Resveratrol alleviates DSS-induced IBD in mice by regulating the intestinal microbiota-macrophage-arginine metabolism axis

Abstract

Abstract Background Inflammatory bowel disease (IBD) is a global disease with a growing public health concern and is associated with a complex interplay of factors, including the microbiota and immune system. Resveratrol, a natural anti-inflammatory and antioxidant agent, is known to relieve IBD but the mechanism involved is largely unexplored. Methods This study examines the modulatory effect of resveratrol on intestinal immunity, microbiota, metabolites, and related functions and pathways in the BALB/c mice model of IBD. Mouse RAW264.7 macrophage cell line was used to further explore the involvement of the macrophage-arginine metabolism axis. The treatment outcome was assessed through qRT-PCR, western blot, immunofluorescence, immunohistochemistry, and fecal 16S rDNA sequencing and UHPLC/Q-TOF–MS. Results Results showed that resveratrol treatment significantly reduced disease activity index (DAI), retained mice weight, repaired colon and spleen tissues, upregulated IL-10 and the tight junction proteins Occludin and Claudin 1, and decreased pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Resveratrol reduced the number of dysregulated metabolites and improved the gut microbial community structure and diversity, including reversing changes in the phyla Bacteroidetes, Proteobacteria, and Firmicutes, increasing ‘beneficial’ genera, and decreasing potential pathogens such as Lachnoclostridium, Acinobacter, and Serratia. Arginine–proline metabolism was significantly different between the colitis-treated and untreated groups. In the colon mucosa and RAW264.7 macrophage, resveratrol regulated arginine metabolism towards colon protection by increasing Arg1 and Slc6a8 and decreasing iNOS. Conclusion This uncovers a previously unknown mechanism of resveratrol treatment in IBD and provides the microbiota-macrophage-arginine metabolism axis as a potential therapeutic target for intestinal inflammation.

Keywords

• Inflammatory bowel disease
• Resveratrol
• Microbiota
• Arginine metabolism
• Macrophage