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

Gut-microbiota membership is associated with diverse neuropsychological-diseases, including substance use disorders (SUDs). Unravelling mechanistic interactions between gut microbes and the host during psychostimulant use remains challenging. Here we show that cocaine exposure increases intestinal levels of norepinephrine, sensed through the bacterial adrenergic receptor QseC, promoting intestinal colonization of g-Proteobacteria. Gut colonization by g-Proteobacteria depletes the neuroactive metabolite glycine (used as a nitrogen source) both in the gut and cerebrospinal fluid, enhancing host cocaine-induced behaviors. Glycine repletion reversed this response, and intestinal colonization by g-Proteobacteria unable to uptake glycine did not alter the host response to cocaine. Transcriptomic profiling indicates a role of g-Proteobacteria modulated glycine levels in cocaine induced transcriptional plasticity in the nucleus accumbens through the glutamatergic transmission. Altogether, we introduce a mechanism by which intestinal bacteria alter the host's brain responses to cocaine that could be exploited to modulate reward-related brain circuits that contribute to SUDs. Overall design: RNA-Seq was performed on brain punches of the NAcc of mice collected 24 hs after the last injection of a repeated cocaine treatment. Three different groups were evaluated: mice microbiota-depleted reconstituted with a full microbiota (FMT, fecal microbiota transplant); mice microbiota-depleted reconstituted with a proteobacteria representative (Citrobacter rodentium DescN or Escherichia coli HS: Proteo animals). Cocaine treatment was administered once a day for 5 consecutive days using a dose of 15 mg/hg, i.p. The FMT groups was used as control. Each of the three conditions was performed in triplicate, resulting in a total of nine samples.