PubMed

Metabolomics. 2024 Mar 5;20(2):35. doi: 10.1007/s11306-024-02091-5.ABSTRACTINTRODUCTION: Longitudinal biomarkers in patients with community-acquired pneumonia (CAP) may help in monitoring of disease progression and treatment response. The metabolic host response could be a potential source of such biomarkers since it closely associates with the current health status of the patient.OBJECTIVES: In this study we performed longitudinal metabolite profiling in patients with CAP for a comprehensive range of metabolites to identify potential host response biomarkers.METHODS: Previously collected serum samples from CAP patients with confirmed Streptococcus pneumoniae infection (n = 25) were used. Samples were collected at multiple time points, up to 30 days after admission. A wide range of metabolites was measured, including amines, acylcarnitines, organic acids, and lipids. The associations between metabolites and C-reactive protein (CRP), procalcitonin, CURB disease severity score at admission, and total length of stay were evaluated.RESULTS: Distinct longitudinal profiles of metabolite profiles were identified, including cholesteryl esters, diacyl-phosphatidylethanolamine, diacylglycerols, lysophosphatidylcholines, sphingomyelin, and triglycerides. Positive correlations were found between CRP and phosphatidylcholine (34:1) (cor = 0.63) and negative correlations were found for CRP and nine lysophosphocholines (cor = - 0.57 to - 0.74). The CURB disease severity score was negatively associated with six metabolites, including acylcarnitines (tau = - 0.64 to - 0.58). Negative correlations were found between the length of stay and six triglycerides (TGs), especially TGs (60:3) and (58:2) (cor = - 0.63 and - 0.61).CONCLUSION: The identified metabolites may provide insight into biological mechanisms underlying disease severity and may be of interest for exploration as potential treatment response monitoring biomarker.PMID:38441696 | DOI:10.1007/s11306-024-02091-5

Protein Cell. 2024 Mar 5:pwae006. doi: 10.1093/procel/pwae006. Online ahead of print.ABSTRACTThe current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) remains a threat to pregnant women. However, the impact of early pregnancy SARS-CoV-2 infection on the maternal-fetal interface remains poorly understood. Here, we present a comprehensive analysis of single-cell transcriptomics and metabolomics in placental samples infected with SARS-CoV-2 during early pregnancy. Compared to control placentas, SARS-CoV-2 infection elicited immune responses at the maternal-fetal interface and induced metabolic alterations in amino acid and phospholipid profiles during the initial weeks post infection. However, subsequent immune cell activation and heightened immune tolerance in trophoblast cells established a novel dynamic equilibrium that mitigated the impact on the maternal-fetal interface. Notably, the immune response and metabolic alterations at the maternal-fetal interface exhibited a gradual decline during the second-trimester. Our study underscores the adaptive immune tolerance mechanisms and establishment of immunological balance during the first two trimesters following maternal SARS-CoV-2 infection.PMID:38441496 | DOI:10.1093/procel/pwae006

Adv Sci (Weinh). 2024 Mar 5:e2307263. doi: 10.1002/advs.202307263. Online ahead of print.ABSTRACTFerroptosis and apoptosis are key cell-death pathways implicated in several human diseases including cancer. Ferroptosis is driven by iron-dependent lipid peroxidation and currently has no characteristic biomarkers or gene signatures. Here a continuous phenotypic gradient between ferroptosis and apoptosis coupled to transcriptomic and metabolomic landscapes is established. The gradual ferroptosis-to-apoptosis transcriptomic landscape is used to generate a unique, unbiased transcriptomic predictor, the Gradient Gene Set (GGS), which classified ferroptosis and apoptosis with high accuracy. Further GGS optimization using multiple ferroptotic and apoptotic datasets revealed highly specific ferroptosis biomarkers, which are robustly validated in vitro and in vivo. A subset of the GGS is associated with poor prognosis in breast cancer patients and PDXs and contains different ferroptosis repressors. Depletion of one representative, PDGFA-assaociated protein 1(PDAP1), is found to suppress basal-like breast tumor growth in a mouse model. Omics and mechanistic studies revealed that ferroptosis is associated with enhanced lysosomal function, glutaminolysis, and the tricarboxylic acid (TCA) cycle, while its transition into apoptosis is attributed to enhanced endoplasmic reticulum(ER)-stress and phosphatidylethanolamine (PE)-to-phosphatidylcholine (PC) metabolic shift. Collectively, this study highlights molecular mechanisms underlying ferroptosis execution, identified a highly predictive ferroptosis gene signature with prognostic value, ferroptosis versus apoptosis biomarkers, and ferroptosis repressors for breast cancer therapy.PMID:38441406 | DOI:10.1002/advs.202307263

Food Funct. 2024 Mar 5. doi: 10.1039/d3fo03575a. Online ahead of print.ABSTRACTObjective: To examine the associations of dietary patterns with frailty and whether metabolic signatures (MSs) mediate these associations. Methods: We used UK Biobank data to examine (1) the associations of four dietary patterns (i.e., alternate Mediterranean diet [aMED], Recommended Food Score [RFS], Dietary Approaches to Stop Hypertension [DASH] and Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet) with frailty (measured by the frailty phenotype and the frailty index) using multivariable logistic regression (analytic sample 1: N = 124 261; mean age = 57.7 years), and (2) the mediating role of MSs (weighted sums of the metabolites selected from 168 plasma metabolites using the LASSO algorithm) in the above associations via mediation analysis (analytic sample 2: N = 26 270; mean age = 57.7 years). Results: Four dietary patterns were independently associated with frailty (all P < 0.001). For instance, compared to participants in the lowest tertile for RFS, those in the intermediate (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.74, 0.89) and highest (OR: 0.62; 95% CI: 0.56, 0.68) tertiles had a lower risk of frailty. We found that 98, 68, 123 and 75 metabolites were associated with aMED, RFS, DASH and MIND, respectively, including 16 common metabolites (e.g., fatty acids, lipoproteins, acetate and glycoprotein acetyls). The MSs based on these metabolites partially mediated the association of the four dietary patterns with frailty, with the mediation proportion ranging from 26.52% to 45.83%. The results were robust when using another frailty measure, the frailty index. Conclusions: The four dietary patterns were associated with frailty, and these associations were partially mediated by MSs. Adherence to healthy dietary patterns may potentially reduce frailty development by modulating metabolites.PMID:38441259 | DOI:10.1039/d3fo03575a

J Trauma Acute Care Surg. 2024 Mar 4. doi: 10.1097/TA.0000000000004298. Online ahead of print.ABSTRACTPost-injury infection continues to plague trauma and emergency surgery patients fortunate enough to survive the initial injury. Rapid response systems, massive transfusion protocols, the development of level 1 trauma centers, etc., have improved the outcome for millions of patients worldwide. Yet despite this excellent initial care, patients still remain vulnerable to post-injury infections that can result in organ failure, prolonged critical illness and even death. While risk factors have been identified (degree of injury, blood loss, time to definitive care, immunocompromise, etc.) they remain probabilistic, not deterministic, and do not explain outcome variability at the individual case level. Here, we assert that analysis of the social determinants of health, as reflected in the patient's microbiome composition (i.e. community structure, membership) and function (metabolomic output), may offer a "window" with which to define individual variability following traumatic injury. Given emerging knowledge in the field, a more comprehensive evaluation of biomarkers within the patient's microbiome, from stool-based microbial metabolites to those in plasma and those present in exhaled breath, when coupled with clinical metadata and machine learning, could lead to a more deterministic assessment of an individual's risk for a poor outcome and those factors that are modifiable. The aim of this piece is to examine how measurable elements of the social determinants of health and the life-history of the patient may be buried within the ecologic memory of the gut microbiome. Here we posit that interrogation of the gut microbiome in this manner may be used to inform novel approaches to drive recovery following a surgical injury.PMID:38441071 | DOI:10.1097/TA.0000000000004298

J Agric Food Chem. 2024 Mar 5. doi: 10.1021/acs.jafc.3c06864. Online ahead of print.ABSTRACTThe present study evaluated the potential of endogenous enzymes and probiotics in transforming bioactive metabolites to reduce the purgative effect and improve the functional activity of Cassiae Semen and verified and revealed the biotransformation effect of endogenous enzymes. Although probiotics, especially Lactobacillus rhamnosus, exerted the transformation effect, the endogenous enzymes proved to be more effective in transforming the components of Cassiae Semen. After biotransformation by endogenous enzymes for 12 h, the levels of six anthraquinones in Cassiae Semen increased by at least 2.98-fold, and free anthraquinones, total phenolics, and antioxidant activity also showed significant improvement, accompanied by an 82.2% reduction in combined anthraquinones responsible for the purgative effect of Cassiae Semen. Further metabolomic analysis revealed that the biotransformation effect of endogenous enzymes on the bioactive metabolites of Cassiae Semen was complex and diverse, and the biotransformation of quinones and flavonoids was particularly prominent and occurred by three primary mechanisms, hydrolyzation, methylation, and dimerization, might under the action of glycosyl hydrolases, SAM-dependent methyltransferases, and CYP450s. Accordingly, biotransformation by endogenous enzymes emerges as a mild, economical, food safety risk-free, and effective strategy to modify Cassiae Semen into an excellent functional food.PMID:38441033 | DOI:10.1021/acs.jafc.3c06864

mSystems. 2024 Mar 5:e0140123. doi: 10.1128/msystems.01401-23. Online ahead of print.ABSTRACTThe microbial utilization of dietary carbohydrates is closely linked to the pivotal role of the gut microbiome in human health. Inherent to the modulation of complex microbial communities, a prebiotic implies the selective utilization of a specific substrate, relying on the metabolic capacities of targeted microbes. In this study, we investigated the metabolic capacities of 17 commensal bacteria of the human gut microbiome toward dietary carbohydrates with prebiotic potential. First, in vitro experiments allowed the classification of bacterial growth and fermentation profiles in response to various carbon sources, including agave inulin, corn fiber, polydextrose, and citrus pectin. The influence of phylogenetic affiliation appeared to statistically outweigh carbon sources in determining the degree of carbohydrate utilization. Second, we narrowed our focus on six commensal bacteria representative of the Bacteroidetes and Firmicutes phyla to perform an untargeted high-resolution liquid chromatography-mass spectrometry metabolomic analysis: Bacteroides xylanisolvens, Bacteroides thetaiotaomicron, Bacteroides intestinalis, Subdoligranulum variabile, Roseburia intestinalis, and Eubacterium rectale exhibited distinct metabolomic profiles in response to different carbon sources. The relative abundance of bacterial metabolites was significantly influenced by dietary carbohydrates, with these effects being strain-specific and/or carbohydrate-specific. Particularly, the findings indicated an elevation in short-chain fatty acids and other metabolites, including succinate, gamma-aminobutyric acid, and nicotinic acid. These metabolites were associated with putative health benefits. Finally, an RNA-Seq transcriptomic approach provided deeper insights into the underlying mechanisms of carbohydrate metabolization. Restricting our focus on four commensal bacteria, including B. xylanisolvens, B. thetaiotaomicron, S. variabile, and R. intestinalis, carbon sources did significantly modulate the level of bacterial genes related to the enzymatic machinery involved in the metabolization of dietary carbohydrates. This study provides a holistic view of the molecular strategies induced during the dynamic interplay between dietary carbohydrates with prebiotic potential and gut commensal bacteria.IMPORTANCE: This study explores at a molecular level the interactions between commensal health-relevant bacteria and dietary carbohydrates holding prebiotic potential. We showed that prebiotic breakdown involves the specific activation of gene expression related to carbohydrate metabolism. We also identified metabolites produced by each bacteria that are potentially related to our digestive health. The characterization of the functional activities of health-relevant bacteria toward prebiotic substances can yield a better application of prebiotics in clinical interventions and personalized nutrition. Overall, this study highlights the importance of identifying the impact of prebiotics at a low resolution of the gut microbiota to characterize the activities of targeted bacteria that can play a crucial role in our health.PMID:38441031 | DOI:10.1128/msystems.01401-23

mBio. 2024 Mar 5:e0029824. doi: 10.1128/mbio.00298-24. Online ahead of print.ABSTRACTObservational evidence suggests that human milk oligosaccharides (HMOs) promote the growth of commensal bacteria in early life and adulthood. However, the mechanisms by which HMOs benefit health through modulation of gut microbial homeostasis remain largely unknown. 2'-fucosyllactose (2'-FL) is the most abundant oligosaccharide in human milk and contributes to the essential health benefits associated with human milk consumption. Here, we investigated how 2'-FL prevents colitis in adulthood through its effects on the gut microbial community. We found that the gut microbiota from adult mice that consumed 2'-FL exhibited an increase in abundance of several health-associated genera, including Bifidobacterium and Lactobacillus. The 2'-FL-modulated gut microbial community exerted preventive effects on colitis in adult mice. By using Bifidobacterium infantis as a 2'-FL-consuming bacterial model, exploratory metabolomics revealed novel 2'-FL-enriched secretory metabolites by Bifidobacterium infantis, including pantothenol. Importantly, pantothenate significantly protected the intestinal barrier against oxidative stress and mitigated colitis in adult mice. Furthermore, microbial metabolic pathway analysis identified 26 dysregulated metabolic pathways in fecal microbiota from patients with ulcerative colitis, which were significantly regulated by 2'-FL treatment in adult mice, indicating that 2'-FL has the potential to rectify dysregulated microbial metabolism in colitis. These findings support the contribution of the 2'-FL-shaped gut microbial community and bacterial metabolite production to the protection of intestinal integrity and prevention of intestinal inflammation in adulthood.IMPORTANCEAt present, neither basic research nor clinical studies have revealed the exact biological functions or mechanisms of action of individual oligosaccharides during development or in adulthood. Thus, it remains largely unknown whether human milk oligosaccharides could serve as effective therapeutics for gastrointestinal-related diseases. Results from the present study uncover 2'-FL-driven alterations in bacterial metabolism and identify novel B. infantis-secreted metabolites following the consumption of 2'-FL, including pantothenol. This work further demonstrates a previously unrecognized role of pantothenate in significantly protecting the intestinal barrier against oxidative stress and mitigating colitis in adult mice. Remarkably, 2'-FL-enhanced bacterial metabolic pathways are found to be dysregulated in the fecal microbiota of ulcerative colitis patients. These novel metabolic pathways underlying the bioactivities of 2'-FL may lay a foundation for applying individual oligosaccharides for prophylactic intervention for diseases associated with impaired intestinal homeostasis.PMID:38441000 | DOI:10.1128/mbio.00298-24

mSystems. 2024 Mar 5:e0089123. doi: 10.1128/msystems.00891-23. Online ahead of print.ABSTRACTMycoplasma species are able to produce and release secreted proteins, such as toxins, adhesins, and virulence-related enzymes, involved in bacteria adhesion, invasion, and immune evasion between the pathogen and host. Here, we investigated a novel secreted protein, MbovP0725, from Mycoplasma bovis encoding a putative haloacid dehalogenase (HAD) hydrolase function of a key serine/threonine phosphatase depending on Mg2+ for the dephosphorylation of its substrate pNPP, and it was most active at pH 8 to 9 and temperatures around 40°C. A transposon insertion mutant strain of M. bovis HB0801 that lacked the protein MbovP0725 induced a stronger inflammatory response but with a partial reduction of adhesion ability. Using transcriptome sequencing and quantitative reverse transcription polymerase chain reaction analysis, we found that the mutant was upregulated by the mRNA expression of genes from the glycolysis pathway, while downregulated by the genes enriched in ABC transporters and acetate kinase-phosphate acetyltransferase pathway. Untargeted metabolomics showed that the disruption of the Mbov_0725 gene caused the accumulation of 9-hydroxyoctadecadienoic acids and the consumption of cytidine 5'-monophosphate, uridine monophosphate, and adenosine monophosphate. Both the exogenous and endogenous MbvoP0725 protein created by purification and transfection inhibited lipopolysaccharide (LPS)-induced IL-1β, IL-6, and TNF-α mRNA production and could also attenuate the activation of MAPK-associated pathways after LPS treatment. A pull-down assay identified MAPK p38 and ERK as potential substrates for MbovP0725. These findings define metabolism- and virulence-related roles for a HAD family phosphatase and reveal its ability to inhibit the host pro-inflammatory response.IMPORTANCE: Mycoplasma bovis (M. bovis) infection is characterized by chronic pneumonia, otitis, arthritis, and mastitis, among others, and tends to involve the suppression of the immune response via multiple strategies to avoid host cell immune clearance. This study found that MbovP0725, a haloacid dehalogenase (HAD) family phosphatase secreted by M. bovis, had the ability to inhibit the host pro-inflammatory response induced by lipopolysaccharide. Transcriptomic and metabolomic analyses were used to identify MbovP0725 as an important phosphatase involved in glycolysis and nucleotide metabolism. The M. bovis transposon mutant strain T8.66 lacking MbovP0725 induced a higher inflammatory response and exhibited weaker adhesion to host cells. Additionally, T8.66 attenuated the phosphorylation of MAPK P38 and ERK and interacted with the two targets. These results suggested that MbovP0725 had the virulence- and metabolism-related role of a HAD family phosphatase, performing an anti-inflammatory response during M. bovis infection.PMID:38440990 | DOI:10.1128/msystems.00891-23

Microbiol Spectr. 2024 Mar 5:e0405223. doi: 10.1128/spectrum.04052-23. Online ahead of print.ABSTRACT"Candidatus Liberibacter asiaticus" (CLas), the causal agent of citrus Huanglongbing (HLB), is able to multiply to a high abundance in citrus fruit pith. However, little is known about the biological processes and phytochemical substances that are vital for CLas colonization and growth in fruit pith. In this study, CLas-infected fruit pith of three citrus cultivars ("Shatangju" mandarin, "Guanxi" pomelo, and "Shatian" pomelo) exhibiting different tolerance to CLas were collected and used for dual RNA-Seq and untargeted metabolome analysis. Comparative transcriptome analysis found that the activation of the CLas noncyclic TCA pathway and pathogenic-related effectors could contribute to the colonization and growth of CLas in fruit pith. The pre-established Type 2 prophage in the CLas genome and the induction of its CRISPR/cas system could enhance the phage resistance of CLas and, in turn, facilitate CLas population growth in fruit pith. CLas infection caused the accumulation of amino acids that were correlated with tolerance to CLas. The accumulation of most sugars and organic acids in CLas-infected fruit pith, which could be due to the phloem blockage caused by CLas infection, was thought to be beneficial for CLas growth in localized phloem tissue. The higher levels of flavonoids and terpenoids in the fruit pith of CLas-tolerant cultivars, particularly those known for their antimicrobial properties, could hinder the growth of CLas. This study advances our understanding of CLas multiplication in fruit pith and offers novel insight into metabolites that could be responsible for tolerance to CLas or essential to CLas population growth.IMPORTANCECitrus Huanglongbing (HLB, also called citrus greening disease) is a highly destructive disease currently threatening citrus production worldwide. HLB is caused by an unculturable bacterial pathogen, "Candidatus Liberibacter asiaticus" (CLas). However, the mechanism of CLas colonization and growth in citrus hosts is poorly understood. In this study, we utilized the fruit pith tissue, which was able to maintain the CLas at a high abundance, as the materials for dual RNA-Seq and untargeted metabolome analysis, aiming to reveal the biological processes and phytochemical substances that are vital for CLas colonization and growth. We provided a genome-wide CLas transcriptome landscape in the fruit pith of three citrus cultivars with different tolerance and identified the important genes/pathways that contribute to CLas colonization and growth in the fruit pith. Metabolome profiling identified the key metabolites, which were mainly affected by CLas infection and influenced the population dynamic of CLas in fruit pith.PMID:38440971 | DOI:10.1128/spectrum.04052-23

Front Plant Sci. 2024 Feb 19;15:1325365. doi: 10.3389/fpls.2024.1325365. eCollection 2024.ABSTRACTChemical priming has emerged as a promising area in agricultural research. Our previous studies have demonstrated that pretreatment with a low concentration of ethanol enhances abiotic stress tolerance in Arabidopsis and cassava. Here, we show that ethanol treatment induces heat stress tolerance in tomato (Solanum lycopersicon L.) plants. Seedlings of the tomato cultivar 'Micro-Tom' were pretreated with ethanol solution and then subjected to heat stress. The survival rates of the ethanol-pretreated plants were significantly higher than those of the water-treated control plants. Similarly, the fruit numbers of the ethanol-pretreated plants were greater than those of the water-treated ones. Transcriptome analysis identified sets of genes that were differentially expressed in shoots and roots of seedlings and in mature green fruits of ethanol-pretreated plants compared with those in water-treated plants. Gene ontology analysis using these genes showed that stress-related gene ontology terms were found in the set of ethanol-induced genes. Metabolome analysis revealed that the contents of a wide range of metabolites differed between water- and ethanol-treated samples. They included sugars such as trehalose, sucrose, glucose, and fructose. From our results, we speculate that ethanol-induced heat stress tolerance in tomato is mainly the result of increased expression of stress-related genes encoding late embryogenesis abundant (LEA) proteins, reactive oxygen species (ROS) elimination enzymes, and activated gluconeogenesis. Our results will be useful for establishing ethanol-based chemical priming technology to reduce heat stress damage in crops, especially in Solanaceae.PMID:38439987 | PMC:PMC10909983 | DOI:10.3389/fpls.2024.1325365

iScience. 2024 Feb 17;27(3):109263. doi: 10.1016/j.isci.2024.109263. eCollection 2024 Mar 15.ABSTRACTEnhancers of polycomb 1 (EPC1) and 2 (EPC2) are involved in multiple biological processes as components of histone acetyltransferases/deacetylase complexes and transcriptional cofactors, and their dysfunction was associated with developmental defects and diseases. However, it remains unknown how their dysfunction induces hematopoietic stem and progenitor cell (HSPC) defects. Here, we show that depletion of EPC1/2 significantly reduced the number of hematopoietic stem and progenitor cells (HSPCs) in the aorta-gonad mesonephros and caudal hematopoietic tissue regions by impairing HSPC proliferation, and consistently downregulated the expression of HSPC genes in K562 cells. This study demonstrates the functions of EPC1/2 in regulating histone H3 acetylation, and in regulating DLST (dihydrolipoamide S-succinyltransferase) via H3 acetylation and cooperating with transcription factors serum response factor and FOXR2 together, and in the subsequent HSPC emergence and proliferation. Our results demonstrate the essential roles of EPC1/2 in regulating H3 acetylation, and DLST as a linkage between EPC1 and EPC2 with mitochondria metabolism, in HSPC emergence and proliferation.PMID:38439957 | PMC:PMC10910311 | DOI:10.1016/j.isci.2024.109263

Heliyon. 2024 Feb 20;10(5):e26565. doi: 10.1016/j.heliyon.2024.e26565. eCollection 2024 Mar 15.ABSTRACTCulex pipiens (Linnaeus, 1758) mosquitoes search plant sources of sugars to cope with the energetic demand of various physiological processes. The crop as part of the digestive system is devoted to the storage of sugar-based meal obtained from various nectars sources. The profiling of sugars and metabolites in the Culex pipiens' crop is scarce, and only few studies used Liquid Chromatography - Mass Spectrometry (LC-MS), which provides broad detection for biomonitoring environmental substances and even contaminants in the sugar diet of mosquitoes populations. Therefore, sugar and metabolite profiling were performed on crops obtained from mosquitoes exposed to plant nectar under laboratory or natural conditions by Ultra High-Performance LC-MS (UHPLC-MS). This method allowed us a precise quantitative and qualitative identification of sugar diet and associated environmental compounds in the crop of the mosquito C. pipiens. Under laboratory condition, mosquitoes were allowed to feed on either glucose solution, commercially-available flowers or field collected flowers. In addition, we collected mosquitoes from the field to compare those crop metabolomes with metabolome patterns occurring after nectar feeding in the lab. The sugar quantities and quality obtained from the crops of mosquitoes collected in the field were similar to those crops obtained from mosquitoes that fed on commercially-available flowers and from field collected flowers with a limit of detection of 10 μg/L for sucrose, glucose and sucrose. Next to sugar compounds, we identified 2 types of amino acids, 12 natural products, and 9 pesticides. Next to the diversity of sugar compounds, we could confirm that secondary metabolites and environmental pollutants are typically up taken from floral nectar sources by C. pipiens. The in-depth knowledge on mosquito-plant interactions may inspire the development and further optimization of mosquito trap systems and arboviral surveillance systems.PMID:38439850 | PMC:PMC10909667 | DOI:10.1016/j.heliyon.2024.e26565

Gut Microbes. 2024 Jan-Dec;16(1):2300847. doi: 10.1080/19490976.2023.2300847. Epub 2024 Mar 4.ABSTRACTDietary patterns and corresponding gut microbiota profiles are associated with various health conditions. A diet rich in polyphenols, primarily plant-based, has been shown to promote the growth of probiotic bacteria in the gastrointestinal tract, subsequently reducing the risk of metabolic disorders in the host. The beneficial effects of these bacteria are largely due to the specific metabolites they produce, such as short-chain fatty acids and membrane proteins. In this study, we employed a metabolomics-guided bioactive metabolite identification platform that included bioactivity testing using in vitro and in vivo assays to discover a bioactive metabolite produced from probiotic bacteria. Through this approach, we identified 5'-methylthioadenosine (MTA) as a probiotic bacterial-derived metabolite with anti-obesity properties. Furthermore, our findings indicate that MTA administration has several regulatory impacts on liver functions, including modulating fatty acid synthesis and glucose metabolism. The present study elucidates the intricate interplay between dietary habits, gut microbiota, and their resultant metabolites.PMID:38439565 | DOI:10.1080/19490976.2023.2300847

Genome Biol. 2024 Mar 4;25(1):64. doi: 10.1186/s13059-024-03205-x.ABSTRACTBACKGROUND: The function of diverse ruminal microbes is tightly linked to rumen development and host physiology. The system of ruminal microbes is an excellent model to clarify the fundamental ecological relationships among complex nutrient-microbiome-host interactions. Here, neonatal lambs are introduced to different dietary regimes to investigate the influences of early-life crosstalk between nutrients and microbiome on rumen development.RESULTS: We find starchy corn-soybean starter-fed lambs exhibit the thickest ruminal epithelia and fiber-rich alfalfa hay-fed lambs have the thickest rumen muscle. Metabolome and metagenome data reveal that indole-3-carboxaldehyde (3-IAld) and prostaglandin D2 (PGD2) are the top characteristic ruminal metabolites associated with ruminal epithelial and muscular development, which depend on the enhanced ruminal microbial synthesis potential of 3-IAld and PGD2. Moreover, microbial culture experiment first demonstrates that Bifidobacterium pseudolongum is able to convert tryptophan into 3-IAld and Candida albicans is a key producer for PGD2. Transcriptome sequencing of the ruminal epithelia and smooth muscle shows that ruminal epithelial and muscular development is accompanied by Wnt and Ca2+ signaling pathway activation. Primary cell cultures further confirm that 3-IAld promotes ruminal epithelial cell proliferation depending on AhR-wnt/β-catenin signaling pathway and PGD2 accelerates ruminal smooth muscle cell proliferation via Ca2+ signaling pathway. Furthermore, we find that 3-IAld and PGD2 infusion promote ruminal epithelial and musculature development in lambs.CONCLUSIONS: This study demonstrates that early-life ruminal microbiome-derived 3-IAld and PGD2 are effective promoters of rumen development, which enhances our understanding of nutrient-microbiome-host interactions in early life.PMID:38438919 | DOI:10.1186/s13059-024-03205-x

BMC Bioinformatics. 2024 Mar 4;25(1):93. doi: 10.1186/s12859-024-05719-4.ABSTRACTAn organism's observable traits, or phenotype, result from intricate interactions among genes, proteins, metabolites and the environment. External factors, such as associated microorganisms, along with biotic and abiotic stressors, can significantly impact this complex biological system, influencing processes like growth, development and productivity. A comprehensive analysis of the entire biological system and its interactions is thus crucial to identify key components that support adaptation to stressors and to discover biomarkers applicable in breeding programs or disease diagnostics. Since the genomics era, several other 'omics' disciplines have emerged, and recent advances in high-throughput technologies have facilitated the generation of additional omics datasets. While traditionally analyzed individually, the last decade has seen an increase in multi-omics data integration and analysis strategies aimed at achieving a holistic understanding of interactions across different biological layers. Despite these advances, the analysis of multi-omics data is still challenging due to their scale, complexity, high dimensionality and multimodality. To address these challenges, a number of analytical tools and strategies have been developed, including clustering and differential equations, which require advanced knowledge in bioinformatics and statistics. Therefore, this study recognizes the need for user-friendly tools by introducing Holomics, an accessible and easy-to-use R shiny application with multi-omics functions tailored for scientists with limited bioinformatics knowledge. Holomics provides a well-defined workflow, starting with the upload and pre-filtering of single-omics data, which are then further refined by single-omics analysis focusing on key features. Subsequently, these reduced datasets are subjected to multi-omics analyses to unveil correlations between 2-n datasets. This paper concludes with a real-world case study where microbiomics, transcriptomics and metabolomics data from previous studies that elucidate factors associated with improved sugar beet storability are integrated using Holomics. The results are discussed in the context of the biological background, underscoring the importance of multi-omics insights. This example not only highlights the versatility of Holomics in handling different types of omics data, but also validates its consistency by reproducing findings from preceding single-omics studies.PMID:38438871 | DOI:10.1186/s12859-024-05719-4

BMC Neurol. 2024 Mar 4;24(1):87. doi: 10.1186/s12883-024-03571-w.ABSTRACTBACKGROUND: RARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE).CASE PRESENTATION: Here, we describe a six-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), which has not previously been observed in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fissures, and he did not demonstrate progressive microcephaly. Whole genome sequencing identified two variants in RARS2, c.36 + 1G > T, a previously unpublished variant that is predicted to affect splicing and is, therefore, likely pathogenic and c.419 T > G (p.Phe140Cys), a known pathogenic variant. He exhibited significant, progressive generalized brain atrophy and ex vacuo dilation of the supratentorial ventricular system on brain MRI and did not demonstrate PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled him to make developmental progress. Plasma untargeted metabolomics analysis showed increased levels of lysophospholipid and sphingomyelin-related metabolites.CONCLUSIONS: Our work expands the clinical spectrum of RARS2-related mitochondrial disorder, demonstrating that patients can present with dysmorphic features and an absence of progressive microcephaly, which can help guide the diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping in this condition and indicates that patients can develop LGS, for which a KD may be a viable therapeutic option. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction.PMID:38438854 | DOI:10.1186/s12883-024-03571-w

BMC Bioinformatics. 2024 Mar 4;25(1):94. doi: 10.1186/s12859-024-05686-w.ABSTRACTBACKGROUND: Analysis of time-resolved postprandial metabolomics data can improve the understanding of metabolic mechanisms, potentially revealing biomarkers for early diagnosis of metabolic diseases and advancing precision nutrition and medicine. Postprandial metabolomics measurements at several time points from multiple subjects can be arranged as a subjects by metabolites by time points array. Traditional analysis methods are limited in terms of revealing subject groups, related metabolites, and temporal patterns simultaneously from such three-way data.RESULTS: We introduce an unsupervised multiway analysis approach based on the CANDECOMP/PARAFAC (CP) model for improved analysis of postprandial metabolomics data guided by a simulation study. Because of the lack of ground truth in real data, we generate simulated data using a comprehensive human metabolic model. This allows us to assess the performance of CP models in terms of revealing subject groups and underlying metabolic processes. We study three analysis approaches: analysis of fasting-state data using principal component analysis, T0-corrected data (i.e., data corrected by subtracting fasting-state data) using a CP model and full-dynamic (i.e., full postprandial) data using CP. Through extensive simulations, we demonstrate that CP models capture meaningful and stable patterns from simulated meal challenge data, revealing underlying mechanisms and differences between diseased versus healthy groups.CONCLUSIONS: Our experiments show that it is crucial to analyze both fasting-state and T0-corrected data for understanding metabolic differences among subject groups. Depending on the nature of the subject group structure, the best group separation may be achieved by CP models of T0-corrected or full-dynamic data. This study introduces an improved analysis approach for postprandial metabolomics data while also shedding light on the debate about correcting baseline values in longitudinal data analysis.PMID:38438850 | DOI:10.1186/s12859-024-05686-w

BMC Genomics. 2024 Mar 4;25(1):239. doi: 10.1186/s12864-024-10167-8.ABSTRACTBACKGROUND: Acute diarrhea, dehydration and death in piglets are all symptoms of transmissible gastroenteritis virus (TGEV), which results in significant financial losses in the pig industry. It is important to understand the pathogenesis and identify new antiviral targets by revealing the metabolic interactions between TGEV and host cells.RESULTS: We performed metabolomic and transcriptomic analyses of swine testicular cells infected with TGEV. A total of 1339 differential metabolites and 206 differentially expressed genes were detected post TEGV infection. The differentially expressed genes were significantly enriched in the HIF-1 signaling pathway and PI3K-Akt signaling. Integrated analysis of differentially expressed genes and differential metabolites indicated that they were significantly enriched in the metabolic processes such as nucleotide metabolism, biosynthesis of cofactors and purine metabolism. In addition, the results showed that most of the detected metabolites involved in the bile secretion was downregulated during TGEV infection. Furthermore, exogenous addition of key metabolite deoxycholic acid (DCA) significantly enhanced TGEV replication by NF-κB and STAT3 signal pathways.CONCLUSIONS: We identified a significant metabolite, DCA, related to TGEV replication. It added TGEV replication in host cells by inhibiting phosphorylation of NF-κB and STAT3. This study provided novel insights into the metabolomic and transcriptomic alterations related to TGEV infection and revealed potential molecular and metabolic targets for the regulation of TGEV infection.PMID:38438836 | DOI:10.1186/s12864-024-10167-8

Lab Anim (NY). 2024 Mar;53(3):63. doi: 10.1038/s41684-024-01347-w.NO ABSTRACTPMID:38438745 | DOI:10.1038/s41684-024-01347-w