Temporary consumption of western diet trains the immune system to reduce future gut inflammation

Urbanization drives the popularity of western diet (WD), which increased burden in metabolic diseases but also in inflammatory diseases. Here, we show continuous WD disrupted the gut barrier, initiating low-grade inflammation and enhancing the colitis response. Nevertheless, transient WD consumption followed by ad libitum normal diet enhanced mucin production and tight junction protein expression in recovered mice. Furthermore, transient WD consumption surprisingly reduced the subsequent inflammatory response in DSS colitis and Citrobacter rodentium-infection induced colitis. The protective effect ofWDtraining was not sex-dependent, and co-housing experiments suggested microbiota changes were not responsible. We identified important roles for cholesterol biosynthesis pathway and macrophages, pointing to innate myeloid training. Together, these data suggest detrimental effects of WD consumption can be reversed on return to a healthier diet. Furthermore, transient WD consumption leads to beneficial immune training, suggesting an evolutionary mechanism to benefit from feasting when abundant food is available.