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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

37 Pages Posted: 4 Apr 2019

See all articles by Ravinder Nagpal

Ravinder Nagpal

Wake Forest University - Department of Internal Medicine-Molecular Medicine

Bryan J. Neth

Wake Forest University - Department of Gerontology and Geriatric Medicine

Shaohua Wang

Wake Forest University - Department of Internal Medicine-Molecular Medicine

Suzanne Craft

Wake Forest University - Department of Gerontology and Geriatric Medicine

Hariom Yadav

Wake Forest University - Department of Internal Medicine-Molecular Medicine; Wake Forest University - Department of Microbiology and Immunology

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Abstract

Background: Alzheimer'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.

Methods: A randomized crossover pilot study of modified Mediterranean-ketogenic diet (MMKD) and American Heart Association Diet (AHAD) intervention is performed on 17 subjects (age: 63.4±3.7yr), of which 11 have mild cognitive impairment (MCI), while 6 are cognitively normal (CN). 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 cerebrospinal fluid (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.

Findings: At baseline, MCI and CN subjects show no notable difference in microbiome diversity but several unique microbial signatures are detected in MCI subjects. Proteobacteria correlate positively with Aβ-42: Aβ-40 while fecal propionate and butyrate correlates negatively with Aβ-42 in MCI subjects. Several bacteria are differently affected by the two diets with distinct patterns between CN and MCI 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.

Interpretation: The data suggest that specific gut microbial signatures may predict the MCI and that the MMKD can modulate the gut microbiome and metabolites in association with improved AD biomarkers.

Funding Statement: The work was supported by National Institutes of Health grant P30AG049638; R01AG055122 (SC), the Department of Defense funding W81XWH-18-1-0118 (HY), as well as the funds and services provided from Center for Diabetes, Obesity and Metabolism, Wake Forest Baptist Medical Center and National Center for Advancing Translational Sciences (NCATS), National Institutes of Health funded Wake Forest Clinical and Translational Science Institute (WF CTSI) through Grant Award Number UL1TR001420.

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: The study was approved by the Institutional Review Boards of the Wake Forest School of Medicine and was conducted in the Wake Forest Clinical Research Units. All protocols related to the cohorts involved in the study have been reviewed and approved by the Institutional Review Board of the Wake Forest School of Medicine. All experiments and samplings were carried out in accordance with ethical and biosafety protocols approved by the Institutional guidelines.

Keywords: Alzheimer, dementia, microbiota, diet, nutrition, ketogenic, high fat, short-chain fatty acids

Suggested Citation

Nagpal, Ravinder and Neth, Bryan J. and Wang, Shaohua and Craft, Suzanne and Yadav, Hariom, 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 (April 1, 2019). Available at SSRN: https://ssrn.com/abstract=3363786

Ravinder Nagpal

Wake Forest University - Department of Internal Medicine-Molecular Medicine

Winston-Salem, NC
United States

Bryan J. Neth

Wake Forest University - Department of Gerontology and Geriatric Medicine

Winston-Salem, NC
United States

Shaohua Wang

Wake Forest University - Department of Internal Medicine-Molecular Medicine

Winston-Salem, NC
United States

Suzanne Craft

Wake Forest University - Department of Gerontology and Geriatric Medicine ( email )

Winston-Salem, NC
United States

Hariom Yadav (Contact Author)

Wake Forest University - Department of Internal Medicine-Molecular Medicine ( email )

Winston-Salem, NC
United States

Wake Forest University - Department of Microbiology and Immunology ( email )

Winston-Salem, NC
United States

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