UNDERSTANDING THE INFLUENCE OF THE GUT MICROBIOME ON THE MESOLIMBIC SYSTEM AND ITS RESPONSE TO NICOTINE

Emerging evidence suggests a role for gut bacteria in the pathophysiology of substance use disorders (SUD), yet their impact on brain and behavioral responses to drugs remains poorly studied. We previously showed that gut dysbiosis enhances nicotine-induced activation of the mesolimbic system and alters nicotine’s motivational properties in mice. However, the mechanisms linking gut bacteria to mesolimbic responses to nicotine remain unclear. Microbial products might mediate these effects by influencing gene expression, host immune and glial activation, and synaptic signalling. In particular, short-chain fatty acids (SCFAs), major microbial by-products of dietary fiber fermentation, are considered key targets for understanding the role of the gut microbiome in SUD, as they regulate gut hormone secretion, cross the blood-brain barrier, and affect epigenetic signaling in the brain. Here, we investigated the role of SCFAs in the consequences of several types of gut dysbiosis on mesolimbic system function and nicotine response in mice. We replicated and refined previous finding showing that microbiota depletion enhances nicotine-evoked neuronal activation in the ventral tegmental area and nucleus accumbens shell, and demonstrated that this effect also occurs in mice fed a Western diet inducing severe gut dysbiosis. Importantly, our data indicate that SCFA supplementation modulates neuronal activation in conditions of microbiota alteration and also shed light on the processes underlying this effect. Our findings contribute to identifying mechanisms by which gut microbiome alterations modulate the brain response to nicotine, potentially improving our understanding of individual vulnerability to develop nicotine addiction.