Alterations in microbiome composition and metabolic byproducts drive behavioral and transcriptional responses to
Rebecca S Hofford1,2, Nicholas L Mervosh1,2, Tanner J Euston1,2
1Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abstract:
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 × 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.
Insights
The gut microbiome influences morphine reward and behavior. Restoring short-chain fatty acids (SCFAs) reversed these effects, highlighting their role in gut-brain communication for substance use disorders.
Area of Science:
- Neuroscience
- Microbiology
- Pharmacology
Background:
- The gut microbiome significantly impacts brain function and behavior.
- Microbial disturbances are linked to neuropsychiatric disorders, but their role in substance use disorders is understudied.
Purpose of the Study:
- To investigate the role of the gut microbiome in morphine-related behaviors and molecular changes.
- To identify the mechanisms mediating the microbiome's influence on substance use disorders.
Main Methods:
- Male mice were treated with nonabsorbable antibiotics (Abx) to deplete the gut microbiome.
- Morphine conditioned place preference and locomotor sensitization were assessed.
- Gene expression in the nucleus accumbens (NAc) was analyzed.
- Short-chain fatty acid (SCFA) metabolites were administered to assess their effects.
Main Results:
- Microbiome depletion (Abx) decreased morphine conditioned place preference and locomotor sensitization.
- Abx treatment altered NAc gene expression in response to morphine.
- SCFA replacement reversed the behavioral and transcriptional effects of microbiome depletion.
Conclusions:
- The gut microbiome plays a critical role in modulating morphine reward and related behaviors.
- Short-chain fatty acids (SCFAs) are key mediators of microbiome-brain communication in substance use.
- These findings provide mechanistic insights into gut-brain signaling in substance use disorders.
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