Intermittent Fasting as a Neuroprotective Strategy: Gut-Brain Axis Modulation and Metabolic Reprogramming in Neurodegenerative Disorders

Abstract

Intermittent fasting (IF) is emerging as a heterogeneous neurometabolic intervention with the possibility of changing the course of neurodegenerative diseases. Through the modulation of the gut-brain axis (GBA), cellular bioenergetics (or metabolic) reprogramming, and involvement in preserved stress adaptation pathways, IF influences a range of physiological mechanisms, including mitobiogenesis, autophagy, circadian rhythm alignment, and neuroinflammation. This review critically synthesises current preclinical and early clinical evidence illustrating IF's capability to supplement synaptic plasticity and integrity, reduce toxic proteins (proteotoxic) burden, and rehabilitate glial and immune homeostasis across models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The key players behind these effects are bioactive metabolites such as short-chain fatty acids (SCFA) and β-hydroxybutyrate (BHB), and molecular mediators such as brain-derived neurotrophic factor (BDNF). We feature the therapeutic pertinence of IF-induced changes in gut microbiota composition, immune response, and mitochondrial dynamics, and we discuss emerging approaches for merging IF into precision medicine frameworks. Crucial challenges include individual variability, protocol optimisation, safety in cognitively vulnerable populations, and the need for biomarker-guided, ethically grounded clinical trials. Finally, we propose IF as a scalable and flexible intervention that, when personalised and integrated with other modalities, may reframe neurodegeneration from a model of irreversible decline to one of modifiable resilience.

Keywords: SCFAs; autophagy; gut–brain axis; intermittent fasting; metabolic reprogramming; neurodegenerative diseases.

Figure 1

Gut–brain axis (GBA) pathways modulated by intermittent fasting (IF). Schematic diagram showing that IF alters the gut microbiota, increasing taxa associated with short-chain fatty acid (SCFA) production. SCFA, particularly butyrate, enhances gut barrier integrity, reduces neuroinflammation, and increases brain-derived neurotrophic factor (BDNF) expression via epigenetic mechanisms. These changes influence the GBA, improving hippocampal synaptic plasticity and cognitive function in neurodegenerative disease in both pre-clinical and clinical models. HDAC, histone deacetylase. Upward arrow (↑) indicates increase/heighten; downward arrow (↓) indicates decrease/reduce; forward arrow (→) indicates leading to/causing.

Figure 2

Neuroprotective mechanisms of intermittent fasting (IF) via metabolic reprogramming. This figure summarizes how IF promotes neuroprotection through three main pathways: (A) Mitochondrial bioenergetics and oxidative stress: IF increases β-hydroxybutyrate (BHB) and short chain fatty acids (SCFAs) (e.g., butyrate), enhancing mitochondrial respiration, biogenesis (via PGC-1α, TFAM), and antioxidant defence (via Nrf2, SOD2, CAT, HO-1), while reducing oxidative stress and supporting synaptic and cognitive function. (B) Autophagy and protein clearance: Through mTOR inhibition and SIRT1 activation, IF enhances autophagy and mitophagy (upregulates PINK1, Parkin), promoting clearance of toxic protein aggregates and improving neuronal health in neurodegenerative models. (C) Neuroimmune interaction: IF modulates microglia (M1→M2), reduces NLRP3 inflammasome activity, and strengthens blood–brain barrier integrity. These changes lower neuroinflammation and support cognitive resilience. Upward arrow (↑) indicates increase/heighten; downward arrow (↓) indicates decrease/reduce; forward arrow (→) indicates leading to/causing.