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Our previous study revealed that\n                      <jats:italic toggle=\"yes\">S. mutans<\/jats:italic>\n                      cultured under air-restricted conditions accelerated the development of dental caries in adult rats, compared with those grown in routinely air-unrestricted conditions. Here, we first confirmed this enhancement in a weaning rat model that mimics early childhood caries, and then further demonstrated that air restriction not only enhanced biofilm formation of\n                      <jats:italic toggle=\"yes\">S. mutans,<\/jats:italic>\n                      but also upregulated gene expression in five Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with sugar uptake and metabolism, with lactose metabolism being most pronounced. Concurrently, genes involved in the conversion of pyruvate to acetyl-CoA were downregulated, shifting metabolic flux toward lactic acid production. This effect was markedly amplified in the presence of lactose, implying a critical role for lactose-derived fermentation in cariogenicity. Collectively, these findings indicate that air-restricted culturing enhances the cariogenic metabolic activity of\n                      <jats:italic toggle=\"yes\">S. mutans<\/jats:italic>\n                      , with lactose emerging as a significant dietary risk factor for dental caries.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Dental caries remains one of the most prevalent chronic diseases worldwide, affecting billions of individuals globally, which poses a major burden to public oral health. A systematic understanding of environmental factors that modulate the virulence of cariogenic bacteria, such as\n                        <jats:italic toggle=\"yes\">Streptococcus mutans<\/jats:italic>\n                        (\n                        <jats:italic toggle=\"yes\">S. mutans<\/jats:italic>\n                        ), provides valuable insights into the pathogenesis of caries and informs the development of prevention strategies. Our findings demonstrate that reduced air availability dramatically enhances the cariogenicity of\n                        <jats:italic toggle=\"yes\">S. mutans in vitro<\/jats:italic>\n                        and\n                        <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                        , which is mechanistically associated with metabolic reprogramming toward preferential lactose utilization. Notably, our study bridges a critical knowledge gap by elucidating how environmental air tension drives\n                        <jats:italic toggle=\"yes\">S. mutans<\/jats:italic>\n                        virulence and highlights lactose metabolism as a previously overlooked risk factor, prompting reconsideration of preventive strategies for vulnerable populations.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.03920-25","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:01:27Z","timestamp":1777467687000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Air restriction enhances\n                    <i>Streptococcus mutans<\/i>\n                    cariogenicity via preferential lactose metabolism"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7785-8716","authenticated-orcid":false,"given":"Bowen","family":"Liu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Public Health Clinical Center, Fudan University","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/01jxjav08","id-type":"ROR","asserted-by":"publisher"}],"name":"Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Public Health Clinical Center, Fudan University","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/01jxjav08","id-type":"ROR","asserted-by":"publisher"}],"name":"Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Public Health Clinical Center, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Xu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Public Health Clinical Center, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Public Health Clinical Center, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Yan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Public Health Clinical Center, Fudan University","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/01jxjav08","id-type":"ROR","asserted-by":"publisher"}],"name":"Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8572-2405","authenticated-orcid":false,"given":"Min","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Public Health Clinical Center, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4640-664X","authenticated-orcid":true,"given":"Jingyi","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Public Health Clinical Center, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1177\/0022034514557546"},{"key":"e_1_3_5_3_2","first-page":"661","article-title":"The global burden of oral diseases and risks to oral health","volume":"83","author":"Petersen PE","year":"2005","unstructured":"Petersen PE, Bourgeois D, Ogawa H, Estupinan-Day S, Ndiaye C. 2005. 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