Periodontitis is increasingly recognized as a disease sustained by both oral-gut microbiota dysbiosis and inflammasome activation, yet effective natural therapeutic strategies remain scarce. This study investigated naringin (Nar), a flavonoid derived from grapefruit peel, in a rat model of ligature-induced periodontitis and in LPS-stimulated RAW264.7 macrophages.

Naringin treatment significantly reduced alveolar bone loss and inhibited NLRP3 inflammasome activation, with measurable decreases in NLRP3 and IL-1β expression. The compound also suppressed key inflammatory mediators including COX2, iNOS, IL-6, and TNF-α, while improving collagen organization in periodontal tissues.

Microbiome analysis revealed a dual-site effect: naringin suppressed pathogenic bacteria — Veillonella in the oral cavity and Escherichia-Shigella in the gut — while enriching beneficial Lactobacillus populations. Metabolomics analysis uncovered a critical finding: arginyl-glutamine (arg-gln) abundance was significantly decreased in the intestines of periodontitis rats, and both naringin and arg-gln independently activated the AMPK/Nrf2 pathway, thereby suppressing NLRP3 activation.

Fecal microbiota transplantation from naringin-treated donors reproduced the anti-inflammatory effects, confirming the gut-mediated mechanism. The study concludes that naringin works primarily through direct AMPK/Nrf2 pathway activation and NLRP3 inhibition in periodontal tissues. The gut microbiota reshaping and subsequent arg-gln elevation amplify this effect but are insufficient alone for structural repair. These findings establish a novel framework for natural compound-mediated microbiota and inflammatory regulation in periodontitis management.