{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T14:40:48Z","timestamp":1791729648186,"version":"4.3.4"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background and aim<\/jats:title>\n                    <jats:p>Immunosenescence involves age-related immune decline and chronic inflammation, with the spleen serving as a critical hub for immune dysregulation. While gut microbiota influences systemic immunity, its specific role and the potential existence of a gut-spleen axis in mediating splenic aging remains unclear. Therefore, we investigated whether metformin, a microbiota-modulating geroprotective drug, alleviates splenic immunosenescence in aged mice, specifically exploring the link between gut microbiota remodeling and splenic immune rejuvenation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Aged C57BL\/6 mice (15-month-old) received oral metformin (300 mg\/kg\/day) or vehicle for 5 months. Systemic toxicity and metabolism were monitored. Splenic immune subsets were analyzed using flow cytometry and immunohistochemistry. Gut microbiota composition (16S rRNA sequencing), cytokine levels (RT-qPCR), and functional pathways were assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Metformin caused no hepatorenal toxicity or weight changes. Treated mice exhibited increased cytotoxic T cells (Tc) and macrophages in the spleen, with reduced Th\/Tc ratios and M1\/M2 polarization. Pro-inflammatory cytokines (Ifng, Il17a, Il1b, Il6) decreased, while anti-inflammatory markers (Arg1, Tgfb1) rose. Gut microbiota showed enriched\n                      <jats:italic>Akkermansia<\/jats:italic>\n                      ,\n                      <jats:italic>Muribaculum<\/jats:italic>\n                      , and\n                      <jats:italic>Duncaniella<\/jats:italic>\n                      , but reduced\n                      <jats:italic>Lactobacillus<\/jats:italic>\n                      .\n                      <jats:italic>Akkermansia\/Muribaculum<\/jats:italic>\n                      negatively correlated with pro-inflammatory cytokines, whereas\n                      <jats:italic>Lactobacillus<\/jats:italic>\n                      and\n                      <jats:italic>Lachnospiraceae<\/jats:italic>\n                      linked to pro-inflammatory responses. Functional prediction analysis based on 16S rRNA sequencing data indicated upregulation of bile acid metabolism and oxidative phosphorylation pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Metformin reshapes the gut microbiota, which is associated with mitigation of age-associated splenic immune dysregulation, favoring anti-inflammatory macrophage polarization and cytotoxic T cell expansion. Critically, our findings establish the gut-spleen axis as a key mediator of splenic immunosenescence and a novel therapeutic target, which positions metformin as a promising microbiota-directed geroprotective agent. Future research should prioritize mechanistic dissection of gut-spleen communication and clinical validation of metformin\u2019s geroprotective efficacy in human populations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1633486","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T04:17:04Z","timestamp":1758773824000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Metformin-associated gut microbiota remodeling correlates with reinvigorated splenic immunity in aged mice: microbiome-immune crosstalk via the gut-spleen axis"],"prefix":"10.3389","volume":"16","author":[{"given":"Shu-Qin","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Yi","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Yu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Wan","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Xin","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang-Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He-Zuo","family":"L\u00fc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41392-023-01451-2","article-title":"Immunosenescence: 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