Morphine tolerance is attenuated in germ-free mice and reversed by probiotics implicating the role of gut microbiome

The last decade has seen an exponential increase in opioid use in the United States resulting in a subset of the population developing opioid tolerance. In this paper, we unequivocally demonstrate that the gut microbiota plays a significant role in morphine analgesic tolerance. Our studies show that morphine tolerant mice have a distinct gut microbial composition. Morphine tolerance is dramatically reduced in two microbiota depletion models: germ-free mice and pan-antibiotics-treated mice. Reconstitution of the gut microbiota in germ-free mice restores morphine tolerance. Furthermore, probiotics, which restores depleted microbial communities, attenuates morphine analgesic tolerance. These studies have significant clinical relevance and support manipulating the gut microbiota as a potential therapeutic target for the prevention, treatment, and management of opioid analgesic tolerance.