Gut microbiota as a participant: oral melatonin links to ferroptosis to rescue Alzheimer’s disease brain and colon in iron overload

Gut-brain axis dysfunction contributes to Alzheimer’s disease (AD) beyond amyloid/tau pathology, yet it remains unclear whether oral melatonin (MT) alleviates cognitive impairment and gut comorbidities in AD, and whether these effects are independent of the gut microbiota. To investigate whether oral administration of MT can mitigate cognitive impairment and gut comorbidities in AD mouse models, linking the gut microbiota with oxidative stress and ferroptosis protein. AD was induced in mice used AlCl₃/D-gal, followed by 6 weeks of oral MT (10 mg/kg/day). Cognitive function, oxidative stress, gut microbiota (16S rRNA), ferroptosis-related proteins, and fecal metabolites were assessed. Antibiotic intervention and fecal microbiota transplantation (FMT) validated microbiota dependency. Oral MT reshaped gut microbiota and metabolites, significantly improving cognitive deficits, reducing brain β-amyloid 1–42 (Aβ 1–42 ) and phosphorylated tau protein (P-Tau), alleviating colonic iron overload and dysfunction, and attenuating gut-brain oxidative stress. MT can repair the intestinal barrier and the blood-brain barrier (BBB), and regulate central ferroptosis; its effects may be related to changes in the expression levels of proteins in the kelch-like ECH-related protein 1/nuclear factor erythropoietin-related factor 2/heme oxygenase-1 (Keap-1/Nrf-2/HO-1) axis. Antibiotic-induced dysbiosis exacerbated AD pathology. Notably, FMT from MT-treated donors partially recapitulated MT’s protective effects, suggesting that the microbiota is associated with the anti-AD effects of MT. Oral MT shows therapeutic potential for managing AD gut-brain comorbidity, and the gut microbiota contributes to the suppression of AD-like pathology by MT, supporting microbiota-based AD treatment strategies.