KETOGENIC DIET MODULATES GUT–BRAIN AXIS DYSFUNCTION IN A SEX-DEPENDENT MANNER IN A NEUROMELANIN-BASED PARKINSON’S DISEASE MOUSE MODEL

Our group has developed a novel transgenic mouse model of Parkinson’s disease (PD) characterized by neuromelanin accumulation and neurodegeneration affecting dopaminergic, noradrenergic, and cholinergic systems. This model (tgNM) reproduces motor and non-motor symptoms across defined disease stages: preclinical (3 months), prodromal (12 months), and early PD (20 months) (Laguna et al., 2024). TgNM mice display gut dysbiosis, increased intestinal permeability, and systemic inflammation, contributing to neurodegeneration (Lorente et al., in preparation).

We investigated whether a ketogenic diet (KD) could ameliorate the parkinsonian phenotype in tgNM mice. Sex-specific effects were evaluated by administering a KD (90% lipids—20% MCTs, 10% protein, 0% carbohydrates) for four months to 8-month-old tgNM mice.

Male tgNM mice achieved deep nutritional ketosis, whereas females reached only mild ketosis. KD improved glucose regulation in males but not in females. Feeding regulation patterns also differed between sexes, with females showing greater susceptibility to weight gain. Dietary adaptation induced hepatic hypertrophy in males and pancreatic hypertrophy in females, accompanied by brown adipose tissue accumulation in males and white adipose, in females. KD reduced intestinal permeability, improved systemic metabolic and inflammatory profiles, and ameliorated neurodegeneration through modulation of the gut–brain axis. Behaviorally, KD reduced sensorimotor dysfunction and depression-like behavior, improved long-term memory, and partially restored vocalization deficits, although anxiety levels increased. Overall, beneficial effects were more pronounced in males.

These findings highlight sex-dependent responses to ketogenic interventions and emphasize the importance of considering biological sex when evaluating dietary strategies for Parkinson’s disease.