{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T14:59:45Z","timestamp":1790261985443,"version":"4.1.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008771","name":"Animal and Plant Quarantine Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008771","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Commercial foot-and-mouth disease (FMD) vaccines have several drawbacks, including a short duration of the immune response after vaccination and local adverse reactions at the vaccination site. Therefore, we developed a new vaccination strategy that simultaneously improves the health status of the host and stimulates systemic immunity by combining the oral administration of glycyrrhizic acid (GA) and intramuscular injection of the FMD vaccine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated the efficacy of the oral immune enhancer GA in conjunction with an intramuscular injection of the FMD vaccine. After vaccination, the experimental (mice) and target animals (pigs) were orally administered GA daily for 4 weeks and once a week for the next 4 weeks. Subsequently, we evaluated safety using various biochemical serum assays, the efficacy of inducing immune responses using serological assays, and the expression of genes related to systemic immunity induction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Oral administration of GA in combination with an intramuscular injection of the FMD vaccine enhanced early, mid-term, and long-term immunity in experimental and target animals. We also confirmed that this co-administration increased the expression of secretory IgA (sIgA), an important indicator of mucosal immunity. Additionally, significant gene elevations in systemic immune markers along with T helper (Th) immune responses were observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings suggest that combining the oral administration of GA with the intramuscular injection of an inactivated FMD vaccine can induce a potent and sustained immune response and stimulate the systemic immune system by promoting sIgA and cytokine gene expression. Our research can be used to enhance the efficacy of existing commercial vaccines as well as control other animal diseases by improving the host\u2019s immune system.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmicb.2025.1502630","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T06:51:38Z","timestamp":1739947898000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Oral administration of glycyrrhizic acid with intramuscular injection of foot-and-mouth disease vaccine enhances the adaptive immune system"],"prefix":"10.3389","volume":"16","author":[{"given":"Seokwon","family":"Shin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeong Won","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Kyeong","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Hui","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-Hyeon","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Mi","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Ja","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1111\/j.1365-2249.2004.02440.x","article-title":"Molecular analysis of B-cell differentiation in selective or partial IgA deficiency.","volume":"136","author":"Asano","year":"2004","journal-title":"Clin. Exp. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1146\/annurev.immunol.18.1.767","article-title":"Immunobiology of dendritic cells.","volume":"18","author":"Banchereau","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1080\/03601234.2023.2186669","article-title":"Improving meat qualities of pigs after deworming against ascariasis with administered glycyrrhizic acid.","volume":"58","author":"Bazekin","year":"2023","journal-title":"J. Environ. Sci. Health B"},{"key":"B4","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3109\/08820131003680369","article-title":"Function of mucosa-associated lymphoid tissue in antibody formation.","volume":"39","author":"Brandtzaeg","year":"2010","journal-title":"Immunol. Invest."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1126\/science.1092385","article-title":"Neutrophil extracellular traps kill bacteria.","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.antiviral.2017.01.023","article-title":"Rational design and efficacy of a multi-epitope recombinant protein vaccine against foot-and-mouth disease virus serotype A in pigs.","volume":"140","author":"Cao","year":"2017","journal-title":"Antiviral Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1177\/0960327112446843","article-title":"Licorice induced hypokalemia, edema, and thrombocytopenia.","volume":"31","author":"Celik","year":"2012","journal-title":"Hum. Exp. Toxicol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"6659","DOI":"10.1016\/j.vaccine.2020.08.054","article-title":"Adjuvants for swine vaccines: Mechanisms of actions and adjuvant effects.","volume":"38","author":"Charerntantanakul","year":"2020","journal-title":"Vaccine"},{"key":"B9","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/s0168-3659(00)00199-1","article-title":"Recent advances in mucosal vaccine development.","volume":"67","author":"Chen","year":"2000","journal-title":"J. Control Release"},{"key":"B10","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/mi.2016.39","article-title":"Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals.","volume":"10","author":"Chen","year":"2017","journal-title":"Mucosal Immunol."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01499","article-title":"M cells: Intelligent engineering of mucosal immune surveillance.","volume":"10","author":"Dillon","year":"2019","journal-title":"Front. Immunol."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/emi.2013.5","article-title":"Pathogen-host-environment interplay and disease emergence.","volume":"2","author":"Engering","year":"2013","journal-title":"Emerg. Microbes Infect."},{"key":"B13","article-title":"EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed).","author":"Hogstrand","year":"2015","journal-title":"Scientific Opinion on the safety and efficacy of glycyrrhizic acid ammoniated (chemical group 30, miscellaneous substances) when used as a flavouring for all animal species."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1084\/jem.191.8.1381","article-title":"Localization of distinct Peyer\u2019s patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3\u03b1, MIP-3\u03b2, and secondary lymphoid organ chemokine.","volume":"191","author":"Iwasaki","year":"2000","journal-title":"J. Exp. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"4884","DOI":"10.4049\/jimmunol.166.8.4884","article-title":"Unique functions of CD11b+, CD8\u03b1+, and double-negative Peyer\u2019s patch dendritic cells.","volume":"166","author":"Iwasaki","year":"2001","journal-title":"J. Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1297-9716-44-116","article-title":"Foot-and-mouth disease: Past, present and future.","volume":"44","author":"Jamal","year":"2013","journal-title":"Vet. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1038\/nature06536","article-title":"Global trends in emerging infectious diseases.","volume":"451","author":"Jones","year":"2008","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.670290","article-title":"The wanderings of gut-derived IgA plasma cells: Impact on systemic immune responses.","volume":"12","author":"Keppler","year":"2021","journal-title":"Front. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"423","DOI":"10.2183\/pjab.91.423","article-title":"The mucosal immune system: From dentistry to vaccine development.","volume":"91","author":"Kiyono","year":"2015","journal-title":"Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.prevetmed.2013.07.013","article-title":"The economic impacts of foot and mouth disease\u2013What are they, how big are they and where do they occur?","volume":"112","author":"Knight-Jones","year":"2013","journal-title":"Prev. Vet. Met."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02345","article-title":"The roles of Peyer\u2019s patches and microfold cells in the gut immune system: Relevance to autoimmune diseases.","volume":"10","author":"Kobayashi","year":"2019","journal-title":"Front. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.vetmic.2016.07.007","article-title":"DNA vaccine (P1-2A-3C-pCDNA) co-administered with Bovine IL-18 gives protective immune response against foot and mouth disease in cattle.","volume":"193","author":"Kotla","year":"2016","journal-title":"Vet. Microbiol."},{"key":"B23","article-title":"*Liver function tests","author":"Lala","year":"2023","journal-title":"StatPearls"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02509","article-title":"Mincle and STING-stimulating adjuvants elicit robust cellular immunity and drive long-lasting memory responses in a foot-and-mouth disease vaccine.","volume":"10","author":"Lee","year":"2019","journal-title":"Front. Immunol."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-022-00496-8","article-title":"The C3d-fused foot-and-mouth disease vaccine platform overcomes maternally-derived antibody interference by inducing a potent adaptive immunity.","volume":"7","author":"Lee","year":"2022","journal-title":"npj Vaccines"},{"key":"B26","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.imlet.2019.10.013","article-title":"Mucosal vaccines: Strategies and challenges.","volume":"217","author":"Li","year":"2020","journal-title":"Immunol. Lett."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/2032057","article-title":"The effects of secretory IgA in the mucosal immune system.","volume":"2020","author":"Li","year":"2020","journal-title":"BioMed. Res. Int."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.621105","article-title":"Multi-source pathways of T follicular helper cell differentiation.","volume":"12","author":"Ma","year":"2021","journal-title":"Front. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"E3119","DOI":"10.1073\/pnas.1302799110","article-title":"MAIT cells are critical for optimal mucosal immune responses during in vivo pulmonary bacterial infection.","volume":"110","author":"Meierovics","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B30","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1016\/j.immuni.2022.04.013","article-title":"Mucosal immune responses to infection and vaccination in the respiratory tract.","volume":"55","author":"Mettelman","year":"2022","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/s41385-021-00389-4","article-title":"Human gut-associated lymphoid tissues (GALT); diversity, structure, and function.","volume":"14","author":"M\u00f6rbe","year":"2021","journal-title":"Mucosal Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1038\/ni.3732","article-title":"Identification of subepithelial mesenchymal cells that induce IgA and diversify gut microbiota.","volume":"18","author":"Nagashima","year":"2017","journal-title":"Nat. Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1038\/s41385-021-00391-w","article-title":"MAIT cells, guardians of skin and mucosa?","volume":"14","author":"Nel","year":"2021","journal-title":"Mucosal Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1038\/nri1777","article-title":"Mucosal vaccines: The promise and the challenge.","volume":"6","author":"Neutra","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"2323","DOI":"10.1002\/ptr.6178","article-title":"Liquorice (Glycyrrhiza glabra): A phytochemical and pharmacological review.","volume":"32","author":"Pastorino","year":"2018","journal-title":"Phytother. Res."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/ijms2123925","article-title":"Secretory IgA in intestinal mucosal secretions as an adaptive barrier against microbial cells.","volume":"21","author":"Pietrzak","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1084\/jem.20130958","article-title":"Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells.","volume":"210","author":"Reantragoon","year":"2013","journal-title":"J. Exp. Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1111\/imr.12400","article-title":"Peyer\u2019s patches: Organizing B-cell responses at the intestinal frontier.","volume":"271","author":"Reboldi","year":"2016","journal-title":"Immunol. Rev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1146\/annurev-immunol-103019-085803","article-title":"In vivo CD4+ T cell differentiation and function: Revisiting the Th1\/Th2 paradigm.","volume":"38","author":"Ruterbusch","year":"2020","journal-title":"Annu. Rev. Immunol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.ijpharm.2019.01.047","article-title":"Glycyrrhizic acid as a multifunctional drug carrier\u2013From physicochemical properties to biomedical applications: A modern insight on the ancient drug.","volume":"559","author":"Selyutina","year":"2019","journal-title":"Int. J. Pharm."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2023.1289065","article-title":"Inactivated vaccine with glycyrrhizic acid adjuvant elicits potent innate and adaptive immune responses against foot-and-mouth disease.","volume":"14","author":"Shin","year":"2023","journal-title":"Front. Microbiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1002\/eji.201847759","article-title":"Tissue-resident MAIT cell populations in human oral mucosa exhibit an activated profile and produce IL-17.","volume":"49","author":"Sobkowiak","year":"2019","journal-title":"Eur. J. Immunol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.immuni.2010.07.003","article-title":"The sensing of environmental stimuli by follicular dendritic cells promotes immunoglobulin A generation in the gut.","volume":"33","author":"Suzuki","year":"2010","journal-title":"Immunity"},{"key":"B44","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/eji.201343509","article-title":"CD 161++ CD 8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+ IL-18 in a TCR-independent manner.","volume":"44","author":"Ussher","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1191\/096032700682694251","article-title":"Glycyrrhizic acid: The assessment of a no effect level.","volume":"19","author":"Van Gelderen","year":"2000","journal-title":"Hum. Exp. Toxicol."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3390\/plants10122751","article-title":"\u201cGlycyrrhiza glabra (Licorice): A comprehensive review on its phytochemistry, biological activities, clinical evidence and toxicology.","volume":"10","author":"Wahab","year":"2021","journal-title":"Plants"},{"key":"B47","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1007\/s13238-015-0164-2","article-title":"Intranasal and oral vaccination with protein-based antigens: Advantages, challenges and formulation strategies.","volume":"6","author":"Wang","year":"2015","journal-title":"Protein Cell"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2024.1360256","article-title":"Foot and mouth disease vaccine efficacy in Africa: A systematic review and meta-analysis.","volume":"11","author":"Wubshet","year":"2024","journal-title":"Front. Vet. Sci."},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1186\/s12896-016-0285-6","article-title":"Large-scale production of foot-and-mouth disease virus (serotype Asia1) VLP vaccine in Escherichia coli and protection potency evaluation in cattle.","volume":"16","author":"Xiao","year":"2016","journal-title":"BMC Biotechnol."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1265172","article-title":"Advances in the roles of glycyrrhizic acid in cancer therapy.","volume":"14","author":"Zhang","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.57417","article-title":"Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy.","volume":"10","author":"Zhou","year":"2021","journal-title":"Elife"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1502630\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T06:51:42Z","timestamp":1739947902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2025.1502630\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,19]]},"references-count":51,"alternative-id":["10.3389\/fmicb.2025.1502630"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2025.1502630","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,19]]},"article-number":"1502630"}}