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However, how microbial colonization integrates systemic metabolic cues with skeletal remodeling under metabolic stress remains unclear. We used germ\u2010free (GF) and gnotobiotic C57BL\/6J mice colonized with the defined 12\u2010member Oligo\u2010Mouse\u2010Microbiota (Oligo\u2010MM\n                    <jats:sup>12<\/jats:sup>\n                    ) to dissect microbiota\u2010dependent bone adaptation during high\u2010fat diet (HFD)\u2013induced obesity. Micro\u2010CT analysis revealed that only colonized mice exhibited structural adaptations, namely increased cortical thickness and trabecular area, in response to HFD, whereas GF mice failed to remodel their skeleton despite broadly comparable weight gain trajectories and adiposity. Serum metabolomics uncovered distinct microbiota\u2010specific metabolic signatures. GF mice accumulated bone\u2010relevant metabolites including lysine, uridine, DHA, and pyruvate, suggesting altered systemic handling of bone\u2010relevant metabolites, whereas colonized mice displayed reduced circulating levels associated with skeletal remodeling. These metabolic patterns correlated with reduced \u03b2\u2010CTX levels in colonized mice, indicative of microbiota\u2010mediated suppression of bone resorption. Our findings identify the gut microbiota as a key determinant of skeletal adaptation to diet\u2010induced obesity, presumably acting through systemic metabolic reprogramming and modulation of bone turnover. The defined\u2010microbiota mouse model provides a powerful framework to disentangle the gut\u2013bone axis at a systems and metabolic level.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600564rr","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T14:56:40Z","timestamp":1776783400000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Defined Microbiota Modulates Host Metabolome and Skeletal Adaptation to Diet\u2010Induced Obesity"],"prefix":"10.1096","volume":"40","author":[{"given":"Melanie Cristine","family":"Scalise","sequence":"first","affiliation":[{"name":"Institute for Infectious Diseases University of Bern  Bern Switzerland"},{"name":"Diabetes Center Berne  Bern Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences University of Bern  Bern 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