Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer's disease markers in subjects with mild cognitive impairment

Abstract

BackgroundAlzheimer's disease (AD) prevalence is increasing, but its etiology remains elusive. Gut microbes can contribute to AD pathology and may help identifying novel markers and therapies against AD. Herein, we examine how the gut microbiome differs in older adults with mild cognitive impairment compared to cognitively normal counterparts, and whether and how a modified Mediterranean-ketogenic diet (MMKD) alters the gut microbiome signature in association with cerebrospinal fluid (CSF) AD biomarkers.MethodsA randomized, double-blind, cross-over, single-center pilot study of MMKD versus American Heart Association Diet (AHAD) intervention is performed on 17 subjects (age: 64.6 ± 6.4 yr), of which 11 have mild cognitive impairment, while 6 are cognitively normal. Subjects undergo MMKD and AHAD intervention for 6-weeks separated by 6-weeks washout periods. Gut microbiome, fecal short-chain fatty acids (SCFAs), and markers of AD in CSF including amyloid β (Aβ)-40 and Aß-42, total tau, and phosphorylated tau-181 (tau-p181) are measured at before and after diet interventions.FindingsAt baseline, subjects with normal vs. impaired cognition show no notable difference in microbiome diversity but several unique microbial signatures are detected in subjects with mild cognitive impairment. Proteobacteria correlate positively with Aβ-42: Aβ-40 while fecal propionate and butyrate correlates negatively with Aβ-42 in subjects with mild cognitive impairment. Several bacteria are differently affected by the two diets with distinct patterns between cognitively normal and impaired subjects. Notably, the abundance of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae and Erysipelotriaceae increases while that of Bifidobacterium and Lachnobacterium reduces on MMKD, while AHAD increases Mollicutes. MMKD slightly reduces fecal lactate and acetate while increasing propionate and butyrate. Conversely, AHAD increases acetate and propionate while reducing butyrate.InterpretationThe data suggest that specific gut microbial signatures may depict the mild cognitive impairment and that the MMKD can modulate the gut microbiome and metabolites in association with improved AD biomarkers in CSF.

Supplement of microbiota-accessible carbohydrates prevents neuroinflammation and cognitive decline by improving the gut microbiota-brain axis in diet-induced obese mice

“…A cross-sectional study reported lower abundance of Bacteroides genus in the gut microbiota of dementia patients [51]. Furthermore, individuals with mild cognitive impairment have a significantly higher abundance of phylum Proteobacteria compared to cognitively healthy participants [52]. In our current study, the correlation analysis further illustrated a significant association between the abundance of phylum Bacteroidetes and Proteobacteria with cognition index in nesting behavioral and temporal order memory tests.…”

Altered Diversity and Composition of Gut Microbiota in Wilson's disease

“…Firmicutes covers the majority of butyrate-producing bacteria in human bacterial communities, and is known for its function in transforming undigested proteins and carbohydrates into acetic acid, and producing energy for the organism of host [12]. Meanwhile, the crucial short-chain fatty acids (SCFAs) butyrate participates in activating multiple physiological signal pathways, such as anti-inflammatory activities, and the differentiation and proliferation of regulatory T cells [13,14]. Under this circumstance, the lower abundance of Firmicutes in present study may be more reasonable.…”

“…We speculated that microbiota-derived products may be act as triggers for promoting a proinflammatory and metabolically dysfunctional environment in WD patients. Microbiota-produced butyrate has been reported to provide energy for colonocytes and then prevent autophagy in the intestine of host [13]. Additionally, physiological homeostasis may be disrupted by gut microbiota, resulting in host metabolism disruption, and immune, neurological or cognitive system dysregulation and others [25,26].…”

The role of innate immunity in Alzheimer's disease

“…274 Dietary changes in patients with MCI also appear to alter the microbiota population and their association with Aβ and p-Tau levels in the CSF. 275 These data convey how peripheral inflammation induced by dysbiosis in the gut can have broad clinical applications for mitigating AD risk and pathology in the future.…”