Bovine milk fat globule membrane ameliorates Alzheimer's disease-associated cognitive impairments via modulation of the microbiota-butyrate-FFAR2 signaling axis

• BMFGM enhanced cognitive function and alleviated neuropathology in AD mice. • BMFGM reshaped gut microbiota to boost butyrate production. • Disrupted butyrate-FFAR2 signaling abolished the protective effects of BMGFM on neural and intestinal barriers. • A microbiota-butyric acid-FFAR2 axis mediated the neuroprotective effects of BMFGM. The gut-brain axis is increasingly implicated in Alzheimer's disease (AD), offering a promising target for nutritional interventions. Bovine milk fat globule membrane (BMFGM) is a bioactive component known to modulate gut microbiota and confer neuroprotection. However, the precise molecular mechanisms linking BMFGM to AD amelioration remain elusive. This study demonstrates that BMFGM supplementation significantly improves cognitive performance in 5xFAD transgenic mice, accompanied by reduced amyloid-beta deposition, suppressed neuroinflammation, enhanced brain-derived neurotrophic factor (BDNF) expression, and recovered gut barrier integrity. Importantly, BMFGM significantly reduced interleukin-1β (IL-1β) expression in the colon, serum, and cortex, indicating IL-1β suppression as a central mechanism linking gut, systemic, and neuroinflammation. BMFGM reshaped the gut microbiota and increased fecal butyrate level, which correlated positively with cognitive outcomes. Crucially, antibiotic-induced microbiota depletion or pharmacological blockade of free fatty acid receptor 2 (FFAR2) via GLPG097 abrogated the cognitive, inflammatory, and neuropathological benefits conferred by BMFGM. Collectively, this study elucidates a specific microbiota-metabolite-receptor axis for dietary neuroprotection and highlights butyrate signaling as a critical pathway for AD prevention and management.