Stimulation of specific pathways for systemic inflammation in alcohol dependent subjects and relation with psychological symptoms

Leclercq, Sophie [UCL] De Saeger, Christine [UCL] Delzenne, Nathalie M. [UCL] de Timary, Philippe [UCL] Starkel, Peter [UCL]

Background: In a previous study, we observed increased intestinal permeability, elevated blood lipopolysaccharides (LPS) and inflammation in AD subjects. Inflammation was correlated with depression and alcohol craving, suggesting it may play a role in the motivation for drinking. However, the source of this systemic inflammation is unknown. Gut-derived bacterial products, such as LPS and peptidoglycans (PG), are known to stimulate inflammation. LPS has been shown to play a role in animal models of alcoholic liver inflammation trough TLR4 interaction and NFKB activation. Conversely, the role of PG which are recognized by TLR2 and NOD2 and can activate NFKB, AP-1 and inflammasome, is not known in AD patients. The aim of our study was to analyse into details the different inflammatory pathways of AD subjects. Material and Methods: 63 non-cirrhotic AD subjects were included in the study. PBMC of these patients were used to analyse the mRNA and protein levels of TLR signalling molecules and inflammatory cytokines by qPCR and western-blot. A subset of 20 patients was also subjected to psychological tests to assess depression, craving and working memory (WM). The AD group was compared to 14 healthy controls matched for age and gender. Results: TLR4, TLR2 and NOD2 expressions were increased in PBMC of AD patients and MyD88-dependent pathway was activated. Unexpectedly, the transcription factor NFκB was strongly inhibited whereas AP-1 was activated and induces IL1β, IL8 and IL18 transcription. Finally, we observed that the signaling molecules dependent of AP-1 and inflammasome correlated with alcohol consumption, craving and WM. Conclusion: The specific pathways of inflammation activated in AD subjects may play a role in alcohol drinking motivation.