Thread by @_SantiagoCuesta

Incredibly happy to have this paper out! We demonstrated that cocaine exposure affects gut microbiota composition and that this compositional change modulates neurobehavioral plasticity: sciencedirect.com/science/articl… @cellhostmicrobe #gutbrain #microbiome #OpenAccess
A long thread😅

Thanks to all the co-authors! @pauburdisso and of course @VanessaSperand2. Also, the twitterless Amir Segev and Said Kourrich. @TheEllermannLab and @AGJimenezLopez thanks for all the feedback!

Cocaine and other psychostimulants act by blocking catecholamine reuptake. Citrobacter rodentium is a mouse γ-Proteobacteria that can sense host norepinephrine to colonize the gut, inducing dysbiosis.

We used it as a model to test whether cocaine, by increasing catecholamine levels, could modify microbiota composition. We found that cocaine exposure facilitates gut colonization and infectious disease induced by C. rodentium, an effect dependent on the adrenergic receptor QseC

We then validated the role of norepinephrine (NE). First, we confirmed that cocaine elevates the levels of norepinephrine in the gut. Then we showed that preventing cocaine from increasing NE was sufficient to block the cocaine modulation of C. rodentium colonization

To start evaluating for behavioral effects, we measured cocaine-induced locomotion in C. rodentium-colonized mice. We found that infected mice showed higher behavioral responses than their control, non-infected counterparts.

C. rodentium colonization leads to gut inflammation and modifies microbiota composition (increasing γ-Proteobacteria abundance).

We ruled out inflammation as the main cause of the behavioral phenotype and recapitulated the behavioral effect in mice colonized with Escherichia coli HS, a human commensal γ-Proteobacteria, proposing the involvement of microbiota composition.

Using metabolomics, we found that the increase in γ-Proteobacteria significantly altered the host’s metabolomic profile. More specifically, γ-Proteobacteria colonization depleted glycine, a bacterial nitrogen source, in both the gut and the cerebrospinal fluid.

Transcriptomic analysis also revealed that γ-Proteobacteria-colonized mice presented altered cocaine-induced plasticity in the Nucleus Accumbens in pathways associated with glycine

In line with a role of glycine as a mediator of γ-Proteobacteria increased response to cocaine, systemic restoration of glycine or administration of the glycine agonist sarcosine, prevented the changes in the behavioral responses induced by the drug

Remarkably, the increase in cocaine-induced locomotion was no longer observed in animals reconstituted with E. coli HS ΔcycA, a mutant that cannot uptake glycine

Finally, we recapitulated this microbiota effect using conditioned place preference, supporting the hypothesis that γ-Proteobacteria-driven glycine depletion can also modulate drug-seeking and rewarding responses

A summary (artwork by Flor Cerchiara instagram.com/florecercreati…)