PubMed

Gastro Hep Adv. 2026 Jan 17;5(4):100883. doi: 10.1016/j.gastha.2026.100883. eCollection 2026.ABSTRACTBACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is characterized by intestinal barrier disruption and dysregulated interactions between host immunity and gut microbiota. Osteopontin (OPN) is considered a proinflammatory mediator in IBD, but nonhematopoietic cell-derived OPN may exert barrier-protective functions. This study aimed to determine the effects of OPN in a murine model of acute colitis.METHODS: We examined wild-type and OPN knockout mice under steady-state conditions and in dextran sulfate sodium-induced colitis, including bone marrow chimeras to distinguish the effects of hematopoietic and nonhematopoietic OPN.RESULTS: Overt colitis did not occur under steady-state conditions. Compared with wild-type mice, OPN knockout mice exhibited crypt elongation, goblet cell hyperplasia, and increased epithelial proliferation. Gene expression analysis revealed reduced interleukin (IL)-22, IL-23, and IL-13 levels alongside increased interferon-γ, IL-1β, and IL-17A levels. 16S rRNA sequencing revealed increased alpha diversity, expansion of Akkermansia and Prevotellaceae, and reduced Lactobacillus abundance. Functional prediction identified enrichment of microbial sulfur metabolism pathways, and metabolomic analysis demonstrated increased L-proline and L-(-)-fucose levels and reduced β-sitosterol levels. These shifts indicate enhanced mucinolytic activity and altered energy metabolism, consistent with a latent "preinflammatory state." Bone marrow chimera experiments demonstrated that OPN deficiency in the recipients reproduced changes in the microbiota composition and lipocalin-2 expression at the steady state and conferred heightened susceptibility to dextran sulfate sodium-induced acute colitis, irrespective of donor genotype.CONCLUSION: These findings indicate that nonhematopoietic cell-derived "guardian-type" OPN preserves barrier integrity, sustains IL-22/IL-23 production, and maintains microbiota-metabolome balance, whereas its loss induces a preinflammatory state that predisposes to acute mucosal injury. These findings provide a conceptual basis for stage- and source-specific therapeutic strategies in IBD.PMID:41768524 | PMC:PMC12938857 | DOI:10.1016/j.gastha.2026.100883

Front Plant Sci. 2026 Feb 12;16:1690517. doi: 10.3389/fpls.2025.1690517. eCollection 2025.ABSTRACTINTRODUCTION: This study aimed to identify the specific genes, key metabolic pathways, and differential metabolites associated with flower color formation in Dendranthema morifolium "Boju" (hereinafter, referred to as "Boju"). These analyses were intended to elucidate the causes underlying different flower colors in "Boju" and provide a theoretical basis for optimal breeding of "Boju".METHODS: "Boju" varieties with pink-white (FB group), yellow-white (HB group), and pure yellow flowers (CH group) were subjected to transcriptomic and metabolomic analyses to identify the differentially expressed genes (DEGs) and differential metabolites in these varieties.RESULTS: Transcriptomic analysis showed varying enrichment pathways of the DEGs in the three groups. The pathways with higher numbers of enriched genes in the FB vs. CH and FB vs. HB groups were the same, including protein processing in endoplasmic reticulum, plant-pathogen interaction, plant hormone signal transduction, and mitogen-activated protein kinase signal pathway. In the HB vs. CH group, among the four pathways with a larger number of DEGs, three were consistent with the previous two groups. In addition, the number of enriched genes in the starch and sucrose metabolism pathways was also relatively large in this group. Metabolomic analysis indicated that the differential metabolites in the varieties were primarily enriched in the isoflavonoid and flavonoid biosynthesis pathways. In the FB vs. CH, FB vs. HB, and HB vs. CH groups, 28, 29, and 5 differential metabolites were enriched, with most of these metabolites enriched in either isoflavonoid or flavonoid biosynthesis pathways. These findings, combined with real-time quantitative polymerase chain reaction analysis, revealed a significant distribution of the flavonoid synthesis pathway, exceeding the significance threshold line. The differential expression of flavonoid metabolites and genes related to their biosynthetic pathways might primarily impact the formation of different flower colors in "Boju".DISCUSSION: Transcriptomic and metabolomic analyses indicated that the types and contents of anthocyanins varied across the "Boju" varieties, resulting in varying flower color. The key differential metabolites were primarily enriched in the isoflavonoid and flavonoid biosynthesis pathways. The DEGs in the different comparison groups exhibited varying enrichment in different pathways, but the enriched pathways were the same across the varieties.PMID:41768480 | PMC:PMC12935939 | DOI:10.3389/fpls.2025.1690517

MedComm (2020). 2026 Feb 26;7(3):e70629. doi: 10.1002/mco2.70629. eCollection 2026 Mar.ABSTRACTBipolar disorder (BD) research confronts challenges: blood-based biomarkers offer limited insights into neurobiology, while cerebrospinal fluid (CSF) collection is clinically unusual. Linking genetic susceptibility to pathophysiology remains crucial for biologically informed risk stratification. We integrated cohort data and genome-wide association study (GWAS) summary statistics: the largest BD meta-analysis, CSF multi-omics profiles including 3107 proteomic and 2602 metabolomic participants, and a validation cohort of 247,834 UK Biobank participants. Unsupervised clustering revealed four single-nucleotide variant (SNV) clusters: metabolic-imbalance, metabolic-active, human leukocyte antigen (HLA)+immune, and HLA-immune. These clusters exhibited distinct clinical features, with the metabolic-imbalance cluster showing multi-directional associations with 21 psychiatric traits, while the HLA-immune cluster was associated with emotional instability in BD patients (odds ratio [OR] = 1.14, p = 0.027). The optimized multimodal cluster-specific polygenic risk scores (PRS) model significantly outperformed clinical-only prediction factors (C-index = 0.77), with the metabolic-imbalance PRS contributing a 22.6% incremental predictive value (hazard ratio [HR] = 1.23, 95% CI: 1.04-1.45, p = 0.016). Risk reclassification showed an 84% reduction in false-negative rates in the low-risk subgroup, identifying a high-risk layer with a 17.6-fold increased BD incidence. Altogether, genetically informed substitutes for CSF biomarkers emerged as a scalable tool for risk prediction, overcoming the barriers of CSF collection while capturing neurobiological heterogeneity.PMID:41768366 | PMC:PMC12946660 | DOI:10.1002/mco2.70629

Front Bioeng Biotechnol. 2026 Feb 13;14:1752619. doi: 10.3389/fbioe.2026.1752619. eCollection 2026.ABSTRACTPURPOSE: Anastomotic leakage and impaired healing remain major complications in gastrointestinal (GI) surgery. Small intestinal submucosa (SIS), a biological scaffold, has shown regenerative potential but its mechanisms in GI anastomotic healing remain unclear. This study aimed to investigate the effects of an SIS bio-patch on intestinal anastomotic healing, focusing on immune modulation, microbiota reshaping, and metabolic changes.METHODS: C57BL/6 mice underwent GI anastomosis with or without SIS bio-patch implantation. Five days post-operation, tissues were collected for histology, immunofluorescence, flow cytometry, 16S and ITS sequencing, and untargeted metabolomics. Immune cell composition, barrier protein expression, microbiota composition, and metabolic signatures were analyzed.RESULTS: SIS bio-patch significantly reduced inflammation and enhanced mucosal barrier integrity, as evidenced by reduced TNF-α and IL-6 and increased ZO-1 and occludin expression. SIS increased IL-22+ILC3s (type 3 innate lymphoid cells) and decreased the Th17/Treg ratio without altering macrophage polarization. Microbiota analysis showed increased abundance of Bifidobacterium and Alloprevotella, correlating positively with IL-22+ILC3s. Fungal sequencing revealed higher Fungi gen. Incertae sedis levels, associated with beneficial immune profiles. Metabolomics showed elevated amino acids and biotin metabolism in SIS-treated tissues, which may support epithelial regeneration.CONCLUSION: SIS bio-patch promotes anastomotic healing by enhancing IL-22+ILC3-mediated repair, rebalancing adaptive immunity, reshaping microbial communities, and upregulating pro-regenerative metabolic pathways. These findings support the use of SIS as an immunomodulatory biomaterial for gastrointestinal repair.PMID:41768136 | PMC:PMC12946001 | DOI:10.3389/fbioe.2026.1752619

Front Plant Sci. 2026 Feb 12;17:1712811. doi: 10.3389/fpls.2026.1712811. eCollection 2026.ABSTRACTINTRODUCTION: Leaf variegation is a key ornamental trait of Cymbidium ensifolium (Jianlan); however, the molecular mechanisms underlying leaf color mutations in variegated sectors remain poorly understood. Elucidating the regulatory networks associated with pigment variation is essential for both basic research and ornamental improvement.METHODS: Wild-type plants and two leaf color mutants-spot variegation type (BanYi) and line variegation type (XianYi)-were analyzed. Samples were divided into five groups based on leaf origin and color: CK (wild type), B (yellow sectors of BanYi), BL (green sectors of BanYi), X (yellow sectors of XianYi), and XL (green sectors of XianYi). Integrated transcriptomic and metabolomic analyses were performed. Differential expression analysis was conducted across four comparison groups (B vs BL, B vs CK, X vs CK, and X vs XL). Co-expression analysis, metabolite profiling, correlation analysis, and weighted gene co-expression network analysis (WGCNA) were used to identify key regulatory genes and modules associated with pigment accumulation.RESULTS: A total of 6,716 differentially expressed genes (DEGs) were identified, with 141 shared among all comparison groups. These DEGs were significantly enriched in phenylpropanoid biosynthesis, zeatin biosynthesis, and flavonoid biosynthesis pathways. Twenty-four DEGs involved in flavonoid biosynthesis, including structural genes such as CCOAMT, TT4, and HCT, showed elevated expression in variegated leaf sectors. In addition, 80 transcription factors from the MYB, bHLH, and WRKY families were co-expressed with 50 pigment-related DEGs, suggesting coordinated transcriptional regulation. Metabolomic analysis identified 3,024 differentially accumulated metabolites (DAMs), of which 56 were shared across all groups. Correlation analysis revealed strong associations between co-DEGs and co-DAMs. WGCNA further identified key modules, including the "MEtan" module, which contained 83 genes significantly correlated with pigment-related metabolites such as 1'-Hydroxy-γ-carotene and violaxanthin.DISCUSSION: These results demonstrate that leaf variegation in C. ensifolium is regulated by coordinated transcriptional and metabolic networks, particularly involving flavonoid and carotenoid-related pathways. The identified structural genes, transcription factors, and co-expression modules provide novel insights into the genetic basis of leaf color variation and offer valuable candidate targets for the ornamental improvement of Jianlan.PMID:41768069 | PMC:PMC12935976 | DOI:10.3389/fpls.2026.1712811

Front Plant Sci. 2026 Feb 12;17:1757471. doi: 10.3389/fpls.2026.1757471. eCollection 2026.ABSTRACTGlyphosate, a widely used herbicide, inhibits 5-enolpyruvylshikimate-3-phosphate synthase in the shikimate pathway, and its repeated application has led to resistance in several crops, including potato. In this study, we investigated the molecular and metabolic mechanisms underlying glyphosate resistance in two contrasting potato cultivars, DP (glyphosate-tolerant) and MA (glyphosate-sensitive), using integrated transcriptomic and metabolomic analyses. Glyphosate treatment triggered cultivar-specific responses: although both cultivars activated early stress-related pathways, DP exhibited a more coordinated and sustained transcriptional response, particularly in pathways associated with detoxification, redox homeostasis, and energy regulation, whereas MA showed a broader but less organized response mainly enriched in photosynthesis and carbohydrate metabolism. Metabolomic analysis revealed pronounced metabolic reprogramming in DP, including enhanced flux through the shikimate and phenylpropanoid pathways and increased accumulation of tyrosine, ferulic acid, and flavonoids, which contribute to oxidative stress mitigation and structural defense. In contrast, MA displayed weaker metabolic adjustments, especially in secondary metabolism. Overall, these results demonstrate that glyphosate resistance in potato is driven by transcriptional plasticity and metabolic reprogramming that enhance secondary metabolism and stress tolerance, providing new insights into herbicide resistance mechanisms.PMID:41768057 | PMC:PMC12935873 | DOI:10.3389/fpls.2026.1757471

J Anal Methods Chem. 2026 Feb 27;2026:4116313. doi: 10.1155/jamc/4116313. eCollection 2026.ABSTRACTInborn errors of metabolism such as phenylketonuria (PKU) and maple syrup urine disease (MSUD) can cause severe developmental problems. Both conditions can lead to harmful levels of keto acids in biofluids-phenylpyruvic acid (PPA) in PKU and branched-chain α-keto acids in MSUD. Monitoring urinary keto acids helps track dietary adherence and reduces the risk of metabolic crisis. However, current at-home tests are qualitative and difficult to interpret, while existing metabolomic assays require expensive equipment and must be conducted in a lab. This study aimed to develop a simple, quantitative, rapid, at-home assay for detecting multiple urinary keto acids associated with PKU and MSUD. A modified two-step 2,4-dinitrophenylhydrazine (DNPH)-based multimetabolite assay was developed, where sodium hydroxide (NaOH) converts the yellow hydrazone precipitate to a stable amber solution, enabling quantification of multiple keto acids (700-7200 μM) within 10 min. The assay was validated using spiked urine samples and adapted into a prototype at-home kit using caprolactam-immobilized NaOH. Nuclear magnetic resonance (NMR)-based metabolomics was used as a reference method to authenticate readings from a PKU patient. Correlation studies demonstrated strong linearity for MSUD (R 2 = 0.91-0.96)- and PKU (R 2 = 0.95-0.99)-spiked samples. Quantification of keto acids in authentic PKU urine samples showed excellent agreement with the results of quantitative NMR-based metabolomics assays (R 2 = 0.99). Low-cost, at-home colorimetric tests for urinary keto acids could enable screening, detection, and monitoring of PKU and MSUD in the 90% of the world without access to advanced metabolic clinics.PMID:41767879 | PMC:PMC12949077 | DOI:10.1155/jamc/4116313

Kidney Med. 2026 Jan 5;8(3):101245. doi: 10.1016/j.xkme.2026.101245. eCollection 2026 Mar.ABSTRACTRATIONALE & OBJECTIVE: Additional investigations into the causal effects of kidney function on various metabolites, particularly lipoprotein lipids in detailed subfractions of lipoprotein particles, in the general population are warranted.STUDY DESIGN: Integrated cross-sectional observational and Mendelian randomization (MR) analyses.SETTING & PARTICIPANTS: We included 157,541 participants aged 40-69 years from the UK Biobank study, a population-scale prospective cohort. Genetic instruments for estimated glomerular filtration rate (eGFR) were developed from the Chronic Kidney Disease Genetics genome-wide association study meta-analysis results, which comprised 567,460 individuals of European ancestry.EXPOSURE: eGFR for observational analysis and genetically predicted eGFR for MR analysis.OUTCOMES: Each of the 178 metabolites from recently updated metabolomics data, including detailed lipoprotein components within 14 subclasses of lipoprotein particles.ANALYTICAL APPROACH: Observational analysis was performed using multivariate linear regression adjusted for various clinicodemographic characteristics. A 2-sample MR analysis was performed using the random-effects inverse-variance weighted method as the main MR method.RESULTS: In the integrated results of the observational and MR analyses, 25 metabolites were causally associated with eGFR. A lower eGFR causally decreased lipoprotein components of high-density lipoprotein and several of its subclasses, particularly medium-sized high-density lipoprotein. Conversely, a lower eGFR causally increased triglyceride levels in smaller-sized very low-density lipoprotein and intermediate-density lipoprotein, as well as increased lipoprotein particle concentrations and total lipids in small very low-density lipoprotein. Additionally, a lower eGFR causally increased the ratio of monounsaturated fatty acids to total fatty acids and that of apolipoprotein B to apolipoprotein A-1.LIMITATIONS: Possibility of false-negative findings when integrating observational and MR analyses.CONCLUSIONS: Decreased kidney function causally aggravates lipoprotein lipid profiles; therefore, clinicians should closely monitor the lipid profiles of individuals with impaired kidney function.PMID:41767688 | PMC:PMC12937174 | DOI:10.1016/j.xkme.2026.101245

Food Chem X. 2026 Feb 18;34:103688. doi: 10.1016/j.fochx.2026.103688. eCollection 2026 Feb.ABSTRACTThis study integrated metabolomics, electronic tongue, and molecular docking to investigate how a multi-stage steam-drying process influences the flavor characteristics of pomelo black tea. Results showed that continuous steam-drying can significantly reduce bitterness and umami, and it could also promote the hydrolysis of flavonoid glycosides such as naringenin and the accumulation of organic acids such as linolenic acid, thereby increasing acidity while reducing bitterness. Volatile component analysis indicated that heat-sensitive terpenes such as γ-terpinene was significantly reduced due to oxidative degradation. Aldehydes and esters, including undecanal and neryl acetate, might compensate for this loss of aroma through thermal conversion. This research also found that hydrogen bonds and hydrophobic interactions were key to the binding of aroma compounds to olfactory receptors. Overall, this study provides molecular- and sensory-level evidence linking moist heat processing to coordinated changes in taste- and aroma-related compounds in pomelo black tea.PMID:41767662 | PMC:PMC12938864 | DOI:10.1016/j.fochx.2026.103688

Research (Wash D C). 2026 Feb 19;9:1081. doi: 10.34133/research.1081. eCollection 2026.ABSTRACTExposures that disrupt the immune system can affect human health. This study aimed to understand immune variability influenced by exposures from the perspectives of systems biology and multiomics. We recruited 1,001 healthy participants and collected 183 exposures, 1,332 immunophenotypes, whole blood transcriptome, and plasma metabolome. Through exposure-immune wide association analysis, we identified 81 significant signals, with sleep and diet emerging as dominant exposures affecting the immunity. Sleep and diet influence the proportions of innate immune cells and the expression levels of immune cell surface proteins such as CD85j and CD16, respectively. Notably, distinct from the increase in interleukin-1β secretion caused by short-term late sleep onset, long-term late sleep onset triggered chronic inflammation with more metabolic changes. On the basis of the intracorrelation structure of exposure data, composite exposures were constructed and were found to have additional effects on immunophenotypes. Bidirectional mediation analysis revealed that sleep effects on immunity are commonly linked to the transcriptome, whereas dietary influences on immunity are primarily associated with the metabolome. We quantified the mediation effects of exposures, omics, and immunophenotypes and further demonstrated that these effects reflect human immune health or chronic diseases. Our study drew a comprehensive map of "exposure-immunome-omics" and is expected to provide guidance for future health assessment and management.PMID:41767601 | PMC:PMC12943795 | DOI:10.34133/research.1081

Front Oncol. 2026 Feb 12;15:1703182. doi: 10.3389/fonc.2025.1703182. eCollection 2025.ABSTRACTINTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) originates from intrahepatic bile duct epithelial cells and its global incidence is rising. Surgery remains the primary treatment, but postoperative recurrence rates remain high.METHODS: We analyzed ICC patients' gut microbiota at four stages (preoperative, 7 days postoperative, 1 month postoperative, and during recurrence) using 16S rRNA sequencing and their serum metabolome via LC-MS/MS. Correlations among gut microbiota, metabolome, and clinical indicators were investigated, and candidate microorganisms and metabolites were integrated for multiomics clustering and staging.RESULTS: This revealed significant increases in Bacteroides, Veillonella, and Enterococcus in ICC patients compared to healthy controls across all stages, suggesting these bacteria as potential markers of ICC progression. Microbial and metabolite changes were observed, with gut microbes influencing ICC development through kynurenic acid, linoleic acid, creatine, cholic acid, L-arginine, and the tumor microenvironment. Multiomics analysis showed that cholangiocarcinoma staging improves patient prognosis, particularly highlighting bile acids' role in type II hepatic phenotypes related to cholesterol metabolism.DISCUSSION: Our study provides insights into ICC microbiome and metabolome associations with clinical features and survival.PMID:41767584 | PMC:PMC12935644 | DOI:10.3389/fonc.2025.1703182

Front Microbiol. 2026 Feb 13;17:1726349. doi: 10.3389/fmicb.2026.1726349. eCollection 2026.ABSTRACTPseudomonas protegens CHA0 and other fluorescent pseudomonads suppress plant diseases by producing a number of metabolites with antibiotic activities in the rhizosphere. However, limited information is available on the physiological functions of most of these metabolites. We herein describe the detection of 3-mercaptopropionic acid (3-MPA), a thiol compound, based on the metabolome of the supernatant of strain CHA0. 3-MPA exhibited antibiotic activity against oomycete and fungal pathogens and suppressed Pythium damping-off and root rot in cucumber. 3-MPA also exhibited antibiotic activity without direct contact with pathogens, indicating the volatilization effect of this compound. We identified a homologous gene encoding 3-MPA dioxygenase in the CHA0 genome and the production level of 3-MPA was elevated in a 3mdo-negative mutant. Growth inhibitory activity against oomycete and fungal pathogens and plant protection efficacy exhibited by the 3mdo-negative mutant were stronger than those of wild-type CHA0. These results suggest that 3-MPA is biocontrol factor of strain CHA0.PMID:41767571 | PMC:PMC12947264 | DOI:10.3389/fmicb.2026.1726349

Front Microbiol. 2026 Feb 12;17:1765127. doi: 10.3389/fmicb.2026.1765127. eCollection 2026.ABSTRACTINTRODUCTION: Severe acute pancreatitis (SAP) is frequently complicated by intestinal barrier disruption, bacterial translocation, and systemic inflammation. Emerging evidence indicates that gut microbial metabolic disturbances, particularly altered short-chain fatty acids (SCFAs), may contribute to epithelial injury, yet the mechanistic links between microbial metabolites and host inflammatory signaling remain insufficiently defined. We therefore investigated whether Lactobacillus paracasei LP18 protects against SAP-associated intestinal barrier dysfunction by reshaping gut metabolism, restoring butyrate availability, and attenuating NF-κB activation.METHODS: A mouse model of SAP was established and animals received LP18 intervention. Intestinal injury and barrier integrity were evaluated by histopathology, tight junction protein assessment, and inflammatory cytokine measurements. Metabolic alterations were profiled using untargeted metabolomics and targeted quantification of SCFAs was performed. NF-κB signaling was assessed by measuring p65 phosphorylation and nuclear translocation. Correlation analyses were conducted to relate SCFA levels to barrier markers.RESULTS: SAP induced pronounced epithelial injury, including villus atrophy, Tight junction disruption, elevated pro-inflammatory cytokines, and robust NF-κB activation. Untargeted metabolomics revealed extensive metabolic perturbations, with significant changes in butanoate metabolism and lipid-associated pathways. LP18 administration partially reversed these abnormalities and shifted the metabolomic profile toward a mucosa-protective signature. Targeted SCFA analysis showed marked butyrate depletion in SAP mice, whereas LP18 significantly increased butyrate levels and partially normalized acetate and propionate. Higher butyrate concentrations correlated with improved intestinal integrity and reduced inflammatory response. Mechanistically, LP18 suppressed inflammatory signaling by inhibiting p65 phosphorylation and nuclear translocation, consistent with attenuated NF-κB pathway activation.CONCLUSION: Lactobacillus paracasei LP18 attenuates SAP-associated intestinal inflammation and barrier dysfunction, primarily through modulation of gut microbial composition, restoration of butyrate-associated metabolic profiles, and suppression of NF-κB-related inflammatory signaling.PMID:41767557 | PMC:PMC12936515 | DOI:10.3389/fmicb.2026.1765127

J Diabetes Metab Disord. 2026 Feb 26;25(1):90. doi: 10.1007/s40200-026-01918-3. eCollection 2026 Jun.ABSTRACTPURPOSE: Poor diet quality is a known risk factor for type 2 diabetes and related outcomes, including declines in insulin sensitivity. Biological changes that occur in response to diet may explain this relationship.METHODS: This study was conducted in a cohort of young adults (the MetaAIR study, n = 77, 52% female, 57% Hispanic). High dimensional mediation analyses (HIMA) were performed to identity potential metabolite, protein, and miRNA mediators of the relationship between the Healthy Eating Index-2015 (HEI) and insulin sensitivity (Matsuda Index) over a four year follow up period. Features identified by HIMA and significant after correction for multiple comparisons (q < 0.05) were assessed using causal mediation analyses. The indirect effects and proportion mediated by each feature were calculated independently.RESULTS: Each point increase in HEI was associated with a 0.051 (95% CI:0.004, 0.098) point increase in Matsuda Index. Four potential mediators were identified using HIMA: three metabolites (5Z,8Z,11Z-eicosatrienoic acid, pipecolic acid, and biotin), and one protein (F9). Each of these features exhibited a positive indirect effect and independently mediated between 35 and 43% of the total effect. No miRNAs were selected as potential mediators.CONCLUSION: These findings suggest that specific metabolites and proteins may mediate the association between diet and diabetes-related outcomes such as declines in insulin sensitivity, likely through pathways related to inflammation. F9, biotin, pipecolic acid, and 5Z,8Z,11Z-eicosatrienoic acid may be potential targets for monitoring efforts for diet adherence or disease prevention.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-026-01918-3.PMID:41767436 | PMC:PMC12946319 | DOI:10.1007/s40200-026-01918-3

Front Endocrinol (Lausanne). 2026 Feb 12;17:1736270. doi: 10.3389/fendo.2026.1736270. eCollection 2026.ABSTRACTINTRODUCTION: High-altitude environments impose unique physiological stresses that may alter metabolic dysregulation in individuals with type 2 diabetes mellitus (T2DM). However, the key determinants driving altitude-specific metabolic differences in diabetic patients remain insufficiently characterized. This study aimed to identify critical metabolic biomarkers and pathways distinguishing T2DM patients residing at high versus low altitudes.METHODS: Serum samples were collected from 100 participants stratified into four matched groups: high-altitude T2DM (H_T2DM), high-altitude healthy controls (H_HC), low-altitude T2DM (L_T2DM), and low-altitude healthy controls (L_HC). Metabolomic profiling was performed using ultra-performance liquid chromatography‒quadrupole time-of-flight mass spectrometry (UPLC‒Q‒TOF‒MS) to compare endogenous metabolite abundance across groups. Pathway topology analysis was conducted to annotate functional metabolic pathways, and multicenter validation was implemented to verify the robustness of candidate biomarkers.RESULTS: A total of 26 differentially abundant endogenous metabolites were identified in H_T2DM patients relative to the other three groups, with 18 metabolites significantly upregulated and 8 downregulated. Pipecolic acid, lauric acid, guanosine, and kaempferol were identified as potential early biomarkers for high-altitude diabetes, collectively achieving a prediction accuracy of 92%. These biomarkers were linked to core metabolic pathways including lysine degradation, fatty acid biosynthesis, and purine metabolism. Multicenter validation further confirmed guanosine as the most robust and altitude-specific biomarker for T2DM.DISCUSSION: Our comprehensive metabolomic analysis reveals distinct metabolic perturbations in T2DM patients under high-altitude conditions, highlighting guanosine as a unique biomarker for identifying altitude-related diabetic metabolic dysregulation. These findings advance our understanding of the pathophysiological mechanisms underlying T2DM in high-altitude environments and provide a potential diagnostic target for clinical management of diabetic populations in such regions.PMID:41767400 | PMC:PMC12935616 | DOI:10.3389/fendo.2026.1736270

Front Endocrinol (Lausanne). 2026 Feb 13;17:1754743. doi: 10.3389/fendo.2026.1754743. eCollection 2026.ABSTRACTOBJECTIVE: Diabetic foot ulcers (DFU) are a severe complication with high amputation and mortality rates, involving profound metabolic dysregulation. Current treatments lack interventions targeting the metabolic microenvironment. Chenodeoxycholic acid (CDCA) regulates glucose/lipid metabolism and inflammation, but its role in DFU remains unknown. This study aims to identify key metabolites in the serum of patients with diabetic foot ulcers. For the first time, it focuses on and identifies CDCA, a key bile acid, as an endogenous protective factor, and validates the biological role of CDCA in promoting wound healing, thereby providing a foundation for novel therapeutic strategies targeting the "metabolic microenvironment."METHODS: Untargeted metabolomics (UHPL-MS/MS) was performed on serum from 18 healthy controls, 18 diabetes mellitus (DM) patients, and 18 DFU patients. Multivariate statistics and logistic regression were used to identify differential metabolites and protective factors. In vitro, human skin fibroblasts under high glucose (30 mM) were treated with CDCA (5-25 nM). Proliferation, migration, and repair gene expression were assessed.RESULTS: Clinical evaluation revealed that DF patients exhibited more pronounced systemic inflammation (elevated hs-CRP, ESR, and WBC), coagulation abnormalities (increased fibrinogen and D-dimer levels), and higher prevalence of vascular complications compared to other groups. Metabolomic analysis identified 41 significantly altered metabolites between the DM and DF groups, among which CDCA was markedly downregulated in the DF group (fold change = 0.66, VIP = 2.09, P = 0.008). Logistic regression analysis confirmed CDCA as an independent protective factor against DFU (OR = 0.429, 95% CI: 0.225-0.815, P = 0.010). In vitro studies demonstrated that CDCA dose-dependently reversed high glucose-induced impairment of HSF function, significantly enhancing cell proliferation and migration, and upregulating mRNA expression of PCNA, α-SMA, and Vimentin.CONCLUSION: This study identifies CDCA as a key protective metabolite in DF. Reduced serum CDCA levels are independently associated with increased risk of DF. Functional evidence confirms that CDCA mitigates high glucose-induced fibroblast dysfunction and promotes wound repair processes. Targeting the CDCA signaling pathway or supplementing CDCA may represent a novel therapeutic strategy for DF by remodeling the "metabolic microenvironment".PMID:41767398 | PMC:PMC12945834 | DOI:10.3389/fendo.2026.1754743

iScience. 2026 Feb 5;29(3):114916. doi: 10.1016/j.isci.2026.114916. eCollection 2026 Mar 20.ABSTRACTUbiquitin-specific protease 5 (USP5) is frequently overexpressed in lung adenocarcinoma (LUAD) and correlates with advanced stage and poor prognosis. This study demonstrates that USP5 binds directly to CD73 and removes K48-linked polyubiquitin chains, thereby blocking its proteasomal degradation and increasing CD73 protein stability. In contrast, the E3 ligase tripartite motif-containing protein 28 (TRIM28) promotes CD73 ubiquitination and turnover. Functionally, USP5 enhances LUAD cell proliferation, migration, invasion, and tumor growth in vivo in a CD73-dependent manner. Metabolomic profiling and Seahorse assays reveal that the USP5/CD73 axis activates PI3K/AKT/mTOR signaling and drives glycolytic reprogramming, augmenting lactate production. Moreover, this axis contributes to acquired resistance to osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI); combined inhibition of USP5 and osimertinib synergistically induces apoptosis and suppresses tumor growth in vitro and in vivo. These findings establish USP5-mediated stabilization of CD73 as a central mechanism underlying glycolytic metabolism and osimertinib resistance in LUAD, highlighting the USP5/CD73 pathway as a promising prognostic indicator and therapeutic target for LUAD treatment.PMID:41767275 | PMC:PMC12936848 | DOI:10.1016/j.isci.2026.114916

Front Psychiatry. 2026 Feb 13;17:1736206. doi: 10.3389/fpsyt.2026.1736206. eCollection 2026.ABSTRACTMental disorders remain diagnosed primarily through symptom-based classification systems that overlook biological heterogeneity, preventing the identification of mechanistically distinct patient subgroups and precluding pathophysiology-guided treatment selection. Metabolomics offers a promising pathway towards precision psychiatry by capturing dynamic biochemical readouts at the functional endpoint of the omics cascade, integrating genetic, environmental, and pharmacological influences on cellular metabolism. Over the past 15 years, untargeted and targeted metabolomics studies using nuclear magnetic resonance spectroscopy and mass spectrometry have identified consistent patterns of metabolic dysregulation across psychiatric disorders, particularly involving amino acid metabolism, lipid signaling, energy homeostasis, and oxidative stress pathways. Schizophrenia presents disruptions in arginine and proline metabolism, glutathione metabolism, and energy-related processes. Bipolar disorder shows perturbations in branched-chain and aromatic amino acids, kynurenine pathway, and tricarboxylic acid cycle dysfunction with phase-specific metabolic signatures. Major depressive disorder exhibits widespread alterations in amino acid turnover, bioenergetic processes, membrane lipid homeostasis, and glutamate-GABA cycling, with treatment-responsive metabolic changes. Despite these advances, substantial challenges remain: heterogeneous findings with disorder overlap, limited replication cohorts, predominance of cross-sectional designs, confounding by medication and lifestyle factors, pre-analytical variability, and high-dimensional data complexity. Future research requires harmonized multi-site protocols, longitudinal validation studies, multi-platform analytical approaches, integration with genomics, proteomics, and digital phenotyping, and implementation of artificial intelligence frameworks to enhance phenotype discrimination and predictive accuracy. In this mini-review, we provide an overview of current methodologies, major findings, strengths, challenges, and emerging directions in psychiatric metabolomics, with the goal of facilitating the translation of metabolomic insights into clinically applicable, personalized psychiatric treatment.PMID:41767152 | PMC:PMC12946017 | DOI:10.3389/fpsyt.2026.1736206

Front Immunol. 2026 Feb 6;17:1682589. doi: 10.3389/fimmu.2026.1682589. eCollection 2026.ABSTRACTBACKGROUND: Oral lichen planus (OLP) is a chronic T-cell-mediated inflammatory disorder of unknown etiology. Accumulating evidence has demonstrated elevated cholesterol levels in OLP, and its oxidation products --oxysterols have been implicated in T cell dysfunction. However, whether the oxysterol is involved in OLP pathogenesis remains to be fully elucidated.METHODS: Metabolomics was performed to profile oxysterols in the plasma of OLP patients, followed by functional enrichment analysis. Single-cell RNA sequencing was utilized to characterize gene expression dysregulation in tissue-resident T cells isolated from OLP lesions. Flow cytometry, immunofluorescence, and qRT-PCR were collectively used to quantify Ca2+ concentration, cell apoptosis, protein expression, intracellular signaling, and gene transcription levels. Functional validation was conducted through a co-culture model and Transwell migration assays to assess the cytotoxic and migratory capacity of OLP T cells.RESULTS: The oxysterol profiles were aberrant in OLP plasma, with marked accumulation of 7-ketocholesterol (7KC). Functional analysis identified significant enrichment of differential metabolites in androstenedione metabolism. 7KC upregulated the expression of cholesterol regulators (SREBP2/LXR) in OLP T cells. Pro-7-ketocholesterogenic gene sets were dysregulated in OLP tissues, with localized T cells exhibiting enriched Ca2+ -NFATc1 signaling and coordinated F-actin polymerization/ITGAL (LFA-1α) upregulation, positively correlating with migration signatures. Peripheral OLP T cells showed elevated Ca2+, nuclear NFATc1, F-actin polymerization, and LFA-1α, all of which, along with ITGAL/IL1B/CCL4/IL6 levels, were further potentiated by 7KC treatment. 7KC was confirmed to enhance migrations of primary OLP T cells and OLP plasma-pretreated Jurkat T cells toward LPS-treated keratinocytes, without affecting keratinocyte apoptosis. Furthermore, CM4620-mediated blockade of Ca2+ -NFATc1 pathway in OLP T cells inhibited 7KC-induced NFATc1 activation, reduced the expressions of F-actin and its modulators ACTB/DIAPH1, and IL1B/CCL4/IL6 gene expressions, with migration suppressions of both primary OLP T cells and OLP plasma-pretreated Jurkat T cells.CONCLUSIONS: 7KC could promote T cell migration through Ca2+ -NFATc1 pathway-mediated F-actin polymerization and expression of IL1B/CCL4/IL6 in OLP.PMID:41766904 | PMC:PMC12946749 | DOI:10.3389/fimmu.2026.1682589

Aquac Nutr. 2026 Feb 27;2026:9336162. doi: 10.1155/anu/9336162. eCollection 2026.ABSTRACTViral diseases represent one of the major threats to the global aquaculture industry. In recent years, the relationship between gut microbiota and viral infections in fish has garnered increasing attention. The gut microbiota contributes critically to fish health and is involved in antiviral defense through immune regulation, secretion of microbial metabolites, as well as enhancement of barrier function. The gut microbiota, host immunity, and viral infection form a complex and dynamic interaction network. A substantial body of 16S rRNA and metabolomics correlation studies has indicated that viral infections can alter the gut microbiota in fish, while changes in the gut microbiota can, in turn, influence viral infection. In this review, we summarize the regulatory effects of gut microbiota on fish viral infections, explore the interactions between the gut microbiota, immune system, and viral pathogenesis, and discuss future research directions and potential application prospects. By outlining the three-dimensional interaction network of "microbiota-immune-virus" in fish, this review not only lays a theoretical foundation for developing targeted microecological strategies for green disease control but also provides an evolutionary perspective for understanding host-microbe coevolution in vertebrates.PMID:41766780 | PMC:PMC12948727 | DOI:10.1155/anu/9336162