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
Open accessAbstract
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. 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. METHODS: A 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. FINDINGS: At 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. INTERPRETATION: The 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.
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In older adults at risk of developing Alzheimer's disease, microbial changes after consumption of a modified Mediterranean diet correlated with improved Alzheimer's disease biomarkers in cerebrospinal fluid.
“In a population of older adults at risk of developing Alzheimer's disease, microbial changes after consumption of a modified Mediterranean diet correlated with improved biomarkers of Alzheimer's disease in the cerebrospinal fluid (333)”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [333]
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Phan, J., Nair, D., Jain, S., Montagne, T., Flores, D. V., Nguyen, A., Dietsche, S., Gombar, S., & Cotter, P. (2021) · mSystems · doi:10.1128/msystems.01215-21 · Cited by 33 · see citing works
- Authors
- Nagpal, R., Neth, B. J., Wang, S., Craft, S., & Yadav, H.
- Affiliations
- Mayo Clinic (US)
- Wake Forest University Health Sciences (US)
- Corresponding author
- Craft, Suzanne
- Yadav, Hariom
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 47
- Pages
- 529-542
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC6796564
- OpenAlex
- W2970854520
- Cited by
- 653
- References
- 61
- Citations by year
- 2026: 75 · 2025: 119 · 2024: 128 · 2023: 102 · 2022: 101 · 2021: 75 · 2020: 51 · 2019: 2
- FWCI
- 18.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (R01AG055122, P30AG049638, UL1TR001420)
- National Center for Advancing Translational Sciences
- U.S. Department of Defense (W81XWH-18-1-0118, W81XWH-19-1-0236)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Keywords
- gut microbiota, short-chain fatty acids, Alzheimer's disease, mild cognitive impairment, cerebrospinal fluid biomarkers, amyloid-beta, tau protein, dietary intervention, Akkermansia, butyrate, propionate, Enterobacteriaceae, Christensenellaceae, older adults
- MeSH terms
- Gastrointestinal Microbiome, Aged, Alzheimer Disease, Fatty Acids, Volatile, Female, Humans, Male, Middle Aged, Biomarkers, Diet, Mediterranean, Apolipoprotein E4, Diet, Ketogenic, Cognitive Dysfunction
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