Orally administered gold nanoparticles protect against colitis by attenuating Toll-like receptor 4- and reactive oxygen/nitrogen species-mediated inflammatory responses but could induce gut dysbiosis in mice

Abstract

Background: Gold nanoparticles (AuNPs) are attracting interest as potential therapeutic agents to treat inflammatory diseases, but their anti-inflammatory mechanism of action is not clear yet. In addition, the effect of orally administered AuNPs on gut microbiota has been overlooked so far. Here, we evaluated the therapeutic and gut microbiota-modulating effects, as well as the anti-inflammatory paradigm, of AuNPs with three different coatings and five difference sizes in experimental mouse colitis and RAW264.7 macrophages. Results: Citrate- and polyvinylpyrrolidone (PVP)-stabilized 5-nm AuNPs (Au-5 nm/Citrate and Au-5 nm/PVP) and tannic acid (TA)-stabilized 5-, 10-, 15-, 30- and 60-nm AuNPs were intragastrically administered to C57BL/6 mice daily for 8 days during and after 5-day dextran sodium sulfate exposure. Clinical signs and colon histopathology revealed more marked anti-colitis effects by oral administration of Au-5 nm/Citrate and Au-5 nm/PVP, when compared to TA-stabilized AuNPs. Based on colonic myeloperoxidase activity, colonic and peripheral levels of interleukin-6 and tumor necrosis factor-α, and peripheral counts of leukocyte and lymphocyte, Au-5 nm/Citrate and Au-5 nm/PVP attenuated colonic and systemic inflammation more effectively than TA-stabilized AuNPs. High-throughput sequencing of fecal 16S rRNA indicated that AuNPs could induce gut dysbiosis in mice by decreasing the α-diversity, the Firmicutes/Bacteroidetes ratio, certain short-chain fatty acid-producing bacteria and Lactobacillus. Based on in vitro studies using RAW264.7 cells and electron spin resonance oximetry, AuNPs inhibited lipopolysaccharide (LPS)-triggered inducible nitric oxide (NO) synthase expression and NO production via reduction of Toll-like receptor 4 (TLR4), and attenuated LPS-induced nuclear factor kappa beta activation and proinflammatory cytokine production via both TLR4 reduction and catalytic detoxification of peroxynitrite and hydrogen peroxide. Conclusions: AuNPs have promising potential as anti-inflammatory agents; however, their therapeutic applications via the oral route may have a negative impact on the gut microbiota.[Figure not available: see fulltext.]