Several lines of evidence from animal and in vitro studies suggest that polyphenols, notably flavonoids, provide protective benefits Alzheimer?s disease (AD). In rodent models of AD, oral administration of extracts containing mixtures of flavonoids reduced inflammation, oxidative stress, and Amyloid beta (Ab) in the brain, while attenuating the decline in cognitive functions. Similar benefits have been reported for individual flavonoid classes, including flavanones, flavones, flavan-3-ols (catechins), and anthocyanins. Several mechanisms for how these compounds confer their benefits have been proposed, including scavenging of reactive oxygen species (ROS), modulation of the inflammatory cascade of the central nervous system (CNS) neurons, and slowing or halting the formation of cytotoxic Ab oligomers. A key question that arises when investigating these mechanisms is whether the effects are due to the original phytochemical or due to a metabolite that derives from the flavonoid. Dietary flavonoids are typically present in their glycoside form, which have poor bioavailability. In contrast, phenolic acids and other metabolic products are readily absorbed and accumulate in tissues, including the brain. For example, phenyl-?-valerolactones (PVL), metabolites derived from flava-3-ols by gut bacterial metabolism, inhibit Ab oligomerization in vitro, and improved novel object recognition in mice injected with Ab oligomers. This raises the intriguing hypothesis that the effects of flavonoids on the brain are mediated by metabolic derivatives generated by gut bacteria. There is considerable evidence that gut bacteria are capable of fully metabolizing polyphenol glycosides to bioactive phenolic compounds. In our ongoing R01 project, we have identified naringenin chalcone as a significant metabolic product of naringenin, and determined that the chalcone product more strongly activates the aryl hydrocarbon receptor (AhR), a key nuclear receptor regulating intestinal xenobiotic metabolism immune homeostasis. The goal for this Administrative Supplement request is to investigate the above hypothesis by extending our current studies on flavonoid-gut microbiota interactions to AD-related pathways in the brain. To address the hypothesis, we propose to 1) identify flavonoid derived compounds that unambiguously derive from gut bacterial metabolism and 2) evaluate the efficacy of the metabolites to modulate AD markers using a novel 3D-tissue engineered brain model. We will combine computational prediction and in vitro fecal culture experiments to determine bacterial metabolites of representative flavonoids previously shown to protect against AD-related cognitive decline. Metabolic modeling will be used to associate flavonoid metabolites with species that contribute to the metabolites? synthesis. A bioengineered 3D brain-like tissue model generated using human induced pluripotent stem cells (hiPSC) will provide an ideal testbed to characterize the flavonoid metabolites.
The proposed experiments will identify novel dietary flavonoid-derived metabolites that are produced in the GI tract due to microbiota metabolism and exert their beneficial effects on inflammation in the brain through the arylhydrocarbon (AhR) receptor.
