O consumo problemático de etanol e suas interconexões com o sistema imune, dieta, microbiota intestinal e o gene Lrrk2

Abstract

Mechanisms that dictate the preference for ethanol and its addiction are not only restricted to the central nervous system (CNS). An increasing body of evidence has suggested that abusive consumption of ethanol directly affects the gut microbiota and the immune system, which in turn interact with the CNS, triggering neuronal responses and changes, resulting in addition by the drug. It is a fact that the gut microbiota communicates with the CNS through the gut-brain axis, and there is an increase in neuroinflammation as a result of the ethanol consumption. Nevertheless, there are few studies linking these findings to the tran- scriptional profile of genes associated with heavy ethanol consumption. In this regard, there is a belief that, in the groove, an integrating region of the brain reward system, the interac- tion of the immune response and gut microbiota with the transcriptional profile of the Lrrk2 gene (associated with loss of control and addiction to ethanol) may influence the heavy consumption and preference of ethanol. Given this information, this study aimed at evalu- ating the interconnections between the gut microbiota, immune system, transcriptional pro- file of the Lrrk2 gene, and heavy ethanol consumption. For this purpose, an animal model, developed by our research group, is adopted, in which male C57BL/6 mice and knockouts for the Il6 and Nfat genes were subjected to each of the following stages: Stage 1 (T1) ‒ Dietary treatment, for eight weeks, in which the animals receive high-calorie diet, High Sugar and Butter (HSB group), or standard diet, American Institute of Nutrition 93-Growth (AIN93G group); and Stage 2 (T2) ‒ Ethanol consumption, in which the animals are sub- mitted, for four weeks, to ethanol within the free choice paradigm, being each of them di- vided into six groups: [1] AIN93G + H2O; [2] AIN93G + EtOH; [3] HSB + H2O; [4] HSB + EtOH; [5] HSB-AIN93G + H2O; [6] HSB-AIN93G + EtOH; [7] HSB-AIN93G Il6 KO + H2O; [8] HSB-AIN93G Il6 KO + EtOH; [9] HSB-AIN93G Nfat + H2O and [10] HSB-AIN93G Nfat + EtOH. The five groups (+H2O) had access to only water, while the five others (+ EtOH) had free choice between water and a 10% ethanol solution. The HSB diet is substituted by the AIN93G diet in the HSB-AIN93G groups. At the end of the 12-week experiment, animals in the HSB-AIN93G + EtOH, HSB-AIN93G Il6 + EtOH e HSB-AIN93G Nfat + EtOH groups had a high preference and consume excessive amounts of ethanol. Thus, we observed that ethanol consumption leads to (1) alterations in the composition and abundance of gut mi- crobiota; (2) increased gut permeability; (3) elevation of inflammatory cells in the groove; (4) overregulation of genes associated with proinflammatory cytokines; and (5) under reg- ulation of the Lrrk2 gene. The findings suggest interactions among the gut microbiota, im- mune system, and transcriptional profile of the Lrrk2 gene influence the preferential and heavy ethanol consumption. Nevertheless, further studies will be necessary to understand the interaction of these factors.