T‐2 Toxin Exploits Gut‐Derived Staphylococcus Saprophyticus to Disrupt Hepatic Macrophage Homeostasis

Abstract T‐2 toxin, a mycotoxin that frequently causes hidden contamination in food and animal feed, poses a substantial threat to both human and animal health. Staphylococcus saprophyticus ( S. saprophyticus ) is an opportunistic pathogen that widely infects humans and various animals. However, the specific conditions under which it becomes pathogenic, as well as the mechanisms underlying its pathogenicity remain unknown. In this study, it is found that a sub‐cytotoxic dose of T‐2 toxin in piglet and mouse models promotes the proliferation of intestinal S. saprophyticus and facilitates its translocation to the liver. Subsequent mechanistic investigations reveal that the translocated bacterium activates the nucleotide‐binding oligomerization domain 2 (NOD2)‐microtubule‐associated protein 1 light chain 3 and NOD2‐C‐C motif chemokine ligand 2 signaling pathways in Kupffer cells (KCs), thereby provoking autophagy in KCs and recruiting monocytes to the liver, alongside the M1 polarization of hepatic macrophages. Furthermore, modulation of the intestinal microbiota by xylo‐oligosaccharides, as opposed to antibacterial agents, effectively mitigates the disruption of hepatic macrophage homeostasis. This work shows, for the first time, the pivotal role of S. saprophyticus in mycotoxin‐induced impairment of liver immune function. It reveals the interaction between opportunistic pathogens, environmental toxins, and immune homeostasis.