The role of morphine‐ and fentanyl‐induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota‐gut‐brain axis

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. Chronic opioid treatment disrupts intestinal epithelial barrier function by reducing antimicrobial peptides, thus causing an expansion of the mucin‐degrading, Akkermansia muciniphila, “leaky” epithelium and inflammation. This contributes to the development of antinociceptive tolerance. Oral administration of butyrate or FMT prevents opioid‐induced epithelial barrier disruption by increasing antimicrobial activity and reducing epithelial permeability and A. muciniphila. Improved epithelial barrier function results in a significant decrease in antinociceptive tolerance.