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Experimental design 1 (ED1) Ten-week-old C57BL/6 mice on normal diet were placed on GFD 1 day before the experiment and fasted for 1 h prior to administration to minimise gastrointestinal content interference

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Abbreviations Abcc5: ABC transporter C family member 5 ADAMTS5: A disintegrin and metalloproteinase with thrombospondin motifs 5 Adcyap1R1: Pituitary adenylate cyclase-activating polypeptide type I receptor AHR: Aryl hydrocarbon receptor ANGPTL3: Angiopoietin-related protein 3 AI: Artificial Intelligence AUC: Area Under the ROC curve ApoA-IV: Apolipoprotein A-IV ApoC-II: Apolipoprotein C-II APOE: Apolipoprotein E APOH: Apolipoprotein H ATIII: Antithrombin-III BAG5: BAG family molecular chaperone regulator 5 BDNF: Brain-derived neurotrophic factor BERT: Bidirectional Encoder Representations from Transformers BHLHE22: Class E basic helix-loop-helix protein 22 BTN3A3: Butyrophilin subfamily 3 member A3 CAMK2A: Calcium/calmodulin-dependent protein kinase type II subunit alpha CARTPT: Cocaine- and amphetamine-regulated transcript protein CCK: Cholecystokinin CDK: Cyclin-dependent kinase Cfb: Complement factor B CFI: Complement factor I CGANs: Conditional Generative Adversarial Networks CpG: Cytosine-phosphate-Guanine CpGs: Cytosine-phosphate-Guanines CLEC4A: C-type lectin domain family 4 member A CMS: chronic mild stressed CNNs: convolutional neural networks CNTNAP4: Contactin-associated protein-like 4 COL1A2: Collagen alpha-2(I) chain CORT: corticosterone COX5B: Cytochrome c oxidase subunit 5B CREB: cAMP response element-binding protein CRP: C-reactive protein CRS: chronic restraint stress CSDS: chronic social defeated stress CUMS: chronic unpredictable mild stress CVS: chronic variable stress DBNL: Drebrin-like protein DBN1: Drebrin DEFB1: Beta-defensin 1 DEGs: differentially expressed genes DIA: Data Independent Acquisition DNMT: DNA methyltransferase DNMT1: DNA (cytosine-5)-methyltransferase 1 DRL: deep reinforcement learning ECG: electrocardiogram EFNA5: Ephrin-A5 EGF: Epidermal growth factor EHRs: electronic health records EPHA4: Ephrin type-A receptor 4 EPHB4: Ephrin type-B receptor 4 ESR1: Estrogen Receptor 1 ESR2: Estrogen Receptor 2 EWAS: epigenome-wide association study FGFR1: Fibroblast growth factor receptor 1 FGF21: Fibroblast growth factor 21 FISH: fluorescence in situ hybridization FNDC3B: Fibronectin type III domain-containing protein 3B FOXO1: Forkhead box protein O1 FSMKL: Multiple Kernel Learning with Feature Selection GANs: generative adversarial networks GAPDH: Glyceraldehyde-3-phosphate dehydrogenase GC: gas chromatography GC-MS: gas chromotography/mass spectrometry GEO: Gene Expression Omnibus GHSR: Growth hormone secretagogue receptor type 1 GO: Gene Ontology Gpc3: Glypican-3 GPR173: Probable G-protein coupled receptor 173 GPT: Generative Pre-trained Transformer GRIA4: Glutamate receptor 4 GRUs: Gated Recurrent Units GWAMA: genome-wide association meta-analyses GWAS: genome wide association study HACE1: HECT Domain and Ankyrin Repeat Containing E3 Ubiquitin Protein Ligase 1 HAMD: Hamilton Depression Scale HBA: Hemoglobin subunit alpha HBEGF: Heparin-binding EGF-like growth factor HILIC-MS: liquid chromatography-mass spectrometry HOMER1: Homer protein homolog 1 HPA: hypothalamic-pituitary-adrenal HPLC-MS: high performance liquid chromatography and mass spectrum HSP90AA1: Heat shock protein HSP 90-alpha HTS: high-throughput screening IGFBP1: Insulin-like growth factor-binding protein 1 IL-1: interleukin-1 IL-6: interleukin-6 IL8: Interleukin-8 ISS: in situ sequencing ITIH1: Inter-alpha-trypsin inhibitor heavy chain H1 ITIH4: Inter-alpha-trypsin inhibitor heavy chain H4 iTRAQ: isobaric tags for relative and absolute quantitation KEGG: Kyoto Encyclopedia of Genes and Genomes KRT23: Keratin, type I cytoskeletal 23 LC: liquid chromatography LC-MS: liquid chromatography mass spectrometry LC-MS/MS: liquid chromatography-tandem mass spectrometry LC-TOFMS: LC-time-of-flight mass spectrometry LHPP: Phospholysine phosphohistidine inorganic pyrophosphate phosphatase LIN28B: Protein lin-28 homolog B LLD: late-life depression Lmx1b: LIM homeobox transcription factor 1-beta LRFN5: Leucine-rich repeat and fibronectin type-III domain-containing protein 5 LRG: Leucine-rich alpha-2-glycoprotein LSTM: Long Short-Term Memory LSTMs: Long Short-Term Memorys L1CAM: Neural cell adhesion molecule L1 L3MBTL2: Lethal(3)malignant brain tumor-like protein 2 MALDI-TOF MS: matrix-assisted laser desorption ionization time of flight mass spectrometry MALDI-TOF-MS/MS: matrix-assisted laser desorption ionization-time of flight-tandem mass spectrometry MALDI-TOF/TOF MS: matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight tandem mass spectrometry MAOIs: monoamine oxidase inhibitors MAPK1: Mitogen-activated protein kinase 1 MDD: major depressive disorder MEF2C: Myocyte-specific enhancer factor 2C MHC: Myosin heavy chain MIF: Macrophage migration inhibitory factor MLC1: megalencephalic leukoencephalopathy with subcortical cysts 1 MLF1: Myeloid leukemia factor 1 MMP-9: Matrix metalloproteinase-9 MOLI: MultiOmics Factor Analysis MPC: model predictive control MPO: Myeloperoxidase MRM-MS: targeted proteomic approach, Multiple reaction monitoring-mass spectrometry MRPL46: Large ribosomal subunit protein mL46 MS: mass spectrometry Mt1: Metallothionein-1 MWAS: Methylome-wide association study MYH9: Myosin-9 MYO16: Unconventional myosin-XVI MYRF: Myelin regulatory factor NB: Naive Bayes NCAM1: Neural cell adhesion molecule 1 NCOA2: Nuclear receptor coactivator 2 NECAB2: N-terminal EF-hand calcium-binding protein 2 NEGR1: Neuronal growth regulator 1 NEMO: NEighborhood based Multi-Omics clustering NF-B: nuclear factor B NGS: next-generation sequencing NLP: natural language processing NMF: Non-negative Matrix Factorisation NMR: nuclear magnetic resonance NMT: neural machine translation NPY: Pro-neuropeptide Y NRCAM: Neuronal cell adhesion molecule NRXN3: Neurexin-3-beta NTRK3: NT-3 growth factor receptor OGDH: 2-oxoglutarate dehydrogenase complex component E1 OLFM4: Olfactomedin-4 PACAP: pituitary adenylate cyclase-activating polypeptide PCA: Principal Component Analysis PDCD6IP: Programmed cell death 6-interacting protein PDE3A: cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A PFC: prefrontal cortex PFN1: Profilin-1 PHLD: Phloroglucinol synthase PHQ-9: Patient Health Questionaire-9 PLSCR1: Phospholipid scramblase 1 PPARA: Peroxisome proliferator-activated receptor alpha PPARGC1A: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha PPT: 20(S)-protopanaxatriol PPTC7: Protein phosphatase PTC7 homolog PPI: proteinprotein interaction PRDM1: PR domain zinc finger protein 1 PRDX2: Peroxiredoxin-2 PRKACA: cAMP-dependent protein kinase catalytic subunit alpha PRKRA: Interferon-inducible double-stranded RNA-dependent protein kinase activator A PROK2: Prokineticin-2 PROX2: Prospero homeobox protein 2 PRS: polygenic risk scores PSDF: Patient-Specific Data Fusion PSMB4: Proteasome subunit beta type-4 PYHIN1: Pyrin and HIN domain-containing protein 1 P2RX7: P2X purinoceptor 7 qPCR: Quantitative real-time polymerase chain reaction OR8B4: Olfactory receptor 8B4 R-CNN: Region-based Convolutional Neural Network REST: RE1-silencing transcription factor RF: random forest RGS2: Regulator of G-protein signaling 2 rMKL-LPP: regularised multiple kernel learning for Locality Preserving Projections RNF150: RING finger protein 150 RNNs: recurrent neural networks ROBO1: Roundabout homolog 1 RPLC-MS: reversed-phase liquid chromatography-mass spectrometry RPN: Region Proposal Network Rps12: Small ribosomal subunit protein eS12 Rps4x: Small ribosomal subunit protein eS4 RTN1: Reticulon-1 RUNX1: Runt-related transcription factor 1 SAA1: Serum amyloid A-1 protein SCFAs: short-chain fatty acids SCN9A: Sodium channel protein type 9 subunit alpha SDP-SVM: Semi-Definite Programming SVM SEMA7A: Semaphorin-7A SERPINH1: Serpin H1 SDHA: Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial SHANK2: SH3 and multiple ankyrin repeat domains protein 2 SLC12A5: Solute carrier family 12 member 5 SLC6A15: Sodium-dependent neutral amino acid transporter B(0)AT2 SLC6A4: Sodium-dependent serotonin transporter SLC7A8: Large neutral amino acids transporter small subunit 2 SLIT2: Slit homolog 2 protein SMS: shotgun metagenomics sequencing SNF: Similarity Network Fusion SNPs: single nucleotide polymorphisms SNVs: whole-genome single nucleotide variants SpaMV: Spatial Multi-View SPATA31D1: Spermatogenesis-associated protein 31D1 SSRIs: selective serotonin reuptake inhibitors STAT3: Signal transducer and activator of transcription 3 STK32C: Serine/threonine-protein kinase 32C SVM: Support Vector Machines TCM: traditional Chinese medicine TCMSP: Traditional Chinese Medicine Systems Pharmacology Database TCF4: Transcription factor 4 TGGR: total ginsenoside ginseng root TIMP4: Metalloproteinase inhibitor 4 TMCO5A: Transmembrane and coiled-coil domain-containing protein 5A TMEM161B: Transmembrane protein 161B TMSB4X: Thymosin beta-4 TMT: Tandem Mass Tag TNF-: tumor necrosis factor- TNRC6B: Trinucleotide repeat-containing gene 6B protein TRAPPC11: Trafficking protein particle complex subunit 11 TRMT10C: tRNA methyltransferase 10 homolog C TRPV2: Transient receptor potential cation channel subfamily V member 2 TSLP: Thymic stromal lymphopoietin Tuba1b: Tubulin alpha-1B chain TWAS: transcriptome-wide association study Uba1: Ubiquitin-activating enzyme E1 1 UCH-L1: Ubiquitin carboxyl-terminal hydrolase isozyme L1 UCN2: urocortin 2 UGBBP: Ulm Gene Brain Behavior Project UFLC/MS-IT-TOF: fast liquid chromatography coupled with ion trap-time of flight mass spectrometry UFLC/Q-TOF-MS: ultra-fast liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry UHPLC-MS: ultra high-performance liquid chromatography-mass spectrometry UHPLC-QTOF-MS: ultra-high performance liquid chromatography quadrupole/time of flight-mass spectrometry UPLC-MS/MS: ultra performance liquid chromatography tandem mass spectrometry UPLC-QTOF-MS: ultra-performance liquid chromatography quadrupole/time of flight-mass spectrometry UPLC-QQQ-MS/MS: ultra-high-performance liquid chromatography-tandem quadrupole mass spectrometry VAMP-2: Vesicle-associated membrane protein 2 WDR26: WD repeat-containing protein 26 WGBS: Whole-genome bisulfite sequencing WGS: whole-genome sequencing WWOX: WW domain-containing oxidoreductase XAI: Explainable AI XGBoost: extreme gradient boosting YOLO: You Only Look Once ZBTB16: Zinc finger and BTB domain-containing protein 16 Zmynd11: Zinc finger MYND domain-containing protein 11 ZNF184: Zinc finger protein 184 ZNF248: Zinc finger protein 248 ZNF713: Zinc finger protein 713 ZNF804A: Zinc finger protein 804A 2-DE: proteomes by two-dimensional electrophoresis 5-HT: 5-hydroxytryptamine References Chen Y, et al

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