Role of mucin glycosylation in the gut microbiota-brain axis of core 3 O-glycan deficient mice

Alterations in intestinal mucin glycosylation have been associated with increased intestinal permeability and sensitivity to inflammation and infection. Here we used mice lacking core 3–derived O-glycans (C3GnT-/-) to investigate the role of mucin glycans in the gut-brain axis. C3GnT-/- mice showed altered microbial metabolites in the caecum associated with brain function such as dimethylglycine and N-acetyl-L-tyrosine profiles as compared to C3GnT+/+ littermates. In the brain, mice showed no significant changes in glial cell distribution, but C3GnT-/- mice exhibited an aberrant phenotype, namely polysialylated-neural cell adhesion molecule (PSA- NCAM)-positive granule cells in the dentate gyrus. This was accompanied by decreased expression levels of PSA as well as a reduction in ZO-1 and occludin expression in the brain as compared to C3GnT+/+. Behavioural studies showed a decrease in the recognition memory of C3GnT-/- mice as compared to C3GnT+/+. Combined, these results support the role of mucin O-glycosylation in influencing brain function via microbial metabolites passing through an impaired gut barrier