Parkinson's disease (PD) is a progressive neurodegenerative disorder with limited disease-modifying treatments. Dysregulation of tryptophan metabolism via the gut-brain axis has emerged as a key pathogenic mechanism. Astaxanthin (AX), a dietary ketocarotenoid abundant in Haematococcus pluvialis and marine organisms, possesses potent antioxidant and anti-inflammatory properties; however, it remains unclear whether AX exerts neuroprotection in PD through specific modulation of tryptophan metabolism via the signal transducer and activator of transcription 3 (STAT3)/ indoleamine 2,3-dioxygenase 1 (IDO1) pathway and gut microbiota remodeling. In this study, an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced mouse model of PD was used to evaluate the neuroprotective effects of AX. AX ameliorated motor deficits, attenuated dopaminergic neuron loss in the substantia nigra (SN), suppressed neuroinflammation, and enhanced mitophagy. Mechanistically, AX directly inhibited STAT3 activation and downregulated IDO1 expression in the brain, reducing the conversion of tryptophan to neurotoxic quinolinic acid (QUIN). Concurrently, AX reshaped the gut microbiota by enriching Lactobacillus, which redirected tryptophan metabolism toward the production of neuroprotective indole derivatives, including indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA). Fecal microbiota transplantation (FMT) from AX-treated donors recapitulated key aspects of these effects, including suppression of signal transducer and activator of transcription 3(STAT3)/ indoleamine 2,3-dioxygenase 1(IDO1), elevation of IPA/IAA, and improvement of motor function, confirming that the gut microbiota mediates AX's neuroprotective action. These findings demonstrate that AX alleviates PD pathology through a dual mechanism: central inhibition of the STAT3/IDO1 pathway to block neurotoxic quinolinic acid production, and peripheral gut microbiota remodeling to enhance neuroprotective indole derivatives. This study positions AX as a promising functional food ingredient targeting tryptophan metabolism for PD intervention.
