Navigating contradictions:SalmonellaTyphimurium chemotactic responses to conflicting effector stimuli

Chemotaxis controls motility and colonization in many enteric pathogens, yet most studies have examined bacterial responses to single effectors in isolation. Previously, we reported thatSalmonellaTyphimurium uses the chemoreceptor Tsr to detect L-serine (L-Ser) in human blood serum, promoting invasion of damaged vasculature (Glenn et al., eLife2024¹). Tsr also mediates sensing of indole, a microbiota-derived chemorepellent and bactericide proposed to protect against enteric infection by deterring pathogen colonization. The major biological reservoir of indole in the gut is feces, where it accumulates to millimolar levels. Here, we tested whether indole-rich human fecal material is protective against infection and found that exposure to feces instead enhances intestinal invasion in an explant model. Surprisingly, diverse non-typhoidalSalmonellaserovars were strongly attracted to feces despite its high indole content. We found that while pure indole is a strong repellent sensed through Tsr, its effects are overridden in the presence of nutrient attractants, including L-Ser. Moreover, indole only minimally impairs growth in the presence of sufficient nutrients. Using video microscopy, we observed that Tsr integrates L-Ser and indole signals in real time, biasing bacterial movement based on the relative concentrations of attractant and repellent. We propose that this chemotactic compromise optimizes pathogen fitness by guiding bacteria to niches with a favorable L-Ser-to-indole ratio, balancing nutrient acquisition and avoidance of high microbial competitor density. These findings highlight the limitations of single-effector studies in predicting bacterial navigation in complex environments, where chemotaxis is shaped by the integration of multiple, often opposing, chemical cues.