Alterations in microbiome composition and metabolic byproducts drive behavioral and transcriptional responses to morphine

Recent evidence has demonstrated that the gut microbiome has marked effects on neuronal function and behavior. Disturbances to microbial populations within the gut have been linked to myriad models of neuropsychiatric disorders. However, the role of the microbiome in substance use disorders remains understudied. Here we show that male mice with their gut microbiome depleted by nonabsorbable antibiotics (Abx) exhibit decreased formation of morphine conditioned place preference across a range of doses (2.5-15 mg/kg), have decreased locomotor sensitization to morphine, and demonstrate marked changes in gene expression within the nucleus accumbens (NAc) in response to high-dose morphine (20 mg/kg x 7 days). Replacement of short-chain fatty acid (SCFA) metabolites, which are reduced by microbiome knockdown, reversed the behavioral and transcriptional effects of microbiome depletion. This identifies SCFA as the crucial mediators of microbiome-brain communication responsible for the effects on morphine reward caused by microbiome knockdown. These studies add important new behavioral, molecular, and mechanistic insight to the role of gut-brain signaling in substance use disorders.

Automated summary

Recent evidence has shown the significant impact of the gut microbiome on neuronal function and behavior, with disruptions linked to various neuropsychiatric disorders. While the role of the microbiome in substance use disorders is not fully understood, a study on male mice with depleted gut microbiome showed decreased morphine conditioned place preference and gene expression changes in response to high-dose morphine. Short-chain fatty acids were identified as crucial mediators of gut-brain communication responsible for the effects on morphine reward caused by microbiome depletion.