<p><i>Vibrio cholerae</i> is a human diarrheal pathogen and an estuarine organism that associates with both terrestrial and aquatic arthropods. Using the model terrestrial arthropod <i>Drosophila melanogaster</i>, we previously showed that <i>V. cholerae</i> adheres to the arthropod intestine and activates the enteroendocrine cell innate immune response to augment expression of the enteroendocrine peptide tachykinin (Tk). Here we show that enteroendocrine innate immune signaling and Tk promote <i>V. cholerae</i> colonization of the arthropod intestine. To investigate this, we measure the impact of <i>Tk</i>^RNAi on intestinal gene expression. In addition to decreasing expression of antimicrobial peptides and lipases, <i>Tk</i>^RNAi reduced the expression of chitinases and chitin-binding proteins including the small, secreted chitin-binding protein Peritrophin-15a (Peri-15a). Peri-15a interacts with chitin fibrils in the peritrophic matrix, a protective coating that overlies the arthropod intestinal epithelium. We uncover that Peri-15a is essential for robust <i>V. cholerae</i> colonization of the gut. Homologs of Peri-15a are widespread in both terrestrial and aquatic organisms including marine non-biting midges, marine copepods, rotifers, and cyanobacteria. We propose that <i>V. cholerae</i> activation of the enteroendocrine cell innate immune response and Peri-15a expression represents a strategy to maximize colonization of the arthropod host intestine.</p>