L. johnsonii alleviates methamphetamine craving via the metabolism of tyrosine

Background: Methamphetamine (MA) abuse is a global public problem and methamphetamine addiction lacks of effective treatment. The gut microbes, involved in the gut-brain axis, remotely regulate methamphetamine addiction. Results: In this study, we identified that Lactobacillus johnsonii (L. johnsonii) is involved in the metabolism of tyrosine. MA addiction disrupts the balance of gut microbes, reducing the abundance of L. johnsonii, destroying intestinal barrier integrity, and increasing the tyrosine level. The outbreak of tyrosine promotes a greater craving for MA in mice since it transfers from the intestine to VTA and NAc to promote microglia immune reactivity, which reduces energy supply to neurons and decreases presynaptic mitochondria in dopaminergic neurons. As a consequence, the dopaminergic presynaptic membrane reuptake process based on vesicular transport is affected, leading to maintain of dopamine in the synaptic cleft acting on the postsynaptic membrane with synaptic plasticity changes, resulting in MA craving. L. johnsonii transplantation rescues mice from MA craving by promoting the metabolism of tyrosine in intestine and improves the neuronal function in NAc and VTA. Conclusions: Our results reveal that MA addiction disrupts gut microbiota homeostasis and promotes tyrosine-mediated dopamine system dysfunction. L. johnsonii transplantation is recommended for the treatment of methamphetamine craving.