Effects of a Ketogenic and Low Fat Diet on the Human Metabolome, Microbiome and Food-ome in Adults at Risk for Alzheimer’s Disease

Abstract

INTRODUCTION: The ketogenic diet (KD) is an intriguing candidate for neuroprotection in Alzheimer's disease (AD) given its protective effects against metabolic dysregulation and seizures. The diet's neuroprotective effects have been shown to be gut microbiome-dependent in mice; thus we examined KD-induced changes in the gut microbiome and metabolome in patients at-risk for AD. METHODS: We compared the low-carbohydrate modified Mediterranean Ketogenic Diet (MMKD) to the low-fat American Heart Association Diet (AHAD) in adults with mild cognitive impairment (MCI) and control participants. We collected stool samples for shotgun metagenomics and untargeted metabolomics at five timepoints to interrogate the microbiome and metabolome. RESULTS: Individuals with MCI on the MMKD had lower levels of GABA-producing microbes Alistipes sp. CAG:514 and GABA, and higher levels of GABA-regulating microbes Akkermansia muciniphila. DISCUSSION: We hypothesize that MMKD protects individuals with MCI in part via influencing on GABA levels and gut-transit time.

A Modified Mediterranean Ketogenic Diet mitigates modifiable risk factors of Alzheimer’s Disease: a serum and CSF-based metabolic analysis

“…We utilized a Negative Binomial Linear Mixed Effect model to ensure that our statistics agreed with our study design; we modeled time, dietary sequence (whether MMKD intervention was first or second), cognitive status, and diet (whether a given individual was on MMKD or AHAD at a given time point) as fixed effects while subject identity was modeled as a random effect. Microbes, food features, and metabolites were ordered by the log-ratio of their relative abundances in objectively normal cognition to mild cognitive impairment or MMKD to AHAD individuals, respectively 92,93 and the top and bottom ten features were examined more closely 21 .…”

“…We used samples from a randomized crossover pilot trial of a Modified Mediterranean-Ketogenic Diet (MMKD) or the American Heart Association Diet (AHAD) ( Figure 1 ) in a cohort of prediabetic participants that were either mildly cognitively impaired (MCI, n = 9) or cognitively normal (CN, n = 10) 20 . In a series of studies using the same cohort, we previously found that MMKD leads to increased Aβ42 and decreased tau in CSF 20 , changes in the gut microbiome 21 , and reversal of serum-based AD-associated lipid signature 25 . In the current study, we broaden the scope of blood biomarkers by using an NMR-metabolomics platform that measured amino acids, ketone bodies, triglycerides, and lipoprotein levels and lipoprotein composition.…”

“…Consequently, KD induces various system-wide metabolic alterations which lead to positive health benefits, including increased insulin sensitivity 17 , weight reduction in overweight individuals, and improved lipid profiles 18 . KD has also been linked to neuroprotective effects, including the promotion of more efficient mitochondrial activity and reduction of mitochondria-derived reactive oxygen species 19 , as well as a decrease in neuronal excitotoxicity 20,21 . Given the role of metabolic dysregulation, oxidative stress, and excitotoxicity in the pathogenesis of AD 13 , the potential metabolic shifts related to KD could provide beneficial alterations in disease progression 19,22 .…”