Hyaluronan-induced alterations of the gut microbiome protects mice against Citrobacter rodentium infection and intestinal inflammation

Abstract

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.

The prebiotic and anti-fatigue effects of hyaluronan

“…HA is widely applied in the commercial field, such as skin care, cosmetic products, eye drops, and health supplements for various medicinal purposes ( 20 , 31 , 32 ). However, the physiological effect of the ingested HA is unclear.…”

“…This finding supports the notion that HA could be readily fermented by the host's gut microbes and elicited various biological functions in the host. A piece of good evidence came from a recent report showing HA could alter gut microbiome composition and metabolites in mice, in turn, effectively reducing enteric infection and inflammation ( 20 ).…”

Fecal microbiota transplantation is safe and tolerable in patients with multiple sclerosis: A pilot randomized controlled trial

“…Although hyaluronic acid in the brain is associated with demyelinated lesions, 48 intestinal hyaluronic acid is known to decrease intestinal permeability by upregulating tight junction protein expression. 49 Hyaluronan has also been shown to greatly enrich the abundance of Akkermansia muciniphila, 49 a bacterium which is associated with MS but has only recently been linked to lower disability, and the potentially compensatory decreased immune response and amelioration of experimental autoimmune encephalomyelitis. 50 These factors all point to the ability for FMT to potentially exert clinically significant protective and preventative functional alterations to the MS microbiota.…”

Enhanced Stability and Function of Probiotic Streptococcus thermophilus with Self-Encapsulation by Increasing the Biosynthesis of Hyaluronan

“…S. thermophilus and HA have positive regulatory effects on the intestinal barrier. 49,50 This encouraged us to study the effects of coated S. thermophilus on the mucus barrier produced by mucin of goblet cells. PAS staining of distal colon tissues of mice showed that there was no difference in the number of goblet cells between the HA group and the control group, but the numbers of goblet cells in the WT and WT + HA groups were significantly increased (to around 16 goblet cells per crypt).…”