Metabolites

9 pages, 1359 KiB

Open AccessArticle

Clay Attenuates Diarrhea Induced by Fat in a Mouse Model

by Shalom Emmanuel, Nyma Siddiqui, Ting Du, Eric Asare, Yuan Chen, Huan Xie, Dong Liang and Song Gao

Metabolites 2025, 15(7), 483; https://doi.org/10.3390/metabo15070483 - 17 Jul 2025

Abstract

Background: Diarrhea induced by an excessive amount of fat is a prevalent gastrointestinal disorder. Currently, there are limited animal models and treatment options for diarrhea associated with fat. This study aims to develop a mouse model of high-fat-associated diarrhea using glyceryl-trioleate (GTO) and [...] Read more.

Background: Diarrhea induced by an excessive amount of fat is a prevalent gastrointestinal disorder. Currently, there are limited animal models and treatment options for diarrhea associated with fat. This study aims to develop a mouse model of high-fat-associated diarrhea using glyceryl-trioleate (GTO) and evaluate the potential of montmorillonite clay (MMT) in mitigating this condition. Methods: GTO was administered to mice at different doses through oral gavage to induce diarrhea. Clay was treated through oral gavage to evaluate its anti-diarrhea effect. Fecal conditions were monitored. Intestinal tissues were subjected to histological examination to assess structural integrity. The total fecal bile acids were evaluated using a bile acid assay kit to determine the mechanism of action. Results: The results showed that a diarrhea model was established by administering GTO at 2000 mg/kg. When the animals were treated with clay, diarrhea incidence and severity were decreased significantly in a dose-dependent manner. Compared to the untreated group receiving GTO alone, clay co-administration at 2000 mg/kg reduced diarrhea scores by approximately 48%, while the higher dose of 4000 mg/kg achieved an 83% reduction. Fecal bile acid analysis showed that diarrhea is associated with total bile acid levels in the feces. Histological exams showed that diarrhea is associated with tissue inflammation in the colon. Conclusions: This study showed that GTO administration induced diarrhea in mice, and clay effectively alleviates fat-induced diarrhea through modulation of fecal bile acid composition. These findings suggest that this model can be used to evaluate diarrhea associated with excessive amounts of fat and clay that can be further tested for diarrhea attenuation. Full article

(This article belongs to the Special Issue Advances in Murine Models for Metabolic Diseases: Insights into Diabetes, Obesity, and Cardiovascular Conditions)

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13 pages, 3191 KiB

Open AccessArticle

Assessment of Fatty Acid Concentrations Among Blood Matrices

by Ysphaneendra Mallimoggala, Monalisa Biswas, Leslie Edward S. Lewis, Vijetha Shenoy Belle, Arjun Asok and Varashree Bolar Suryakanth

Metabolites 2025, 15(7), 482; https://doi.org/10.3390/metabo15070482 - 17 Jul 2025

Abstract

Background/Objectives: Fatty acids, the building blocks of lipids, contribute to numerous crucial life processes and are implicated in numerous disease pathologies. Circulating fatty acids can be extracted/trans-esterified to their respective methyl ester forms and quantified from a variety of biological samples. This [...] Read more.

Background/Objectives: Fatty acids, the building blocks of lipids, contribute to numerous crucial life processes and are implicated in numerous disease pathologies. Circulating fatty acids can be extracted/trans-esterified to their respective methyl ester forms and quantified from a variety of biological samples. This study aims to identify quantifiable fatty acids (through alkali trans-esterification) in human circulation, assess the correlation of the detectable fatty acid methyl esters (FAMEs) compounds between whole blood, serum and plasma matrices and propose the most ideal matrix for quantification of FAMEs. Methods: This anonymised study was carried out in a tertiary hospital after obtaining ethical approval and involved analysis of residual fasting whole blood, serum and plasma samples obtained from 20 apparently healthy subjects attending the routine health check services at the study centre. Fatty acids were converted to its methyl ester form by methanolic KOH trans-esterification and subjected to GCMS analysis. Paired t test, Pearsons’s correlation, linear regression and Bland Altman test were employed to assess the agreeability between matrices. Results: 9 out of 37 FAME compounds were detected in all three matrices. Strong correlations and statistically significant regression equations were obtained for the 9 compounds between plasma and serum matrices. Undecanoate, pentadecanoate, linolenate, and palmitate levels were lowest in plasma, while stearate, heptadecanoate levels were highest in whole blood. Myristate was highest in serum, dodecanoate was highest in plasma while docosahexanoate was found to be comparable in all three matrices. Methyl ester forms of dodeconate, myristate, pentadecanoate, palmitate, heptadecanoate, stearate, and linolenate were observed in higher concentrations in plasma when compared to serum. Conclusions: The current study shows similar & correlating FAME concentrations between serum and plasma matrix; however, whole blood FAME concentrations appear significantly different. Plasma serves as the most ideal matrix for detection and quantification of circulating fatty acids. Full article

(This article belongs to the Special Issue Advances in Metabolomics for Precision Medicine: From Biomarker Discovery to Clinical Applications)

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17 pages, 1902 KiB

Open AccessArticle

Enhanced Mitochondrial Dynamics and Reactive Oxygen Species Levels with Reduced Antioxidant Defenses in Human Epicardial Adipose Tissue

by Ana Burgeiro, Diana Santos, Ana Catarina R. G. Fonseca, Inês Baldeiras, Ermelindo C. Leal, João Moura, João Costa-Nunes, Patrícia Monteiro Seraphim, Aryane Oliveira, António Canotilho, Gonçalo Coutinho, David Prieto, Pedro Antunes, Manuel Antunes and Eugenia Carvalho

Metabolites 2025, 15(7), 481; https://doi.org/10.3390/metabo15070481 - 16 Jul 2025

Abstract

Background/Objectives: Epicardial adipose tissue (EAT) is metabolically active and is in dynamic crosstalk with the surrounding cardiomyocytes, modulating their function and metabolism. Oxidative stress is a key contributor to cell death and cardiac remodeling, is a hallmark of diabetes (DM) and cardiovascular [...] Read more.

Background/Objectives: Epicardial adipose tissue (EAT) is metabolically active and is in dynamic crosstalk with the surrounding cardiomyocytes, modulating their function and metabolism. Oxidative stress is a key contributor to cell death and cardiac remodeling, is a hallmark of diabetes (DM) and cardiovascular disease, such as coronary artery disease (CAD). However, little is known about these processes in EAT from patients undergoing cardiac surgery. This study investigates changes in mitochondrial dynamics, reactive oxygen species (ROS) production, and antioxidant defense levels in EAT compared to subcutaneous adipose tissue (SAT) in patients undergoing cardiac surgery, with a focus on the impact of DM and CAD. Methods: Adipose tissue biopsies were collected from 128 patients undergoing surgical cardiac intervention. Mitochondrial dynamics and oxidative stress markers were analyzed. Results: EAT exhibited increased expression of mitochondrial fusion markers [mitofusin 1 (p ≤ 0.001), mitofusin 2 (p = 0.038), and optic atrophy 1 (p ≤ 0.001)], as well as fission markers [fission 1 (p ≤ 0.001) and dynamin-related protein 1 (p ≤ 0.001)] relative to SAT. Additionally, ROS levels (dihydroethidium, p = 0.004) were elevated, while lipid peroxidation (malondialdehyde, p ≤ 0.001) was reduced in EAT compared to SAT. Reduced glutathione (GSH) levels (p ≤ 0.001) and the redox buffer ratio between reduced and oxidized glutathione (GSH/GSSG, p ≤ 0.001) were significantly increased in EAT. Interestingly, glutathione peroxidase activity (p ≤ 0.001) and the antioxidant defense markers catalase (p ≤ 0.001) and superoxide dismutase 2 (p = 0.001) were significantly reduced in EAT compared to SAT. Conclusions: The findings provide a unique molecular insight into the mitochondrial dynamics and oxidative stress profiles of EAT, highlighting potential avenues for a novel diagnostic method and therapeutic strategies for cardiac disease. Full article

(This article belongs to the Special Issue Interplay Between Metabolism, Oxidative Stress, and Cellular Signaling in Health and Disease)

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12 pages, 894 KiB

Open AccessReview

Review: Piglets’ (Re)Feeding Patterns, Mineral Metabolism, and Their Twisty Tail

by Theo van Kempen and Eugeni Roura

Metabolites 2025, 15(7), 480; https://doi.org/10.3390/metabo15070480 - 16 Jul 2025

Abstract

The appearance rate of nutrients into systemic circulation affects hormones like insulin and through that efficiency of growth. This also affects mineral requirements critical for metabolism, notably phosphate (P), magnesium (Mg), and potassium (K). Fasting animals have a downregulated metabolism, upon which P, [...] Read more.

The appearance rate of nutrients into systemic circulation affects hormones like insulin and through that efficiency of growth. This also affects mineral requirements critical for metabolism, notably phosphate (P), magnesium (Mg), and potassium (K). Fasting animals have a downregulated metabolism, upon which P, Mg, and K are exported from their cells into the blood and are subsequently excreted in their urine. Abrupt resumption of feed intake, especially of highly glycemic feeds, creates an acute need for these minerals, which can result in deficiency symptoms, particularly with P deficiency. In human medicine, this is called refeeding syndrome: a large meal after a period of fasting can prove fatal. Young animals seem to be especially sensitive, likely driven by their ability to grow rapidly and thus to drastically upregulate their metabolism in response to insulin. Symptoms of P deficiency are fairly a-specific and, consequently, not often recognized. They include edema, which makes it appear as if piglets are growing well, explaining the high gain/feed rate typically seen immediately after weaning, even when piglets are eating at or below the maintenance requirements. Phosphate deficiency can also result in hypoxia and hypercarbia, which may trigger ear necrosis, Streptococcus suis infections, or even death. Hypophosphatemia can also trigger rhabdomyolysis, which may contribute to tail-biting, but this requires further study. Arguably, when fasting cannot be avoided, diets for newly weaned piglets should be formulated to avoid these problems by lowering their glycemic load and by formulating diets according to the piglets’ actual requirements inspired by their genuine intake and health and not simply by extrapolating from older animals. Full article

(This article belongs to the Special Issue Nutritional and Metabolic Influences on Animal Growth and Reproduction)

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19 pages, 1309 KiB

Open AccessReview

The Complexity of Oxidative Stress in Human Age-Related Diseases—A Review

by Alicja Płóciniczak, Ewelina Bukowska-Olech and Ewa Wysocka

Metabolites 2025, 15(7), 479; https://doi.org/10.3390/metabo15070479 - 15 Jul 2025

Abstract

The aging process is a complex and dynamic phenomenon influenced by genetic, environmental, and biochemical factors. One of the key contributors to aging and age-related diseases is oxidative stress, resulting from an imbalance between the generation of reactive oxygen species (ROS) and the [...] Read more.

The aging process is a complex and dynamic phenomenon influenced by genetic, environmental, and biochemical factors. One of the key contributors to aging and age-related diseases is oxidative stress, resulting from an imbalance between the generation of reactive oxygen species (ROS) and the efficiency of antioxidant defense systems. In this review, we introduce the concept of the oxidative stress complexity—a network encompassing ROS-generating systems, enzymatic and non-enzymatic antioxidants, and genetic determinants that collectively shape redox homeostasis. Emerging research highlights the significant influence of genetic variability on the activity and expression of selected and most examined antioxidant enzymes, including superoxide dismutase (SOD), paraoxonase 1 (PON1), catalase (CAT), and glutathione peroxidase (GPx), thereby modulating individual susceptibility to oxidative damage, disease onset, and the pace of aging. Particular attention is paid to the interplay among oxidative stress, chronic inflammation, and metabolic dysfunction in the pathogenesis of various age-related disorders. By integrating findings from molecular studies, clinical research, and population genetics, we discuss the diagnostic and prognostic potential of antioxidant enzymes as biomarkers of aging and explore strategies for redox-modulating interventions. Understanding these interrelations is essential for identifying biomarkers of biological aging and developing personalized strategies aimed at promoting healthy aging and reducing the risk of chronic disease. Full article

(This article belongs to the Special Issue Inflammation and Oxidative Stress in Age-Related Metabolic Changes and Disorders)

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31 pages, 2163 KiB

Open AccessReview

The Role of Probiotics, Prebiotics, Synbiotics, and Postbiotics in Livestock and Poultry Gut Health: A Review

by Taojing Yue, Yanan Lu, Wenli Ding, Bowen Xu, Cai Zhang, Lei Li, Fuchun Jian and Shucheng Huang

Metabolites 2025, 15(7), 478; https://doi.org/10.3390/metabo15070478 - 15 Jul 2025

Abstract

Background: The gut health of livestock and poultry is of utmost importance as it significantly impacts their growth performance, disease resistance, and product quality. With the increasing restrictions on antibiotic use in animal husbandry, probiotics, prebiotics, synbiotics, and postbiotics (PPSP) have emerged as [...] Read more.

Background: The gut health of livestock and poultry is of utmost importance as it significantly impacts their growth performance, disease resistance, and product quality. With the increasing restrictions on antibiotic use in animal husbandry, probiotics, prebiotics, synbiotics, and postbiotics (PPSP) have emerged as promising alternatives. This review comprehensively summarizes the roles of PPSP in promoting gut health in livestock and poultry. Results: Probiotics, such as Lactobacillus, Bifidobacterium, and Saccharomyces, modulate the gut microbiota, enhance the gut barrier, and regulate the immune system. Prebiotics, including fructooligosaccharides, isomalto-oligosaccharides, galactooligosaccharides, and inulin, selectively stimulate the growth of beneficial bacteria and produce short-chain fatty acids, thereby improving gut health. Synbiotics, combinations of probiotics and prebiotics, have shown enhanced effects in improving gut microbiota and animal performance. Postbiotics, consisting of inanimate microorganisms and their constituents, restore the gut microbiota balance and have anti-inflammatory and antibacterial properties. Additionally, the review looks ahead to the future development of PPSP, emphasizing the importance of encapsulation technology and personalized strategies to maximize their efficacy. Conclusions: Our aim is to provide scientific insights for PPSP to improve the gut health of livestock and poultry. Full article

(This article belongs to the Special Issue Metabolomics Approaches to Nutrition, Intestine and Farm Animal)

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15 pages, 1363 KiB

Open AccessArticle

The Effects of Dietary Supplementation of Chestnut Tannic Acid on the Growth Performance, Gut Morphology and Microbiota of Weaned Piglets

by Jinzhou Zhang, Yuting Zhang, Yuya Wang, Yanwei Li, Dongyang Liu, Hongbing Xie, Yongqiang Wang, Meinan Chang, Liping Guo and Zhiguo Miao

Metabolites 2025, 15(7), 477; https://doi.org/10.3390/metabo15070477 - 15 Jul 2025

Abstract

Background/Objectives: This study investigated the effects of chestnut tannic acid (TA) on the growth performance, the expression of tight junction proteins and the composition of the gut microbiota of weaned piglets, which could provide novel insights into the application of TA in [...] Read more.

Background/Objectives: This study investigated the effects of chestnut tannic acid (TA) on the growth performance, the expression of tight junction proteins and the composition of the gut microbiota of weaned piglets, which could provide novel insights into the application of TA in swine production. Methods: In a 42-day trial, 180 healthy, 21-day-old Duroc × Landrace × Yorkshire piglets were randomly assigned to a Control group and four treatment groups (TA1–4), fed commercial diets supplemented with 0, 0.06%, 0.12%, 0.18% or 0.24% TA. Each group had six replicates of six pigs each. Results: The average daily gain in all TA groups, the jejunal and ileal villus height and the villus height-to-crypt depth ratio in the TA3 and TA4 groups were markedly increased (p < 0.05). The mRNA levels of MUC2 and ZO-1 were upregulated in the TA3 group, as were those of MUC4 in the jejunum and ileum and claudin in the duodenum and ileum; glutathione peroxidase and total antioxidant capacity were upregulated in the duodenum and jejunum in the TA3 group, and total superoxide dismutase was increased in all the TA2 groups (p < 0.05). Conversely, the malondialdehyde significantly decreased in all the TA groups (p < 0.05). TA supplementation improved the alpha diversity of the intestinal microflora and augmented probiotic abundance while reducing that of pathogenic bacteria. The contents of acetic, isobutyric, valeric, isovaleric, hexanoic and propionic acids, as well as total short-chain fatty acids (SCFA), were higher in the TA2 and TA3 groups (p < 0.05). Conclusions: TA inclusion in piglet diets improved the intestinal environment by upregulating the antioxidant enzymes, improving intestinal morphology and promoting probiotic growth and SCFA production while reducing pathogenic bacterial abundance, consequently enhancing the gut barrier and the growth of weaned piglets. Full article

(This article belongs to the Section Animal Metabolism)

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21 pages, 5607 KiB

Open AccessArticle

EM Dipeptide Enhances Milk Protein Secretion: Evidence from Integrated Metabolomic and Transcriptomic Analysis

by Yuqing Liu, Yuhao Yan, Runjun Yang, Xiaohui Li, Chuang Zhai, Xuan Wu, Xibi Fang and Boqun Liu

Metabolites 2025, 15(7), 476; https://doi.org/10.3390/metabo15070476 - 14 Jul 2025

Abstract

Background/Objectives: Breast milk provides essential nutrition and immune protection to support infant growth and development. However, insufficient breast milk remains a serious issue, and bioactive peptides represent a potential strategy to promote lactation. In this study, we investigated the impact of a methionine-containing [...] Read more.

Background/Objectives: Breast milk provides essential nutrition and immune protection to support infant growth and development. However, insufficient breast milk remains a serious issue, and bioactive peptides represent a potential strategy to promote lactation. In this study, we investigated the impact of a methionine-containing dipeptide, EM, on MCF-10A mammary epithelial cells. Methods: MCF-10A cells were treated with EM, and cell proliferation and the expression of key milk protein genes were assessed. Integrated transcriptomic and untargeted metabolomic analyses were performed to identify EM-induced changes in metabolic and gene expression pathways. Results: EM treatment significantly enhanced cell proliferation and upregulated the expression of key milk protein genes (CSN1S1 (casein alpha-S1, encoding alpha-S1 casein), CSN2 (casein beta, encoding beta-casein), and CSN3 (casein kappa, encoding kappa-casein)) at both transcriptional and protein levels compared to controls. Integrated transcriptomic and metabolomic analyses revealed that EM reprogrammed amino acid metabolism, lipid biosynthesis, and nutrient transport pathways. Core genes such as SLC7A11, APOE, and ABCA1 were identified as critical nodes linking metabolic and transcriptional networks. Conclusions: These findings indicate that EM may promote lactogenic activity by modulating metabolic and transcriptional networks in vitro, highlighting the potential of dipeptide-based nutritional interventions, which warrants further in vivo validation. Full article

(This article belongs to the Section Nutrition and Metabolism)

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14 pages, 1915 KiB

Open AccessArticle

Preliminary Study to Understand the Role of Gut Microbiota in Coronary Slow Flow Phenomenon (CSFP)

by Tayfun Gurol, Tayyip Karaman, Yesim Gurol, Osman Ugur Sezerman and Sinem Oktem Okullu

Metabolites 2025, 15(7), 475; https://doi.org/10.3390/metabo15070475 - 14 Jul 2025

Abstract

Background/Objectives: Coronary slow flow phenomenon (CSFP) is a cardiovascular condition characterized by delayed passage of contrast medium through the coronary arteries, predominantly affecting young male smokers admitted with acute coronary syndrome. Although over 80% of patients experience recurrent chest pain and more than [...] Read more.

Background/Objectives: Coronary slow flow phenomenon (CSFP) is a cardiovascular condition characterized by delayed passage of contrast medium through the coronary arteries, predominantly affecting young male smokers admitted with acute coronary syndrome. Although over 80% of patients experience recurrent chest pain and more than 20% require readmission, the etiology of CSFP remains poorly understood. Given the emerging role of gut microbiome in cardiovascular diseases, this study investigates the microbial composition associated with CSFP. Methods: Stool samples were collected from patients diagnosed with CSFP and healthy control individuals. Microbiota profiling was performed using 16S rRNA sequencing. Taxonomic differences were evaluated to identify microbial markers potentially associated with CSFP. Results: The analysis revealed a notable enrichment of the genus Gemmiger and the species Anaerobutyricum in CSFP patients, specifically within the selenium metabolism pathway. This is of particular interest given the established link between selenium deficiency and heightened cardiovascular risk, suggesting a possible microbiome-mediated modulation of selenium bioavailability in CSFP pathophysiology. Moreover, a marked increase in taxa associated with the biosynthesis of trimethylamine (TMA), a proatherogenic metabolite implicated in the onset and progression of various cardiovascular disorders, was observed in the CSFP cohort, further supporting a potential mechanistic role of gut microbiota in the disease’s underlying etiology. Conclusions: Although statistical significance could not be established due to the limited sample size, the observed trends support the hypothesis that specific gut microbes and metabolic pathways, particularly those linked to selenium metabolism and TMA production, may serve as potential microbial indicators for CSFP. These preliminary findings warrant further investigation in larger cohorts. Full article

(This article belongs to the Special Issue Environmental Exposure and Its Effects on Cardio-Respiratory and Metabolic Health)

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15 pages, 444 KiB

Open AccessArticle

Cross-Sectional and Longitudinal Assessment of Sociodemographic and Lifestyle Determinants of Metabolic Syndrome and Hypertriglyceridemic Waist Phenotypes in 139,634 Spanish Workers

by Joan Obrador de Hevia, Ángel Arturo López-González, José Ignacio Ramírez-Manent, Carla Busquets-Cortés, Pedro Juan Tárraga López and Pere Riutord-Sbert

Metabolites 2025, 15(7), 474; https://doi.org/10.3390/metabo15070474 - 14 Jul 2025

Abstract

Objective: The objective of this study was to analyze the prevalence and key sociodemographic and lifestyle determinants of metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTGW) phenotype in a large occupational cohort. Background: Metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTGW) phenotype, defined [...] Read more.

Objective: The objective of this study was to analyze the prevalence and key sociodemographic and lifestyle determinants of metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTGW) phenotype in a large occupational cohort. Background: Metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTGW) phenotype, defined as the simultaneous presence of elevated waist circumference and high triglyceride levels, are major predictors of cardiometabolic morbidity and mortality. Despite their clinical relevance, data on their distribution and determinants in large occupational populations remain limited. Methods: A cross-sectional analysis was conducted on 139,634 employed adults (56,352 women and 83,282 men) across Spain, based on standardized clinical evaluations and validated questionnaires assessing physical activity, diet, smoking, alcohol consumption, education, and occupational class. Logistic regression models were used to estimate associations with MetS and HTGW. A longitudinal subsample of 40,431 individuals was followed over a 10-year period (2009–2019) to assess trends in metabolic risk phenotypes. Results: Male sex, older age, lower educational attainment, and unhealthy lifestyle behaviors were associated with a higher prevalence of both MetS and the HTGW phenotype. Physical inactivity, low adherence to the Mediterranean diet, and alcohol consumption were significantly associated with increased risk. The HTGW phenotype proved useful in identifying high-risk individuals, with a steadily increasing prevalence over time. Conclusions: Sociodemographic disparities and modifiable lifestyle factors significantly influence the prevalence and progression of MetS and HTGW in the Spanish workforce. Preventive strategies should emphasize early workplace screening, promotion of healthy behaviors, and reduction in educational and socioeconomic inequalities to mitigate cardiometabolic risk. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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15 pages, 972 KiB

Open AccessArticle

Pharmacometabolomics Study of Sulfamethoxazole and Trimethoprim in Kidney Transplant Recipients: Real-World Metabolism and Urinary Excretion

by Marieke A. J. Hof, Hessel de Haan, Stepan Stepanovic, Stephan J. L. Bakker, Eelko Hak, Gérard Hopfgartner, Frank Klont and TransplantLines Investigators

Metabolites 2025, 15(7), 473; https://doi.org/10.3390/metabo15070473 - 11 Jul 2025

Abstract

Background/Objectives: The increased use of antibiotics is raising concerns about environmental contamination and antibiotic resistance, exemplified by the case of cotrimoxazole, a widely prescribed combination of sulfamethoxazole and trimethoprim. After oral administration and absorption, both drugs are excreted in their parent and [...] Read more.

Background/Objectives: The increased use of antibiotics is raising concerns about environmental contamination and antibiotic resistance, exemplified by the case of cotrimoxazole, a widely prescribed combination of sulfamethoxazole and trimethoprim. After oral administration and absorption, both drugs are excreted in their parent and metabolized forms, which is a factor that is commonly considered in environmental studies. Many studies, however, rely on pharmacokinetic data from drug developers, who mostly investigate drug metabolism in healthy male volunteers rather than in actual patient populations. Methods: We investigated the real-world metabolism and urinary excretion of cotrimoxazole in an LC-SWATH/MS-based pharmacometabolomics study of 149 kidney transplant recipients who took part in the TransplantLines Biobank and Cohort Study (NCT0327284). Results: Our study confirmed (as “putatively characterized compound classes”) the presence of all the expected metabolites, and we (putatively) identified several previously unreported metabolites, including glucuronide conjugates of both drugs and two isoxazole ring-opened variants of sulfamethoxazole. The relative metabolite profiles furthermore indicated that the active drug trimethoprim accounted for 75% of the total signal intensity. For sulfamethoxazole, its acetylated metabolite was the main metabolite (59%), followed by the active parent drug (17%) and its glucuronide (7%). Alongside trimethoprim, these substances could serve as analytical targets for environmental cotrimoxazole monitoring, given their abundance (all three substances), activity (parent drug), and/or back-transformation potential (both conjugated metabolites). The isoxazole ring-opened variants (2–3%) may also warrant attention, considering their (presumed) absolute excreted quantities and potential pharmacological activity. Conclusions: This study underscores the value of pharmacometabolomics in elucidating real-world metabolite profiles, and it provides novel insights into cotrimoxazole metabolism and excretion, with implications for environmental and clinical monitoring. Full article

(This article belongs to the Special Issue Drug Metabolism: Latest Advances and Prospects)

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17 pages, 3763 KiB

Open AccessArticle

Aerobic Exercise Delays Age-Related Sarcopenia in Mice via Alleviating Imbalance in Mitochondrial Quality Control

by Danlin Zhu, Lian Wang, Haoyang Gao, Ze Wang, Ke Li, Xiaotong Ma, Linlin Zhao and Weihua Xiao

Metabolites 2025, 15(7), 472; https://doi.org/10.3390/metabo15070472 - 11 Jul 2025

Abstract

Background: Sarcopenia is a syndrome associated with aging, characterized by a progressive decline in skeletal muscle mass and function. Its onset compromises the health and longevity of older adults by increasing susceptibility to falls, fractures, and various comorbid conditions, thereby diminishing quality of [...] Read more.

Background: Sarcopenia is a syndrome associated with aging, characterized by a progressive decline in skeletal muscle mass and function. Its onset compromises the health and longevity of older adults by increasing susceptibility to falls, fractures, and various comorbid conditions, thereby diminishing quality of life and capacity for independent living. Accumulating evidence indicates that moderate-intensity aerobic exercise is an effective strategy for promoting overall health in older adults and exerts a beneficial effect that mitigates age-related sarcopenia. However, the underlying molecular mechanisms through which exercise confers these protective effects remain incompletely understood. Methods: In this study, we established a naturally aging mouse model to investigate the effects of a 16-week treadmill-based aerobic exercise regimen on skeletal muscle physiology. Results: Results showed that aerobic exercise mitigated age-related declines in muscle mass and function, enhanced markers associated with protein synthesis, reduced oxidative stress, and modulated the expression of genes and proteins implicated in mitochondrial quality control. Notably, a single session of aerobic exercise acutely elevated circulating levels of β-hydroxybutyrate (β-HB) and upregulated the expression of BDH1, HCAR2, and PPARG in the skeletal muscle, suggesting a possible role of β-HB–related signaling in exercise-induced muscle adaptations. However, although these findings support the beneficial effects of aerobic exercise on skeletal muscle aging, further investigation is warranted to elucidate the causal relationships and to characterize the chronic signaling mechanisms involved. Conclusions: This study offers preliminary insights into how aerobic exercise may modulate mitochondrial quality control and β-HB–associated signaling pathways during aging. Full article

(This article belongs to the Special Issue Nutrition and Metabolic Changes in Aging and Age-Related Diseases)

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14 pages, 1006 KiB

Open AccessArticle

Investigating Systemic Metabolic Effects of Betula alba Leaf Extract in Rats via Urinary Metabolomics

by Gregorio Peron, Alina Yerkassymova, Gokhan Zengin and Stefano Dall’Acqua

Metabolites 2025, 15(7), 471; https://doi.org/10.3390/metabo15070471 - 10 Jul 2025

Abstract

Background/Objectives: Herbal extracts from Betula alba (birch) are traditionally used for their purported diuretic effects, but scientific evidence supporting these claims remains limited. In this pilot study, we evaluated the short-term effects of a standardized B. alba leaf extract in healthy adult rats [...] Read more.

Background/Objectives: Herbal extracts from Betula alba (birch) are traditionally used for their purported diuretic effects, but scientific evidence supporting these claims remains limited. In this pilot study, we evaluated the short-term effects of a standardized B. alba leaf extract in healthy adult rats using an untargeted urinary metabolomics approach based on UPLC-QTOF. Methods: Two doses, 25 or 50 mg/kg, of a standardized B. alba extract were orally administered to rats. The extract contains hyperoside (0.53%), quercetin glucuronide (0.36%), myricetin glucoside (0.32%), and chlorogenic acid (0.28%) as its main constituents. After 3 days of treatment, the 24 h urine output was measured. Results: While no statistically significant changes were observed in the 24 h urine volume or the urinary Na⁺ and K⁺ excretion, multivariate metabolomic analysis revealed treatment-induced alterations in the urinary metabolic profile. Notably, the levels of two glucocorticoids, i.e., corticosterone and 11-dehydrocorticosterone, were increased in treated animals, suggesting that the extract may influence corticosteroid metabolism or excretion, potentially impacting antidiuretic hormone signaling. Elevated bile-related compounds, including bile acids and bilin, and glucuronidated metabolites were also observed, indicating changes in bile acid metabolism, hepatic detoxification, and possibly gut microbiota activity. Conclusions: Although this study did not confirm a diuretic effect of B. alba extract, the observed metabolic shifts suggest broader systemic bioactivities that warrant further investigation. Overall, the results indicate that the approach based on urinary metabolomics may be valuable in uncovering the mechanisms of action and evaluating the bioactivity of herbal extracts with purported diuretic properties. Full article

(This article belongs to the Special Issue Advances in Food Metabolomics for Functional Food Development and Analysis)

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17 pages, 1736 KiB

Open AccessArticle

The Adjuvant Effect of Hyperbaric Oxygenation for Loxosceles rufescens Bite: A Case Series

by Simona Mrakic-Sposta, Alessandra Vezzoli, Carmela Graci, Maristella Gussoni, Attilio Cimmino, Cinzia Dellanoce, Enrico Maria Camporesi, Giovanni Sesana and Gerardo Bosco

Metabolites 2025, 15(7), 470; https://doi.org/10.3390/metabo15070470 - 10 Jul 2025

Abstract

Background. The venom of Loxoscelesrufescens (L.r.), also known as the violin and/or brown spider, contains a wide variety of proteins and can induce a complex, intense, and uncontrolled inflammatory response, hemolysis, thrombocytopenia, dermo-necrosis, and renal failure. Studies have postulated the efficacy of [...] Read more.

Background. The venom of Loxoscelesrufescens (L.r.), also known as the violin and/or brown spider, contains a wide variety of proteins and can induce a complex, intense, and uncontrolled inflammatory response, hemolysis, thrombocytopenia, dermo-necrosis, and renal failure. Studies have postulated the efficacy of hyperbaric oxygen therapy (HBOT) for Loxosceles bites. However, data describing the use and beneficial effects of HBO are, to date, relatively scarce. Only a few cases of Loxosceles bites in Northern Italy have been documented, and there is no laboratory test available for the diagnosis. Objectives. We present seven cases (aged 54.5 ± 4.2 years) of patients who presented to the emergency room (E.R.) of Niguarda Hospital in Milan from March to October 2022. Methods. Blood and urine samples were collected and biomarkers of oxidative stress (OxS) (reactive oxygen species (ROS), total antioxidant capacity (TAC), lipid peroxidation (8iso-PFG2α), DNA damage (8-OH-dG)), inflammation (IL-6, IL-1β, TNF-α, sICAM1), and renal function (creatinine, neopterin, uric acid) before (T0), during (T1, T2), and after (1–2 wk T3–T4; 1 month T5) the HBOT treatment (US Navy Treatment Table 15 protocol) were studied. Results. At T0, patients showed a significant unbalance of OxS; high levels of ROS, 8-isoPGF2α, and inflammatory status (IL-6, TNF-α; sICAM); and a low level of antioxidant capacity. At the end of HBOT (T2), a significant reduction in Oxy-inflammation levels over time—8-iso −26%, 8-OH-dG −9%, IL-6 −71%, IL-1bβ −12%, TNF-α −13%, and sICAM1 −17%—associated with clinical improvement was shown. Conclusions. These reductions, along with those in renal function markers, mirrored the observed improvement in the evolution of the skin lesion and the patients’ self-reported general wellness and pain. In conclusion, HBOT should be considered a valuable therapeutic tool after L.r. bites. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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15 pages, 3716 KiB

Open AccessArticle

Prediagnostic Plasma Metabolomic Profiles Using NMR for Exfoliation Glaucoma Among US Health Professionals

by Akiko Hanyuda, Oana A. Zeleznik, Yoshihiko Raita, Danielle E. Haslam, Qi Sun, Kazuno Negishi, Louis R. Pasquale, Jessica Lasky-Su, Janey L. Wiggs and Jae H. Kang

Metabolites 2025, 15(7), 469; https://doi.org/10.3390/metabo15070469 - 9 Jul 2025

Abstract

Background: Exfoliation glaucoma (XFG) represents a form of deleterious ocular aging of unclear etiology. We evaluated prediagnostic nuclear magnetic resonance (NMR)-based metabolites in relation to XFG risk, expanding on our prior findings of XFG-related metabotypes using liquid chromatography-mass spectrometry (LC-MS). Methods: We identified [...] Read more.

Background: Exfoliation glaucoma (XFG) represents a form of deleterious ocular aging of unclear etiology. We evaluated prediagnostic nuclear magnetic resonance (NMR)-based metabolites in relation to XFG risk, expanding on our prior findings of XFG-related metabotypes using liquid chromatography-mass spectrometry (LC-MS). Methods: We identified 217 XFG cases and 217 matched controls nested within three prospective health professional cohorts with plasma collected a mean 11.8 years before case identification. Plasma metabolites were analyzed using the targeted NMR Nightingale platform. Conditional logistic models and Metabolite Set Enrichment Analysis were performed. Multiple comparison issues were addressed using the number of effective tests (NEF) and false discovery rate (FDR). Results: Among 235 profiled metabolites, higher glucose was significantly associated with a lower risk of XFG (odds ratio (95%CI) = 0.42 (0.26, 0.7); NEF = 0.03). Among metabolite classes, lipoprotein subclasses and branched-chain amino acids were inversely associated, while relative lipoprotein lipid concentrations were adversely associated (FDR < 0.05). Conclusion: NMR profiling revealed that glucose, branched-chain amino acids, lipoprotein subclasses, and relative lipoprotein lipid concentrations may play important roles in XFG etiology. Full article

(This article belongs to the Special Issue Metabolomics of the Eye and Adnexa)

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10 pages, 1166 KiB

Open AccessArticle

Avian Influenza Virus Strain Specificity in the Volatile Metabolome

by Young Eun Lee, Richard A. Bowen and Bruce A. Kimball

Metabolites 2025, 15(7), 468; https://doi.org/10.3390/metabo15070468 - 9 Jul 2025

Abstract

Background/Objectives: Outbreaks of highly pathogenic avian influenza virus (AIV) result in significant financial losses and the death or depopulation of millions of domestic birds. Early and rapid detection and surveillance are needed to slow the spread of AIV and prevent its spillover to [...] Read more.

Background/Objectives: Outbreaks of highly pathogenic avian influenza virus (AIV) result in significant financial losses and the death or depopulation of millions of domestic birds. Early and rapid detection and surveillance are needed to slow the spread of AIV and prevent its spillover to humans. The volatile metabolome (i.e., the pattern of volatile metabolites emitted by a living subject) represents one such source of health information that can be monitored for disease diagnosis. Indeed, dogs have been successfully trained to recognize patterns of “body odors” associated with many diseases. Because little is known regarding the mechanisms involved in the alteration of the volatile metabolome in response to health perturbation, questions still arise regarding the specificity, or lack thereof, of these alterations. Methods: To address this concern, we experimentally infected twenty mallard ducks with one of two different strains of low-pathogenic AIV (ten ducks per strain) and collected cloacal swabs at various time points before and after infection. Results: Headspace analyses revealed that four volatiles were significantly altered following infection, with distinct profiles associated with each viral strain. The volatiles that differed between strains among post-infection sampling periods included ethylbenzyl ether (p = 0.00006), 2-phenoxyethanol (p = 0.00017), 2-hydroxybenzaldehyde (p = 0.00022), and 6-methyl-5-hepten-2-one (p = 0.00034). Conclusions: These findings underscore that AIV-induced changes to the volatile metabolome are strain-specific, emphasizing the need for disease-specific profiling in diagnostic development. Full article

(This article belongs to the Special Issue Advanced Metabolic Profiling via Gas Chromatography–Mass Spectrometry and Liquid Chromatography–Mass Spectrometry)

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30 pages, 2043 KiB

Open AccessReview

Berberine as a Bioactive Alkaloid: Multi-Omics Perspectives on Its Role in Obesity Management

by Bartłomiej Zieniuk and Magdalena Pawełkowicz

Metabolites 2025, 15(7), 467; https://doi.org/10.3390/metabo15070467 - 9 Jul 2025

Abstract

Berberine, a bioactive isoquinoline alkaloid derived from medicinal plants such as Berberis and Coptis species, shows significant promise for managing obesity and associated metabolic disorders. This review synthesizes evidence on its modulation of AMP-activated protein kinase (AMPK) signaling, gut microbiota composition, lipid metabolism, [...] Read more.

Berberine, a bioactive isoquinoline alkaloid derived from medicinal plants such as Berberis and Coptis species, shows significant promise for managing obesity and associated metabolic disorders. This review synthesizes evidence on its modulation of AMP-activated protein kinase (AMPK) signaling, gut microbiota composition, lipid metabolism, and adipokine networks, elucidating how these actions converge to suppress adipogenesis and improve insulin sensitivity. Metabolomic profiling reveals critical shifts in bile acid metabolism, short-chain fatty acid production, and mitochondrial function. Recent studies also highlight berberine’s anti-inflammatory effects and regulatory influence on glucose homeostasis. Despite its promise, challenges in oral bioavailability and drug interactions necessitate the development of advanced delivery strategies. We further discuss nanoformulations and multi-omics approaches, which integrate data from genomics, transcriptomics, proteomics, and metabolomics, provide new insights into berberine’s mechanisms, and may guide personalized therapeutic applications. While promising, further studies are needed to validate these findings in humans and translate them into effective clinical strategies. Full article

(This article belongs to the Special Issue Secondary Metabolites and Their Activities: From the Identification to the Biological Investigation)

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27 pages, 3492 KiB

Open AccessArticle

Amelioration of Metabolic Syndrome by Co-Administration of Lactobacillus johnsonii CRL1231 and Wheat Bran in Mice via Gut Microbiota and Metabolites Modulation

by Matias Russo, Antonela Marquez, Estefanía Andrada, Sebastián Torres, Arlette Santacruz, Roxana Medina and Paola Gauffin-Cano

Metabolites 2025, 15(7), 466; https://doi.org/10.3390/metabo15070466 - 9 Jul 2025

Abstract

Background/Objectives: Lactobacillus johnsonii CRL1231 (Lj CRL1231) is a strain with feruloyl esterase (FE) activity that enhances ferulic acid (FA) release from wheat bran (WB) and has potential as a probiotic for metabolic syndrome (MS). Given the potential health benefits of FA and [...] Read more.

Background/Objectives: Lactobacillus johnsonii CRL1231 (Lj CRL1231) is a strain with feruloyl esterase (FE) activity that enhances ferulic acid (FA) release from wheat bran (WB) and has potential as a probiotic for metabolic syndrome (MS). Given the potential health benefits of FA and its microbial metabolites, this study aimed to evaluate the therapeutic effect of Lj CRL1231 co-administered with WB in a mouse model of metabolic syndrome (MS) induced by a high-fat diet (HFD). Methods: Mice were divided into three groups and fed for 14 weeks as follows: the Control group (standard diet), the MS group (HFD+WB), and the MS+Lj group (HFD+WB and Lj CRL1231-dose 10⁸ cells/day). Specifically, we analyzed the changes in the intestinal microbiota (IM), colonic FE activity, generation of FA-derived and fermentation metabolites, and metabolic and inflammatory parameters. Results: Improvements in the MS+Lj group compared to the MS group included the following: a—a 38% increase in colonic FE activity, leading to elevated levels of FA-derived metabolites (e.g., dihydroferulic, dihydroxyphenylpropionic, and hydroxyphenylpropionic acids); b—a significant shift in the IM composition, with a 3.4-fold decrease in Firmicutes and a 2.9-fold increase in Bacteroidetes; c—a decrease in harmful bacteria (Desulfovibrio) by 93%, and beneficial bacteria like Bifidobacterium increased significantly (6.58 log cells/g); d—a 33% increase in total SCFAs; e—a 26% reduction in the adiposity index; f—a 12% increase in HDL cholesterol and a 19% reduction in triglycerides; g—normalized glucose and insulin resulting in a 2-fold lower HOMA-IR index; h—an improved inflammatory profile by decreasing TNF-α, IFN-γ, and IL-6 (3-, 5-, and 2-fold, respectively) and increasing IL-10 by 2-fold; i—alleviation of liver damage by normalizing of transaminases AST (19.70 ± 2.97 U/L) and ALT (13.12 ± 0.88 U/L); j—evidence of reduced oxidative damage. Conclusions: The co-administration of L. johnsonii CRL1231 and WB exerts a synergistic effect in mitigating the features of MS in HFD-fed mice. This effect is mediated by modulation of the gut microbiota, increased release of bioactive FA-derived compounds, and restoration of metabolic and inflammatory homeostasis. This strategy represents a promising dietary approach for MS management through targeted microbiota–metabolite interactions. Full article

(This article belongs to the Special Issue Functional Foods and Natural Bioactive Compounds: Strategies to Face Metabolic Syndrome and Related Non-Communicable Diseases)

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Graphical abstract

12 pages, 1407 KiB

Open AccessArticle

Amide Proton Transfer-Weighted MR Imaging and Signal Variations in a Rat Model of Lipopolysaccharide-Induced Sepsis-Associated Encephalopathy

by Donghoon Lee, HyunJu Ryu, Yeon Ji Chae, Hind Binjaffar, Chul-Woong Woo, Dong-Cheol Woo and Do-Wan Lee

Metabolites 2025, 15(7), 465; https://doi.org/10.3390/metabo15070465 - 9 Jul 2025

Abstract

Introduction: Sepsis-associated encephalopathy (SAE) is an acute brain dysfunction secondary to systemic infection, occurring without direct central nervous system involvement. Despite its clinical relevance, reliable biomarkers for diagnosing SAE and assessing its severity remain limited. This study aimed to evaluate the feasibility of [...] Read more.

Introduction: Sepsis-associated encephalopathy (SAE) is an acute brain dysfunction secondary to systemic infection, occurring without direct central nervous system involvement. Despite its clinical relevance, reliable biomarkers for diagnosing SAE and assessing its severity remain limited. This study aimed to evaluate the feasibility of amide proton transfer-weighted (APTw) chemical exchange saturation transfer (CEST) MRI as a non-invasive molecular imaging technique for detecting metabolic alterations related to neuroinflammation in SAE. Using a lipopolysaccharide (LPS)-induced rat model, we focused on hippocampal changes associated with neuronal inflammation. Materials and Methods: Twenty-one Sprague–Dawley rats (8 weeks old, male) were divided into three groups: control (CTRL, n = 7), LPS-induced sepsis at 5 mg/kg (LPS05, n = 7), and 10 mg/kg (LPS10, n = 7). Sepsis was induced via a single intraperitoneal injection of LPS. APTw imaging was performed using a 7 T preclinical MRI system, and signal quantification in the hippocampus was conducted using the magnetization transfer ratio asymmetry analysis. Results and Discussion: APTw imaging at 7 T demonstrated significantly elevated hippocampal APTw signals in SAE model rats (LPS05 and LPS10) compared to the control (CTRL) group: CTRL (−1.940 ± 0.207%) vs. LPS05 (−0.472 ± 0.485%) (p < 0.001) and CTRL vs. LPS10 (−0.491 ± 0.279%) (p < 0.001). However, no statistically significant difference was observed between the LPS05 and LPS10 groups (p = 0.994). These results suggest that APTw imaging can effectively detect neuroinflammation-related metabolic alterations in the hippocampus. Conclusion: Our findings support the feasibility of APTw CEST imaging as a non-invasive molecular MRI technique for SAE, with potential applications in diagnosis, disease monitoring, and therapeutic evaluation. Full article

(This article belongs to the Section Pharmacology and Drug Metabolism)

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