Cumulative evidence suggests that somatosensorial stimulation through exposure to enriched environments improves homeostasis and enhances central nervous system functions. Immune system functions are also modulated by exposure to enriched environments, which enhance phagocytosis and chemotaxis while attenuating the inflammatory response induced by lipopolysaccharide exposure or hypercaloric diets. Consistent with these, here we show that exposure to an enriched environment attenuates inflammation in the colon in two colitis experimental models. Exposing animals to an enriched environment reduced weight loss, colon length shortening, and decreased disease activity index after dextran sodium sulfate or trinitrobenzene sulfonic acid treatment, compared with animals housed in a normal environment. Histologically, after colitis induction, exposure to an enriched environment reduced epithelial damage, lessened the inflammation, and attenuated loss of goblet cells compared to animals housed in a normal environment. Our results also show that brain stimulation by exposure to an enriched environment attenuates inflammation in the intestinal mucosa by preventing epithelial barrier dysfunction through BDNF-mediated expression of cell adhesion molecules. At the molecular level, there is a global change in gene expression and gene regulatory networks as a response to dextran treatment. Interestingly, a Myc-driven gene regulatory network enhanced by colitis is attenuated by exposure to an enriched environment, via downmodulation of Myc protein levels. Together, our results show that brain stimulation by exposure to an enriched environment attenuates inflammation in the gut mucosa by fine-tuning an inflammatory gene expression program, opening new venues of investigation for colitis treatment.