Li et al. report that Edwardsiella piscicida employs HigA, an anti-toxin protein, to facilitate the diversion of tryptophan metabolism to the kynurenine pathway, rather than the serotonin pathway, by directly activating IDO1 in a T6SS-dependent manner as a cross-kingdom effector. The serotonin-level fluctuation modulates host intestinal histological damage and bacterial infection.