Gut microbial release of ferulic acid from germinated quinoa alleviates obesity-associated cognitive impairment via activation of PINK1/Parkin-mediated mitophagy in the hippocampus

Background Obesity is a major risk factor for cognitive impairment and related neurodegenerative disorders. Whole grains are rich in polyphenols and dietary fiber, and their consumption has been associated with improvements in obesity and cognitive deficits. Gut microbial genes encode enzymes that metabolize dietary components, influencing host health. However, the specific microbes and enzymes involved are largely unknown. Here, we explore the potential modulating effects of dietary supplementation of germinated quinoa (GQF) on obesity-related cognitive deficits and elucidate the underlying molecular mechanisms.
Results We first found that GQF, a polyphenol-rich grain-based diet, more effectively attenuates high-fat diet-induced cognitive decline and loss of gut microbial diversity compared with native quinoa. These benefits are associated with an increased abundance of Roseburia and enrichment of carbohydrate-active enzyme gene clusters following GQF intervention. Although the neuroprotective effects of GQF are not entirely dependent on the gut microbiota, GQF selectively promotes the proliferation of feruloyl esterase (FAE)-expressing Roseburia hominis and R. intestinalis, thereby facilitating the release of free ferulic acid (FA). These findings underscore the pivotal role of gut microorganisms in mediating dietary nutritional interventions. Mechanistically, FA enhances mitophagy by activating the hippocampal PINK1/Parkin signaling pathway and increasing LC3 protein colocalization with cytochrome c (CYCS), thereby restoring synaptic structural and functional integrity.
Conclusions Collectively, our findings suggest that R. hominis and R. intestinalis, enriched by GQF intake, release bound FA via feruloyl esterase to prevent obesity-induced cognitive decline. GQF and its microbiota-derived FA can be considered a natural food-based “nutrition-microbiota-brain axis” delivery system, offering a promising therapeutic strategy for metabolic-associated cognitive impairment.