Bacterial anti-toxin HigA dysregulates host intestinal serotonin homeostasis in a T6SS-dependent manner

Intestinal serotonin not only plays crucial roles in the gut-brain axis but also participates in host-microbial interactions. However, the underlying mechanism of serotonin-level fluctuations remains elusive. Here, we demonstrate that host intestinal serotonin levels are elevated during the early stage of Edwardsiella piscicida infection. Upon perceiving serotonin, HigA, an anti-toxin protein, is translocated into the host nucleus in a T6SS-dependent manner as a cross-kingdom effector. HigA directly binds to the promoter region of the main rate-limiting enzyme IDO1 and upregulates its expression, facilitating the diversion of tryptophan metabolism to the kynurenine pathway, which impairs serotonin production. Moreover, the decreased intestinal serotonin exacerbates host histological damage and promotes Edwardsiella infection. Furthermore, a HigA homolog modulates serotonin metabolism and intestinal histological damage in a Salmonella-infected murine model. Overall, our study elucidates the host-pathogen interaction involving serotonin, in which pathogens intelligently modulate host intestinal serotonin to achieve systemic infection, given the widespread presence of the T6SS-HigA-serotonin axis.