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Figure 1. The Interplay of sialylated glycans with the gastrointestinal (GI) microbiota and their dual role in physiological and pathological conditions. Mucins are highly O-glycosylated proteins and represent the main functional component of the mucosal layer - the body’s first line of defense in the GI tract. Sialylation of the GI mucosa by intestinal epithelial cells is critical for maintaining homeostasis, contributing to mucus hydration, lubrication, microbial barrier functions, and immune modulation. In a healthy GI tract (right side of figure), sialylated glycans on mucins protect the intestinal epithelium by preventing degradation by mucin-degrading bacteria and by supporting balanced microbiota colonization. In contrast, under pathological conditions such as CRC (left side of figure), sialic acids can promote tumor development and progression. Tumor cells frequently express aberrant sialylated O-glycans (e.g., sialyl-Tn, sialyl Lewis x/a), which enable immune evasion (immunotolerance) and foster a chronically inflamed tumor microenvironment. This inflammatory state not only supports tumor growth, but also induces microbiota dysbiosis by favoring the proliferation and colonization of pathogenic bacteria, particularly sialic acid-binding species that attach to tumor-associated hypersialylated mucins. In turn, these microbes exacerbate inflammation and compromise the mucin barrier by degrading this protective layer, thereby facilitating tumor expansion and metastatic behavior in the GI tract. Overall, this figure illustrates the complex, context-dependent duality of sialylation - protective under physiological conditions, but pro-tumorigenic in CRC. Image created using BioRender (www.biorender.com).