Capsular polysaccharides of the human gut microbiota: Structural diversity, functional plasticity, and roles in...

Capsular polysaccharides (CPS) of the human gut microbiota are structurally diverse surface glycopolymers whose monosaccharide composition, linkage patterns, charge properties, and strain-specific modifications directly encode multifaceted biological functions. This review systematically examines the CPS structural landscape across major gut commensals, including Bacteroides spp., Lacticaseibacillus spp., Bifidobacterium spp., Enterococcus spp., and members of the Enterobacteriaceae family. We integrate recent findings to show how CPS architecture governs three interconnected functional domains: environmental fitness (resistance to gastric acid, bile salts, antibiotics, and phage predation), immune modulation (engagement of TLR2, Dectin-1, DC-SIGN, Siglecs, and MHC-II pathways to orchestrate regulatory T- and B-cell responses, macrophage polarization, and epithelial barrier maintenance), and ecological integration (cross-feeding and carbon reservoir functions). We identify critical knowledge gaps-most notably, the lack of high-resolution structure-activity relationships that link three-dimensional CPS conformations to specific immunological outcomes, compounded by a persistent Bacteroides-centric bias and underexplored ecological functions. Emerging tools, including cryo-electron microscopy, solid-state nuclear magnetic resonance, glycan arrays, and machine learning, offer unprecedented potential to advance the nascent field of CPS structure-activity relationships. We propose that a deeper understanding of CPS structural features, once achieved, may eventually inform the rational design of precision interventions that harness host-microbe mutualism for therapeutic benefit.