P3‐220: CHARACTERISTIC GUT MICROBIOME COMPOSITION IN ALZHEIMER'S DISEASE SUGGESTS THE POSSIBILITY OF HIGH POTENCY IN ENHANCING COLONIC TREG CELLS ABUNDANCE CLOSELY RELATED TO PROGRESSIVE COGNITIVE DYSFUNCTION

Recent study in transgenic APPPS1 mouse model of Alzheimer's disease (AD) strongly indicates involvement of gut microbiome (GMB) in the amyloid pathology. However, there have been few comprehensive surveys of GMB composition including the bacterial species level in humans with AD. To investigate the characteristics of GMB composition in AD, we performed bacterial 16S ribosomal RNA gene sequencing of DNA isolated from fecal samples in AD patients (n=65) with dementia, and age- and gender-matched cognitively normal control patients (n=41). GMB analysis revealed that AD patients has significantly increased alpha diversity (chao1: p=0.049 and shannon's index: p=0.004) and significantly different composition in weighted Unifrac analysis (PERMANOVA: R2=0.022, p=0.037), compared to control. We observed significantly increased relative abundance of Verrucomicrobia at the phylum level, and markedly higher abundance of Clostridium (13.0±1.1>7.0±0.8, p=2.2E-05) and Blautia (10.0±0.9>5.6±0.7, p=0.0002) which are the predominant genera of Clostridia clusters IV, XIVa, and XVIII inducing colonic regulatory T (Treg) cells essential for maintaining immune tolerance and immuno homeostasis, and higher abundance of Roseburia (2.5±0.3>1.9±0.3, p=0.033), but significantly lower abundance of Lactobacillus (2.0±0.7<4.9±1.5, p=0.031) at the the genus level in AD patients compared to control. The additional abundance of Clostridium and Blautia genus significantly negatively related to progressive decrease of cognitive function (r=−0.418, p<0.01, n=104). From the analysis of operational taxonomic units which showed significantly different abundance between AD and control patients (relative abundance≧0.1%), twenty best-hit bacterial species were identified. Fifteen of these species fall within the Clostridia clusters IV (n=5), XIVa (n=9), and XVIII (n=1) enhancing Treg cells abundance, and seventeen belong to the species producing short-chain fatty acids which regulates the differentiation and expansion of colonic Treg cells: eleven species producing acetate which is rerouted into butyrate, four butyrate-producing species, and two propionate-producing species. Recent evidence in transgenic 5xFAD mouse model indicates that Treg-mediated systemic immune suppression is involved in the pathogenesis of AD. Present GMB analysis in AD patients suggests the possibility of high potency in enhancing colonic Treg cells abundance closely related to progressive decline in cognitive function.