Metabolic Adaptation Establishes Disease Tolerance to Sepsis

TLDR

Sepsis is a lethal syndrome caused by maladaptive immune and metabolic responses, while disease tolerance preserves host homeostasis without directly harming pathogens. FTH protects by countering iron‑driven oxidative inhibition of liver glucose‑6‑phosphatase, thereby sustaining endogenous glucose production through gluconeogenesis. Induction of ferritin H chain is essential for disease tolerance to sepsis, preventing hypoglycemia and enabling therapeutic tolerance via ferritin administration, highlighting a critical iron–glucose metabolic crosstalk that maintains physiological blood glucose for survival.

Abstract

Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival.