Paeonol Ameliorates Ulcerative Colitis in Mice by Modulating the Gut Microbiota and its Metabolites

BACKGROUND: Ulcerative colitis (UC) is a chronic recurrent inflammatory disease of the gastrointestinal tract. Recent studies demonstrate that the phenolic tannin paeonol (Pae) attenuates UC in mouse models by downregulating inflammatory factors; however, molecular mechanisms linking the gut microbiota and microbial metabolism with Pae remain elusive.
METHODS: The UC mouse model was induced using 3% dextran sodium sulfate (DSS). Clinical symptoms were assessed, hematoxylin-eosin staining were used to analyze the effect of Pae on pathological changes to mouse colons, and ELISA was used to evaluate inflammatory factor expression in the serum. Transmission electron microscopy and immunohistochemistry were used to examine the structure of the colonic epithelial barrier and its tight junction proteins. Potential mechanisms of Pae were explored by 16S rRNA-based gut microbiota analysis, fecal metabolomics and construction of a multiscale, multifactorial network.
RESULTS: Pae treatment significantly reduced the weight loss and disease activity index, colon shortening, tissue damage, and changes in TNF-α, IL-1β, IL-6, and IL-4 cytokine levels. Conversely, Pae restored the integrity of the intestinal epithelial barrier by increasing the expression of Occludin and ZO-1. Pae also partially reverted the DSS-induced disturbance in intestinal flora composition by increasing the proportion of probiotic bacteria and inhibiting UC-associated dysregulation of gut microbiota metabolites such as bile acids (BA) and short chain fatty acids. Network analysis demonstrated that Lactobacillus was associated with increased levels of unbound BAs, which in turn were strongly associated with inflammatory factor levels. The results suggest that Pae influences BA synthesis by regulating hepatic FXR-SHP/LRH-1 and ileum FXR-FGF15 signaling pathways to maintain intestinal integrity in UC mice.
CONCLUSION: Pae can alleviate DSS-induced UC in mice by restoring dysregulated intestinal microbiota and BA metabolism, which improves intestinal barrier function and colonic inflammation, thus suggesting a new mechanism for Pae treatment of UC.