Peripheral Effects of the Gut-Derived Metabolite TMAO in Two MPTP-Challenged Disease Animal Models

Parkinson’s disease (PD) remains incompletely understood despite its high social and economic burden, with oxidative stress, neuroinflammation, and mitochondrial dysfunction recognized as central pathogenic mechanisms. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a complex I inhibitor, is widely used as a model of dopaminergic neurodegeneration, while growing evidence highlights the gut–liver–brain and kidney–brain axes as important contributors to PD progression. Within this framework, trimethylamine N-oxide (TMAO) has emerged as a molecule of interest, linked to dementia risk and proinflammatory effects. Our study aimed to evaluate the peripheral oxidative and inflammatory consequences of acute and semi-acute MPTP exposure, alone and in combination with TMAO. In total, 96 male CD-1 mice were equally divided across two experimental settings: a semi-acute protocol (30 mg/kg i.p., MPTP once daily for five consecutive days) and an acute protocol (20 mg/kg i.p., four administrations of MPTP at two-hour intervals), with TMAO administration remaining identical across both experimental settings. The animals were randomized into four groups (control group, a TMAO-only group (40 mg/kg/day, gavage, days 0–42), an MPTP-only group, and a combined TMAO + MPTP group), with MPTP showing consistently depleted liver SOD activity across both models. In the liver, MPTP showed consistently depleted SOD activity in both models, whereas glutathione disruption and lipid peroxidation were most evident in the combined TMAO + MPTP group. These effects were explained mainly by the additive main effects of MPTP and TMAO, as no significant MPTP × TMAO interaction was found for any oxidative stress marker. Nonetheless, a significant MPTP × TMAO interaction was confirmed for liver and kidney IL-1β in the acute model. IL-1β and IL-6 were significantly elevated in the liver and kidney by both MPTP alone and its combination with TMAO, with the combined groups consistently showing the largest increases (TMAO + MPTP semi-acute vs. control and vs. TMAO, p < 0.001–0.01; TMAO + MPTP acute vs. all groups, p < 0.0001–0.01). In the kidney, the contribution of MPTP and TMAO to oxidative stress was model-dependent: in the semi-acute protocol, both MPTP and TMAO contributed to increased MDA and glutathione ratio disruption, while in the acute protocol, TMAO alone was the dominant driver of SOD depletion and MDA elevation, with their combination further amplifying IL-6 secretion. TMAO also independently drove lipid peroxidation in the heart and intestine. The acute MPTP model produced more extensive redox imbalance independently of TMAO, whereas in the semi-acute model, a comparable degree of redox disruption was only achieved through combined TMAO + MPTP exposure.