Hyaluronan is a
glycosaminoglycan polymer that has been shown to play an important role in homeostasis of the gastrointestinal tract. However, its mechanistic significance in gastrointestinal epithelial barrier elements remain unexplored. Here, our results revealed that
hyaluronan treatment resulted in significant changes in the gut microbiota in mice. To demonstrate the functional consequences of
hyaluronan-treatment and
hyaluronan-induced microbiota alterations, Citrobacter rodentium- and DSS-induced
colitis models and microbiota
transplantation approaches were utilized. We showed that
hyaluronan alleviated intestinal
inflammation in both pathogen and chemically induced intestinal mucosal damage. The protection in bacterial
colitis was associated with enhanced C. rodentium clearance and alleviation of pathogen-induced gut
dysbiosis. Microbiota
transplantation experiments showed that the
hyaluronan-altered microbiota is sufficient to confer protection against C. rodentium
infection. Colonization with Akkermansia muciniphila, a commensal bacterium that is greatly enriched by
hyaluronan treatment, alleviated C. rodentium-induced bacterial
colitis in mice. Additionally, Akkermansia-induced protection was found to be associated with the induction of goblet cells and the production of
mucins and epithelial
antimicrobial peptides. Collectively, these results provide novel insights into the regulatory role of
hyaluronan in modulating the gut microbiota and immunity in enteric
infection and
inflammation, with therapeutic potential for gut microbiome-targeted
immunotherapy.