Polysaccharides and the colon mucus barrier: a review of biophysical interactions and functional impacts

Polysaccharides are structurally diverse biopolymers that interact intimately with the colonic mucus barrier, modulating its physicochemical properties and biological functions. This review explores direct and indirect interactions between polysaccharides and colonic mucus that collectively shape mucus rheology, penetrability, and barrier function. After brief, separate descriptions of colonic mucus (bilayered architecture and goblet cell-driven secretion) and polysaccharide structural classes (e.g., charge, molecular weight, branching, and substitution patterns), we dissect the molecular and biophysical mechanisms governing polysaccharide-mucus interactions-including electrostatic and hydrogen bonding, hydrophobic association, and steric or depletion effects-and integrate evidence from in vitro, ex vivo, in vivo, organoid, and gut-on-a-chip models. Functional consequences for mucin secretion and degradation, mucus viscosity and structure, barrier integrity, and epithelial and immune signalling are critically evaluated, with particular focus on protection against oxidative stress-induced mucosal dysfunction. By linking specific physicochemical features of polysaccharides to their behaviour within the mucus barrier, we outline design principles for improving gastrointestinal health, optimising mucosal drug delivery, and guiding the development of next-generation polysaccharide-based therapeutics.