Jeong_2025_Gut__

BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4is) have been reported to exhibit therapeutic effects in Parkinson's disease (PD), increasing their potential for drug repurposing. One aspect of PD pathogenesis is thought to be associated with the gut-brain axis, where alpha-synuclein from the gut is transmitted to the brain via the vagus nerve (VN). OBJECTIVE: We explored whether sitagliptin, a DPP-4i, exhibits a protective effect in a low-dose rotenone-treated gut-brain axis-associated PD model. DESIGN: To explore the effect of sitagliptin, we used the oral rotenone-treated mouse model, which showed spreading of pathological alpha-synuclein from the intestine in a stereotypic manner via the VN into the midbrain with motor deficits. RESULTS: Sitagliptin mitigated rotenone-induced gut inflammation and toll-like receptor 2 (TLR2) expression, reduced alpha-synuclein accumulation in the gut, VN and brain and lessened neuronal loss in the medulla and midbrain with recovery of motor performance. In addition, sitagliptin suppressed inflammation in response to a TLR2 agonist and rotenone in macrophages, enteric glial cells and enteroendocrine cell lines in vitro. In secretin tumour cell 1, an enteroendocrine cell line, sitagliptin also decreased rotenone-induced endogenous alpha-synuclein levels. The beneficial effects of sitagliptin were maintained even under glucagon-like peptide-1 receptor blockade. Notably, sitagliptin significantly altered the gut microbiome, shifting towards a profile that may counteract PD pathology. CONCLUSION: These findings demonstrated that sitagliptin alleviated alpha-synuclein deposition in the gut and brain through modulation of TLR2-mediated inflammation and altered the gut microbiome composition towards a more favourable profile, which indicates that DPP-4is can offer a novel therapeutic avenue for managing PD.