The gut microbiomes of people with amphetamine use disorder often have higher numbers of opportunistic residents like Fusobacterium nucleatum, a microbe that is typically found in the mouth but can sometimes make itself at home in the intestines. When researchers put F. nucleatum into the guts of fruit flies and gave them amphetamines, the flies responded more strongly to the drug — a behavioral shift that the team tied to dopamine activity. Turns out the bacteria secrete a compound that ultimately boosts the expression of dopamine transporters, which amphetamine then causes to pump dopamine out of neurons instead of into them — all of which results in greater dopamine release and a stronger “reward” feeling from the drug.
The discovery raises the possibility of hacking this pathway to tamp down on amphetamine’s effects, making it easier for people who are addicted to stop using it. One possibility, the team noted, is to target Fusobacterium nucleatum with a specific bacteria-killing virus.
Editor’s summary
Amphetamine is a stimulant that is used to treat various neurological disorders. It is also misused and induces changes in the gut microbiome. Mabry et al. found that Fusobacterium nucleatum in the guts of flies enhanced the psychomotor effects of amphetamine by increasing the amount of dopamine transporters in the brain. F. nucleatum produces butyrate, a short-chain fatty acid that inhibits chromatin-modifying enzymes called HDACs. Manipulating this axis in flies suggested that butyrate increased the expression of the gene encoding the dopamine transporter through HDAC1 inhibition, thus enhancing dopamine-motivated behaviors. The findings reveal a potentially targetable gut-brain axis to treat amphetamine use disorder. —Leslie K. Ferrarelli
Abstract
Amphetamines are psychostimulants that are commonly used to treat neuropsychiatric disorders and are prone to misuse. The pathogenesis of amphetamine use disorder (AUD) is associated with dysbiosis (an imbalance in the body’s microbiome) and bacterially produced short-chain fatty acids (SCFAs), which are implicated in the gut-brain axis. Amphetamine exposure in both rats and humans increases the amount of intestinal Fusobacterium nucleatum, which releases SFCAs. Here, we found that colonization of gnotobiotic Drosophila melanogaster with F. nucleatum or supplementing the flies’ diet with the SCFA butyrate enhanced the psychomotor and reward properties of amphetamine. Butyrate inhibits histone deacetylases (HDACs), and knockdown of HDAC1 recapitulated the effects induced by F. nucleatum or butyrate. The enhancement in amphetamine-induced behaviors was mediated by an increase in the amount of released dopamine that resulted from amphetamine-induced reversal of dopamine transporter (DAT) function, termed nonvesicular dopamine release (NVDR). The magnitude of amphetamine-induced NVDR was partially mediated by an increase in DAT abundance stimulated at a transcriptional level, and the administration of F. nucleatum or butyrate enhanced NVDR by increasing DAT expression. The findings indicate that F. nucleatum supports AUD through epigenetic regulation of dopamine signaling and identify potential targets for AUD treatment.
REFERENCE: Molecular Biology; Science Signaling; 09 SEP 2025