonalcoholic steatohepatitis with the aim of identifying novel therapeutic targets. We recruited patients with severe obesity with or without nonalcoholic steatohepatitis and obtained liver and plasma samples before and after laparoscopic sleeve gastrectomy for immunoblotting, immunocytochemical, metabolomic, transcriptomic and epigenetic analyses. Functional studies were performed in HepG2 cells and primary hepatocytes. Surgery was associated with a decrease in the inflammatory response and revealed the role of mitogen-activated protein kinases. Nonalcoholic steatohepatitis was associated with an increased glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy and affected methylation-related epigenomic remodelling enzymes. Hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis. Our results suggest that the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation play a crucial role in the inefficient adaptive responses leading to steatohepatitis in obesity.
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Laparoscopia , Hepatopatia Gordurosa não Alcoólica , Obesidade Mórbida , Gastrectomia/métodos , Humanos , Ácidos Cetoglutáricos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade Mórbida/cirurgia , Serina-Treonina Quinases TORRESUMO
BACKGROUND & AIMS: A holistic insight on the relationship between obesity and metabolic dysfunction-associated fatty liver disease is an unmet clinical need. Omics investigations can be used to investigate the multifaceted role of altered mitochondrial pathways to promote nonalcoholic steatohepatitis, a major risk factor for liver disease-associated death. There are no specific treatments but remission via surgery might offer an opportunity to examine the signaling processes that govern the complex spectrum of chronic liver diseases observed in extreme obesity. We aim to assess the emerging relationship between metabolism, methylation and liver disease. METHODS: We tailed the flow of information, before and after steatohepatitis remission, from biochemical, histological, and multi-omics analyses in liver biopsies from patients with extreme obesity and successful bariatric surgery. Functional studies were performed in HepG2 cells and primary hepatocytes. RESULTS: The reversal of hepatic mitochondrial dysfunction and the control of oxidative stress and inflammatory responses revealed the regulatory role of mitogen-activated protein kinases. The reversible metabolic rearrangements leading to steatohepatitis increased the glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy. The signaling activity of α-ketoglutarate and the associated metabolites also affected methylation-related epigenomic remodeling enzymes. Integrative analysis of hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis. CONCLUSION: We provide evidence supporting the multifaceted potential of the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation as a conceivable source of the inefficient adaptive responses leading to steatohepatitis. LAY SUMMARY: Steatohepatitis is a frequent and threatening complication of extreme obesity without specific treatment. Omics technologies can be used to identify therapeutic targets. We highlight increased glutaminolysis-induced α-ketoglutarate production as a potential source of signals promoting and exacerbating steatohepatitis.
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PURPOSE: To assess the sustained and acute effects, as well as the influence of sustained consumption on the acute effects, of orange juice (OJ) with a natural hesperidin content and hesperidin-enriched OJ (EOJ) on blood (BP) and pulse (PP) pressures in pre- and stage-1 hypertensive individuals. METHODS: In a randomized, parallel, double-blind, placebo-controlled trial, participants (n = 159) received 500 mL/day of control drink, OJ, or EOJ for 12 weeks. Two dose-response studies were performed at baseline and after 12 weeks. RESULTS: A single EOJ dose (500 mL) reduced systolic BP (SBP) and PP, with greater changes after sustained treatment where a decrease in diastolic BP (DBP) also occurred (P < 0.05). SBP and PP decreased in a dose-dependent manner relative to the hesperidin content of the beverages throughout the 12 weeks (P < 0.05). OJ and EOJ decreased homocysteine levels at 12 weeks versus the control drink (P < 0.05). After 12 weeks of EOJ consumption, four genes related to hypertension (PTX3, NLRP3, NPSR1 and NAMPT) were differentially expressed in peripheral blood mononuclear cells (P < 0.05). CONCLUSION: Hesperidin in OJ reduces SBP and PP after sustained consumption, and after a single dose, the chronic consumption of EOJ enhances its postprandial effect. Decreases in systemic and transcriptomic biomarkers were concomitant with BP and PP changes. EOJ could be a useful co-adjuvant tool for BP and PP management in pre- and stage-1 hypertensive individuals.
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Citrus sinensis , Citrus , Hesperidina , Hipertensão , Pressão Sanguínea , Método Duplo-Cego , Humanos , Hipertensão/tratamento farmacológico , Leucócitos Mononucleares , Receptores Acoplados a Proteínas GRESUMO
The administration of anti-obesity bioactive compounds and/or functional foods in rodents fed energy restriction diets based on chow food can be difficult to interpret. We propose an energy restricted cafeteria (CAF) diet as a dietetic intervention to be combined with other therapies. Postweaning male rats were fed standard chow, CAF diet or 30% energy restricted CAF diet (CAF-R) for 8 weeks. The CAF-R diet lowered energy intake and the increase of body weight and body mass index due to the CAF diet, lead to an intermediate feed efficiency, and dampened the CAF diet-induced alterations on body composition, serum levels of triacylglycerides and NEFAs, and insulin resistance. These effects were associated with diminished Ucp1, Nrf1 and Tfam1 gene expression in brown adipose tissue. In conclusion, the CAF-R diet ameliorated obesity and related metabolic disorders induced by a regular CAF diet, turning it in a useful tool to study anti-obesity compounds.
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Dieta , Metaboloma , Obesidade/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Ingestão de Energia , Masculino , Obesidade/etiologia , RatosRESUMO
Background: Histamine intolerance manifests when there is an imbalance between the production of histamine and the body's capacity to metabolise it. Within the gastrointestinal tract, diamine oxidase (DAO) plays a pivotal role in breaking down ingested histamine. Insufficient levels of DAO have been linked to various diseases affecting the respiratory, cardiovascular, nervous, muscular, and digestive systems; some of these symptoms are evidenced in fibromyalgia syndrome. This underscores the crucial role of DAO in maintaining the histamine balance and highlights its association with diverse physiological systems and health conditions. The management of fibromyalgia commonly involves the use of psychotropic medications; however, their potential interactions with DAO remain not fully elucidated. Methods: This study delved into the influence of various psychotropic medications on DAO activity through in vitro experiments. Additionally, we explored their impact on the human intestinal cell line Caco-2, examining alterations in DAO expression at both the mRNA and protein levels along with DAO activity. Results: Notably, the examined drugs-sertraline, pregabalin, paroxetine, alprazolam, and lorazepam-did not exhibit inhibitory effects on DAO activity or lead to reductions in DAO levels. In contrast, citalopram demonstrated a decrease in DAO activity in in vitro assays without influencing DAO levels and activity in human enterocytes. Conclusions: These findings imply that a collaborative approach involving psychotropic medications and DAO enzyme supplementation for individuals with fibromyalgia and a DAO deficiency could offer potential benefits for healthcare professionals in their routine clinical practice.
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In this study, we examined the metabolic and gut microbiome responses to paraquat (PQ) in male Wistar rats, focusing on oxidative stress effects. Rats received a single intraperitoneal injection of PQ at 15 and 30 mg/kg, and various oxidative stress parameters (i.e., MDA, SOD, ROS, 8-isoprostanes) were assessed after three days. To explore the omic profile, GC-qTOF and UHPLC-qTOF were performed to assess the plasma metabolome; 1H-NMR was used to assess the urine metabolome; and shotgun metagenomics sequencing was performed to study the gut microbiome. Our results revealed reductions in body weight and tissue changes, particularly in the liver, were observed, suggesting a systemic effect of PQ. Elevated lipid peroxidation and reactive oxygen species levels in the liver and plasma indicated the induction of oxidative stress. Metabolic profiling revealed changes in the tricarboxylic acid cycle, accumulation of ketone body, and altered levels of key metabolites, such as 3-hydroxybutyric acid and serine, suggesting intricate links between energy metabolism and redox reactions. Plasma metabolomic analysis revealed alterations in mitochondrial metabolism, nicotinamide metabolism, and tryptophan degradation. The gut microbiome showed shifts, with higher PQ doses influencing microbial populations (e.g., Escherichia coli and Akkermansia muciniphila) and metagenomic functions (pyruvate metabolism, fermentation, nucleotide and amino acid biosynthesis). Overall, this study provides comprehensive insights into the complex interplay between PQ exposure, metabolic responses, and gut microbiome dynamics. These findings enhance our understanding of the mechanisms behind oxidative stress-induced metabolic alterations and underscore the connections between xenobiotic exposure, gut microbiota, and host metabolism.
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BACKGROUND: Personalized nutrition (PN) has been proposed as a strategy to increase the effectiveness of dietary recommendations and ultimately improve health status. OBJECTIVES: We aimed to assess whether including omics-based PN in an e-commerce tool improves dietary behavior and metabolic profile in general population. METHODS: A 21-wk parallel, single-blinded, randomized intervention involved 193 adults assigned to a control group following Mediterranean diet recommendations (n = 57, completers = 36), PN (n = 70, completers = 45), or personalized plan (PP, n = 68, completers = 53) integrating a behavioral change program with PN recommendations. The intervention used metabolomics, proteomics, and genetic data to assist participants in creating personalized shopping lists in a simulated e-commerce retailer portal. The primary outcome was the Mediterranean diet adherence screener (MEDAS) score; secondary outcomes included biometric and metabolic markers and dietary habits. RESULTS: Volunteers were categorized with a scoring system based on biomarkers of lipid, carbohydrate metabolism, inflammation, oxidative stress, and microbiota, and dietary recommendations delivered accordingly in the PN and PP groups. The intervention significantly increased MEDAS scores in all volunteers (control-3 points; 95% confidence interval [CI]: 2.2, 3.8; PN-2.7 points; 95% CI: 2.0, 3.3; and PP-2.8 points; 95% CI: 2.1, 3.4; q < 0.001). No significant differences were observed in dietary habits or health parameters between PN and control groups after adjustment for multiple comparisons. Nevertheless, personalized recommendations significantly (false discovery rate < 0.05) and selectively enhanced the scores calculated with biomarkers of carbohydrate metabolism (ß: -0.37; 95% CI: -0.56, -0.18), oxidative stress (ß: -0.37; 95% CI: -0.60, -0.15), microbiota (ß: -0.38; 95% CI: -0.63, -0.15), and inflammation (ß: -0.78; 95% CI: -1.24, -0.31) compared with control diet. CONCLUSIONS: Integration of personalized strategies within an e-commerce-like tool did not enhance adherence to Mediterranean diet or improved health markers compared with general recommendations. The metabotyping approach showed promising results and more research is guaranteed to further promote its application in PN. This trial was registered at clinicaltrials.gov as NCT04641559 (https://clinicaltrials.gov/study/NCT04641559?cond=NCT04641559&rank=1).
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Dieta Mediterrânea , Medicina de Precisão , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Método Simples-Cego , Metabolômica , Estado Nutricional , Biomarcadores/sangue , Comportamento AlimentarRESUMO
Histamine intolerance occurs when there is an imbalance between histamine production and the capacity for histamine degradation. Diamine oxidase (DAO) is the main enzyme for the catabolism of ingested histamine degradation in the gastrointestinal tract and its deficiency has been linked to allergy-like symptoms. Psychostimulant drugs are commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD), but their interaction with DAO is not well characterized. In this work, we evaluated the effects of psychostimulant drugs (methylphenidate and lisdexamfetamine) on in vitro DAO activity and in the human cell line of enterocytes (Caco-2), evaluating DAO expression (mRNA and protein) and DAO activity. Methylphenidate and lisdexamfetamine did not repress the in vitro DAO activity. In addition, in Caco-2 cells, lisdexamfetamine promoted a strong upregulation of DAO mRNA levels, whereas methylphenidate tended to induce DAO activity. To sum up, methylphenidate and lisdexamfetamine treatments do not reduce DAO activity. These findings could be useful for physicians prescribing these two drugs to ADHD patients affected by DAO deficiency.
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Histamine intolerance arises when there is a disparity between the production of histamine and the body's ability to break it down. In the gastrointestinal tract, the primary enzyme responsible for metabolizing ingested histamine is diamine oxidase (DAO), and a shortage of this enzyme has been associated with some diseases related to the respiratory, cardiovascular, nervous, muscular, and digestive systems, in addition to migraines. The treatment of migraines typically revolves around the utilization of both anti-migraine and anti-inflammatory drugs, but their interaction with DAO is not thoroughly understood. In this study, we examined the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-migraine medications on DAO activity through in vitro experiments. We also investigated their effects on the human intestinal cell line Caco-2, assessing changes in DAO expression (both at the mRNA and protein levels) as well as DAO activity. The tested drugs, including ibuprofen, acetylsalicylic acid, paracetamol, a combination of acetylsalicylic acid with paracetamol and caffeine, zolmitriptan, and sumatriptan, did not inhibit DAO activity or reduce their levels. However, naproxen reduced DAO protein levels in human enterocyte cultures while not affecting DAO activity. These results suggest that combining anti-inflammatory and anti-migraine drugs with DAO enzyme supplementation for migraine patients with DAO deficiency could be beneficial for healthcare professionals in their daily practice.
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Hypertriglyceridemia (HTG) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). One of the multiple origins of HTG alteration is impaired lipoprotein lipase (LPL) activity, which is an emerging target for HTG treatment. We hypothesised that early, even mild, alterations in LPL activity might result in an identifiable metabolomic signature. The aim of the present study was to assess whether a metabolic signature of altered LPL activity in a preclinical model can be identified in humans. A preclinical LPL-dependent model of HTG was developed using a single intraperitoneal injection of poloxamer 407 (P407) in male Wistar rats. A rat metabolomics signature was identified, which led to a predictive model developed using machine learning techniques. The predictive model was applied to 140 humans classified according to clinical guidelines as (1) normal, less than 1.7 mmol/L; (2) risk of HTG, above 1.7 mmol/L. Injection of P407 in rats induced HTG by effectively inhibiting plasma LPL activity. Significantly responsive metabolites (i.e. specific triacylglycerols, diacylglycerols, phosphatidylcholines, cholesterol esters and lysophospholipids) were used to generate a predictive model. Healthy human volunteers with the impaired predictive LPL signature had statistically higher levels of TG, TC, LDL and APOB than those without the impaired LPL signature. The application of predictive metabolomic models based on mechanistic preclinical research may be considered as a strategy to stratify subjects with HTG of different origins. This approach may be of interest for precision medicine and nutritional approaches.
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Hipertrigliceridemia , Lipase Lipoproteica , Animais , Humanos , Masculino , Ratos , Ésteres do Colesterol/metabolismo , Lipase Lipoproteica/metabolismo , Ratos Wistar , TriglicerídeosRESUMO
The aim of this study was to assess the effects of a mixture of four dietary fibers on obese rats. Four groups of male Wistar rats were fed with either standard chow (STD) or cafeteria diet (CAF) and were orally supplemented with either fibre mixture (2 g kg-1 of body weight) (STD+F or CAF+F groups) or vehicle (STD+VH or CAF+VH groups). We studied a wide number of biometric, biochemical, transcriptomic, metagenomic and metabolomic variables and applied an integrative multivariate approach based on multiple factor analysis and Pearson's correlation analysis. A significant reduction in body weight, adiposity, HbA1c and HDL-cholesterol serum levels, and colon MPO activity was observed, whereas cecal weight and small intestine length:weight ratio were significantly increased in F-treated groups compared to control animals. CAF+F rats displayed a significant enhancement in energy expenditure, fat oxidation and fresh stool weight, and a significant reduction in adiponectin and LPS serum levels, compared to control group. Animals in STD+F group showed reduced serum LDL-cholesterol levels and a significant reduction in total cholesterol levels in the liver compared to STF+VH group. The intervention effect was reflected at the metabolomic (i.e., production of short-chain fatty acids, phenolic acids, and amino acids), metagenomic (i.e., modulation of Ruminococcus and Lactobacillus genus) and transcriptomic (i.e., expression of tight junctions and proteolysis) levels. Altogether, our integrative multi-omics approach highlights the potential of supplementation with a mixture of fibers to ameliorate the impairments triggered by obesity in terms of adiposity, metabolic profile, and intestinal health.
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Fibras na Dieta , Obesidade , Animais , Masculino , Ratos , Adiposidade , Colesterol , Fibras na Dieta/farmacologia , Fibras na Dieta/uso terapêutico , Metaboloma , Obesidade/dietoterapia , Obesidade/metabolismo , Ratos WistarRESUMO
The gut microbiota contributes to the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Histidine is a key energy source for the microbiota, scavenging it from the host. Its role in NAFLD is poorly known. Plasma metabolomics, liver transcriptomics, and fecal metagenomics were performed in three human cohorts coupled with hepatocyte, rodent, and Drosophila models. Machine learning analyses identified plasma histidine as being strongly inversely associated with steatosis and linked to a hepatic transcriptomic signature involved in insulin signaling, inflammation, and trace amine-associated receptor 1. Circulating histidine was inversely associated with Proteobacteria and positively with bacteria lacking the histidine utilization (Hut) system. Histidine supplementation improved NAFLD in different animal models (diet-induced NAFLD in mouse and flies, ob/ob mouse, and ovariectomized rats) and reduced de novo lipogenesis. Fecal microbiota transplantation (FMT) from low-histidine donors and mono-colonization of germ-free flies with Enterobacter cloacae increased triglyceride accumulation and reduced histidine content. The interplay among microbiota, histidine catabolism, and NAFLD opens therapeutic opportunities.
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Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Obesidade Mórbida , Humanos , Camundongos , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Histidina/uso terapêutico , Microbioma Gastrointestinal/fisiologia , Dieta HiperlipídicaRESUMO
In vitro cell-based reporter assays are a useful tool for the discovery and characterization of nuclear receptor modulators. However, the properties of a given molecule can differ when tested in vitro and in vivo as a result of the molecule's bioavailability. In this work, we describe a methodology that allows the detection of the PPARγ (peroxisome proliferator-activated receptor gamma) agonist bezafibrate in rat serum by an in vitro cell-based reporter assay. This methodology could be adapted to the detection and characterization of bioavailable PPARγ or other nuclear receptor modulators in serum, extending the possibilities of the classical in vitro assays.
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Bezafibrato/sangue , Hipolipemiantes/sangue , Luciferases de Renilla/análise , Proteínas Mutantes Quiméricas/agonistas , PPAR gama/agonistas , Animais , Bezafibrato/farmacocinética , Disponibilidade Biológica , Genes Reporter , Células HeLa , Humanos , Hipolipemiantes/farmacocinética , Ligantes , Proteínas Mutantes Quiméricas/genética , Proteínas Mutantes Quiméricas/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Plasmídeos , Ratos , Ratos Wistar , TransfecçãoRESUMO
Increased oxidative stress has been linked to the pathogenic process of obesity and can trigger inflammation, which is often linked with the risk factors that make up metabolic syndrome (MetS), including obesity, insulin resistance, dyslipidaemia and hypertension. TetraSOD®, a natural marine vegan ingredient derived from the microalgae Tetraselmis chuii that is high in the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) has recently demonstrated in vitro increased activity of these key antioxidant enzymes. In the present study, the potential bioactive effects of three dietary dosages of TetraSOD® in enhancing antioxidant and anti-inflammatory mechanisms to combat the metabolic disturbances that compose MetS were assessed in rats given a cafeteria (CAF) diet. Chronic supplementation with 0.17, 1.7, and 17 mg kg-1 day-1 of TetraSOD® for 8 weeks ameliorated the abnormalities associated with MetS, including oxidative stress and inflammation, promoting endogenous antioxidant defence mechanisms in the liver (GPx and GSH), modulating oxidative stress and inflammatory markers in plasma (NOx, oxLDL and IL-10), and regulating genes involved in antioxidant, anti-inflammatory and immunomodulatory pathways in the liver, mesenteric white adipose tissue (MWAT), thymus, and spleen. Overall, TetraSOD® appears to be a potential therapeutic option for the management of MetS.