Dietary soy fiber limits Salmonella infection by disrupting the self-reinforcing loop between pathogen virulence and host inflammation.

The global threat of Salmonella Enteritidis (S. Enteritidis) is exacerbated by its ability to exploit host inflammation for colonization. Here, we find that dietary soy fiber (SF) confers colonization resistance by suppressing S. Enteritidis virulence and host inflammatory amplification. We identify harmaline (HAL), derived from Akkermansia, as a key effector. On the pathogen side, HAL disrupts tetrathionate respiration, induces oxidative stress, and inactivates Fur, thereby suppressing HilD-dependent virulence. On the host side, HAL enhances type I interferon signaling and promotes SUMOylation of AP-1 transcription factors, reducing binding to inflammatory chemokine promoters and limiting excessive inflammatory output, thereby reducing the concentration of tetrathionate and limiting the expansion of S. Enteritidis. This study illustrates HAL-mediated disruption of the self-reinforcing loop between Salmonella virulence and host inflammation, highlighting the therapeutic potential of SF and identifying HAL as a lead compound for developing next-generation anti-infectives that bypass traditional antibiotic resistance.