Short-term dietary changes lead to windows of mucosal and systemic immune depression

Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time. The health consequences of this short-term consumption of energy-dense nutrients still remains unclear. We found that every short-term, reiterated switch to feast diets mimicking our social eating behavior, breached the potential buffering effect of the intestinal microbiota and deeply reorganized the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity leading to higher susceptibility to Salmonella Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4+ T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to withdrawal of microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored both mucosal and systemic CD4+ T cell functions and immunity. Finally, dietary intervention studies in human volunteers confirmed the impact of short-term dietary switches on human CD4+ T cell functionality. This work reveals that short-term nutritional changes cause a transient depression of both mucosal and systemic immunity, creating windows of opportunities for pathogenic infections.