Neuroprotective effects of Opuntia ficus-indica fruit in high-fat-diet-induced obese mice: evidence for a role of the gut microbiota

Obesity and high-fat diet (HFD) consumption are associated with cognitive decline and increased risk of neurodegenerative disorders, including Alzheimer’s disease (AD). Gut microbiota dysbiosis is a key factor for obesity-related brain dysfunctions. Opuntia ficus-indica fruit (OFIF) has shown beneficial metabolic and neuroprotective effects, but the contribution of the gut microbiota has not been explored yet. This study investigated whether OFIF exerts neuroprotective effects in HFD mice through microbiota-dependent mechanisms. C57BL/6 mice were fed a standard diet or HFD for 16 weeks, with or without OFIF supplementation. A subgroup of HFD + OFIF mice received a broad-spectrum antibiotic cocktail to deplete gut microbiota. Metabolic parameters, cognitive performance, brain morphology, AD–related gene expression (PCR array), and gut microbiota composition were assessed. OFIF supplementation improved insulin resistance in HFD-mice, also in the presence of antibiotics, suggesting microbiota-independent metabolic benefits. In contrast, OFIF prevented HFD-induced reduced brain weight, neuronal damage, and partially restored cognitive impairment, effects that were abolished following microbiota depletion. At the molecular level, OFIF modulated the expression of multiple AD-related genes in the cortex and hippocampus, including pathways involved in amyloid processing, synaptic function, and lipid metabolism. These transcriptional changes were absent in antibiotic-treated mice. Microbiota analysis revealed that OFIF positively modulated gut microbiota composition, leading to enrichment of genera such as Duncaniella and Paramuribaculum, which positively correlated with brain structural. In conclusion, our findings suggest that microbiota is a critical mediator of OFIF-driven brain protection and supports the potential of OFIF as a dietary strategy to counteract obesity-associated cognitive decline.