A thermogenic fat-epithelium cell axis regulates intestinal tissue tolerance

Disease tolerance is a host defense strategy that protects tissues from damage caused by pathogens or the immune system. While the importance of disease tolerance is well established in pathogenic infections, its role in tissue protection in non-infectious diseases remains less well understood. Here, we provide a framework for investigating the mechanisms of disease tolerance in experimental models of colitis. We find that the program of disease tolerance is preferentially expressed in thermoneutral mice, which protects them from injury-induced colitis and inflammation-induced colon cancer. The expression of intestinal disease tolerance is mediated by an unexpected cross-talk between thermogenic adipocytes and intestinal epithelial cells, suggesting that disease tolerance programs are metabolically expensive and dependent on the energetic state of the host.