Iron Homeostasis and Reproduction: Unveiling the Microbiome-Gut-Brain-Axis Connection in the Mosquito <em>Anopheles culicifacies</em>

Our study investigated how adult female mosquitoes regulate systemic iron homeostasis after blood feeding, a process essential for reproduction, and revealed striking parallels to iron deficiency disorders in mammals. This study shows that a coordinated transcriptional regulation of Ferritin (Fer) and Transferrin (Trf) plays a crucial role in follicle development and egg maturation. Silencing of both genes using RNA interference (RNAi) led to severe reproductive impairment, including ovarian arrest in 50% of females, 40% reduction in oocyte number, and a decrease in first instar larval size. These outcomes correlate with increased reactive oxygen species (ROS) and altered serotonin receptor (5-HTR) expression in the brain, possibly driven by microbial Gut-Brain-Axis communication alteration due to disrupted iron metabolism. Additionally, we also report the discovery of a previously unknown mosquito gene encoding a hepcidin-like peptide (AcHep), expressed in the fat body. This finding reflects the role of mammalian hepcidin, a central regulator of iron homeostasis, suggesting a conserved evolutionary mechanism. In summary, our research provides the first molecular proof and new conceptual understanding that iron metabolism disorders may affect mGBA communication and, in turn, reproductive outcomes.