Microbial extracellular vesicles in the lung: friends in health, agents in disease

Abstract

Microbial extracellular vesicles (mEVs) are emerging as key mediators at the host-microbe interface in the lung, playing a remarkable dual role as both pathogenic drivers and therapeutic modulators. These nano-sized, membrane-bound structures (20-400 nm) secreted by bacteria, fungi, and other microorganisms carry diverse bioactive cargo including lipids, proteins, and nucleic acids that can profoundly influence host immune responses and tissue homeostasis. mEVs derived from probiotic bacteria demonstrate significant therapeutic potential as immunomodulatory agents capable of reducing pulmonary inflammation and enhancing epithelial barrier function. These probiotic-derived vesicles represent a novel class of postbiotics - bioactive microbial products that confer health benefits without requiring live microbial cells. Conversely, in pathogenic contexts, mEVs from bacteria such as Pseudomonas aeruginosa and Escherichia coli trigger robust inflammatory responses in the lung through pattern recognition receptor activation, particularly Toll-like receptors (TLRs)-2 and TLR-4, leading to upregulation of pro-inflammatory cytokines and contributing to chronic respiratory conditions including asthma and chronic obstructive pulmonary disease. Given its extensive surface area and highly specialized immune network, the lung represents a highly receptive site for mEV-mediated interactions. This review synthesizes evidence on pathogenic mechanisms of mEVs and explores their therapeutic potential in respiratory medicine, with specific focus on: (1) the role of environmentally-derived mEVs from dust and airborne sources in chronic respiratory inflammation; (2) recent experimental evidence of probiotic-derived mEVs therapeutic effects across diverse pulmonary conditions and (3) the concept of mEVs as both protective postbiotics and inflammatory triggers in the lung.

Keywords

Microbial extracellular vesicles / respiratory diseases / probiotic extracellular vesicles / host-microbe interactions / postbiotics

References

[1] Zhang R,Wu Y,Luan Q.Pathogenic mechanisms and potential applications of extracellular vesicles from periodontal pathogens in periodontitis.Front Immunol2024;15:1513983 PMCID:PMC11695242

[2] Gill S,Forterre P.Extracellular membrane vesicles in the three domains of life and beyond.FEMS Microbiol Rev2019;43:273-303 PMCID:PMC6524685

[3] Di Naro M,Mukhtar F.Extracellular vesicles in bacteria, archaea, and eukaryotes: mechanisms of inter-kingdom communication and clinical implications.Microorganisms2025;13:636 PMCID:PMC11944275

[4] Toyofuku M,Hasegawa Y,Nomura N.Bacterial membrane vesicles, an overlooked environmental colloid: biology, environmental perspectives and applications.Adv Colloid Interface Sci2015;226:65-77

[5] Toyofuku M,Kaparakis-Liaskos M.Composition and functions of bacterial membrane vesicles.Nat Rev Microbiol2023;21:415-30

[6] Brown L,Prados-Rosales R.Through the wall: extracellular vesicles in Gram-positive bacteria, mycobacteria and fungi.Nat Rev Microbiol2015;13:620-30 PMCID:PMC4860279

[7] Mashburn-Warren L,Whiteley M.Gram-negative outer membrane vesicles: beyond the cell surface.Geobiol2008;6:214-9 PMCID:PMC3113409

[8] Bose S,Singh DV.Extracellular vesicles: an emerging platform in gram-positive bacteria.Microb Cell2020;7:312-22 PMCID:PMC7713254

[9] Morishita M,Yamawaki Y,Katsumi H.Activation of host immune cells by probiotic-derived extracellular vesicles via TLR2-mediated signaling pathways.Biol Pharm Bull2022;45:354-9

[10] Chen X,Xie J.Immunomodulatory effects of probiotic-derived extracellular vesicles: opportunities and challenges.J Agric Food Chem2024;72:19259-73

[11] Li Z,Fang X,Hu X.Dietary Lactobacillus johnsonii-derived extracellular vesicles ameliorate acute colitis by regulating gut microbiota and maintaining intestinal barrier homeostasis.Food Funct2024;15:11757-79

[12] Rima M,El Hayek E,Fajloun Z.Unveiling the wonders of bacteria-derived extracellular vesicles: from fundamental functions to beneficial applications.Heliyon2025;11:e42509 PMCID:PMC11869109

[13] Lima S,Tamagnini P.Extracellular vesicles: an overlooked secretion system in cyanobacteria.Life2020;10:129 PMCID:PMC7459746

[14] Bril’kov MS,Jakubec M.Bacterial extracellular vesicles: towards realistic models for bacterial membranes in molecular interaction studies by surface plasmon resonance.Front Mol Biosci2023;10:1277963 PMCID:PMC10751319

[15] Díaz-Garrido N,Baldomà L.Microbiota-derived extracellular vesicles in interkingdom communication in the gut.J Extracell Vesicles2021;10:e12161 PMCID:PMC8568775

[16] Welsh JA, Goberdhan DCI, O’Driscoll L, et al.; MISEV Consortium. Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J Extracell Vesicles. 2024;13:e12404. PMCID:PMC11082720

[17] Ahmadi Badi S,Fateh A.Microbiota-derived extracellular vesicles as new systemic regulators.Front Microbiol2017;8:1610 PMCID:PMC5573799

[18] Xiu L,Lin G,Huang L.Bacterial membrane vesicles: orchestrators of interkingdom interactions in microbial communities for environmental adaptation and pathogenic dynamics.Front Immunol2024;15:1371317 PMCID:PMC10991846

[19] Zhang Y,Fan J,Tao S.Impact of probiotics-derived extracellular vesicles on livestock gut barrier function.J Anim Sci Biotechnol2024;15:149 PMCID:PMC11542448

[20] Wu Q,Fu C.Insights into the unique roles of extracellular vesicles for gut health modulation: mechanisms, challenges, and perspectives.Curr Res Microb Sci2024;7:100301 PMCID:PMC11550031

[21] O’Donoghue EJ.Mechanisms of outer membrane vesicle entry into host cells.Cell Microbiol2016;18:1508-17 PMCID:PMC5091637

[22] Kaparakis-Liaskos M.Immune modulation by bacterial outer membrane vesicles.Nat Rev Immunol2015;15:375-87

[23] Chen S,Zou X.The role and mechanisms of gram-negative bacterial outer membrane vesicles in inflammatory diseases.Front Immunol2023;14:1157813 PMCID:PMC10313905

[24] Kaparakis M,Carneiro L.Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells.Cell Microbiol2010;12:372-85

[25] Wang X,Lee JC.Orchestration of human macrophage NLRP3 inflammasome activation by Staphylococcus aureus extracellular vesicles.Proc Natl Acad Sci U S A2020;117:3174-84 PMCID:PMC7022218

[26] Deo P,Han ML.Mitochondrial dysfunction caused by outer membrane vesicles from Gram-negative bacteria activates intrinsic apoptosis and inflammation.Nat Microbiol2020;5:1418-27

[27] Liu T,Joo D.NF-κB signaling in inflammation.Signal Transduct Target Ther2017;2:17023 PMCID:PMC5661633

[28] Chen Z,Morelli AE.Impact of extracellular vesicles on innate immunity.Curr Opin Organ Transplant2019;24:670-8 PMCID:PMC7328797

[29] Rodovalho VR,Rabah H.Extracellular vesicles produced by the probiotic Propionibacterium freudenreichii CIRM-BIA 129 mitigate inflammation by modulating the NF-κB pathway.Front Microbiol2020;11:1544 PMCID:PMC7359729

[30] Melo-Marques I,Empadinhas N.Bacterial extracellular vesicles at the interface of gut microbiota and immunity.Gut Microbes2024;16:2396494 PMCID:PMC11444517

[31] Alvarez CS,Bosch M,Baldomà L.Outer membrane vesicles and soluble factors released by probiotic Escherichia coli nissle 1917 and commensal ECOR63 enhance barrier function by regulating expression of tight junction proteins in intestinal epithelial cells.Front Microbiol2016;7:1981 PMCID:PMC5156689

[32] Lee HJ.Microbe-host communication by small RNAs in extracellular vesicles: vehicles for transkingdom RNA transportation.Int J Mol Sci2019;20:1487 PMCID:PMC6472211

[33] Kim HJ,Kim KH.The microbiome of the lung and its extracellular vesicles in nonsmokers, healthy smokers and COPD patients.Exp Mol Med2017;49:e316 PMCID:PMC5420800

[34] Kageyama T,Tanaka S.Physiological and immunological barriers in the lung.Semin Immunopathol2024;45:533-47 PMCID:PMC11136722

[35] Lloyd CM.Lung homeostasis: influence of age, microbes, and the immune system.Immunity2017;46:549-61

[36] Dickson RP,Martinez FJ.The microbiome and the respiratory tract.Annu Rev Physiol2016;78:481-504 PMCID:PMC4751994

[37] Man WH,Bogaert D.The microbiota of the respiratory tract: gatekeeper to respiratory health.Nat Rev Microbiol2017;15:259-70 PMCID:PMC7097736

[38] O’Dwyer DN,Moore BB.The lung microbiome, immunity, and the pathogenesis of chronic lung disease.J Immunol2016;196:4839-47 PMCID:PMC4894335

[39] Shen Y,Lawson GW,Ashwell JD.Outer membrane vesicles of a human commensal mediate immune regulation and disease protection.Cell Host Microbe2012;12:509-20 PMCID:PMC3895402

[40] Keshavarz Aziziraftar S,Hashemi D.The beneficial effects of Akkermansia muciniphila and its derivatives on pulmonary fibrosis.Biomed Pharmacother2024;180:117571

[41] Fadaee M,Lahouty M,Nezhadi J.Postbiotics and extracellular vesicles: mechanisms of action and clinical promise in respiratory infections and inflammation.Infect Genet Evol2025;135:105837

[42] Bisaccia P,Hochuli AHD.Overview of extracellular vesicles as biomarkers and therapeutic tools in pediatric diseases: focus on the gut-lung axis.Extracell Vesicles Circ Nucl Acids2025;6:921-36 PMCID:PMC12809682

[43] Albano GD.From microbiota to cancer: role of extracellular vesicles in gut-lung axis.Cancers2025;17:3946 PMCID:PMC12730553

[44] Cordaillat-Simmons M,Pot B.Live biotherapeutic products: the importance of a defined regulatory framework.Exp Mol Med2020;52:1397-406 PMCID:PMC8080583

[45] Butel MJ.Probiotics, gut microbiota and health.Med Mal Infect2014;44:1-8

[46] Macia L,Hosseini-Beheshti E.Host- and microbiota-derived extracellular vesicles, immune function, and disease development.Int J Mol Sci2019;21:107 PMCID:PMC6982009

[47] Krzyżek P,Vitale I.Extracellular vesicles of probiotics: shedding light on the biological activity and future applications.Pharmaceutics2023;15:522 PMCID:PMC9967243

[48] Raja M,Sudhakaran G,Arockiaraj J.Exploring the potential of bacterial-derived EVs for targeted enzyme replacement therapy: mechanisms, applications, and future directions.Arch Microbiol2025;207:118

[49] Molina-Tijeras JA,Rodríguez-Cabezas ME.The immunomodulatory properties of extracellular vesicles derived from probiotics: a novel approach for the management of gastrointestinal diseases.Nutrients2019;11:1038 PMCID:PMC6567093

[50] Domínguez Rubio AP, D’Antoni CL, Piuri M, Pérez OE. Probiotics, their extracellular vesicles and infectious diseases.Front Microbiol2022;13:864720 PMCID:PMC9006447

[51] Piqué N,Miñana-Galbis D.Health benefits of heat-killed (tyndallized) probiotics: an overview.Int J Mol Sci2019;20:2534 PMCID:PMC6566317

[52] Durack J.Promotion of epithelial barrier integrity via probiotic-derived products.J Pediatr Gastroenterol Nutr2017;64:335-6

[53] Liu L,Xu Z.Intranasal administration of Clostridium butyricum and its derived extracellular vesicles alleviate LPS-induced acute lung injury.Microbiol Spectr2024;12:e0210824 PMCID:PMC11619349

[54] Zhao Q,Jiang Y.Lactiplantibacillus plantarum -derived extracellular vesicles alleviate acute lung injury by inhibiting ferroptosis of macrophages.J Nanobiotechnol2025;23:307 PMCID:PMC12016285

[55] Ciprandi G.Probiotics in children with asthma.Childre2022;9:978 PMCID:PMC9316460

[56] Sim S,Kim KS.Micrococcus luteus-derived extracellular vesicles attenuate neutrophilic asthma by regulating miRNAs in airway epithelial cells.Exp Mol Med2023;55:196-204 PMCID:PMC9898544

[57] Lee DH,Lee HR.Immunoregulatory effects of Lactococcus lactis-derived extracellular vesicles in allergic asthma.Clin Transl Allergy2022;12:e12138 PMCID:PMC8967260

[58] Ciprandi G,Cioffi L,Drago L.The probiotics in pediatric asthma management (PROPAM) study: a post hoc analysis in allergic children.Ann Allergy Asthma Immunol2022;129:111-3

[59] La Mantia I,Drago L.Probiotics in the add-on treatment of rhinosinusitis: a clinical experience.J Biol Regul Homeost Agents2020;3:27-34

[60] Drago L,Giuliano M.The probiotics in pediatric asthma management (PROPAM) study in the primary care setting: a randomized, controlled, double-blind trial with Ligilactobacillus salivarius LS01 (DSM 22775) and Bifidobacterium breve B632 (DSM 24706).J Immunol Res2022;2022:3837418 PMCID:PMC8786459

[61] Schmid AM,Wysmołek M.Extracellular vesicles of the probiotic bacteria E. coli O83 activate innate immunity and prevent allergy in mice.Cell Commun Signal2023;21:297 PMCID:PMC10588034

[62] Preet R,Shim J.Gut commensal Bifidobacterium-derived extracellular vesicles modulate the therapeutic effects of anti-PD-1 in lung cancer.Nat Commun2025;16:3500 PMCID:PMC11993705

[63] Park KS,Lötvall J.Extracellular vesicles and the lung: from disease pathogenesis to biomarkers and treatments.Physiol Rev2025;105:1733-821

[64] Yang J,Park HJ,Kim YK.The impact of bacteria-derived ultrafine dust particles on pulmonary diseases.Exp Mol Med2020;52:338-47 PMCID:PMC7156658

[65] Kim YY,Lee JY.Importance of microbial extracellular vesicle in the pathogenesis of asthma and chronic obstructive pulmonary disease and its diagnostic potential.Asia Pac Allergy2020;10:e25 PMCID:PMC7402947

[66] Yang J,Kim YS.Lung disease diagnostic model through IgG sensitization to microbial extracellular vesicles.Allergy Asthma Immunol Res2020;12:669-83 PMCID:PMC7224999

[67] Kim YS,Kim MH.IgG sensitization to extracellular vesicles in indoor dust is closely associated with the prevalence of non-eosinophilic asthma, COPD, and lung cancer.Allergy Asthma Immunol Res2016;8:198-205 PMCID:PMC4773207

[68] Yun H,Kim YK.Examining the bacterial diversity including extracellular vesicles in air and soil: implications for human health.PLoS ONE2025;20:e0320916 PMCID:PMC11960916

[69] Jang JY,Choi JJ.Insight into microbial extracellular vesicles as key communication materials and their clinical implications for lung cancer (Review).Int J Mol Med2025;56:119 PMCID:PMC12176265

[70] Park KS,Jang SC.Pulmonary inflammation induced by bacteria-free outer membrane vesicles from Pseudomonas aeruginosa.Am J Respir Cell Mol Biol2013;49:637-45

[71] Kim YS,Choi EJ.Extracellular vesicles derived from Gram-negative bacteria, such as Escherichia coli, induce emphysema mainly via IL-17A-mediated neutrophilic inflammation.J Immunol2015;194:3361-8

[72] Kim YS,Lee WH.Extracellular vesicles, especially derived from Gram-negative bacteria, in indoor dust induce neutrophilic pulmonary inflammation associated with both Th1 and Th17 cell responses.Clin Exp Allergy2013;43:443-54

[73] Qin S,Zhou C.Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics.Signal Transduct Target Ther2022;7:199 PMCID:PMC9233671

[74] Xie Y,Wang LL,Wu M.Outer membrane vesicle contributes to the Pseudomonas aeruginosa resistance to antimicrobial peptides in the acidic airway of bronchiectasis patients.MedComm2025;6:e70084 PMCID:PMC11782972

[75] Yang D,Wang J.Dysregulated lung commensal bacteria drive interleukin-17B production to promote pulmonary fibrosis through their outer membrane vesicles.Immunity2019;50:692-706.e7

[76] Moghaddam ZS,Halimi S.Bacterial extracellular vesicles: bridging pathogen biology and therapeutic innovation.Acta Biomater2025;200:1-20

[77] Hong SW,Lee EY.Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation.Allergy2011;66:351-9 PMCID:PMC3052535

[78] Hong SW,Min TK.An important role of α-hemolysin in extracellular vesicles on the development of atopic dermatitis induced by Staphylococcus aureus.PLoS ONE2014;9:e100499 PMCID:PMC4084635

[79] Verta R,Skovronova R.Generation of spike-extracellular vesicles (S-EVs) as a tool to mimic SARS-CoV-2 interaction with host cells.Cells2022;11:146 PMCID:PMC8750506

[80] Fu Y.Tagged extracellular vesicles with the RBD of the viral spike protein for delivery of antiviral agents against SARS-COV-2 infection.J Control Release2021;335:584-95 PMCID:PMC8172277

[81] Giordano NP,Dalebroux ZD.Outer membrane lipid secretion and the innate immune response to gram-negative bacteria.Infect Immun2020;88:e00920-19 PMCID:PMC7309610

[82] Chen MY,Pan YC.Endotoxin-free outer membrane vesicles for safe and modular anticancer immunotherapy.ACS Synth Biol2025;14:148-60 PMCID:PMC11744915

[83] Rossi O,Giannelli C.Modulation of endotoxicity of Shigella generalized modules for membrane antigens (GMMA) by genetic lipid A modifications: relative activation of TLR4 and TLR2 pathways in different mutants.J Biol Chem2014;289:24922-35 PMCID:PMC4155660

[84] Sartorio MG,Feldman MF.Bacterial outer membrane vesicles: from discovery to applications.Annu Rev Microbiol2021;75:609-30 PMCID:PMC8500939

[85] Kawasaki T,Kumanogoh A.Proteomics of blood extracellular vesicles in inflammatory respiratory diseases for biomarker discovery and new insights into pathophysiology.Inflamm Regen.2024;44:38 PMCID:PMC11409490

[86] An J,Kim YK.Extracellular vesicle-derived microbiome obtained from exhaled breath condensate in patients with asthma.Ann Allergy Asthma Immunol2021;126:729-31

[87] McDowell A,Yang J.Machine-learning algorithms for asthma, COPD, and lung cancer risk assessment using circulating microbial extracellular vesicle data and their application to assess dietary effects.Exp Mol Med2022;54:1586-95 PMCID:PMC9534896

[88] Park J,Hong Y,Shin TS.Metagenomic analysis of plasma microbial extracellular vesicles in patients receiving mechanical ventilation: a pilot study.J Pers Med2022;12:564 PMCID:PMC9031263

[89] Su KY,Chua YW.Bacterial extracellular vesicles in biofluids as potential diagnostic biomarkers.Expert Rev Mol Diagn2022;22:1057-62