Pasteurized Akkermansia muciniphila alleviates high-fat diet-induced bone loss via Nr4a1-dependent Treg differentiation

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Background 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—especially in pasteurized form (pAkk)—and underlying mechanisms remain unclear. Methods High-fat diet (HFD)-induced obese mice were used to establish bone loss models, with fecal microbiota transplantation to verify gut microbiota’s role. Mice were gavaged with live Akk, pAkk, or control for 4 weeks. Bone microarchitecture was assessed via micro-computed tomography (μCT), 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’ inhibitory effect on osteoclastogenesis. Results 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 (β-CTX), and inhibited osteoclast differentiation. pAkk promoted CD4 + CD25 + Foxp3 + Treg differentiation in the intestine and spleen via CD103 + 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’s bone-protective effects. Conclusion 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.

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