{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:39:28Z","timestamp":1789043968742,"version":"build-2803163510"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T00:00:00Z","timestamp":1738540800000},"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. Cell. Infect. Microbiol."],"abstract":"<jats:p>Indole, a crucial bacterial signaling molecule, plays a fundamental role in regulating various physiological processes within bacteria, including growth, acid tolerance, biofilm development, motility, and other cellular functions. Its regulatory influence extends beyond indole-producing bacteria, significantly impacting the physiological activities in non-indole-producing species. In this study, we demonstrate that indole enhances the pathogenicity and viability of <jats:italic>Klebsiella pneumoniae<\/jats:italic> using the <jats:italic>Galleria mellonella<\/jats:italic> infection model and serum killing assay. Concurrently, indole has varying effects on biofilm formation in <jats:italic>K. pneumoniae<\/jats:italic>, with some strains showing enhanced biofilm formation ability. To elucidate the underlying molecular mechanisms, transcriptome analysis revealed that indole exposure in <jats:italic>K. pneumoniae<\/jats:italic> led to the upregulation of genes associated with pili formation and iron acquisition systems, while simultaneously inducing oxidative stress responses. Additionally, our analysis uncovered extensive metabolic remodeling. Specifically, we observed significant upregulation of genes involved in simple carbohydrate utilization pathways, including those responsible for galactose, mannose, and maltose metabolism, as well as enhanced expression of genes associated with pyrimidine biosynthesis. These findings collectively indicate that indole enhances the intestinal colonization and pathogenicity of <jats:italic>K. pneumoniae<\/jats:italic> primarily by modulation of fimbriae expression and metabolic pathway regulation.<\/jats:p>","DOI":"10.3389\/fcimb.2025.1546991","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T06:35:44Z","timestamp":1738564544000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Modulation of virulence and metabolic profiles in Klebsiella pneumoniae under indole-mediated stress response"],"prefix":"10.3389","volume":"15","author":[{"given":"Xueyao","family":"Fang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longhua","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumin","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Hang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingwei","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuwen","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianhua","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoshi","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"129","DOI":"10.4161\/viru.22974","article-title":"Multi-functional analysis of Klebsiella pneumoniae fimbrial types in adherence and biofilm formation","volume":"4","author":"Alc\u00e1ntar-Curiel","year":"2013","journal-title":"Virulence"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuad011","article-title":"Galleria mellonella\u2013intracellular bacteria pathogen infection models: the ins and outs","volume":"47","author":"Asai","year":"2023","journal-title":"FEMS Microbiol. Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1007\/s12192-023-01392-3","article-title":"A review on oligomeric polydispersity and oligomers-dependent holding chaperone activity of the small heat-shock protein IbpB of Escherichia coli","volume":"28","author":"Azaharuddin","year":"2023","journal-title":"Cell Stress Chaperones"},{"key":"B4","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.jgar.2024.04.013","article-title":"The correlation between intestinal colonization and infection of carbapenem-resistant Klebsiella pneumoniae: A systematic review","volume":"38","author":"Cai","year":"2024","journal-title":"J. Global Antimicrobial Resistance"},{"key":"B5","doi-asserted-by":"publisher","first-page":"7427","DOI":"10.1073\/pnas.0307888101","article-title":"Carbon nutrition of Escherichia coli in the mouse intestine","volume":"101","author":"Chang","year":"2004","journal-title":"Proc. Natl. Acad. Sci. United States America"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2023.106026","article-title":"Molecular basis of Klebsiella pneumoniae colonization in host","volume":"177","author":"Chen","year":"2023","journal-title":"Microbial Pathogenesis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1002\/cphc.201200793","article-title":"The effect of bacterial signal indole on the electrical properties of lipid membranes","volume":"14","author":"Chimerel","year":"2013","journal-title":"Chemphyschem"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.micres.2020.126551","article-title":"Phenotypical and molecular assessment of the virulence potential of KPC-3-producing Klebsiella pneumoniae ST392 clinical isolates","volume":"240","author":"D\u2019Apolito","year":"2020","journal-title":"Microbiological Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"8093","DOI":"10.1128\/AEM.02787-15","article-title":"A rapid and specific method for the detection of indole in complex biological samples","volume":"81","author":"Darkoh","year":"2015","journal-title":"Appl. Environ. Microbiol."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/srep38879","article-title":"The mechanism of a formaldehyde-sensing transcriptional regulator","volume":"6","author":"Denby","year":"2016","journal-title":"Sci. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1086\/322972","article-title":"Biofilm formation: A clinically relevant microbiological process","volume":"33","author":"Donlan","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1074\/jbc.REV118.002806","article-title":"Hsp90 and Hsp70 chaperones: Collaborators in protein remodeling","volume":"294","author":"Genest","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B13","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1093\/cid\/cix270","article-title":"Gastrointestinal carriage is a major reservoir of Klebsiella pneumoniae infection in intensive care patients","volume":"65","author":"Gorrie","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1007\/s12192-015-0623-y","article-title":"Interactions of Escherichia coli molecular chaperone HtpG with DnaA replication initiator DNA","volume":"20","author":"Grudniak","year":"2015","journal-title":"Cell Stress Chaperones"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.01277-21","article-title":"Bidirectional cell-cell communication via indole and cyclo(Pro-tyr) modulates interspecies biofilm formation","volume":"87","author":"Hashidoko","year":"2021","journal-title":"Appl. Environ. Microbiol."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI174726","article-title":"Dietary carbohydrates regulate intestinal colonization and dissemination of Klebsiella pneumoniae","volume":"134","author":"Hecht","year":"2024","journal-title":"J. Clin. Invest."},{"key":"B17","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1099\/mic.0.020420-0","article-title":"Secreted indole serves as a signal for expression of type III secretion system translocators in enterohaemorrhagic Escherichia coli O157\u200a:\u200aH7","volume":"155","author":"Hirakawa","year":"2009","journal-title":"Microbiology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1093\/infdis\/jiy615","article-title":"A novel role for the Klebsiella pneumoniae sap (Sensitivity to antimicrobial peptides) transporter in intestinal cell interactions, innate immune responses, liver abscess, and virulence","volume":"219","author":"Hsu","year":"2019","journal-title":"J. Infect. Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.1111\/mmi.14386","article-title":"The Escherichia coli MarA protein regulates the ycgZ-ymgABC operon to inhibit biofilm formation","volume":"112","author":"Kettles","year":"2019","journal-title":"Mol. Microbiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1007\/s12275-015-5273-3","article-title":"Indole: a signaling molecule or a mere metabolic byproduct that alters bacterial physiology at a high concentration","volume":"53","author":"Kim","year":"2015","journal-title":"J. Microbiol."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/jb.00024-24","article-title":"Siderophore-mediated iron acquisition by Klebsiella pneumoniae","volume":"206","author":"Kumar","year":"2019","journal-title":"J. Bacteriol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e01031","DOI":"10.1128\/mBio.01031-19","article-title":"Indole signaling at the host-microbiota-pathogen interface","volume":"10","author":"Kumar","year":"2019","journal-title":"mBio"},{"key":"B23","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1128\/AEM.01144-08","article-title":"F1C fimbriae play an important role in biofilm formation and intestinal colonization by the Escherichia coli commensal strain Nissle 1917","volume":"75","author":"Lasaro","year":"2009","journal-title":"Appl. Environ. Microbiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1111\/j.1751-7915.2008.00061.x","article-title":"Indole and 7-hydroxyindole diminish Pseudomonas aeruginosa virulence","volume":"2","author":"Lee","year":"2009","journal-title":"Microbial Biotechnol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"4543","DOI":"10.1007\/s00253-012-4674-z","article-title":"Indole and 7-benzyloxyindole attenuate the virulence of Staphylococcus aureus","volume":"97","author":"Lee","year":"2013","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1111\/1462-2920.12560","article-title":"The multifaceted roles of the interspecies signalling molecule indole in Agrobacterium tumefaciens","volume":"17","author":"Lee","year":"2015","journal-title":"Environ. Microbiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1111\/j.1574-6976.2009.00204.x","article-title":"Indole as an intercellular signal in microbial communities","volume":"34","author":"Lee","year":"2010","journal-title":"FEMS Microbiol. Rev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.tim.2015.08.001","article-title":"Roles of indole as an interspecies and interkingdom signaling molecule","volume":"23","author":"Lee","year":"2015","journal-title":"Trends Microbiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1007\/s10096-020-03890-z","article-title":"Identification of hypervirulent Klebsiella pneumoniae isolates using the string test in combination with Galleria mellonella infectivity","volume":"39","author":"Li","year":"2020","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1093\/jac\/dkz023","article-title":"Whole genome assembly and functional portrait of hypervirulent extensively drug-resistant NDM-1 and KPC-2 co-producing Klebsiella pneumoniae of capsular serotype K2 and ST86","volume":"74","author":"Liu","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00261-16","article-title":"Molecular epidemiology of colonizing and infecting isolates of Klebsiella pneumoniae","volume":"1","author":"Martin","year":"2016","journal-title":"mSphere"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/aem.65.8.3433-3440.1999","article-title":"Heat-induced expression and chemically induced expression of the escherichia coli stress protein htpG are affected by the growth environment","volume":"65","author":"Mason","year":"1999","journal-title":"Appl. Environ. Microbiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"6363","DOI":"10.1016\/j.tet.2014.05.089","article-title":"Controlling bacterial behavior with indole-containing natural products and derivatives","volume":"70","author":"Melander","year":"2014","journal-title":"Tetrahedron"},{"key":"B34","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/s41522-024-00546-0","article-title":"Klebsiella pneumoniae AI-2 transporters mediate interspecies interactions and composition in a three-species biofilm community","volume":"10","author":"Muzaki","year":"2024","journal-title":"NPJ Biofilms Microbiomes"},{"key":"B35","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1046\/j.1365-2958.1998.01062.x","article-title":"Flagellar and twitching motility are necessary for Pseudomonas aeruginosa biofilm development","volume":"30","author":"O\u2019Toole","year":"1998","journal-title":"Mol. Microbiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.micres.2018.08.010","article-title":"Transcriptional regulation of galF by RcsAB affects capsular polysaccharide formation in Klebsiella pneumoniae NTUH-K2044","volume":"216","author":"Peng","year":"2018","journal-title":"Microbiological Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.coi.2021.02.006","article-title":"Indole derivatives, microbiome and graft versus host disease","volume":"70","author":"Qayed","year":"2021","journal-title":"Curr. Opin. Immunol."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112245","article-title":"Indole-based derivatives as potential antibacterial activity against methicillin-resistance Staphylococcus aureus (MRSA)","volume":"194","author":"Qin","year":"2020","journal-title":"Eur. J. Medicinal Chem."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00001-19","article-title":"Hypervirulent klebsiella pneumoniae","volume":"32","author":"Russo","year":"2019","journal-title":"Clin. Microbiol. Rev."},{"key":"B40","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1186\/s12866-024-03443-w","article-title":"Downregulation of Klebsiella pneumoniae RND efflux pump genes following indole signal produced by Escherichia coli","volume":"24","author":"Salama","year":"2024","journal-title":"BMC Microbiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.ijantimicag.2015.04.012","article-title":"Effect of plasmids harbouring blaCTX-M on the virulence and fitness of Escherichia coli ST131 isolates","volume":"46","author":"Shin","year":"2015","journal-title":"Int. J. Antimicrobial Agents"},{"key":"B42","doi-asserted-by":"publisher","first-page":"4055","DOI":"10.1128\/IAI.00494-08","article-title":"Characterization of Klebsiella pneumoniae Type 1 Fimbriae by Detection of Phase Variation during Colonization and Infection and Impact on Virulence","volume":"76","author":"Struve","year":"2008","journal-title":"Infection Immun."},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1093\/ismejo\/wrae054","article-title":"Hypervirulent Klebsiella pneumoniae employs genomic island encoded toxins against bacterial competitors in the gut","volume":"18","author":"Tan","year":"2024","journal-title":"ISME J."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms10050930","article-title":"Production of indole and indole-related compounds by the intestinal microbiota and consequences for the host: the good, the bad, and the ugly","volume":"10","author":"Tennoune","year":"2022","journal-title":"Microorganisms"},{"key":"B45","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1101\/gad.499409","article-title":"The BLUF-EAL protein YcgF acts as a direct anti-repressor in a blue-light response of Escherichia coli","volume":"23","author":"Tschowri","year":"2009","journal-title":"Genes Dev."},{"key":"B46","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1111\/j.1365-2958.2012.08147.x","article-title":"Molecular function and potential evolution of the biofilm-modulating blue light-signalling pathway of Escherichia coli","volume":"85","author":"Tschowri","year":"2012","journal-title":"Mol. Microbiol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/nchembio.915","article-title":"Signaling-mediated bacterial persister formation","volume":"8","author":"Vega","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"14420","DOI":"10.1073\/pnas.1308085110","article-title":"Salmonella typhimurium intercepts Escherichia coli signaling to enhance antibiotic tolerance","volume":"110","author":"Vega","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B49","doi-asserted-by":"publisher","first-page":"5181","DOI":"10.1128\/AEM.00242-10","article-title":"Requirement of purine and pyrimidine synthesis for colonization of the mouse intestine by escherichia coli","volume":"76","author":"Vogel-Scheel","year":"2010","journal-title":"Appl. Environ. Microbiol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1007\/s12088-019-00830-0","article-title":"Indole and derivatives modulate biofilm formation and antibiotic tolerance of Klebsiella pneumoniae","volume":"59","author":"Yaikhan","year":"2019","journal-title":"Indian J. Microbiol."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20143423","article-title":"Biofilms: the microbial \u201cProtective clothing\u201d in extreme environments","volume":"20","author":"Yin","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.tim.2020.02.007","article-title":"Local and universal action: the paradoxes of indole signalling in bacteria","volume":"28","author":"Zarkan","year":"2020","journal-title":"Trends Microbiol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1546991\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T06:35:48Z","timestamp":1738564548000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1546991\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,3]]},"references-count":52,"alternative-id":["10.3389\/fcimb.2025.1546991"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2025.1546991","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,3]]},"article-number":"1546991"}}