{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:18:29Z","timestamp":1787318309086,"version":"build-2736575974"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004319","name":"Shin Kong Wu Ho-Su Memorial Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Chronic radiation proctitis (RP) is characterized by persistent inflammation and impaired tissue repair. This study investigates the potential of a metformin\u2013butyrate (MeBu) combination to modulate radiation-induced senescence-associated changes in macrophages to mitigate chronic injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      BALB\/c mice received a 15 Gy fraction of rectal brachytherapy. From weeks 4 to 8 post-irradiation, mice were treated with rectal enemas of metformin, butyrate, or the MeBu combination. Tissue histology (H&amp;amp;E and Masson\u2019s Trichrome staining), macrophage polarization (iNOS\/CD163) were evaluated. Effects on senescence markers were analyzed in irradiated bone marrow\u2013derived macrophages (BMDMs) using SA-\u03b2-gal staining and qPCR for\n                      <jats:italic>p16<\/jats:italic>\n                      and\n                      <jats:italic>p21<\/jats:italic>\n                      . A composite Senescence Burden Index (SBI) was developed to integrate transcriptional senescence signals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MeBu treatment was associated with a reduction in mucosal fibrosis and a phenotypic shift in macrophages toward a more reparative M2-like profile (increased CD163\/iNOS ratio). In BMDMs, MeBu significantly reduced SA-\u03b2-Gal positivity and suppressed\n                      <jats:italic>p21<\/jats:italic>\n                      expression (p = 0.0074), with a downward trend in\n                      <jats:italic>p16<\/jats:italic>\n                      (p = 0.0568). The integrated SBI demonstrated that MeBu significantly attenuated the overall senescence burden compared to the irradiated group (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.01). This combined effect was more robust than that of either metformin or butyrate alone.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest that the MeBu combination may attenuate chronic RP by modulating macrophage-associated senescence and inflammation. These results indicate that metabolic-based senomorphic strategies hold potential to mitigate chronic inflammatory sequelae following pelvic radiotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1802803","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T05:24:50Z","timestamp":1775107490000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Metformin and butyrate attenuate chronic radiation proctitis by alleviating inflammation and macrophage senescence"],"prefix":"10.3389","volume":"17","author":[{"given":"Mau-Shin","family":"Chi","sequence":"first","affiliation":[{"name":"Department of Radiation Therapy & Oncology, Shin Kong Wu Ho-Su Memorial Hospital","place":["Taipei, Taiwan"]},{"name":"Institute of Veterinary Clinical Science, School of Veterinary Medicine, National Taiwan University","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan-I","family":"Jen","sequence":"additional","affiliation":[{"name":"Department of Radiation Therapy & Oncology, Shin Kong Wu Ho-Su Memorial Hospital","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Yi","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Radiation Therapy & Oncology, Shin Kong Wu Ho-Su Memorial Hospital","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Lin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Radiation Therapy & Oncology, Shin Kong Wu Ho-Su Memorial Hospital","place":["Taipei, Taiwan"]},{"name":"School of Medicine, Fu Jen Catholic University","place":["New Taipei City, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Ling","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Radiation 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