{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:11:10Z","timestamp":1790079070089,"version":"4.0.1"},"reference-count":65,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs Merit Review Awards","doi-asserted-by":"publisher","award":["BX002011"],"award-info":[{"award-number":["BX002011"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs Merit Review Awards","doi-asserted-by":"publisher","award":["BX006626"],"award-info":[{"award-number":["BX006626"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs Merit Review Awards","doi-asserted-by":"publisher","award":["BX002867"],"award-info":[{"award-number":["BX002867"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs Merit Review Awards","doi-asserted-by":"publisher","award":["BX006177"],"award-info":[{"award-number":["BX006177"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"award":["BX002011"],"award-info":[{"award-number":["BX002011"]}],"id":[{"id":"https:\/\/ror.org\/05dbx6743","id-type":"ROR","asserted-by":"publisher"}]},{"award":["BX006626"],"award-info":[{"award-number":["BX006626"]}],"id":[{"id":"https:\/\/ror.org\/05dbx6743","id-type":"ROR","asserted-by":"publisher"}]},{"award":["BX002867"],"award-info":[{"award-number":["BX002867"]}],"id":[{"id":"https:\/\/ror.org\/05dbx6743","id-type":"ROR","asserted-by":"publisher"}]},{"award":["BX006177"],"award-info":[{"award-number":["BX006177"]}],"id":[{"id":"https:\/\/ror.org\/05dbx6743","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"VA-BCCMA Award","doi-asserted-by":"publisher","award":["BX005862"],"award-info":[{"award-number":["BX005862"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"name":"VA Senior Research Career Scientist Award","award":["1IK6BX005242"],"award-info":[{"award-number":["1IK6BX005242"]}]},{"DOI":"10.13039\/100000062","name":"NIH\/NIDDK grants","doi-asserted-by":"publisher","award":["R01 DK 54016"],"award-info":[{"award-number":["R01 DK 54016"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"NIH\/NIDDK grants","doi-asserted-by":"publisher","award":["R56 DK92441"],"award-info":[{"award-number":["R56 DK92441"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Down-regulated in adenoma (DRA\/SLC26A3), an IBD (Inflammatory Bowel Diseases) susceptibility gene and major colonic Cl\u2212\/HCO3\u2212 exchanger, is reduced in ulcerative colitis (UC). Whether reduced DRA is linked to broader metabolic remodeling during intestinal inflammation remains unclear. We therefore examined DRA-associated metabolic pathways in human UC datasets and metabolic changes across mucosal, luminal, and systemic compartments in DRA-deficient mice. Methods: Six publicly available human colonic transcriptomic cohorts were analyzed to infer KEGG metabolic pathway activity, compare UC with healthy mucosa, and assess associations with DRA expression using random-effects meta-analysis. DRA knockout mice were evaluated by colonic mucosal RNA sequencing, untargeted LC\u2013MS metabolomics of colonic mucosa, feces, and serum, targeted bile acid profiling, MetOrigin analysis, and fecal 16S rRNA sequencing. Results: In the human cohorts, DRA expression was consistently lower in UC. Of the 75 KEGG metabolic pathways evaluated, 48 were altered in UC relative to healthy mucosa, and 45 of these were also associated with DRA expression levels among UC samples. In DRA knockout mice, colonic RNA sequencing identified broad metabolic transcriptional remodeling across 39 KEGG pathways, with metabolic themes that overlapped with the human UC findings. Multi-compartment metabolomics further revealed alterations involving amino acid, nitrogen, redox\/cofactor, polyamine, and bile acid metabolism, together with inferred host-microbiota co-metabolic signatures. Conclusions: DRA deficiency was accompanied by broad metabolic remodeling across mucosal, luminal, and systemic compartments. These changes overlapped with DRA-associated signatures in human UC, supporting a role for DRA in epithelial\u2013luminal metabolic homeostasis beyond ion transport.<\/jats:p>","DOI":"10.3390\/metabo16090690","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:09:35Z","timestamp":1790075375000},"page":"690","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-Compartment Metabolic Remodeling in DRA-Deficient Mice Overlaps with Ulcerative Colitis Metabolic Signatures"],"prefix":"10.3390","volume":"16","author":[{"given":"Jayson M.","family":"Antonio","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubha","family":"Priyamvada","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0231-9272","authenticated-orcid":false,"given":"Arivarasu N.","family":"Anbazhagan","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Harris","family":"J. B.","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Calzadilla","sequence":"additional","affiliation":[{"name":"Section of Plastic and Reconstructive Surgery, Department of Surgery, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Rengul C.","family":"Atalay","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Reena","family":"Sethi","sequence":"additional","affiliation":[{"name":"Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2166-6317","authenticated-orcid":false,"given":"Seema","family":"Saksena","sequence":"additional","affiliation":[{"name":"Jesse Brown VA Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5337-2567","authenticated-orcid":false,"given":"Ravinder K.","family":"Gill","sequence":"additional","affiliation":[{"name":"Jesse Brown VA Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Gokhan M.","family":"Mutlu","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Waddah A.","family":"Alrefai","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"},{"name":"Jesse Brown VA Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"given":"Ece A.","family":"Mutlu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"},{"name":"Jesse Brown VA Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7915-3365","authenticated-orcid":false,"given":"Anoop","family":"Kumar","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"},{"name":"Jesse Brown VA Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2252-7703","authenticated-orcid":false,"given":"Pradeep K.","family":"Dudeja","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"},{"name":"Jesse Brown VA Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1093\/ibd\/izaa256","article-title":"Slc26a3 (DRA) in the Gut: Expression, Function, Regulation, Role in Infectious Diarrhea and Inflammatory Bowel Disease","volume":"27","author":"Yu","year":"2021","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1002\/ibd.21432","article-title":"New Therapeutic Targets in Ulcerative Colitis: The Importance of Ion Transporters in the Human Colon","volume":"17","author":"Farkas","year":"2011","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Donowitz, M., Sarker, R., Lin, R., McNamara, G., Tse, C.M., and Singh, V. (2022). Identification of Intestinal NaCl Absorptive-Anion Secretory Cells: Potential Functional Significance. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.892112"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1097\/MIB.0000000000000504","article-title":"Mechanisms Underlying Dysregulation of Electrolyte Absorption in Inflammatory Bowel Disease\u2013Associated Diarrhea","volume":"21","author":"Priyamvada","year":"2015","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"101383","DOI":"10.1016\/j.jcmgh.2024.101383","article-title":"COVID-19 Diarrhea Is Inflammatory, Caused by Direct Viral Effects Plus Major Role of Virus-Induced Cytokines","volume":"18","author":"Donowitz","year":"2024","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"37962","DOI":"10.1074\/jbc.M607527200","article-title":"Slc26a3 (Dra)-Deficient Mice Display Chloride-Losing Diarrhea, Enhanced Colonic Proliferation, and Distinct Up-Regulation of Ion Transporters in the Colon","volume":"281","author":"Schweinfest","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/humu.10139","article-title":"SLC26A3 Mutations in Congenital Chloride Diarrhea","volume":"20","author":"Kere","year":"2002","journal-title":"Hum. Mutat."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1038\/ng.482","article-title":"A Genome-Wide Association Study Identifies Three New Susceptibility Loci for Ulcerative Colitis in the Japanese Population","volume":"41","author":"Asano","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1007\/s00384-018-3097-4","article-title":"Association of Ulcerative Colitis with Solute-Linked Carrier Family 26 Member A3 Gene Polymorphisms and Its Expression in Colonic Tissues in Chinese Patients","volume":"33","author":"Shao","year":"2018","journal-title":"Int. J. Color. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1093\/ecco-jcc\/jjab056","article-title":"Inflammatory Bowel Disease in Patients with Congenital Chloride Diarrhoea","volume":"15","author":"Norsa","year":"2021","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/ng.3359","article-title":"Association Analyses Identify 38 Susceptibility Loci for Inflammatory Bowel Disease and Highlight Shared Genetic Risk across Populations","volume":"47","author":"Liu","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1053\/j.gastro.2020.11.008","article-title":"A Novel Role of SLC26A3 in the Maintenance of Intestinal Epithelial Barrier Integrity","volume":"160","author":"Kumar","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/apha.12220","article-title":"Slc26a3 Deficiency Is Associated with Loss of Colonic HCO3\u2212 Secretion, Absence of a Firm Mucus Layer and Barrier Impairment in Mice","volume":"211","author":"Xiao","year":"2014","journal-title":"Acta Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2041943","DOI":"10.1080\/19490976.2022.2041943","article-title":"Upregulation of Antimicrobial Peptide Expression in Slc26a3-\/- Mice with Colonic Dysbiosis and Barrier Defect","volume":"14","author":"Kini","year":"2022","journal-title":"Gut Microbes"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.jcmgh.2022.12.009","article-title":"Loss of SLC26A3 Results in Colonic Mucosal Immune Dysregulation via Epithelial-Immune Cell Crosstalk","volume":"15","author":"Jayawardena","year":"2023","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1136\/gut.2008.148395","article-title":"Regional Variation in Gene Expression in the Healthy Colon Is Dysregulated in Ulcerative Colitis","volume":"57","author":"Noble","year":"2008","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1136\/gutjnl-2012-303333","article-title":"Transcriptional Analysis of the Intestinal Mucosa of Patients with Ulcerative Colitis in Remission Reveals Lasting Epithelial Cell Alterations","volume":"62","author":"Planell","year":"2013","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Soendergaard, C., Kvist, P.H., Thygesen, P., Reslow, M., Nielsen, O.H., Kopchick, J.J., and Holm, T.L. (2017). Characterization of Growth Hormone Resistance in Experimental and Ulcerative Colitis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102046"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5820","DOI":"10.1038\/s41467-022-33331-8","article-title":"Interleukin-22 Regulates Neutrophil Recruitment in Ulcerative Colitis and Is Associated with Resistance to Ustekinumab Therapy","volume":"13","author":"Pavlidis","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1093\/hmg\/ddv192","article-title":"Mobilization of Epithelial Mesenchymal Transition Genes Distinguishes Active from Inactive Lesional Tissue in Patients with Ulcerative Colitis","volume":"24","author":"Zhao","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1097\/MIB.0000000000000535","article-title":"Strong Upregulation of AIM2 and IFI16 Inflammasomes in the Mucosa of Patients with Active Inflammatory Bowel Disease","volume":"21","author":"Vanhove","year":"2015","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"H\u00e4nzelmann, S., Castelo, R., and Guinney, J. (2013). GSVA: Gene Set Variation Analysis for Microarray and RNA-Seq Data. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-7"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting Meta-Analyses in R with the Metafor Package","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast Universal RNA-Seq Aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Pluskal, T., Castillo, S., Villar-Briones, A., and Oresic, M. (2010). MZmine 2: Modular Framework for Processing, Visualizing, and Analyzing Mass Spectrometry-Based Molecular Profile Data. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-395"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1021\/ac051632c","article-title":"Probabilistic Quotient Normalization as Robust Method to Account for Dilution of Complex Biological Mixtures. Application in 1H NMR Metabonomics","volume":"78","author":"Dieterle","year":"2006","journal-title":"Anal. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"W652","DOI":"10.1093\/nar\/gkp356","article-title":"MetaboAnalyst: A Web Server for Metabolomic Data Analysis and Interpretation","volume":"37","author":"Xia","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"W398","DOI":"10.1093\/nar\/gkae253","article-title":"MetaboAnalyst 6.0: Towards a Unified Platform for Metabolomics Data Processing, Analysis and Interpretation","volume":"52","author":"Pang","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s11306-007-0082-2","article-title":"Proposed Minimum Reporting Standards for Chemical Analysis Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI)","volume":"3","author":"Sumner","year":"2007","journal-title":"Metabolomics"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wang, Y., Tai, Y.-L., Zhao, D., Zhang, Y., Yan, J., Kakiyama, G., Wang, X., Gurley, E.C., Liu, J., and Liu, J. (2021). Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways. Cells, 10.","DOI":"10.3390\/cells10020210"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e246","DOI":"10.1002\/imt2.246","article-title":"MetOrigin 2.0: Advancing the Discovery of Microbial Metabolites and Their Origins","volume":"3","author":"Yu","year":"2024","journal-title":"iMeta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nmeth.3869","article-title":"DADA2: High-Resolution Sample Inference from Illumina Amplicon Data","volume":"13","author":"Callahan","year":"2016","journal-title":"Nat. Methods"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nmeth.f.303","article-title":"QIIME Allows Analysis of High-Throughput Community Sequencing Data","volume":"7","author":"Caporaso","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1198\/jasa.2001.s411","article-title":"Mixed-Effects Models in S and S-Plus","volume":"96","author":"Carey","year":"2001","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex Heatmaps Reveal Patterns and Correlations in Multidimensional Genomic Data","volume":"32","author":"Gu","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Stat. Methodol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s12964-025-02622-0","article-title":"Intestinal Amino Acid Metabolic Response and Its Roles in Inflammatory Bowel Disease","volume":"24","author":"Niu","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5120","DOI":"10.1038\/s41467-025-60233-2","article-title":"Metabolic Modeling Reveals a Multi-Level Deregulation of Host-Microbiome Metabolic Networks in IBD","volume":"16","author":"Taubenheim","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.chom.2024.04.004","article-title":"Microbiota Metabolism of Intestinal Amino Acids Impacts Host Nutrient Homeostasis and Physiology","volume":"32","author":"Li","year":"2024","journal-title":"Cell Host Microbe"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1093\/nutrit\/nuac070","article-title":"Arginine Metabolism Regulates the Pathogenesis of Inflammatory Bowel Disease","volume":"81","author":"Li","year":"2023","journal-title":"Nutr. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1097\/MIB.0000000000000790","article-title":"L-Arginine Availability and Metabolism Is Altered in Ulcerative Colitis","volume":"22","author":"Coburn","year":"2016","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"G162","DOI":"10.1152\/ajpgi.00366.2024","article-title":"Lacticaseibacillus Rhamnosus GG -Driven Remodeling of Arginine Metabolism Mitigates Gut Barrier Dysfunction","volume":"329","author":"Antonio","year":"2025","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1006\/bmmb.1994.1062","article-title":"Glutathione Metabolism in Crohn\u2032s Disease","volume":"53","author":"Iantomasi","year":"1994","journal-title":"Biochem. Med. Metab. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.freeradbiomed.2025.11.057","article-title":"Elevated Serum Glutathione Reflects Endoscopic Disease Activity in Inflammatory Bowel Disease","volume":"243","author":"Geertsema","year":"2026","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"110042","DOI":"10.1016\/j.jnutbio.2025.110042","article-title":"Gut Microbiota-Related Glutathione Metabolism Is Key Mechanism for Sulforaphane Ameliorating Ulcerative Colitis","volume":"146","author":"Lv","year":"2025","journal-title":"J. Nutr. Biochem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Thomas, J.P., Modos, D., Rushbrook, S.M., Powell, N., and Korcsmaros, T. (2022). The Emerging Role of Bile Acids in the Pathogenesis of Inflammatory Bowel Disease. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.829525"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00253-016-8006-6","article-title":"Interaction of Gut Microbiota with Bile Acid Metabolism and Its Influence on Disease States","volume":"101","author":"Staley","year":"2017","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1007\/s10620-020-06715-3","article-title":"Bile Acid Signaling in Inflammatory Bowel Diseases","volume":"66","author":"Fiorucci","year":"2021","journal-title":"Dig. Dis. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1136\/gutjnl-2018-317571","article-title":"Structural Weakening of the Colonic Mucus Barrier Is an Early Event in Ulcerative Colitis Pathogenesis","volume":"68","author":"Jabbar","year":"2019","journal-title":"Gut"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nature17186","article-title":"The Amino Acid Sensor GCN2 Controls Gut Inflammation by Inhibiting Inflammasome Activation","volume":"531","author":"Ravindran","year":"2016","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"153454","DOI":"10.1016\/j.bbrc.2026.153454","article-title":"Intestinal Stem Cell Damage Caused by Specific Amino Acid Deprivation Is Linked to a Potent Integrated Stress Response Triggered by the Direct Sensing of Stem Cells","volume":"807","author":"Kozai","year":"2026","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.molmet.2018.01.007","article-title":"Metabolic Intermediates\u2014Cellular Messengers Talking to Chromatin Modifiers","volume":"14","author":"Nieborak","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.arr.2014.05.004","article-title":"Krebs Cycle Intermediates Regulate DNA and Histone Methylation: Epigenetic Impact on the Aging Process","volume":"16","author":"Salminen","year":"2014","journal-title":"Ageing Res. Rev."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Eugene, S.P., Reddy, V.S., and Trinath, J. (2020). Endoplasmic Reticulum Stress and Intestinal Inflammation: A Perilous Union. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.543022"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.cell.2008.08.023","article-title":"Unresolved ER Stress Inflames the Intestine","volume":"134","author":"Ma","year":"2008","journal-title":"Cell"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Coleman, O.I., and Haller, D. (2019). ER Stress and the UPR in Shaping Intestinal Tissue Homeostasis and Immunity. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02825"},{"key":"ref_59","first-page":"123","article-title":"Serum Concentrations of 7alpha-Hydroxy-4-Cholesten-3-One Reflect Bile Acid Synthesis in Humans","volume":"24","author":"Sauter","year":"1996","journal-title":"Hepatology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1136\/gut.34.5.698","article-title":"Serum 7 Alpha-Hydroxy-4-Cholesten-3-One Concentrations in the Evaluation of Bile Acid Malabsorption in Patients with Diarrhoea: Correlation to SeHCAT Test","volume":"34","author":"Eusufzai","year":"1993","journal-title":"Gut"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1093\/toxsci\/kfn268","article-title":"Bile Acid Sulfation: A Pathway of Bile Acid Elimination and Detoxification","volume":"108","author":"Alnouti","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"49036","DOI":"10.1074\/jbc.M205288200","article-title":"In Vivo Evidence for Interferon-Gamma-Mediated Homeostatic Mechanisms in Small Intestine of the NHE3 Na+\/H+ Exchanger Knockout Model of Congenital Diarrhea","volume":"277","author":"Woo","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"965\u2013975.e10","DOI":"10.1053\/j.gastro.2009.05.043","article-title":"Changes in Mucosal Homeostasis Predispose NHE3 Knockout Mice to Increased Susceptibility to DSS-Induced Epithelial Injury","volume":"137","author":"Kiela","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Xue, J., Dominguez Rieg, J.A., Thomas, L., White, J.R., and Rieg, T. (2022). Intestine-Specific NHE3 Deletion in Adulthood Causes Microbial Dysbiosis. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.896309"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1053\/j.gastro.2024.05.002","article-title":"A Direct Link Implicating Loss of SLC26A6 to Gut Microbial Dysbiosis, Compromised Barrier Integrity, and Inflammation","volume":"167","author":"Anbazhagan","year":"2024","journal-title":"Gastroenterology"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/9\/690\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:41:16Z","timestamp":1790077276000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/9\/690"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,18]]},"references-count":65,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["metabo16090690"],"URL":"https:\/\/doi.org\/10.3390\/metabo16090690","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,18]]}}}