Abstract
High-sugar diets (HSD) represent a pervasive environmental stressor with significant health risks, yet the comparative toxicology and underlying molecular mechanisms of its impact on the central nervous system remain poorly understood. This study investigated the neurobehavioral toxicity of HSD and elucidated its mechanism of action, utilizing the invertebrate model Drosophila melanogaster to explore conserved physiological responses. Chronic exposure to a 20% HSD induced significant sleep impairment, a key neurobehavioral endpoint, characterized by reduced total sleep time and increased activity duration without affecting core circadian rhythmicity. Mechanistically, we identified a novel, indirect neurotoxic pathway originating in the gut, highlighting a conserved gut-brain axis. HSD exposure acted as a potent disruptor of gut homeostasis, inducing microbiota dysbiosis (notably decreasing Acetobacter aceti abundance) and triggering a robust intestinal inflammatory response, marked by the upregulation of pro-inflammatory cytokines Upd3 and Eiger (homologs of mammalian IL-6 and TNF-α). This peripheral immunotoxicity was causally linked to central neurochemical disruption, leading to significant neurotransmitter imbalances in the brain. Critically, targeting the initial site of toxicity-the gut-by genetically reducing Upd3 or Eiger expression specifically in intestinal epithelial cells was sufficient to rescue both the sleep deficits and the altered neurotransmitter profiles. Furthermore, ameliorating gut dysbiosis via dietary supplementation with A. aceti reversed the intestinal inflammation and normalized sleep behavior. These findings demonstrate that HSD exerts its neurobehavioral toxicity through a conserved gut-brain axis mechanism, where microbiota dysbiosis and intestinal inflammation drive central neurotransmitter dysregulation. This work highlights a critical toxicological pathway for dietary stressors with broad comparative and physiological relevance and identifies the gut inflammatory axis as a potential therapeutic target.
