{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T06:11:32Z","timestamp":1760595092949,"version":"build-2065373602"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Intestinal inflammation is a chronic, relapsing disorder of the gastrointestinal tract characterized by dysregulated immune responses, microbial dysbiosis, and environmental influence. Pathogen clearance is related to the severity of intestinal diseases and macrophage apoptosis. Escherichia coli Nissle 1917 (EcN) alleviates the intestinal inflammation caused by Salmonella enterica serotype Salmonella Typhimurium (Salmonella Typhimurium, S. Tm) infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Through gene editing, we found that the regulatory gene arcA largely affects arginine production in EcN via the arginine deiminase pathway. In vitro studies demonstrated that EcN alleviates S. Tm-induced apoptosis in RAW264.7 cells by enhancing intracellular arginine levels. Specifically, arginine generated by EcN can reduce S. Tm infection-induced generation of reactive oxygen species (ROS), chromatin condensation, DNA fragmentation, disruption of plasma membrane integrity, and decrease in mitochondrial membrane potential. Additionally, arginine administration in S. Tm-challenged mice decreased bacterial burden in the gut, suppressed Caspase-3 (CASPASE3) activation, mitigated both inflammation and apoptosis, and maintained epithelial barrier.<\/jats:p><\/jats:sec><jats:sec><jats:title>Result and discussion<\/jats:title><jats:p>Mechanistically, arginine suppresses S. Tm-driven B-cell lymphoma-2 (BCL2) downregulation, inhibiting apoptosis. Further analysis revealed that arginine may disrupt the interaction between ribosomal protein S3 (RPS3) and serine\/serine and arginine rich splicing factor 3 (SRSF3), thereby further suppressing the expression of apoptosis-related proteins induced by S. Tm. Our research offers new targets and approaches for treating bacterial infection-induced intestinal inflammation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1684234","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T05:31:17Z","timestamp":1760592677000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Arginine-mediated inhibition of macrophage apoptosis by Escherichia coli nissle 1917 in Salmonella typhimurium-induced intestinal inflammation"],"prefix":"10.3389","volume":"16","author":[{"given":"Lu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahui","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qixue","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanyan","family":"Chu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiarui","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenglong","family":"Shang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changlin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingman","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1053\/j.gastro.2023.09.019","article-title":"Pathobionts in inflammatory bowel disease: origins, underlying mechanisms, and implications for clinical care","volume":"166","author":"Gilliland","year":"2024","journal-title":"Gastroenterology."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2024.1410506","article-title":"Risk factors for inflammatory bowel disease: an umbrella review","volume":"14","author":"Wu","year":"2025","journal-title":"Front Cell Infect Microbiol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature10209","article-title":"Genetics and pathogenesis of inflammatory bowel disease","volume":"474","author":"Khor","year":"2011","journal-title":"Nature."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1016\/j.chom.2024.05.022","article-title":"Discovery of disease-adapted bacterial lineages in inflammatory bowel diseases","volume":"32","author":"Kumbhari","year":"2024","journal-title":"Cell Host Microbe"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i1.9","article-title":"Inflammatory bowel disease: pathogenesis","volume":"20","author":"Zhang","year":"2014","journal-title":"World J Gastroenterol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.733992","article-title":"The gut microbiota in inflammatory bowel disease","volume":"12","author":"Qiu","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0268-7","article-title":"Host-microbiota interactions in inflammatory bowel disease","volume":"20","author":"Caruso","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.chom.2025.02.004","article-title":"Neutrophil recruitment during intestinal inflammation primes Salmonella elimination by commensal E. coli in a context-dependent manner","volume":"33","author":"Cherrak","year":"2025","journal-title":"Cell Host Microbe"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05438-x","article-title":"Enterococci enhance Clostridioides difficile pathogenesis","volume":"611","author":"Smith","year":"2022","journal-title":"Nature."},{"key":"B10","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/nature18849","article-title":"Interactions between the microbiota and pathogenic bacteria in the gut","volume":"535","author":"B\u00e4umler","year":"2016","journal-title":"Nature."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2023.2172667","article-title":"Mouse models for bacterial enteropathogen infections: insights into the role of colonization resistance","volume":"15","author":"Herzog","year":"2023","journal-title":"Gut Microbes"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2010.223396","article-title":"Enteric Salmonella or Campylobacter infections and the risk of inflammatory bowel disease","volume":"60","author":"Jess","year":"2011","journal-title":"Gut."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1084\/jem.179.2.601","article-title":"and persist within spacious phagosomes","volume":"179","author":"Alpuche-Aranda","year":"1994","journal-title":"J Exp Med"},{"key":"B14","first-page":"599","article-title":"The treatment of intestinal diseases with Mutaflor. A multicenter retrospective study","volume":"107","author":"Sch\u00fctz","year":"1989","journal-title":"Fortschr Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/ibd.20377","article-title":"Clinical use of E. coli Nissle 1917 in inflammatory bowel disease","volume":"14","author":"Schultz","year":"2008","journal-title":"Inflammation Bowel Dis"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1159\/000333307","article-title":"Escherichia coli Nissle 1917 (Mutaflor): new insights into an old probiotic bacterium","volume":"29","author":"Jacobi","year":"2011","journal-title":"Dig Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1039\/d2fo00226d","article-title":"Probiotic Escherichia coli NISSLE 1917 for inflammatory bowel disease applications","volume":"13","author":"Zhao","year":"2022","journal-title":"Food Funct"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v22.i24.5505","article-title":"Role and mechanisms of action of Escherichia coli Nissle 1917 in the maintenance of remission in ulcerative colitis patients: An update","volume":"22","author":"Scaldaferri","year":"2016","journal-title":"World J Gastroenterol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.05.003","article-title":"Gut microbiota regulation of tryptophan metabolism in health and disease","volume":"23","author":"Agus","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0258-z","article-title":"Gut microbiota-derived metabolites as key actors in inflammatory bowel disease","volume":"17","author":"Lavelle","year":"2020","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B21","doi-asserted-by":"publisher","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":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cvsm.2016.09.011","article-title":"Managing fluid and electrolyte disorders in kidney disease","volume":"47","author":"Langston","year":"2017","journal-title":"Vet Clin North Am Small Anim Pract"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-003-1746-7","article-title":"Lactic acidosis","volume":"29","author":"De Backer","year":"2003","journal-title":"Intensive Care Med."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2007-0114OC","article-title":"Cyclic stretch of human lung cells induces an acidification and promotes bacterial growth","volume":"38","author":"Pugin","year":"2008","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1186\/s40001-023-01257-6","article-title":"Resveratrol alleviates DSS-induced IBD in mice by regulating the intestinal microbiota-macrophage-arginine metabolism axis","volume":"28","author":"Xu","year":"2023","journal-title":"Eur J Med Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.11.4304","article-title":"The ability of Salmonella to enter mammalian cells is affected by bacterial growth state","volume":"87","author":"Lee","year":"1990","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3791\/51759","article-title":"High-throughput assay to phenotype Salmonella enterica typhimurium association, invasion, and replication in macrophages","volume":"90","author":"Wu","year":"2014","journal-title":"J Vis Exp"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.04023-14","article-title":"Multigene editing in the Escherichia coli genome via the CRISPR-Cas9 system","volume":"81","author":"Jiang","year":"2015","journal-title":"Appl Environ Microbiol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/620834","article-title":"Conditional inactivation of pten with EGFR overexpression in schwann cells models sporadic MPNST","volume":"2012","author":"Keng","year":"2012","journal-title":"Sarcoma."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function","volume":"38","author":"Warde-Farley","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq897","article-title":"HitPredict: a database of quality assessed protein-protein interactions in nine species","volume":"39","author":"Patil","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"B32","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.chom.2013.06.007","article-title":"Probiotic bacteria reduce salmonella typhimurium intestinal colonization by competing for iron","volume":"14","author":"Deriu","year":"2013","journal-title":"Cell Host Microbe"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.0901811","article-title":"An integrated imaging approach to the study of oxidative stress generation by mitochondrial dysfunction in living cells","volume":"118","author":"Cheng","year":"2010","journal-title":"Environ Health Perspect"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.5.2839-2858.2003","article-title":"Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host","volume":"71","author":"Barthel","year":"2003","journal-title":"Infect Immun"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2023.1158888","article-title":"Salmonella Enteritidis activates inflammatory storm via SPI-1 and SPI-2 to promote intracellular proliferation and bacterial virulence","volume":"13","author":"Xiong","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1039\/d4fo02810d","article-title":"Dietary limonin alleviates Salmonella Typhimurium-induced colitis via dual targeting virulence SopB and SopE2 and inhibiting RAC1\/CDC42\/Arp2\/3 pathway and regulating gut microbiota","volume":"16","author":"Cui","year":"2025","journal-title":"Food Funct"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/cells9102325","article-title":"SRSF3 is a critical requirement for inclusion of exon 3 of BIS pre-mRNA","volume":"9","author":"Baek","year":"2020","journal-title":"Cells."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203043","article-title":"Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death","volume":"18","author":"Lee","year":"1999","journal-title":"Oncogene."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.26396-0","article-title":"H and X determinants encode microcins M and H47, which might utilize the catecholate siderophore receptors FepA, Cir, Fiu and IroN","volume":"149","author":"Patzer","year":"2003","journal-title":"Microbiology."},{"key":"B40","doi-asserted-by":"publisher","first-page":"21381","DOI":"10.1038\/s41598-025-99160-z","article-title":"Extracellular vesicles derived from Lactobacillus gasseri GFC-1220 alleviate inflammation via the TLR4\/NF-\u03baB signaling pathway in LPS-stimulated RAW264.7 macrophages","volume":"15","author":"Koh","year":"2025","journal-title":"Sci Rep"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.31083\/IJVNR31275","article-title":"Lactiplantibacillus plantarum YDJ-03 and limosilactobacillus fermentum YDJ-6 alleviate metabolic syndrome in mice","volume":"95","author":"Chen","year":"2025","journal-title":"Int J Vitam Nutr Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2024.10.001","article-title":"Short-chain fatty acids in viral infection: the underlying mechanisms, opportunities, and challenges","volume":"33","author":"Tsui","year":"2025","journal-title":"Trends Microbiol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.engmic.2022.100012","article-title":"A comparative study on the genomes, transcriptomes, and metabolic properties of Escherichia coli strains Nissle 1917, BL21(DE3), and MG1655","volume":"2","author":"Zhao","year":"2022","journal-title":"Eng Microbiol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"5068","DOI":"10.1016\/j.cell.2023.09.011","article-title":"Arginine reprograms metabolism in liver cancer via RBM39","volume":"186","author":"Mossmann","year":"2023","journal-title":"Cell."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.127801","article-title":"Arginine metabolic control of airway inflammation","volume":"5","author":"Asosingh","year":"2020","journal-title":"JCI Insight"},{"key":"B46","doi-asserted-by":"publisher","first-page":"2581","DOI":"10.1016\/j.molcel.2025.05.035","article-title":"BAG2 releases SAMD4B upon sensing of arginine deficiency to promote tumor cell survival","volume":"85","author":"Chen","year":"2025","journal-title":"Mol Cell"},{"key":"B47","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1136\/ard-2022-223626","article-title":"L-arginine metabolism inhibits arthritis and inflammatory bone loss","volume":"83","author":"Cao","year":"2024","journal-title":"Ann Rheum Dis"},{"key":"B48","doi-asserted-by":"publisher","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":"B49","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1053\/j.gastro.2022.07.004","article-title":"Altered gut microbiome composition and function are associated with gut barrier dysfunction in healthy relatives of patients with crohn\u2019s disease","volume":"163","author":"Leibovitzh","year":"2022","journal-title":"Gastroenterology."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00120-23","article-title":"Arginine metabolism powers salmonella resistance to oxidative stress","volume":"91","author":"Margolis","year":"2023","journal-title":"Infect Immun"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3390\/cells12081164","article-title":"Timing of Interleukin-4 Stimulation of Macrophages Determines Their Anti-Microbial Activity during Infection with Salmonella enterica Serovar Typhimurium","volume":"12","author":"Brigo","year":"2023","journal-title":"Cells."},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13805","article-title":"HN1 Functions in Protein Synthesis Regulation via mTOR-RPS6 Axis and Maintains Nucleolar Integrity","volume":"58","author":"\u00d6zduman","year":"2025","journal-title":"Cell Prolif."},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202502412","article-title":"Gasdermin D-mediated pyroptosis exerts two opposite effects of resisting enzymatic digestion and expanding inflammatory response in acute pancreatitis","volume":"29","author":"Liu","year":"2025","journal-title":"Adv Sci (Weinh)."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113995","article-title":"ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition","volume":"43","author":"Zou","year":"2024","journal-title":"Cell Rep"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/j.ccell.2025.03.015","article-title":"Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion","volume":"43","author":"Zhu","year":"2025","journal-title":"Cancer Cell"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1684234\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T05:31:19Z","timestamp":1760592679000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1684234\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,16]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2025.1684234"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1684234","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,16]]},"article-number":"1684234"}}