Glycosylation in gut-brain communication: from the intestinal barrier and microbiota to immune and neural signaling

The gut-brain axis is a complex bidirectional communication network linking the gastrointestinal tract and the central nervous system. Its dysregulation is closely associated with a wide range of gastrointestinal, metabolic, and neuropsychiatric disorders. Glycosylation, one of the most prevalent and structurally diverse post-translational modifications of proteins and lipids, is increasingly recognized as a regulator of multiple processes within the gut-brain axis. In this review, we summarize evidence that glycosylation influences several steps of gut-brain communication, including intestinal barrier function, microbial glycan metabolism, immune signaling, enteric and vagal pathways, blood-brain barrier integrity, and neural responses. We distinguish direct mechanistic findings from associative observations and discuss the more limited evidence for brain-to-gut regulation of intestinal glycosylation. In addition, we discuss the potential of glycosylation-targeted nutritional and microbiota-based interventions and highlight emerging opportunities to integrate glycomics with other omics approaches to dissect the complex regulatory networks underlying the gut-brain axis. In conclusion, elucidating how glycosylation shapes signaling along the gut-brain axis may open new avenues for understanding disease pathogenesis and for developing targeted therapeutic strategies.