{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:00:37Z","timestamp":1789999237095,"version":"4.0.1"},"reference-count":34,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention","award":["37014"],"award-info":[{"award-number":["37014"]}],"id":[{"id":"https:\/\/ror.org\/04wktzw65","id-type":"ROR","asserted-by":"crossref"}]},{"award":["37014"],"award-info":[{"award-number":["37014"]}],"id":[{"id":"https:\/\/ror.org\/04wktzw65","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["81021"],"award-info":[{"award-number":["81021"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Douzhier, a traditional Chinese fermented food with a history spanning over 1000 years, harbors a complex community of beneficial microbiota. In this study, we isolated Lactococcus lactis subsp. cremoris (designated L. cremoris D2022), one of the dominant bacterial species in Douzhier, and evaluated its efficacy against influenza A virus (IAV) infection. Methods: A murine model of IAV infection was established using C57BL\/6J mice. Following oral administration of L. cremoris D2022, treated and model control groups (IAV-infected model control group received phosphate-buffered saline (PBS)) were comparatively assessed through clinical outcomes (body weight dynamics and survival), pathological parameters (colon length, lung index, and lung histopathology), inflammatory cytokine profiling, multi-omics analyses (lung transcriptomics and cecal metabolomics), and adaptive immune responses. Results: Administration of L. cremoris D2022 markedly alleviated IAV-induced pathology compared with PBS-treated model controls, as evidenced by improved survival (30% vs. 0%, p = 0.006), reduced body weight loss, decreased lung index, and preservation of colon length. D2022 treatment accelerated viral clearance, accompanied by enhanced early interferon beta (IFN-\u03b2) production. This was followed by suppression of late-stage hyperinflammation, including reduced levels of interleukin-1\u03b2 (IL-1\u03b2), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-\u03b1) at 7 dpi. Metabolomic analysis revealed increased levels of deaminotyrosine (DAT), short-chain fatty acids (SCFAs), and microbially conjugated bile acids (e.g., ursodeoxycholic acid (UDCA) and isoallolithocholic acid (isoalloLCA)). Furthermore, IAV-specific adaptive immune responses were significantly enhanced. Conclusions: L. cremoris D2022 protects mice against IAV infection, with enhanced early IFN-\u03b2 responses, reduced late-stage inflammation, and associated changes in intestinal microbial metabolites. The causal roles of these metabolites remain to be established. These findings support further evaluation of D2022 as a probiotic candidate for adjunctive influenza prevention.<\/jats:p>","DOI":"10.3390\/nu18183089","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:50:03Z","timestamp":1789995003000},"page":"3089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Dominant Probiotic from the Traditional Chinese Fermented Food Douzhier Exhibits Anti-Influenza Activity"],"prefix":"10.3390","volume":"18","author":[{"given":"Xiao","family":"Zhang","sequence":"first","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention & Chinese Academy of Preventive Medicine, Beijing 102206, China"},{"name":"School of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"given":"Yuewen","family":"Yang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention & Chinese Academy of Preventive Medicine, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Siqin","family":"He","sequence":"additional","affiliation":[{"name":"Hunan Prevention and Treatment Institute for Occupational Diseases, Affiliated Prevention and Treatment Institute for Occupational Diseases of University of South China, Changsha 410007, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Yuanming","family":"Huang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention & Chinese Academy of Preventive Medicine, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8762-2600","authenticated-orcid":false,"given":"Zhihong","family":"Ren","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention & Chinese Academy of Preventive Medicine, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Liqiong","family":"Song","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention & Chinese Academy of Preventive Medicine, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Han, D., Bao, X., Wang, Y., Liao, X., Wang, K., Chen, J., Li, X., Yang, Z., and Wang, Y. (2024). The Impact of Lactic Acid Bacteria Inoculation on the Fermentation and Metabolomic Dynamics of Indigenous Beijing Douzhi Microbial Communities. Front. Microbiol., 15.","DOI":"10.3389\/fmicb.2024.1435834"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.foodcont.2009.02.005","article-title":"Microbiological and Biochemical Changes during Processing of the Traditional Chinese Food Douzhi","volume":"20","author":"Ding","year":"2009","journal-title":"Food Control"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Xu, Y., Yu, Y., Tian, Y., Su, Y., Li, X., Zhang, Z., Zhu, H., Han, J., Zhang, H., and Liu, L. (2018). Analysis of Beijing Douzhir Microbiota by High-Throughput Sequencing and Isolation of Acidogenic, Starch-Flocculating Strains. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.01142"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nri3665","article-title":"Innate Immunity to Influenza Virus Infection","volume":"14","author":"Iwasaki","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.coi.2013.07.005","article-title":"Correlates of Protection against Influenza Infection in Humans\u2014On the Path to a Universal Vaccine?","volume":"25","author":"Li","year":"2013","journal-title":"Curr. Opin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1016\/S0140-6736(03)14854-4","article-title":"Influenza","volume":"362","author":"Nicholson","year":"2003","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hu, X., Zhao, Y., Yang, Y., Gong, W., Sun, X., Yang, L., Zhang, Q., and Jin, M. (2021). Akkermansia muciniphila Improves Host Defense Against Influenza Virus Infection. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.586476"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jounai, K., Sugimura, T., Ohshio, K., and Fujiwara, D. (2015). Oral Administration of Lactococcus lactis Subsp. lactis JCM5805 Enhances Lung Immune Response Resulting in Protection from Murine Parainfluenza Virus Infection. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119055"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jtcme.2022.08.004","article-title":"Potential Probiotics for Regulation of the Gut-Lung Axis to Prevent or Alleviate Influenza in Vulnerable Populations","volume":"13","author":"Wang","year":"2023","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Saito, S., Okuno, A., Peng, Z., Cao, D.-Y., and Tsuji, N.M. (2024). Probiotic Lactic Acid Bacteria Promote Anti-Tumor Immunity through Enhanced Major Histocompatibility Complex Class I-Restricted Antigen Presentation Machinery in Dendritic Cells. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1335975"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/j.1472-765X.2012.03270.x","article-title":"Oral administration of milk fermented with Lactococcus lactis subsp. cremoris FC protects mice against influenza virus infection","volume":"55","author":"Maruo","year":"2012","journal-title":"Lett. Appl. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"112169","DOI":"10.1016\/j.intimp.2024.112169","article-title":"Lactobacillus plantarum GUANKE Modulate Anti-Viral Function of Dendritic Cells in Mice","volume":"134","author":"Lu","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"133453","DOI":"10.1016\/j.ijbiomac.2024.133453","article-title":"The Recombinant Vaccine of Lactobacillus Plantarum Elicits Immune Protection against H1N1 and H9N2 Influenza Virus Infection","volume":"275","author":"Zhou","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1365-2672.2012.05326.x","article-title":"Evaluation of Leuconostoc mesenteroides YML003 as a Probiotic against Low-Pathogenic Avian Influenza (H9N2) Virus in Chickens","volume":"113","author":"Seo","year":"2012","journal-title":"J. Appl. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2406379","DOI":"10.1080\/19490976.2024.2406379","article-title":"Akkermansia in the Gastrointestinal Tract as a Modifier of Human Health","volume":"16","author":"Panzetta","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/j.cell.2020.10.047","article-title":"Commensal Microbiota Modulation of Natural Resistance to Virus Infection","volume":"183","author":"Stefan","year":"2020","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"110974","DOI":"10.1016\/j.biopha.2020.110974","article-title":"Kefir: A Protective Dietary Supplementation against Viral Infection","volume":"133","author":"Hamida","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.intimp.2012.10.007","article-title":"Lactococcus lactis Subsp. cremoris FC Triggers IFN-\u03b3 Production from NK and T Cells via IL-12 and IL-18","volume":"14","author":"Kosaka","year":"2012","journal-title":"Int. Immunopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Uchida, K., Iida, K., Fujioka, I., Hachimura, S., and Kaminuma, O. (2022). Suppressive Effect of Lactococcus lactis Subsp. cremoris YRC3780 on a Murine Model of Japanese Cedar Pollinosis. Pathogens, 11.","DOI":"10.3390\/pathogens11111347"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/1465-9921-10-112","article-title":"Impaired Immune Responses in the Lungs of Aged Mice Following Influenza Infection","volume":"10","author":"Toapanta","year":"2009","journal-title":"Respir. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6015","DOI":"10.1039\/D4FO00118D","article-title":"Lactococcus cremoris D2022 Alleviates Hyperuricemia and Suppresses Renal Inflammation via Potential Gut-Kidney Axis","volume":"15","author":"Wang","year":"2024","journal-title":"Food Funct."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Song, L., Huang, Y., Liu, G., Li, X., Xiao, Y., Liu, C., Zhang, Y., Li, J., Xu, J., and Lu, S. (2021). A Novel Immunobiotics Bacteroides Dorei Ameliorates Influenza Virus Infection in Mice. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.828887"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Wei, W., Du, H., Shao, C., Zhou, H., Lu, Y., Yu, L., Wan, H., and He, Y. (2019). Screening of Antiviral Components of Ma Huang Tang and Investigation on the Ephedra Alkaloids Efficacy on Influenza Virus Type A. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00961"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7S","DOI":"10.1177\/0192623312438738","article-title":"International Harmonization of Toxicologic Pathology Nomenclature: An Overview and Review of Basic Principles","volume":"40","author":"Mann","year":"2012","journal-title":"Toxicol. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1084\/jem.176.6.1693","article-title":"Generation of Large Numbers of Dendritic Cells from Mouse Bone Marrow Cultures Supplemented with Granulocyte\/Macrophage Colony-Stimulating Factor","volume":"176","author":"Inaba","year":"1992","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1039\/C9AY02753J","article-title":"Effects of Harvesting and Extraction Methods on Metabolite Recovery from Adherently Growing Mammalian Cells","volume":"12","author":"Luo","year":"2020","journal-title":"Anal. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1126\/science.aam5336","article-title":"The Microbial Metabolite Desaminotyrosine Protects from Influenza through Type I Interferon","volume":"357","author":"Steed","year":"2017","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nature12726","article-title":"Metabolites Produced by Commensal Bacteria Promote Peripheral Regulatory T-Cell Generation","volume":"504","author":"Arpaia","year":"2013","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hu, M., Alashkar Alhamwe, B., Santner-Nanan, B., Miethe, S., Harb, H., Renz, H., Potaczek, D.P., and Nanan, R.K. (2022). Short-Chain Fatty Acids Augment Differentiation and Function of Human Induced Regulatory T Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105740"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jaci.2025.09.029","article-title":"Human Milk Oligosaccharides and Polyphenols: Mechanisms, Effects, and Applications in Allergies","volume":"157","author":"Carvalho","year":"2026","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41586-019-1785-z","article-title":"Bile Acid Metabolites Control TH17 and Treg Cell Differentiation","volume":"576","author":"Hang","year":"2019","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41586-022-04480-z","article-title":"Human Gut Bacteria Produce TH17-Modulating Bile Acid Metabolites","volume":"603","author":"Paik","year":"2022","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41392-025-02552-w","article-title":"A Microbiota-Dependent Bile Acid Reprograms Alveolar Macrophages to Control Lung Inflammation","volume":"11","author":"Wolska","year":"2026","journal-title":"Sig. Transduct. Target. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9250235","DOI":"10.26599\/FSHW.2024.9250235","article-title":"Gallic Acid Ameliorates Colitis by Modulating the Treg\/Th17 Balance via Microbiota-Derived Secondary Bile Acids","volume":"14","author":"Zhang","year":"2025","journal-title":"Food Sci. Hum. Wellness"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/18\/3089\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:03:18Z","timestamp":1789995798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/18\/3089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":34,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["nu18183089"],"URL":"https:\/\/doi.org\/10.3390\/nu18183089","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]}}}