Melatonin remodels gut microbiota and tryptophan metabolism to ameliorate methamphetamine-induced cognitive impairment.

Methamphetamine (Meth) is known to cause cognitive impairment in drug abusers, but the underlying mechanisms remain unclear. Given that Meth is also an emerging environmental contaminant detected in surface waters, understanding its neurotoxic mechanisms has implications for health risk assessment. Melatonin, a natural neuroprotective agent, shows promise in alleviating cognitive deficits, but its mechanism of action in Meth exposure is unclear. We found that melatonin treatment alleviated Meth-induced cognitive deficits, microglial activation, and synaptic damage, while also mitigating colonic inflammation and altering gut microbiota composition. Antibiotics treatment and fecal microbiota transplantation experiments validated the indispensable role the gut microbiota in melatonin's mitigation of Meth-induced cognitive impairment. Mechanistically, melatonin significantly elevates levels of the tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) by reshaping the gut microbiota. Exogenous supplementation of this compound reproduces melatonin's protective effects. Combining proteomic and transcriptomic analyses, we found that 3-HAA downregulates NLRP3 expression in hippocampal microglia to suppress neuroinflammation and synaptic damage, thereby alleviating Meth-induced cognitive impairment. Conversely, overexpression of NLRP3 abolishes the protective effects of 3-HAA. Collectively, our findings uncover a gut‑brain axis mechanism by which melatonin counteracts Meth‑induced neurotoxicity, providing a potential therapeutic target and informing the health risk assessment of Meth as an environmental contaminant.