Sialidases and sialylated oligosaccharides in intestinal homeostasis and inflammation

Despite the variety of hosts, anatomical locations, and symptoms associated with infection, many bacteria have developed mechanisms that allow them to adhere to the cells via carbohydrates. Some of the most dangerous bacterial pathogens including Clostridium perfringens possess sialidases that are capable of removing sialic acid from termini of complex sialyl-glycans. By doing so, the enzyme is able to both impair the mucosal glycocalyx barrier and provide a source of nutrients for the bacteria. This is achieved by either utilizing the released sialic acid directly or accessing the underlying carbohydrates. As such, it can be noted that variations in the metabolism of sialic acid and terminal carbohydrates could lead to dysbiosis or cause inflammation. In addition, mammalian sialidases seem to have varying and specialized roles in intestinal homeostasis and inflammation. Especially, NEU3 is most strongly implicated in proinflammatory signaling in the intestine, potentially through asialylation of intestinal alkaline phosphatase and disruption of the mucin-associated mucus barrier. This suggests that targeted inhibition of sialidase activity, and particularly NEU3-mediated asialylation, could be a means of protecting endogenous anti-inflammatory proteins, maintaining mucosal integrity, and preventing dysbiosis-associated inflammation. Meanwhile, exogenous sialylated oligosaccharides can have protective effects on the intestinal mucosa. Sialylated human milk oligosaccharides can modulate innate immunity by suppressing epithelial TLR4/NF-κB signaling and downstream proinflammatory cytokine production and enhancing tight-junction integrity. Among the discussed molecules, 6'-SL and disialyllacto-N-tetraose (DSLNT) stand out due to their protective effects on the neonatal intestine, including the prevention of intestinal inflammation and necrotizing enterocolitis (NEC). The latter is especially essential because it has a complex structure that includes two types of sugar chains: Neu5Acα2,3Gal and Neu5Acα2,6GlcNAc. Studies have shown that lower DSLNT levels are associated with higher NEC risk and disrupted microbiota progression in preterm infants. In addition, DSLNT plays an essential role in maintaining the integrity of the epithelium, as well as regulating the immune response via Siglec receptors. Altogether, the data underscore the significance of sialic acid metabolism and related molecules for the homeostasis of the microbiota-immune system interface.