Alterations in the gut microbiome associated with feeding, development and infection could modulate the following immune response pathways in ticks: A. Toll pathway. Microbiota-induced activation of Spatzle, enabling Spatzle-Toll interaction and initiation of the signaling cascade resulting in the production of antimicrobial peptides (AMPs). B. Immunodeficiency (IMD) pathway. Sensing of Gram-negative peptidoglycan (Peptidoglycan) by the peptidoglycan recognition protein (PGRP-LC) to activate the signaling cascade leading to AMP production. C. Janus kinase/Signal transducer and activator of transcription JAK-STAT pathway. Microbiota and pathogen-induced activation of Dual oxidase (DUOX) results in the reactive oxygen species (ROS) production to control bacteria. ROS-mediated collateral damage to the gut epithelial cells initiates the release of cytokine-like molecule Unpaired 3 Upd that engages with its receptor, DOME, a signal transducing transmembrane protein receptor, to activate the JAK-STAT signaling pathway. STAT transcriptionally regulates pathways leading to immune responses, epithelial regeneration and repair, and peritrophic membrane integrity. AMPs and immune responses generated by Toll, IMD and JAK-STAT pathways influence pathogen survival, and also facilitate bacterial homeostasis (Based on citations 58, 87, 88 and 89).