Arbutin alleviates intestinal colitis by regulating neutrophil extracellular traps formation and microbiota composition

Abstract

Background: Ulcerative colitis (UC) is a chronic recurrent intestinal disease lacking effective treatments. β-arbutin, a glycoside extracted from the Arctostaphylos uva-ursi leaves, that can regulate many pathological processes. However, the effects of β-arbutin on UC remain unknown.

Purpose: In this study, we investigated the role of β-arbutin in relieving colitis and explored its potential mechanisms in a mouse model of dextran sulfate sodium (DSS)-induced colitis.

Methods: In C75BL/6 J mice, DSS was used to induce colitis and concomitantly β-arbutin (50 and 100 mg/kg) was taken orally to evaluate its curative effect by evaluating disease activity index (DAI) score, colon length and histopathology. Alcian blue periodic acid schiff (AB-PAS) staining, immunohistochemistry (IHC), immunofluorescence (IF) and TdT-mediated dUTP Nick-End Labeling (Tunel) staining were used to assess intestinal barrier function. Flow cytometry, double-IF and western blotting (WB) were performed to verify the regulatory mechanism of β-arbutin on neutrophil extracellular traps (NETs) in vivo and in vitro. NETs depletion experiments were used to demonstrate the role of NETs in UC. Subsequently, the 16S rRNA gene sequencing was used to analyze the intestinal microflora of mouse.

Results: Our results showed that β-arbutin can protect mice from DSS-induced colitis characterized by a lower DAI score and intestinal pathological damage. β-arbutin reduced inflammatory factors secretion, notably regulated neutrophil functions, and inhibited NETs formation in an ErK-dependent pathway, contributing to the resistance to colitis as demonstrated by in vivo and in vitro experiments. Meanwhile, remodeled the intestinal flora structure and increased the diversity and richness of intestinal microbiota, especially the abundance of probiotics and butyric acid-producing bacteria. It further promoted the protective effect in the resistance of colitis.

Conclusion: β-arbutin promoted the maintenance of intestinal homeostasis by inhibiting NETs formation, maintaining mucosal-barrier integrity, and shaping gut-microbiota composition, thereby alleviating DSS-induced colitis. This study provided a scientific basis for the rational use of β-arbutin in preventing colitis and other related diseases.

Keywords: Colitis; Gut microbiome; Intestinal homeostasis; NETs; β-arbutin.