Gut-derived inflammatory cytokines modulate olfactory perception through metabolic reprogramming of ensheathing glia.Â

Infection-induced aversion against enteropathogens is a conserved sickness behavior that can promote host survival1-3. The etiology of this behavior remains poorly understood, but studies in Drosophila have linked olfactory and gustatory perception to avoidance behaviors against toxic microbes4-6. Whether and how enteric infections directly influence sensory perception to induce or modulate such behaviors remains unknown. Here we show that enteropathogen infection in Drosophila can modulate olfactory perception through metabolic reprogramming of ensheathing glia of the antennal lobe. This reprogramming depends on JAK/STAT signaling activation in ensheathing glia as a consequence of infection-induced Unpaired cytokine expression in the intestine. JAK/STAT signaling induces the expression of glial monocarboxylate transporters (MCTs) and the apolipoprotein glial lazarillo (Glaz), resulting in changes in glial lipid metabolism. This modulates olfaction sensitivity, promoting avoidance of bacteria-laced food and increasing animal survival. While transient in young animals, gut-induced metabolic reprogramming of ensheathing glia becomes constitutive in old animals due to age-related intestinal inflammation, contributing to an age-related decline in olfaction sensitivity. Our findings identify adaptive glial metabolic reprogramming by gut-derived cytokines as a mechanism causing lasting changes in neuronal activity in the aging animal.