{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:43:27Z","timestamp":1792799007221,"version":"4.5.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"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<\/jats:title>\n                    <jats:p>Obesity, a global epidemic, disrupts bone metabolism via gut microbiota dysbiosis, and probiotic\/postbiotic supplementation emerges as a promising intervention. Akkermansia muciniphila (Akk), a next-generation probiotic, exerts metabolic benefits in obesity, yet its effects on bone homeostasis\u2014especially in pasteurized form (pAkk)\u2014and underlying mechanisms remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>High-fat diet (HFD)-induced obese mice were used to establish bone loss models, with fecal microbiota transplantation to verify gut microbiota\u2019s role. Mice were gavaged with live Akk, pAkk, or control for 4 weeks. Bone microarchitecture was assessed via micro-computed tomography (\u03bcCT), and bone formation\/resorption were detected by histomorphometry, ELISA, and TRAP staining. Flow cytometry, immunofluorescence, and qRT-PCR analyzed regulatory T (Treg) cell differentiation. RNA sequencing identified key genes, and Nr4a1 knockout mice validated the mechanism. Cell coculture confirmed pAkk-induced Tregs\u2019 inhibitory effect on osteoclastogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Obesity-related gut microbiota induced trabecular bone loss, with reduced intestinal Akk abundance. pAkk (but not live Akk) rescued HFD-induced bone loss, increased bone formation marker (P1NP), decreased resorption marker (\u03b2-CTX), and inhibited osteoclast differentiation. pAkk promoted CD4\n                      <jats:sup>+<\/jats:sup>\n                      CD25\n                      <jats:sup>+<\/jats:sup>\n                      Foxp3\n                      <jats:sup>+<\/jats:sup>\n                      Treg differentiation in the intestine and spleen via CD103\n                      <jats:sup>+<\/jats:sup>\n                      dendritic cells, and these Tregs suppressed osteoclastogenesis. Transcriptomic and functional validation showed Nr4a1 was upregulated by pAkk and essential for Treg differentiation; Nr4a1 knockout abrogated pAkk\u2019s bone-protective effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Pasteurized Akkermansia muciniphila alleviates HFD-induced bone loss in obese mice by promoting intestinal and systemic Treg differentiation to inhibit osteoclastogenesis, dependent on the nuclear hormone receptor Nr4a1. Our findings identify pAkk as a promising postbiotic for obesity-related bone loss and uncover a novel Nr4a1\/Treg axis linking gut microbiota to bone homeostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1833607","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T04:53:28Z","timestamp":1779425608000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Pasteurized Akkermansia muciniphila alleviates high-fat diet-induced bone loss via Nr4a1-dependent Treg differentiation"],"prefix":"10.3389","volume":"17","author":[{"given":"Si","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Multidisciplinary Consultant Center, Shanghai Stomatological Hospital and School of Stomatology, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiying","family":"Zhu","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University","place":["Shanghai, China"]},{"name":"Department of Oral Implantology, Shanghai Stomatological Hospital and School of Stomatology, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenguang","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Endodontics, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Clinical Research Center for Oral Diseases, National Center for Stomatology, Shanghai Key Laboratory of Stomatology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqi","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Multidisciplinary Consultant Center, Shanghai Stomatological Hospital and School of Stomatology, Fudan University","place":["Shanghai, China"]},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/obr.13562","article-title":"Overweight, obesity and risk of multimorbidity: a systematic review and meta-analysis of longitudinal studies","volume":"24","author":"Delpino","year":"2023","journal-title":"Obes Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1168687","article-title":"The complex pathophysiology of bone fragility in obesity and type 2 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