Indoleamine 2, 3-dioxygenase 1 inhibition mediates the therapeutic effects in Parkinson's disease mice by modulating inflammation and neurogenesis in a gut microbiota dependent manner

Abnormal tryptophan metabolism is closely linked with neurological disorders. Research has shown that indoleamine 2,3-dioxygenase 1 (IDO-1), the first rate-limiting enzyme in tryptophan degradation, is upregulated in Parkinson's disease (PD). However, the precise role of IDO-1 in PD pathogenesis remains elusive. In this study, we administered 1-methyl-tryptophan (1-MT), an IDO-1 inhibitor, intraperitoneally at 15 mg/kg daily for 21 days to PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 30 mg/kg daily for 5 days. Our results show that IDO-1 inhibition improves behavioral performance, reduces dopaminergic neuron loss, and decreases serum quinolinic acid (QA) content and the aryl hydrocarbon receptor (AHR) expression in the striatum and colon. It also alleviates glial-associated neuroinflammation and mitigates colonic inflammation (decreasing iNOS, COX2) by suppressing the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway. Furthermore, IDO-1 inhibition promotes hippocampal neurogenesis (increasing doublecortin positive (DCX + ) cells and SOX2 + cells), which have recently been recognized as key pathological features and potential therapeutic targets in PD, likely through the activation of the BDNF/TrkB pathway. We further explored the gut-brain connection by depleting the gut microbiota in mice using antibiotics. Notably, the neuroprotective effects of IDO-1 inhibition were completely abolished in pseudo-germ-free mice (administrated an antibiotic mixture orally for 14 days prior to 1-MT treatment), highlighting the dependency of 1-MT's neuroprotective effects on the presence of gut microbiota. Finally, we found IDO-1 inhibition corrects the abnormal elevation of fecal short chain fatty acids (SCFAs). Collectively, these findings suggest that IDO-1 inhibition may represent a promising therapeutic approach for PD.