Modulation of gut microbiota by nardosinone augments the efficacy of levodopa in rotenone-induced Parkinson's disease rats

Abstract Levodopa (L-DOPA) is the mainstay treatment for Parkinson’s disease (PD), but its long-term use can cause adverse effects. Nardosinone enhances L-DOPA efficacy, yet the underlying mechanism is unclear. This study investigated whether the gut microbiota is associated with this synergism in a rotenone-induced PD rat model. Coadministration of nardosinone and L-DOPA increased L-DOPA and dopamine levels in the feces, plasma, and striatum of normal rats but not in antibiotic-treated rats with perturbed gut microbiota, suggesting a microbiota-correlated effect. Fecal microbiota transplantation from donors receiving the combination therapy alleviated motor deficits and dopaminergic neuron loss in recipient PD rats. This combination was associated with upregulated expression of tyrosine hydroxylase, DOPA decarboxylase, and their cofactors tetrahydrobiopterin and vitamin B6, as well as increased PINK1 and Parkin levels. It also reshaped the gut microbiota composition, enhanced intestinal and blood–brain barrier tight junction protein expression, and reduced c-Jun N-terminal kinase protein expression and neuroinflammation. In conclusion, these findings indicate that nardosinone coadministration is associated with alterations in the gut microbiota, improved barrier integrity markers, attenuated inflammation, and enhanced therapeutic effects of L-DOPA in this PD rat model. Definitive mechanistic pathways underlying the observed associations remain to be established.