The Role of Gut Brain Axis in Neurodegenerative Disorders

Age-related cognitive decline and neurodegenerations represent a heavy burden on modern society due to the increasing aging population. Neurodegenerations are due to neuronal loss and disruption in neuronal structure and function that cause the impairment of brain function, cognition, memory retention, learning abilities, emotions, and motor functions. It is accepted that gene–environment interaction determines the risk of developing neurodegenerative disorders (NDDs). The gut-brain axis (GBA) represents the bidirectional communication between the gut microbiota and the brain and there is an interactive relationship between NDDs and gut dysbiosis. Dietary intervention targeting gut microbiota could be a promising strategy for treating symptoms and slowing down degenerative processes in NDDs. In this PhD thesis, the effects of probiotic formulation SLAB51 on NDDs-related metabolic changes and sleep deprivation was explored. Furthermore, the effect of polyphenol microbial metabolites on aberrant proteolysis, which is considered as a hallmark of NDDs was analyzed. In addition, a functional prebiotic- based cookie enriched with probiotics, more suitable for elderly people, counteracting cognitive decline was designed. Specifically, upon probiotics administration to Alzheimer’s disease (AD) mice, cholesterol biosynthesis was inhibited with a process involving sterol regulatory element binding protein 1c and liver X receptors mediated pathways. Decreased plasma and brain concentration of 27-hydroxycholesterol and increased brain expression of cholesterol 24S-hydroxylase indicated that alternative pathways of bile acid synthesis are influenced. The plasmatic increase of arachidonic acid in treated AD mice reflects dynamic interactions among several actors of a complex inflammatory response, in which polyunsaturated fatty acids can compete each other and simultaneously cooperate in the resolution of inflammation. In addition, chronic sleep deprivation (CSR) is another condition characterized by increased oxidative stress and inflammation and altered gut-brain axis hormones. Probiotics oral administration boosted the antioxidant capacity of the brain, thus limiting the oxidative damage provoked by loss of sleep. Moreover, it positively regulated gut-brain axis hormones and reduced peripheral and brain inflammation induced by CSR. In vitro and in silico studies demonstrated that the flavan-3-ol microbial metabolite phenyl-ߛ- valerolactones modulated cellular proteolysis via proteasome inhibition and compensatory autophagy upregulation, and inhibits cathepsin B activity, ultimately reducing the amount of intracellular and extracellular amyloid-beta (Aβ) (1-42) peptides in SH-SY5Y neuroblastoma cells stably transfected with the 717 valine-to glycine amyloid precursor protein mutated gene. Driven by global dramatic demographic and lifestyle changes and based on the growing interest on on- the-go healthy snacks, a prebiotic-based cookie prototype enriched with probiotics with proved neuroprotective properties have been designed and developed. The functional cookie contains the optimal combination of selected prebiotics and probiotics resulting in a natural, safe, appealing and sustainable people-centred food counteracting cognitive decline. Chronic consumption of the functional cookie improved glucose and lipid profiles, restored neuroprotective gut hormones plasma levels in 3xTg-AD mice, ultimately reducing Aβ load and improving cognitive performance, thereby delaying AD progression. Collectively, our study makes an important contribution to the development of new therapeutic options for NDDs targeting the gut-brain axis. We have demonstrated that diet, prebiotics, probiotics and synbiotics can modulate the gut microbiome and effectively alleviate the hallmarks of NDDs through the gut-brain axis including pathological protein aggregation, neuroinflammation, oxidative stress, metabolic disorders, and neuronal death. Therapeutic strategies targeting the gut-brain axis are a promising approach to prevent and treat NDDs.