The role of gut microbiota in the efficacy of ketogenic diet to ameliorate Alzheimer's disease
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Project Summary/Abstract Alzheimer’s disease (AD) prevalence is increasing and no treatment exists to date. Emerging evidence show that healthy diets such as ketogenic diet (KD) lowers the risk of AD in humans. However, only a subset of patients experiences the beneficial effects of KD (responders), while others do not (non-responders). The basis for this tremendous individual variations in response is not known. This study will test the hypothesis that gut microbiota is causal for non-responsiveness of KD and that a unique synbiotic therapy can reverse it. Our hypothesis is based on multiple lines of emerging evidence, including our preliminary data indicating that: (i) gut microbiota composition is significantly different in mild-cognitive impairment (MCI; an early stage of AD) and AD patients; (ii) a modified Mediterranean-style KD beneficially modulates gut microbiota and increases production of beneficial microbial metabolites like butyrate; (iii) these changes were associated with reduction of AD markers in the cerebrospinal fluid (CSF) of MCI patients; (iv) KD improves gut microbiota and reduces AD markers in CSF of responders, but not on non-responders; and (v) a novel synbiotic (i.e. probiotics and prebiotics mix) yogurt that incorporates human-origin probiotics (5 lactobacilli) and a novel prebiotics from sago (palm starch), beneficially modulates gut microbiota and increases production of butyrate. Our interesting and strong preliminary data raise important questions such as: (a) Does gut microbiota cause non-responsiveness of KD to ameliorate AD? (b) To what extent does non-responder microbiota impact the production of microbial metabolites and ketone bodies? And (c) Can we reverse KD’s non-responsiveness by modulating non-responder microbiota using a unique synbiotic therapy? To address these important gaps in knowledge and gain translational insight, we will investigate two specific aims. In aim 1, we will determine the causal role of gut microbiota in non- responsiveness of KD’s benefits to AD, using an innovative humanized microbiota harboring AD (3xTg) mouse model developed by transplanting responder and non-responder human microbiota. In aim 2, we will determine the effect of a synbiotic yogurt therapy in rescuing KD’s non-responsiveness, by feeding synbiotic yogurt- supplemented KD to AD mice harboring non-responder and responder microbiota. We anticipate to establish a proof-of-concept that gut microbiota causes KD’s non-responsiveness using a humanized microbiota-harboring AD mice model, and that these studies will explain the personalized effects of KD and point the direction of a new therapy to improve AD pathology. If our unique synbiotic therapy could reverse KD’s non-responsiveness, then it could be studied as a complementary regimen with KD, which may enhance long-term adherence and safety of KD, and pave the way to reduce the burden of AD - a debilitating public health problem in older adults.
