MetaboLights

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metabolites were annotated using the KEGG database(https://www.genome.jp/kegg/pathway.html), HMDB database (https://hmdb.ca/metabolites) and LIPIDMaps database (http://www.lipidmaps.org/). Principalcomponents analysis (PCA) and Partial least squares discriminant analysis (PLS-DA)were performed at metaX[6] (a flexible and comprehensive software for processingmetabolomics data).We applied univariate analysis (t-test) to calculate the statisticalsignificance (P-value).The metabolites with VIP > 1 and P-value< 0.05 and foldchange≥2 or FC≤0.5 were considered to be differential metabolites. Volcano plotswere used to filter metabolites of interest which based on log2(FoldChange) and-log10(p-value) of metabolites by ggplot2 in R language.MetaboLightsPublicLiquid Chromatography MS - positive - hilicLiquid Chromatography MS - negative - hilicUHPLC-MS/MS analyses were performed using a Vanquish UHPLC system(ThermoFisher, Germany) coupled with an Orbitrap Q ExactiveTM HF massspectrometer or Orbitrap Q ExactiveTMHF-X mass spectrometer (Thermo Fisher,Germany) in Novogene Co., Ltd. (Beijing, China). Samples were injected onto aHypersil Goldcolumn (100×2.1 mm, 1.9μm) using a 12-min linear gradient at a flowrate of 0.2 mL/min. The eluents for the positive and negative polarity modes wereeluent A (0.1% FA in Water) and eluent B (Methanol). The solvent gradient was setas follows: 2% B, 1.5 min; 2-85% B, 3 min; 85-100% B, 10 min; 100-2% B, 10.1 min; 2% B,, 12 min.Multi-omics analysis identifies gut microbiota-glutamine axis contributing to the pathogenesis of reflux esophagitis.Zhiyi Zhangbeijing children's hospitalserummass spectrometry assayThe samples (100 μL) were placed in the EP tubes and resuspended with prechilled 80%methanol by well vortex. Then the samples were incubated on ice for 5 min andcentrifuged at 15,000 g, 4°C for 20 min. Some of supernatant was diluted to finalconcentration containing 53% methanol by LC-MS grade water.The samples weresubsequently transferred to a fresh Eppendorf tube and then were centrifuged at15000 g, 4°C for 20 min. Finally, the supernatant was injected into the LC-MS/MSsystem analysisHomo sapienshttps://www.ebi.ac.uk/metabolights/MTBLS14421Qi Zhang. Tianjin Medical University Affiliated Nankai Hospital. zhangqi@tmu.edu.cn.Jing Xun. Tianjin Medical University Affiliated Nankai Hospital. zhiyi_zhang1@163.com.The raw data files generated by UHPLC-MS/MS were processed using the CompoundDiscoverer 3.3 (CD3.3, ThermoFisher) to perform peak alignment, peak picking, andquantitation for each metabolite. The main parameterswere set as follows:peak areawas corrected with the first QC, actual mass tolerance, 5ppm; signal intensitytolerance, 30%; and minimum intensity, et al. After that, peak intensities werenormalized to the total spectral intensity.The normalized data was used to predict themolecular formula based on additive ions, molecular ion peaks and fragment ions.And then peaks were matched with the mzCloud (https://www.mzcloud.org/), mzVault and MassList database to obtain the accurate qualitative and relativequantitative results.Statistical analyses were performed using the statistical software R(R version R-3.4.3), Python (Python 2.7.6 version) and CentOS (CentOS release 6.6),When data were not normally distributed, standardize according to the formula:sample raw quantitation value / (The sum of sample metabolite quantitation value /The sum of QC1 sample metabolite quantitation value ) to obtain relative peak areas; And compounds whose CVs of relative peak areas in QC samples were greater than30% were removed, and finally the metabolites' identification and relativequantification results were obtained.Treatmentzhiyi_zhang1@163.comThe serum of patients and healthy volunteers were sampled at Tianjin Nankai Hospital and sent to an external company for untargeted metabolomics analysis.MetabolomicsThermo Scientific Vanquish UHPLC SystemMetabolomicsD-glutamine and D-glutamate metabolic pathwayEsophagitis, Pepticuntargeted analysisGastrointestinal MicrobiomeHomo sapiensexperimental blankglutamineThermo Scientific Q Exactive HFserumNeuroimmunomodulationThermo Scientific Vanquish UHPLC SystemMetabolomicsD-glutamine and D-glutamate metabolic pathwayEsophagitis, Pepticuntargeted analysisGastrointestinal MicrobiomeHomo sapiensexperimental blankglutamineThermo Scientific Q Exactive HFserumNeuroimmunomodulationQ ExactiveTM HF mass spectrometer was operated in positive/negativepolarity mode with spray voltage of 3.5 kV, capillary temperature of 320°C, sheathgas flow rate of 35 psi and aux gas flow rate of 10 L/min, S-lens RF level of 60, Auxgas heater temperature of 350°C.CAR 5:02-morpholino-1-phenyl-1-ethanolCorticosteroneProstaglandin G24-heptyl-3-methyl-1H-pyrazol-5-olPhenylacetylglutaminePC 16:1_17:2Monolaurin13(S)-HOTrEWLH8-Aminooctanoic acidDG 18:2_18:2Methyl nicotinateKinetin1-(3,4-dimethoxyphenyl)ethan-1-one oximePC O-32:2XLR11 N-(4-hydroxypentyl) metabolite-d5L-HistidineIsobutyryl carnitinePC 19:2_20:5LPC 16:0-SN1Cholest-4-en-3-oneNormorphine2-Arachidonoyl glycerolSM 8:1;2O/28:71-[(3,5-dimethylisoxazol-4-yl)sulfonyl]piperidineD-Sphingosine2,3-Dinor-TXB24-methylphenyl 1-ethyl-3-methyl-1H-pyrazole-5-carbothioate3-[(4-chlorophenyl)thio]-1-phenylprop-2-en-1-one3-(4-methoxyphenyl)-1-methyl-1H-1,2,4-triazol-5-olN-[1-(4-methoxy-2-oxo-2H-pyran-6-yl)-2-methylbutyl]acetamideLaudanosineMethyl indole-3-acetateethyl 2-amino-2-phenylacetate hydrochlorideSildenafil N-oxide3-(5,7-dimethoxy-4-oxo-4H-chromen-2-yl)propanoic acid4-bromo-3-[({[(methylamino)carbonyl]oxy}imino)methyl]-1H-pyrazoleHexanoylcarnitineN1-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2,2-dimethylpropanamideL-lysine8,8-dimethyl-2H,8H-pyrano[3,2-g]chromen-2-oneProstaglandin E1PC 15:0_16:2PC 15:0_16:0WNKPyridoxamine 5-phosphate3-(propan-2-yl)-octahydropyrrolo[1,2-a]pyrazine-1,4-dione2-hydroxy-6-[(8Z,11Z)-pentadeca-8,11,14-trien-1-yl]benzoic acidBoldione5'-Adenylic acid2-oxa-4-azatetracyclo[6.3.1.1~6,10~.0~1,5~]tridecan-3-oneMethyltestosterone6-MethylquinolineFMKTetrahydrocorticosteroneOxohongdenafilD-(+)-Maltose1-(4-hydroxyphenyl)propane-1,2-diolOmeprazole sulphoneN-(4-piperidinophenyl)benzamideFNHVindolinePC 16:4_18:53-hydroxy-2-octylpentanedioic acid5-fluoro AB-PINACA N-(4-hydroxypentyl) metaboliteIrganox 259L-OrnithineD-Glucosamine 6-phosphatePC 30:7_30:84-amino-1-(2-furylmethyl)-6-hydroxy-1,2-dihydropyrimidine-2-thione5,6-dimethyl-4-oxo-4H-pyran-2-carboxylic acid5-Fluoro-2-[(3S)-1-(2-fluorobenzyl)-3-pyrrolidinyl]-1H-benzimidazolePE O-17:1_20:4N-FormylkynureninePC 8:0_9:0NeosaxitoxinS-LactoyglutathioneEthyl chrysanthemumateCAR 18:2CAR 18:1OxaceprolMelicopidineCAR 18:0methyl 4-oxo-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazine-2-carboxylateCAR 18:44-oxododecanedioic acid3-(3,4,5-trimethoxyphenyl)propanoic acidPE 18:2_18:2Mupirocin16,16-Dimethyl prostaglandin A2SM 8:1;2O/40:10(12Z)-9,10,11-trihydroxyoctadec-12-enoic acid5-Henicosyl-1,3-benzenediol2-PhenylglycineWampetin4-(pentyloxy)benzene-1-carbohydrazideSulfaquinoxaline16,16-Dimethyl prostaglandin A1FPH4,4'-dimethoxy[1,1'-biphenyl]-2-carbonitrileFPKDLKIndoleN-(5-Aminopentyl)acetamidePC 17:1_18:2Prostaglandin A22-(methylthio)-5-[(5-nitro-1,3-thiazol-2-yl)thio]-1,3,4-thiadiazoleBenzamideLPC 24:0-SN1Prostaglandin A3DL-Arginine4-(2,3-dihydro-1,4-benzodioxin-6-yl)butanoic acidDL-3,4-Dihydroxyphenyl glycolL-CarnitineZeatin-7-N-glucoside4,6,8-trihydroxy-7-methoxy-3-methyl-3,4-dihydro-1H-2-benzopyran-1-oneVardenafil N-oxideSM 8:1;2O/28:2o-CresolSM 8:1;2O/28:113-OxoODESM 8:1;2O/28:0beta-Nicotinamide mononucleotideAdenosinePC 40:6PC O-38:10Prostaglandin B22-Hydroxycinnamic acid23-Norcholic acidNoroxycodone-d3SM 14:3;2O/9:02-(14,15-Epoxyeicosatrienoyl) glycerolD-Erythrose 4-phosphate2-[5-(2-hydroxypropyl)oxolan-2-yl]propanoic acidFRHSM 8:1;2O/17:2CitralCAR 7:04-Hydroxyretinoic AcidL-Phenylalanine5,6-diphenyl-2,3-dihydropyrazineAla-LeuTraumatic acidPC O-36:5LPE 20:2PC O-36:4PC O-36:7N'3-(3,4,5-trimethoxybenzylidene)pyridine-3-carbohydrazidePC O-36:6tert-Butyl N-[1-(aminocarbonyl)-3-methylbutyl]carbamatePC O-36:8PC(16:0/16:0)MinocyclinePC 16:0_17:0PC 16:0_17:2PC 16:0_17:1PC O-36:3PC O-36:2gamma-GlutamylleucineS-Sulfo-L-cysteineTetrahydrocortisoneCAR 16:1ThreonineEpitestosterone glucuronideSorbic acidLPC 36:2-SN1L-Cystathionine12,13-EODE11-dehydro Thromboxane B2DL-TryptophanLPC 22:5-SN1Cyclopentyl fentanyl-d5GuaninePC O-14:0Taurolithocholic acidCiticolineL-serine6-(3-hydroxybutan-2-yl)-5-(hydroxymethyl)-4-methoxy-2H-pyran-2-onePC 18:1_19:23-(4-hydroxy-3-methoxyphenyl)propanoic acidDRHCAR 9:1D-(+)-TryptophanOleoyl ethylamidebicyclo[2.2.2]oct-2-en-1-yl 4-methylbenzene-1-sulfonate2-[(3S)-1-Cyclobutyl-3-pyrrolidinyl]-1H-benzimidazole-5-carbonitrileProstaglandin K2GalanginN'2-cinnamoyl-3-(1H-pyrrol-1-yl)thiophene-2-carbohydrazideTauroursodeoxycholic acidPipecolic acidIndole-3-acrylic acidPC O-34:6PC O-34:9PC O-34:0PC O-34:3PC O-34:2PC 16:0_19:2PC O-34:511-KetoetiocholanolonePC O-36:10Asp-Phe2-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one(2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(2-phenylethoxy)oxane-3,4,5-triolPC 19:1_19:12-{[(4,5-dimethoxy-2-nitrophenethyl)imino]methyl}phenol2-(2-oxo-2-{[2-(2-oxo-1-imidazolidinyl)ethyl]amino}ethoxy)acetic acidMonobutyl phthalateCafestol1,4-dihydroxy-1,4-dimethyl-7-(propan-2-ylidene)-decahydroazulen-6-one5-hydroxy-2-phenyl-4H-chromen-4-oneLPC 22:6-SN2LPC 22:6-SN1(2R)-5-hydroxy-7-methoxy-2-phenyl-3,4-dihydro-2H-1-benzopyran-4-onePC O-12:0¦Â-AsaroneCholecalciferol4-(4-chlorophenoxy)-3,5-dimethyl-1H-pyrazoleN-benzoyl-N'-(2-chlorophenyl)thiourea(3R)-4,4-Dimethyl-2-oxotetrahydro-3-furanyl beta-D-glucopyranosideOleoyl-L-alpha-lysophosphatidic acidDiethyl maleate(4-benzoylpiperidino)[4-(tert-butyl)phenyl]methanonePC 18:1_17:24-HydroxyisoleucineEthyl myristateaminoimidazole carboxamide ribonucleotideSinomenineCoenzyme Q24-(2,4-dichlorophenoxy)-3-methyl-4,5-dihydro-1H-pyrazol-5-one3-Hydroxy-3-methylbutanoic acidN1-pyrazin-2-yl-4-chlorobenzamidePE O-16:1_22:4PC 17:0_17:0PC 17:0_17:1Andrographolide3-(5-phenyl-1,3-oxazol-2-yl)-4-(trifluoromethyl)pyridineLSD-d3Chlorogenic Acid Methyl EsterFebuxostat5,8-dihydroxy-10-methyl-5,8,9,10-tetrahydro-2H-oxecin-2-oneCAR 12:05-Hydroxyindole-3-acetic acid1-benzyl-4-(4-nitrophenyl)piperazine(+/-)11(12)-EETCAR 12:3SM 9:1;2O/26:1Sildenafil-d3SM 8:1;2O/31:03-MethoxyflavonePC 20:2_20:2PC 20:2_20:3CryptotanshinoneArtemisininSM 9:1;2O/26:52,3-dihydroxypropyl 12-methyltridecanoateSM 9:1;2O/26:61-(3-ethyl-2,4-dihydroxy-6-methoxyphenyl)butan-1-oneSM 9:1;2O/26:7L-PalmitoylcarnitinePE O-20:2_20:5RhoifolinLPC 20:2-SN1PC O-18:0PC O-18:1PC O-18:2PC O-18:3Octanedioic acidOctopamineHomosildenafilOrlistat5-oxo-3-phenyl-5-(2-quinolinylamino)pentanoic acidN-{6-[4-(tert-butyl)phenoxy]-3-pyridinyl}-N'-(2-thienyl)ureagamma-TocopherolGlycitinCholesterolPyrogallolLevothyroxineTestosteroneO-DesmethylnaproxenSM 34:2;2OL-Kynurenineethyl 2-[(4-methyl-2-oxo-2H-chromen-8-yl)oxy]acetatePC 18:4_18:4CreatinePE O-16:1_20:5PC O-38:5(¡À)13-HpODEPE O-16:1_20:3PC O-38:4PC O-38:7PC O-38:6PC O-38:9NordiazepamPC O-38:86-chloro-3-[(dimethylamino)methylidene]chroman-4-one2-{[methyl(2,3,4,5,6-pentahydroxyhexyl)amino]methylidene}malononitrilePC 19:2_18:5(S)-Leucic acidPC 19:2_18:3PC 19:2_18:4LPC 16:0CAR 10:211-Deoxy prostaglandin F1¦ÁCAR 10:15-HydroxyomeprazoleN-acetyl-L-ornithineParaxanthineGluconolactoneIsorhapontigeninLysopc 14:05,7-dihydroxy-6-methoxy-2-phenyl-3,4-dihydro-2H-1-benzopyran-4-one3-(3,4-dimethylphenyl)-3,4-dihydro-1,2,3-benzotriazin-4-onePC 20:2_22:6SM 8:0;2O/12:0PC 36:43-Hydroxypicolinic acidSM 9:1;2O/28:4PC 36:5PC 36:35-amino-1-(4-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide2-MethoxybenzaldehydeDiacetoxyscirpenolLPC O-13:1PC O-16:0PC O-16:1LPC 20:3-SN14-HydroxytamoxifenKKKSM 15:3;2O/18:5Desmethyldoxepinethyl 4-methyl-2-(1H-pyrrol-1-yl)-1,3-thiazole-5-carboxylatePC 9:0_9:0LPC 22:4-SN1LPC O-24:1LPC O-24:2SM 12:2;2O/3:0L-(+)-CitrullineLysoPC 20:2N-(2,4-Dimethylphenyl)formamideUR-144 N-(2-hydroxypentyl) metabolitePC 36:10_38:10Sodium cholateStearamideTyramine2-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)benzonitrile(6E)-7-(2H-1,3-benzodioxol-5-yl)-1-(piperidin-1-yl)hept-6-en-1-oneSphingosine (d18:1)N-[methyl(oxo)phenyl-lambda~6~-sulfanylidene]-N'-phenylureaSedanolideGly-ValPC 42:5_44:124-Pregnen-17alpha,20alpha-Diol-3-OneAsp-Phe methyl esterPC O-40:5PC O-40:6SM 8:1;2O/35:0PC O-40:9PC O-40:7LPE 17:0PC O-40:83-(3-Methoxyphenyl)propionic acidPC 21:1_44:12CyclohexylsulfamateLPC 20:0-SN125-hydroxycholecalciferolP-Hydroxybenzaldehyde2-phenyl-2,4,6,7-tetrahydrothiino[4,3-c]pyrazol-3-olSM 8:1;2O/22:05-[(10Z)-14-(3,5-dihydroxyphenyl)tetradec-10-en-1-yl]benzene-1,3-diol6beta-Naltrexol-d34-Hydroxy-3-methylbenzoic acidLPC O-19:1PC 18:0_18:0Choline GlycerophosphateSM 8:1;2O/22:4LPC 26:4-SN1Luteolin2-Aminobenzenesulfonic acidCystamineDL-¦Á-Tocopherol12-Oxo phytodienoic acidAll-Trans-13,14-Dihydroretinol15-Deoxy-¦¤12,14-prostaglandin A1DiflorasoneSM 14:3;2O/7:0GemifloxacinDecanoylcarnitineCholinePE 17:1_17:1MGDG O-13:0_3:0KPH(5E)-7-methylidene-10-oxo-4-(propan-2-yl)undec-5-enoic acidAcetylcysteinePE O-18:1_20:44-(dimethylamino)-1,1-diphenylbut-3-en-2-onePE O-18:1_20:5PC 19:0_19:1SM 8:1;2O/26:77-MethylxanthinePC 18:2_19:23-Methoxycinnamic acidHomo-Gamma-Linolenic Acid (C20:3)Palmitoylcarnitine3-MethylindoleGlycyl-L-leucine3-[3-(beta-D-Glucopyranosyloxy)-2-methoxyphenyl]propanoic acidDiosgeninLysopc 18:3Lysopc 18:2Lysopc 18:1PC O-42:118-HydroxymirtazapinePC 32:1Lipoic acid9-benzyl-2,3,4,9-tetrahydro-1H-carbazol-4-oneLPC 26:3-SN1albiflorinThromboxane B1methyl 2-(2-acetyl-4,5-dimethoxyphenyl)acetateL-Argininosuccinate3-Oxo-7alpha,12alpha-hydroxy-5beta-cholanoic acidBitertanolDihydrothymineSM 8:1;2O/24:2LPC O-17:1SM 8:1;2O/24:1LPC O-17:05-Methoxyindole-3-CarbaldehydeDL-GlutaminePC 38:9_38:101-(3,4-dimethylphenyl)-3-piperidinopyrrolidine-2,5-dionePhosphocholineindoline-2-carboxylic acidpentane-1,2,3,4,5-pentolLysopc 16:2 (2N Isomer)5-(hydroxymethyl)-4-methoxy-2,5-dihydrofuran-2-oneacetoacetatelithocholic acid 3-sulfate4-(5-pentylpyrimidin-2-yl)benzonitrileo-VeratraldehydeMilbemycin A3 oximeEstroneSM 8:1;2O/13:1SM 8:1;2O/13:0LPC 20:1-SN113,14-Dihydro-15-keto Prostaglandin E2O-Phospho-L-serinealpha-Farnesene1-morpholino-3-(4-nitrophenoxy)propan-2-olPC O-20:0Riboflavin2-MethoxyresorcinolPC 18:1_20:5DeoxyinosineSM 9:1;2O/30:6SM 9:1;2O/30:7Gamma-Caprolactone2-[(3S)-1-(1H-Indol-3-ylmethyl)-3-pyrrolidinyl]-1H-benzimidazolemesaconic acid2-mercapto-4,6-dimethylnicotinonitrileLenalidomide3-amino-4-(propylamino)cyclobut-3-ene-1,2-dionePhenylglyoxylic acidAll trans-Retinal2-Anisic acidBiotinLDGCC 36:8DL-¦Á-Aminocaprylic acid5-HydroxypiroxicamD-RaffinoseMeconin5-trans prostaglandin F2¦Â¦Á-Aspartylphenylalanine2-MethylbutyroylcarnitineLPE 36:4LPC 20:5-SN1PC O-44:5PC O-44:6SM 8:1;2O/16:12-phenyl-4H-furo[2,3-h]chromen-4-oneN'2-acetylpyridine-2-carbohydrazidePC 16:1_16:1PC 16:1_16:2THCPC O-33:7ParacetamolGuanosine monophosphatePC 14:0_14:0(+/-)11(12)-DiHETPC O-33:0Estriol2-[(3S)-1-Benzyl-3-pyrrolidinyl]-1,3-benzothiazolePC O-33:4Aflatoxin G1N'-[4-(tert-butyl)phenyl]-N-cyclohexyl-N-methylureaCAR 19:1Corey Lactone DiolLysopc 20:4PC 17:2_17:2Lysopc 20:0Glyciteingamma-NonanolactoneAmitriptyline-d33'-O-MethylcytidinePC O-40:11PC 32:4_34:9PC O-40:103-[(3-chloro-4-hydroxy-5-methylanilino)methylidene]pentane-2,4-dioneLPC 18:1-SN1PC O-22:44-methyl-5-phenoxy-6-piperidino-2-(trifluoromethyl)pyrimidineGPHCinchophen2,4-dihydroxyheptadec-16-en-1-yl acetateTyrosylalanine13,14-dihydro-15-keto Prostaglandin A2N2-tetrahydrofuran-2-ylmethyl-4-(4-fluorophenyl)-1,3-thiazol-2-amineSM 9:1;2O/32:2VNHDL-Lysine(1E,4E)-1,5-bis(4-methoxyphenyl)penta-1,4-dien-3-one4-Methoxycinnamic acidSM 9:1;2O/32:7methyl 2-(benzoylamino)acetate1,7-bis(4-hydroxyphenyl)-5-methoxyheptan-3-one4,6-dimethyl-2,7-diphenyl-3,7-dihydro-2H-pyrazolo[3,4-b]pyridin-3-oneBoc-beta-cyano-L-alanine17¦Á-HydroxyprogesteroneBiliverdin2-(4,4-diphenyl-1-piperidinobuta-1,3-dienyl)phenyl acetateLPC 20:4-SN1SM 14:3;2O/8:0Palmitoyl sphingomyelinPC O-42:9Sulfamethazine1-MethylguaninePC O-42:3Spinosyn AN-Acetyl-DL-tryptophanPC O-42:5PC O-42:6D-Erythro-sphingosine 1-phosphateLPC 20:3HomotaurineArachidonoyl ethanolamide phosphateHydroxyprogesterone caproateProlinecGMPU-44069Acipimox2-[(3S)-1-(3,4-Difluorobenzyl)-3-pyrrolidinyl]-1,3-benzoxazoleO-Phospho-L-TyrosinePC 14:0_16:36-Keto-prostaglandin f1alpha2-(3-chloro-2-methylanilino)benzoic acid(2E)-6-hydroxy-2-methyl-6-(4-methylphenyl)hept-2-enoic acidEmetineFasciculic acid C6,7,8-trimethoxy-2-[3-(trifluoromethyl)phenyl]-4H-3,1-benzoxazin-4-one1,2-dihydroxyheptadec-16-yn-4-yl acetateLPC 18:0-SN1Indole-3-acetic acid3-methyl-5-oxo-5-(4-toluidino)pentanoic acid2-(2,6-dimethoxyphenyl)-5,6-dimethoxy-4H-chromen-4-onePC O-31:0D-¦Ä-Tocopherol7-alpha-carboxy-17-alpha-carboxyethylandrostan lactone phenyl esterL-Methionine Methyl Ester(2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(propan-2-yloxy)oxane-3,4,5-triolPC O-20:2PC 36:10_40:11PC O-20:4PC O-20:3PC O-20:5(-)-Caryophyllene oxidePhe-ProLPC 19:0-SN13-hydroxy-3-methylpentanedioic acid4-methoxy-6-(prop-2-en-1-yl)-2H-1,3-benzodioxoleTerephthalic Acidmethyl 4-methyl-2-oxo-2H-pyran-6-carboxylatePC 17:1_17:2gamma-Glutamyltyrosine4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoic acidPC 17:1_17:1N-(5-acetamidopentyl)acetamidemethyl 3,4,5-trihydroxycyclohex-1-ene-1-carboxylateSpermidinePC 18:2_20:5PC 18:2_20:3PC 18:0_20:5Meperidine-d5Valeryl fentanyl-d5Propionylcarnitine4-decyl-3-hydroxy-5-oxooxolane-2,3-dicarboxylic acidERHp-Mentha-1,3,8-trieneN1-{4-[(2-hydroxybenzoyl)amino]phenyl}-2-nitrobenzamideCAR 26:23-Acetyl-11-keto-¦Â-boswellic acidTramadol N-OxideHydroxyprolineJNJ-1661010CAR 26:1CAR 26:03-HydroxyfluorenePC O-37:6PC O-37:5PiperinePC O-37:7Dehydroepiandrosterone (DHEA)PC 16:0_16:15¦Á-Dihydrotestosterone glucuronidePC O-37:2PC 21:1_22:6Acetyl-L-carnitinePyridoxineTQHCAR 15:0LPC O-22:2SM 38:6;3OGlycolithocholic acidValine2-PhenylacetamideLPC O-22:4SM 32:1;2Otetranor-12(R)-HETEStiripentolLysoPE 18:2LPC 32:9-SN2TheobromineCortisolBilirubinRNKXLR11 N-(2-fluoropentyl) isomer6-(trifluoromethoxy)quinolin-4-olPC 15:0_15:1PC 15:0_15:0BetainePC 18:3_18:3PC 18:3_18:47-hydroxy-5-methoxy-2-phenyl-3,4-dihydro-2H-1-benzopyran-4-oneJasmonic acidAL 8810 Methyl esterHesperetinPelargonidinL-Leucyl-L-AlanineCytidineEnrofloxacinN-DesmethylvenlafaxinePC O-46:7PC 18:1_18:1Isoquinolineoctadec-9-ynoic acidANHMorphine-3-glucuronide3-(2-morpholinophenyl)-2-(phenylsulfonyl)acrylonitrileNAT13-331713_POSMethylbenzethonium chloride7-methyl-3-nitroimidazo[1,2-a]pyridine1-MethylhistidineCAR 24:1CAR 24:0PC 16:0_18:5PC O-35:5PC O-35:7DL-5-MethoxytryptophanDeoxycorticosterone 21-glucosidePC O-35:4PC O-35:32-Thio-acetyl MAGE4-acetyl-4-(ethoxycarbonyl)heptanedioic acid7-Ketolithocholic acid1-[(1-benzylpiperidin-4-yl)amino]-3-[(4-fluorophenyl)thio]propan-2-ol1-PalmitoylglycerolCAR 13:0LPC O-20:4LPC O-20:1LPC O-20:2PC 22:6_22:6Testosterone glucuronidePC 20:3_20:4AL 8810PC 20:3_20:317beta-TrenbolonedUMPN-(6-methoxypyridin-3-yl)thiophene-2-carboxamideProgesteroneAPK(5S)-5-hydroxy-1,7-diphenylheptan-3-oneProlylleucineAllantoinPNHDL-DipalmitoylphosphatidylcholineMAG (18:2)5-(6-hydroxy-6-methyloctyl)-2,5-dihydrofuran-2-onePC 16:3_16:4ethyl 5-methoxy-2-methyl-1-phenyl-1H-indole-3-carboxylateLPC O-14:0PC O-17:0MethylmalonatePC 18:3_20:5MusconeMethionineN1-(4-cyclohexylphenyl)-2-[(4-methylphenyl)thio]acetamideDeisopropylatrazineNKKGuggulsteroneEstazolam1H-indol-3-yl(pyridin-2-yl)methanolDl-2-Amino-3-phosphonopropionic acidC-8 Ceramide-1-phosphateCAR 22:7CAR 22:6PC 28:6_30:82,6-Di-tert-butyl-1,4-benzoquinoneCAR 22:0LPC 17:1-SN1CAR 22:5CAR 22:43-MethoxytyramineLPE 40:6PC 17:0_18:5SM 42:1;2O1-Stearoylglycerol6-Deoxy-D-glucosePC 17:0_18:04-ButylresorcinolPC 17:0_18:4PapaverinePC 17:0_18:1PC 17:0_18:2Glu-GlnPC 19:0_20:5PC 19:0_20:4Phenylacetylglycine4-chlorophenyl 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxylateN-Stearoyl taurineCAR 11:0SM 8:1;2O/30:3SM 8:1;2O/30:2LeucylprolineLPC 15:0-SN13-hydroxy-N-(1-hydroxy-4-methylpentan-2-yl)-5-oxo-6-phenylhexanamideSM 8:1;2O/30:66-(4-methoxybenzyl)-3-methyl-5,6,7,8-tetrahydroquinolineGlu-Glu6¦Â-Oxycodol N-oxide8-Hydroxyquinoline5-hydroxy-4-methoxy-5,6-dihydro-2H-pyran-2-onePC 17:2_22:6N-AcetylserotoninDehydrocholic acidD-(-)-GlutamineLPC 19:1-SN1PC 16:3_18:5PAF C-16¦¤17-6-keto prostaglandin F1¦ÁLPC 18:4-SN1PC O-15:0N2-phenyl-4-(piperidinomethyl)-1,3-thiazol-2-amine2-[(butylamino)(imino)methyl]-1-oxohydrazinium-1-olateDL-Carnitine1-[2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-nitrophenyl]-1H-imidazoleHomoarginineL-aspartic AcidCoumarinNicotinate ribonucleosideSpermine1,2-DipalmitoylphosphatidylglycerolLPC 17:0-SN1Hypoxanthine1-(2-furyl)pentane-1,4-dionePalmitoyl ethanolamide2-Phenylpropionic acidHeptadecanoic AcidN-(cyclopropylmethyl)-N'-phenylureaCAR 20:3CAR 20:2CAR 20:1CAR 20:0CAR 20:5CAR 20:415-Deoxy-¦¤12,14-prostaglandin J2-2-glycerol esterPC O-39:4PC O-39:5PC O-39:7LDGCC 20:2Methyl palmitate4-(3-methoxyphenyl)-4-methyl-2,6-dioxopiperidine-3,5-dicarbonitrile5-Hydroxyindole5-MethyluridinePalmitoleic AcidLMHLPC 17:0(2E)-3-(3,4-dimethoxyphenyl)prop-2-enoic acidChlorogenic acidNicotinuric acidCortisoneGly-Phe4'-methyl Acetyl fentanyl-d53-Nitro-L-TyrosineGenistein 4'-O-glucuronideD-ProlineSM 8:1;2O/32:0N1-(1H-indol-4-yl)cyclohexane-1-carboxamideSM 8:1;2O/32:5InosineSM 8:1;2O/32:3SM 8:1;2O/32:8D-PhenylalanineSM 8:1;2O/32:7LPC 15:1-SN1LPC 18:3-SN1Glycerophospho-N-palmitoyl ethanolamineOuabainTetranor-12(S)-HETEPanthenolSM 8:1;2O/38:105-[4-(tert-butyl)phenyl]-1,3,4-oxadiazole-2-thiolPC 19:1_20:5isoleucine3,5,7-trihydroxy-2-phenyl-4H-chromen-4-one1,7-bis(4-hydroxyphenyl)heptan-3-oneN-AcetylmethionineSM 9:1;2O/34:4Ellagic acidSM 9:1;2O/34:7LPC O-18:3LPC O-18:0LPC O-18:1N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2-thiophenecarboxamideN-cyclohexyl-1-methyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-4-carboxamideCaffeine2-(cyclopropylcarbonyl)-3-(4-fluoroanilino)acrylonitrile1,7-bis(3,4-dihydroxyphenyl)heptan-3-one7-AminoclonazepamSM 9:1;2O/34:8PC 20:4_22:66-Ketoprostaglandin F1¦ÁSebacic acid6-phenyl-1,2,3,4-tetrahydro-2,5-benzodiazocin-1-onePC 17:1_20:4LPC 16:2-SN11-(4-nitrophenyl)piperidineSM 8:1;2O/12:011(Z),14(Z),17(Z)-Eicosatrienoic acid13-HPODESM 8:1;2O/34:9N-(2,5-diethoxy-4-morpholinophenyl)thiophene-2-carboxamideN-(4-butyl-2-methylphenyl)-N'-[4-(4-methylpiperazino)phenyl]ureaPicolinic acidOleoyl ethanolamideLDGCC 22:6LDGCC 22:5LDGCC 22:4ethyl 4-[2-(3,4,5-trimethoxybenzylidene)hydrazino]benzoatePyridoxamineL-Pyroglutamic acid9-Oxo-ODEBiochanin APC 19:2_19:22-[4-(tert-butyl)-2-chlorophenoxy]-3-nitropyridine6-AminonicotinamideSM 8:1;2O/34:0Quinic acidLPE 18:0PC O-41:4SM 8:1;2O/34:5PC O-41:5AcetylcholineSM 8:1;2O/34:75-OxoETESM 8:1;2O/34:1Choline bitartratePC O-41:6PC O-41:7SM 8:1;2O/34:4LPC 18:2-SN1Thymidine2-(benzylamino)-1,3-thiazole-5-carboxylic acidPantetheine4-[(1-acetyl-1H-indol-3-yl)methylene]-2-phenyl-1,3-oxazol-5(4H)-oneOleandomycinPC O-19:4Lysopa 18:08-(1,2-dihydroxy-3-methylbut-3-en-1-yl)-7-methoxy-2H-chromen-2-oneTryptophanolLPC O-16:0CotinineLPC O-16:1Proscillaridin ALPC 16:1-SN1N-Arachidonoyl-L-serinePC 20:4_20:4SM 9:1;2O/36:8DL-StachydrinePC 26:7_30:8T-2 TriolDextromethorphan hydrobromideDihydrokawain2-(2-amino-3-methylbutanamido)-3-phenylpropanoic acidNonadecanoic acidEthyl oleatecis-gondoic acid(5-L-Glutamyl)-L-Amino AcidPhe-PheN-Desmethyl sildenafilMethionine sulfoxide18-¦Â-Glycyrrhetinic acidAzelaic acidLPC 17:2-SN15-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1H-indole-3-carbonitrileLPC 11:0-SN11-(4-benzylpiperazino)-2-(pyridin-2-ylamino)propan-1-one(1R,2R)-trans-N-Boc-1,2-cyclohexanediamineN-Acetyl-L-leucineD-TagatosePC 18:2_18:3PC 18:2_18:22,5-Furandicarboxylic acidPE O-18:2_18:2SM 8:1;2O/36:4SM 8:1;2O/36:52-(1,3-benzodioxol-5-yl)-6-chloro-4-phenylquinolineSM 8:1;2O/36:6LPE 16:1falseMulti-omics analysis identifies gut microbiota-glutamine axis contributing to the pathogenesis of reflux esophagitisBackground: Reflux esophagitis (RE), a common gastroesophageal reflux disease characterized by esophageal mucosal inflammation, is closely associated with gut microbiota dysbiosis and metabolic abnormalities. The glutamine-glutamate metabolic pathway regulates inflammation and mucosal barrier function, but its role in RE and association with gut microbiota remain unclear. This study aimed to characterize gut microbiota and serum metabolites in RE patients via integrated multi-omics (focusing on the gut microbiota-glutamine axis), and verify the activation status of this pathway in RE inflammatory models and the anti-inflammatory effect of its targeted inhibition.Methods: RE patients and healthy controls (HCs) were enrolled. Fecal metagenomic sequencing and serum untargeted metabolomics (LC-MS/MS) were performed to identify differential gut microbiota and serum metabolites between the two groups, followed by Pearson correlation analysis to explore their associations. In vitro experiments were conducted on human esophageal epithelial cells (HEECs) divided into four groups: normal, inflammatory, glutamine-supplemented, and inflammatory + glutamine + glutaminase inhibitor (BPTES) groups. qPCR was used to detect the mRNA expression of glutamine-glutamate pathway molecules (GLS, c-Myc, SLC1A5), mucosal barrier markers (ZO-1, Occludin), and pro-inflammatory cytokines (IL-8, IL-6, IL-1β, TNF-α). Intracellular concentrations of glutamine, glutamate, and α-ketoglutarate were measured, and the anti-inflammatory effect of BPTES was verified.Results: RE patients showed significant differences in gut microbiota diversity and composition compared with HCs, with Bacteroidota, Pseudomonadota, Escherichia coli, and Klebsiella pneumoniae as dominant taxa. Serum metabolomics revealed elevated glutamine and glutamate in RE patients, which were identified as key differential metabolites related to RE pathogenesis. Pearson analysis revealed that alterations in serum metabolite profiles of RE patients were significantly correlated with changes in gut bacterial abundance. Notably, glutamate-glutamate (Glu-Glu) metabolism exhibited negative correlations with multiple bacterial genera (Acrocarpospora, Limnobacter, Pseudobacter, Shewanella, and Tropicimonas). In vitro, inflammatory HEECs exhibited increased intracellular glutamine, glutamate, and α-ketoglutarate, upregulated glutamine-glutamate pathway molecules and pro-inflammatory cytokines, and downregulated mucosal barrier markers. Exogenous glutamine alone failed to alleviate inflammation, while combined with BPTES significantly reversed pathway activation and mitigated inflammation in inflammatory HEECs.Conclusion: RE patients exhibit significant gut microbiota dysbiosis (dominated by Bacteroidota, Pseudomonadota, Escherichia coli, and Klebsiella pneumoniae) and abnormal glutamine metabolism (elevated serum glutamine and glutamate). Pearson analysis reveals that the glutamine-glutamate pathway correlates negatively with multiple bacterial genera (Acrocarpospora, Limnobacter, Pseudobacter, Shewanella, and Tropicimonas). The glutamine-glutamate pathway is activated in inflammatory esophageal epithelial cells, and targeted GLS inhibition by BPTES reverses pathway activation and mitigates inflammation. These findings highlight the gut microbiota-glutamine axis as potential diagnostic biomarkers and therapeutic targets for RE, providing new insights into pathogenesis and a basis for novel clinical interventions.  2026-05-032026-05-03MTBLS14421Com_44_negCom_62_negCom_121_negCom_189_negCom_327_negCom_337_negCom_409_negCom_706_negCom_727_negCom_1024_negCom_1073_negCom_1261_negCom_1410_negCom_1602_negCom_1656_negCom_1728_negCom_2372_negCom_2423_negCom_2510_negCom_2671_negCom_3119_negCom_3429_negCom_4453_negCom_5128_negCom_5569_negCom_6613_negCom_8986_negCom_9162_negCom_10125_negCom_10616_negCom_14704_negCom_25_negCom_160_negCom_135_negCom_86_negCom_10_negCom_55_negCom_191_negCom_227_negCom_2262_negCom_923_negCom_2947_negCom_76_negCom_165_negCom_5453_negCom_2170_negCom_1190_negCom_10012_negCom_4655_negCom_952_negCom_26_negCom_3_negCom_9_negCom_14_negCom_36_negCom_50_negCom_52_negCom_59_negCom_79_negCom_101_negCom_103_negCom_117_negCom_119_negCom_146_negCom_148_negCom_154_negCom_161_negCom_181_negCom_194_negCom_224_negCom_226_negCom_233_negCom_269_negCom_314_negCom_316_negCom_324_negCom_340_negCom_349_negCom_362_negCom_365_negCom_368_negCom_394_negCom_436_negCom_444_negCom_470_negCom_533_negCom_541_negCom_558_negCom_581_negCom_587_negCom_622_negCom_657_negCom_683_negCom_690_negCom_705_negCom_740_negCom_755_negCom_763_negCom_840_negCom_879_negCom_902_negCom_904_negCom_931_negCom_932_negCom_997_negCom_1034_negCom_1043_negCom_1056_negCom_1057_negCom_1060_negCom_1159_negCom_1181_negCom_1213_negCom_1274_negCom_1299_negCom_1371_negCom_1373_negCom_1392_negCom_1405_negCom_1422_negCom_1424_negCom_1442_negCom_1478_negCom_1533_negCom_1581_negCom_1606_negCom_1613_negCom_1664_negCom_1669_negCom_1699_negCom_1764_negCom_1766_negCom_1772_negCom_1783_negCom_1813_negCom_1824_negCom_1847_negCom_1865_negCom_1887_negCom_1949_negCom_1962_negCom_1966_negCom_2051_negCom_2110_negCom_2115_negCom_2133_negCom_2146_negCom_2265_negCom_2266_negCom_2278_negCom_2348_negCom_2376_negCom_2390_negCom_2527_negCom_2534_negCom_2548_negCom_2625_negCom_2632_negCom_2649_negCom_2723_negCom_2753_negCom_2762_negCom_2839_negCom_2875_negCom_2893_negCom_2932_negCom_2945_negCom_2992_negCom_3015_negCom_3168_negCom_3172_negCom_3194_negCom_3220_negCom_3235_negCom_3290_negCom_3300_negCom_3304_negCom_3306_negCom_3326_negCom_3399_negCom_3408_negCom_3469_negCom_3496_negCom_3546_negCom_3717_negCom_3750_negCom_3842_negCom_3843_negCom_3847_negCom_3856_negCom_3889_negCom_3906_negCom_3960_negCom_3961_negCom_4004_negCom_4106_negCom_4112_negCom_4118_negCom_4146_negCom_4160_negCom_4267_negCom_4378_negCom_4382_negCom_4387_negCom_4398_negCom_4399_negCom_4415_negCom_4480_negCom_4487_negCom_4492_negCom_4493_negCom_4554_negCom_4614_negCom_4644_negCom_4705_negCom_4733_negCom_4740_negCom_4799_negCom_4848_negCom_4892_negCom_4897_negCom_4935_negCom_4947_negCom_4984_negCom_5013_negCom_5240_negCom_5285_negCom_5309_negCom_5316_negCom_5395_negCom_5423_negCom_5429_negCom_5462_negCom_5470_negCom_5476_negCom_5497_negCom_5604_negCom_5635_negCom_5679_negCom_5735_negCom_5765_negCom_5800_negCom_5811_negCom_5842_negCom_5857_negCom_5865_negCom_5893_negCom_5925_negCom_5926_negCom_6010_negCom_6080_negCom_6140_negCom_6221_negCom_6235_negCom_6256_negCom_6308_negCom_6315_negCom_6317_negCom_6377_negCom_6454_negCom_6486_negCom_6505_negCom_6527_negCom_6571_negCom_6575_negCom_6649_negCom_6651_negCom_6806_negCom_6810_negCom_6924_negCom_6964_negCom_6983_negCom_6986_negCom_7005_negCom_7032_negCom_7056_negCom_7081_negCom_7104_negCom_7107_negCom_7108_negCom_7126_negCom_7131_negCom_7154_negCom_7162_negCom_7231_negCom_7446_negCom_7470_negCom_7511_negCom_7546_negCom_7621_negCom_7627_negCom_7656_negCom_7707_negCom_7741_negCom_7742_negCom_7747_negCom_7962_negCom_7982_negCom_8068_negCom_8089_negCom_8113_negCom_8137_negCom_8167_negCom_8269_negCom_8279_negCom_8467_negCom_8473_negCom_8508_negCom_8576_negCom_8669_negCom_8689_negCom_8728_negCom_8738_negCom_8746_negCom_8758_negCom_8760_negCom_8768_negCom_8866_negCom_9008_negCom_9021_negCom_9081_negCom_9091_negCom_9103_negCom_9153_negCom_9190_negCom_9243_negCom_9290_negCom_9321_negCom_9349_negCom_9361_negCom_9406_negCom_9417_negCom_9469_negCom_9563_negCom_9576_negCom_9605_negCom_9616_negCom_9649_negCom_9685_negCom_9840_negCom_9865_negCom_9932_negCom_10109_negCom_10223_negCom_10257_negCom_10298_negCom_10309_negCom_10364_negCom_10391_negCom_10410_negCom_10561_negCom_10689_negCom_10738_negCom_10823_negCom_10824_negCom_10875_negCom_11190_negCom_11300_negCom_11346_negCom_11358_negCom_11367_negCom_11497_negCom_11684_negCom_11685_negCom_11845_negCom_11846_negCom_11927_negCom_11934_negCom_11958_negCom_11967_negCom_11977_negCom_12052_negCom_12055_negCom_12064_negCom_12179_negCom_12264_negCom_12269_negCom_12351_negCom_12388_negCom_12402_negCom_12428_negCom_12472_negCom_12487_negCom_12584_negCom_12610_negCom_12676_negCom_12725_negCom_12790_negCom_12801_negCom_12816_negCom_13036_negCom_13067_negCom_13199_negCom_13206_negCom_13437_negCom_13439_negCom_13525_negCom_13526_negCom_13543_negCom_13680_negCom_13783_negCom_13807_negCom_13825_negCom_13833_negCom_13959_negCom_14076_negCom_14121_negCom_14134_negCom_14152_negCom_14224_negCom_14225_negCom_14327_negCom_14335_negCom_14549_negCom_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