The cafeteria diet (CAF) is a superior diet model in animal experiments compared with the conventional high-fat diet (HFD), effectively inducing obesity, metabolic disturbances, and multi-organ damage. Nevertheless, its impact on gut microbiota composition during the progression of obesity, along with its repercussions on the enteric nervous system (ENS) and gastrointestinal motility has not been completely elucidated. To gain more insight into the effects of CAF diet in the gut, C57BL/6 mice were fed with CAF or a standard diet for 2 or 8 wk. CAF-fed mice experienced weight gain, disturbed glucose metabolism, dysregulated expression of colonic IL-6, IL-22, TNFα, and TPH1, and altered colon morphology, starting at