Gut-to-brain signaling restricts dietary protein intake during recovery from catabolic states.

Dietary needs are dynamic, with optimal ranges for nutrients varying over time and across physiological states. How optimal nutrient set points are established and why they are adjusted remains largely unknown. In our efforts to understand the physiology of recovery, we made the surprising observation that mice restrict protein intake at the expense of caloric supply. We identified three amino acids-glutamine (Q), lysine (K), and threonine (T)-within dietary protein, which are necessary and sufficient for protein aversion during recovery from catabolic states. The anorexigenic effects of QKT are driven by ammoniagenesis in the gut, sensed by enterochromaffin cells in a TRPA1-dependent fashion and transduced to brainstem neurons via serotonin signaling, inducing anorexia. We propose that this mechanism serves as a first-line defense against ammonia toxicity. In summary, we identified a set of adaptive food preferences during recovery ("recovery behavior"), with implications for understanding diseases of pathologic recovery and the development of therapeutic interventions deployed to enhance recovery.