PubMed

Mass Spectrom (Tokyo). 2024;13(1):A0155. doi: 10.5702/massspectrometry.A0155. Epub 2024 Nov 12.ABSTRACTSeveral database search methods have been employed in untargeted metabolomics utilizing high-resolution mass spectrometry to comprehensively annotate acquired product ion spectra. Recent technical advancements in in silico analyses have facilitated the sorting of the degree of coincidence between a query product ion spectrum, and the molecular structures in the database. However, certain search results may be false positives, necessitating a method for controlling the false discovery rate (FDR). This study proposes 4 simple methods for controlling the FDR in compound search results. Instead of preparing a decoy compound database, a decoy spectral dataset was created from the measured product-ion spectral dataset (target). Target and decoy product ion spectra were searched against an identical compound database to obtain target and decoy hits. FDR was estimated based on the number of target and decoy hits. In this study, 3 decoy generation methods, polarity switching, mirroring, and spectral sampling, were compared. Additionally, the second-rank method was examined using second-ranked hits in the target search results as decoy hits. The performances of these 4 methods were evaluated by annotating product ion spectra from the MassBank database using the SIRIUS 5 CSI:FingerID scoring method. The results indicate that the FDRs estimated using the second-rank method were the closest to the true FDR of 0.05. Using this method, a compound search was performed on 4 human metabolomic data-dependent acquisition datasets with an FDR of 0.05. The FDR-controlled compound search successfully identified several compounds not present in the Human Metabolome Database.PMID:39555379 | PMC:PMC11565486 | DOI:10.5702/massspectrometry.A0155

Front Cell Infect Microbiol. 2024 Nov 1;14:1482919. doi: 10.3389/fcimb.2024.1482919. eCollection 2024.ABSTRACTAerobic respiration is the key driver of Vibrio cholerae proliferation and infection. Our previous transcriptome results suggested that degS knockout downregulates a few genes involved in NADH and ATP synthesis in the aerobic respiratory pathway. In this study, non-targeted metabolomics results showed that the differential metabolites affected by degS knockout were associated with aerobic respiration. Further results suggested that the key products of aerobic respiration, NADH and ATP, were reduced upon degS deletion and were not dependent on the classical σE pathway. The two-component system response factor aerobic respiration control A (ArcA) is involved in regulating NADH and ATP levels. qRT-PCR demonstrated that DegS negatively regulates the transcription of the arcA gene, which negatively regulates the expression of isocitrate dehydrogenase (ICDH), a key rate-limiting enzyme of the tricarboxylic acid cycle. NADH and ATP levels were partially restored with the knockout of the arcA gene in the ΔdegS strain, while levels were partially restored with overexpression of ICDH in the ΔdegS strain. In a growth experiment, compared to the ΔdegS strain, the growth rates of ΔdegSΔarcA and ΔdegS-overexpressed icdh strains (ΔdegS+icdh) were partially restored during the logarithmic growth period. Colonization of the intestines of suckling mice showed a significant reduction in the colonizing ability of the ΔdegS strain, similar colonizing ability of the ΔdegS::degS strain and the wild-type strain, and a partial recovery of the colonizing ability of the ΔdegS+icdh strain. Overall, these findings suggest that the DegS protease regulates the expression of ICDH through ArcA, thereby affecting the NADH and ATP levels of V. cholerae and its growth and intestinal colonization ability.PMID:39554810 | PMC:PMC11564185 | DOI:10.3389/fcimb.2024.1482919

Drug Des Devel Ther. 2024 Nov 12;18:5087-5108. doi: 10.2147/DDDT.S476494. eCollection 2024.ABSTRACTPURPOSE: Inflammatory bowel disease (IBD) is a serious disease that affects the metabolism and inflammatory responses of human beings. From the perspective of traditional Chinese medicine, damp-heat syndrome is one of the main syndromes of IBD. Rhizoma Paridis, also known as the root of Paris polyphylla, a well-known herbal medicine used in China, is used to treat IBD with damp-heat syndrome (IBD-DH). However, uncertainty still exists regarding the underlying mechanisms and the impact of Rhizoma Paridis on IBD-DH.METHODS: The rats in the model (DAT) and medication administration (Rhizoma Paridis total saponins (RPTS) and Pennogenin (PN)) groups were given a high temperature and high humidity environment, high fat and high sugar diet combined with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to establish the model of experimental colitis of damp-heat type, and the normal control group (RNC) rats were given a normal diet at normal temperature and humidity. Damp-heat control group (DNC) was set with the same condition as DAT without TNBS. Hematoxylin-Eosin (HE) staining was used to observe the histopathological morphology of the rat colorectum. The expression of the metabolism-related genes (Phospholipase A2 (sPLA2, cPLA2), and phosphatidylethanolamine N-methyltransferase (PEMT)) was assessed by using real-time quantitative PCR analysis (RT-qPCR). And the levels of the metabolism-related proteins (sPLA2, cPLA2), S100A8/9, Arg-1, and cytokines were detected by enzyme-linked immunosorbent assay (ELISA) kit. To investigate lipids and amino acids which closely associated with the IBD and IBD-DH, lipid pseudotargeted metabolomics with UHPLC-TQ/MS analysis method, as well as targeted quantitative amino acid analysis were performed.RESULTS: Our data showed that RPTS (50 mg/kg) and PN (20 mg/kg) significantly ameliorated the severity of TNBS-induced colitis and downregulated the levels of circulating proinflammatory cytokines. Compared with RNC group, lipid pseudotargeted metabolomics demonstrated that glycerophospholipids, sphingolipids, carnitine, and glycerolipids were the four most perturbed lipid classes, and amino acids targeted metabolomics demonstrated that serine, N-acetylneuraminic acid, histidine, proline, taurine, and kynurenine changed significantly in DAT group . Correlation analyses showed tight associations between most of differential metabolites and proinflammatory cytokines. RPTS and PN both regulated glycerophospholipid metabolism and sphingolipid metabolism. However, both of them did not have a significant effect on amino acid modulation. RPTS and PN potentially regulated sPLA2, cPLA2, and PEMT.CONCLUSION: These results showed that RPTS (50 mg/kg) and PN (20 mg/kg) effectively alleviated rats' colitis of damp-heat type, affected cytokines, and altered lipid metabolism without significant modulation on amino acid metabolism.PMID:39554759 | PMC:PMC11568858 | DOI:10.2147/DDDT.S476494

Front Plant Sci. 2024 Nov 1;15:1461357. doi: 10.3389/fpls.2024.1461357. eCollection 2024.ABSTRACTBACKGROUND: Gongju is recognized as one of the four traditional Chinese medicinal herbs, and its main constituents are chlorogenic acid (CGA) and its derivative material. CGA content in autooctoploid Gongju are considerably elevated compared with those in parental tetraploid Gongju at different flowering stages. However, the underlying molecular mechanisms governing the regulation CGA content remain poorly understood.METHODS: Therefore, we conducted integrated transcriptome and metabolome analyses of different flowering stages in autooctoploid and tetraploid Gongju to elucidate the underlying molecular mechanisms governing CGA biosynthesis.RESULTS: Transcriptome analysis showed that the number of differentially expressed genes in the budding stage (BS), early flowering stage (EF), and full flowering stage (FF) of tetraploid and octoploid Gongju were 3859, 11,211, and 6837, respectively. A total of 563, 466, and 394 differential accumulated metabolites were respectively identified between the bud stages of tetraploid and octoploid Gongju (4BS vs. 8BS), between the early flowering stages of tetraploid and octoploid Gongju (4EF vs. 8EF), and the full flowering stages of tetraploid and octoploid Gongju (4FF vs. 8FF) groups. The integrated analysis of transcriptomics and metabolomics revealed that the expression of pma6460 and mws0178, which are key enzymes involved in the CGA synthesis pathway, increased during the flowering stages of octoploid Gongju relative to that of tetraploid Gongju. The expression levels of CmHQT and CmC3H genes associated with CGA synthesis were higher in octoploid plants than in tetraploid plants at various flowering stages. To investigate the potential regulation of transcription factors involved in CGA synthesis, we analyzed the coexpression of CmC3H and CmHQT with CmMYBs and CmbHLHs. Results indicated that transcription factors, such as CmMYB12 (Cluster-30519.0), CmMYB26 (Cluster-75874.0), CmMYB5 (Cluster-94106.0), CmMYB1 (Cluster-71968.7), CmbHLH62 (Cluster-32024.1), CmbHLH75 (Cluster-62341.0), CmbHLH62 (Cluster-32024.8), CmbHLH75 (Cluster-60210.0), and CmbHLH16 (Cluster-90665.1) play a pivotal role in CGA synthesis regulation. The present study provides novel insights into the molecular mechanisms underlying CGA accumulation in autopolyploid Gongju.PMID:39554524 | PMC:PMC11563975 | DOI:10.3389/fpls.2024.1461357

Food Sci Nutr. 2024 Jun 14;12(9):6284-6297. doi: 10.1002/fsn3.4266. eCollection 2024 Sep.ABSTRACTSweet pepper, a globally commercialized horticultural crop, has been demonstrated to impede fat accumulation, but its mechanism remains incompletely understood. This study was designed to explore the potential mechanism of sweet pepper in reducing fat accumulation in Caenorhabditis elegans through RNA-seq and metabolome analysis. A total of 22 metabolites were identified from sweet pepper by UHPLC-ESI-TOF-MS analysis. In vivo, sweet pepper significantly inhibited α-glucosidase activity and reduced the levels of glucose, triglycerides (TG), total cholesterol (TC), and the area stained with oil red O. Additionally, it increased body length and the number of head swings in C. elegans compared to the control group. The KEGG enrichment analysis revealed significant enrichment of the biosynthesis of unsaturated fatty acids signaling pathway among the differentially expressed genes and metabolites. Furthermore, the mRNA levels of sterol regulatory element-binding proteins (SREBPs) ortholog SBP-1, as well as the stearyl CoA desaturase-1 (SCD1), including fat-5, fat-6, and fat-7, were significantly decreased after treatment with sweet pepper. Collectively, sweet pepper effectively reduces fat accumulation, which is probably related to downregulating the SREBP-SCD axis, offering new insights for future functional food development.PMID:39554335 | PMC:PMC11561784 | DOI:10.1002/fsn3.4266

Food Sci Nutr. 2024 Jun 26;12(9):6648-6659. doi: 10.1002/fsn3.4264. eCollection 2024 Sep.ABSTRACTThe pomegranate fruit is valued for its nutritional and medicinal properties, and the composition and content of primary and secondary metabolites are the main factors impacting its nutritional and medicinal properties. However, a deep understanding of metabolites in different parts of fruit is still lacking. Here, the peel, aril, and seed of mature pomegranate fruits were analyzed separately to compare metabolic component differences using UPLC/MS-MS. A total of 858 metabolites belonging to 11 classes were identified, of which flavonoids, such as delphinidin-3-O-glucoside and cyanidin-3-O-glucoside; tannins, such as ellagic acid and punicalin; and terpenoids, such as corosolic acid and madasiatic acid, were upregulated in the peel. Lipids, such as punicic acid, methyl linolenate, and linoleic acid; alkaloids, such as indole and choline; nucleotides and derivatives mainly including 2-deoxyribose-1-phosphate and 9-(arabinosyl)-hypoxanthine, were upregulated in seeds. Phenolic acids, such as 1-O-galloyl-4,6-(S)-HHDP-β-D-glucose and 1,7-di-O-galloyl-D-sedoheptulose, and flavonoids, such as cyanidin-3-O-glucoside, cyanidin-3-O-(2″-O-xylosyl) galactoside, and delphinidin-3-O-glucoside, were upregulated in aril. The flavone and flavonol biosynthesis (ko00944) pathways were significantly enriched between the peel and seed, as were the anthocyanin biosynthesis (ko00944) pathways between the aril and seed and the flavonoid biosynthesis (ko00941) pathways between the peel and aril. Additionally, functional antioxidants, such as 10,16-dihydroxypalmitic acid, 3-O-methylellagic acid, and 3,3'-O-dimethylellagic acid, were first identified in pomegranate fruits. Our results revealed the composition and abundance of primary and secondary metabolites in pomegranate fruit, which can lay the foundation for further elucidation of its nutritional and medicinal properties.PMID:39554325 | PMC:PMC11561811 | DOI:10.1002/fsn3.4264

Food Sci Nutr. 2024 Jun 18;12(9):6442-6460. doi: 10.1002/fsn3.4279. eCollection 2024 Sep.ABSTRACTNonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease, but there is currently no effective treatment method. Probiotics have been used as an adjunct therapy for NAFLD, but the mechanism is not clear. This study used Bifidobacterium longum BL19 (BL-19) to treat the NAFLD mice induced by a high-fat diet, and explored the treatment mechanism through gut microbiota and serum metabolomics techniques. We found that BL-19 effectively prevented rapid weight gain in NAFLD mice and reduced their overall food and energy intake, decreased liver inflammatory factors expressions, and increased the bile acid synthetase enzyme CYP7A1 and superoxide dismutase. After BL-19 treatment, the abundances of butyric acid bacteria (Oscillospira and Coprococcus) in the feces of mice increased significantly, and the concentration of butyric acid also increased significantly. We believe that BL-19 promotes the production of butyrate in the intestines, which in turn regulates the activity of CYP7A1 in the liver and bile acid synthesis, ultimately treating liver inflammation and lipid accumulation in NAFLD mice. Serum metabolomics results indicated that BL-19 affected multiple pathways related to inflammation and lipid metabolism in NAFLD mice. These findings suggest that BL-19 shows promise as an adjunct therapy for NAFLD, as it can significantly improve oxidative stress, reduce inflammation in the liver, and decrease lipid accumulation.PMID:39554323 | PMC:PMC11561819 | DOI:10.1002/fsn3.4279

bioRxiv [Preprint]. 2024 Nov 2:2024.10.29.620864. doi: 10.1101/2024.10.29.620864.ABSTRACTBACKGROUND: Breast cancer, the most common cancer type among women, was recently found to contain a specific tumor microbiome, but its impact on host biology remains unclear. CD8 + tumor-infiltrating lymphocytes (TILs) are pivotal effectors of anti-tumor immunity that influence cancer prognosis and response to therapy. This study aims to elucidate interactions between CD8 + TILs and the breast tumor microbiome and metabolites, as well as how the breast tumor microbiome may affect the tumor metabolome.METHODS: We investigated the interplay among CD8 + TILs, the tumor microbiome, and the metabolome in a cohort of 46 breast cancer patients with mixed subtypes (Cohort A). We characterized the tumor metabolome by mass spectrometry and CD8 + TILs by immunohistochemistry. Microbiome composition and T cell gene transcript levels were obtained from data from our previous study, which utilized 16S rRNA gene sequencing and a targeted mRNA expression panel. To examine interactions between intratumoral Staphylococcus and specific breast cancer subtypes, we analyzed RNA sequencing data from an independent cohort of 370 breast cancer patients (Cohort B). We explored the functions of the tumor microbiome using mouse models of triple-negative breast cancer (TNBC).RESULTS: In tumors from Cohort A, the relative abundance of Staphylococcus positively correlated with the expression of T cell activation genes. The abundances of multiple metabolites exhibited significant correlations with CD8 + TILs, of which NADH, γ-glutamyltryptophan, and γ-glutamylglutamate displayed differential abundance in Staphylococcus -positive versus Staphylococcus -negative breast tumors. In a larger breast cancer cohort (Cohort B), we observed positive correlations between tumoral Staphylococcus and CD8 + TIL activity exclusively in TNBC. Preclinical experiments demonstrated that intratumoral administration of S. aureus , the predominant species of Staphylococcus in human breast tumors, resulted in a depletion of total NAD metabolites, and reduced the growth of TNBC tumors by activating CD8 + TILs.CONCLUSIONS: We identified specific metabolites and microbial taxa associated with CD8 + TILs, delineated interactions between the breast tumor microbiome and metabolome, and demonstrated that intratumoral Staphylococcus influences anti-tumor immunity and TIL-associated metabolites. These findings highlight the role of low-biomass microbes in tumor tissues and provide potential biomarkers and therapeutic agents for breast cancer immunotherapy that merit further investigation.PMID:39554133 | PMC:PMC11565759 | DOI:10.1101/2024.10.29.620864

bioRxiv [Preprint]. 2024 Nov 2:2024.10.31.621412. doi: 10.1101/2024.10.31.621412.ABSTRACTN -acyl lipids are important mediators of several biological processes including immune function and stress response. To enhance the detection of N -acyl lipids with untargeted mass spectrometry-based metabolomics, we created a reference spectral library retrieving N -acyl lipid patterns from 2,700 public datasets, identifying 851 N -acyl lipids that were detected 356,542 times. 777 are not documented in lipid structural databases, with 18% of these derived from short-chain fatty acids and found in the digestive tract and other organs. Their levels varied with diet, microbial colonization, and in people living with diabetes. We used the library to link microbial N -acyl lipids, including histamine and polyamine conjugates, to HIV status and cognitive impairment. This resource will enhance the annotation of these compounds in future studies to further the understanding of their roles in health and disease and highlight the value of large-scale untargeted metabolomics data for metabolite discovery.PMID:39554097 | PMC:PMC11565975 | DOI:10.1101/2024.10.31.621412

bioRxiv [Preprint]. 2024 Oct 28:2024.10.27.620437. doi: 10.1101/2024.10.27.620437.ABSTRACTIn multiple sclerosis (MS) the circulating metabolome is dysregulated, with indole lactate (ILA) being one of the most significantly reduced metabolites. We demonstrate that oral supplementation of ILA impacts key MS disease processes in two preclinical models. ILA reduces neuroinflammation by dampening immune cell activation/ infiltration; and promotes remyelination and in vitro oligodendrocyte differentiation through the aryl hydrocarbon receptor (AhR). Supplementation of ILA, a reductive indole metabolite, restores the gut microbiome's oxidative/reductive metabolic balance by lowering circulating indole acetate (IAA), an oxidative indole metabolite, that blocks remyelination and oligodendrocyte maturation. The ILA-induced reduction in circulating IAA is linked to changes in IAA-producing gut microbiota taxa and pathways that are also dysregulated in MS. Notably, a lower ILA:IAA ratio correlates with worse MS outcomes. Overall, these findings identify ILA as a new potential anti-inflammatory remyelinating agent and provide novel insights into the role of gut dysbiosis-related metabolic alterations in MS progression.PMID:39554063 | PMC:PMC11565924 | DOI:10.1101/2024.10.27.620437

bioRxiv [Preprint]. 2024 Nov 3:2024.10.30.621159. doi: 10.1101/2024.10.30.621159.ABSTRACTThe cellular metabolism of macrophages depends on tissue niches and can control macrophage inflammatory or resolving phenotypes. Yet, the identity of signals within tissue niches that control macrophage metabolism is not well understood. Here, using single-cell RNA sequencing of macrophages in early mouse wounds, we find that, rather than gene expression of canonical inflammatory or resolving polarization markers, metabolic gene expression defines distinct populations of early wound macrophages. Single-cell secretomics and transcriptomics identify inflammatory and resolving cytokines expressed by early wound macrophages, and we show that these signals drive metabolic inputs and mitochondrial metabolism in an age-dependent manner. We show that aging alters the metabolome of early wound macrophages and rewires their metabolism from mitochondria to glycolysis. We further show that macrophage-derived Chi3l3 and IGF-1 can induce metabolic inputs and mitochondrial mass/metabolism in aged and bone marrow-derived macrophages. Together, these findings reveal that macrophage-derived signals drive the mitochondrial metabolism of macrophages within early wounds in an age-dependent manner and have implications for inflammatory diseases, chronic injuries, and age-related inflammatory diseases.IN BRIEF: This study reveals that macrophage subsets in early inflammatory stages of skin wound healing are defined by their metabolic profiles rather than polarization phenotype. Using single-cell secretomics, we establish key macrophage cytokines that comprise the in vivo wound niche and drive mitochondrial-based metabolism. Aging significantly alters macrophage heterogeneity and increases glycolytic metabolism, which can be restored to OxPHOS-based metabolism with young niche cytokines. These findings highlight the importance of the tissue niche in driving macrophage phenotypes, with implications for aging-related impairments in wound healing.HIGHLIGHTS: Single cell transcriptional analysis reveals that reveals that metabolic gene expression identifies distinct macrophage populations in early skin wounds.Single-cell secretomic data show that young macrophages contribute to the wound bed niche by secreting molecules such as IGF-1 and Chi3l3.Old wound macrophages display altered metabolomics, elevated glycolytic metabolism and glucose uptake, and reduced lipid uptake and mitochondrial mass/metabolism.Chi3l3 but not IGF-1 secretion is altered in macrophages in an age dependent manner.Chi3l3 can restore mitochondrial mass/metabolism in aged macrophages.PMID:39553941 | PMC:PMC11565841 | DOI:10.1101/2024.10.30.621159

J Thorac Dis. 2024 Oct 31;16(10):6936-6954. doi: 10.21037/jtd-24-1201. Epub 2024 Oct 14.ABSTRACTBACKGROUND: The gut microbiota and its associated metabolites play a critical role in shaping the systemic immune response and influencing the efficacy of immunotherapy. In this study, patients with extensive-stage small cell lung cancer (ES-SCLC) were included to explore the correlation between gut microbiota and metabolites and immunotherapy efficacy in patients with ES-SCLC.METHODS: Pre- and post-treatment, we collected stool samples from 49 ES-SCLC patients treated with an anti-programmed death-ligand 1 (PD-L1) antibody. We then applied 16S ribosomal RNA (rRNA) sequencing and liquid chromatography-mass spectrometry (LC-MS) non-targeted metabolomics technology. Subsequently, the gut microbiota and metabolites were identified and classified.RESULTS: The results showed no statistical difference in gut microbiota alpha and beta diversity between the responder (R) and non-responder (NR) patients at baseline. However, the alpha diversity of the R patients was significantly higher than that of the NR patients after treatment. There were also differences in the microbiome composition at the baseline and post-treatment. Notably, after treatment, Faecalibacterium, Clostridium_sensu_stricto_1, and [Ruminococcus]_torques were enriched in the R group, while Dubosiella, coriobacteriaceae_UCG-002 was enriched in the NR group. The non-targeted metabolomics results also indicated that short-chain fatty acids (SCFAs) were up-regulated in the R group after treatment. More, differential metabolites were enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including the PD-L1 expression and programmed death 1 (PD-1) checkpoint pathway in cancer.CONCLUSIONS: These findings are anticipated to provide novel markers for predicting the efficacy of immune checkpoint inhibitors (ICIs) in patients with ES-SCLC, and offer new directions for further research on molecular mechanisms.PMID:39552845 | PMC:PMC11565349 | DOI:10.21037/jtd-24-1201

Genes Dis. 2024 Feb 3;12(1):101239. doi: 10.1016/j.gendis.2024.101239. eCollection 2025 Jan.ABSTRACTIn precision cancer therapy, addressing intra-tumor heterogeneity poses a significant obstacle. Due to the heterogeneity of each cell subtype and between cells within the tumor, the sensitivity and resistance of different patients to targeted drugs, chemotherapy, etc., are inconsistent. Concerning a specific tumor type, many feasible treatments or combinations can be used by specifically targeting the tumor microenvironment. To solve this problem, it is necessary to further study the tumor microenvironment. Single-cell sequencing techniques can dissect distinct tumor cell populations by isolating cells and using statistical computational methods. This technology may assist in the selection of targeted combination therapy, and the obtained cell subset information is crucial for the rational application of targeted therapy. In this review, we summarized the research and application advances of single-cell sequencing technology in the tumor microenvironment, including the most commonly used single-cell genomic and transcriptomic sequencing, and their future development direction was proposed. The application of single-cell sequencing technology has been expanded to include epigenomics, proteomics, metabolomics, and microbiome analysis. The integration of these different omics approaches has significantly advanced the development of single-cell multiomics sequencing technology. This innovative approach holds immense potential for various fields, such as biological research and medical investigations. Finally, we discussed the advantages and disadvantages of using single-cell sequencing to explore the tumor microenvironment.PMID:39552788 | PMC:PMC11566696 | DOI:10.1016/j.gendis.2024.101239

Front Microbiol. 2024 Nov 1;15:1485936. doi: 10.3389/fmicb.2024.1485936. eCollection 2024.ABSTRACTBACKGROUND: Dysbiosis of gut microbiota (GM) is intricately linked with cognitive impairment and the incidence of traumatic brain injury (TBI) in both animal models and human subjects. However, there is limited understanding of the impact and mechanisms of fecal microbiota transplantation (FMT) on brain and gut barrier function in the treatment of TBI induced by gas explosion (GE).METHODS: We have employed FMT technology to establish models of gut microbiota dysbiosis in male rats, and subsequently conducted non-targeted metabolomics and microbiota diversity analysis to explore the bacteria with potential functional roles.RESULTS: Hematoxylin-eosin and transmission electron microscopy revealed that GE induced significant pathological damage and inflammation responses, as well as varying degrees of mitochondrial impairment in neuronal cells in the brains of rats, which was associated with cognitive decline. Furthermore, GE markedly elevated the levels of regulatory T cell (Tregs)-related factors interleukin-10, programmed death 1, and fork head box protein P3 in the brains of rats. Similar changes in these indicators were also observed in the colon; however, these alterations were reversed upon transfer of normal flora into the GE-exposed rats. Combined microbiome and metabolome analysis indicated up-regulation of Clostridium_T and Allobaculum, along with activation of fatty acid biosynthesis after FMT. Correlation network analysis indirectly suggested a causal relationship between FMT and alleviation of GE-induced TBI. FMT improved intestinal structure and up-regulated expression of tight junction proteins Claudin-1, Occludin, and ZO-1, potentially contributing to its protective effects on both brain and gut.CONCLUSION: Transplantation of gut microbiota from healthy rats significantly enhanced cognitive function in male rats with traumatic brain injury caused by a gas explosion, through the modulation of gut microbiome composition and the improvement of both gut and brain barrier integrity via the gut-brain axis. These findings may offer a scientific foundation for potential clinical interventions targeting gas explosion-induced TBI using FMT.PMID:39552646 | PMC:PMC11564976 | DOI:10.3389/fmicb.2024.1485936

Transfusion. 2024 Nov 17. doi: 10.1111/trf.18063. Online ahead of print.ABSTRACTBACKGROUND: Pathogen reduction technology (PRT)-treated apheresis platelets (APs) were returned without platelet swirl and with pH22°C < 6.2. The platelet donor was taking prescription levothyroxine and metformin plus over-the-counter medications and supplements. We hypothesized that either PRT or medication was causative.STUDY DESIGN AND METHODS: One AP from a double AP collection from this donor was PRT-treated, the other unit untreated. Units were assessed over 7-day storage with a standard panel of platelet assays and metabolomics using high resolution mass spectrometry. The dose effect of metformin on platelets over storage was evaluated in vitro using APs obtained from non-medicated donors.RESULTS: This donor's PRT- and non-PRT treated paired units had pH values <6.2 by the end of day 2. Lactate generation rates in the PRT- and non-PRT units were very high compared to previously reported values and approached that reported for anaerobic storage. Metabolomic analysis revealed impairments in a number of energy metabolic pathways between PRT- and non-PRT platelets; however, this did not support a major causative role of PRT in the significant upregulation of lactic acid production. Metformin caused a dose-dependent upregulation of glycolysis, resulting in pH decline.DISCUSSION: We conclude that metformin is the most likely cause for this donor's stored platelet pH failures. Metformin is commonly used to treat type 2 diabetes and is not a donor deferral medication. Further investigation is indicated into the potential impact of metformin on platelet storage characteristics, the potential implications for medication deferral, and the need for additional screening tools in the laboratory.PMID:39552144 | DOI:10.1111/trf.18063

Environ Sci Technol. 2024 Nov 17. doi: 10.1021/acs.est.4c05208. Online ahead of print.ABSTRACTThe extensive application of plastic products in daily human life has led to the accumulation of microplastics (MPs) in agricultural soil. However, little is known about the cross-generational toxicity of MPs on terrestrial invertebrates. In this study, two-generational Eisenia fetida was exposed to low-density polyethylene (LDPE, 0-5%, w/w) for 98 days to reveal the cross-generational toxicity and the underlying mechanisms. Results showed that LDPE-MPs not only perpetrated deleterious effects on the development, hatchability, and fecundity of the F0 generation but also stimulated the antioxidant defense activity, inhibited lipid peroxidation, and disordered neurotransmission in F1 generation individuals. The susceptibility of the epidermal-intestinal barrier to LDPE-MPs was dose-dependent. According to the transcriptomic analysis, the cross-generational earthworms confirmed significant perturbances in the cell cycle, neural activity-related pathways, and amino acid metabolism pathways (p < 0.05). Nevertheless, the metabolomic profile of F1 generation individuals exhibited significant hyperactive responses in glutathione metabolism and alanine, aspartate, and glutamate metabolism (p < 0.05). This study provides a comprehensive knowledge of LDPE-MPs toxicity on cross-generational earthworms and highlights the hyperactive responses in the antioxidant defense performance of the offsprings. Our findings also underscore the necessity for long-term investigations in assessing the adverse impacts of emerging pollutants.PMID:39552075 | DOI:10.1021/acs.est.4c05208

Signal Transduct Target Ther. 2024 Nov 18;9(1):320. doi: 10.1038/s41392-024-02020-x.ABSTRACTThe heterogeneity of Parkinson's disease (PD) has been recognized in clinical, with patients categorized into distinct subsets based on motor phenotype, such as tremor-dominant PD (TD), postural instability and gait difficulty-dominant PD (PIGD) and mixed PD (Mix). Despite this categorization, the underlying mechanisms of this heterogeneity remain poorly understood, and there is no personalized effective treatment for each PD subtype. To address this, a rat model for PD subtypes was established by unilateral stereotaxic injection of 6-OHDA, followed by cluster analysis of behavioral data. The serum neurofilament light chain (NfL) and uric acid (UA) levels as well as alterations in brain autonomic activity in rats were consistent with clinical patients, and metabolomics results showed that more than 70% of the metabolites in the serum of different subtypes of PD rats and clinical patients appeared to be consistently altered. Further transcriptomic analysis by RNA-seq has elucidated that the development of PD subtypes is associated with altered gene expression in neurotransmitter, neuronal damage in the central or peripheral nervous system, and lipid metabolism. In addition, based on the subtype-specific differentially expressed genes, 25 potential drug candidates were identified. Notably, the Alox15 inhibitor baicalein showed a greater efficacy on Mix rats, highlighting the possibility of selecting targeted treatments for well-defined individuals.PMID:39551798 | DOI:10.1038/s41392-024-02020-x

Environ Res. 2024 Nov 15:120373. doi: 10.1016/j.envres.2024.120373. Online ahead of print.ABSTRACTThe relationship between structure and function in microbial communities is intriguing and complex. In this study, we used single-carbon source domestication to derive consortium YL from the straw-degrading consortium Y. Y and YL exhibited similar straw degradation capabilities, yet YL harbored only half the species diversity of Y, with distinct dominant species. The most enriched microorganisms in Y were Ureibacillus, Acetanaerobacterium, and Hungateiclostridiaceae, whereas Bacillaceae, Bacillus, and Peptostreptococcales-Tissierellales were most enriched in YL. In-depth analysis revealed that Y and YL had comparable abundances of core lignocellulose-degrading genes, as validated by lignocellulolytic enzyme activity assays. However, the number of species harboring these key lignocellulose-degrading genes (K01179, K01181, K00432) in YL was reduced by over 50%, suggesting that functional redundancy enabled YL to maintain similar degradation capabilities to Y despite reduced diversity. Further analyses of key degradative species and co-occurrence networks highlighted the critical functional roles of dominant degradative species within these communities. An analysis of the overall functional pathways in the two microbial consortia revealed distinct metabolic characteristics between them. Pathways such as polycyclic aromatic hydrocarbon degradation and fluorobenzoate degradation were down-regulated in YL compared to Y, a finding corroborated by the metabolomic data. These results suggest a coupling between community structure and functional capacities within these microbial consortia. Overall, our findings deepen our understanding of the structure-function relationship in microbial communities and provide valuable insights for the design of lignocellulose-degrading consortia.PMID:39551375 | DOI:10.1016/j.envres.2024.120373

Life Sci. 2024 Nov 15:123244. doi: 10.1016/j.lfs.2024.123244. Online ahead of print.ABSTRACTAIMS: In light of the evidence supporting a significant role of the gut microbiome in Gulf War Illness (GWI) pathology, we sought to examine its contribution to GWI susceptibility in a mouse model. We also aimed to identify bacterial taxa and microbially-derived metabolites associated with disease susceptibility.MAIN METHODS: Male mice receiving pyridostigmine bromide (PB) orally, and controls were evaluated for symptoms of GWI at 8 weeks post-treatment. The Kansas criteria were adapted to assess behaviors associated with the following domains: gastrointestinal alterations, pain, mood, cognitive function, skin and respiratory disturbances. PB-treated subjects were classified into susceptible (GWI-S) or resilient (GWI-R). The status of the gut microbiome was assessed via analyses of the 16S rRNA gene and microbial-derived metabolites were evaluated with metabolomics tools.KEY FINDINGS: Our results indicate that application of the Kansas criteria to behavioral outcomes in PB-treated mice resulted in a GWI susceptibility rate of ~35 %, similar to the one reported in humans. The composition and structure of the gut microbiome was different in GWI-S subjects compared to both control and GWI-R mice at 8 weeks but differences in microbial community structure were observed prior to PB treatment between GWI-R and GWI-S mice. GWI-S subjects exhibited a pattern of differentially abundant bacterial taxa and microbial metabolites.SIGNIFICANCE: To our knowledge, this is the first preclinical report in which a stratification by susceptibility to GWI and its association with the gut microbiome is described. In light of the research conundrum that vulnerability to GWI represents, the use of tools that could provide further insight into this complex factor should be considered.PMID:39551360 | DOI:10.1016/j.lfs.2024.123244

J Nutr. 2024 Nov 15:S0022-3166(24)01180-5. doi: 10.1016/j.tjnut.2024.11.013. Online ahead of print.ABSTRACTBACKGROUND: The pro-fertility diet is a dietary pattern composed of nutrients and foods most consistently associated with in vitro fertilization (IVF) endpoints in women.OBJECTIVE: We examined the potential biological mechanisms underlying the association between adherence to a pro-fertility diet and IVF endpoints using high-resolution metabolomics.METHODS: Among 120 women undergoing an autologous oocyte IVF cycle (2007-2015) in Northeast United States, we collected a serum sample during controlled ovarian stimulation and a follicular fluid sample on the day of oocyte retrieval. Women completed a food frequency questionnaire upon enrollment into the study to examine adherence to the pro-fertility diet pattern. Liquid chromatography with high-resolution mass spectrometry was used for untargeted metabolomics analysis of biospecimens. We identified metabolic features (and enriched biological pathways) associated with the pro-fertility diet and two IVF endpoints, live birth and clinical pregnancy, via a meet-in-the-middle approach.RESULTS: In the follicular fluid metabolome, vitamin D3 metabolism was associated with adherence to the pro-fertility diet pattern and live birth. Additionally, vitamin D3 metabolism, vitamin B6 metabolism, and bile acid biosynthesis, were associated with both adherence to the pro-fertility diet pattern and clinical pregnancy. In the serum metabolome, only tryptophan metabolism was associated with adherence to the pro-fertility diet pattern and live birth. We confirmed the chemical identity of one metabolite with Level-1 evidence, 4-pyridoxate, which was higher in the serum and follicular fluid among women with stronger adherence to the pro-fertility diet pattern and among women with a live birth.CONCLUSIONS: The beneficial association between adherence to the pro-fertility diet and IVF outcomes may be mediated through vitamin D3 metabolism, vitamin B6 metabolism, and bile acid biosynthesis in the follicular fluid and tryptophan metabolism in the serum. These results provide new insight in the important biological pathways underlying a dietary pattern providing optimal fertility benefits to women.PMID:39551358 | DOI:10.1016/j.tjnut.2024.11.013