Betaine and betaine-fortified fermented quinoa ameliorates aging-induced learning and memory decline: Perspectives on the interplay between gut microbiota modulation and neuroprotection

Abstract Aging is a major risk factor for cognitive decline, making early detection and intervention essential. Betaine has shown potential in combating Alzheimer’s disease; however, its effects on age-related cognitive decline remain unclear. In this study, aging mice fed with betaine demonstrated improved performance in the Morris water maze test, locating the platform more quickly and frequently. To elucidate the underlying mechanisms, a gut–brain axis investigation was conducted. The betaine treatment increased gut microbiota diversity, enriching beneficial families such as Ruminococcaceae, Lactobacillaceae, and Prevotellaceae while reducing the abundance of Bacteroidaceae and Paraprevotellaceae. Additionally, levels of short-chain fatty acids (SCFAs) were elevated. Betaine also enhanced antioxidant defenses and reduced inflammation in both brain and gut tissues-evidenced by increased IL-10 and decreased IFN-γ and TNF-α levels-likely through modulation of microbial metabolites. Furthermore, neuronal architecture was preserved, and neurotransmitter levels were restored, leading to the alleviation of cognitive deficits in aging mice. Notably, the betaine content in quinoa was increased by 42.1% through fermentation with Lacticaseibacillus paracasei, and this betaine-rich fermented quinoa exhibited greater efficacy than pure betaine alone. Together, these findings highlight the critical role of betaine in preventing age-related cognitive decline via the microbiota–gut–brain axis and support the development of functional foods and supplements targeting memory impairment.