A thermogenic fat-epithelium cell axis regulates intestinal disease tolerance

Disease tolerance, the capacity of tissues to withstand damage caused by a stimulus without a decline in host fitness, varies across tissues, environmental conditions, and physiologic states. While disease tolerance is a known strategy of host defense, its role in noninfectious diseases has been understudied. Here, we provide evidence that a thermogenic fat–epithelial cell axis regulates intestinal disease tolerance during experimental colitis. We find that intestinal disease tolerance is a metabolically expensive trait, whose expression is restricted to thermoneutral mice and is not transferable by the microbiota. Instead, disease tolerance is dependent on the adrenergic state of thermogenic adipocytes, which indirectly regulate tolerogenic responses in intestinal epithelial cells. Our work has identified an unexpected mechanism that controls intestinal disease tolerance with implications for colitogenic diseases.

Resistance and disease tolerance are two distinct strategies a host can use to mitigate the negative impact of disease on tissue function and host fitness (1, 2). For example, during pathogenic infections, the detection and elimination of pathogens is mediated by resistance, whereas disease tolerance minimizes the negative impact of pathogens on host fitness without affecting pathogen burden. Although disease tolerance is a well-appreciated strategy of host defense against pathogens in both the plant and animal kingdoms (3–5), its importance in noninfectious diseases is largely unknown (1, 6).Recent studies have demonstrated that metabolic adaptations mediate disease tolerance during viral, bacterial, and parasitic infections (7–12). These findings suggest that disease tolerance programs are metabolically expensive and compete for energy with other tissue maintenance programs. Because homeothermy, the stable maintenance of core temperature, is a major energy consuming program in mammals (13), we postulated that it might energetically compete with disease tolerance programs to limit their expression in noninfectious diseases. We tested this hypothesis using murine models of colitis because the high regenerative capacity of the intestinal epithelium has been postulated to increase its intrinsic tolerance capacity (1).