Gut colonization by Proteobacteria alters host metabolism and modulates cocaine neurobehavioral responses

Gut-microbiota membership is associated with diverse neuropsychological outcomes, including substance use disorders (SUDs). Here, we use mice colonized with Citrobacter rodentium or the human gamma-Proteobacteria commensal Escherichia coli HS as a model to examine the mechanistic interactions between gut microbes and host responses to cocaine. We find that cocaine exposure increases intestinal norepinephrine levels that are sensed through the bacterial adrenergic receptor QseC to promote intestinal colonization of gamma-Proteobacteria. Colonized mice show enhanced host cocaine-induced behaviors. The neuroactive metabolite glycine, a bacterial nitrogen source, is depleted in the gut and cerebrospinal fluid of colonized mice. Systemic glycine repletion reversed, and gamma-Proteobacteria mutated for glycine uptake did not alter the host response to cocaine. gamma-Proteobacteria modulated glycine levels are linked to cocaine-induced transcriptional plasticity in the nucleus accumbens through glutamatergic transmission. The mechanism outline here could potentially be exploited to modulate reward-related brain circuits that contribute to SUDs.

Automated summary

The study on the mechanism of the interaction between gut microbiota and cocaine found that cocaine exposure increases intestinal norepinephrine levels, which promotes intestinal colonization and leads to a series of behavioral responses. Gut microbiota affects glycine levels, and through glutamatergic transmission, influences transcriptional plasticity in the nucleus accumbens, thereby modulating reward-related brain circuits associated with SUDs.