PubMed

Sci Adv. 2023 Jun 9;9(23):eade9933. doi: 10.1126/sciadv.ade9933. Epub 2023 Jun 9.ABSTRACTIn recent years, ambient ionization mass spectrometry (AIMS) including laser ablation rapid evaporation IMS, has enabled direct biofluid metabolome analysis. AIMS procedures are, however, still hampered by both analytical, i.e., matrix effects, and practical, i.e., sample transport stability, drawbacks that impede metabolome coverage. In this study, we aimed at developing biofluid-specific metabolome sampling membranes (MetaSAMPs) that offer a directly applicable and stabilizing substrate for AIMS. Customized rectal, salivary, and urinary MetaSAMPs consisting of electrospun (nano)fibrous membranes of blended hydrophilic (polyvinylpyrrolidone and polyacrylonitrile) and lipophilic (polystyrene) polymers supported metabolite absorption, adsorption, and desorption. Moreover, MetaSAMP demonstrated superior metabolome coverage and transport stability compared to crude biofluid analysis and was successfully validated in two pediatric cohorts (MetaBEAse, n = 234 and OPERA, n = 101). By integrating anthropometric and (patho)physiological with MetaSAMP-AIMS metabolome data, we obtained substantial weight-driven predictions and clinical correlations. In conclusion, MetaSAMP holds great clinical application potential for on-the-spot metabolic health stratification.PMID:37294759 | DOI:10.1126/sciadv.ade9933

J Med Microbiol. 2023 Jun;72(6). doi: 10.1099/jmm.0.001708.ABSTRACTOrganic acids (short chain fatty acids, amino acids, etc.) are common metabolic byproducts of commensal bacteria of the gut and oral cavity in addition to microbiota associated with chronic infections of the airways, skin, and soft tissues. A ubiquitous characteristic of these body sites in which mucus-rich secretions often accumulate in excess, is the presence of mucins; high molecular weight (HMW), glycosylated proteins that decorate the surfaces of non-keratinized epithelia. Owing to their size, mucins complicate quantification of microbial-derived metabolites as these large glycoproteins preclude use of 1D and 2D gel approaches and can obstruct analytical chromatography columns. Standard approaches for quantification of organic acids in mucin-rich samples typically rely on laborious extractions or outsourcing to laboratories specializing in targeted metabolomics. Here we report a high-throughput sample preparation process that reduces mucin abundance and an accompanying isocratic reverse phase high performance liquid chromatography (HPLC) method that enables quantification of microbial-derived organic acids. This approach allows for accurate quantification of compounds of interest (0.01 mM - 100 mM) with minimal sample preparation, a moderate HPLC method run time, and preservation of both guard and analytical column integrity. This approach paves the way for further analyses of microbial-derived metabolites in complex clinical samples.PMID:37294285 | DOI:10.1099/jmm.0.001708

J Agric Food Chem. 2023 Jun 9. doi: 10.1021/acs.jafc.3c02642. Online ahead of print.ABSTRACTChondroitin sulfate (CS) is a special bioactive substance with lipid metabolism regulation functions; its molecular mechanisms, however, need further study. This study aimed to study the role of gut microbiota and liver metabolome in the anti-obesity effects of CS. The results demonstrated that CS significantly reduced body weight gain and alleviated insulin resistance and dyslipidemia induced by high-fat diet treatment. Moreover, CS interestingly increased the content of Firmicutes in intestinal microbiota. Further studies showed that there were 11 different metabolites involved in metabolic pathways, including the unsaturated fatty acid biosynthesis pathway, primary bile acid biosynthesis, and taurine and hypotaurine metabolism. In addition, Spearman's correlation analysis indicated that the anti-obesity effect of CS is closely related to liver metabolic regulation. Overall, these results provide a possible molecular mechanism by which CS reduces body weight and lipid accumulation.PMID:37294270 | DOI:10.1021/acs.jafc.3c02642

J Exp Bot. 2023 Jun 9:erad223. doi: 10.1093/jxb/erad223. Online ahead of print.ABSTRACTAnthocyanin-less (white) instead of black/red (coloured) fruits develop in grapevine cultivars without functional VviMYBA1 and VviMYBA2 genes, which conditions the colour of wines that can be produced. To evaluate whether this genetic variation has additional consequences on fruit ripening and composition, we performed microenvironment, transcriptomics and metabolomics comparisons of developing grapes between near-isogenic white- and black-berried somatic variants of Garnacha and Tempranillo cultivars. Berry temperature was up to 3.5ºC lower in white- compared to black-berried Tempranillo. An RNA-seq study combined with targeted and untargeted metabolomics revealed that ripening fruits of white-berried variants were characterized by the upregulation of photosynthesis and other light-responsive genes and their higher accumulation of specific terpene aroma precursors, fatty acid-derived aldehyde volatiles and phenylpropanoid precursor amino acids. MYBA1-MYBA2 function proved essential for flavonol trihydroxylation in black-berried somatic variants, which were also characterized by enhanced pathogen defence gene expression in berry skin and increased accumulation of C6-derived alcohol and ester volatiles and GABA. Collectively, our results indicate that anthocyanin depletion entails side effects on grape composition by altering the berry internal microenvironment and the partition of the phenylpropanoid pathway. These findings show how fruit colour can condition other fruit features, such as flavour potential and stress homeostasis.PMID:37294268 | DOI:10.1093/jxb/erad223

Front Microbiomes. 2023;2:1153691. doi: 10.3389/frmbi.2023.1153691. Epub 2023 May 5.ABSTRACTObesity and associated changes to the gut microbiome worsen airway inflammation and hyperresponsiveness in asthma. Obesogenic host-microbial metabolomes have altered production of metabolites that may influence lung function and inflammatory responses in asthma. To understand the interplay of the gut microbiome, metabolism, and host inflammation in obesity-associated asthma, we used a multi-omics approach to profile the gut-lung axis in the setting of allergic airway disease and diet-induced obesity. We evaluated an immunomodulator, nitro-oleic acid (NO2-OA), as a host- and microbial-targeted treatment intervention for obesity-associated allergic asthma. Allergic airway disease was induced using house dust mite and cholera toxin adjuvant in C57BL6/J mice with diet-induced obesity to model obesity-associated asthma. Lung function was measured by flexiVent following a week of NO2-OA treatment and allergen challenge. 16S rRNA gene (from DNA, taxa presence) and 16S rRNA (from RNA, taxa activity) sequencing, metabolomics, and host gene expression were paired with a Treatment-Measured-Response model as a data integration framework for identifying latent/hidden relationships with linear regression among variables identified from high-dimensional meta-omics datasets. Targeting both the host and gut microbiota, NO2-OA attenuated airway inflammation, improved lung elastance, and modified the gut microbiome. Meta-omics data integration and modeling determined that gut-associated inflammation, metabolites, and functionally active gut microbiota were linked to lung function outcomes. Using Treatment-Measured-Response modeling and meta-omics profiling of the gut-lung axis, we uncovered a previously hidden network of interactions between gut levels of amino acid metabolites involved in elastin and collagen synthesis, gut microbiota, NO2-OA, and lung elastance. Further targeted metabolomics analyses revealed that obese mice with allergic airway disease had higher levels of proline and hydroxyproline in the lungs. NO2-OA treatment reduced proline biosynthesis by downregulation of pyrroline-5-carboxylate reductase 1 (PYCR1) expression. These findings are relevant to human disease: adults with mild-moderate asthma and BMI ≥ 25 had higher plasma hydroxyproline levels. Our results suggest that changes to structural proteins in the lung airways and parenchyma may contribute to heightened lung elastance and serve as a potential therapeutic target for obese allergic asthma.PMID:37293566 | PMC:PMC10249466 | DOI:10.3389/frmbi.2023.1153691

Front Mol Biosci. 2023 May 24;10:1192088. doi: 10.3389/fmolb.2023.1192088. eCollection 2023.ABSTRACTBamboo species have traditionally been used as building material and potential source of bioactive substances, as they produce a wide variety of phenolic compounds, including flavonoids and cinnamic acid derivatives that are considered biologically active. However, the effects of growth conditions such as location, altitude, climate, and soil on the metabolome of these species still need to be fully understood. This study aimed to evaluate variations in chemical composition induced by altitudinal gradient (0-3000 m) by utilizing an untargeted metabolomics approach and mapping chemical space using molecular networking analysis. We analyzed 111 samples from 12 bamboo species collected from different altitudinal ranges using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). We used multivariate and univariate statistical analyses to identify the metabolites that showed significant differences in the altitude environments. Additionally, we used the Global Natural Products Social Molecular Networking (GNPS) web platform to perform chemical mapping by comparing the metabolome among the studied species and the reference spectra from its database. The results showed 89 differential metabolites between the altitudinal ranges investigated, wherein high altitude environments significantly increased the profile of flavonoids. While, low altitude environments significantly boosted the profile of cinnamic acid derivatives, particularly caffeoylquinic acids (CQAs). MolNetEnhancer networks confirmed the same differential molecular families already found, revealing metabolic diversity. Overall, this study provides the first report of variations induced by altitude in the chemical profile of bamboo species. The findings may possess fascinating active biological properties, thus offering an alternative use for bamboo.PMID:37293555 | PMC:PMC10246775 | DOI:10.3389/fmolb.2023.1192088

Front Mol Biosci. 2023 May 24;10:1156310. doi: 10.3389/fmolb.2023.1156310. eCollection 2023.ABSTRACTIn order to provide new insights into the physiological responses of lenok (Brachymystax lenok: Salmonidae) to acute and severe heat stress (25°C, 48 h), dynamic changes in redox state and metabolic responses are studied combined biochemical index and non-targeted metabolome. Nicotinamide adenine dinucleotide (NAD+) consumption causes significant increases in ratio of reduced NADH to NAD+ and ratio of reduced nicotinamide adenine dinucleotide phosphate (NADPH) to NADP+, which induced the redox imbalance in heat stressed lenok. Lowered reduced glutathione/oxidized glutathione (GSH/GSSG) ratios suggested that more oxidized conditions occurred in heat-stressed lenok, leading to membrane lipid oxidation. The first few hours of heat stress promoted the activity of enzymes involved in anaerobic glycolysis (hexokinase, pyruvate kinase, lactic dehydrogenase) and glutamicpyruvic transaminase and glutamic oxaloacetic transaminase, which might lead to consumption of many carbohydrates and amino acid catabolism. These enzyme activities decreased with time in a possible compensatory strategy to manage anabolic and catabolic metabolism, maintaining the redox homeostasis. After 48 h of recovery, NAD+, carbohydrate levels and enzyme activities had returned to control levels, whereas many amino acids were consumed for repair and new synthesis. GSH remained at levels lower than controls, and the more oxidized conditions had not recovered, aggravating oxidative damage. Glutamic acid, glutamine, lysine and arginine may play important roles in survival of heat-stressed lenok.PMID:37293553 | PMC:PMC10244579 | DOI:10.3389/fmolb.2023.1156310

bioRxiv. 2023 May 22:2023.05.20.541585. doi: 10.1101/2023.05.20.541585. Preprint.ABSTRACTAIMS: Mitochondria play a vital role in cellular metabolism and energetics and support normal cardiac function. Disrupted mitochondrial function and homeostasis cause a variety of heart diseases. Fam210a (family with sequence similarity 210 member A), a novel mitochondrial gene, is identified as a hub gene in mouse cardiac remodeling by multi-omics studies. Human FAM210A mutations are associated with sarcopenia. However, the physiological role and molecular function of FAM210A remain elusive in the heart. We aim to determine the biological role and molecular mechanism of FAM210A in regulating mitochondrial function and cardiac health in vivo .METHODS AND RESULTS: Tamoxifen-induced αMHC MCM -driven conditional knockout of Fam210a in the mouse cardiomyocytes induced progressive dilated cardiomyopathy and heart failure, ultimately causing mortality. Fam210a deficient cardiomyocytes exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of cardiomyopathy. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in cardiomyocytes at the early stage before contractile dysfunction and heart failure. Multi-omics analyses indicate that FAM210A deficiency persistently activates integrated stress response (ISR), resulting in transcriptomic, translatomic, proteomic, and metabolomic reprogramming, ultimately leading to pathogenic progression of heart failure. Mechanistically, mitochondrial polysome profiling analysis shows that FAM210A loss of function compromises mitochondrial mRNA translation and leads to reduced mitochondrial encoded proteins, followed by disrupted proteostasis. We observed decreased FAM210A protein expression in human ischemic heart failure and mouse myocardial infarction tissue samples. To further corroborate FAM210A function in the heart, AAV9-mediated overexpression of FAM210A promotes mitochondrial-encoded protein expression, improves cardiac mitochondrial function, and partially rescues murine hearts from cardiac remodeling and damage in ischemia-induced heart failure.CONCLUSION: These results suggest that FAM210A is a mitochondrial translation regulator to maintain mitochondrial homeostasis and normal cardiomyocyte contractile function. This study also offers a new therapeutic target for treating ischemic heart disease.TRANSLATIONAL PERSPECTIVE: Mitochondrial homeostasis is critical for maintaining healthy cardiac function. Disruption of mitochondrial function causes severe cardiomyopathy and heart failure. In the present study, we show that FAM210A is a mitochondrial translation regulator required for maintaining cardiac mitochondrial homeostasis in vivo . Cardiomyocyte-specific FAM210A deficiency leads to mitochondrial dysfunction and spontaneous cardiomyopathy. Moreover, our results indicate that FAM210A is downregulated in human and mouse ischemic heart failure samples and overexpression of FAM210A protects hearts from myocardial infarction induced heart failure, suggesting that FAM210A mediated mitochondrial translation regulatory pathway can be a potential therapeutic target for ischemic heart disease.PMID:37293097 | PMC:PMC10245825 | DOI:10.1101/2023.05.20.541585

bioRxiv. 2023 May 24:2023.05.23.541633. doi: 10.1101/2023.05.23.541633. Preprint.ABSTRACTBioactive metabolites produced by symbiotic microbiota causally impact host health and disease, nonetheless, incomplete functional annotation of genes as well as complexities and dynamic nature of microbiota make understanding species-level contribution in production and actions difficult. Alpha-galactosylceramides produced by Bacteroides fragilis (BfaGC) are one of the first modulators of colonic immune development, but biosynthetic pathways and the significance of the single species in the symbiont community still remained elusive. To address these questions at the microbiota level, we have investigated the lipidomic profiles of prominent gut symbionts and the metagenome-level landscape of responsible gene signatures in the human gut. We first elucidated the chemical diversity of sphingolipid biosynthesis pathways of major bacterial species. In addition to commonly shared ceramide backbone synthases showing two distinct intermediates, alpha-galactosyltransferase (agcT), the necessary and sufficient component for BfaGC production and host colonic type I natural killer T (NKT) cell regulation by B. fragilis, was characterized by forward-genetics based targeted metabolomic screenings. Phylogenetic analysis of agcT in human gut symbionts revealed that only a few ceramide producers have agcT and hence can produce aGCs, on the other hand, structurally conserved homologues of agcT are widely distributed among species lacking ceramides. Among them, alpha-glucosyl-diacylglycerol(aGlcDAG)-producing glycosyltransferases with conserved GT4-GT1 domains are one of the most prominent homologs in gut microbiota, represented by Enterococcus bgsB . Of interest, aGlcDAGs produced by bgsB can antagonize BfaGC-mediated activation of NKT cells, showing the opposite, lipid structure-specific actions to regulate host immune responses. Further metagenomic analysis of multiple human cohorts uncovered that the agcT gene signature is almost exclusively contributed by B. fragilis , regardless of age, geographical and health status, where the bgsB signature is contributed by >100 species, of which abundance of individual microbes is highly variable. Our results collectively showcase the diversities of gut microbiota producing biologically relevant metabolites in multiple layers-biosynthetic pathways, host immunomodulatory functions and microbiome-level landscapes in the host.PMID:37293019 | PMC:PMC10245877 | DOI:10.1101/2023.05.23.541633

bioRxiv. 2023 May 22:2023.05.20.541602. doi: 10.1101/2023.05.20.541602. Preprint.ABSTRACTThe Sorting and Assembly Machinery (SAM) Complex functions in the assembly of β-barrel in the mitochondrial membrane. The SAM complex is made up of three subunits, Sam35, Sam37, and Sam50. While both Sam35 and Sam37 are peripheral membrane proteins that are not required for survival, Sam50 interacts with the MICOS complex to connect the inner and outer mitochondrial membranes and forms the mitochondrial intermembrane space bridging (MIB) complex. Specifically, Sam50 stabilizes the MIB complex for protein transport, respiratory chain complex assembly, and cristae integrity regulation. To structurally form and sustain the cristae, the MICOS complex assembles at the cristae junction and binds directly to Sam50. However, the role of Sam50 in overall mitochondrial structure and metabolism in skeletal muscle remains unclear. Here, we use SBF-SEM and Amira software perform 3D renderings of mitochondria and autophagosomes in human myotubes. Beyond this, Gas Chromatography-Mass Spectrometry-based metabolomics was utilized to interrogate differential changes of the metabolites in wild-type (WT) and Sam50 deficient myotubes. Ablation of Sam50 , revealed increases in ß-Alanine, propanoate, and phenylalanine, and tyrosine metabolism. Additionally, we observed that mitochondrial fragmentation and autophagosome formation was increased in Sam50 -deficient myotubes compared to control myotubes. Beyond this, the metabolomic analysis revealed an increase in amino acid metabolism and fatty acid metabolism. XF24 Seahorse Analyzer shows that oxidative capacity is further impaired upon ablation of Sam50 in both murine and human myotubes. Together, these data suggest Sam50 is critical for establishing and maintaining mitochondria, mitochondrial cristae structure, and mitochondrial metabolism.PMID:37292887 | PMC:PMC10245823 | DOI:10.1101/2023.05.20.541602

medRxiv. 2023 May 24:2023.05.17.23289772. doi: 10.1101/2023.05.17.23289772. Preprint.ABSTRACTPulmonary hypertension (PH) is a severe hemodynamic, progressive condition associated with high morbidity and mortality where early and less invasive diagnostics could crucially improve management. There is a need for biomarkers in PH that are functional, diagnostic, and prognostic. We used a broad metabolomics approach with machine learning analysis and specific free fatty acid (FFA)/lipid-ratios to develop diagnostic and prognostic PH biomarkers. In a training cohort of 74 PH patients, 30 disease controls without PH, and 65 healthy controls, we identified diagnostic and prognostic markers that were validated in an independent cohort of 64 subjects. Markers based on lipophilic metabolites were more robust than those based on hydrophilic metabolites. FFA/lipid-ratios provided excellent diagnostic accuracy for PH with an AUC of up to 0.89 and 0.90 in the training and the validation cohorts, respectively. The ratios provided age-independent prognostic information and a combination of a ratio with established clinical scores increased the hazard ratio (HR) for FPHR4p and COMPERA2 from 2.5 to 4.3 and from 3.3 to 5.6, respectively. Pulmonary arteries (PA) of idiopathic PAH (IPAH) lungs show lipid accumulation and altered expression of lipid homeostasis-related genes that may explain this accumulation. Our functional studies in PA endothelial and smooth muscle cells have shown that increased FFA levels caused excessive proliferation and PA endothelial barrier dysfunction, both hallmarks of pulmonary artery hypertension (PAH). In conclusion, lipidomic changes in PH provide novel diagnostic and prognostic biomarkers and may point to new metabolic therapy targets.PMID:37292870 | PMC:PMC10246148 | DOI:10.1101/2023.05.17.23289772

bioRxiv. 2023 May 26:2023.05.26.542501. doi: 10.1101/2023.05.26.542501. Preprint.ABSTRACTArthropod-borne microbes rely on the metabolic state of a host to cycle between evolutionarily distant species. For instance, arthropod tolerance to infection may be due to redistribution of metabolic resources, often leading to microbial transmission to mammals. Conversely, metabolic alterations aids in pathogen elimination in humans, who do not ordinarily harbor arthropod-borne microbes. To ascertain the effect of metabolism on interspecies relationships, we engineered a system to evaluate glycolysis and oxidative phosphorylation in the tick Ixodes scapularis . Using a metabolic flux assay, we determined that the rickettsial bacterium Anaplasma phagocytophilum and the Lyme disease spirochete Borrelia burgdorferi , which are transstadially transmitted in nature, induced glycolysis in ticks. On the other hand, the endosymbiont Rickettsia buchneri, which is transovarially maintained, had a minimal effect on I. scapularis bioenergetics. Importantly, the metabolite β-aminoisobutyric acid (BAIBA) was elevated during A. phagocytophilum infection of tick cells following an unbiased metabolomics approach. Thus, we manipulated the expression of genes associated with the catabolism and anabolism of BAIBA in I. scapularis and detected impaired feeding on mammals, reduced bacterial acquisition, and decreased tick survival. Collectively, we reveal the importance of metabolism for tick-microbe relationships and unveil a valuable metabolite for I. scapularis fitness.PMID:37292783 | PMC:PMC10245996 | DOI:10.1101/2023.05.26.542501

Front Immunol. 2023 May 24;14:1203015. doi: 10.3389/fimmu.2023.1203015. eCollection 2023.ABSTRACTBACKGROUND: Postpartum depression has a crucial impact on the physical and psychological comfort and the work of postnatal women, the growth and development of infants and mental health in adulthood. Finding a safe and effective anti-postnatal depression drug is currently an important research goal in this field.METHODS: In this study, the forced swimming test (FST) and tail suspension test (TST) were used to evaluated the depressive behaviors of mice, and the changes of metabolites and intestinal microflora in mice with postpartum depression were examined through non-target metabolomics and 16S RNA sequencing respectively.RESULTS: We found that traditional Chinese medicine compound 919 Syrup could alleviate postpartum depression in mice and inhibit the elevated erucamide level in depressive hippocampus. However, mice treated with antibiotics were not sensitive to the anti-postnatal depression effect of 919 Syrup, and the level of 5-aminovaleric acid betaine (5-AVAB) in their hippocampus was significantly decreased. Transplanting fecal microflora treated with 919 Syrup could effectively improve the depressive behaviors of mice, upregulate the level of gut-derived 5-AVAB in the hippocampus, and downregulate the level of erucamide. Erucamide was significantly negatively correlated with increased Bacteroides in intestine after 919 Syrup treatment or fecal transplantation, and significantly positively correlated with Ruminococcaceae UCG-014 which was increased in feces of mice with postpartum depression. The increase of Bacteroides, Lactobacillus, and Ruminiclostridium in intestine after fecal transplantation had a clearly positive correlation with 5-AVAB.CONCLUSION: In brief, 919 Syrup may downregulate the ratio of hippocampal metabolites erucamide to 5-AVAB by regulating intestinal flora to alleviate postpartum depression, laying a scientific foundation for future pathological research and development of therapeutic drugs for postpartum depression.PMID:37292211 | PMC:PMC10244653 | DOI:10.3389/fimmu.2023.1203015

Front Immunol. 2023 May 23;14:1159112. doi: 10.3389/fimmu.2023.1159112. eCollection 2023.ABSTRACTPURPOSE: Olfactory dysfunction (OD) is a debilitating symptom frequently reported by patients with chronic rhinosinusitis (CRS) and it is associated with a dysregulated sinonasal inflammation. However, little information is available about the effect of the inflammation-related nasal microbiota and related metabolites on the olfactory function in these patients. Therefore, the current study aimed to investigate the nasal microbiota-metabolites-immune interactions and their role in the pathogenesis of OD in CRS patients.METHODS: 23 and 19 CRS patients with and without OD, respectively, were enrolled in the present study. The "Sniffin' Sticks" was used to measure the olfactory function, while the metagenomic shotgun sequencing and the untargeted metabolite profiling were performed to assess the differences in terms of the nasal microbiome and metabolome between the two groups. The levels of nasal mucus inflammatory mediators were investigated by a multiplex flow Cytometric Bead Array (CBA).RESULTS: A decreased diversity in the nasal microbiome from the OD group compared to the NOD group was evidenced. The metagenomic analysis revealed a significant enrichment of Acinetobacter johnsonii in the OD group, while Mycoplasma arginini, Aeromonas dhakensis, and Salmonella enterica were significantly less represented (LDA value > 3, p < 0.05). The nasal metabolome profiles were significantly different between the OD and NOD groups (P < 0.05). The purine metabolism was the most significantly enriched metabolic subpathway in OD patients compared with NOD patients (P < 0.001). The expressions of IL-5, IL-8, MIP-1α, MCP-1, and TNF were statistically and significantly increased in the OD group (P < 0.05). All these data, including the dysregulation of the nasal microbiota, differential metabolites, and elevated inflammatory mediators in OD patients demonstrated a clear interaction relationship.CONCLUSION: The disturbed nasal microbiota-metabolite-immune interaction networks may be implicated in the pathogenesis of OD in CRS patients and the underlying pathophysiological mechanisms need to be further investigated in future studies.PMID:37292198 | PMC:PMC10245275 | DOI:10.3389/fimmu.2023.1159112

Front Immunol. 2023 May 24;14:1151728. doi: 10.3389/fimmu.2023.1151728. eCollection 2023.ABSTRACTINTRODUCTION: Sepsis is intricately linked to intestinal damage and barrier dysfunction. At present times, there is a growing interest in a metabolite-based therapy for multiple diseases.METHODS: Serum samples from septic patients and healthy individuals were collected and their metabonomics profiling assessed using Ultra-Performance Liquid Chromatography-Time of Flight Mass Spectrometry (UPLC-TOFMS). The eXtreme Gradient Boosting algorithms (XGBOOST) method was used to screen essential metabolites associated with sepsis, and five machine learning models, including Logistic Regression, XGBoost, GaussianNB(GNB), upport vector machines(SVM) and RandomForest were constructed to distinguish sepsis including a training set (75%) and validation set(25%). The area under the receiver-operating characteristic curve (AUROC) and Brier scores were used to compare the prediction performances of different models. Pearson analysis was used to analysis the relationship between the metabolites and the severity of sepsis. Both cellular and animal models were used to HYPERLINK "javascript:;" assess the function of the metabolites.RESULTS: The occurrence of sepsis involve metabolite dysregulation. The metabolites mannose-6-phosphate and sphinganine as the optimal sepsis-related variables screened by XGBOOST algorithm. The XGBoost model (AUROC=0.956) has the most stable performance to establish diagnostic model among the five machine learning methods. The SHapley Additive exPlanations (SHAP) package was used to interpret the XGBOOST model. Pearson analysis reinforced the expression of Sphinganine, Mannose 6-phosphate were positively associated with the APACHE-II, PCT, WBC, CRP, and IL-6. We also demonstrated that sphinganine strongly diminished the LDH content in LPS-treated Caco-2 cells. In addition, using both in vitro and in vivo examination, we revealed that sphinganine strongly protects against sepsis-induced intestinal barrier injury.DISCUSSION: These findings highlighted the potential diagnostic value of the ML, and also provided new insight into enhanced therapy and/or preventative measures against sepsis.PMID:37292192 | PMC:PMC10245321 | DOI:10.3389/fimmu.2023.1151728

Front Pharmacol. 2023 May 24;14:1205323. doi: 10.3389/fphar.2023.1205323. eCollection 2023.ABSTRACTBackground: The relationships among intestinal dysbiosis, bile acid (BA) metabolism disorders, and ulcerative colitis pathogenesis are now recognized. However, how specific strains regulate BA metabolism to alleviate colitis is still unclear. This study investigated the effects of Bacteroides dorei on the development of acute colitis and elucidated the underlying mechanisms. Methods: The safety of BDX-01 was evaluated in vitro and in vivo. 2.5% dextran sulfate sodium (DSS) induced colitis in C57BL/6 mice, Caco-2, and J774A.1 cells were used to evaluate the anti-inflammatory effect of BDX-01. qPCR and Western blotting were used to detect the expression of inflammatory pathways. Microbiota composition was analyzed by 16S rRNA gene sequencing. Enzyme activity analysis and targeted metabolomics were used to analyze fecal bile salt hydrolase (BSH) and BA levels. Antibiotic-induced pseudo-germ-free mice were used to investigate the role of gut microbiota in the alleviation of colitis by BDX-01. Results: We confirmed the safety of novel strain Bacteroides dorei BDX-01 in vitro and in vivo. Oral BDX-01 administration significantly ameliorated the symptoms and pathological damage of DSS-induced acute colitis. Moreoever, 16S rRNA sequencing and enzyme activity analysis showed that BDX-01 treatment increased intestinal BSH activity and the abundance of bacteria harboring this enzyme. Targeted metabolomics revealed that BDX-01 significantly increased intestinal BA excretion and deconjugation. Certain BAs act as FXR agonists. The β-muricholic acid (βMCA): taurine β-muricholic acid (T-βMCA) and cholic acid (CA): taurocholic acid (TCA) ratios and the deoxycholic acid (DCA) level decreased markedly in the colitis models but increased substantially in BDX-01-treated mice. The colonic farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15) were upregulated in mice treated with BDX-01. BDX-01 downregulated the expression of colonic proinflammatory cytokines pyrin domain-containing 3 (NLRP3), ASC, cleaved caspase-1, and IL-1β. Antibiotic treatment didn't abolish the protective effect of BDX-01 on colitis. In vitro studies showed TβMCA abolished the effects of BDX-01 on FXR activation and inhibition of the NLRP3 inflammasome activation. Conclusion: BDX-01 improved DSS-induced acute colitis by regulating intestinal BSH activity and the FXR-NLRP3 signaling pathway. Our findings indicate that BDX-01 is a promising probiotic to improve the management of ulcerative colitis.PMID:37292154 | PMC:PMC10244678 | DOI:10.3389/fphar.2023.1205323

EMBO Rep. 2023 Jun 9:e56352. doi: 10.15252/embr.202256352. Online ahead of print.ABSTRACTFetal development and parturition are precisely regulated processes that involve continuous crosstalk between the mother and the fetus. Our previous discovery that wild-type mice carrying steroid receptor coactivator (Src)-1 and Src-2 double-deficient fetuses exhibit impaired lung development and delayed labor, which indicates that the signals for parturition emanate from the fetus. In this study, we perform RNA sequencing and targeted metabolomics analyses of the lungs from fetal Src-1/-2 double-knockout mice and find that expression of arginase 1 (Arg1) is significantly decreased, accompanied by increased levels of the Arg1 substrate L-arginine. Knockdown of Arg1 in the lungs of fetal mice induces apoptosis of epithelial cells and dramatically delays initiation of labor. Moreover, treatment of human myometrial smooth muscle cells with L-arginine significantly inhibits spontaneous contractions by attenuating activation of NF-κB and downregulating expression of contraction-associated protein genes. Transcription factors GR and C/EBPβ increase transcription of Arg1 in an Src-1/Src-2-dependent manner. These findings provide new evidence that fetus-derived factors may play dual roles in coordinating fetal lung development and the initiation of labor.PMID:37291976 | DOI:10.15252/embr.202256352

J Obstet Gynaecol Res. 2023 Jun 9. doi: 10.1111/jog.15709. Online ahead of print.ABSTRACTAIM: Uterine cervical cancer (UCC) is the fourth most common cancer in women, responsible for more than 300 000 deaths worldwide. Its early detection, by cervical cytology, and prevention, by vaccinating against human papilloma virus, greatly contribute to reducing cervical cancer mortality in women. However, penetration of the effective prevention of UCC in Japan remains low. Plasma metabolome analysis is widely used for biomarker discovery and the identification of cancer-specific metabolic pathways. Here, we aimed to identify predictive biomarkers for the diagnosis and radiation sensitivity of UCC using wide-targeted plasma metabolomics.METHODS: We analyzed 628 metabolites in plasma samples obtained from 45 patients with UCC using ultra-high-performance liquid chromatography with tandem mass spectrometry.RESULTS: The levels of 47 metabolites were significantly increased and those of 75 metabolites were significantly decreased in patients with UCC relative to healthy controls. Increased levels of arginine and ceramides, and decreased levels of tryptophan, ornithine, glycosylceramides, lysophosphatidylcholine, and phosphatidylcholine were characteristic of patients with UCC. Comparison of metabolite profiles in groups susceptible and non-susceptible to radiation therapy, a treatment for UCC, revealed marked variations in polyunsaturated fatty acid, nucleic acid, and arginine metabolism in the group not susceptible to treatment.CONCLUSIONS: Our findings suggest that the metabolite profile of patients with UCC may be an important indicator for distinguishing these patients from healthy cohorts, and may also be useful for predicting sensitivity to radiotherapy.PMID:37291943 | DOI:10.1111/jog.15709

Physiol Plant. 2023 Jun 8. doi: 10.1111/ppl.13950. Online ahead of print.ABSTRACTPlant acclimation to salt and alkali stress is closely linked to the ability of the antioxidant system to mediate the scavenging of reactive oxygen species (ROS). In this study, we investigated the effects of salt stress and alkali stress on ROS, antioxidant enzymes, transcriptome, and metabolome. The results showed that the levels of superoxide anions, hydrogen peroxide, malondialdehyde, and electrolyte leakage increased under salt and alkali stress, with higher concentrations observed under alkali stress than salt stress. The activities of superoxide dismutase (EC 1.15.1.1), peroxidase (EC 1.11.1.7), catalase (EC 1.11.1.6), ascorbate peroxidase (EC 1.11.1.11), glutathione reductase (EC 1.6.4.2), dehydroascorbate reductase (EC 1.8.5.1), and monodehydroascorbate reductase (EC 1.6.5.4) varied under salt and alkali stress. The transcriptome analysis revealed the induction of signal transduction and metabolic processes and differential expression of genes encoding antioxidant enzymes in response to salt and alkali stress. The metabolome analysis demonstrated increased ascorbic acid and glutathione under salt stress, while most phenolic acids, flavonoids, and alkaloids increased under salt and alkali stress. Integrative analysis of the metabolome and transcriptome data revealed that the flavonoid biosynthesis pathway played a key role in the grapevine's response to salt stress. The total flavonoid content increased under salt and alkali stress, but the accumulation of flavonoids was higher under salt stress than alkali stress. In conclusion, our findings indicate significant differences in the antioxidant defense of grapevines under these two stresses, providing insight into distinct acclimation mechanisms in grapevine under salt and alkali stress. This article is protected by copyright. All rights reserved.PMID:37291799 | DOI:10.1111/ppl.13950

Kidney360. 2023 Jun 9. doi: 10.34067/KID.0000000000000158. Online ahead of print.ABSTRACTBACKGROUND: Since chronic kidney disease (CKD) is caused by genetic and environmental factors, biomarker development through metabolomic analysis, which reflects gene-derived downstream effects and host adaptation to the environment, is warranted.METHODS: We measured the metabolites in urine samples collected from 789 patients at the time of kidney biopsy and from urine samples from 147 healthy subjects using nuclear magnetic resonance (NMR). The composite outcome was defined as a 30% decline in estimated glomerular filtration rate (eGFR), doubling of serum creatinine levels, or end-stage kidney disease.RESULTS: Among the 28 candidate metabolites, we identified 7 metabolites showing 1) good discrimination between healthy controls and patients with stage 1 CKD and 2) a consistent change in pattern from controls to patients with advanced-stage CKD. Among the 7 metabolites, betaine, choline, glucose, fumarate, and citrate showed significant associations with the composite outcome after adjustment for age, sex, eGFR, the urine protein-creatinine ratio, and diabetes. Furthermore, adding choline, glucose, or fumarate to traditional biomarkers, including eGFR and proteinuria, significantly improved the ability of the net reclassification improvement (P<0.05) and integrated discrimination improvement (P<0.05) to predict the composite outcome.CONCLUSION: Urinary metabolites, including betaine, choline, fumarate, citrate, and glucose, were found to be significant predictors of the progression of CKD. As a signature of kidney injury-related metabolites, it would be warranted to monitor to predict the renal outcome.PMID:37291728 | DOI:10.34067/KID.0000000000000158