Atherosclerotic-dose TMAO accentuates redox imbalances and motor dysfunctions in a MPTP mouse model of Parkinson’s disease
TL;DR
These findings carry clinical relevance in the context of Parkinson’s disease, suggesting that gut microbiome-derived metabolites may represent a pathological connection capable of increasing both cardiovascular risk and the progression of neurodegenerative disorders.
Abstract
Parkinson’s Disease (PD) involves the loss of dopaminergic neurons and the formation of Lewy bodies consisting of alpha-synuclein (αSin) aggregates. Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, has emerged as a molecule of interest due to pro-inflammatory, pro-oxidative, and neurodegenerative effects. We aim to assess whether lower doses of TMAO (40 mg/kg bw, gavage, once daily, day 0–42), as those used in atherosclerosis experimental models, can exacerbate oxidative stress, neuroinflammation, motor dysfunction, and neurodegeneration in a semi-acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD model (30 mg/kg bw MPTP, intraperitoneal, once daily, day 20–24). Motor behavioral testing functionally validated the model, with MPTP impairing performance across Rotarod latency time (p < 0.05), Wire Hang number of reaches and falls (p < 0.05), and Pole test time to descent (p < 0.01 MPTP vs. Control, p < 0.05 MPTP+TMAO vs. Control). A synergistic effect between TMAO and MPTP was observed in pole-turning time (p < 0.05). Increased TMAO serum was confirmed in treated animals (p < 0.05 TMAO vs. Control; p < 0.001 MPTP+TMAO vs. Control). Loss of tyrosine hydroxylase (TH) positive thalamic fibers, as well as substantia nigra neuronal fiber degeneration, and dopamine depletion was observed in the MPTP groups. A significant reduction in tyrosine hydroxylase (TH) expression in the midbrain was observed exclusively in the TMAO+MPTP group (p < 0.05 vs. Control). Neuroinflammatory profiling revealed selective elevation of IL-6 in the TMAO+MPTP group (p < 0.05), without microglial activation (p > 0.05), whereas NF-κB p65 was paradoxically increased only in the TMAO (p < 0.05) and MPTP (p < 0.05) groups. We hypothesize that this divergent pattern may indicate a shift toward necrotic rather than apoptotic cell death in the combined exposure group. MPTP and TMAO independently induced pro-oxidative states, evidenced by GSH depletion (p < 0.0001 MPTP vs. Control; p < 0.001 MPTP+TMAO vs. Control) and compensatory SOD upregulation (p < 0.01 TMAO vs. Control; p < 0.05 MPTP vs. Control and MPTP+TMAO vs. Control). The combination amplified the redox imbalance with significant elevation of MDA in the TMAO+MPTP group (p < 0.001 vs. Control and vs. TMAO; p < 0.01 vs. MPTP). These findings carry clinical relevance in the context of Parkinson’s disease, suggesting that gut microbiome-derived metabolites may represent a pathological connection capable of increasing both cardiovascular risk and the progression of neurodegenerative disorders.