Short-chain fatty acids as key mediators of the microbiota-gut-brain axis in chronic cerebral hypoperfusion: mechanisms and therapeutics.

Chronic cerebral hypoperfusion (CCH) is an important contributor to vascular cognitive impairment and neurodegenerative disorders, characterized by neuronal injury, blood-brain barrier (BBB) disruption, neuroinflammation, mitochondrial dysfunction, and synaptic impairment. Increasing evidence suggests that the microbiota-gut-brain axis plays a crucial role in ischemic brain injury. CCH is associated with gut microbiota dysbiosis, intestinal barrier dysfunction, and reduced production of microbiota-derived short-chain fatty acids (SCFAs), which may be linked to cognitive decline through bidirectional gut-brain communication. This review summarizes the mechanisms potentially involved in CCH-related neurological damage and highlights the potential neuroprotective effects of SCFAs, including regulation of neuroinflammation, BBB integrity, mitochondrial homeostasis, neuronal apoptosis, and synaptic plasticity. Furthermore, potential microbiota-targeted therapeutic strategies, such as fecal microbiota transplantation, probiotics/prebiotics, and SCFA supplementation, are discussed. Targeting gut microbiota-derived SCFAs may represents a promising approach for improving CCH-associated cognitive impairment, although further clinical validation is required.