1. The role of morphine- and fentanyl-induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota-gut-brain axis.
- Author
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Muchhala KH, Kallurkar PS, Kang M, Koseli E, Poklis JL, Xu Q, Dewey WL, Fettweis JM, Jimenez NR, and Akbarali HI
- Subjects
- Animals, Mice, Male, Brain-Gut Axis drug effects, Fecal Microbiota Transplantation, Pancreatitis-Associated Proteins metabolism, Akkermansia drug effects, Antimicrobial Peptides pharmacology, Bacteroidetes drug effects, Morphine pharmacology, Dysbiosis chemically induced, Dysbiosis microbiology, Gastrointestinal Microbiome drug effects, Intestinal Mucosa metabolism, Intestinal Mucosa drug effects, Intestinal Mucosa microbiology, Fentanyl pharmacology, Analgesics, Opioid pharmacology, Mice, Inbred C57BL
- Abstract
Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced 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-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis., (© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
- Published
- 2024
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