Naringin alleviates periodontitis via direct AMPK/Nrf2 activation and NLRP3 inhibition, amplified by gut microbiota/Arg-Gln modulation

Periodontitis, driven by oral-gut microbiota dysbiosis and NLRP3 inflammasome activation, lacks effective natural therapeutic strategies. This study investigated naringin (Nar), a grapefruit peel flavonoid, using ligature-induced periodontitis in rats and LPS-stimulated RAW264.7 cells. Nar treatment significantly reduced alveolar bone loss, inhibited NLRP3 inflammasome activation (NLRP3, IL-1β), and suppressed inflammatory mediators (COX2, iNOS, IL-6, TNF-α) while improving collagen organisation. Microbiome analysis revealed that Nar suppressed pathogenic bacteria (Veillonella orally, Escherichia-Shigella in the gut) and enriched beneficial Lactobacillus. Metabolomics analysis revealed a significant decrease in the abundance of arginyl-glutamine (arg-gln) in the intestines of rats with periodontitis. Both Nar and arg-gln activated the AMPK/Nrf2 pathway, suppressing NLRP3 activation. FMT from Nar-treated donors had similar anti-inflammatory effects. In conclusion, Nar alleviates periodontitis primarily by directly activating the AMPK/Nrf2 pathway and inhibiting NLRP3 inflammasome activation in periodontal tissues. Additionally, Nar reshapes the gut microbiota to elevate arg-gln levels, which further amplifies AMPK activation and contributes to inflammation control, but is not sufficient alone to drive structural repair. These findings provide a novel theoretical basis for natural compound-mediated microbiota and inflammatory regulation in periodontitis treatment.