Synbiotic-Derived Metabolites Reduce Neuroinflammatory Symptoms of Alzheimer’s Disease

Synbiotics, the combination of probiotics and prebiotics, can be designed to produce specific bioavailable metabolites that penetrate the blood-brain-barrier and reduce neuropathologies associated with Alzheimer's Disease (AD). We designed an in vitro model of the human gastrointestinal tract that can be used to optimize the production of metabolites from synbiotic formulations using machine learning algorithms that can then be tested in animal models of AD. Our objective is to optimize/characterize a synbiotic's metabolite production using an in vitro bioreactor as a therapeutic tool against AD. We hypothesize that a synbiotic designed towards the production of specific brain-bioactive metabolites will synergistically mitigate the neuro- and systemic-pathologies associated with AD. Using the in vitro model of the human gastrointestinal tract, we have used this optimized combination of polyphenols and tested 15 combinations of 6 probiotic bacteria as a synbiotic to optimize metabolite production using a multivariate regression algorithm (MARS) and found that three probiotic bacteria, Lactobacillus plantarum, Bifidobacterium infantis and L. salivarius together synergistically improve the production of brain bioavailable metabolites including quercetin, kamferin, 4-hydroxyphenylpyruvic acid and 4-hydroxyphenylacetic acid. We have found that two polyphenolic metabolites 3-hydroxybenzoic acid and 3-(3′-hydroxyphenyl) propionic acid derived from a grapeseed polyphenolic extract (GSPE) can penetrate the blood-brain-barrier and in vitro, inhibit the aggregation of amyloid plaques and tau fibrils. By increasing the diversity of the polyphenolic pool by adding a concord grape extract and resveratrol to the GSPE, we provided greater protection against cognitive impairment and amyloid aggregation in an AD mouse model than the components alone. In vitro studies have confirmed that these metabolites have potent anti-inflammatory activity. This synbiotic combining potent grape-derived polyphenolic precursors with bioactive probiotic bacteria has the potential to slow the progression and treat AD by synergistically targeting multiple of its neuropathologies including inflammation, amyloid aggregation and tau fibril formation. These studies were funded by the NCCIH.