biostudies-literatureZhang HTechnology Major Project of HohhotDistinguished Youth Fund Project of Inner Mongolia Autonomous Region Natural Science Foundationthe Clinical Need Oriented Basic Research Project of Inner Mongolia Academy of Medical Sciencesthe China Postdoctoral Science Foundationthe National Natural Science Foundation of China235https://www.ebi.ac.uk/biostudies/studies/S-EPMC12628892biostudies-literatureUnknown13(1)<h4>Background</h4>Pulmonary commensals play a crucial role in regulating host immune homeostasis and combating infections. Nevertheless, the deep mechanisms remain unclear.<h4>Results</h4>Long-term antibiotics pre-exposure enhanced the susceptibility to bacterial pneumonia, while intranasal reconstitution of the pulmonary microbiota mitigated these adverse effects, restoring host resilience to infections. We isolated two pulmonary commensals, Lactobacillus plantarum and Lactobacillus murinus, demonstrating that they induced IL-17A-mediated antibacterial immunity and promoted resistance to lung infections. Moreover, antibiotics-treatment reduced the frequency of pulmonary IL-17A secreting Vγ4⁺ γδ T cells and made the mice more susceptible to pneumonia, which was reversed by transferring pulmonary Lactobacillus commensals. In addition, our data indicated that L. plantarum and L. murinus-derived metabolites, particularly extracellular polysaccharides, can activate lung Vγ4⁺ γδ T cells to secrete IL-17A in defense against bacterial lung infections.<h4>Conclusions</h4>In this study, we report for the first time that pulmonary commensal Lactobacillus, specifically L. plantarum and L. murinus, activate Vγ4⁺ γδ T cells to secrete IL-17A, thereby mitigating susceptibility to Staphylococcus aureus and Pseudomonas aeruginosa infections. Additionally, we identified the metabolite of L. plantarum and L. murinus, extracellular polysaccharides, as the key immunomodulatory molecules. This research highlights the importance of pulmonary commensals in the regulation of anti-infection immunity and provides a theoretical foundation for clinical studies on the role of lung microbiota in combating infections. Video Abstract.MicrobiomeThe pulmonary commensal Lactobacillus regulated lung γδ T cells to enhance resistance against bacterial infections.PMC12628892322601842023MD7341802023JQ082024GLLH03472023-JieBangGuaShuaiMa BLi CChen JLiang YZhang HBao XWang TFu YZhang LWang XPan NfalseThe pulmonary commensal Lactobacillus regulated lung γδ T cells to enhance resistance against bacterial infections.<h4>Background</h4>Pulmonary commensals play a crucial role in regulating host immune homeostasis and combating infections. Nevertheless, the deep mechanisms remain unclear.<h4>Results</h4>Long-term antibiotics pre-exposure enhanced the susceptibility to bacterial pneumonia, while intranasal reconstitution of the pulmonary microbiota mitigated these adverse effects, restoring host resilience to infections. We isolated two pulmonary commensals, Lactobacillus plantarum and Lactobacillus murinus, demonstrating that they induced IL-17A-mediated antibacterial immunity and promoted resistance to lung infections. Moreover, antibiotics-treatment reduced the frequency of pulmonary IL-17A secreting Vγ4⁺ γδ T cells and made the mice more susceptible to pneumonia, which was reversed by transferring pulmonary Lactobacillus commensals. In addition, our data indicated that L. plantarum and L. murinus-derived metabolites, particularly extracellular polysaccharides, can activate lung Vγ4⁺ γδ T cells to secrete IL-17A in defense against bacterial lung infections.<h4>Conclusions</h4>In this study, we report for the first time that pulmonary commensal Lactobacillus, specifically L. plantarum and L. murinus, activate Vγ4⁺ γδ T cells to secrete IL-17A, thereby mitigating susceptibility to Staphylococcus aureus and Pseudomonas aeruginosa infections. Additionally, we identified the metabolite of L. plantarum and L. murinus, extracellular polysaccharides, as the key immunomodulatory molecules. This research highlights the importance of pulmonary commensals in the regulation of anti-infection immunity and provides a theoretical foundation for clinical studies on the role of lung microbiota in combating infections. Video Abstract.2025-01-01T00:00:00Z2025 Nov2026-06-05T17:16:13.651Z2026-05-19T03:11:54.969ZS-EPMC126288924125805810.1186/s40168-025-02205-8