PubMed

Metallomics. 2022 Dec 30:mfac100. doi: 10.1093/mtomcs/mfac100. Online ahead of print.ABSTRACTThe influence of the fermentation process on selenite metabolism by a probiotic Bifidobacterium longum DD98 (B. longum DD98), and its consequent enrichment in selenium (Se) were studied. The effects of sodium selenite (Na2SeO3) concentration (18-400 μg/mL), feeding time (12, 16, and 24 h), and fermentation stage (secondary and tertiary fermentation) were evaluated by measuring i) the total Se content and its distribution between the water-soluble metabolome fraction and the water-insoluble fraction; ii) the total concentrations of the two principal Se-compounds produced: selenomethionine (SeMet) and γ-glutamyl-selenomethionine (γ-Glu-SeMet), and iii) the speciation of Se in the metabolite fraction. The results revealed that the fermentation process notably changed the Se incorporation into metabolites (γ-Glu-SeMet and free SeMet) and proteins (bound-SeMet) in B. longum DD98. In particular, the production of SeMet was negatively correlated to that of γ-Glu-SeMet when no red precipitate was seen in the bacteria. The study offers a tool for the control of the optimization of the fermentation process towards the desired molecular speciation of the incorporated Se and hence contributes to the production of Se-enriched probiotics with good qualities and bioactivities.PMID:36583695 | DOI:10.1093/mtomcs/mfac100

Plant Cell Environ. 2022 Dec 30. doi: 10.1111/pce.14529. Online ahead of print.ABSTRACTDuring leaf senescence, nitrogen is remobilized and carbon backbones are replenished by amino acid catabolism, with many of the key reactions occurring in mitochondria. The intermediate Δ1 -pyrroline-5-carboxylate (P5C) is common to some catabolic pathways, thus linking the metabolism of several amino acids, including proline and arginine. Specifically, mitochondrial proline catabolism involves sequential action of proline dehydrogenase (ProDH) and P5C dehydrogenase (P5CDH) to produce P5C and then glutamate. Arginine catabolism produces urea and ornithine, the latter in the presence of α-ketoglutarate being converted by ornithine δ-aminotransferase (OAT) into P5C and glutamate. Metabolic changes during dark-induced leaf senescence (DIS) were studied in Arabidopsis thaliana leaves of Col-0 and in prodh1prodh2, p5cdh, and oat mutants. Progression of DIS was followed by measuring chlorophyll and proline contents for 5 days. Metabolomic profiling of 116 compounds revealed similar profiles of Col-0 and oat metabolism, distinct from prodh1prodh2 and p5cdh metabolism. Metabolic dynamics were accelerated in p5cdh by one day. Notably, more P5C and proline accumulated in p5cdh than in prodh1prodh2. ProDH1 enzymatic activity and protein amount were significantly down-regulated in p5cdh mutant at day 4 of DIS. Mitochondrial P5C levels appeared critical in determining the flow through interconnected amino acid remobilisation pathways to sustain senescence. This article is protected by copyright. All rights reserved.PMID:36583533 | DOI:10.1111/pce.14529

Microb Biotechnol. 2022 Dec 30. doi: 10.1111/1751-7915.14200. Online ahead of print.ABSTRACTHuangkui capsule (HKC), a traditional Chinese medicine, has been used for medication of kidney diseases, including diabetic nephropathy (DN). The current study aimed to evaluate the effects of HKC in the modulation of gut microbiota and the amelioration of metabolite levels by using non-obese diabetes (NOD) mice with DN. The microbiota from three parts of intestines (duodenum, ileum and colon) in NOD mice with and without HKC treatment were analysed using 16S rDNA sequencing techniques. Untargeted metabolomics in plasma of NOD mice were analysed with liquid mass spectrometry. Results showed that HKC administration ameliorated DN in NOD mice and the flora in duodenum were more sensitive to HKC intervention, while the flora in colon had more effects on metabolism. The bacterial genera such as Faecalitalea and Muribaculum significantly increased and negatively correlated with most of the altered metabolites after HKC treatment, while Phyllobacterium, Weissella and Akkermansia showed an opposite trend. The plasma metabolites, mainly including amino acids and fatty acids such as methionine sulfoxide, BCAAs and cis-7-Hexadecenoic acid, exhibited a distinct return to normal after HKC treatment. The current study thereby provides experimental evidence suggesting that HKC may modulate gut microbiota and subsequently ameliorate the metabolite levels in DN.PMID:36583468 | DOI:10.1111/1751-7915.14200

Elife. 2022 Dec 30;11:e83658. doi: 10.7554/eLife.83658.ABSTRACTThe combined use of multiple omics allows to study complex interrelated biological processes in their entirety. We applied a combination of metabolomics, lipidomics and proteomics to human bones to investigate their combined potential to estimate time elapsed since death (i.e., the postmortem interval [PMI]). This 'ForensOMICS' approach has the potential to improve accuracy and precision of PMI estimation of skeletonized human remains, thereby helping forensic investigators to establish the timeline of events surrounding death. Anterior midshaft tibial bone was collected from four female body donors before their placement at the Forensic Anthropology Research Facility owned by the Forensic Anthropological Center at Texas State (FACTS). Bone samples were again collected at selected PMIs (219-790-834-872days). Liquid chromatography mass spectrometry (LC-MS) was used to obtain untargeted metabolomic, lipidomic, and proteomic profiles from the pre- and post-placement bone samples. The three omics blocks were investigated independently by univariate and multivariate analyses, followed by Data Integration Analysis for Biomarker discovery using Latent variable approaches for Omics studies (DIABLO), to identify the reduced number of markers describing postmortem changes and discriminating the individuals based on their PMI. The resulting model showed that pre-placement metabolome, lipidome and proteome profiles were clearly distinguishable from post-placement ones. Metabolites in the pre-placement samples suggested an extinction of the energetic metabolism and a switch towards another source of fuelling (e.g., structural proteins). We were able to identify certain biomolecules with an excellent potential for PMI estimation, predominantly the biomolecules from the metabolomics block. Our findings suggest that, by targeting a combination of compounds with different postmortem stability, in the future we could be able to estimate both short PMIs, by using metabolites and lipids, and longer PMIs, by using proteins.PMID:36583441 | DOI:10.7554/eLife.83658

Emerg Microbes Infect. 2022 Dec 30:2164217. doi: 10.1080/22221751.2022.2164217. Online ahead of print.ABSTRACTCSFV (classical swine fever virus) is currently endemic in developing countries in Asia and has recently re-emerged in Japan. Under the pressure of natural selection pressure, CSFV keeps evolving to maintain its ecological niche in nature. CSFV has evolved mechanisms that induce immune depression, but its pathogenic mechanism is still unclear. In this study, using transcriptomics and metabolomics methods, we found that CSFV infection alters innate host immunity by activating the interferon pathway, inhibiting host inflammation, apoptosis, and remodeling host metabolism in porcine alveolar macrophages. Moreover, we revealed that autophagy could alter innate immunity and metabolism induced by CSFV infection. Enhanced autophagy further inhibited CSFV-induced RIG-I-IRF3 signal transduction axis and JAK-STAT signaling pathway and blocked type I interferon production while reducing autophagy inhibition of the NF-κB signaling pathway and apoptosis in CSFV infection cells. Furthermore, the level of CSFV infection-induced glycolysis and the content of lactate and pyruvate, as well as 3-phosphoglyceraldehyde, a derivative of glycolysis converted to serine, was altered by autophagy. We also found that silencing HK2 (hexokinase 2), the rate-limiting enzyme of glycolytic metabolism, could induce autophagy but reduce the interferon signaling pathway, NF-κB signaling pathway, and inhibition of apoptosis induced by CSFV infection. In addition, inhibited cellular autophagy by silencing ATG5 or using 3-Methyladenine, could backfill the inhibitory effect of silencing HK2 on the cellular interferon signaling pathway, NF-κB signaling pathway, and apoptosis.PMID:36583373 | DOI:10.1080/22221751.2022.2164217

Drug Des Devel Ther. 2022 Dec 22;16:4343-4364. doi: 10.2147/DDDT.S384607. eCollection 2022.ABSTRACTPURPOSE: Shaoyao decoction (SYD) is a traditional Chinese medicine used to treat ulcerative colitis (UC). The exact mechanism of action of SYD in UC treatment is still unclear. Here, we examined the therapeutic effects of SYD in mice with dextran sulfate sodium (DSS)-induced colitis and explored the underlying mechanism.METHODS: The experimental group was divided into normal control, UC, and SYD treatment groups. The UC model of C57BL/6 mice was induced using 3% (w/v) DSS for 7 days. SYD was orally administered for 7 days. The proximal and distal colonic metabolic profiles were detected using quadrupole-time-of-flight mass spectrometry-based untargeted metabolomics.RESULTS: SYD significantly increased weight, reduced disease activity index scores, and ameliorated colon length shortening and pathological damage in mice. In the distal colon, SYD increased the abundance of phosphatidic acid and lysophosphatidylethanolamine and decreased the abundance of lactosylceramide, erythrodiol 3-palmitate, and lysophosphatidylcholine. In the proximal colon, SYD increased the abundance of palmitic acid, cyclonormammein, monoacylglyceride, 13S-hydroxyoctadecadienoic acid, and ceanothine C and decreased the abundance of tetracosahexaenoic acid, phosphatidylserine, and diglyceride.CONCLUSION: Our findings revealed that SYD could alleviate UC by regulating metabolic dysfunction, which provides a reference for further studies on SYD.PMID:36583115 | PMC:PMC9792814 | DOI:10.2147/DDDT.S384607

Front Mol Neurosci. 2022 Dec 13;15:999938. doi: 10.3389/fnmol.2022.999938. eCollection 2022.ABSTRACTOBJECTIVE: In this study, we aimed to characterize the plasma metabolic profiles of brain atrophy and alcohol dependence (s) and to identify the underlying pathogenesis of brain atrophy related to alcohol dependence.METHODS: We acquired the plasma samples of alcohol-dependent patients and performed non-targeted metabolomic profiling analysis to identify alterations of key metabolites in the plasma of BA-ADPs. Machine learning algorithms and bioinformatic analysis were also used to identify predictive biomarkers and investigate their possible roles in brain atrophy related to alcohol dependence.RESULTS: A total of 26 plasma metabolites were significantly altered in the BA-ADPs group when compared with a group featuring alcohol-dependent patients without brain atrophy (NBA-ADPs). Nine of these differential metabolites were further identified as potential biomarkers for BA-ADPs. Receiver operating characteristic curves demonstrated that these potential biomarkers exhibited good sensitivity and specificity for distinguishing BA-ADPs from NBA-ADPs. Moreover, metabolic pathway analysis suggested that glycerophospholipid metabolism may be highly involved in the pathogenesis of alcohol-induced brain atrophy.CONCLUSION: This plasma metabolomic study provides a valuable resource for enhancing our understanding of alcohol-induced brain atrophy and offers potential targets for therapeutic intervention.PMID:36583081 | PMC:PMC9792671 | DOI:10.3389/fnmol.2022.999938

Brain Behav Immun Health. 2022 Dec 17;27:100573. doi: 10.1016/j.bbih.2022.100573. eCollection 2023 Feb.ABSTRACTThe spleen is a key immune-related organ that plays a role in communication between the brain and the immune system through the brain-spleen axis and brain-gut-microbiota axis. However, how the gut microbiota affects spleen and brain function remains unclear. Here, we investigated whether microbiome depletion induced by administration of an antibiotic cocktail (ABX) affects spleen and brain function. Treatment with ABX for 14 days resulted in a significant decrease in spleen weight and significant alterations in splenic functions, including the percentage of neutrophils, NK cells, macrophages, and CD8+ T cells. Furthermore, ABX treatment resulted in the depletion of a large portion of the gut microbiota. Untargeted metabolomics analysis showed that ABX treatment caused alterations in the levels of certain compounds in the plasma, spleen, and brain. Moreover, ABX treatment decreased the expression of microglia marker Iba1 in the cerebral cortex. Interestingly, correlations were found between the abundance of different microbiome components and metabolites in various tissues, as well as splenic cell populations and spleen weight. These findings suggest that ABX-induced microbiome depletion and altered metabolite levels may affect spleen and brain function through the gut-microbiota-spleen-brain axis.PMID:36583066 | PMC:PMC9793168 | DOI:10.1016/j.bbih.2022.100573

Front Pharmacol. 2022 Dec 13;13:1090599. doi: 10.3389/fphar.2022.1090599. eCollection 2022.ABSTRACTIntroduction: The clinical efficacy of Yiqi Sanjie (YQSJ) formula in the treatment of stage III colorectal cancer (CRC) has been demonstrated. However, the underlying antitumor mechanisms remain poorly understood. Materials and methods: The aim of the present study was to comprehensively characterize the molecular and microbiota changes in colon tissues and fecal samples from CRC mice and in CRC cell lines treated with YQSJ or its main active component, peiminine. Integrative tandem mass tag-based proteomics and ultra-performance liquid chromatography coupled with time-of-flight tandem mass spectrometry metabolomics were used to analyze azoxymethane/dextran sulfate sodium-induced CRC mouse colon tissues. Results: The results showed that 0.8% (57/7568) of all detected tissue proteins and 3.2% (37/1141) of all detected tissue metabolites were significantly changed by YQSJ treatment, with enrichment in ten and six pathways associated with colon proteins and metabolites, respectively. The enriched pathways were related to inflammation, sphingolipid metabolism, and cholesterol metabolism. Metabolomics analysis of fecal samples from YQSJ-treated mice identified 121 altered fecal metabolites and seven enriched pathways including protein digestion and absorption pathway. 16S rRNA sequencing analysis of fecal samples indicated that YQSJ restored the CRC mouse microbiota structure by increasing the levels of beneficial bacteria such as Ruminococcus_1 and Prevotellaceae_UCG_001. In HCT-116 cells treated with peiminine, data-independent acquisition-based proteomics analysis showed that 1073 of the 7152 identified proteins were significantly altered and involved in 33 pathways including DNA damage repair, ferroptosis, and TGF-β signaling. Conclusion: The present study identified key regulatory elements (proteins/metabolites/bacteria) and pathways involved in the antitumor mechanisms of YQSJ, suggesting new potential therapeutic targets in CRC.PMID:36582529 | PMC:PMC9792787 | DOI:10.3389/fphar.2022.1090599

Front Pharmacol. 2022 Dec 13;13:1080226. doi: 10.3389/fphar.2022.1080226. eCollection 2022.ABSTRACTBackground: Liver fibrosis is a common outcome of the pathological progression of chronic liver disease; however, no specific and effective therapeutic agent has been approved for its treatment. We investigated the effects of Kuhuang on liver fibrosis and the underlying mechanisms of action. Materials and methods: To induce hepatic fibrosis, either 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) diet was administered, or bile duct ligation (BDL) surgery was performed on C57BL/6 mice. Kuhuang was orally administered to mice for 7 days before and after bile duct ligation or 4 weeks with a DDC diet. Hematoxylin and eosin, Sirius red staining, and immunohistochemical analyses were performed to evaluate hepatic pathology. Hepatic interferon-β (IFN-β) levels were measured using an enzyme-linked immunosorbent assay. RNA sequencing was performed to examine the gene expression profiles of liver tissues. The mRNA expression of inflammatory, profibrotic, and bile acid (BA)-related genes was further validated by qRT-PCR. A targeted metabolomics assay revealed the alteration of the hepatic bile acid (BA) composition. The composition of the gut microbiota was determined via 16S rRNA sequencing. Results: Treatment with Kuhuang attenuated liver fibrosis and reduced the inflammatory response in bile duct ligation and DDC mouse models. In addition, the hepatic IFN signaling pathway was activated following Kuhuang treatment. Kuhuang treatment also significantly decreased hepatic levels of both primary and secondary BAs. In addition, Kuhuang treatment altered gut microbiota composition, with an increased abundance of interferon-inducing Akkermansia and decreased abundance of bile salt hydrolase-producing Lactobacillus, Clostridium, and Bifidobacterium. Furthermore, the abundance of Akkermansia was positively correlated with the hepatic mRNA expression levels of Ifna4, Ifnb, and Isg15, whereas that of Lactobacillus, Clostridium - sensu - stricto - 1, and Bifidobacterium was positively correlated with levels of bile acid synthesis-related genes. Conclusion: Our results suggest that Kuhuang plays a protective role during the progression of liver fibrosis, potentially by altering the composition of the gut microbiota, which consequently activates interferon signaling and inhibits bile acid synthesis in the liver.PMID:36582518 | PMC:PMC9792617 | DOI:10.3389/fphar.2022.1080226

Curr Res Food Sci. 2022 Dec 10;6:100409. doi: 10.1016/j.crfs.2022.100409. eCollection 2023.ABSTRACTBoiling has important effects on the texture of chicken eggs, but its effects on egg nutrients have not been systematically investigated. In this study, changes in the metabolites of egg yolks boiled under different heating intensities were quantified and compared by metabolomic analysis. A total of 797 metabolites were identified, and the abundance of 162 metabolites changed significantly after boiling. The significant reduction of L-lysine and D-fructose suggested that Maillard reactions occurred in over-boiled egg yolks. Egg yolk endogenous enzymes might induce a partial hydrolysis of proteins and phospholipids during the warm-up period of boiling, as the abundance of dipeptides, lysophospholipids, and free fatty acids was significantly increased in boiled egg yolks. Boiling increased the detectable abundance of fat-soluble vitamins, riboflavin, and biotin, possibly by altering the complex structure of protein-lipid-lipophilic compounds or denaturing vitamin-binding proteins. The results of metabolomic analyses provide important information for understanding the nutritional changes of egg yolk boiled under different heating intensities.PMID:36582447 | PMC:PMC9792406 | DOI:10.1016/j.crfs.2022.100409

Front Immunol. 2022 Dec 13;13:1095038. doi: 10.3389/fimmu.2022.1095038. eCollection 2022.ABSTRACT[This corrects the article DOI: 10.3389/fimmu.2021.811351.].PMID:36582251 | PMC:PMC9793797 | DOI:10.3389/fimmu.2022.1095038

Front Immunol. 2022 Dec 13;13:1033393. doi: 10.3389/fimmu.2022.1033393. eCollection 2022.ABSTRACTBACKGROUND: The profile of gut microbiota, serum metabolites, and lipids of type 1 diabetes (T1D) patients with different human leukocyte antigen (HLA) genotypes remains unknown. We aimed to explore gut microbiota, serum metabolites, and lipids signatures in individuals with T1D typed by HLA genotypes.METHODS: We did a cross-sectional study that included 73 T1D adult patients. Patients were categorized into two groups according to the HLA haplotypes they carried: those with any two of three susceptibility haplotypes (DR3, DR4, DR9) and without any of the protective haplotypes (DR8, DR11, DR12, DR15, DR16) were defined as high-risk HLA genotypes group (HR, n=30); those with just one or without susceptibility haplotypes as the non-high-risk HLA genotypes group (NHR, n=43). We characterized the gut microbiome profile with 16S rRNA gene amplicon sequencing and analyzed serum metabolites with liquid chromatography-mass spectrometry.RESULTS: Study individuals were 32.5 (8.18) years old, and 60.3% were female. Compared to NHR, the gut microbiota of HR patients were characterized by elevated abundances of Prevotella copri and lowered abundances of Parabacteroides distasonis. Differential serum metabolites (hypoxanthine, inosine, and guanine) which increased in HR were involved in purine metabolism. Different lipids, phosphatidylcholines and phosphatidylethanolamines, decreased in HR group. Notably, Parabacteroides distasonis was negatively associated (p ≤ 0.01) with hypoxanthine involved in purine metabolic pathways.CONCLUSIONS: The present findings enabled a better understanding of the changes in gut microbiome and serum metabolome in T1D patients with HLA risk genotypes. Alterations of the gut microbiota and serum metabolites may provide some information for distinguishing T1D patients with different HLA risk genotypes.PMID:36582242 | PMC:PMC9794034 | DOI:10.3389/fimmu.2022.1033393

Pediatr Transplant. 2022 Dec 29:e14460. doi: 10.1111/petr.14460. Online ahead of print.ABSTRACTBACKGROUND: Despite the common use of mycophenolate in pediatric renal transplantation, lack of effective therapeuic drug monitoring increases uncertainty over optimal drug exposure and risk for adverse reactions. This study aims to develop a novel urine test to estimate MPA exposure based using metabolomics.METHODS: Urine samples obtained on the same day of MPA pharmacokinetic testing from two prospective cohorts of pediatric kidney transplant recipients were assayed for 133 unique metabolites by mass spectrometry. Partial least squares (PLS) discriminate analysis was used to develop a top 10 urinary metabolite classifier that estimates MPA exposure. An independent cohort was used to test pharmacodynamic validity for allograft inflammation (urinary CXCL10 levels) and eGFR ratio (12mo/1mo eGFR) at 1 year.RESULTS: Fifty-two urine samples from separate children (36.5% female, 12.0 ± 5.3 years at transplant) were evaluated at 1.6 ± 2.5 years post-transplant. Using all detected metabolites (n = 90), the classifier exhibited strong association with MPA AUC by principal component regression (r = 0.56, p < .001) and PLS (r = 0.75, p < .001). A practical classifier (top 10 metabolites; r = 0.64, p < .001) retained similar accuracy after cross-validation (LOOCV; r = 0.52, p < .001). When applied to an independent cohort (n = 97 patients, 1053 samples), estimated mean MPA exposure over Year 1 was inversely associated with mean urinary CXCL10:Cr (r = -0.28, 95% CI -0.45, -0.08) and exhibited a trend for association with eGFR ratio (r = 0.35, p = .07), over the same time period.CONCLUSIONS: This urinary metabolite classifier can estimate MPA exposure and correlates with allograft inflammation. Future studies with larger samples are required to validate and evaluate its clinical application.PMID:36582125 | DOI:10.1111/petr.14460

J Transl Med. 2022 Dec 29;20(1):629. doi: 10.1186/s12967-022-03809-6.ABSTRACTBACKGROUND: Obesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment.METHODS: Fasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC-QTOF-MS metabolomics, targeted LC-MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment.RESULTS: Participants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism.CONCLUSIONS: Our results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14.PMID:36581893 | DOI:10.1186/s12967-022-03809-6

Microbiome. 2022 Dec 30;10(1):245. doi: 10.1186/s40168-022-01437-2.ABSTRACTBACKGROUND: The early life gut microbiome is crucial in maintaining host metabolic and immune homeostasis. Though neonates with critical congenital heart disease (CCHD) are at substantial risks of malnutrition and immune imbalance, the microbial links to CCHD pathophysiology remain poorly understood. In this study, we aimed to investigate the gut microbiome in neonates with CCHD in association with metabolomic traits. Moreover, we explored the clinical implications of the host-microbe interactions in CCHD.METHODS: Deep metagenomic sequencing and metabolomic profiling of paired fecal samples from 45 neonates with CCHD and 50 healthy controls were performed. The characteristics of gut microbiome were investigated in three dimensions (microbial abundance, functionality, and genetic variation). An in-depth analysis of gut virome was conducted to elucidate the ecological interaction between gut viral and bacterial communities. Correlations between multilevel microbial features and fecal metabolites were determined using integrated association analysis. Finally, we conducted a subgroup analysis to examine whether the interactions between gut microbiota and metabolites could mediate inflammatory responses and poor surgical prognosis.RESULTS: Gut microbiota dysbiosis was observed in neonates with CCHD, characterized by the depletion of Bifidobacterium and overgrowth of Enterococcus, which was highly correlated with metabolomic perturbations. Genetic variations of Bifidobacterium and Enterococcus orchestrate the metabolomic perturbations in CCHD. A temperate core virome represented by Siphoviridae was identified to be implicated in shaping the gut bacterial composition by modifying microbial adaptation. The overgrowth of Enterococcus was correlated with systemic inflammation and poor surgical prognosis in subgroup analysis. Mediation analysis indicated that the overgrowth of Enterococcus could mediate gut barrier impairment and inflammatory responses in CCHD.CONCLUSIONS: We demonstrate for the first time that an aberrant gut microbiome associated with metabolomic perturbations is implicated in immune imbalance and adverse clinical outcomes in neonates with CCHD. Our data support the importance of reconstituting optimal gut microbiome in maintaining host metabolic and immunological homeostasis in CCHD. Video Abstract.PMID:36581858 | DOI:10.1186/s40168-022-01437-2

Clin Immunol. 2022 Dec 26:109219. doi: 10.1016/j.clim.2022.109219. Online ahead of print.ABSTRACTBACKGROUND: HLA-A29-positive birdshot chorioretinitis (BCR) is an inflammatory eye disorder that is generally assumed to be caused by an autoimmune response to HLA-A29-presented peptides from retinal arrestin (SAG), yet the epitopes recognized by CD8+ T cells from patients remain to be identified.OBJECTIVES: The identification of natural ligands of SAG presented by HLA-A29. To quantify CD8+ T cells reactive to antigenic SAG peptides presented by HLA-A29 in patients and controls.METHODS: We performed mass-spectrometry based immunopeptidomics of HLA-A29 of antigen-presenting cell lines from patients engineered to express SAG. MHC-I Dextramer technology was utilised to determine expansion of antigen-specific CD8+ T cells reactive to SAG peptides in complex with HLA-A29 in a cohort of BCR patients, HLA-A29-positive controls, and HLA-A29-negative controls.RESULTS: We report on the naturally presented antigenic SAG peptides identified by sequencing the HLA-A29 immunopeptidome of antigen-presenting cells of patients. We show that the N-terminally extended SAG peptide precursors can be trimmed in vitro by the antigen-processing aminopeptidases ERAP1 and ERAP2. Unexpectedly, no enhanced antigen engagement by CD8+ T cells upon stimulation with SAG peptides was observed in patients or HLA-A29-positive controls. Multiplexed HLA-A29-peptide dextramer profiling of a case-control cohort revealed that CD8+ T cells specific for these SAG peptides were neither detectable in peripheral blood nor in eye biopsies of patients.CONCLUSIONS: Collectively, these findings demonstrate that SAG is not a CD8+ T cell autoantigen and sharply contrast the paradigm in the pathogenesis of BCR. Therefore, the mechanism by which HLA-A29 is associated with BCR does not involve SAG.PMID:36581221 | DOI:10.1016/j.clim.2022.109219

Prog Neurobiol. 2022 Dec 26:102400. doi: 10.1016/j.pneurobio.2022.102400. Online ahead of print.ABSTRACTFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease with multiple histopathological subtypes. FTD patients share similar symptoms with Alzheimer's disease (AD). Hence, FTD patients are commonly misdiagnosed as AD, despite the consensus clinical diagnostic criteria. It is therefore of great clinical need to identify a biomarker that can distinguish FTD from AD and control individuals, and potentially further differentiate between FTD pathological subtypes. We conducted a metabolomic analysis on post-mortem human brain tissue from three regions: cerebellum, frontal cortex and occipital cortex from control, FTLD-TDP type A, type A-C9, type C and AD. Our results indicate that the brain subdivisions responsible for different functions show different metabolic patterns. We further explored the region-specific metabolic characteristics of different FTD subtypes and AD patients. Different FTD subtypes and AD share similar metabolic phenotypes in the cerebellum, but AD exhibited distinct metabolic patterns in the frontal and occipital regions compared to FTD. The identified brain region-specific metabolite biomarkers could provide a tool for distinguishing different FTD subtypes and AD and provide the first insights into the metabolic changes of FTLD-TDP type A, type A-C9, type C and AD in different regions of the brain. The importance of protein arginine methylation in neurodegenerative disease has come to light, so we investigated whether the arginine methylation level contributes to disease pathogenesis. Our findings provide new insights into the relationship between arginine methylation and metabolic changes in FTD subtypes and AD that could be further explored, to study the molecular mechanism of pathogenesis.PMID:36581185 | DOI:10.1016/j.pneurobio.2022.102400

J Ethnopharmacol. 2022 Dec 26:116112. doi: 10.1016/j.jep.2022.116112. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu Decoction (BYHW) is a classic representative formula for treating qi deficiency and the blood stasis syndrome of stroke in the Qing Dynasty physician Wang Qingren's Correction on the Errors of Medical Works. However, the research on the mechanism of BYHW in the treatment of stroke is not systematic and comprehensive.AIM OF THE STUDY: Combined with multi-omics analysis methods to explore the potential targets of BYHW in the treatment of cerebral ischemia-reperfusion (I/R).MATERIALS AND METHODS: The rat middle cerebral artery occlusion (MCAO) model was established to study the effect of BYHW on cerebral I/R injury in rats. Then, the potential targets and pathways of BYHW in the treatment of cerebral I/R injury were analyzed by proteomic, transcriptomic, and metabolomic methods. Finally, 4D-PRM was used to validate potential targets.RESULTS: BYHW effectively improved the neurological function scores of MCAO rats and significantly reduced the rate of cerebral infarction in MCAO rats. Multi-omics analysis had identified 15 potential targets and 4 potential signaling pathways. The results of 4D-PRM targeted proteomics verification showed that Pde1b was reversed up-regulated, and Aprt, Gpd1, Glb1, HEXA, and HEXB were reversed down-regulated.CONCLUSION: BYHW may improve cerebral I/R through Aprt, Pde1b, Gpd1, Glb1, HEXA and HEXB targets, and Glycerophospholipid metabolism, Purine metabolism and Glycosphingolipid biosynthesis - globoseries pathway.PMID:36581164 | DOI:10.1016/j.jep.2022.116112

J Ethnopharmacol. 2022 Dec 26:116082. doi: 10.1016/j.jep.2022.116082. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Terminalia bellirica (Gaertn.) Roxb. (TB) is a traditional Tibetan medicine used to treat hepatobiliary diseases. However, modern pharmacological evidence of the activities and potential mechanisms of TB against nonalcoholic fatty liver disease (NAFLD) are still unknown.AIM OF THE STUDY: This study aimed to evaluate the anti-NAFLD effect of ethanol extract of TB (ETB) and investigate whether its ameliorative effects are associated with the regulation of intestinal microecology.MATERIALS AND METHODS: In this study, the curative effects of ETB on NAFLD were evaluated in mice fed a choline-deficient, L-amino acid defined, high fat diet (CDAHFD). Biochemical markers and hepatic histological alterations were detected. Gut microbiota and faecal metabolites were analyzed by 16S rRNA gene sequencing and liquid chromatograph mass spectrometer (LC‒MS) profiling.RESULTS: The results showed that oral treatment with middle- and high-dose ETB significantly improved features of NAFLD, reducing the levels of TG, LDL-C, ALT and AST, and increasing the level of HDL-C. Liver histopathologic examination demonstrated that ETB attenuated lipid accumulation and hepatocellular necrosis. ETB treatment restored the structural disturbances of gut microbiota induced by CDAHFD, reduced the levels of Intestinimonas, Lachnoclostridium, and Lachnospirace-ae_FCS020_group, and increased Akkermansia and Bifidobacterium. Moreover, untargeted metabolomics analysis revealed that ETB could restore the disrupted taurine and hypotaurine metabolism, glycine, serine and threonine metabolism, and glutathione metabolism of the intestinal bacterial community in NAFLD mice.CONCLUSIONS: ETB was effective in ameliorating the NAFLD, possibly by remodelling the gut microbiota composition and modulating the faecal metabolism metabolites of the host, highlighting the potential of TB as a resource for the development of anti-NAFLD drugs.PMID:36581163 | DOI:10.1016/j.jep.2022.116082