Abstract
BackgroundRecently, we reported that patients with mild cognitive impairment (MCI) harbor specific signature of bacteria in their gut and that a modified Mediterranean ketogenic diet (MMKD) improves Alzheimer's disease (AD) markers in cerebrospinal fluid (CSF) and the signatures of gut bacteria. However, other microbial population such as gut fungi (mycobiome) in relation to MCI/AD pathology, gut bacteria and diet remain unknown.MethodsWe measure gut mycobiome by sequencing of the fungal rRNA ITS1 gene in 17 older adults (11 MCI; 6 cognitively normal [CN]) in a single-center, randomized, double-blind, crossover pilot study, before and after 6 weeks intervention of MMKD and American Heart Association Diet (AHAD), and determine its correlation with AD markers in CSF and gut bacteria.FindingsCompared to CN counterparts, patients with MCI have higher proportion of families Sclerotiniaceae, Phaffomyceteceae, Trichocomaceae, Cystofilobasidiaceae, Togniniaceae and genera Botrytis, Kazachstania, Phaeoacremonium and Cladosporium and lower abundance of Meyerozyma. Specific fungal taxa exhibit distinct correlation arrays with AD markers and gut bacteria in subjects with versus without MCI. MMKD induces broader effect on fungal diversity in subjects with MCI and increases Agaricus and Mrakia while decreasing Saccharomyces and Claviceps with differential response in subjects with or without MCI.InterpretationThe study reveals MCI-specific mycobiome signatures and demonstrates that distinct diets modulate the mycobiome in association with AD markers and fungal-bacterial co-regulation networks in patients with MCI. The findings corroborate the notion of considering gut mycobiome as a unique factor that can affect cognitive health/AD by interacting with gut bacteria and diet and facilitate better understanding of the AD and related microbiome, using unique diet or microbiome modulators.
Highlights
Research in contextEvidence before this studyDespite extensive research in understanding the genetic and molecular risk factors of Alzheimer’s disease (AD) pathogenesis, there is currently no established therapy to prevent or ameliorate AD pathology
The study identifies mild cognitive impairment (MCI)-specific gut mycobiome signatures and demonstrates how these signatures correlate with gut bacteria as well as with cerebrospinal fluid (CSF) AD biomarkers including the deposition of b-amyloid (Ab)À40, AbÀ42 and total and phosphorylated tau
In addition to the distinct correlation arrays of fungal taxa with CSF markers, we find distinct fungal-bacterial inter-relationship networks in cognitively normal (CN) subjects versus patients with MCI, wherein these networks differ during modified Mediterranean-style ketogenic diet (MMKD) versus American Heart Association Diet (AHAD) interventions (Fig. 5)
Summary
Despite extensive research in understanding the genetic and molecular risk factors of Alzheimer’s disease (AD) pathogenesis, there is currently no established therapy to prevent or ameliorate AD pathology. Several studies have reported a dysbiotic gut fungal microbiota in patients with Autism spectrum disorder [52,53,54] These studies underline the need to examine the gut mycobiome more broadly, which would help in identifying potential disease-contributing fungal clades while uncovering fungal-bacterial relationships important for host health. In this addendum, we for the first time demonstrate distinct gut mycobiome signatures in patients with MCI, along with potential interactions of the gut mycobiome signatures with host diet, gut bacteria and CSF AD biomarkers
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