Fig. 12

Schematic illustration of the mechanism by which SA facilitates gut dysbiosis-induced mastitis through the microbiota-gut-mammary axis. ① Under gut homeostasis conditions, sialic acids bind to mucus, with few free SAs present in the intestinal lumen, which are then degraded by polysaccharide-degrading commensal bacteria (e.g., Lactobacillaceae and Prevotellaceae). ② Gut dysbiosis caused by a changed dietary pattern (e.g., high-grain diet-induced SARA) or antibiotic reduces polysaccharide-degrading commensal bacteria and prompts free SAs production by increasing sialidase, causing abundant free SAs in the intestinal lumen which fuels polysaccharide-degrading opportunistic pathogen (e.g., Enterobacteriaceae and Moraxellaceae). ③ Polysaccharide-degrading opportunistic pathogen, such as Enterobacteriaceae, proliferate by using SAs as an energy source, which facilitates their expansion and virulence enhancement, prompting the degradation of the mucus layer and gut barrier damage. ④ A leaky gut barrier allows toxic factors (e.g., LPS) to enter intestinal tissues and induces immune cell activation through TLR4-NF-κB/NLRP3 signatures, causing intestinal inflammation. ⑤ The increased LPS derived from expansion of gut opportunistic pathogen subsequently enters the blood and, together with proinflammatory cytokines, induces systemic inflammation. ⑥ Persistent chronic systemic low-grade inflammation disrupts the blood-milk barrier, causing cytokines and LPS to enter and accumulate in the mammary gland, inducing mastitis through TLR4-NF-κB/NLRP3 pathways