Treadmill Exercise Alleviates Motor Deficits of PD Mice via Regulating STING-Mediated Valeric Acid-Th17/Treg-IL-17A Axis.

The objective of this study is to investigate the effects of treadmill exercise on motor deficits in chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced chronic Parkinson's disease (PD) mice and the underlying mechanisms. Healthy male C57BL/6 mice were randomly divided into the following groups: Control, PD model (PD), treadmill exercise (PD+Exe8), and treadmill exercise combined with the STING agonist DMXAA (PD+Exe8+DMXAA). Motor function was assessed using gait analysis, rota-rod test, wire hang test, pole test, and open field test. Fecal short-chain fatty acid (SCFA) levels were measured by gas chromatography-mass spectrometry (GC-MS). Colonic morphological changes were observed via H&E and PAS staining. Immunofluorescence staining was used to examine the colonic barrier and pathological protein accumulation. Western blot, qPCR, and ELISA were performed to assess immune responses, gut barrier integrity, blood-brain barrier (BBB) function, and inflammatory markers. (1) Chronic PD mice exhibited significant motor deficits, a decreased number of tyrosine hydroxylase (TH)-positive cells in the substantia nigra, and increased α-synuclein (α-syn) expression. (2) Treadmill exercise increased fecal valeric acid levels, ameliorated Th17/Treg immune imbalance in the colon and brain, and these beneficial effects were abolished by DMXAA. (3) Treadmill exercise improved gut barrier and BBB integrity, reversed colon pathology, and these improvements were blunted by DMXAA. (4) Treadmill exercise reduced inflammatory responses in both the colon and brain, and this anti-inflammatory effect was abolished by DMXAA. (5) DMXAA blunted the improvement in motor dysfunction induced by 8-week treadmill exercise. Treadmill exercise significantly improves motor dysfunction in mice with chronic PD, this effect is associated with STING-mediated SCFA valeric acid-Th17/Treg immune imbalance and impaired intestinal and blood-brain barriers.