Vibrio cholerae-synthesized tryptophan activates innate immune signaling in enteroendocrine cells via phosphorylation of the nuclear receptor ultraspiracle.

The Gram-negative rod Vibrio cholerae causes profuse diarrhea in humans and is found in close association with both terrestrial and aquatic arthropods in the environment. Here we show that tryptophan produced by V. cholerae in the arthropod intestine activates expression of the host colonization factor Peritrophin-15a (Peri-15a). V. cholerae-derived tryptophan is used by host enterocytes to synthesize serotonin, which signals to enteroendocrine cells (EECs) to activate the TNF-like immune deficiency pathway IMD. We define the EEC serotonin signaling pathway, which involves a subset of serotonin G protein-coupled receptors, Gαq, phospholipase C, and protein kinase C. This pathway culminates in phosphorylation and potentiation of the nuclear receptor ultraspiracle, which binds the sex hormone ecdysone to activate IMD signaling. IMD signaling in EECs uniquely activates expression of the enteroendocrine peptide Tachykinin, which increases expression of Peri-15a. We propose that, because V. cholerae-synthesized tryptophan increases host Peri-15a expression, it has evolved to exploit the arthropod intestinal innate immune response to maximize intestinal adhesion.