The role of the gut microbiota in the vulnerability to alcohol use disorders

Alcohol use represents a significant public health concern, accounting for 4.5% of global disease burden. Only a small proportion of individuals develop persistent alcohol used disorder though. With current pharmacotherapies largely unsatisfying, discovering novel alternatives to prevent alcohol use disorder becomes a priority. Hence, identifying biological markers predicting vulnerability to develop excessive alcohol consumption may lead to real improvement of clinical care. Converging evidence suggests that gut microbiota is capable of influencing immunity, brain and behavior. We thus investigated gut microbiome and signs of peripheral inflammation in stressed rats exhibiting uncontrolled alcohol seeking behaviors defined as: 1) inability to abstain during a signaled period of reward unavailability, 2) increased motivation assessed in a progressive effortful task and 3) persistent alcohol seeking despite aversive foot shocks. Compared to controls (n=10), rats exposed to chronic stress during adolescence (n=11) exhibited impulsive, inattentive and disinhibited behaviors. After 33 sessions of daily alcohol (10%weight/volume) self-administration, all rats were screened according to the 3 criteria defined above. 7/9 of the vulnerable group was composed of stressed rats, and 8/12 of the resilient group was composed of controls, confirming that stress during adolescence increases the vulnerability to develop AUD-like behavior (addiction score for controls -1.086±1.75; addiction score for stressed rats 0.98 ± 1.93; unpaired t-test, p=0.0190). All rats were then given access to 2 sources of reward: 0,1mL 10% w/v ethanol and 0.1mL saccharine (0.2 %, 0.00625%, 0%), 2 consecutive sessions for each concentration, during which stressed rats exhibited a clear-cut preference for alcohol compared to controls (2-way ANOVA, group effect (F1,21=10.73, p=0.0036). Strikingly, we identify a long-lasting peripheral inflammation in stressed rats (with increased blood levels of (Rantes (CCL5) and Interleukin-4), and not only fecal microbiota transfer lowered stressed rats’ preference for alcohol but it restored inflammation modulators levels to those observed in controls.