Objective: To explore the role and related mechanism of gut microbiota metabolites short-chain fatty acids(SCFAs) in the pathogenesis of Parkinson’s disease(PD).

Background: Growing research have shown that gut microbiota disturbance is involved in the pathogenesis of Parkinson’s disease, and its metabolites SCFAs may play an important role in it by triggering neuroinflammation. NLRP3 inflammasomes activation can induce PD by releasing inflammatory factors and inducing abnormal aggregation of a-synuclein(aSyn).

Method: 1) Mouse enteroendocrine cells STC-1 were treated with SCFAs, and the aSyn, phosphorylated aSyn(p-aSyn) expression levels were detected.
2) SH-SY5Y cells were cultured with the supernatant of SCFAs-treated STC-1, then transfected with NLRP3 siRNA or GPR43 siRNA, successively, and then we detected apoptosis, apoptosis-related proteins and tyrosine hydroxylase(TH), aSyn(p-aSyn), GPR43, NLRP3 inflammasomes expression.
3) C57BL/6 mice were administered MPTP twice per week for 5 weeks via intraperitoneal injection, fed with water containing SCFAs, then treated with NLRP3 inhibitor (CY-09) or GPR43 inhibitor (GLPG0974), successively, and then the motor function, defecation rate, fecal water content, aSyn(p-aSyn), TH, GPR43 and NLRP3 inflammasomes in the midbrain and ileum were detected.

Results: 1) SCFAs can increase aSyn expression in STC-1, and their supernatant can induce SH-SY5Y apoptosis, increase the expression of apoptosis-related proteins, p-aSyn, GPR43, NLRP3 inflammasomes, reduce TH expression.
2) NLRP3 siRNA and GPR43 siRNA can reduce the apoptosis, the expression of apoptosis-related proteins, p-aSyn, increase TH expression in SH-SY5Y cultured by SCFAs-treated STC-1 supernatant, and GPR43 siRNA can reduce NLRP3 inflammasomes expression.
3) SCFAs can induce dyskinesia in MPTP-treated mice, reduce defecation rate, fecal water content, increase aSyn deposition, the expression of GPR43 and NLRP3 inflammasome, reduce TH expression in midbrain and ileum. CY-09 and GLPG0974 can alleviate the dyskinesia of PD, increase the defecation rate, fecal water content，reduce aSyn deposition, increase TH expression in midbrain and ileum, and GLPG0974 can reduce NLRP3 inflammasomes expression.

Conclusion: SCFAs participate in the pathogenesis of PD by regulating NLRP3 inflammasomes activation through GPR43.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/scfas-participate-in-the-pathogenesis-of-parkinsons-disease-by-regulating-nlrp3-inflammasomes-activation/