Trimethylamine activates the Type III Secretion System of Salmonella to enhance host cell invasion.

Epidemiological evidence has revealed that elevated plasma trimethylamine N-oxide (TMAO) levels are associated with the pathogenesis of multiple human diseases. As trimethylamine (TMA) is the key dietary precursor for TMAO biosynthesis in both mice and humans, inhibition of TMA production can effectively lower the risk of these diseases. In the anaerobic intestinal environment, dietary TMAO is enzymatically reduced to TMA by TMAO reductase by Proteobacteria. Here, we demonstrate that endogenously produced TMA potently activates the Type III Secretion System (T3SS) of Salmonella by binding to the transcriptional regulator HilD and enhancing its DNA-binding affinity. This TMA-HilD interaction enhances bacterial invasion of host cells without affecting bacterial growth. Crucially, inhibition of microbial TMAO reductase (TorA) - mediated TMA production can not only attenuates Salmonella virulence by disrupting TMA-HilD-driven T3SS activation but also reduces plasma TMAO levels to alleviate the risk of metabolic diseases. Therefore, targeting TMAO-microbiota-TMA axis represents a promising therapeutic strategy for combating both bacterial infections and metabolic disorders.