PubMed

BMC Genomics. 2023 Jun 26;24(1):352. doi: 10.1186/s12864-023-09463-6.ABSTRACTBACKGROUND: Clonostachys rosea is an established biocontrol agent. Selected strains have either mycoparasitic activity against known pathogens (e.g. Fusarium species) and/or plant growth promoting activity on various crops. Here we report outcomes from a comparative 'omics analysis leveraging a temporal variation in the in vitro antagonistic activities of C. rosea strains ACM941 and 88-710, toward understanding the molecular mechanisms underpinning mycoparasitism.RESULTS: Transcriptomic data highlighted specialized metabolism and membrane transport related genes as being significantly upregulated in ACM941 compared to 88-710 at a time point when the ACM941 strain had higher in vitro antagonistic activity than 88-710. In addition, high molecular weight specialized metabolites were differentially secreted by ACM941, with accumulation patterns of some metabolites matching the growth inhibition differences displayed by the exometabolites of the two strains. In an attempt to identify statistically relevant relationships between upregulated genes and differentially secreted metabolites, transcript and metabolomic abundance data were associated using IntLIM (Integration through Linear Modeling). Of several testable candidate associations, a putative C. rosea epidithiodiketopiperazine (ETP) gene cluster was identified as a prime candidate based on both co-regulation analysis and transcriptomic-metabolomic data association.CONCLUSIONS: Although remaining to be validated functionally, these results suggest that a data integration approach may be useful for identification of potential biomarkers underlying functional divergence in C. rosea strains.PMID:37365507 | DOI:10.1186/s12864-023-09463-6

BMC Genomics. 2023 Jun 26;24(1):355. doi: 10.1186/s12864-023-09342-0.ABSTRACTBACKGROUND: Domestic geese are seasonal breeders and have the lowest reproductive capacity among all poultry species. Magang geese is a topical short-day breeder, short photoperiod exposure stimulates its reproductive activity while long photoperiod inhibits. To explore epigenetic change that could influence reproductive activity, we performed whole genome bisulfite sequencing and transcriptome sequencing in the hypothalamus at three reproductive stages during long-light exposure in male Magang geese.RESULTS: A total number of 10,602 differentially methylated regions (DMRs) were identified among three comparison groups. We observed that the vast majority of DMRs were enriched in intron regions. By integrating the BS-sequencing and RNA-seq data, the correlation between methylation changes of CG DMRs and expression changes of their associated genes was significant only for genes containing CG DMRs in their intron. A total of 278 DMR-associated DEGs were obtained among the three stages. KEGG analysis revealed that the DMR-associated DEGs were mainly involved in 11 pathways. Among them, the neuroactive ligand-receptor interaction pathway was significantly enriched in both two comparisons (RA vs.RD and RD vs.RI); the Wnt signaling pathway, apelin signaling pathway, melanogenesis, calcium signaling pathway, focal adhesion, and adherens junction were significantly enriched in the RA vs. RI comparison. In addition, the expression level of two serotonin-metabolic genes was significantly altered during reproductive axis inactivation by the methylation status of their promoter region (TPH2) and intron region (SLC18A2), respectively. These results were confirmed by Bisulfite sequencing PCR (BSP), pyrosequencing, and real-time qPCR, indicating that serotonin metabolic signaling may play a key role in decreasing the reproductive activity of Magang geese induced by long-light exposure. Furthermore, we performed a metabolomics approach to investigate the concentration of neurotransmitters among the three stages, and found that 5-HIAA, the last product of the serotonin metabolic pathway, was significantly decreased in the hypothalamus during RI.CONCLUSIONS: Our study reveals that the methylation status of the serotonin metabolic pathway in the hypothalamus is associated with reproductive inactivation, and provided new insight into the effect of DNA methylation on the reproductive regulation of the hypothalamus in Magang geese.PMID:37365488 | DOI:10.1186/s12864-023-09342-0

Nat Rev Clin Oncol. 2023 Jun 26. doi: 10.1038/s41571-023-00785-8. Online ahead of print.ABSTRACTOncogenesis is associated with intestinal dysbiosis, and stool shotgun metagenomic sequencing in individuals with this condition might constitute a non-invasive approach for the early diagnosis of several cancer types. The prognostic relevance of antibiotic intake and gut microbiota composition urged investigators to develop tools for the detection of intestinal dysbiosis to enable patient stratification and microbiota-centred clinical interventions. Moreover, since the advent of immune-checkpoint inhibitors (ICIs) in oncology, the identification of biomarkers for predicting their efficacy before starting treatment has been an unmet medical need. Many previous studies addressing this question, including a meta-analysis described herein, have led to the description of Gut OncoMicrobiome Signatures (GOMS). In this Review, we discuss how patients with cancer across various subtypes share several GOMS with individuals with seemingly unrelated chronic inflammatory disorders who, in turn, tend to have GOMS different from those of healthy individuals. We discuss findings from the aforementioned meta-analysis of GOMS patterns associated with clinical benefit from or resistance to ICIs across different cancer types (in 808 patients), with a focus on metabolic and immunological surrogate markers of intestinal dysbiosis, and propose practical guidelines to incorporate GOMS in decision-making for prospective clinical trials in immuno-oncology.PMID:37365438 | DOI:10.1038/s41571-023-00785-8

J Med Toxicol. 2023 Jun 26. doi: 10.1007/s13181-023-00957-z. Online ahead of print.NO ABSTRACTPMID:37365428 | DOI:10.1007/s13181-023-00957-z

Nat Neurosci. 2023 Jun 26. doi: 10.1038/s41593-023-01361-0. Online ahead of print.ABSTRACTAutism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD.PMID:37365313 | DOI:10.1038/s41593-023-01361-0

Sci Rep. 2023 Jun 26;13(1):10332. doi: 10.1038/s41598-023-37009-z.ABSTRACTObesity contributes to physical comorbidities and mental health consequences. We explored whether physical activity could influence more than metabolic regulation and result in psychological benefits through the brain-gut microbiome (BGM) system in a population with high BMI. Fecal samples were obtained for 16 s rRNA profiling and fecal metabolomics, along with psychological and physical activity questionnaires. Whole brain resting-state functional MRI was acquired, and brain connectivity metrics were calculated. Higher physical activity was significantly associated with increased connectivity in inhibitory appetite control brain regions, while lower physical activity was associated with increased emotional regulation network connections. Higher physical activity was also associated with microbiome and metabolite signatures protective towards mental health and metabolic derangements. The greater resilience and coping, and lower levels of food addiction seen with higher physical activity, may be explained by BGM system differences. These novel findings provide an emphasis on the psychological and resilience benefits of physical activity, beyond metabolic regulation and these influences seem to be related to BGM interactions.PMID:37365200 | DOI:10.1038/s41598-023-37009-z

Nat Commun. 2023 Jun 26;14(1):3620. doi: 10.1038/s41467-023-39210-0.ABSTRACTMetastasis is the major cause of cancer-related deaths. Neuroblastoma (NB), a childhood tumor has been molecularly defined at the primary cancer site, however, the bone marrow (BM) as the metastatic niche of NB is poorly characterized. Here we perform single-cell transcriptomic and epigenomic profiling of BM aspirates from 11 subjects spanning three major NB subtypes and compare these to five age-matched and metastasis-free BM, followed by in-depth single cell analyses of tissue diversity and cell-cell interactions, as well as functional validation. We show that cellular plasticity of NB tumor cells is conserved upon metastasis and tumor cell type composition is NB subtype-dependent. NB cells signal to the BM microenvironment, rewiring via macrophage mgration inhibitory factor and midkine signaling specifically monocytes, which exhibit M1 and M2 features, are marked by activation of pro- and anti-inflammatory programs, and express tumor-promoting factors, reminiscent of tumor-associated macrophages. The interactions and pathways characterized in our study provide the basis for therapeutic approaches that target tumor-to-microenvironment interactions.PMID:37365178 | DOI:10.1038/s41467-023-39210-0

Nat Commun. 2023 Jun 26;14(1):3803. doi: 10.1038/s41467-023-39514-1.ABSTRACTThe serine/threonine kinase AKT is a central node in cell signaling. While aberrant AKT activation underlies the development of a variety of human diseases, how different patterns of AKT-dependent phosphorylation dictate downstream signaling and phenotypic outcomes remains largely enigmatic. Herein, we perform a systems-level analysis that integrates methodological advances in optogenetics, mass spectrometry-based phosphoproteomics, and bioinformatics to elucidate how different intensity, duration, and pattern of Akt1 stimulation lead to distinct temporal phosphorylation profiles in vascular endothelial cells. Through the analysis of ~35,000 phosphorylation sites across multiple conditions precisely controlled by light stimulation, we identify a series of signaling circuits activated downstream of Akt1 and interrogate how Akt1 signaling integrates with growth factor signaling in endothelial cells. Furthermore, our results categorize kinase substrates that are preferably activated by oscillating, transient, and sustained Akt1 signals. We validate a list of phosphorylation sites that covaried with Akt1 phosphorylation across experimental conditions as potential Akt1 substrates. Our resulting dataset provides a rich resource for future studies on AKT signaling and dynamics.PMID:37365174 | DOI:10.1038/s41467-023-39514-1

Trends Biotechnol. 2023 Jun 24:S0167-7799(23)00157-9. doi: 10.1016/j.tibtech.2023.05.010. Online ahead of print.ABSTRACTProteogenomics (PG) integrates the proteome with the genome and transcriptome to refine gene models and annotation. Coupled with single-cell (SC) assays, PG effectively distinguishes heterogeneity among cell groups. Affiliating spatial information to PG reveals the high-resolution circuitry within SC atlases. Additionally, PG can investigate dynamic changes in protein-coding genes in plants across growth and development as well as stress and external stimulation, significantly contributing to the functional genome. Here we summarize existing PG research in plants and introduce the technical features of various methods. Combining PG with other omics, such as metabolomics and peptidomics, can offer even deeper insights into gene functions. We argue that the application of PG will represent an important font of foundational knowledge for plants.PMID:37365082 | DOI:10.1016/j.tibtech.2023.05.010

Mar Pollut Bull. 2023 Jun 24;193:115192. doi: 10.1016/j.marpolbul.2023.115192. Online ahead of print.ABSTRACTExtreme events like Marine Heatwaves (MHWs) are becoming more intense, severe, and frequent, threatening benthic communities, specifically bivalves. However, the consequences of non-lethal MHWs on animals are still poorly understood. Here, we exposed the Manila clam Ruditapes philippinarum to non-lethal MHW for 30 days and provided an integrative view of its effects. Our result indicated that albeit non-lethal, MHW reduced clam's energy reserves (by reducing their hepato-somatic index), triggered antioxidant defenses (particularly in males), impaired reproduction (via the production of smaller oocytes in females), triggered dysbiosis in the digestive gland microbiota and altered animals' behaviour (by impacting their burying capacity) and filtration rate. Such effects were seen also at RNA-seq (i.e. many down-regulated genes belonged to reproduction) and metabolome level. Interestingly, negative effects were more pronounced in males than in females. Our results show that MHWs influence animal physiology at multiple levels, likely impacting its fitness and its ecosystem services.PMID:37364338 | DOI:10.1016/j.marpolbul.2023.115192

Proc Natl Acad Sci U S A. 2023 Jul 4;120(27):e2301170120. doi: 10.1073/pnas.2301170120. Epub 2023 Jun 26.ABSTRACTBacterial antimicrobial resistance (AMR) is among the most significant challenges to current human society. Exposing bacteria to antibiotics can activate their self-saving responses, e.g., filamentation, leading to the development of bacterial AMR. Understanding the molecular changes during the self-saving responses can reveal new inhibition methods of drug-resistant bacteria. Herein, we used an online microfluidics mass spectrometry system for real-time characterization of metabolic changes of bacteria during filamentation under the stimulus of antibiotics. Significant pathways, e.g., nucleotide metabolism and coenzyme A biosynthesis, correlated to the filamentation of extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-E. coli) were identified. A cyclic dinucleotide, c-di-GMP, which is derived from nucleotide metabolism and reported closely related to bacterial resistance and tolerance, was observed significantly up-regulated during the bacterial filamentation. By using a chemical inhibitor, ebselen, to inhibit diguanylate cyclases which catalyzes the synthesis of c-di-GMP, the minimum inhibitory concentration of ceftriaxone against ESBL-E. coli was significantly decreased. This inhibitory effect was also verified with other ESBL-E. coli strains and other beta-lactam antibiotics, i.e., ampicillin. A mutant strain of ESBL-E. coli by knocking out the dgcM gene was used to demonstrate that the inhibition of the antibiotic resistance to beta-lactams by ebselen was mediated through the inhibition of the diguanylate cyclase DgcM and the modulation of c-di-GMP levels. Our study uncovers the molecular changes during bacterial filamentation and proposes a method to inhibit antibiotic-resistant bacteria by combining traditional antibiotics and chemical inhibitors against the enzymes involved in bacterial self-saving responses.PMID:37364094 | DOI:10.1073/pnas.2301170120

Bioinformatics. 2023 Jun 26:btad406. doi: 10.1093/bioinformatics/btad406. Online ahead of print.ABSTRACTMOTIVATION: Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) experiments aim to produce high quality fragmentation spectra which can be used to annotate metabolites. However, current Data-Dependent Acquisition (DDA) approaches may fail to collect spectra of sufficient quality and quantity for experimental outcomes, and extend poorly across multiple samples by failing to share information across samples or by requiring manual expert input.RESULTS: We present TopNEXt, a real-time scan prioritisation framework that improves data acquisition in multi-sample LC-MS/MS metabolomics experiments. TopNEXt extends traditional DDA exclusion methods across multiple samples by using a Region of Interest (RoI) and intensity-based scoring system. Through both simulated and lab experiments we show that methods incorporating these novel concepts acquire fragmentation spectra for an additional 10% of our set of target peaks and with an additional 20% of acquisition intensity. By increasing the quality and quantity of fragmentation spectra, TopNEXt can help improve metabolite identification with a potential impact across a variety of experimental contexts.AVAILABILITY: TopNEXt is implemented as part of the ViMMS framework and the latest version can be found at https://github.com/glasgowcompbio/vimms. A stable version used to produce our results can be found at 10.5281/zenodo.7468914. Data can be found at 10.5525/gla.researchdata.1382.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.PMID:37364005 | DOI:10.1093/bioinformatics/btad406

PLoS Negl Trop Dis. 2023 Jun 26;17(6):e0011344. doi: 10.1371/journal.pntd.0011344. Online ahead of print.ABSTRACTDuring chronic schistosome infections, a complex regulatory network is induced to regulate the host immune system, in which IL-10-producing regulatory B (Breg) cells play a significant role. Schistosoma mansoni soluble egg antigens (SEA) are bound and internalized by B cells and induce both human and mouse IL-10 producing Breg cells. To identify Breg-inducing proteins in SEA, we fractionated SEA by size exclusion chromatography and found 6 fractions able to induce IL-10 production by B cells (out of 18) in the high, medium and low molecular weight (MW) range. The high MW fractions were rich in heavily glycosylated molecules, including multi-fucosylated proteins. Using SEA glycoproteins purified by affinity chromatography and synthetic glycans coupled to gold nanoparticles, we investigated the role of these glycan structures in inducing IL-10 production by B cells. Then, we performed proteomics analysis on active low MW fractions and identified a number of proteins with putative immunomodulatory properties, notably thioredoxin (SmTrx1) and the fatty acid binding protein Sm14. Subsequent splenic murine B cell stimulations and hock immunizations with recombinant SmTrx1 and Sm14 showed their ability to dose-dependently induce IL-10 production by B cells both in vitro and in vivo. Identification of unique Breg cells-inducing molecules may pave the way to innovative therapeutic strategies for inflammatory and auto-immune diseases.PMID:37363916 | DOI:10.1371/journal.pntd.0011344

Integr Med (Encinitas). 2023 May;22(2):18-25.ABSTRACTBACKGROUND: A The author's comprehensive evaluation of the biochemical metabolomic literature over more than 40 years discusses multiple studies documenting abnormal elevations of the neurotransmitter dopamine and its metabolites as well as inhibitors of dopamine beta hydroxylase (DBH) from Clostridia bacteria in urine samples and cerebrospinal fluid samples of children with autism.AIMS OF REVIEW: The evaluation intends to elucidate the reasons for the elevation of dopamine and its metabolites in urine and their relationship to increased Clostridia colonization of the gastrointestinal tract in children with autism. In addition, to the evaluation of Clostridia metabolism and its effects on abnormal dopamine metabolism in autism, a secondary aim intends to demonstrate as a hypothesis that one particular metabolite of Clostridia bacteria-3-hydroxy-(3-hydroxyphenyl)- 3-hydroxypropionic acid (HPHPA)-may cause even more severe effects on in autism than other metabolites by leading to depletion of free coenzyme A (CoASH). This depletion of free Coenzyme A leads to a deficiency of cholesterol and activated palmitic acid needed for activation of the key brain developmental protein sonic hedgehog, which has recently been research has shown to be severely abnormal in severe autism.KEY SCIENTIFIC CONCEPTS OF REVIEW: Laboratories throughout the world have consistently found high quantities of HPHPA and 4-cresol in high percentages of urine samples of children with autism. Those inhibitors, which intestinal Clostridia bacteria produce, cause an elevation in dopamine and its metabolites, which affect the brain's and the sympathetic nervous system's key enzyme dopamine-beta-hydroxylase (DBH). Excessive dopamine and its toxic metabolites due to these DBH inhibitors may cause brain damage due to excessive unstable dopamine quinones, toxic adducts of dopamine disrupting brain mitochondrial energy production, and oxygen superoxide. HPHPA, a short chain phenyl compound, may have additional biochemical effects on the brain in autism, causing a reduction in free CoASH needed to produce the CoA palmitic acid derivative necessary to activate the key brain developmental protein sonic hedgehog. The depletion of CoASH appears to be a new therapeutic target to reverse the adverse effects of the HPHPA metabolite on the beta oxidation of fatty acids and cholesterol synthesis that are prevalent in autism.CONCLUSIONS: Variations in the severity of autism could be based on the types and concentrations of the Clostridia markers produced and the extent to which these markers, such as HPHPA, have depleted critical lipids, such as cholesterol and CoA palmitic acid derivative. Patients need those lipids for the activation of the developmental protein sonic hedgehog. In addition, the sequestration of coenzyme A by short chain adducts of Clostridia leads to the depletion of critical free CoASH, needed throughout intermediary metabolism, and creates a biochemical storm that especially affects brain function.PMID:37363147 | PMC:PMC10289112

Front Microbiol. 2023 Jun 9;14:1159534. doi: 10.3389/fmicb.2023.1159534. eCollection 2023.ABSTRACTFusarium wilt of bananas (FWB) is seriously affecting the sustainable development of the banana industry and is caused by the devastating soil-borne fungus Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4). Biological control is a promising strategy for controlling Fusarium wilt in bananas. We previously identified Streptomyces hygroscopicus subsp. hygroscopicus 5-4 with strong antifungal activity against the FWB. The most possible antimicrobial mechanism of strain 5-4 was explored using the metabolomics approach, light microscopy imaging, and transmission electron microscopy (TEM). The membrane integrity and ultrastructure of Foc TR4 was damaged after extract treatment, which was supported by the degradation of mycelium, soluble protein content, extracellular reducing sugar content, NADH oxidase activity, malondialdehyde content, mitochondrial membrane potential, and mitochondrial respiratory chain complex enzyme activity. The extracts of strain 5-4 cultivated at different times were characterized by a liquid chromatography-mass spectrometer (LC-MS). 647 known metabolites were detected in the extracts of strains 5-4. Hygromycin B, gluten exorphin B4, torvoside G, (z)-8-tetradecenal, piperitoside, sarmentosin, pubescenol, and other compounds were the main differential metabolites on fermentation culture for 7 days. Compared with strain 5-4 extracts, hygromycin B inhibited the mycelial growth of Foc TR4, and the EC50 concentration was 7.4 μg/mL. These results showed that strain 5-4 could destroy the cell membrane of Foc TR4 to inhibit the mycelial growth, and hygromycin B may be the key antimicrobial active metabolite. Streptomyces hygroscopicus subsp. hygroscopicus 5-4 might be a promising candidate strain to control the FWB and provide a scientific basis for the practical application of hygromycin B as a biological control agent.PMID:37362932 | PMC:PMC10289025 | DOI:10.3389/fmicb.2023.1159534

Front Microbiol. 2023 Jun 9;14:1185463. doi: 10.3389/fmicb.2023.1185463. eCollection 2023.ABSTRACTINTRODUCTION: Short bowel syndrome (SBS) is featured by impaired nutrients and fluids absorption due to massive small intestine resection. Gut dysbiosis has been implicated in SBS, this study aimed to characterize the metagenomic and metabolomic profiles of SBS and identify potential therapeutic targets.METHODS: Fecal samples from SBS and Sham rats (n = 8 per group) were collected for high-throughput metagenomic sequencing. Fecal metabolomics was measured by untargeted liquid chromatography-mass spectrometry.RESULTS: We found that the species-level α-diversity significantly decreased in SBS rats, accompanied by altered microbiome compositions. The beneficial anaerobes from Firmicutes and Bacteroidetes were depleted while microorganisms from Lactobacillus, Escherichia, Enterococcus, and Streptococcus were enriched in faces from SBS rats. LEfSe analysis identified 17 microbial species and 38 KEGG modules that were remarkably distinct between SBS and Sham rats. In total, 1,577 metabolites with known chemical identity were detected from all samples, among them, 276 metabolites were down-regulated and 224 metabolites were up-regulated in SBS group. The typical signatures of SBS fecal metabolome comprised reduced short-chain fatty acids and products of amino acid metabolism (indole derivatives and p-cresol), as well as altered bile acid spectrum. We revealed 215 robust associations between representative differentially abundant microbial species and metabolites, the species with the same changing trend tended to have a similar correlation with some certain metabolites.CONCLUSION: The fecal microbiome and metabolome significantly altered in SBS. Our findings may lay the foundation for developing new strategies to facilitate intestinal adaptation in SBS patients.PMID:37362931 | PMC:PMC10289890 | DOI:10.3389/fmicb.2023.1185463

Front Microbiol. 2023 Jun 9;14:1195360. doi: 10.3389/fmicb.2023.1195360. eCollection 2023.ABSTRACTOBJECTIVE: Lactate dehydrogenase (ldh) in lactic acid bacteria is an important enzyme that is involved in the process of milk fermentation. This study aimed to explore the changes and effects of fermented milk metabolites in mutant strains after knocking out the ldh gene of Lacticaseibacillus paracasei.METHODS: The ldh mutant ΔAF91_07315 was obtained from L. paracasei using clustered regularly interspaced short palindromic repeats technology, and we determined fermented milk pH, titratable acidity, viable count, and differential metabolites in the different stages of milk fermentation that were identified using metabolomic analysis.RESULTS: The results showed that the growth rate and acidification ability of the mutant strain were lower than those of the wild-type strain before the end of fermentation, and analysis of the differential metabolites showed that lactate, L-cysteine, proline, and intermediate metabolites of phenylalanine, tryptophan, and methionine were downregulated (P < 0.05), which affected the growth initiation rate and acidification ability of the strain. At the end of fermentation (pH 4.5), the fermentation time of the mutant strain was prolonged and all differential metabolites were upregulated (P < 0.05), including amino acids and precursors, acetyl coenzyme A, and other metabolites involved in amino acid and fatty acid synthesis, which are associated with the regulation of fermented milk flavors. In addition, riboflavin was upregulated to promote the growth of the strain and compensate for the growth defects caused by the mutation.CONCLUSION: Our data established a link between the AF91_07315 gene and strain growth and metabolism and provided a target for the regulation of fermented milk flavor substances.PMID:37362929 | PMC:PMC10288368 | DOI:10.3389/fmicb.2023.1195360

Front Microbiol. 2023 Jun 9;14:1194401. doi: 10.3389/fmicb.2023.1194401. eCollection 2023.ABSTRACTBACKGROUND: Qing-Kai-Ling (QKL) oral liquid, evolving from a classical Chinese formula known as An-Gong-Niu-Huang pills, is a well-established treatment for pneumonia with its mechanism remaining muddled. Studies have shown that the regulation of both intestinal flora and host-microbiota co-metabolism may contribute to preventing and treating pneumonia. The study aimed to investigate the potential mechanism by which QKL alleviates pneumonia from the perspective of 'microbiota-metabolites-host' interaction.METHODS: We evaluated the therapeutic effects of QKL on lipopolysaccharide (LPS)-induced pneumonia rats. To explore the protective mechanism of QKL treatment, a multi-omics analysis that included 16S rDNA sequencing for disclosing the key intestinal flora, the fecal metabolome to discover the differential metabolites, and whole transcriptome sequencing of lung tissue to obtain the differentially expressed genes was carried out. Then, a Spearman correlation was employed to investigate the association between the intestinal flora, the fecal metabolome and inflammation-related indices.RESULTS: The study demonstrated that pneumonia symptoms were significantly attenuated in QKL-treated rats, including decreased TNF-α, NO levels and increased SOD level. Furthermore, QKL was effective in alleviating pneumonia and provided protection equivalent to that of the positive drug dexamethasone. Compared with the Model group, QKL treatment significantly increased the richness and αlpha diversity of intestinal flora, and restored multiple intestinal genera (e.g., Bifidobacterium, Ruminococcus_torques_group, Dorea, Mucispirillum, and Staphylococcus) that were correlated with inflammation-related indices. Interestingly, the intestinal flora demonstrated a strong correlation with several metabolites impacted by QKL. Furthermore, metabolome and transcriptome analyses showed that enrichment of several host-microbiota co-metabolites [arachidonic acid, 8,11,14-eicosatrienoic acid, LysoPC (20:0/0:0), LysoPA (18:0e/0:0), cholic acid, 7-ketodeoxycholic acid and 12-ketodeoxycholic acid] levels and varying lung gene (Pla2g2a, Pla2g5, Alox12e, Cyp4a8, Ccl19, and Ccl21) expression were observed in the QKL group. Moreover, these metabolites and genes were involved in arachidonic acid metabolism and inflammation-related pathways.CONCLUSION: Our findings indicated that QKL could potentially modulate intestinal flora dysbiosis, improve host-microbiota co-metabolism dysregulation and regulate gene expression in the lungs, thereby mitigating LPS-induced pneumonia in rats. The study may provide new ideas for the clinical application and further development of QKL.PMID:37362920 | PMC:PMC10288885 | DOI:10.3389/fmicb.2023.1194401

Front Physiol. 2023 Jun 8;14:1163496. doi: 10.3389/fphys.2023.1163496. eCollection 2023.ABSTRACTThe last few years have witnessed dramatic advances in our understanding of the structure and function of the mammalian mito-ribosome. At the same time, the first attempts to elucidate the effects of mito-ribosomal fidelity (decoding accuracy) in disease have been made. Hence, the time is right to push an important frontier in our understanding of mitochondrial genetics, that is, the elucidation of the phenotypic effects of mtDNA variants affecting the functioning of the mito-ribosome. Here, we have assessed the structural and functional role of 93 mitochondrial (mt-) rRNA variants thought to be associated with deafness, including those located at non-conserved positions. Our analysis has used the structural description of the human mito-ribosome of the highest quality currently available, together with a new understanding of the phenotypic manifestation of mito-ribosomal-associated variants. Basically, any base change capable of inducing a fidelity phenotype may be considered non-silent. Under this light, out of 92 previously reported mt-rRNA variants thought to be associated with deafness, we found that 49 were potentially non-silent. We also dismissed a large number of reportedly pathogenic mtDNA variants, 41, as polymorphisms. These results drastically update our view on the implication of the primary sequence of mt-rRNA in the etiology of deafness and mitochondrial disease in general. Our data sheds much-needed light on the question of how mt-rRNA variants located at non-conserved positions may lead to mitochondrial disease and, most notably, provide evidence of the effect of haplotype context in the manifestation of some mt-rRNA variants.PMID:37362424 | PMC:PMC10285412 | DOI:10.3389/fphys.2023.1163496

Evid Based Complement Alternat Med. 2023 Jun 16;2023:8998368. doi: 10.1155/2023/8998368. eCollection 2023.ABSTRACTShudage-4, an ancient and well-known formula in traditional Mongolian medicine comprising four different types of traditional Chinese medicine, is widely used in the treatment of gastric ulcers. However, the potential material basis and molecular mechanism of Shudage-4 in attenuating stress-induced gastric ulcers remain unclear. This study aimed to first explore the potential material basis and molecular mechanism of Shudage-4 in attenuating gastric ulcers in rats. The chemical constituents and transitional components in the blood of Shudage-4 were identified by ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS). The rat gastric ulcer model was induced by water immersion restraint stress (WIRS). The ulcer damage to gastric tissue was measured at the gross anatomical level and pathological level by hematoxylin-eosin (HE) staining of gastric tissue. RNA sequencing of gastric tissue and plasma metabolomics were performed to analyze the mechanism of Shudage-4 against gastric ulcers. A Pearson correlation analysis was performed to explore the association between serum metabolites and gene expression of gastric tissue. A total of 30 chemical constituents were identified in Shudage-4 by UPLC-TOF-MS. Among 30 constituents, 13 transitional components in the blood were considered as the potential material basis. Shudage-4 treatment had a significant effect on WIRS-induced gastric ulcers in rats. HE staining of gastric tissue illustrated that WIRS-induced ulcer damage was suppressed by Shudage-4 treatment. RNA sequencing of gastric tissue showed that 282 reversed expression genes in gastric tissue were related to Shudage-4 treatment, and gene set enrichment analysis revealed that Shudage-4 treatment significantly inhibited gene set expression related to reactive oxygen species (ROS), which was also validated by detecting rat gastric tissue MDA, GSH, SOD, GSH-Px, and CAT activities. The plasma metabolomic data demonstrated that 23 significantly differential metabolites were closely associated with the Shudage-4 treatment. The further multiomics joint analysis found that significantly upregulated 5 plasma metabolites in Shudage-4-treated rats compared to model rats were negatively correlated with gene set expression related to ROS in gastric tissue. Shudage-4 alleviated WIRS-induced gastric ulcers by inhibiting ROS generation, which was achieved by regulating plasma metabolites level.PMID:37362100 | PMC:PMC10289874 | DOI:10.1155/2023/8998368