Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupt the intestinal epithelial layer and cause intestinal dysbiosis. Inhibiting opioid-induced dysbiosis can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. However, the mechanism underlying opioid-induced dysbiosis 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 exposure reduces expression of the antimicrobial peptide, Regenerating islet-derived 3 gamma (Reg3γ), in the ileum resulting in reduced intestinal antimicrobial activity against Gram-positive bacteria, L. reuteri. Fecal samples from morphine-treated mice had reduced levels of the phylum, Firmicutes, concomitant with reduced levels of short-chain fatty acid, butyrate. Fecal microbial transplant (FMT) from morphine-naïve mice restored the antimicrobial activity, the expression of Reg3γ, and prevented the increase in intestinal permeability and the development of antinociceptive tolerance in morphine-dependent mice. Similarly, oral gavage with sodium butyrate dose-dependently reduced the development of antinociceptive tolerance, and prevented the downregulation of Reg3γ and the reduction in antimicrobial activity. The alpha diversity of the microbiome was also restored by oral butyrate 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.

cautioned against the use of these medications in cases of diarrhea caused by highly inflammatory bacterial pathogens because of their potential association with complications such as toxic dilation of the colon or prolonged illness. This concern was based on the results of two RCTs: one investigating diphenoxylate/ atropine (Lomotil) therapy in shigellosis used in combination with oxolinic acid and the other investigating antimotility agent use in the treatment of diarrhea related to Clostridium difficile. The ACG guidelines did not specifically recommend for or against the use of loperamide in patients with dysentery.

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-naïve 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 (Reg3γ), 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.