Dietary methionine mitigates immune-mediated damage by enhancing renal clearance of cytokines

The immune system defends against pathogens but can also cause tissue damage, energetic costs, and even death through excessive cytokine and chemokine production. Because antimicrobial responses are necessary for host defense, hosts have evolved cooperative defenses to mitigate the costs of immunity. Using Yersinia pseudotuberculosis infection in mice, we demonstrate that dietary methionine supplementation protects against cytokine-mediated anorexia, wasting, blood-brain barrier dysfunction, and lethality without impairing microbial killing. Methionine and its metabolite S -adenosyl methionine (SAM) activate renal mTORC1 signaling, promoting renal growth and enhanced glomerular filtration function. This enables urinary clearance of pro-inflammatory cytokines from the circulation, limiting their systemic accumulation and the resulting sickness and lethality. This work reveals an unappreciated role for the kidneys in controlling systemic cytokine responses during infection. It also suggests that nutrient-based interventions targeting metabolic signaling can mitigate the harmful trade-offs of immune defense, offering potential therapeutic avenues to reduce infection-related costs, including death. • Met supplementation limits systemic cytokine load without hindering microbial defense • Met and its metabolite SAM activate renal mTORC1 signaling during infection • mTORC1 activation drives renal growth and enhanced glomerular filtration function • Enhanced renal function enables urinary clearance of cytokines to promote survival Troha et al. found that dietary methionine enhances kidney filtration and promotes urinary excretion of inflammatory cytokines during infection. By improving cytokine clearance, this pathway mitigates immune-mediated damage and reveals a nutritional strategy to promote cooperative defenses.