Transition From a High‐Sugar and Butter to a Standard Diet Leads to Cecal Dysbiosis, Disrupts Intestinal Homeostasis, and Favors Increased Ethanol Consumption and Preference

Excessive consumption of high-fat, high-sugar diets promotes obesity, metabolic syndrome, and chronic inflammation through increased fat accumulation. While adopting a balanced diet promotes weight loss and improvements in various physiological parameters, persistent alterations in microbiota composition and function, metabolic imbalances, and behavioral changes may increase vulnerability to ethanol consumption and preference. In this context, the present study aims to investigate how switching from a high-sugar, high-saturated fat diet (HSB) to a standard diet (AIN93G) affects: (I) cecal microbiota composition and function, (II) colonic homeostasis, and (III) vulnerability to voluntary ethanol consumption in mice. To conduct the study, six animals were maintained on the standard diet, while 12 were given the HSB diet for 8 weeks. After this period, the HSB mice were switched to AIN93G for 4 weeks, with one subgroup given access exclusively to water (SWITCH) and another to water or a 10% ethanol solution (SWITCH+EtOH). The evaluation included measurements of body weight, adiposity index, cecal microbial composition, metabolomic profile, gut and hepatic morphology, transcriptional regulation of genes involved in colonic homeostasis and striatal dopaminergic neurotransmission, as well as ethanol consumption and preference. The results indicate that switching to the standard diet does not completely reverse obesity-induced alterations. Persistent cecal dysbiosis, metabolic imbalances, and dopaminergic sensitization increase the predisposition to compulsive alcohol consumption and perpetuate epithelial and hepatic dysfunction. Therefore, post-obesity interventions should combine weight management with strategies to restore microbiota and intestinal barrier function, along with measures to reduce vulnerability to reinforcement-seeking behaviors.