Gut-Retentive Nanocarriers Suppress TMAO and Modulate Macrophage Nrf2/NF-κB for Diet-Induced Periodontitis

Background High-fat diet (HFD) is known to promote periodontitis progression via gut microbial imbalance. However, the redox-related molecular events linking these processes have yet to be fully elucidated. We propose that the gut microbiota, trimethylamine N-oxide (TMAO) and macrophage polarisation cascade constitute a pivotal pathway through which HFD aggravates periodontal destruction, and we further assess the efficacy of a gut-retentive genistein-loaded zein/fucoidan nanoparticle (G@Z/F) as an intervention. Methods A ligature-induced periodontitis model was established in C57BL/6 mice fed normal or HFD. Gut microbiota was analysed by 16S rRNA sequencing, and circulating TMAO levels were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS). Macrophage polarisation and signalling changes were evaluated by immunofluorescence, Western blot, and qPCR in vivo and in vitro. G@Z/F nanoparticles were prepared via anti-solvent precipitation and characterised for their physicochemical properties, stability and intestinal retention capability. Therapeutic efficacy against HFD-associated periodontitis was assessed by micro-CT, histological staining and molecular assays, with mechanistic validation using antibiotic depletion (ABX) and fecal microbiota transplantation (FMT). Results HFD feeding led to expansion of TMA-generating bacterial taxa and a rise in systemic TMAO. TMAO suppressed nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant axis while activating nuclear factor kappa B (NF-κB), skewing macrophages toward M1, amplifying oxidative stress and aggravating alveolar bone resorption. G@Z/F administration reestablished eubiosis, lowered TMAO and improved intestinal barrier function. Mechanistically, G@Z/F shifted M1/M2 balance via upregulating Nrf2/HO-1 and inhibiting NF-κB. Both ABX and FMT confirmed therapeutic benefits were dependent on gut microbiota. Conclusions Collectively, four findings lend support to the notion that the gut-TMAO-macrophage axis could serve as an important contributing mediator in diet-exacerbated periodontitis. G@Z/F emerges as a promising gut-retentive nanotherapeutic agent capable of counteracting periodontal inflammation by modulating redox-sensitive signalling pathways and restoring gut microbiome homeostasis.