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Depleting gut bacteria can preclude the development of tolerance to opioid\u2010induced antinociception, suggesting an important role of the gut\u2010brain axis in mediating opioid effects. The mechanism underlying opioid\u2010induced dysbiosis, however, remains unclear. Host\u2010produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine\u2010treated mice had increased levels of\n                    <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                    with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine\u2010na\u00efve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3\u03b3, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine\u2010dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin\u2010degrading\n                    <jats:italic>A. muciniphila<\/jats:italic>\n                    in morphine\u2010dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota\u2010gut\u2010brain axis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202301590rr","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T14:30:25Z","timestamp":1713796225000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The role of morphine\u2010 and fentanyl\u2010induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota\u2010gut\u2010brain axis"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2594-1347","authenticated-orcid":false,"given":"Karan H.","family":"Muchhala","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology Virginia Commonwealth University  Richmond Virginia 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