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Opioids also drive gut microbiota dysbiosis which is linked to altered opioid responses tied to OUD. To interrogate the role of the gut microbiota in a mouse model of OUD, we used a longitudinal paradigm of voluntary oral morphine self-administration to capture multiple facets of drug seeking and preserve both individual behavioral response and gut microbiota variation to examine associations between these two variables. After prolonged morphine consumption, only a subset of mice transitioned to a state we define statistically as compulsive. In compulsive mice, morphine fragmented the microbiota networks which subsequently reorganized to form robust novel connections. In contrast, the communities of non-compulsive mice also changed but were highly interconnected during morphine disturbance and maintained more continuity post morphine suggesting dynamic flexibility. Compulsive mice displayed a greater loss of functional diversity and a shift towards a new stable state dominated by potential pathobionts, whereas non-compulsive mice better preserved genera associated with gut health and broader functional diversity. These findings highlight how persistent and stable gut microbiota dysbiosis aligns with long-term behavioral changes underlying OUD, potentially contributing to relapse.<\/jats:p>","DOI":"10.1101\/2025.06.01.657215","type":"posted-content","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T23:50:16Z","timestamp":1748821816000},"source":"Crossref","is-referenced-by-count":0,"title":["Dynamic flexibility of the murine gut microbiota to morphine disturbance enables escape from the stable dysbiosis associated with addiction-like 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