Regulating environmental arsenic-mediated gut-brain toxicity using chitosan-conjugated luteolin gold nanoparticles

Anxiety and depression are two major contributors to global disease burden. Amongst various causal factors, exposure to even low doses of environmental heavy metals, like arsenic, can induce anxiety and depression-like behaviour in mammals. Ingestion of arsenic, primarily through contaminated drinking water, severely disrupts the gut microbes, thereby inducing structural and functional abnormalities in the brain. Fecal microbiota transplantation (FMT) from arsenic-exposed mice to recipient healthy mice (As-FMT) enriched LPS-secreting Gram-negative bacteria and upregulated the expression of TLR4 in intestinal epithelial cells. Consequently, inflammation, oxidative stress and compromised barrier integrity in the gut facilitated LPS translocation into the bloodstream and promoted systemic inflammation. The secretomes eventually affected the brain by activating microglia, altering neurotransmitter levels and reducing the glucocorticoid receptor (GR) expression, contributing to appearance of pyknotic nuclei in dentate gyrus of hippocampus and emergence of anxiety- and depression-like behaviour. Luteolin, a flavonoid, devoid of any apparent side-effects, yet known for its anti-inflammatory and antioxidant properties, showed potential in alleviating the gut-brain toxic effects. However, its limited solubility and bioavailability pose challenges for its effectiveness, for which chitosan-conjugated luteolin gold nanoparticles (CH-LuAuNPs) were synthesized. Interestingly, where FMT from arsenic-treated mice to healthy mice showed deleterious effects in the transplanted mice, FMT from arsenic-treated mice co-administered with CH-LuAuNP attenuated As-FMT-mediated disruption of the gut-brain axis. This study highlighted the critical contribution of healthy gut microbiota in preserving neurobehavioural physiology, as well as underscored the potential therapeutic benefits of luteolin nanoparticles in ameliorating arsenic-induced gut dysbiosis and consequent mental disorders.