The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis

Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the gut epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that intestinal antimicrobial activity is reduced, and epithelial permeability is increased in a morphine-dependent mouse model. Antimicrobial activity and permeability are restored by fecal transplant (FMT) from morphine-naive mice or by oral gavage of sodium butyrate. Butyrate levels are reduced in the fecal samples of morphine-treated mice concomitant with a reduction in the phylum, Firmicutes. The alpha diversity of the microbiome is also restored by oral butyrate in morphine-dependent mice. FMT or sodium butyrate prevents downregulation of the antimicrobial peptide, Regenerating islet-derived 3 gamma , and the development of antinociceptive tolerance in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which morphine disrupts the microbiota-gut-brain axis.